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ONE MEDICATION APPROVED TO TREAT ALL BIPOLAR I EPISODES:1 DEPRESSIVE AND ACUTE MANIC OR MIXED EPISODES Visit VRAYLARHCP.com for VRAYLAR bipolar I disorder study results and design, additional dosing information, and more.

Indications and Usage Indicated in adults for the: • Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) • Acute treatment of manic or mixed episodes associated with bipolar I disorder

Important Safety Information WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

VRAYLAR is not approved for treatment of patients with dementia-related psychosis.

• Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies.

Closely monitor antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors.

Safety and effectiveness of VRAYLAR have not been established in pediatric patients.

Contraindication: VRAYLAR is contraindicated in patients with known hypersensitivity. Reactions have included rash, pruritus, urticaria, and events suggestive of angioedema.

Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials with antipsychotic drugs, elderly subjects with dementia had a higher incidence of cerebrovascular adverse reactions, including fatalities vs placebo. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with antipsychotic drugs. NMS may cause hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of developing TD (a syndrome of potentially irreversible, involuntary, dyskinetic movements) and the likelihood it will become irreversible may increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. If signs and symptoms of TD appear, drug discontinuation should be considered.

Late-Occurring Adverse Reactions: Adverse events may first appear several weeks after initiation of VRAYLAR, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer term exposures. Monitor for adverse reactions, including extrapyramidal symptoms (EPS) or akathisia, and patient response for several weeks after starting VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug.

Metabolic Changes: Atypical antipsychotics have caused metabolic changes, such as: • Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases associated with ketoacidosis, hyperosmolar coma, or death, has Please see additional Important Safety Information and Brief Summary of Full Prescribing Information, including Boxed Warnings, on the following pages, or visit https://www.rxabbvie.com/pdf/vraylar_pi.pdf

Full-spectrum relief for all bipolar I symptoms in depressive and acute manic or mixed episodes in adults1 Proven relief for bipolar I depressive symptoms at the starting dose (1.5 mg/day)1 • May increase dose to 3 mg on Day 15. Maximum recommended dose is 3 mg/day, depending on clinical response and tolerability1 Placebo-like impact on lipids and fasting glucose1,2* Weight change ≤1.5 lb1 • 3% of patients reported weight increase of ≥7% in bipolar I depression studies1 The proportion of patients with metabolic shifts* was similar to placebo.1,2 Mean weight change in bipolar I manic or mixed episode trials: placebo (n=439) mean change=+0.4 lb; VRAYLAR 3-6 mg/day (n=259) mean change=+1.1 lb.1 Mean weight change in bipolar I depression trials: placebo (n=463) mean change=-0.2 lb; VRAYLAR 1.5 mg/day (n=467) mean change=+1.5 lb; VRAYLAR 3 mg/day (n=465) mean change=+0.9 lb.1 Proportion of patients with weight increase ≥7% in bipolar I depression trials: placebo (n=463)=1%; VRAYLAR 1.5 mg/day (n=467)=3%; VRAYLAR 3 mg/ day (n=465)=3%.1 *Shift defined as: fasting glucose: normal (<100 mg/dL) to high (≥126 mg/dL), borderline (≥100 mg/dL and <126 mg/dL) to high; total cholesterol: normal/ borderline (<240 mg/dL) to high (≥240 mg/dL); fasting triglycerides: normal/borderline (<200 mg/dL) to high (≥200 mg/dL).1,2

Important Safety Information (continued) been reported in patients treated with atypical antipsychotics. Assess fasting glucose before or soon after initiation of treatment, and monitor periodically during long-term treatment.

• Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after starting an antipsychotic, obtain baseline fasting lipid profile and monitor periodically during treatment.

• Weight Gain: Weight gain has been observed with VRAYLAR. Monitor weight at baseline and frequently thereafter.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia have been reported with antipsychotics, including VRAYLAR. Agranulocytosis (including fatal cases) has been reported with other antipsychotics. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue VRAYLAR at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.

Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope, with the greatest risk during initial titration and with dose increases. Monitor orthostatic vital signs in patients predisposed to hypotension and in those with cardiovascular/ cerebrovascular diseases.

Falls: VRAYLAR may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures, or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotics and recurrently for patients on long-term therapy.

Seizures: Use VRAYLAR with caution in patients with history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: Somnolence was reported with VRAYLAR. Caution patients about performing activities requiring mental alertness (eg, operating hazardous machinery or a motor vehicle).

Body Temperature Dysregulation: Use VRAYLAR with caution in patients who may experience conditions that increase body temperature (eg, strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics. Antipsychotic drugs, including VRAYLAR, should be used cautiously in patients at risk for aspiration.

Drug Interactions: Strong CYP3A4 inhibitors increase VRAYLAR concentrations, so VRAYLAR dose reduction is recommended. Concomitant use with CYP3A4 inducers is not recommended.

Adverse Reactions: In clinical trials, the most common adverse reactions (≥5% and at least twice the rate of placebo) are listed below: • Bipolar mania: The incidences within the recommended dose range (VRAYLAR 3 – 6 mg/day vs placebo) were: EPS (26% vs 12%), akathisia (20% vs 5%), vomiting (10% vs 4%), dyspepsia (7% vs 4%), somnolence (7% vs 4%), and restlessness (7% vs 2%).

• Bipolar depression: The incidences within the recommended doses (VRAYLAR 1.5 mg/day or 3 mg/day vs placebo) were: nausea (7%, 7% vs 3%), akathisia (6%, 10% vs 2%), restlessness (2%, 7% vs 3%), and EPS (4%, 6% vs 2%).

References: 1. VRAYLAR (cariprazine) [package insert]. Madison, NJ: Allergan USA, Inc.; 2019. 2. Data on file. Allergan.

VRAYLAR® and its design are registered trademarks of Forest Laboratories Holdings Ltd., an AbbVie company. © 2021 AbbVie. All rights reserved.

Licensed from Gedeon Richter Plc. VRA149388 08/21

VRAYLAR® (cariprazine) capsules, for oral use Brief Summary of full Prescribing Information Initial U.S. Approval: 2015 WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. VRAYLAR is not approved for the treatment of patients with dementiarelated psychosis [see Warnings and Precautions].

Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for the emergence of suicidal thoughts and behaviors [see Warnings and Precautions]. The safety and effectiveness of VRAYLAR have not been established in pediatric patients [see Use in Specific Populations].

INDICATIONS AND USAGE: VRAYLAR® is indicated for the: Treatment of schizophrenia in adults [see Clinical Studies in the full Prescribing Information]; Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults [see Clinical Studies in the full Prescribing Information]; Treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults [see Clinical Studies in the full Prescribing Information].

CONTRAINDICATIONS: VRAYLAR is contraindicated in patients with history of a hypersensitivity reaction to cariprazine. Reactions have ranged from rash, pruritus, urticaria, and events suggestive of angioedema (e.g., swollen tongue, lip swelling, face edema, pharyngeal edema, and swelling face).

WARNINGS AND PRECAUTIONS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis - Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementiarelated psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions]. Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults - In pooled analyses of placebocontrolled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Table 1 displays the Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients. The table measures the drug-placebo difference in the number of patients with suicidal thoughts or behaviors per 1000 patients treated. There were 14 additional cases reported in patients under the age of 18, while 5 additional cases were reported in patients between 18 and 24 years of age.

Patients between 25 and 64 years of age reported 1 fewer case of suicidal thoughts or behaviors, while patients 65 years of age and over reported 6 fewer cases. *VRAYLAR is not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing VRAYLAR, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis - In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. VRAYLAR is not approved for the treatment of patients with dementiarelated psychosis [see Boxed Warning, Warnings and Precautions]. Neuroleptic Malignant Syndrome (NMS) - Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue VRAYLAR and provide intensive symptomatic treatment and monitoring. Tardive Dyskinesia - Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including VRAYLAR. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. Given these considerations, VRAYLAR should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and 2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.

Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on VRAYLAR, drug discontinuation should be considered. However, some patients may require treatment with VRAYLAR despite the presence of the syndrome. Late-Occurring Adverse Reactions - Adverse events may first appear several weeks after the initiation of VRAYLAR treatment, probably because plasma levels of cariprazine and its major metabolites accumulate over time. As a result, the incidence of adverse reactions in short-term trials may not reflect the rates after longer

term exposures [see Dosage and Administration and Clinical Pharmacology in the full Prescribing Information and Adverse Reactions]. Monitor for adverse reactions, including extrapyramidal symptoms (EPS) or akathisia, and patient response for several weeks after a patient has begun VRAYLAR and after each dosage increase. Consider reducing the dose or discontinuing the drug.

Metabolic Changes - Atypical antipsychotic drugs, including VRAYLAR, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus - Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment.

Schizophrenia - In the 6-week, placebo-controlled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with VRAYLAR and placebo. In the long-term, open-label schizophrenia studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥6.5%). Bipolar Disorder - In six placebo-controlled trials up to 8-weeks of adult patients with bipolar disorder (mania or depression), the proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with VRAYLAR and placebo. In the long-term, open-label bipolar disorder studies, 4% patients with normal hemoglobin A1c baseline values developed elevated levels (≥6.5%). Dyslipidemia - Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Schizophrenia - In the 6-week, placebocontrolled trials of adult patients with schizophrenia, the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with VRAYLAR and placebo. Bipolar Disorder - In six placebo-controlled trials up to 8-weeks of adult patients with bipolar disorder (mania or depression), the proportion of patients with shifts in fasting total cholesterol, LDL, HDL and triglycerides were similar in patients treated with VRAYLAR and placebo. Weight Gain Weight gain has been observed with use of atypical antipsychotics, including VRAYLAR. Monitor weight at baseline and frequently thereafter. Tables 2, 3, and 4 in the full Prescribing Information show the change in body weight occurring from baseline to endpoint in 6-week schizophrenia, 3-week bipolar mania, and 6-week and 8-week bipolar depression trials, respectively. Table 2 displays the Change in Body Weight (kg) in 6-Week Schizophrenia Trials. Values shown in parentheses reflect: Placebo (N=573); VRAYLAR* 1.5 - 3 mg/day (N=512); VRAYLAR* 4.5 - 6 mg/day (N=570); and VRAYLAR* 9 - 12° mg/day (N=203). The Mean Changes at Endpoint are as follows: (+0.3; +0.8; +1; +1). The Proportion of Patients with Weight Increase (≥ 7%) are as follows: (5%; 8%; 8%; 17%). *Data shown by modal daily dose, defined as most frequently administered dose per patient. °The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. In long-term, uncontrolled trials with VRAYLAR in schizophrenia, the mean changes from baseline in weight at 12, 24, and 48 weeks were 1.2 kg, 1.7 kg, and 2.5 kg, respectively. Table 3 displays the Change in Body Weight (kg) in 3-Week Bipolar Mania Trials. Values shown in parentheses reflect: Placebo (N=439); VRAYLAR* 3 - 6 mg/day (N=259); and VRAYLAR* 9 - 12° mg/day (N=360). The Mean Changes at Endpoint are as follows: (+0.2; +0.5; +0.6). The Proportion of Patients with Weight Increase (≥ 7%) are as follows: (2%; 1%; 3%). *Data shown by modal daily dose, defined as most frequently administered dose per patient. °The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Table 4 displays the Change in Body Weight (kg) in two 6-Week and one 8-Week Bipolar Depression Trials. Values shown in parentheses reflect: Placebo (N=463); VRAYLAR 1.5 mg/day (N=467); and VRAYLAR 3 mg/day (N=465). The Mean Changes at Endpoint are as follows: (-0.1; +0.7; +0.4). The Proportion of Patients with Weight Increase (≥ 7%) are as follows: (1%; 3%; 3%). Leukopenia, Neutropenia, and Agranulocytosis - Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including VRAYLAR. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of VRAYLAR at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue VRAYLAR in patients with absolute neutrophil count < 1000/mm3 and follow their WBC until recovery. Orthostatic Hypotension and Syncope - Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Symptomatic orthostatic hypotension was infrequent in trials of VRAYLAR and was not more frequent on VRAYLAR than placebo. Syncope was not observed. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. VRAYLAR has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. Falls - Antipsychotics, including VRAYLAR, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. Seizures - Like other antipsychotic drugs, VRAYLAR may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. Potential for Cognitive and Motor Impairment VRAYLAR, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week schizophrenia trials, somnolence (hypersomnia, sedation, and somnolence) was reported in 7% of VRAYLAR-treated patients compared to 6% of placebo-treated patients. In 3-week bipolar mania trials, somnolence was reported in 8% of VRAYLAR-treated patients compared to 4% of placebo-treated patients. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with VRAYLAR does not affect them adversely. Body Temperature Dysregulation - Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use VRAYLAR with caution in patients who may experience these conditions. Dysphagia - Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia has been reported with VRAYLAR. VRAYLAR and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.

ADVERSE REACTIONS: The following adverse reactions are discussed in more detail in the Boxed Warning, and Warnings and Precautions sections: Increased Mortality in Elderly Patients with Dementia-Related Psychosis; Suicidal Thoughts and Behaviors; Cerebrovascular Adverse Reactions,

Including Stroke, in Elderly Patients with Dementia-Related Psychosis; Neuroleptic Malignant Syndrome; Tardive Dyskinesia; Late Occurring Adverse Reactions; Metabolic Changes; Leukopenia, Neutropenia, and Agranulocytosis; Orthostatic Hypotension and Syncope; Falls; Seizures; Potential for Cognitive and Motor Impairment; Body Temperature Dysregulation; Dysphagia. Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The information below is derived from an integrated clinical study database for VRAYLAR consisting of 4753 adult patients exposed to one or more doses of VRAYLAR for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder, and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 940.3 patient-years. A total of 2568 VRAYLARtreated patients had at least 6 weeks and 296 VRAYLAR-treated patients had at least 48 weeks of exposure. Patients with Schizophrenia - The following findings are based on four placebo-controlled, 6-week schizophrenia trials with VRAYLAR doses ranging from 1.5 to 12 mg once daily. The maximum recommended dosage is 6 mg daily. Adverse Reactions Associated with Discontinuation of Treatment: There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms and akathisia. Adverse Reactions with an incidence of ≥ 2% and greater than placebo, at any dose are shown in Table 5. Table 5 in the full Prescribing Information shows Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 6-Week Schizophrenia Trials. Percentage values shown in parentheses are shown as: Placebo (N=584), VRAYLAR* 1.5 - 3 mg/day (N=539), VRAYLAR* 4.5 - 6 mg/day (N=575), and VRAYLAR* 9 - 12° mg/day (N=203). The adverse reactions

by System Organ Class/Preferred Term are as follows: Cardiac Disorders: Tachycardiaa (1, 2, 2, 3); Gastrointestinal Disorders: Abdominal painb (5, 3, 4, 7); Constipation (5, 6, 7, 10); Diarrheac (3, 1, 4, 5); Dry Mouth (2, 1, 2, 3); Dyspepsia (4, 4, 5, 5); Nausea (5, 5, 7, 8); Toothache (4, 3, 3, 6); Vomiting (3, 4, 5, 5); General Disorders/Administration Site Conditions: Fatigued (1, 1, 3, 2); Infections and Infestations: Nasopharyngitis (1, 1, 1, 2); Urinary tract infection (1, 1, <1, 2); Investigations: Blood creatine phosphokinase increased (1, 1, 2, 3); Hepatic enzyme increasede (<1, 1, 1, 2); Weight increased (1, 3, 2, 3); Metabolism and Nutrition Disorders: Decreased appetite (2, 1, 3, 2); Musculoskeletal and Connective Tissue Disorders: Arthralgia (1, 2, 1, 2); Back pain (2, 3, 3, 1); Pain in extremity (3, 2, 2, 4); Nervous System Disorders: Akathisia (4, 9, 13, 14); Extrapyramidal Symptomsf (8, 15, 19, 20); Headacheg (13, 9, 11, 18); Somnolenceh (5, 5, 8, 10); Dizziness (2, 3, 5, 5); Psychiatric Disorders: Agitation (4, 3, 5, 3); Insomniai (11, 12, 13, 11); Restlessness (3, 4, 6, 5); Anxiety (4, 6, 5, 3); Respiratory, Thoracic and Mediastinal Disorders: Cough (2, 1, 2, 4); Skin and subcutaneous disorders: Rash (1, <1, 1, 2); Vascular Disorders: Hypertensionj (1, 2, 3, 6). Note: Figures rounded to the nearest integer. *Data shown by modal daily dose, defined as most frequently administered dose per patient. aTachycardia terms: heart rate increased, sinus tachycardia, tachycardia. bAbdominal pain terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain. cDiarrhea terms: diarrhea, frequent bowel movements. d Fatigue terms: asthenia, fatigue. eHepatic enzyme increase terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased. fExtrapyramidal Symptoms terms: bradykinesia, cogwheel rigidity, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, masked facies, muscle rigidity, muscle tightness, musculoskeletal stiffness, oculogyric crisis, oromandibular dystonia, parkinsonism, salivary hypersecretion, tardive dyskinesia, torticollis, tremor, trismus. gHeadache terms: headache, tension headache. hSomnolence terms: hypersomnia, sedation, somnolence. iInsomnia terms: initial insomnia, insomnia, middle insomnia, terminal insomnia. j Hypertension terms: blood pressure diastolic increased, blood pressure increased, blood pressure systolic increased, hypertension. °The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Patients with Bipolar Mania - The following findings are based on three placebo-controlled, 3-week bipolar mania trials with VRAYLAR doses ranging from 3 to 12 mg once daily. The maximum recommended dosage is 6 mg daily. Adverse Reactions Associated with Discontinuation of Treatment: The adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo was akathisia (2%). Overall, 12% of the patients who received VRAYLAR discontinued treatment due to an adverse reaction, compared with 7% of placebotreated patients in these trials. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness.

Adverse Reactions with an incidence of ≥ 2% and greater than placebo at any dose are shown in Table 6. Table 6 in the full Prescribing Information shows Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in 3-Week Bipolar Mania Trials.

Percentage values shown in parentheses are shown as: Placebo (N=442), VRAYLAR* 3 - 6 mg/day (N=263), and VRAYLAR* 9 - 12° mg/day (N=360). The adverse reactions by System Organ Class/ Preferred Term are as follows: Cardiac Disorders: Tachycardiaa (1, 2, 1); Eye Disorders: Vision blurred (1, 4, 4); Gastrointestinal Disorders: Nausea (7, 13, 11); Constipation (5, 6, 11); Vomiting (4, 10, 8); Dry mouth (2, 3, 2); Dyspepsia (4, 7, 9); Abdominal painb (5, 6, 8); Diarrheac (5, 5, 6); Toothache (2, 4, 3); General Disorders/Administration Site Conditions: Fatigued (2, 4, 5); Pyrexiae (2, 1, 4); Investigations: Blood creatine phosphokinase increased (2, 2, 3); Hepatic enzymes increasedf (<1, 1, 3); Weight increased (2, 2, 3); Metabolism and Nutrition Disorders: Decreased appetite (3, 3, 4); Musculoskeletal and Connective Tissue Disorders: Pain in extremity (2, 4, 2); Back pain (1, 1, 3); Nervous System Disorders: Akathisia (5, 20, 21); Extrapyramidal Symptomsg (12, 26, 29); Headacheh (13, 14, 13); Dizziness (4, 7, 6); Somnolencei (4, 7, 8); Psychiatric Disorders: Insomniaj (7, 9, 8); Restlessness (2, 7, 7); Respiratory, thoracic and mediastinal disorders: Oropharyngeal pain (2, 1, 3); Vascular Disorders: Hypertensionk (1, 5, 4). Note: Figures rounded to the nearest integer. *Data shown by modal daily dose, defined as most frequently administered dose per patient. a Tachycardia terms: heart rate increased, sinus tachycardia, tachycardia. bAbdominal pain terms: abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness. cDiarrhea terms: diarrhea, frequent bowel movements. dFatigue terms: asthenia, fatigue. ePyrexia terms: body temperature increased, pyrexia. fHepatic enzymes increased terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased. gExtrapyramidal Symptoms terms: bradykinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, oromandibular dystonia, parkinsonism, salivary hypersecretion, tremor. hHeadache terms: headache, tension headache. iSomnolence terms: hypersomnia, sedation, somnolence. jInsomnia terms: initial insomnia, insomnia, middle insomnia. kHypertension terms: blood pressure diastolic increased, blood pressure increased, hypertension. °The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Patients with Bipolar Depression -The following findings are based on three placebo-controlled, two 6-week and one 8-week bipolar depression trials with VRAYLAR doses of 1.5 mg, and 3 mg once daily.

Adverse Reactions Associated with Discontinuation of Treatment: There were no adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in VRAYLAR-treated patients and at least twice the rate of placebo. Overall, 6% of the patients who received VRAYLAR discontinued treatment due to an adverse reaction, compared with 5% of placebo-treated patients in these trials. Common Adverse Reactions (≥ 5% and at least twice the rate of placebo): nausea, akathisia, restlessness, and extrapyramidal symptoms. Adverse Reactions with an incidence of ≥ 2% and greater than placebo at 1.5 mg or 3 mg doses are shown in Table 7. Table 7 in the full Prescribing Information shows

Adverse Reactions Occurring in ≥ 2% of VRAYLAR-treated Patients and > Placebo-treated Adult Patients in two 6-week trials and one 8-week trial. Percentage values shown in parentheses are shown as: Placebo (N=468), VRAYLAR 1.5 mg/day (N=470), and VRAYLAR 3 mg/day (N=469). The adverse reactions are as follows: Restlessness (3, 2, 7); Akathisia (2, 6, 10); Extrapyramidal symptomsa (2, 4, 6); Dizziness (2, 4, 3); Somnolenceb (4, 7, 6); Nausea (3, 7, 7); Increased appetite (1, 3, 3); Weight increase (<1, 2, 2); Fatiguec (2, 4, 3); Insomniad (7, 7, 10). aExtrapyramidal symptoms terms: akinesia, drooling, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, muscle tightness, musculoskeletal stiffness, myoclonus, oculogyric crisis, salivary hypersecretion, tardive dyskinesia, tremor. bSomnolence terms: hypersomnia, sedation, somnolence. cFatigue terms: asthenia, fatigue, malaise. dInsomnia terms: initial insomnia, insomnia, insomnia related to another mental condition, middle insomnia, sleep disorder terminal insomnia. Dystonia - Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. Although these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Extrapyramidal Symptoms (EPS) and Akathisia - In schizophrenia, bipolar mania, and bipolar depression trials, data were objectively collected using the Simpson Angus Scale (SAS) for treatment-emergent EPS (parkinsonism) (SAS total score ≤ 3 at baseline and > 3 post-baseline) and the Barnes Akathisia Rating Scale (BARS) for treatment-emergent akathisia (BARS total score ≤ 2 at baseline and > 2 post-baseline). In 6-week schizophrenia trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness was 17% for VRAYLARtreated patients versus 8% for placebo-treated patients. These events led to discontinuation in 0.3% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 11% for VRAYLAR-treated patients versus 4% for placebo-treated patients. These events led to discontinuation in 0.5% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of EPS is shown in Table 8. Table 8 in the full Prescribing Information shows the Incidence of EPS Compared to Placebo in 6-Week Schizophrenia Studies. Percentage values shown in parentheses are shown as: Placebo (N=584), VRAYLAR* 1.5 - 3 mg/day (N=539), VRAYLAR* 4.5 - 6 mg/day (N=575), and VRAYLAR* 9 - 12° mg/day (N=203). The incidence of EPS by adverse event are as follows: All EPS Events: (14, 24, 32, 33); All EPS Events, excluding Akathisia/ Restlessness: (8, 15, 19, 20); Akathisia (4, 9, 13, 14); Dystonia** (<1, 2, 2, 2); Parkinsonism§ (7, 13, 16, 18); Restlessness (3, 4, 6, 5); Musculoskeletal stiffness (1, 1, 3, 1). Note: Figures rounded to the nearest integer. *Data shown by modal daily dose, defined as most frequently administered dose per patient. **Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, trismus, torticollis. §Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypokinesia, masked facies, muscle rigidity, muscle tightness, parkinsonism, tremor, salivary hypersecretion. °The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. In 3-week bipolar mania trials, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 28% for VRAYLAR-treated patients versus 12% for placebo-treated patients. These events led to a discontinuation in 1% of VRAYLAR-treated patients versus 0.2% of placebo-treated patients. The incidence of akathisia was 20% for VRAYLAR-treated patients versus 5% for placebo-treated patients.

These events led to discontinuation in 2% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of EPS is provided in Table 9. Table 9 in the full Prescribing Information shows the Incidence of EPS Compared to Placebo in 3-Week Bipolar Mania Trials. Percentage values shown in parentheses are shown as: Placebo (N=442), VRAYLAR* 3 - 6 mg/day (N=263), and VRAYLAR* 9 - 12° mg/day (N=360). The incidence of EPS by adverse event are as follows: All EPS Events: (18, 41, 45); All EPS Events, excluding Akathisia/Restlessness: (12, 26, 29); Akathisia (5, 20, 21); Dystonia** (1, 5, 3); Parkinsonism§ (10, 21, 26); Restlessness (2, 7, 7); Musculoskeletal stiffness (1, 2, 2). Note: Figures rounded to the nearest integer. *Data shown by modal daily dose, defined as most frequently administered dose per patient. **Dystonia includes adverse event terms: dystonia, oromandibular dystonia. §Parkinsonism includes adverse event terms: bradykinesia, drooling, dyskinesia, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, parkinsonism, salivary hypersecretion, tremor. °The maximum recommended daily dose is 6 mg.

Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. In the two 6-week and one 8-week bipolar depression trials, the incidence of reported events related to EPS, excluding akathisia and restlessness was 4% for VRAYLAR-treated patients versus 2% for placebo-treated patients. These events led to discontinuation in 0.4% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of akathisia was 8% for VRAYLAR-treated patients versus 2% for placebo-treated patients. These events led to discontinuation in 1.5% of VRAYLAR-treated patients versus 0% of placebo-treated patients. The incidence of EPS is shown in Table 10. Table 10 in the full Prescribing Information shows the Incidence of EPS Compared to Placebo in two 6-Week and one 8-Week Bipolar Depression Trials. Percentage values shown in parentheses are shown as: Placebo (N=468), VRAYLAR 1.5 mg/day (N=470), and VRAYLAR 3 mg/day (N=469). The incidence of EPS by adverse event are as follows: All EPS Events: (7, 10, 19); All EPS Events, excluding Akathisia/Restlessness: (2, 4, 6); Akathisia (2, 6, 10); Dystonia* (<1, <1, <1); Parkinsonism§ (2, 3, 4); Restlessness (3, 2, 7); Musculoskeletal stiffness (<1, <1, 1); Tardive Dyskinesia (0, 0, <1). Note: Figures rounded to the nearest integer. *Dystonia includes adverse event terms: dystonia, myoclonus, oculogyric crisis. §Parkinsonism includes adverse event terms: akinesia, drooling, dyskinesia, extrapyramidal disorder, hypokinesia, muscle tightness, salivary hypersecretion, tremor. Cataracts - In the long-term uncontrolled schizophrenia (48-week) and bipolar mania (16-week) trials, the incidence of cataracts was 0.1% and 0.2%, respectively. The development of cataracts was observed in nonclinical studies [see Nonclinical Toxicology in the full Prescribing Information]. The possibility of lenticular changes or cataracts cannot be excluded at this time. Vital Signs Changes - There were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine blood pressure parameters except for an increase in supine diastolic blood pressure in the 9 - 12 mg/day VRAYLARtreated patients with schizophrenia. Pooled data from 6-week schizophrenia trials are shown in Table 11 and from 3-week bipolar mania trials are shown in Table 12. Table 11 in the full Prescribing Information shows the Mean Change in Blood Pressure at Endpoint in 6-Week Schizophrenia Trials. Values shown in parentheses are shown as: Placebo (N=574), VRAYLAR* 1.5 - 3 mg/day (N=512), VRAYLAR* 4.5 - 6 mg/day (N=570), and VRAYLAR* 9 - 12 mg/day° (N=203). The mean changes at endpoint are as follows: Supine Systolic Blood Pressure (mmHg): (+0.9, +0.6, +1.3, +2.1); Supine Diastolic Blood Pressure (mmHg): (+0.4, +0.2, +1.6, +3.4). *Data shown by modal daily dose, defined as most frequently administered dose per patient. °The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh doserelated adverse reactions. Table 12 in the full Prescribing Information shows the Mean Change in Blood Pressure at Endpoint in 3-Week Bipolar Mania Trials. Values shown in parentheses are shown as: Placebo (N=439), VRAYLAR* 3 - 6 mg/day (N=259), and VRAYLAR* 9 - 12 mg/day° (N=360). The mean changes at endpoint are as follows: Supine Systolic Blood Pressure (mmHg): (-0.5, +0.8, +1.8); Supine Diastolic Blood Pressure (mmHg): (+0.9, +1.5, +1.9). *Data shown by modal daily dose, defined as most frequently administered dose per patient. °The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness

sufficient to outweigh dose-related adverse reactions. In the two 6-week and one 8-week bipolar depression trials, there were no clinically meaningful differences between VRAYLAR-treated patients and placebo-treated patients in mean change from baseline to endpoint in supine systolic and diastolic blood pressure. Table 13 in the full Prescribing Information shows the Mean Change in Blood Pressure at Endpoint in two 6-Week and one 8-Week Bipolar Depression Trials. Values shown in parentheses are shown as: Placebo (N=468), VRAYLAR 1.5 mg/day (N=572), and VRAYLAR 3 mg/day (N=426). The mean changes at endpoint are as follows: Supine Systolic Blood Pressure (mmHg): (-0.2, 0.2, -0.1); Supine Diastolic Blood Pressure (mmHg): (0.2, 0.1, -0.3). Changes in Laboratory Tests - The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week schizophrenia trials ranged between 1% and 2% for VRAYLAR-treated patients, increasing with dose, and was 1% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 3-week bipolar mania trials ranged between 2% and 4% for VRAYLAR-treated patients depending on dose group administered and 2% for placebo-treated patients. The proportions of patients with transaminase elevations of ≥3 times the upper limits of the normal reference range in 6-week and 8-week bipolar depression trials ranged between 0% and 0.5% for VRAYLAR-treated patients depending on dose group administered and 0.4% for placebo-treated patients. The proportions of patients with elevations of creatine phosphokinase (CPK) greater than 1000 U/L in 6-week schizophrenia trials ranged between 4% and 6% for VRAYLAR-treated patients, increasing with dose, and was 4% for placebo-treated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 3-week bipolar mania trials was about 4% in VRAYLAR and placebotreated patients. The proportions of patients with elevations of CPK greater than 1000 U/L in 6-week and 8-week bipolar depression trials ranged between 0.2% and 1% for VRAYLAR-treated patients versus 0.2% for placebo-treated patients. Other Adverse Reactions Observed During the Pre-marketing Evaluation of VRAYLAR - Adverse reactions listed below were reported by patients treated with VRAYLAR at doses of ≥ 1.5 mg once daily within the premarketing database of 3988 VRAYLAR-treated patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions that appear elsewhere in the VRAYLAR label are not included. Reactions are further categorized by organ class and listed in order of decreasing frequency, according to the following definition: those occurring in at least 1/100 patients (frequent) [only those not already listed in the tabulated results from placebo-controlled studies appear in this listing]; those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare). Gastrointestinal Disorders: Infrequent: gastroesophageal reflux disease, gastritis; Hepatobiliary Disorders: Rare: hepatitis; Metabolism and Nutrition Disorders: Frequent: decreased appetite; Infrequent: hyponatremia; Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis; Nervous System Disorders: Rare: ischemic stroke; Psychiatric Disorders: Infrequent: suicide attempts, suicide ideation; Rare: completed suicide; Renal and Urinary Disorders: Infrequent: pollakiuria; Skin and Subcutaneous Tissue Disorders: Infrequent: hyperhidrosis. Postmarketing Experience - The following adverse reaction has been identified during post approval use of VRAYLAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders – Stevens-Johnson syndrome.

DRUG INTERACTIONS: Drugs Having Clinically Important Interactions with VRAYLAR. Table 14 in the full Prescribing Information lists the Clinically Important Drug Interactions with VRAYLAR. Strong CYP3A4 Inhibitors: Clinical Impact: Concomitant use of VRAYLAR with a strong CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of VRAYLAR alone [see Clinical Pharmacology in the full Prescribing Information]. Intervention: If VRAYLAR is used with a strong CYP3A4 inhibitor, reduce VRAYLAR dosage [see Dosage and Administration in the full Prescribing Information]. Examples: itraconazole, ketoconazole. CYP3A4 Inducers: Clinical Impact: CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of VRAYLAR has not been evaluated, and the net effect is unclear [see Clinical Pharmacology in the full Prescribing Information]. Intervention: Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended [see Dosage and Administration in the full Prescribing Information]. Examples: rifampin, carbamazepine.

USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Exposure Registry - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VRAYLAR during pregnancy. For more information, contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/. Risk Summary - Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations).There are no available data on VRAYLAR use in pregnant women to inform any drug-associated risks for birth defects or miscarriage. The major active metabolite of cariprazine, DDCAR, has been detected in adult patients up to 12 weeks after discontinuation of VRAYLAR [see Clinical Pharmacology in the full Prescribing Information]. Based on animal data, VRAYLAR may cause fetal harm. Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the maximum recommended human dose (MRHD) of 6 mg/day. However, cariprazine was not teratogenic in rabbits at doses up to 4.6 times the MRHD of 6 mg/day [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk to a fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions - Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Data - Animal Data - Administration of cariprazine to pregnant rats during the period of organogenesis at oral doses of 0.5, 2.5, and 7.5 mg/kg/day which are 0.2 to 3.5 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC of total cariprazine (i.e. sum of cariprazine, DCAR, and DDCAR) caused fetal developmental toxicity at all doses which included reduced body weight, decreased male anogenital distance and skeletal malformations of bent limb bones, scapula and humerus. These effects occurred in the absence or presence of maternal toxicity. Maternal toxicity, observed as a reduction in body weight and food consumption, occurred at doses 1.2 and 3.5-times the MRHD of 6 mg/day based on AUC of total cariprazine. At these doses, cariprazine caused fetal external malformations (localized fetal thoracic edema), visceral variations (undeveloped/underdeveloped renal papillae and/or distended urethrae), and skeletal developmental variations (bent ribs, unossified sternebrae). Cariprazine had no effect on fetal survival. Administration of cariprazine to pregnant rats during pregnancy and lactation at oral doses of 0.1, 0.3, and 1 mg/kg/day which are 0.03 to 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine caused a decrease in postnatal survival, birth weight, and post-weaning body weight of first generation pups at the dose that is 0.4 times the MRHD of 6 mg/day based on AUC of total cariprazine in absence of maternal toxicity. First generation pups

also had pale, cold bodies and developmental delays (renal papillae not developed or underdeveloped and decreased auditory startle response in males). Reproductive performance of the first generation pups was unaffected; however, the second generation pups had clinical signs and lower body weight similar to those of the first generation pups. Administration of cariprazine to pregnant rabbits during the period of organogenesis at oral doses of 0.1, 1, and 5 mg/kg/day, which are 0.02 to 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine was not teratogenic. Maternal body weight and food consumption were decreased at 4.6 times the MRHD of 6 mg/day based on AUC of total cariprazine; however, no adverse effects were observed on pregnancy parameters or reproductive organs. Lactation - Risk Summary - Lactation studies have not been conducted to assess the presence of cariprazine in human milk, the effects on the breastfed infant, or the effects on milk production.

Cariprazine is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for VRAYLAR and any potential adverse effects on the breastfed infant from VRAYLAR or from the underlying maternal condition. Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Pediatric studies of VRAYLAR have not been conducted. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions in the full Prescribing Information].

Geriatric Use - Clinical trials of VRAYLAR in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and older to determine whether or not they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients with dementia-related psychosis treated with VRAYLAR are at an increased risk of death compared to placebo. VRAYLAR is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions]. Hepatic Impairment - No dosage adjustment for VRAYLAR is required in patients with mild to moderate hepatic impairment (Child-Pugh score between 5 and 9) [see Clinical Pharmacology in the full Prescribing Information]. Usage of VRAYLAR is not recommended in patients with severe hepatic impairment (Child-Pugh score between 10 and 15). VRAYLAR has not been evaluated in this patient population. Renal Impairment - No dosage adjustment for VRAYLAR is required in patients with mild to moderate (CrCL ≥ 30 mL/minute) renal impairment [see Clinical Pharmacology in the full Prescribing Information]. Usage of VRAYLAR is not recommended in patients with severe renal impairment (CrCL < 30 mL/minute). VRAYLAR has not been evaluated in this patient population. Smoking - No dosage adjustment for VRAYLAR is needed for patients who smoke. VRAYLAR is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of VRAYLAR. Other Specific Populations - No dosage adjustment is required based on patient’s age, sex, or race. These factors do not affect the pharmacokinetics of VRAYLAR [see Clinical Pharmacology in the full Prescribing Information].

DRUG ABUSE AND DEPENDENCE: Controlled Substance - VRAYLAR is not a controlled substance.

Abuse - VRAYLAR has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance. Dependence - VRAYLAR has not been systematically studied in animals or humans for its potential for physical dependence.

OVERDOSAGE: Human Experience - In pre-marketing clinical trials involving VRAYLAR in approximately 5000 patients or healthy subjects, accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day. Management of Overdosage - No specific antidotes for VRAYLAR are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. In case of an overdose, consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.

Licensed from Gedeon Richter Plc. Manufactured by: Forest Laboratories Ireland Limited Dublin, IE.

Distributed by: Allergan USA, Inc. Madison, NJ 07940

VRAYLAR® is a registered trademark of Forest Laboratories Holdings Ltd., an Allergan affiliate. © 2021 Allergan. All rights reserved.

Allergan® and its design are trademarks of Allergan, Inc.

VRA148402-T 05/19

CONTENIDO

TRATAMIENTO DE LA PSORIASIS ERITRODÉRMICA CON BIOLÓGICOS: UNA REVISIÓN SISTEMÁTICA

26 10

54

40

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SUBDIAGNÓSTICO DE DERMATITIS ATÓPICA EN NIÑOS PUERTORRIQUEÑOS

UTILIZANDO EL MMSE-2 PARA MEDIR EL DETERIORO COGNITIVO EN UNA MUESTRA DE PACIENTES PSIQUIÁTRICOS VIVIENDO EN PUERTO RICO

DISCAPACIDAD ENTRE ADULTOS CON DIAGNÓSTICO DE VIH EN ESTADOS UNIDOS

PREOCUPACIONES, USO DE ATENCIÓN MÉDICA E INTERRUPCIONES DE TRATAMIENTO EN PACIENTES CON ENFERMEDADES REUMÁTICAS AUTOINMUNES COMUNES DURANTE LA PANDEMIA DE COVID-19

EDITOR FUNDADOR Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD CONSEJO ASESOR Oscar Soto Raíces, MD, Ahmed Morales, MD, FACP, FACG, FASGE, AGAF, Lcda. Wanda González PRINCIPAL OFICIAL EJECUTIVO Pedro Carlos Lugo Hernández III, P.A.C. PRESIDENTA Y FUNDADORA Glorybelle Hernández Figueroa, MBA VICEPRESIDENTA Y FUNDADORA Laila Paloma Lugo, MBA CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA, MARKETING Y SERVICIOS 360 Alexelena Cayere, Yasmin Morell PERIODISTAS Belinda Burgos, Grenda Rivera, Mayra Acevedo, Luis Penchi, Limarys Suárez DIRECCIÓN GRÁFICA Natalia Zoé Rivera Torres DIRECTORA AUDIOVISUAL Fabiola Plaza REALIZADORA AUDIOVISIAL Salomé Mateus FOTOS Revista Medicina y Salud Pública DIRECCIÓN GENERAL / FUNDADOR Carlos Alexis Lugo Marrero DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente Para ventas y otros servicios pueden comunicarse al 787.848.3333, msp@editorialmundo.com o www.medicinaysaludpublica.com Revista Puertorriqueña de Medicina y Salud Pública ISSN 1937-8521 COMITÉ EDITORIAL CIENTÍFICO COMITÉ EDITORIAL Olga Rodríguez, MD - Decana Escuela de Medicina de Ponce (Puerto Rico), Vivian Green, LND, MS, PhD, Sub editora y fundadora (Puerto Rico), José Cordero, MD, MPH - Exdecano Escuela Graduada Salud Pública Recinto de Ciencias Médicas UPR (Puerto Rico), Ángeles Rodríguez, MD, MPH (Puerto Rico), Simón Carlo, MD (Puerto Rico), Bárbara Rosado, MD (Puerto Rico), Idhaliz Flores PhD (Puerto Rico), Jesús Cruz-Correa, MD, FACOG (Puerto Rico), Rafael Bredy, MD, LicMTo, MBE, MS (Puerto Rico), David Caseida, MD, FACOG, (Puerto Rico), José Capriles, MD, MHSA (Puerto Rico) Joaquín Laboy, MD, FACOG (Puerto Rico), Luis Adrian Rivera Pomales, MD, PEMBA, MPH, CMQ (Puerto Rico), Juan Fernández, MS, PhD (Puerto Rico), Nuria Sebate, MD (Puerto Rico), Pedro Amador, MD, MPH (Puerto Rico), Nydia Cappas, PsyD (Puerto Rico), Luis Franco, MD (Puerto Rico), Federico Montealegre, DVM, PhD, Msc (Puerto Rico), Nydia Ortiz, PsyD (Puerto Rico), José Pons, PhD, FPPR (Puerto Rico), Esdrás Vélez, JD, MPH (Puerto Rico), Diego Zavala, MSc, PhD, (Puerto Rico), Ana Torres-Martín, MD (Puerto Rico), Julio Cádiz, MD, MPH (Puerto Rico), Rafael Gómez-Cuevas (Colombia), José Javier Orengo, PhD(c) (España), Cesar A. Del Rey, MD (Panamá), Pedro Serrano, MD, PhD (España), Luis Serra-Majem, MD, PhD (España), José Ramón Calvo, MD, PhD (España).

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EDITORIAL Hablemos más de la Hidradenitis Supurativa

M

ALBERTO SANTIAGO CORNIER, EDITOR JEFE DIVISIÓN DE GENÉTICA DEL SAN JORGE CHILDREN’S HOSPITAL DIRECTOR CENTRO INVESTIGACIONES CLÍNICAS DEL SAN JORGE CHILDREN’S HOSPITAL CATEDRÁTICO ASOCIADO DE LA UNIVERSIDAD CENTRAL DEL CARIBE, DEPARTAMENTO DE PEDIATRÍA CATEDRÁTICO ASOCIADO DE LA PONCE HEALTH SCIENCES UNIVERSITY, DEPARTAMENTO DE SALUD PÚBLICA PRÁCTICA PRIVADA TORRE MÉDICA HOSPITAL SAN JORGE Y SER DE PUERTO RICO

i médico nunca me habló de la hidradenitis supurativa. El doctor solo me dijo que era un nacido. Todo el mundo me pregunta qué es eso o, “¿hidra qué?”.

Mi absceso me explotó en la fila del supermercado y se me manchó toda la ropa de sangre. Pareciera que los médicos no conocen la HS. Esto es el resumen de las expresiones más marcadas que como medio de comunicación leemos a diarios por parte de pacientes diagnosticados con la enfermedad autoinmune junto con el ínfimo número de profesionales de la salud que se han atrevido a estudiar la condición y hasta diagnosticarla, como lo vive a diario la Dra. Alma Cruz, dermatóloga y catedrática del Recinto de Ciencias Médicas.

La hidradenitis supurativa no es una enfermedad nueva. No se descubrió hace una década. No es contagiosa.

No es un simple absceso que ha drenado.

Es la herida son secreciones que te han dejado sin un pedazo de piel en las entrepiernas y que provoca que tengan que asistirte en todo, cargando con el mal olor que pudiera provocar la misma. Es el absceso con pus en tu genitalia, que no te permite tener una relación sexual a plenitud. Es la sangre que se cuela en tus sábanas y mancha tu ropa interior. Es el dolor de aguantar el estigma social de los que no saben la vergüenza que sientes con múltiples remociones de piel en distintas partes del cuerpo que te obligan a tener gasas y hasta toallas sanitarias para taparlas, tal cual hemos sido testigo.

La HS necesita visibilizarse de manera cruda a nivel de determinantes sociales y clínicamente por parte de los médicos. Por tal razón, necesitamos de la mano de nuestros médicos, de maestros en salud pública, de educadores en salud, de más profesionales de la enfermería, de médicos internistas, infectólogos y sobre todo, cirujanos y profesionales de la salud mental que den la cara por estos pacientes.

Tenemos que demostrar que estos pacientes no están solos, que sabemos sospechar de los síntomas de la enfermedad, que sabemos pronunciarla, porque es visible, que los entendemos. Sabemos que como peritos en medicina tenemos el deber de educar a los patronos de los acomodos razonables al que estos pacientes tienen derecho.

Que contamos con nutricionistas y profesionales de la salud mental especializados en esta población.

Que existen más educadores en salud en el área de hidradenitis supurativa, como los hay para diabetes, para mujeres embarazadas, para enfermedades infecciosas.

Si leíste este editorial, te invito a unirte a nosotros para continuar este esfuerzo de educación a través de nuestras plataformas digitales. El cambio empieza hoy.

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SUBDIAGNÓSTICO DE DERMATITIS ATÓPICA EN NIÑOS PUERTORRIQUEÑOS Ge Yang a,b,e, Yueh-Ying Han a, Erick Forno a, Edna Acosta-Perez c, Angel Colon-Semidey c,d, María Alvarez c,d, Glorisa Canino c,d, Wei Chen a, Juan C. Celedon a,* a Division of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA b Department of Neonatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China c Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto Rico d Department of Pediatrics, University of Puerto Rico, San Juan, Puerto Rico e Third Xiangya Hospital, Central South University, Changsha, Hunan, 410083, China

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RESUMEN Antecedentes: poco se sabe sobre la dermatitis atópica (DA) entre los niños de Puerto Rico.

Objetivo: Examinar los factores de riesgo e identificar enfoques para diagnosticar mejor la EA en niños puertorriqueños. Métodos: Estudio de casos y controles de EA entre 540 niños de 6 a 14 años en San Juan, Puerto Rico. La EA se definió como: 1) EA diagnosticada por un médico, 2) RAST-AD: síntomas de EA más IgE positiva para β1 a alérgenos, y 3) STR-AD: síntomas de EA y reactividad de la prueba cutánea al alérgeno β1. Se utilizó la regresión logística para el análisis multivariable.

También evaluamos el rendimiento diagnóstico de varios enfoques al comparar su sensibilidad, especificidad, valor predictivo positivo [VPP], valor predictivo negativo [VPN] y área bajo la curva [AUC]).

Resultados: De los 70 niños con STR-AD, solo 5 (7,1%) tenían PD-AD. En niños sin asma, una IgE positiva para Dermatophagoides (D.) pteronys

sinus y signos de moho/hongos en el hogar se asociaron significativamente con probabilidades 3,3 y 5 veces mayores de STR-AD, respectivamente. Entre los niños con asma, el seguro de salud privado/del empleador y una IgE positiva para D. pteronyssinus se asociaron significativamente con aproximadamente el doble de probabilidades de STR-AD. Una combinación de síntomas de eccema actuales y una IgE positiva para D. pteronyssinus produjo una sensibilidad del 70 %, especificidad y VPN del 95 %, VPP del 88 % y un AUC de 0,85 para STR-AD. Reemplazar una IgE positiva para D. pteronyssinus con una IgE positiva para el alérgeno ??1 aumentó ligeramente la sensibilidad sin afectar otros parámetros.

Conclusiones: la EA está marcadamente subdiagnosticada por los médicos en Puerto Rico.

Esto podría mejorarse evaluando los síntomas del eccema y midiendo las IgE frente a los alérgenos comunes.

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ABSTRACT Background: Little is known about atopic dermatitis (AD) among children in Puerto Rico.

Objective: To examine risk factors and identify approaches to better diagnose AD in Puerto Rican children. Methods: Case-control study of AD among 540 children aged 6–14 years in San Juan, Puerto Rico. AD was defined as: 1) physician-diagnosed AD, 2) RAST-AD: AD symptoms plus 1 positive IgE to allergens, and 3) STR-AD: AD-symptoms and skin test reactivity to 1 allergen.

Logistic regression was used for the multivariable analysis. We also evaluated the diagnostic performance of various approaches by comparing their sensitivity, specificity, positive predicted value [PPV], negative predictive value [NPV], and area under curve [AUC]).

Results: Of the 70 children with STR-AD, only 5 (7.1%) had PD-AD. In children without asthma, a positive IgE to Dermatophagoides (D.) pteronyssinus and signs of mold/ mildew at home were significantly associated with 3.3 and 5 times increased odds of STR-AD, respectively. Among children with asthma, private/employer-based health insurance and a positive IgE to D. pteronyssinus were each significantly associated with approximately twofold increased odds of STR-AD. A combination of current eczema symptoms and a positive IgE to D. pteronyssinus yielded a sensitivity 70%, specificity and NPV 95%, PPV 88%, and an AUC 0.85 for STR-AD. Replacing a positive IgE to D. pteronyssinus with a positive IgE to 1 allergen slightly increased sensitivity without affecting other parameters.

Conclusions: AD is markedly under-diagnosed by physicians in Puerto Rico. This could be improved by assessing eczema symptoms and measuring IgEs to common allergens.

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INTRODUCTION Atopic dermatitis (AD) is a common allergic disease worldwide, affecting over 20% of children in high income countries and rising in prevalence in low to middle income countries.1,2 Among participants in a U.S.-based study, ~17.1% had eczematous symptoms but only 6% were diagnosed with AD, suggesting marked disease under-diagnosis and under-treatment.3 In Puerto Rico, where atopic asthma is a major public health problem, 24.8% of second-grade children attending two schools had parental report of symptoms of atopic dermatitis.4 The “gold standard” for a diagnosis of AD consists of a thorough history and physical exam, combined with allergy skin testing.

Such diagnostic approach, however, may not be feasible in epidemiologic studies or in underserved areas with limited access to an allergist, such as Puerto Rico. Some epidemiologic studies rely on questionnaire-reported symptoms or a physician’s diagnosis to identify AD,5 while others use a G. Yang et al. combination of questionnaire-based data and objectively measured allergic sensitization.6 Since self-reported diagnosis or symptoms are subject to recall and reporting bias, the ideal criteria

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to detect or diagnose AD in population-based studies remains to be established.7 AD frequently occurs during infancy, often serving as a harbinger of other atopic diseases during childhood, including allergic rhinitis and asthma. Indeed, up to 80% of children with AD may develop or have concurrent allergic rhinitis or asthma.8 In addition to such atopic dis-eases, common risk factors or co-morbidities of AD include low income,2 obesity,9 dust mite allergen exposure,10 and an elevated total serum IgE.11,12 We hypothesized that AD would be markedly under-diagnosed among Puerto Rican children living in the island of Puerto Rico, where fewer than fifteen allergists served a population of 3.7 million people before Hurricane Maria. We further hypothesized that such under-diagnosis of AD could be reduced by obtaining a history of symptoms suggestive of eczema and measuring levels of IgE to common allergens.

In this report, we estimated and compared the prevalence of AD identified through self-reported symptoms and objectively measured allergic sensitization against that of physician-diagnosed-AD among 540 Puerto Rican children aged 6–14 years living in the metropolitan area of San Juan, PR.

METHODS Subject recruitment From March of 2009 to June of 2010, children were recruited for a case-control study of asthma from randomly selected households in San Juan (Puerto Rico). As previously described,15 households in the metropolitan area of San Juan were selected by a multistage probability sampling design. Primary sampling units were randomly selected neighborhood clusters based on the 2000 U.S. census. Secondary sam-pling units were randomly selected households within each primary sampling unit. A household was included if 1 resident was a child aged 6–14 years whose four grandparents were all Puerto Rican. In households with >1 eligible child, only one child was randomly selected for screening. On the basis of the sampling design, 7073 households were selected and 6401 (90.5%) were contacted. Of these 6401 households, 1111 had 1 child who met inclusion criteria. In an effort to reach a target sample size of approximately 700 children, we attempted to enroll a random sample (n ¼ 783) of these 1111 eligible children.

We were able to obtain parental consent for 678 of these 783 children. There were no significant differences in age, gender, or area of residence between eligible children who did (n ¼ 678 [86.6%]) and did not (n ¼ 105 [13.4%]) agree to participate. Of the 678 participating children, 540 (79.7%) had complete data on allergy skin testing, levels of allergen specific-IgEs, and parental report of AD symptoms, and were thus included in the current analysis.

Cases had asthma, defined as parental report of physician-diagnosed asthma and at least one episode of wheeze in the previous year. Control subjects had neither parental report of physician-diagnosed asthma nor wheeze in the prior year.

STUDY PROCEDURES Study participants completed a protocol that included questionnaires, allergy skin testing, and collection of blood (for measurement of total and allergen-specific IgEs). One of the child’s parents (usually [>93%] the mother) completed questionnaires about the child’s general and respi-ratory health, socio-demographic and household characteristics, and family history of asthma and allergic diseases.

Height and weight were measured to the nearest centimeter and pound, respectively.

Plasma levels of total IgE and IgEs to five common allergens (dust mite [Der p 1], cockroach [Bla g 2], cat dander [Fel d 1], dog dander [Can f 1], and mouse urinary protein [Mus m 1]) were determined using the UniCAP 100 system (Pharmacia & Upjohn, Kalamazoo, MI). For each allergen, an IgE 0.35 IU/ml was considered positive. Skin test reactivity (STR) to aeroallergens was assessed using a Multi Test device (Lincoln Diagnostics, Decatur, IL).

In addition to histamine (positive control) and saline solution (negative control), allergen extracts from dust mites (Dermatophagoides (D.) pteronyssinus, D. farinae and Blomia tropicalis), house dust, German cockroach (Blatella germanica), cat dander, dog dander, mixed grass pollen, mugwort sage, ragweed, mixed tree pollen, mold mix, Alternaria tenuis and mouse urinary protein were applied to the skin of the forearm in a site free of eczema (Alk-Abello, Round Rock, Texas).

Skin test reactivity (STR) was defined as a maximum wheal diameter exceeding the saline diluent wheal diameter by at least 3 mm.

Written parental consent was obtained for participating children, from whom written assent was also obtained. The study was approved by the Institutional Review Boards of the University of Puerto Rico (San Juan, PR), Brigham and Women’s Hospital (Boston, MA), and the Uni-versity of Pittsburgh (Pittsburgh, PA).

Statistical analysis We analyzed and compared several definitions of AD, as follows: 1) physician-diagnosed AD (PD-AD), 2) current symptoms suggestive of AD (AD symptoms), defined as a positive response to the following two questions (a) “Has your child ever had a prolonged, itchy, scaly or weepy skin rash?” and (b) “Has your child had this rash in the last 12 months?”, 3) RAST-AD, defined as AD-symptoms plus at least one positive IgE to allergens, and 4) STR-AD, defined as AD-symptoms and STR to at least one allergen.

Bivariate analyses were conducted using two-sample t-tests (for continuous variables) and chi-square tests or Fisher’s exact tests (for categorical variables). Logistic regression was used for the multivariable analysis of STR-AD. All multivaria-

ble models included age, gender, body mass index as a z-score (based on 2000 CDC growth charts13), and asthma. The following covariates were also included in the initial multivariable models, if associated with STR-AD at P 0.25 in bivariate analyses: parental education (either parent completed high school vs. none), household income (<vs. 􀀁 $15,000/year [near the median in-come for households in Puerto Rico in 2008–200914]),15 type of health insurance (public vs. private or employer-based), parental history of eczema, current exposure to second-hand smoke (SHS), day care attendance in the first year of life, plasma total IgE, a positive IgE to each allergen, a positive IgE to at least one allergen, and parental report of each of the following: signs of mold or mildew in the house, sighting cockroaches, and sighting mice. Because of collinearity, the initial multivariable models included only one of the significant total or allergen-specific IgE measures (i.e. we did not include total IgE and a positive IgE to dust mite in the same model). These additional covariates remained in the final models if they were associated with AD at P < 0.05 or if they changed the estimate of effect ( )by 10%. For test parameters, we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for STR-AD, as follows: 1) Sensitivity ¼ True positives 100, 2) True positives þ False negatives Specificity ¼ True negatives 100, 3) Positive predictive value was plotted as sensitivity against (1 specificity). The area under the curve (AUC) of ROC was used to assess diagnostic performance. R program (Version 3.4.2) was used for all analyses.

RESULTS eTable 1 shows the comparison of the main characteristics of study participants who were (n ¼ 540) and were not (n ¼ 138) included in the current analysis. Compared with children who were included in the analysis, those excluded were significantly more likely to have a house-hold income >$15,000 per year and a lower BMI z-score, but signifi-cantly less likely to be currently exposed to second-hand smoke. There were no significant differences in age, gender, type of health insurance, parental education, Revista Puertorriqueña de Medicina y Salud Pública

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parental history of eczema, day care attendance in the first year of life, signs of mold or mildew in the home, or sighting pests (cockroaches or mice) between children who were and were not included in the current analysis.

The characteristics of study participants, according to whether they did or did not have STR-AD, as well as asthma, are shown in Table 1.Of the 540 participants, 70 (13.0%) had STR-AD. Among children with asthma, those with STR-AD were significantly more likely to have private or employer-based health insurance than those without STR-AD. Among children without asthma, those with STR-AD were significantly more likely to have a parent report signs of mold or mildew in the home, but less likely to sighting mice, than those without STR-AD. Among children with and without asthma, those with STR-AD were significantly more likely to have current allergic rhinitis, an increased total IgE, and a positive IgE to D. pteronyssinus than children without STR-AD. There was no significant difference in current SHS or any other characteristic between children with and without STR-AD, regardless of asthma status.

We next calculated the proportion of subjects with STR-AD who were also diagnosed by a physician (i.e. who had PD-AD). Of the 70 subjects with STR-AD, only 5 (7.1%) also had PD-AD (Fig. 1, Panel A). This marked under-diagnosis of STR-AD was similar in children with and without asthma (Fig. 1, panels B and C).

Table 2 shows the results of the multivariable analysis of STR-AD, separately in children with and without asthma. In the analysis among children without asthma (which was adjusted for age, gender, and BMI z-score), having a positive IgE to D.pteronyssinus and parental report of mold or mildew at home were significantly associated with 3.3 times and 5 times increased odds of STR-AD, respectively (Model 1). Similar results were obtained when a positive IgE to D. pteronyssinus was replaced with having 1 positive IgE to allergens (Model 2) or with total IgE (Model 3). In all three multivariable models, there was a trend for an inverse asso-ciation between parental report of sighting mice and STR-AD, but such trend was non-statistically significant (models 14

1 and 3) or of borderline statistical significance (model 2). In the multivariable analysis of STR-AD among children with asthma (also adjusted for age, gender, and BMI z-score), having private or employer-based health insurance was signifi-cantly associated with approximately twofold increased odds of STR-AD (Model 1). Similar results were obtained when a positive IgE to D. pteronyssinus was replaced with either 1 positive IgE to allergens (Model 2) or total serum IgE (Model 3).

Table 3 shows the sensitivity, specificity, PPV, NPV and AUC of various approaches to the diagnosis of STR-AD in Puerto Rican children, which were partly based on the results of our multivariable analysis (see Table 2). PD-AD had high specificity but very low sensitivity and a low AUC for STR-AD, both in children with and without asthma. A combination of AD symptoms and a positive IgE to D. pteronyssinus yielded sensitivity 70% and specificity 95%, NPV 95% and PPV 88%, and an AUC 0.85 for STR-AD, both in children with and without asthma. Replacing a positive IgE to D. pteronyssinus with a positive IgE to 1 allergen slightly increased sensitivity (i.e. from 75.7% to 80% in all children) but had minimal impact on all other parameters (specificity, NPV, PPV or the AUC).

DISCUSSION We found that ~93% of cases of STR-AD among children in Puerto Rico had not been diagnosed by a physician, possibly due to limited access to healthcare (particularly allergists) in Puerto Rico.15,16 A previous study of AD among children ages 6–7 years who attended two schools in Puerto Rico found that the prevalence of parental report of current eczema symptoms was 24.8%,4 and that ~70% of children with such symptoms had not been diagnosed with AD by a physician. In contrast to that study, we assessed not only eczema symptoms but also skin test reactivity to allergens and levels of total/allergen-specific IgEs in a population-based sample of school-aged children aged 6–14 years. Moreover, the response rate in the previous study (53%) was substan-tially lower than that in the current study.

Consistent with findings in other popula-

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tions, we show that a positive IgE to common allergens such as house dust mite or an elevated total serum IgE is significantly associated with STR-AD.6 Indeed, dust mite allergen exposure has been linked to eczematous symptoms,2,8 and high dust mite allergen levels have been reported to be both common and associated with asthma and other allergic diseases in Latin America.17 In contrast to our findings for total IgE and STR-AD, Perkins et al reported that total IgE plays little role in prediction of visible eczema at 5 years, despite a significant association between total IgE and eczema severity.12 On the other hand, Ville et al showed that reductions in total IgE are associated with good treatment response and complete remission of AD11 Among children without asthma, we found that signs of mold or mildew in the house are associated with STR-AD. Such exposure could alter the skin barrier, a first step in AD pathogenesis.18 However, the impact of reducing mold or mildew on AD, if any, is unknown.19 Among children with asthma, we show that private or employer-based health insurance is significantly associated with STR-AD, likely due to improved access to healthcare.

We show that a combination of current eczematous symptoms and 1 positive IgE to common allergens could markedly improve the diagnostic rate of STR-AD among physicians in Puerto Rico. Indeed, such approach yielded a sensitivity of 80%, plus high: specificity, PPV, NPV, and AUC for STR-AD in all children. Of interest, replacing 1 positive IgE to al-lergens with a positive IgE to dust mite yielded a comparably high sensitivity (i.e. 76%) for STR-AD in all children, thus supporting a relatively simple and cost-effective approach to AD diagnosis and care in Puerto Rico.

Our study has substantial strengths, including a population-based sample of school-aged children and data on objective measures of allergic sensitization.4 We also recognize several study limitations. First, we cannot assess temporal relationships due to the cross-sectional study G. Yang et al. design. Second, we did not conduct direct skin examinations. However, we used a combination of STR to allergens

and questionnaire-based data for our “reference diagnosis of AD”. Third, selection bias and recall bias are possible in any observational study such as ours.

However, selection bias is an unlikely explanation for our results, since there was no sig-nificant difference in most relevant characteristics (i.e. type of health insurance, parental history of eczema, signs of mold or mildew in the home) between children who were and were not included in our analysis. Similarly, poor parental understanding or recall of a physician’s diagnosis of eczema is not probable as the sole explanation for the marked under-diagnosis of STR-AD in study subjects.

Finally, we had no data on some potential confounders, such as diet.

In summary, only 7.1% of cases of STRAD among school-aged Puerto Rican children were diagnosed by a physician, as reported by the child’s parents. Physicians in Puerto Rico could improve their diagnostic accu-racy for AD by inquiring about current eczematous symptoms, conducting a clinical examination of the skin, and measuring IgEs to a panel of common allergens (or, if that were non-feasible, IgE to house dust mite).

Ethics approval and consent to participate The study was approved by the Institutional Review Boards of the University of Puerto Rico (San Juan, PR), Brigham and Women’s Hospital (Boston, MA), and the University of Pittsburgh (Pittsburgh, PA).

Written parental consent was obtained for participating children, from whom written assent was also obtained.

Consent for publication Not applicable.

Availability of data and material Not applicable. Competing interests Dr. Celedon has received research materials from Merck and GSK (inhaled steroids), and Pharmavite (vitamin D and placebo capsules), to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. The other authors report no competing interests.

Authors’ contributions GY and JCC conceived of the study and participated in its design, and drafted the manuscript. GY, YYH, EF, and WC performed statistical analysis. EAP, ACS, MA, and GC participated in the design and

coordi-nation of the study. All authors read and approved the final manuscript.

Funding This work was supported by the U.S. National Institutes of Health [grants HL079966, HL117191, and HD052892], the Heinz Endowments, the China Scholarship Council, and the Third Xiangya Hospital, Central South University.

ACKNOWLEDGEMENTS We thank children and their families for their participation in this study.

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.waojou.2018.11.003.

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6. Bos JD, Van Leent EJ, Sillevis Smitt JH. The millennium criteria for the diagnosis of atopic dermatitis. Exp Dermatol. 1998 Aug;7(4):132–138. PubMed PMID: 9758407.

Epub 1998/10/03. eng.

7. Brenninkmeijer EEA, Schram ME, Leeflang MMG, Bos JD, Spuls PI. Diagnostic criteria for atopic dermatitis: a systematic review. Br J Dermatol. 2008;158(4): 754–765.

8. Leung DYM, Bieber T. Atopic dermatitis.

Lancet. 2003;361(9352):151–160, 2003/ 01/11/.

9. Koutroulis I, Magnelli L, Gaughan J, Weiner E, Kratimenos P. Atopic dermatitis is more severe in children over the age of two who have an increased body mass index. Acta Paediatr. 2015;104(7):713–717.

10. Bremmer SF, Simpson EL. Dust mite avoidance for the primary prevention of atopic dermatitis: a systematic review and meta-analysis. Pediatr Allergy Immunol. 2015; 26(7):646–654.

11. Kiiski V, Karlsson O, Remitz A, Reitamo S. High serum total IgE predicts poor longterm outcome in atopic dermatitis. Acta Derm Venereol. 2015 Nov;95(8):943–947. PubMed PMID: 25916555. Epub 2015/04/29. eng.

12. Perkin MR, Strachan DP, Williams HC, Kennedy CTC, Golding J. Natural history of atopic dermatitis and its relationship to serum total immunoglobulin E in a population-based birth cohort study. Pediatr Allergy Immunol.

2004;15(3):221–229.

13. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data. 2000 Jun 8;(314):1–27.

PubMed PMID: 11183293. Epub 2001/02/ 24. eng.

14. U.S. Census Bureau. Household Income for States: 2008 and 2009 2010 [cited 2013 September 9]. Available from: http://www. census.gov/prod/2010pubs/acsbr09-2. pdf.

15. Forno E, Celedon JC. Asthma and ethnic minorities: socioeconomic status and beyond. Curr Opin Allergy Clin Immunol.

2009 Apr;9(2):154–160. PubMed PMID: 19326508. Epub 2009/03/28. eng.

16. Nazario S, Acantilado C, Alvarez M, et al. Allergist role in asthma care in Puerto Rico. Bol Asoc Med P R. 2011 Jan- Mar;103(1):18–21. PubMed PMID: 21696098. Epub 2011/06/24. eng.

17. Hunninghake GM, Weiss ST, Celedon JC. Asthma in hispanics. Am J Respir Crit Care Med. 2006;173(2):143–163, 10/06 08/09/received 10/05/accepted. PubMed PMID: PMC2662985.

18. Kim BE, Leung DYM. Significance of skin barrier dysfunction in atopic dermatitis. Allergy Asthma Immunol Res. 2018 May;10(3):207–215. PubM ed PMID: 29676067. Pubmed Central PMCID: PMC5911439. Epub 2018/04/21. eng.

19. Leung DYM, Guttman-Yassky E. Assessing the current treatment of atopic dermatitis: unmet needs. J Allergy Clin Immunol. 2017;139(4, Supplement):S47–S48, 2017/04/ 01/.

Revista Puertorriqueña de Medicina y Salud Pública

15

parental history of eczema, day care attendance in the first year of life, signs of mold or mildew in the home, or sighting pests (cockroaches or mice) between children who were and were not included in the current analysis.

The characteristics of study participants, according to whether they did or did not have STR-AD, as well as asthma, are shown in Table 1.Of the 540 participants, 70 (13.0%) had STR-AD. Among children with asthma, those with STR-AD were significantly more likely to have private or employer-based health insurance than those without STR-AD. Among children without asthma, those with STR-AD were significantly more likely to have a parent report signs of mold or mildew in the home, but less likely to sighting mice, than those without STR-AD. Among children with and without asthma, those with STR-AD were significantly more likely to have current allergic rhinitis, an increased total IgE, and a positive IgE to D. pteronyssinus than children without STR-AD. There was no significant difference in current SHS or any other characteristic between children with and without STR-AD, regardless of asthma status.

We next calculated the proportion of subjects with STR-AD who were also diagnosed by a physician (i.e. who had PD-AD). Of the 70 subjects with STR-AD, only 5 (7.1%) also had PD-AD (Fig. 1, Panel A). This marked under-diagnosis of STR-AD was similar in children with and without asthma (Fig. 1, panels B and C).

Table 2 shows the results of the multivariable analysis of STR-AD, separately in children with and without asthma. In the analysis among children without asthma (which was adjusted for age, gender, and BMI z-score), having a positive IgE to D.pteronyssinus and parental report of mold or mildew at home were significantly associated with 3.3 times and 5 times increased odds of STR-AD, respectively (Model 1). Similar results were obtained when a positive IgE to D. pteronyssinus was replaced with having 1 positive IgE to allergens (Model 2) or with total IgE (Model 3). In all three multivariable models, there was a trend for an inverse asso-ciation between parental report of sighting mice and STR-AD, but such trend was non-statistically significant (models 16

1 and 3) or of borderline statistical significance (model 2). In the multivariable analysis of STR-AD among children with asthma (also adjusted for age, gender, and BMI z-score), having private or employer-based health insurance was signifi-cantly associated with approximately twofold increased odds of STR-AD (Model 1). Similar results were obtained when a positive IgE to D. pteronyssinus was replaced with either 1 positive IgE to allergens (Model 2) or total serum IgE (Model 3).

Table 3 shows the sensitivity, specificity, PPV, NPV and AUC of various approaches to the diagnosis of STR-AD in Puerto Rican children, which were partly based on the results of our multivariable analysis (see Table 2). PD-AD had high specificity but very low sensitivity and a low AUC for STR-AD, both in children with and without asthma. A combi-nation of AD symptoms and a positive IgE to D. pteronyssinus yielded sensitivity 70% and specificity 95%, NPV 95% and PPV 88%, and an AUC 0.85 for STR-AD, both in children with and without asthma. Replacing a positive IgE to D. pteronyssinus with a positive IgE to 1 allergen slightly increased sensitivity (i.e. from 75.7% to 80% in all children) but had minimal impact on all other parameters (specificity, NPV, PPV or the AUC).

DISCUSSION We found that ~93% of cases of STR-AD among children in Puerto Rico had not been diagnosed by a physician, possibly due to limited access to healthcare (particularly allergists) in Puerto Rico.15,16 A previous study of AD among children ages 6–7 years who attended two schools in Puerto Rico found that the prevalence of parental report of current eczema symptoms was 24.8%,4 and that ~70% of children with such symptoms had not been diagnosed with AD by a physician. In contrast to that study, we assessed not only eczema symptoms but also skin test reactivity to allergens and levels of total/allergen-specific IgEs in a population-based sample of school-aged children aged 6–14 years. Moreover, the response rate in the previous study (53%) was substan-tially lower than that in the current study.

Consistent with findings in other popula-

Revista Puertorriqueña de Medicina y Salud Pública

tions, we show that a positive IgE to common allergens such as house dust mite or an elevated total serum IgE is significantly associated with STR-AD.6 Indeed, dust mite allergen exposure has been linked to eczematous symptoms,2,8 and high dust mite allergen levels have been reported to be both common and associated with asthma and other allergic diseases in Latin America.17 In contrast to our findings for total IgE and STR-AD, Perkins et al reported that total IgE plays little role in prediction of visible eczema at 5 years, despite a significant association between total IgE and eczema severity.12 On the other hand, Ville et al showed that reductions in total IgE are associated with good treatment response and complete remission of AD11 Among children without asthma, we found that signs of mold or mildew in the house are associated with STR-AD. Such exposure could alter the skin barrier, a first step in AD pathogenesis.18 However, the impact of reducing mold or mildew on AD, if any, is unknown.19 Among children with asthma, we show that private or employer-based health insurance is significantly associated with STR-AD, likely due to improved access to healthcare.

We show that a combination of current eczematous symptoms and 1 positive IgE to common allergens could markedly improve the diagnostic rate of STR-AD among physicians in Puerto Rico. Indeed, such approach yielded a sensitivity of 80%, plus high: specificity, PPV, NPV, and AUC for STR-AD in all children. Of interest, replacing 1 positive IgE to al-lergens with a positive IgE to dust mite yielded a comparably high sensitivity (i.e. 76%) for STR-AD in all children, thus supporting a relatively simple and cost-effective approach to AD diagnosis and care in Puerto Rico.

Our study has substantial strengths, including a population-based sample of school-aged children and data on objective measures of allergic sensitization.4 We also recognize several study limitations. First, we cannot assess temporal relationships due to the cross-sectional study G. Yang et al. design. Second, we did not conduct direct skin examinations. However, we used a combination of STR to allergens

Discover more at CIBINQOHCP.com AD=atopic dermatitis.

INDICATION

See results on the following pages

CIBINQO is indicated for the treatment of adults with refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.

Limitations of Use: CIBINQO is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.

IMPORTANT SAFETY INFORMATION WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS SERIOUS INFECTIONS Patients treated with CIBINQO may be at increased risk for developing serious infections that may lead to hospitalization or death. The most frequent serious infections reported with CIBINQO were herpes simplex, herpes zoster, and pneumonia.

If a serious or opportunistic infection develops, discontinue CIBINQO and control the infection.

Reported infections from Janus kinase (JAK) inhibitors used to treat inflammatory conditions: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral (including herpes zoster), and other infections due to opportunistic pathogens.

Avoid use of CIBINQO in patients with an active, serious infection, including localized infections. The risks and benefits of treatment with CIBINQO should be carefully considered prior to initiating therapy in patients with chronic or recurrent infections or those who have resided or traveled in areas of endemic tuberculosis or endemic mycoses.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIBINQO, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Consider yearly screening for patients in highly endemic areas for TB. CIBINQO is not recommended for use in patients with active TB. For patients with a new diagnosis of latent TB or prior untreated latent TB, or for patients with a negative test for latent TB but who are at high risk for TB infection, start preventive therapy for latent TB prior to initiation of CIBINQO. Viral reactivation, including herpes virus reactivation (eg, herpes zoster, herpes simplex), was reported in clinical studies with CIBINQO. If a patient develops herpes zoster, consider interrupting CIBINQO until the episode resolves. Hepatitis B virus reactivation has been reported in patients receiving JAK inhibitors.

Perform viral hepatitis screening and monitoring for reactivation in accordance with clinical guidelines before starting therapy and during therapy with CIBINQO. CIBINQO is not recommended for use in patients with active hepatitis B or hepatitis C.

Please see Important Safety Information throughout and Brief Summary of Prescribing Information, including BOXED WARNING, at the end of this advertisement.

Introducing CIBINQO—

a powerful, rapid systemic with the flexibility to increase the dose if needed The recommended dose is CIBINQO 100 mg. If an adequate response is not achieved with 100 mg after 12 weeks, consider increasing dosage to CIBINQO 200 mg. Discontinue therapy if inadequate response is seen after dosage increase to 200 mg.

Powerful skin clearance results without TCS1,2* JADE MONO-1: EASI-75 for CIBINQO 100 mg or 200 mg vs placebo (primary endpoint)

Percentage of patients achieving ≥75% improvement in lesion extent and severity

CIBINQO 100 mg n=156

CIBINQO 200 mg n=154

placebo n=77

100

†P<0.0001 vs placebo

70

62†

60 50

40†

40

>3x

30 20

12

improvement vs placebo for CIBINQO 100 mg as monotherapy

10

2

4

8 Week

12 Primary endpoint

In only 12 weeks, CIBINQO alone achieved significantly clearer skin vs placebo.

IGA 0/1 at week 12 (primary endpoint): 24% of patients taking CIBINQO 100 mg (P<0.01 vs placebo), 44% taking CIBINQO 200 mg (P<0.0001 vs placebo), and 8% taking placebo achieved IGA 0/1 Similar results were observed in MONO-2.

While subjects aged 12 to 17 years were included in MONO-1 and MONO-2 trials, CIBINQO is not approved for use in pediatric subjects.

Full Analysis Set (FAS) was defined as all randomized subjects who received at least one dose of study medication. All missing responses were defined as non-responders.

A responder was defined as achieving IGA 0 or 1 and at least a 2-point improvement from baseline. *Patients were permitted to use nonmedicated emollients during the study.

TCS=topical corticosteroids; EASI-75=≥75% improvement in lesion extent and severity from baseline on the Eczema Area and Severity Index; IGA=Investigator’s Global Assessment.

STUDY DESIGN: JADE MONO-1 and MONO-2 evaluated efficacy and safety endpoints up to 12 weeks in two identically designed double-blind, placebo-controlled clinical trials in which 778 patients aged 12 and older with moderate-to-severe AD received CIBINQO 100 mg, CIBINQO 200 mg, or placebo.2

Scan the QR code or visit CIBINQOHCP.com/efficacy to see additional CIBINQO results with and without TCS

IMPORTANT SAFETY INFORMATION (cont’d) WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS (cont’d) MORTALITY In a large, randomized postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blocker treatment, a higher rate of all-cause mortality (including sudden cardiovascular death) was observed with the JAK inhibitor. CIBINQO is not approved for use in RA patients.

Please see Important Safety Information throughout and Brief Summary of Prescribing Information, including BOXED WARNING, at the end of this advertisement.

Rapid and significant itch relief without TCS1,2* Percentage of patients achieving ≥4-point reduction in PP-NRS

JADE MONO-1: PP-NRS4 for CIBINQO 100 mg or 200 mg vs placebo (key secondary endpoint) 100

‡P<0.05 vs placebo § P<0.0001 vs placebo

30

As early as week 2, CIBINQO demonstrated rapid and superior itch relief vs placebo

28§

25 20 15 10

A higher proportion of patients treated with CIBINQO 100 mg or 200 mg achieved improvement in itching at week 12 vs placebo.||

11‡

5

2 CIBINQO 100 mg n=115

CIBINQO 200 mg n=132

Based on PSAAD at week 12.

||

placebo n=63

Week 2 Key secondary endpoint

Similar results were observed in MONO-2.

While subjects aged 12 to 17 years were included in MONO-1 and MONO-2 trials, CIBINQO is not approved for use in pediatric subjects.

Full Analysis Set (FAS) was defined as all randomized subjects who received at least one dose of study medication. All missing responses were defined as non-responders.

PP-NRS4=≥4-point reduction from baseline on the Peak Pruritus Numerical Rating Scale; PSAAD=Pruritus and Symptoms Assessment for Atopic Dermatitis.

Data limitations • Baseline was defined as the average of all values recorded between day -6 and day 1. Subjects with <4 observations at baseline were excluded from analysis • Proportions for all subjects were based on the average of all values for a 7-day period when at least 4 observations were available, or set to missing if fewer than 4 observations were available • A weekly average of itch responses between day 9 and day 15 was used

Flexibility to increase dose after 12 weeks if uncontrolled on 100 mg1 A once-daily pill that comes in two dosage strengths

100 mg:

Recommended dose

200 mg: Discontinue therapy if an May be considered for patients adequate response is not achieved uncontrolled on 100 mg after 12 weeks on 200 mg once daily

Pills not shown at actual size.

Prior to treatment initiation, perform a TB infection evaluation, a viral hepatitis screening in accordance with clinical guidelines, a complete blood count (CBC), and complete any necessary immunizations.

CIBINQO is not recommended in patients with active TB, active hepatitis B or hepatitis C, severe renal impairment or end stage renal disease, severe hepatic impairment or low platelet, lymphocyte, or neutrophil count, or a low hemoglobin value.

During treatment, laboratory monitoring is recommended due to potential changes in platelets, lymphocytes and lipids.

Interruption of treatment may be needed for management of laboratory abnormalities.

CIBINQO is contraindicated in patients taking antiplatelet therapies except for low dose aspirin during the first 3 months of treatment.

A 50-mg dose is available for special populations or modifications for certain adverse reactions. The 50-mg dose was not studied in clinical trials.

For complete dosing information, monitoring, and treatment considerations, please refer to the Brief Summary.

Important safety considerations1,2

CIBINQO has a BOXED WARNING for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE), and thrombosis BOXED WARNING SUMMARY • Increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including TB. The most frequent serious infections reported with CIBINQO were herpes simplex, herpes zoster and pneumonia.

Discontinue treatment with CIBINQO if serious or opportunistic infection occurs. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. Avoid use of CIBINQO in patients with an active, serious infection including localized infections • Higher rate of all-cause mortality, including sudden cardiovascular death, with another JAK inhibitor vs TNF blockers in RA patients. CIBINQO is not approved for use in RA patients • Malignancies have occurred with CIBINQO. Higher rate of lymphomas and lung cancers with another JAK inhibitor vs TNF blockers in RA patients. Patients who are current or past smokers are at additional increased risk • MACE has occurred with CIBINQO. Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with another JAK inhibitor vs TNF blockers in RA patients. Patients who are current or past smokers are at additional increased risk. Discontinue CIBINQO in patients that have experienced a myocardial infarction or stroke • Thrombosis has occurred with CIBINQO. Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK inhibitor vs TNF blockers Other warnings include potential laboratory abnormalities. Avoid use of live vaccines prior to, during and immediately after TB=tuberculosis; JAK=Janus kinase; TNF=tumor necrosis factor; RA=rheumatoid arthritis.

CIBINQO treatment.

See full Prescribing Information for complete BOXED WARNING.

Skin clearance you can see2 Results seen by week 12, without TCS, in JADE MONO-2 Images of patients from clinical trials. Not everyone will respond to treatment with CIBINQO. Individual results may vary.

Week 12

Baseline

DOSAGE 100 mg

AGE 28

SEX Female

BODY PART Abdomen

Nonmedicated emollients were allowed.

Baseline

DOSAGE 200 mg

Week 12

AGE 43

SEX Female

BODY PART Calf

Clinical trial labels have been blurred in photos.

The recommended dose is CIBINQO 100 mg. If an adequate response is not achieved with 100 mg after 12 weeks, consider increasing dosage to CIBINQO 200 mg.

TB=tuberculosis; JAK=Janus kinase; TNF=tumor necrosis factor; RA=rheumatoid arthritis; TCS=topical corticosteroids.

IMPORTANT SAFETY INFORMATION (cont’d) WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS (cont’d) MALIGNANCIES Malignancies, including non-melanoma skin cancer (NMSC), were reported in patients treated with CIBINQO. Lymphoma and other malignancies have been observed in patients receiving JAK inhibitors used to treat inflammatory conditions.

Perform periodic skin examination for patients who are at increased risk for skin cancer. Exposure to sunlight and UV light should be limited by wearing protective clothing and using broad-spectrum sunscreen.

In a large, randomized postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. CIBINQO is not approved for use in RA patients. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Please see Important Safety Information throughout and Brief Summary of Prescribing Information, including BOXED WARNING, at the end of this advertisement.

Safety and tolerability1,2 The most common adverse reactions (≥1%) of patients taking CIBINQO in placebo-controlled trials for up to 16 weeks The safety of CIBINQO was evaluated in four randomized, placebo-controlled clinical trials (2 monotherapy, 1 combination therapy with topical corticosteroid, and 1 dose-ranging) and one long-term extension trial in subjects with moderate-to-severe AD. CIBINQO 100 mg n=608

CIBINQO 200 mg n=590

placebo n=342

Nasopharyngitis

75 (12.4)

Number (%) of patients* 51 (8.7)

27 (7.9)

Nausea

37 (6.0)

86 (14.5)

7 (2.1)

Headache Herpes simplex†

36 (6.0)

46 (7.8)

12 (3.5)

20 (3.3)

25 (4.2)

6 (1.8)

Increased blood CPK

14 (2.3)

17 (2.9)

5 (1.5)

Dizziness

11 (1.8)

17 (2.9)

3 (0.9)

Urinary tract infection

10 (1.7)

13 (2.2)

4 (1.2)

Fatigue

10 (1.6)

8 (1.3)

2 (0.5)

Acne

10 (1.6)

28 (4.7)

0 (0.0)

Vomiting

9 (1.5)

19 (3.2)

3 (0.9)

Impetigo

9 (1.5)

3 (0.5)

1 (0.3)

Oropharyngeal pain

8 (1.4)

6 (1.0)

2 (0.6)

Hypertension

7 (1.2)

5 (0.8)

2 (0.7)

Influenza

7 (1.2)

6 (1.1)

0 (0.0)

Gastroenteritis

7 (1.1)

8 (1.3)

2 (0.6)

Dermatitis contact

6 (1.1)

3 (0.5)

1 (0.3)

Abdominal pain upper

4 (0.6)

11 (1.9)

0 (0.0)

Abdominal discomfort

3 (0.5)

7 (1.2)

1 (0.3)

Herpes zoster

2 (0.3)

7 (1.2)

0 (0.0)

Thrombocytopenia

0 (0.0)

9 (1.5)

0 (0.0)

• Overall infections were reported in 211 patients (168.8 per 100 patient-years) treated with CIBINQO 100 mg, 204 patients (159.5 per 100 patient-years) treated with CIBINQO 200 mg, and 90 patients (126.8 per 100 patient-years) treated with placebo • Retinal detachment occurred in 1 subject (0.6 per 100 patient-years) treated with CIBINQO 100 mg in the placebo-controlled trials for up to 16 weeks Data shown include one phase 2b and three phase 3 trials. While subjects aged 12 to 17 years were included in these trials, CIBINQO is not approved for use in pediatric subjects. *Study size adjusted percentages. †Herpes simplex includes oral herpes, ophthalmic herpes, herpes dermatitis, and genital herpes.

AD=atopic dermatitis; CPK=creatine phosphokinase.

Visit CIBINQOHCP.com to learn more about CIBINQO clinical trials

References: 1. CIBINQO Package insert. Pfizer Inc; 2022. 2. Data on file. Pfizer Inc; New York, NY.

IMPORTANT SAFETY INFORMATION (cont’d) WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS (cont’d) MALIGNANCIES (cont’d) Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

MAJOR ADVERSE CARDIOVASCULAR EVENTS Major adverse cardiovascular events were reported in patients treated with CIBINQO. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. CIBINQO is not approved for use in RA patients.

Patients who are current or past smokers are at additional increased risk. Discontinue CIBINQO in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

THROMBOSIS Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients treated with CIBINQO. Thrombosis, including PE, DVT, and arterial thrombosis have been reported in patients receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of overall thrombosis, DVT, and PE were observed when compared with TNF blockers.

CIBINQO is not approved for use in RA patients.

Avoid CIBINQO in patients that may be at increased risk of thrombosis. If symptoms of thrombosis occur, discontinue CIBINQO and treat patients appropriately.

CONTRAINDICATION CIBINQO is contraindicated in patients taking antiplatelet therapies, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment.

LABORATORY ABNORMALITIES Hematologic Abnormalities: Treatment with CIBINQO was associated with an increased incidence of thrombocytopenia and lymphopenia. Prior to CIBINQO initiation, perform a complete blood count (CBC). CBC evaluations are recommended at 4 weeks after initiation and 4 weeks after dose increase of CIBINQO. Discontinuation of CIBINQO therapy is required for certain laboratory abnormalities.

Lipid Elevations: Dose-dependent increase in blood lipid parameters were reported in patients treated with CIBINQO. Lipid parameters should be assessed approximately 4 weeks following initiation of CIBINQO therapy, and thereafter patients should be managed according to clinical guidelines for hyperlipidemia. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

IMMUNIZATIONS Prior to initiating CIBINQO, complete all age-appropriate vaccinations as recommended by current immunization guidelines, including prophylactic herpes zoster vaccinations. Avoid vaccination with live vaccines immediately prior to, during, and immediately after CIBINQO therapy.

RENAL IMPAIRMENT Avoid use in patients with severe renal impairment or end stage renal disease, including those on renal replacement therapy.

HEPATIC IMPAIRMENT Avoid use in patients with severe hepatic impairment.

ADVERSE REACTIONS Most common adverse reactions (≥1%) in subjects receiving 100 mg and 200 mg include: nasopharyngitis, nausea, headache, herpes simplex, increased blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis.

Most common adverse reactions (≥1%) in subjects receiving either 100 mg or 200 mg also include: impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, herpes zoster, and thrombocytopenia.

USE IN PREGNANCY Available data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish a drugassociated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise females of reproductive potential that CIBINQO may impair fertility.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIBINQO during pregnancy. Pregnant women exposed to CIBINQO and health care providers are encouraged to call 1-877-311-3770.

LACTATION Advise women not to breastfeed during treatment with CIBINQO and for one day after the last dose.

Please see Brief Summary of Prescribing Information, including BOXED WARNING, on the next page.

© 2022 Pfizer Inc. All rights reserved. February 2022. PP-ABR-USA-0316

CIBINQO™ (abrocitinib) tablets, for oral use

Brief Summary of full Prescribing Information; Initial Approval: January 2022

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS Serious Infections Patients treated with CIBINQO may be at increased risk for developing serious infections that may lead to hospitalization or death; The most frequent serious infections reported with CIBINQO were herpes simplex, herpes zoster, and pneumonia.

If a serious or opportunistic infection develops, discontinue CIBINQO and control the infection.

Reported infections from Janus kinase (JAK) inhibitors used to treat inflammatory conditions: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

Avoid use of CIBINQO in patients with an active, serious infection including localized infections.

The risks and benefits of treatment with CIBINQO should be carefully considered prior to initiating therapy in patients with chronic or recurrent infections.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIBINQO, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Mortality In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blocker treatment, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor. CIBINQO is not approved for use in RA patients.

Malignancies Malignancies were reported in patients treated with CIBINQO. Lymphoma and other malignancies have been observed in patients receiving JAK inhibitors used to treat inflammatory conditions.

In RA patients treated with another JAK inhibitor, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed when compared with TNF blockers.

Patients who are current or past smokers are at additional increased risk.

Major Adverse Cardiovascular Events Major adverse cardiovascular events were reported in patients treated with CIBINQO. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue CIBINQO in patients that have experienced a myocardial infarction or stroke.

Thrombosis Deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients treated with CIBINQO. Thrombosis, including PE, DVT, and arterial thrombosis have been reported in patients receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death.

In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers.

Avoid CIBINQO in patients at risk. If symptoms of thrombosis occur, discontinue CIBINQO and treat appropriately.

INDICATIONS AND USAGE CIBINQO is indicated for the treatment of adults with refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.

Limitations of Use CIBINQO is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.

DOSAGE AND ADMINISTRATION Recommended Testing, Evaluations, and Procedures Prior to Treatment Initiation Perform the following tests and evaluations prior to CIBINQO initiation: • Tuberculosis (TB) infection evaluation – CIBINQO initiation is not recommended in patients with active TB. For patients with latent TB or those with a negative latent TB test who are at high risk for TB, start preventive therapy for latent TB prior to initiation of CIBINQO • Viral hepatitis screening in accordance with clinical guidelines CIBINQO initiation is not recommended in patients with active hepatitis B or hepatitis C • A complete blood count (CBC) – CIBINQO initiation is not recommended in patients with a platelet count <150,000/mm3, an absolute lymphocyte count <500/ mm3, an absolute neutrophil count <1,000/mm3, or a hemoglobin value <8 g/dL Complete any necessary immunizations, including herpes zoster vaccinations, in agreement with current immunization guidelines prior to CIBINQO initiation.

Recommended Dosage The recommended dosage of CIBINQO is 100 mg orally once daily.

If an adequate response is not achieved with CIBINQO 100 mg orally daily after 12 weeks, consider increasing dosage to 200 mg orally once daily. Discontinue therapy if inadequate response is seen after dosage increase to 200 mg once daily.

CIBINQO can be used with or without topical corticosteroids.

If a dose is missed, administer the dose as soon as possible unless it is less than 12 hours before the next dose, in which case skip the missed dose. Thereafter, resume dosing at the regular scheduled time.

Recommended Dosage in Patients with Renal Impairment Renal Impairment CIBINQO dosage recommendation in patients with mild renal impairment (60-89 mL/minute) is 100 mg once daily.

For patients with moderate renal impairment (30-59 mL/ minute), the recommended dosage is 50 mg once daily.

CIBINQO is not recommended for patients with severe or End Stage Renal Disease (ESRD). Severe renal impairment and End-Stage Renal Disease include patients on renal replacement therapy.

In subjects with mild and moderate renal impairment, if an adequate response is not achieved after 12 weeks, dose of CIBINQO can be doubled.

CIBINQO is not recommended for patients with severe renal impairment or ESRD. Recommended Dosage in CYP2C19 Poor Metabolizers In patients who are known or suspected to be CYP2C19 poor metabolizers, the recommended dosage of CIBINQO is 50 mg once daily. If an adequate response is not achieved with CIBINQO 50 mg orally daily after 12 weeks, consider increasing dosage to 100 mg orally once daily. Discontinue therapy if inadequate response is seen after dosage increase to 100 mg once daily.

Dosage Modifications due to Strong Inhibitors In patients taking strong inhibitors of cytochrome P450 (CYP) 2C19 reduce the dosage to 50 mg once daily. If an adequate response is not achieved with CIBINQO 50 mg orally daily after 12 weeks, consider increasing dosage to 100 mg orally once daily. Discontinue therapy if inadequate response is seen after dosage increase to 100 mg once daily.

Treatment Discontinuation due to Serious Infections or Hematologic Adverse Reactions Serious or Opportunistic Infections If a patient develops a serious or opportunistic infection, discontinue CIBINQO and control the infection. The risks and benefits of treatment with CIBINQO should be carefully considered prior to reinitiating therapy with CIBINQO. Hematologic Abnormalities • Discontinue CIBINQO if platelet count <50,000/mm3 and

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follow with CBC until >100,000/mm3 • Treatment should be temporarily discontinued if ALC is less than 500 cells/mm3 and may be restarted once ALC return above this value • Treatment should be temporarily discontinued if ANC is less than 1,000 cells/mm3 and may be restarted once ANC return above this value • Treatment should be temporarily discontinued if Hb is less than 8 g/dL and may be restarted once Hb return above this value CBC evaluations are recommended at baseline, 4 weeks after treatment initiation and 4 weeks after dosing increase of CIBINQO. Laboratory evaluations may be extended for patients on chronic CIBINQO therapy who develop hematologic abnormalities.

DOSAGE FORMS AND STRENGTHS • 50 mg: Pink, oval, film-coated tablet debossed with “PFE” on one side and “ABR 50” on the other.

• 100 mg: Pink, round, film-coated tablet debossed with “PFE” on one side and “ABR 100” on the other.

• 200 mg: Pink, oval, film-coated tablet debossed with “PFE” on one side and “ABR 200” on the other.

CONTRAINDICATIONS CIBINQO is contraindicated in patients taking antiplatelet therapies, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment.

WARNINGS AND PRECAUTIONS Serious Infections The most frequent serious infections reported in clinical studies with CIBINQO for atopic dermatitis were herpes simplex, herpes zoster, and pneumonia. Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving JAK inhibitors used to treat inflammatory conditions.

Avoid use of CIBINQO in patients with active, serious infection including localized infections.

Consider the risks and benefits of treatment prior to initiating CIBINQO in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses • with underlying conditions that may predispose them to infection Closely monitor patients for the development of signs and symptoms of infection during and after treatment with CIBINQO. If a patient develops a serious or opportunistic infection, discontinue CIBINQO. Initiate complete diagnostic testing and appropriate antimicrobial therapy. The risks and benefits of treatment with CIBINQO should be carefully considered prior to reinitiating therapy with CIBINQO. Tuberculosis Evaluate and test patients for TB before starting CIBINQO therapy and consider yearly screening for patients in highly endemic areas for TB. CIBINQO is not recommended for use in patients with active TB. For patients with a new diagnosis of latent TB or prior untreated latent TB, or for patients with a negative test for latent TB but who are at high risk for TB infection, start preventive therapy for latent TB prior to initiation of CIBINQO. Monitor patients for the development of signs and symptoms of TB, including patients who were tested negative for latent TB infection prior to initiating therapy.

Viral Reactivation Viral reactivation, including herpes virus reactivation (e.g., herpes zoster, herpes simplex), was reported in clinical studies with CIBINQO. If a patient develops herpes zoster, consider interrupting CIBINQO until the episode resolves.

Hepatitis B virus (HBV) reactivation has been reported in patients receiving JAK inhibitors. Perform viral hepatitis screening and monitoring for reactivation in accordance with clinical guidelines before starting therapy and during therapy with CIBINQO. CIBINQO is not recommended for use in patients with active hepatitis B or hepatitis C. Monitor patients with inactive HBV for expression of HBV DNA during therapy with CIBINQO. If HBV DNA is detected during therapy with CIBINQO, consult a liver specialist.

Mortality In a large, randomized, postmarketing safety study of another JAK inhibitor in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients

CIBINQO™ (abrocitinib) tablets, for oral use Mortality (continued) treated with the JAK inhibitor compared with TNF blockers.

CIBINQO is not approved for use in RA. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO. Malignancy and Lymphoproliferative Disorders Malignancies, including non-melanoma skin cancer (NMSC), were observed in clinical studies with CIBINQO for atopic dermatitis.

Perform periodic skin examination for patients who are at increased risk for skin cancer. Exposure to sunlight and UV light should be limited by wearing protective clothing and using broad-spectrum sunscreen.

Malignancies, including lymphomas, have occurred in patients receiving JAK inhibitors used to treat inflammatory conditions. In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. CIBINQO is not approved for use in RA. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

Major Adverse Cardiovascular Events Major adverse cardiovascular events were reported in clinical studies of CIBINQO for atopic dermatitis.

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers.

CIBINQO is not approved for use in RA. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

Discontinue CIBINQO in patients that have experienced a myocardial infarction or stroke.

Thrombosis Deep venous thrombosis (DVT) and pulmonary embolism (PE) were observed in patients receiving CIBINQO in the clinical studies for atopic dermatitis.

Thrombosis, including DVT, PE, and arterial thrombosis have been reported in patients receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death.

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers. CIBINQO is not approved for use in RA. Avoid CIBINQO in patients that may be at increased risk of thrombosis. If symptoms of thrombosis occur, discontinue CIBINQO and evaluate and treat patients appropriately.

Laboratory Abnormalities Hematologic Abnormalities Treatment with CIBINQO was associated with an increased incidence of thrombocytopenia and lymphopenia. Prior to CIBINQO initiation, perform a CBC. CBC evaluations are recommended at 4 weeks after initiation and 4 weeks after dose increase of CIBINQO. Discontinuation of CIBINQO therapy is required for certain laboratory abnormalities.

Lipid Elevations Dose-dependent increase in blood lipid parameters were reported in patients treated with CIBINQO. Lipid parameters should be assessed approximately 4 weeks following initiation of CIBINQO therapy and thereafter patients should be managed according to clinical guidelines for hyperlipidemia. The effect of these lipid parameter

elevations on cardiovascular morbidity and mortality has not been determined.

Immunizations Prior to initiating CIBINQO, complete all age-appropriate vaccinations as recommended by current immunization guidelines including prophylactic herpes zoster vaccinations.

Avoid vaccination with live vaccines immediately prior to, during, and immediately after CIBINQO therapy.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Major Adverse • Serious Infections Cardiovascular Events • Mortality • Thrombosis • Malignancy and • Laboratory Abnormalities Lymphoproliferative Disorders Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of CIBINQO was evaluated in four randomized, placebo-controlled clinical trials (2 monotherapy, 1 combination therapy with topical corticosteroid, and 1 dose-ranging) and one long-term extension trial in subjects with moderate to severe atopic dermatitis (AD). A total of 1623 subjects with moderate to severe atopic dermatitis were treated with CIBINQO in these clinical trials representing 1428 patient-years of exposure. There were 634 subjects with at least 1 year of exposure to CIBINQO. In the placebo-controlled clinical trials, a total of 1198 subjects were exposed to CIBINQO with 608 subjects receiving CIBINQO 100 mg once daily and 590 subjects receiving CIBINQO 200 mg once daily for up to 16 weeks.

The median age of subjects was 33.0 years, 124 subjects (8.1%) were 12 to less than 18 years old and 94 subjects (6.1%) were 65 years of age or older. The majority of subjects were White (68.7%) and male (53.9%). While subjects aged 12 to 17 years were included in these trials, CIBINQO is not approved for use in pediatric subjects.

Adverse reactions occurring at ≥1% in any of the treated groups and at a higher rate than in the placebo group are presented in the table below. A total of 61 (5.1%) subjects treated with CIBINQO were discontinued from the trials due to adverse reactions. The safety profile of CIBINQO in the monotherapy and the combination trial(s) were similar.

Adverse Reactions from Placebo-Controlled Trials Reported in ≥1% of CIBINQO Treated Subjects with Moderate to Severe Atopic Dermatitis and at Higher Rate than Placebo for up to 16 Weeks Weeks 0-16 CIBINQO CIBINQO PLACEBO 200 mg 100 mg N=342 N=590 N=608 n (%a) a a n (% ) n (% ) Nasopharyngitis 51 (8.7) 75 (12.4) 27 (7.9) Nausea 86 (14.5) 37 (6.0) 7 (2.1) Headache 46 (7.8) 36 (6.0) 12 (3.5) Herpes simplexb 25 (4.2) 20 (3.3) 6 (1.8) Increased blood 17 (2.9) 14 (2.3) 5 (1.5) creatinine phosphokinase Dizziness 17 (2.9) 11 (1.8) 3 (0.9) Urinary tract infection 13 (2.2) 10 (1.7) 4 (1.2) Fatigue 8 (1.3) 10 (1.6) 2 (0.5) Acne 28 (4.7) 10 (1.6) 0 (0.0) Vomiting 19 (3.2) 9 (1.5) 3 (0.9) Impetigo 3 (0.5) 9 (1.5) 1 (0.3) Oropharyngeal pain 6 (1.0) 8 (1.4) 2 (0.6) Hypertension 5 (0.8) 7 (1.2) 2 (0.7) Influenza 6 (1.1) 7 (1.2) 0 (0.0) Gastroenteritis 8 (1.3) 7 (1.1) 2 (0.6) Dermatitis contact 3 (0.5) 6 (1.1) 1 (0.3) Abdominal pain upper 11 (1.9) 4 (0.6) 0 (0.0) Abdominal discomfort 7 (1.2) 3 (0.5) 1 (0.3) Herpes zoster 7 (1.2) 2 (0.3) 0 (0.0) Thrombocytopenia 9 (1.5) 0 (0.0) 0 (0.0) a b

Study size adjusted percentages Herpes simplex also includes oral herpes, ophthalmic herpes, herpes dermatitis, genital herpes.

Specific Adverse Reactions Exposure adjusted incidence rates were adjusted by trial

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size for all the adverse reactions reported in this section.

Overall Infections In the placebo-controlled trials, for up to 16 weeks, overall infections were reported in 90 subjects (126.8 per 100 patient-years) treated with placebo, 211 subjects (168.8 per 100 patient-years) treated with CIBINQO 100 mg and 204 subjects (159.5 per 100 patient-years) treated with CIBINQO 200 mg. In all 5 clinical trials, including the long-term extension trial, overall infections were reported in 427 subjects (91.8 per 100 patient-years) treated with CIBINQO 100 mg and 394 subjects (103.2 per 100 patient-years) treated with CIBINQO 200 mg.

Serious Infections In the placebo-controlled trials, for up to 16 weeks, serious infections were reported in 2 subjects (2.6 per 100 patient-years) treated with placebo, 6 subjects (3.9 per 100 patient-years) treated with CIBINQO 100 mg, and 2 subjects (1.3 per 100 patient-years) treated with CIBINQO 200 mg. In all 5 clinical trials, including the long-term extension trial, serious infections were reported in 18 subjects (2.3 per 100 patient-years) treated with CIBINQO 100 mg and 16 subjects (2.3 per 100 patient-years) treated with CIBINQO 200 mg. The most commonly reported serious infections were herpes simplex, herpes zoster, and pneumonia.

Herpes Zoster In the placebo-controlled trials, for up to 16 weeks, opportunistic infections were generally cases of multidermatomal cutaneous herpes zoster. Herpes zoster was reported in 0 subjects treated with placebo, 3 subjects (1.9 per 100 patient-years) treated with CIBINQO 100 mg and 8 subjects (5.1 per 100 patient-years) treated with CIBINQO 200 mg. In all 5 clinical trials, including the long-term extension trial, herpes zoster was reported in 16 subjects (2.0 per 100 patient-years) treated with CIBINQO 100 mg and 35 subjects (5.2 per 100 patient-years) treated with CIBINQO 200 mg.

Malignancy In the placebo-controlled trials, for up to 16 weeks, no malignancy was reported in subjects treated with placebo or CIBINQO 100 mg and in 1 patient (0.65 per 100 patient-years) treated with CIBINQO 200 mg. In all 5 clinical trials, including the long-term extension trial, malignancy was reported in 4 subjects (0.5 per 100 patient-years) treated with CIBINQO 100 mg and 2 subjects (0.3 per 100 patient-years) treated with CIBINQO 200 mg.

Thrombosis In all clinical trials, including the long-term extension trial, pulmonary embolism was reported in 3 subjects (0.4 per 100 patient-years), who were treated with CIBINQO 200 mg. Deep vein thrombosis was reported in 2 subjects (0.3 per 100 patient-years) who were treated with CIBINQO 200 mg. No thrombosis occurred in subjects treated with CIBINQO 100 mg.

Major Adverse Cardiovascular Events In the placebocontrolled trials, for up to 16 weeks, major adverse cardiovascular event (MACE) was reported in 1 subject (0.6 per 100 patient-years) treated with CIBINQO 100 mg.

In all 5 clinical trials, including the long-term extension trial, MACE was reported in 1 patient (0.1 per 100 patient-years) treated with CIBINQO 100 mg and 2 subjects (0.3 per 100 patient-years) treated with CIBINQO 200 mg.

Thrombocytopenia In the placebo-controlled trials, for up to 16 weeks, treatment with CIBINQO was associated with a dose-related decrease in platelet count. Maximum effects on platelets were observed within 4 weeks, after which the platelet count returned towards baseline despite continued therapy. In all 5 clinical trials, including the long-term extension trial 6 subjects (0.9 per 100 patient-years) treated with CIBINQO 200 mg had adverse reactions of thrombocytopenia, no subjects treated with CIBINQO 100 mg had an adverse reaction of thrombocytopenia.

Lymphopenia In the placebo-controlled trials, for up to 16 weeks, confirmed ALC <500/mm3 occurred in 2 subjects (1.2 per 100 patient-years) treated with CIBINQO 200 mg and 0 subjects treated with CIBINQO 100 mg or placebo.

Both cases occurred in the first 4 weeks of exposure.

Lipid Elevations In the placebo-controlled trials, for up to 16 weeks, there was a dose-related percent increase in low-density lipoprotein cholesterol (LDL-c), total cholesterol, and high-density lipoprotein cholesterol (HDL-c) relative to placebo at Week 4 which remained elevated through the final visit in the treatment period. Adverse reactions related to hyperlipidemia occurred in 1 subject (0.6 per 100 patient-years) exposed to CIBINQO 100 mg, 3 subjects (2.0 per 100 patient-years) exposed to CIBINQO 200 mg.

Retinal Detachment In the placebo-controlled trials, for up to 16 weeks, retinal detachment occurred in 1 subject (0.6 per 100 patient-years) treated with CIBINQO 100 mg. In all 5 clinical trials, including the long-term extension trial, retinal detachment occurred in 2 subjects (0.3 per 100 patient-years) treated with CIBINQO 100 mg.

CIBINQO™ (abrocitinib) tablets, for oral use Specific Adverse Reactions (continued) Creatine Phosphokinase Elevations (CPK) In the placebo-controlled trials, for up to 16 weeks, events of blood CPK increased were reported in 6 subjects (7.5 per 100 patient-years) treated with placebo, 11 subjects (6.9 per 100 patient-years) treated with 100 mg of CIBINQO and 19 subjects (12.3 per 100 patient-years) treated with 200 mg of CIBINQO. Most elevations were transient, there were no reported adverse reactions of rhabdomyolysis.

DRUG INTERACTIONS Effects of Other Drugs on CIBINQO The table below includes drugs with clinically significant drug interactions affecting CIBINQO. Clinically Significant Drug Interactions Affecting CIBINQO Strong CYP2C19 Inhibitors Clinical Impact

Coadministration of CIBINQO with strong CYP2C19 inhibitors increases the combined exposure of abrocitinib and its two active metabolites, M1 and M2 which may increase the adverse reactions of CIBINQO.

Intervention Dosage reduction of CIBINQO is recommended when coadministered with strong CYP2C19 inhibitors.

Moderate to Strong Inhibitors of both CYP2C19 and CYP2C9 Clinical Impact

Coadministration of CIBINQO with drugs that are moderate to strong inhibitors of both CYP2C19 and CYP2C9 increases the exposure of abrocitinib and its two active metabolites, M1 and M2 which may increase the adverse reactions of CIBINQO.

Intervention Avoid concomitant use of CIBINQO with drugs that are moderate to strong inhibitors of both CYP2C19 and CYP2C9.

Strong CYP2C19 or CYP2C9 Inducers Clinical Impact

Coadministration of CIBINQO with strong CYP2C19 or CYP2C9 inducers decreases the combined exposure of abrocitinib and its two active metabolites, M1 and M2, which may result in loss of or reduced clinical response.

Intervention Avoid concomitant use of CIBINQO with strong CYP2C19 or CYP2C9 inducers.

Effects of CIBINQO on Other Drugs The table below includes clinically significant drug interactions affecting other drugs.

Clinically Significant Interactions Affecting Other Drugs P-gp Substrate Where Small Concentration Changes May Lead to Serious or Life-threatening Toxicities Clinical Coadministration of CIBINQO with P-gp Impact substrate increases plasma concentrations of P-gp substrates and may result in potential adverse reactions of the P-gp substrate where small concentration changes may lead to serious or lifethreatening toxicities (e.g., digoxin).

Intervention Monitor appropriately or dose titrate P-gp substrate where small concentration changes may lead to serious or lifethreatening toxicities when coadministered with CIBINQO. Antiplatelet Therapy Drugs Clinical Coadministration of CIBINQO with antiplatelet Impact therapy drugs may increase the risk of bleeding with thrombocytopenia.

Intervention Antiplatelet drugs, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment are contraindicated with CIBINQO. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIBINQO during pregnancy. Pregnant

women exposed to CIBINQO and health care providers are encouraged to call 1-877-311-3770.

Risk Summary Available data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of abrocitinib to pregnant rats and rabbits during organogenesis at exposure 14 or 5 times the maximum recommended human dose (MRHD) based on AUC comparison, respectively, resulted in maternal dystocia and skeletal variations in rats and no adverse effects in rabbits (see Animal Data).

The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2-4% and 15-20% of clinically recognized pregnancies, respectively.

Animal Data In an embryofetal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, or 60 mg/kg/day during the period of organogenesis. No fetal malformations were observed.

Abrocitinib increased the incidence of skeletal variations of short 13th ribs at 30 mg/kg/day (14 times the MRHD based on AUC comparison). Increased embryofetal lethality and additional skeletal variations (cervical arches with reduced ventral processes, thickened ribs, and unossified metatarsals) were noted at 60 mg/kg/day (22 times the MRHD based on AUC comparison).

In an embryofetal development study, abrocitinib was administered orally to pregnant rabbits at doses of 10, 30, or 75 mg/kg/day during the period of organogenesis. No abrocitinib-related maternal or developmental toxicity was noted at doses up to 75 mg/kg/day (5 times the MRHD based on AUC comparison).

In a prenatal and postnatal development study, abrocitinib was administered orally to pregnant rats at doses of 10, 30, and 60 mg/kg/day beginning on gestation day 6 and continuing through lactation day 20. Dystocia with prolonged parturition and reduced offspring body weights were noted at 30 mg/kg/day (14 times the MRHD based on AUC comparison). Postnatal survival was markedly decreased at 60 mg/kg/day (22 times the MRHD based on AUC comparison). No maternal toxicity was observed at 10 mg/kg/day (3 times the MRHD based on AUC comparison).

No abrocitinib-related effects on postnatal developmental, neurobehavioral, or reproductive performance of offspring was noted at doses up to 30 mg/kg/day (14 times the MRHD based on AUC comparison).

Lactation Risk Summary There are no data on the presence of abrocitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Abrocitinib was secreted in milk of lactating rats (see Animal Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the serious adverse findings in adults, including risks of serious infections, malignancy, and thrombosis, advise women not to breastfeed during treatment with CIBINQO and for one day after the last dose (approximately 5-6 elimination half-lives).

Animal Data Lactating female rats were orally administered a single dose of 10 mg/kg abrocitinib on lactation day 12.

Abrocitinib AUC was approximately 5 times greater in milk than in plasma.

Females and Males of Reproductive Potential Infertility Females Based on the findings in rats, oral administration of CIBINQO may impair female fertility.

Impaired fertility in female rats was reversible 1 month after cessation of abrocitinib oral administration.

Pediatric Use The safety and effectiveness of CIBINQO have not been established in pediatric patients.

Juvenile Animal Toxicity Data In a juvenile animal toxicity study, abrocitinib was administered orally to juvenile rats at doses of 5, 25, and 75 mg/kg/day beginning on postnatal day 10 (approximately equivalent to a human infant) and continuing through postnatal day 63 (approximately equivalent to an adolescent). Abrocitinib caused a reversible, dose-related decrease in the primary spongiosa in the metaphysis of the proximal tibia and distal femur.

Abrocitinib produced adverse effects on bone development at all dose levels. Abrocitinib caused irreversible

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dose-related small or misshapen femoral heads at doses ≥5 mg/kg/day (1.1 times the MRHD based on AUC comparison).

Abrocitinib also irreversibly decreased femur size and caused paw malrotation and limb impairment at doses ≥25 mg/kg/day (10 times the MRHD based on AUC comparison).

At 75 mg/kg/day (36 times the MRHD based on AUC comparison), paw fractures generally corresponded to limb impairment, a fractured tibia was noted in a single female, and effects noted at lower doses were increased in frequency and severity. Irreversible bone findings have not been observed in older animals.

Geriatric Use A total of 145 (4.6%) patients 65 years of age and older, while 25 (0.8%) were 75 years of age and older, were enrolled in CIBINQO clinical trials. Clinical trials of CIBINQO did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

A higher proportion of patients 65 years of age and older discontinued from clinical trials compared to younger patients. Among all patients exposed to CIBINQO, including the long-term extension trial, confirmed ALC <500/mm3 occurred only in patients 65 years of age and older. A higher proportion of patients 65 years of age and older had platelet counts <75,000/mm3. The incidence rate of herpes zoster in patients 65 years of age and older treated with CIBINQO (7.40 per 100 patient-years) was higher than that of patients 18 to less than 65 years of age (3.44 per 100 patient-years).

Renal Impairment In patients with severe (eGFR <30 mL/min) and moderate (eGFR 30-59 mL/min) renal impairment, the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, is increased compared to patients with normal renal function (eGFR ≥90 mL/min). This may increase the risk of adverse reactions such as infections.

CIBINQO is not recommended for use in patients with severe renal impairment and ESRD including those on renal replacement.

A dosage reduction in patient with moderate renal impairment is recommended. No dosage adjustment is required in patients with mild renal impairment (eGFR 60-89 mL/min).

CIBINQO has not been studied in patients on renal replacement therapy. In Phase 3 clinical trials, CIBINQO was not evaluated in patients with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.

Hepatic Impairment Avoid use of CIBINQO in patients with severe (Child Pugh C) hepatic impairment.

Dosage adjustment is not required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment based on similar combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2 compared to patients with normal hepatic function. In clinical trials, CIBINQO was not evaluated in patients with severe (Child Pugh C) hepatic impairment.

CYP2C19 Poor Metabolizers In patients who are CYP2C19 poor metabolizers, the AUC of abrocitinib is increased compared to CYP2C19 normal metabolizers due to reduced metabolic clearance. Dosage reduction of CIBINQO is recommended in patients who are known or suspected to be CYP2C19 poor metabolizers based on genotype or previous history/experience with other CYP2C19 substrates.

OVERDOSAGE There is no experience regarding human overdosage with CIBINQO. There is no specific antidote for overdose with CIBINQO. In case of an overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.

Rx only This brief summary is based on CIBINQO™ (abrocitinib) Prescribing Information LAB-1423-1.0.

Issued: January 2022.

The product's label may have been updated. For full Prescribing Information, visit CIBINQOPI.com.

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Revista Puertorriqueña de Medicina y Salud Pública

TRATAMIENTO DE LA PSORIASIS ERITRODÉRMICA CON BIOLÓGICOS:

UNA REVISIÓN SISTEMÁTICA Osward Y. Carrasquillo, MD, MPH1, Gabriela Pabón-Cartagena, MD2, Leyre A. Falto-Aizpurua, MD1, Marely Santiago-Vázquez, MD1, Karina J. Cancel-Artau, BS3, Gabriel Arias-Berrios, MD1, Rafael F. Martín-García, MD1 University of Puerto Rico School of Medicine Department of Dermatology, San Juan, Puerto Rico.

Transitional Year Program, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.

3 University of Puerto Rico School of Medicine, San Juan, Puerto Rico.

1 2

RESUMEN Antecedentes: Los medicamentos biológicos para la psoriasis en placas se han utilizado para tratar la psoriasis eritrodérmica (EP). Desde que se publicaron las guías para el manejo de la EP, se han aprobado nuevos productos biológicos para el tratamiento de la psoriasis en placas.

Objetivo: Analizar la evidencia de medicamentos biológicos en el tratamiento de la PE en base a respuesta y tolerabilidad.

Métodos: se realizó una búsqueda exhaustiva en las bases de datos PubMed, Cochrane Library, EMBASE y Scopus hasta el 31 de diciembre de 2018. Estudios que informaron uno o más casos de EP, definida como >75% de compromiso del área de superficie corporal, en pacientes ≥18 años Se incluyeron los tratados con biológicos. Se documentaron la puntuación PASI inicial, la mejora de la puntuación PASI y los eventos adversos. Se definió respuesta adecuada al tratamiento como PASI≥ 50.

Resultados: Se incluyeron 43 artículos, arrojando un total de 179 pacientes. La mayoría de los pacientes respondieron en algún momento del tratamiento, con un mayor nivel de evidencia para infliximab, ustekinumab, ixekizumab y guselkumab. La infección fue el evento adverso más común (n=35).

Limitaciones: los datos se limitan a informes de casos, series de casos y estudios no controlados. Conclusiones: Los pacientes con EP tratados con biológicos demostraron respuestas positivas y el tratamiento fue bien tolerado con recomendación débil y calidad de evidencia limitada a favor de infliximab, ustekinumab, ixekizumab y guselkumab.

ABSTRACT Background: Biologic medications for plaque psoriasis have been used to treat erythrodermic psoriasis (EP). Since the guidelines for management of EP were published, new biologics have been approved for the treatment of plaque psoriasis.

Objective: To analyze the evidence of biologic medications in the treatment of EP based on response and tolerability.

Methods: A comprehensive search was conducted with the PubMed, Cochrane Library, EMBASE, and Scopus databases through December 31, 2018. Studies reporting one or more cases of EP, defined as >75% body surface area involvement, in patients ≥18 years old treated with biologics were included. Baseline PASI score, PASI score improvement, and adverse events were documented. Adequate response to treatment was defined as PASI≥ 50.

Results: Forty-three articles were included, yielding a total of 179 patients. Most patients responded at some point during treatment, with a higher level of evidence for infliximab, ustekinumab, ixekizumab, and guselkumab. Infection was the most common adverse event (n=35).

Limitations: Data is limited to case reports, case series, and uncontrolled studies. Conclusions: Patients with EP treated with biologics demonstrated positive responses and treatment was well-tolerated with a weak recommendation and limited quality of evidence in favor of infliximab, ustekinumab, ixekizumab, and guselkumab.

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INTRODUCTION Psoriasis is a chronic inflammatory condition of the skin affecting approximately 2% of the world’s population.1 Several clinically distinct subtypes of psoriasis include chronic plaque psoriasis, nail psoriasis, pustular psoriasis, erythrodermic psoriasis (EP), and guttate psoriasis.2 EP is a rare and severe variant with a prevalence of less than 3% of all cases.3 This condition generally develops in patients with poorly controlled psoriasis. Other factors that may trigger EP are abrupt withdrawal of systemic medications like corticosteroids, drug reactions to medications such as lithium, and underlying systemic infections.4 EP is characterized by generalized erythema and scaling affecting more than 75% of body surface area.3,5 Affected patients can present numerous systemic symptoms such as fever, tachycardia, lymphadenopathy, arthralgia, and fatigue.5 Without appropriate treatment, high output cardiac failure, malabsorption, anemia, and sepsis could occur resulting in increased morbidity, and in some cases, death.2,3 Treatment can be very challenging. The latest National Psoriasis Foundation Consensus Guidelines recommend cyclosporine or infliximab as first-line therapy due to their rapid onset of action. Other recommended first line agents include acitretin and methotrexate.6 However, these recommendations were made before evidence of efficacy and safety in the treatment of EP was available for most biologic agents recently approved to treat psoriasis. Levin et al. reviewed the safety and efficacy of ustekinumab, adalimumab, etanercept, and infliximab in the treatment of EP.7 Since then, additional biologic medications, like ixekizumab, secukinumab, and guselkumab have been approved for the treatment of moderate to severe plaque psoriasis.

The objective of this study is to perform a systematic review to determine the response and tolerability of biologic medications used in the treatment of EP, including adalimumab, etanercept, infliximab, ixekizumab, golimumab, guselkumab, secukinumab, and ustekinumab. We aim to make treatment recommendations based on level of evidence, onset of action, adverse effects, and sustained response with these medications.

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MATERIALS AND METHODS Search Strategy This review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).8 A primary literature search was conducted with the databases PubMed, Scopus, EMBASE, and Cochrane Library.

We identified eligible articles from database inception to December 31, 2018. The search terms were “biologics” AND “erythrodermic psoriasis”, “biologic” AND “erythrodermic psoriasis”, “[drug name]” AND “erythrodermic psoriasis”. Drug names included: secukinumab, ixekizumab, golimumab, guselkumab, infliximab, etanercept, ustekinumab, and adalimumab. Articles written in Spanish and English were included. There were no limitations on article type. After the selection process, the references of all included articles were assessed for missing publications.

The review protocol is registered with PROSPERO (CRD42019133413) (https://www. crd.york.ac.uk/prospero/).

Study eligibility, selection criteria and screening Independent assessment of the titles and abstracts was carried out independently by two of the authors (O.Y.C. and K.J.C.). Disagreements were resolved through discussion with a third author (R.F.M.). All studies reporting one or more cases of EP treated with biologics were included. EP was defined

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Figure 1.

Study selection flow diagram

as >75% of body surface area involvement with inflammatory erythema and scaling at baseline. The following criteria were used to exclude articles: pediatric patients (<18 years); <75% of body surface area involvement; erythroderma caused by a condition other than psoriasis; patient was treated with biologics for a different condition that was not EP; article failed to mention response to treatment. If the full text was not available online, it was ordered at the University of Puerto Rico School of Medicine library.

Data extraction and statistical analysis The following variables were gathered as available: age, sex, body mass index, duration of disease, comorbidities, prior therapies, adjuvant treatments, Psoriasis Area and Severity Index (PASI) score, total follow-up time, PASI score improvement, and adverse events. Adequate response to treatment was defined as PASI≥ 50. Statistical analysis was done using IBM SPSS version 25.

Risk of bias, level of evidence, and grade of recommendation assessment Due to the nature of the condition, we did not expect to find comparative studies. To assess the risk of bias of studies, we used a tool developed by Haffar et al. derived from the New-Castle Ottawa scale.9,10 This tool has been used previously.9,11-14 It consists of 5 criteria in the form of questions with a binary response (yes/no) to indicate whether or not the item is suggestive of bias. The tool is composed of the following questions:

1.Did the patient(s) represent the whole case(s) of the medical center?

2.Was the diagnosis correctly made?

3.Were other important diagnoses excluded?

4.Were all important data cited in the report?

5.Was the outcome correctly ascertained?

Quality of the report was considered good (low risk of bias) when all 5 criteria were fulfilled, moderate (moderate risk of bias) when 4 were fulfilled, and poor (high risk of bias) when ≤ 3 were fulfilled.

Two of the authors (O.Y.C. and G.P.) assessed the risk of bias of the studies with discussion with a third author (R.F.M.) in case of disagreement. Recommendations for each biologic were given based on criteria by Robinson and colleagues.15 RESULTS Systematic search results Forty-three articles were included, yielding a total of 179 patients of EP treated with biologic medications (Figure 1).

The majority of the articles were case reports (65.1%), followed by case series (14.0%) and open label studies (11.6%).

There were 3 retrospective and 1 open prospective study. Sixteen articles reported treatment with infliximab16-31, 10 ustekinumab32-41, 4 etanercept42-45, 5 secukinumab46-50, and 3 adalimumab51-53. Ixekizumab54, golimumab55, and guselkumab56 were each found in one study. One article reported cases treated with either infliximab, adalimumab, etanercept or ustekinumab, and another article reported cases treated with infliximab or etanercept.57,58 Description of cases The mean age at presentation was 46.4 years with a male-to-female ratio of 3.6:1. Table 1 shows baseline characteristics of patients. After assessing all the selected articles, the most common medications reported were ustekinumab and infliximab with 54 and 41 cases, respectively.16-41,58 They were followed by secukinumab (n=19), etanercept (n=14), guselkumab (n=11), ixekizumab (n= 8), adalimumab (n=3), and golimumab (n=1).42-56,58 One article described 42 flares in 28 patients treated with multiple biologic agents (infliximab, adalimumab, etanercept, and ustekinumab) and was not included in the aforementioned analy-

sis as data for individual patients could not be extracted.57 Supplemental Table I shows a summary of the studies where EP was treated with biologics and risk of bias assessment.

Efficacy The majority of patients showed adequate response in their condition at some point during treatment intervention. Out of 122 patients that reported PASI scores following treatment with biologics, 9.0% of patients failed to achieve PASI 50.26,34,39,46 Furthermore, in a multicenter retrospective study with multiple biologics, Viguier and colleagues57 reported PASI 75 at 10-14 weeks in 40% of those treated with infliximab, and equal improvement in 67%, 67%, and 0% of patients treated with etanercept, adalimumab, and ustekinumab, respectively. A smaller proportion of patients maintained PASI 75 at weeks 22-24 (infliximab 20%; etanercept 50%; adalimumab 60%). Below there is a summary of the efficacy of each biologic medication in the treatment of EP based on reduction of PASI score.

Viguier’s study was excluded from the following analysis as the article reported flares instead of patients and thus, we were unable to extract the individual data from the study. Recommendations for each biologic are depicted on Table 2.

Secukinumab A total of 19 patients were administered secukinumab of whom 16 responded to treatment. Four of 8 cases that reported improvement between weeks 2-6 achieved PASI 75.47-49 One of these patients demonstrated continuous improvement and reached PASI 100 by weeks 8-12.

Two additional patients showed PASI 100 within this time frame.47,50 Mateu-Puchades et al., also reported PASI scores

during weeks 16-20 with 5/5 patients reaching PASI 90.48 Weng et al., described that 70% of patients responded to treatment showing evident clearing of psoriasis (PASI> 75) by week 16. One of these patients experienced relapse by week 24. Two patients demonstrated a sustained response after approximately 6 months.46 Infliximab Forty-one patients were treated with infliximab. Seventeen had no PASI score reported but described marked improvement of erythroderma 2 weeks after infliximab infusion.20,22-25,31 One patient evaluated using a modified PASI score achieved significant response.18 In a study by Torii et al., eight patients were treated with infliximab and the median PASI improvement reported was 67.9% at week 10.27 Thus, we were unable to assess if any patient from the aforementioned study did not respond to therapy.

Arroyo-Tridico and colleagues reported a patient who maintained PASI 100 for eleven years.17 Another study reported more than 90% improvement at week 6 in all 7 patients but did not specify which instrument was used to measure this response.19 Six other studies reported significant improvement in 10 patients by weeks 2-12 (PASI≥ 75).16,21,28-30,58 Poulalhon et al. reported PASI score-based outcomes by week 14: three patients achieved PASI≥ 75 and 2 patients did not respond.26 Adalimumab Only three patients received adalimumab for EP. One patient showed remission at week 3 and the other two at week 12.

None of them reported PASI scores.51-53

TABLE I. BASELINE CHARACTERISTICS OF EP PATIENTS TREATED WITH BIOLOGIC MEDICATIONS Characteristic

Total no. reported cases

Mean age at presentation, years

46.4

174

Mean psoriasis duration, years

17.2

140

Male cases, n (%)

134 (78.4%)

171

Mean body mass index (BMI), kg/cm2

24.8

68

Mean baseline PASI score

40.5

152

Mean total follow-up, months

12.3

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TABLE II. ASSESSMENT OF LEVEL OF EVIDENCE AND GRADE OF RECOMMENDATION 487 BY BIOLOGIC MEDICATION Biologic

Level of evidence

Grade of Recommendation

Source

Secukinumab

4

2B

Weng et al.46, MateuPuchades et al.48, Mugheddu et al.47,

5

2B

Galluzo et al.49, Rongioletti et al.50

3

2A

Pescitelli et al.34,

4

2B

Wang et al.39, Concha-

5

2B

Garzón et al.41 Saraceno et al.32, Stinco et al.33,Kim et al.35, Koutsoukou et al.36, Castiñeiras et al.37, SantosJuanes et al.38, Errichetti et al.40

5

2B

Arroyo-Tridico et al.17, Rongioletti et al.18, Takahashi et al.19, Lisby et al.20,O’Quinn et al.22, Fiehn et al.23,

Ustekinumab

Infliximab

Etanercept Fourteen patients were treated with etanercept. One patient did not report PASI scores but described significant improvement. Nevertheless, this patient relapsed during therapy.42 Twelve patients’ PASI scores were reported on weeks 8-12: seven achieved PASI≥ 75, three achieved PASI 50, and two did not respond.44,45,58 Romero-Mate et al. reported a patient with PASI 100 over 34 months.43

week 12, all patients achieved PASI 75, 5/8 achieved PASI 90, and 2/8 achieved PASI 100. By week 24, 100% of patients reached PASI 75, 7/8 reached PASI 90, and 1/8 reached PASI 100. PASI scores were sustained by week 52.54

Ustekinumab Fifty-four patients were administered ustekinumab. A total of sixteen cases reported PASI score improvement at weeks 2-6. Eight of these patients were not responsive during that time frame; all except one of the patients eventually responded to therapy.32,33,38-40 There were 44/46 cases with PASI≥ 50 16-24 weeks after starting medication.33-36,39,41 One patient did not respond to treatment; another patient initially responded but relapsed 28 weeks after intervention.39,41 Another case reported PASI≥ 90 at week 114 of treatment.37 Only 7.4% of patients failed to respond to treatment.34,39,41

Guselkumab Guselkumab was reported in eleven patients and all responded. By week 8, all patients achieved PASI> 50. Fifty-two weeks after treatment, 10 patients demonstrated sustained responses (mean PASI≥ 75).

One patient was lost to follow-up.56

Ixekizumab Eight patients were treated with ixekizumab as part of an open-label study. By 30

Golimumab One patient was treated with golimumab and responded to treatment by week 4 and continued to improve with PASI≥ 75 by week 12.55

Safety Sixty (37.3%) adverse events (AE) were reported secondary to biologic therapy among studies that recorded their occurrence. Infectious events (35/60) were the most common. Further details can be found on Table III. Discussion We aim to update the recommendations for treating EP with biologics published by Levin and colleagues in 2012.7 Since their

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publication, new biologics have been approved for the treatment of plaque psoriasis. There is a lack of randomized, double-blind, controlled trials, and head-to-head comparisons.

Therefore, it is challenging to recommend any of the biologics as a first-line treatment for the management of EP. Recommendations for each biologic are depicted on Table II. Overall, ustekinumab was the most frequent biologic reported. It demonstrated a slower onset of action than infliximab. Nevertheless, patients treated with this medication reported longterm clinical improvement (follow-up period range 3-29 months) with few adverse events.

These findings support the important role of IL-12 and IL-23 inflammatory pathways in the pathogenesis of EP.33 As reported by Stinco and colleagues, ustekinumab seems to be a promising candidate for the long-term control of EP, especially when taking into consideration the well-known possibility of developing tachyphylaxis while on infliximab.7,33 The second most common biologic used was infliximab, demonstrating excellent efficacy with few serious AE that cannot be fully attributed to the medication. The drug had a rapid onset of action, with responses achieved as early as 48 hours after initiation of treatment.22,24.

Most patients demonstrated sustained improvement after 6-10 weeks.17,20,21,26-28 Infliximab was used in combination with methotrexate or acitretin in several cases but these patients failed to respond faster than those on monotherapy. 17,19-21,25,27 For these reasons, we agree with Rosenbach et al. and Levin et al., who suggested that infliximab should be considered a first-line therapeutic agent in the treatment of acute, severe, and/or unstable cases of EP.6,7 Secukinumab, an IL-17A inhibitor, was administered to 19 patients, of which 84.2% showed improvement by ≥8 weeks with no significant AE.46-48,50. However, 31.6% of patients suffered a relapse. Weng et al. attributed these recurrences to history of prior biologic failure in their patients.46 Although this may be a possibility, a proportion of the cases responsive to such agents had also been previously treated with alternate biologic medications. This implies that another mechanism could be responsible for relapses after treatment with secukinumab. Due to its high relapse rate, we recommend using secukinumab as second line therapy for EP based on individual patient characteristics.

Most patients treated with etanercept and adalimumab responded to therapy. Nevertheless, it is important to mention that 21 and 18 cases, respectively, who received other biologics reported prior failure to etanercept or

adalimumab. Etanercept was discontinued in some cases mainly due to its lack of efficacy and AE.44,57 Consequently, we recommend considering etanercept and adalimumab as second-line treatments for EP. Guselkumab (IL-23 inhibitor) and ixekizumab (IL-17 inhibitor) achieved significant improvement after 52 weeks of follow-up.54 Minor infections were a common AE of both medications. However, it is important to note that these studies had longer follow-up time periods when compared to most case reports and case series that reported on the response of other biologics. Due to their level of evidence both guselkumab and ixekizumab can be considered first line treatments for EP. Regardless of which medication is eventually selected for the treatment of EP, adjuvant measures including medium-potency topical steroids, moisturizers, wet dressings, oatmeal baths, and continued supportive care are important.6 Unfortunately, data is limited to case reports, case series, and uncontrolled studies. This could contribute to publication bias, as evidenced by the risk of bias assessment in which most studies had a moderate risk of bias. Furthermore, it is difficult to recommend a specific medication, and despite the suggested therapies it is important to treat every case on an individual basis.

In conclusion, biologic therapy in patients with EP seems to be well-tolerated and demonstrated positive response. Recommendations for biologic agent therapy in EP are based on limited evidence.

We recommend infliximab or ustekinumab in acute, severe cases of EP as first-line biologic agents. IL-23 and IL-17 inhibitor agents seem to be a promising category of biologic treatment of EP and can also be considered as first-line therapy based on their level of evidence. Etanercept and adalimumab can be used in milder, biologically naïve cases. Therapy of patients with EP should be individualized and based on each patient’s disease characteristics, history of previous therapies, and comorbidities. Increased understanding of pathogenic mechanisms in EP and the continued development of newer biologic agents for the treatment of psoriasis will contribute to improve the quality of life in these seriously affected patients.

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44. Esposito M, Mazzotta A, de Felice C, Papoutsaki M, Chimenti S. Treatment of erythrodermic psoriasis with etanercept. Br J Dermatol. 2006 Jul;155(1):156-9.

45. Piqué-Duran E, Pérez-Cejudo JA. [Psoriatic erythroderma treated with etanercept]. Actas Dermosifiliogr. 2007 Sep;98(7):508-10.

46.Weng HJ, Wang TS, Tsai TF. Clinical experience of secukinumab in the treatment of erythrodermic psoriasis: a case series. Br J Dermatol. 2018 Jun;178(6):1439-1440.

47.Mugheddu C, Atzori L, Lappi A, Pau M, Murgia S, Rongioletti F. Successful Secukinumab treatment of generalized pustular psoriasis and erythrodermic psoriasis. J Eur Acad Dermatol Venereol. 2017 Sep;31(9):e420-e421.

48.Mateu-Puchades A, Santos-Alarcón S, Martorell-Calatayud A, Pujol-Marco C, Sánchez-Carazo JL. Erythrodermic psoriasis and secukinumab: Our clinical experience. Dermatol Ther. 2018 Jul;31(4):e12607.

Revista Puertorriqueña de Medicina y Salud Pública

49.Galluzzo M, D’Adamio S, Campione E, Mazzilli S, Bianchi L, Talamonti M. A clinical case of severe disease burden: an erythrodermic psoriatic patient treated with secukinumab. J Dermatolog Treat. 2018 Sep 26:1-11.

50.Rongioletti F, Mugheddu C, Murgia S: Repigmentation and new growth of hairs after anti–interleukin-17 therapy with secukinumab for psoriasis. JAAD Case Rep. 2018 Jun; 4(5): 486–488.

51.Mumoli N, Vitale J, Gambaccini L, Sabatini S, Brondi B, Cei M. Erythrodermic psoriasis. QJM. 2014 Apr;107(4):315.

52.Richetta AG, Maiani E, Carlomagno V et al. Treatment of erythrodermic psoriasis in HCV+ patient with adalimumab. Dermatol Ther. 2009 Nov;22 Suppl 1:S16-8.

53.Vidal D, Peramiquel L, Olivella R, Villar M, Petiti G, González A: Erythrodermic psoriasis successfully treated with adalimumab: A case study. J Eur Acad Dermatol Venereol. 2013, 27(S4):68.

54.Saeki H, Nakagawa H, Nakajo K et al. Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: Results from a 52-week, open-label, phase 3 study (UNCOVER-J). J Dermatol. 2017 Apr;44(4):355-362.

55.Lee WK, Kim GW, Hyun-Ho Cho et al. Erythrodermic Psoriasis Treated with Golimumab: A Case Report. Ann Dermatol 2015;27(4): 446-449.

56.Sano S, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. Guselkumab, a human interleukin-23 monoclonal antibody in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis: Efficacy and safety analyses of a 52-week, phase 3, multicenter, open-label study. J Dermatol. 2018 May;45(5):529-539.

57.Viguier M, Pagès C, Aubin F et al. Efficacy and safety of biologics in erythrodermic psoriasis: a multicentre, retrospective study. Br J Dermatol. 2012 Aug;167(2):41723.

58.Sahel H, Otsmane F, Bouadjar B: Treatment of erythrodermic psoriasis with biological therapies in two cases. J Eur Acad Dermatol Venereol. 2016, 30(S6):102.

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IN IN ADULTS ADULTS WITH WITH ACTIVE ACTIVE PSORIATIC PSORIATIC ARTHRITIS ARTHRITIS (PsA) (PsA)

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In DISCOVER In DISCOVER 2, ACR20 2, ACR20 response response at Week at Week 24 24 (primary (primary endpoint) endpoint)

In DISCOVER In DISCOVER 1, ACR20 1, ACR20 response response at Week at Week 24 24 (primary (primary endpoint) endpoint)

® ® 64%64% of patients of patients receiving receiving TREMFYA TREMFYA q8wq8w (159/248) (159/248) achieved achieved an ACR20 an ACR20 response response vs 33% vs 33% of patients of patients 1-3*†1-3*† receiving receiving placebo placebo (81/246) (81/246) (P<0.0001) (P<0.0001)

® ® 52%52% of patients of patients receiving receiving TREMFYA TREMFYA q8wq8w (66/127) (66/127) achieved achieved an ACR20 an ACR20 response response vs 22% vs 22% of patients of patients 1,2,4*† 1,2,4*† receiving receiving placebo placebo (28/126) (28/126) (P<0.0001) (P<0.0001)

Through Through WeekWeek 24, patients 24, patients werewere considered considered to betononresponders be nonresponders afterafter meeting meeting treatment treatment failure failure criteria: criteria: discontinued discontinued studystudy agentagent for any forreason, any reason, terminated terminated studystudy participation participation for any forreason, any reason, initiated initiated or increased or increased the dose the dose of disease-modifying of disease-modifying antirheumatic antirheumatic drugsdrugs (DMARDs) (DMARDs) or oral or corticosteroids oral corticosteroids over over baseline baseline for PsA, for PsA, or initiated or initiated protocol-prohibited protocol-prohibited medications/therapies medications/therapies for PsA. for PsA. AfterAfter WeekWeek 24, treatment 24, treatment failure failure rulesrules werewere not applied. not applied.

Patients Patients with with missing missing datadata werewere considered considered nonresponders. nonresponders.

Please Please seesee fullfull study study designs designs on the on the following following page. page.

INDICATION INDICATION ® ® TREMFYA TREMFYA (guselkumab) (guselkumab) is indicated is indicated for the for the treatment treatment of adults of adults withwith active active psoriatic psoriatic arthritis. arthritis.

IMPORTANT IMPORTANT SAFETY SAFETY INFORMATION INFORMATION CONTRAINDICATIONS CONTRAINDICATIONS ® ® TREMFYA TREMFYA is contraindicated is contraindicated in patients in patients withwith a history a history of serious of serious hypersensitivity hypersensitivity reaction reaction to guselkumab to guselkumab or toorany to any of the of the excipients. excipients.

WARNINGS WARNINGS ANDAND PRECAUTIONS PRECAUTIONS Hypersensitivity Hypersensitivity Reactions Reactions Serious Serious hypersensitivity hypersensitivity reactions, reactions, including including anaphylaxis, anaphylaxis, havehave ® ® . Some . Some cases cases beenbeen reported reported withwith postmarket postmarket useuse of TREMFYA of TREMFYA required required hospitalization. hospitalization.

If a Ifserious a serious hypersensitivity hypersensitivity reaction reaction ® ® andand initiate initiate appropriate appropriate therapy. therapy. occurs, occurs, discontinue discontinue TREMFYA TREMFYA

Infections Infections ® ® ® ® TREMFYA TREMFYA maymay increase increase the the riskrisk of infection. of infection.

Treatment Treatment withwith TREMFYA TREMFYA should should not not be initiated be initiated in patients in patients withwith a clinically a clinically important important active active infection infection untiluntil the the infection infection resolves resolves or isoradequately is adequately treated. treated.

Consider Consider the the risksrisks andand benefi benefi ts oftstreatment of treatment priorprior to prescribing to prescribing ® ® in patients in patients withwith a chronic a chronic infection infection or aorhistory a history of recurrent of recurrent TREMFYA TREMFYA ® ® infection. infection.

Instruct Instruct patients patients receiving receiving TREMFYA TREMFYA to seek to seek medical medical helphelp if signs if signs or symptoms or symptoms of clinically of clinically important important chronic chronic or acute or acute infection infection occur. occur.

If a Ifpatient a patient develops develops a clinically a clinically important important or serious or serious infection, infection, or or is not is not responding responding to standard to standard therapy, therapy, closely closely monitor monitor andand discontinue discontinue ® ® untiluntil the the infection infection resolves. resolves.

TREMFYA TREMFYA

Pre-Treatment Pre-Treatment Evaluation Evaluation forfor Tuberculosis Tuberculosis (TB) (TB) Evaluate Evaluate patients patients for for TB TB infection infection prior prior to initiating to initiating treatment treatment withwith ® ® . Initiate . Initiate treatment treatment of latent of latent TB TB prior prior to administering to administering TREMFYA TREMFYA ® ® . Monitor . Monitor patients patients for for signs signs andand symptoms symptoms of active of active TB TB TREMFYA TREMFYA ® ® ® ® treatment. treatment.

Do Do notnot administer administer TREMFYA TREMFYA during during andand after after TREMFYA TREMFYA to patients to patients withwith active active TB TB infection. infection.

Immunizations Immunizations ® ® PriorPrior to initiating to initiating TREMFYA TREMFYA , consider , consider completion completion of all of age-appropriate all age-appropriate immunizations immunizations according according to current to current immunization immunization guidelines. guidelines.

Avoid Avoid useuse ® ® . . of live of live vaccines vaccines in patients in patients treated treated withwith TREMFYA TREMFYA

ADVERSE ADVERSE REACTIONS REACTIONS ® ® Most Most common common (≥1%) (≥1%) adverse adverse reactions reactions associated associated withwith TREMFYA TREMFYA include include upper upper respiratory respiratory infections, infections, headache, headache, injection injection sitesite reactions, reactions, arthralgia, arthralgia, bronchitis, bronchitis, diarrhea, diarrhea, gastroenteritis, gastroenteritis, tinea tinea infections, infections, andand herpes herpes simplex simplex infections. infections.

TheThe overall overall safety safety profile profile observed observed in patients in patients withwith psoriatic psoriatic arthritis arthritis is generally is generally consistent consistent withwith thethe safety safety profile profile in patients in patients withwith plaque plaque psoriasis, psoriasis, withwith thethe addition addition of bronchitis of bronchitis andand neutrophil neutrophil count count decreased. decreased.

Please Please seesee thethe Brief Brief Summary Summary of the of the fullfull Prescribing Prescribing Information Information within within thisthis ad.ad. cp-82625v3 cp-82625v3

IN ADULTS IN ADULTS WITHWITH ACTIVE ACTIVE PsA PsA

® ® * * TREMFYA TREMFYA IS IS THE THE FIRST FIRST ALT-MOA ALT-MOA BIOLOGIC BIOLOGIC TOTO INCLUDE INCLUDE FACIT-F FACIT-F ININ THE THE LABEL LABEL FOR FOR ACTIVE ACTIVE PsA PsA ® ® 1 1 TREATMENT TREATMENT WITH WITH TREMFYA TREMFYA RESULTED RESULTED IN IMPROVEMENT IN IMPROVEMENT IN FATIGUE IN FATIGUE AS MEASURED AS MEASURED

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TREMFYA TREMFYA (guselkumab) (guselkumab) ®

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100 mg100 q8w mg(n=246) q8w (n=246)

PLACEBO PLACEBO (n=244) (n=244) 3.73 3.73

IN DISCOVER IN DISCOVER 1 AT1WEEK AT WEEK 24 24 • The • The mean mean change change fromfrom baseline baseline in FACIT-F in FACIT-F score score was was 5.765.76 for for ® ® patients patients receiving receiving TREMFYA TREMFYA q8wq8w (n=127) (n=127) vs 2.15 vs 2.15 for patients for patients 2† 2† receiving receiving placebo placebo (n=126) (n=126) The The FACIT-F FACIT-F endpoints endpoints in in DISCOVER DISCOVER 1 and 1 and DISCOVER DISCOVER 2 2 werewere not adjusted not adjusted for multiplicity. for multiplicity.

Therefore, Therefore, statistical statistical significance significance has not has been not been established. established.

FACIT-F FACIT-F measures measures a patient’s a patient’s levellevel of fatigue of fatigue and and tiredness tiredness overover the last the last 7 days 7 days through through a a 1,5 1,5 questionnaire questionnaire consisting consisting of 13 of questions.

13 questions.

Lower Lower scores scores reflect reflect more more severe severe fatigue. fatigue.

0

0 IN DISCOVER IN DISCOVER 2: 2: 100 mg100 q8w mg(n=246) q8w (n=246) FROM (n=244) (n=244) ≥4-POINT ≥4-POINT PATIENTS PATIENTS WITH WITH IMPROVEMENT IMPROVEMENT FROM BASELINE BASELINE IN FACIT IN FACIT F SCORE F SCORE AT WEEK AT WEEK 24 24

≥4-POINT ≥4-POINT IMPROVEMENT IMPROVEMENT FROM FROM BASELINE BASELINE IN FACIT-F INNRI) FACIT-F SCORE SCORE Blinded, Blinded, placebo-controlled placebo-controlled phase phase (Week 24; (Week 24; NRI) ‡§

‡§

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PERCENTAGE OF PATIENTS PERCENTAGE OF PATIENTS

PERCENTAGE OF PATIENTS PERCENTAGE OF PATIENTS

IN DISCOVER IN DISCOVER 2: 2: ® ® ≥4-POINT ≥4-POINT PATIENTS PATIENTS WITH IMPROVEMENT IMPROVEMENT FROM FROM BASELINE BASELINE IN FACIT IN FACIT F SCORE F SCORE 80% 80% WITH AT WEEK AT WEEK 24 24

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®

% % 6161 (150/248) (150/248)

®

PLACEBO PLACEBO % % 4646 (112/246) (112/246)

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IN DISCOVER 1 AT1WEEK 24 24 IN DISCOVER AT WEEK • The • The percentage percentage of patients of patients withwith ≥4-point improvement ≥4-point improvement fromfrom baseline in FACIT-F score baseline in FACIT-F score was was 54%54% (68/127) for patients (68/127) for patients ® ® receiving TREMFYA receiving TREMFYA q8w q8w vs vs 35%35% (44/126) (44/126) for patients for patients 1‡§ 1‡§ receiving receiving placebo placebo The The FACIT-F FACIT-F endpoints endpoints in in DISCOVER DISCOVER 1 and 1 and DISCOVER DISCOVER 2 2 werewere not adjusted not adjusted for multiplicity. for multiplicity.

Therefore, Therefore, statistical statistical significance significance has not has been not been established. established.

0

(150/248) (150/248)

(112/246) (112/246)

The The threshold threshold for clinically for clinically meaningful meaningful improvement improvement when when assessing assessing fatigue fatigue using using FACIT-F FACIT-F in clinical in clinical trialstrials was was based based on literature on literature in PsA in PsA thatthat supports supports a change a change of ≥4. of6 ≥4.6 5 5 FACIT-F=Functional FACIT-F=Functional Assessment Assessment of Chronic of Chronic IllnessIllness Therapy-Fatigue Therapy-Fatigue ; MOA=mechanism ; MOA=mechanism of action; of action; NRI=nonresponder NRI=nonresponder imputation. imputation. * ® 1 1 Alt-MOA Alt-MOA is a biologic is a biologic not classified not classified as a tumor as a tumor necrosis necrosis factor factor (TNF) blocker.

(TNF) blocker.

TREMFYA TREMFYA is an® interleukin-23 is an interleukin-23 (IL-23)(IL-23) blocker. blocker. † † Through Through Week 24, Week patients 24, patients were considered were considered to havetono have improvement no improvement (change=0) (change=0) after meeting after meeting treatment treatment failurefailure criteria: criteria: discontinued discontinued study agent study agent for anyfor reason, any reason, terminated terminated study participation study participation for anyfor reason, any reason, initiated initiated or increased or increased the dose theofdose DMARDs of DMARDs or oralorcorticosteroids oral corticosteroids over baseline over baseline for PsA, fororPsA, initiated or initiated protocolprotocolprohibited prohibited medications/therapies medications/therapies for PsA. forAfter PsA. Week After Week 24, treatment 24, treatment failurefailure rules were rules not were applied. not applied. ‡ ‡ Patients Patients who met whoany met treatment any treatment failurefailure criteriacriteria prior toprior the to specific the specific visit were visitconsidered were considered as nonresponders as nonresponders at the at said thevisit: saiddiscontinued visit: discontinued study agent study agent for anyfor any reason,reason, terminated terminated study participation study participation for anyfor reason, any reason, initiated initiated or increased or increased the dose theofdose DMARDs of DMARDs or oralorcorticosteroids oral corticosteroids over baseline over baseline for PsA, fororPsA, initiated or initiated protocol-prohibited protocol-prohibited medications/therapies medications/therapies for PsA. forAfter PsA. Week After Week 24, treatment 24, treatment failurefailure rules were rules not were applied. not applied. § § Patients Patients with missing with missing data were dataconsidered were considered nonresponders. nonresponders. *

IN ADULTS IN ADULTS WITH WITH ACTIVE ACTIVE PsAPsA

2 2 DEMONSTRATED DEMONSTRATED SAFETY SAFETY PROFILE PROFILE SAFETY SAFETY PROFILE PROFILE ININ PsA PsA ACROSS ACROSS 22 CLINICAL CLINICAL TRIALS TRIALS

TREATMENT-EMERGENT TREATMENT-EMERGENT ADVERSE ADVERSE EVENTS EVENTS REPORTED REPORTED IN THE IN THE PLACEBO-CONTROLLED PLACEBO-CONTROLLED PHASE PHASE THROUGH THROUGH WEEK WEEK 24: COMBINED 24: COMBINED ACROSS ACROSS DISCOVER DISCOVER 1 AND 1 AND DISCOVER DISCOVER 2 2

Serious Serious Adverse Adverse Events Events Adverse Adverse Events Events Infections Infections ® ® TREMFYA TREMFYA

100 mg 100 q8w mg q8w (48.5%) (48.5%) (n=375), (n=375), n (%) n (%) 182182 [257.30] [257.30] [events[events per 100per 100 patient-years patient-years of follow-up] of follow-up]

PLACEBO PLACEBO

(47.3%) (47.3%) (n=372), (n=372), n (%) n (%) 176176 [events[events per 100per 100 [220.01] [220.01] patient-years patient-years of follow-up] of follow-up]

Serious Serious Infections Infections

7 (1.9%) 7 (1.9%) 73 (19.5%) 73 (19.5%) 1 (0.3%) 1 (0.3%) [4.04][4.04]

[58.27] [58.27]

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NONO ROUTINE ROUTINE LABLAB MONITORING MONITORING REQUIRED REQUIRED DURING DURING 1 1 TREATMENT. TREATMENT.

12 (3.2%) 12 (3.2%) 77 (20.7%) 77 (20.7%) 3 (0.8%) 3 (0.8%) [9.26][9.26]

[58.48] [58.48]

Initially Initially evaluate evaluate for for tuberculosis tuberculosis (TB)(TB) andand monitor monitor for for signs signs andand symptoms symptoms of TB of TB infection infection during during andand after after treatment. treatment.

[4.05][4.05]

® • The • The overall overall safety safety profile profile observed observed in patients in patients withwith PsAPsA treated treated withwith TREMFYA TREMFYA is®generally is generally consistent consistent withwith the the profile profile in patients in patients withwith plaque plaque psoriasis, psoriasis, withwith the the addition addition of bronchitis of bronchitis andand neutrophil neutrophil count count decreased. decreased.

In the In the 24-week, 24-week, 1 placebo-controlled placebo-controlled period, period, combined combined across across the the 2 studies 2 studies : 1: ® ® — Bronchitis — Bronchitis occurred occurred in 1.6% in 1.6% of patients of patients in the in the TREMFYA TREMFYA q8w q8w group group andand 1.1% 1.1% of patients of patients in the in the placebo placebo group group ® ® — Neutrophil — Neutrophil count count decreased decreased occurred occurred in 0.3% in 0.3% of patients of patients in the in the TREMFYA TREMFYA q8w q8w group group compared compared withwith 0%0% of of patients patients in the in the placebo placebo group. group.

TheThe majority majority of events of events of neutrophil of neutrophil count count decreased decreased were were mild, mild, transient, transient, not not associated associated withwith infection, infection, andand did did not not leadlead to discontinuation to discontinuation

® TREMFYA TREMFYA IS ®THE IS THE 1ST 1ST BIOLOGIC BIOLOGIC THAT THAT SELECTIVELY SELECTIVELY INHIBITS INHIBITS IL-23 IL-23 APPROVED APPROVED FORFOR THETHE TREATMENT TREATMENT OF ADULTS OF ADULTS WITH WITH ACTIVE ACTIVE PsAPsA

VISIT VISIT TREMFYAHCP.COM TREMFYAHCP.COM TO TO LEARN LEARN MORE MORE

® ® StudyStudy Designs: Designs: DISCOVER DISCOVER 1 and1DISCOVER and DISCOVER 2 were 2 were PhasePhase 3, multicenter, 3, multicenter, randomized, randomized, double-blind, double-blind, placebo-controlled placebo-controlled studies studies evaluating evaluating the efficacy the efficacy and safety and safety of TREMFYA of TREMFYA administered administered q8w subcutaneously q8w subcutaneously with starter with starter dosesdoses at Week at Week 0 and0Week and Week 4 (n=127 4 (n=127 and n=248, and n=248, respectively) respectively) or placebo or placebo (n=126 (n=126 and n=246, and n=246, respectively) respectively) with starter with starter dosesdoses at Week at Week 0, and0,then and then everyevery 4 weeks 4 weeks in patients in patients with active with active PsA (fulfilling PsA (fulfilling ClASsification ClASsification criteria criteria for Psoriatic for Psoriatic ARthritis ARthritis [CASPAR] [CASPAR] criteria) criteria) despite despite standard standard therapies therapies (nonbiologic (nonbiologic DMARDs), DMARDs), apremilast, apremilast, and non-steroidal and non-steroidal anti-inflammatory anti-inflammatory drugsdrugs [NSAIDs]).

[NSAIDs]).

A stable A stable dose dose of 1 selected of 1 selected nonbiologic nonbiologic DMARD, DMARD, corticosteroids, corticosteroids, and NSAIDs and NSAIDs was permitted was permitted but not but not required. required.

In DISCOVER In DISCOVER 1, eligible 1, eligible patients patients (≥18 (≥18 yearsyears of age) of age) had active had active PsA (swollen/tender PsA (swollen/tender jointsjoints ≥3, C-reactive ≥3, C-reactive protein protein [CRP][CRP] ≥0.3 ≥0.3 mg/dL) mg/dL) for atfor least at least 6 months 6 months and included and included patients patients with awith prior a prior biologic biologic experience experience of ≤2ofanti-TNFα ≤2 anti-TNFα treatments. treatments.

Patients Patients with other with other inflammatory inflammatory diseases diseases and those and those who had whopreviously had previously received received JanusJanus kinase kinase (JAK)(JAK) inhibitors inhibitors or biologics or biologics otherother than than TNFαTNFα inhibitors inhibitors were were excluded. excluded.

In DISCOVER In DISCOVER 2, eligible 2, eligible patients patients (≥18 (≥18 yearsyears of age) of age) had active had active PsA (swollen/tender PsA (swollen/tender jointsjoints ≥5, CRP ≥5, ≥0.6 CRP ≥0.6 mg/dL) mg/dL) for atfor least at least 6 months 6 months and no andprior no prior JAK inhibitor JAK inhibitor or biologic or biologic experience. experience.

At Week At Week 16, patients 16, patients in allintreatment all treatment groups groups who had who<5% had <5% improvement improvement from from baseline baseline in both in both swollen swollen and and tendertender joint joint counts counts were were considered considered as meeting as meeting early early escape escape criteria criteria and were and were allowed allowed to initiate to initiate or increase or increase the dose the dose of oneofofone theofpermitted the permitted concomitant concomitant medications medications up toup theto the ® ® maximum maximum dose dose allowed. allowed.

In DISCOVER In DISCOVER 1 and1DISCOVER and DISCOVER 2, 1282,patients 128 patients and 246 andpatients, 246 patients, respectively, respectively, were were randomized randomized to a q4w to a dosing q4w dosing regimen. regimen.

TREMFYA TREMFYA dosed dosed everyevery 4 weeks 4 weeks is notisannotapproved an approved dosing dosing regimen. regimen.

The primary The primary endpoint endpoint in both in both DISCOVER DISCOVER 1 and1DISCOVER and DISCOVER 2 was2 ACR20 was ACR20 response response at Week at Week 24.2-424.2-4

Please Please see see the the BriefBrief Summary Summary of the of the full full Prescribing Prescribing Information Information on the on the following following pages. pages. ® ® References: References: 1. TREMFYA 1. TREMFYA (guselkumab) (guselkumab) [Prescribing [Prescribing Information].

Information].

Horsham, Horsham, PA: Janssen PA: Janssen Biotech, Biotech, Inc. 2.Inc. Data 2. Data on on file. Janssen file. Janssen Biotech, Biotech, Inc. 3.Inc. Mease 3. Mease PJ, Rahman PJ, Rahman P, Gottlieb P, Gottlieb AB, etAB, al.etGuselkumab al. Guselkumab in biologic-naïve in biologic-naïve patients patients with with activeactive psoriatic psoriatic arthritis arthritis (DISCOVER-2): (DISCOVER-2): a double-blind, a double-blind, randomised, randomised, placebo-controlled placebo-controlled phasephase 3 trial.

3 trial.

Lancet.

Lancet.

2020;395(10230):1126-1136.

2020;395(10230):1126-1136.

4. Deodhar 4. Deodhar A, Helliwell A, Helliwell PS, Boehncke PS, Boehncke WH, et WH, al.etGuselkumab al. Guselkumab in patients in patients with active with active psoriatic psoriatic arthritis arthritis who were who were biologic-naïve biologic-naïve or hadorpreviously had previously received received TNFαTNFα inhibitor inhibitor treatment treatment (DISCOVER-1): (DISCOVER-1): a a double-blind, double-blind, randomised, randomised, placebo-controlled placebo-controlled phasephase 3 trial.

3 trial.

Lancet.

Lancet.

2020;395(10230):1115-1125.

2020;395(10230):1115-1125.

5. Cella 5. Cella D, D, YountYount S, Sorensen S, Sorensen M, etM, al.etValidation al. Validation of theofFunctional the Functional Assessment Assessment of Chronic of Chronic Illness Illness Therapy Therapy Fatigue Fatigue ScaleScale relative relative to other to other instrumentation instrumentation in patients in patients with with rheumatoid rheumatoid arthritis. arthritis.

J Rheumatol.

J Rheumatol.

2005;32(5):811-819.

2005;32(5):811-819.

6. Cella 6. Cella D, Wilson D, Wilson H, Shalhoub H, Shalhoub H, et H, al.etContent al. Content validity validity and psychometric and psychometric evaluation evaluation of Functional of Functional Assessment Assessment of Chronic of Chronic Illness Illness Therapy-Fatigue Therapy-Fatigue in patients in patients with with psoriatic psoriatic arthritis. arthritis.

Journal Journal of Patient-Reported of Patient-Reported Outcomes.

Outcomes.

2019;3(30):1-12.

2019;3(30):1-12.

© Janssen © Janssen Biotech, Biotech, Inc. 2022 Inc. 2022 01/22 01/22 cp-200392v2 cp-200392v2

Brief Summary of Prescribing Information for TREMFYA® (guselkumab) TREMFYA® (guselkumab) injection, for subcutaneous use See package insert for full Prescribing Information.

INDICATIONS AND USAGE Plaque Psoriasis: TREMFYA® is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Psoriatic Arthritis: TREMFYA is indicated for the treatment of adult patients with active psoriatic arthritis. CONTRAINDICATIONS TREMFYA is contraindicated in patients with a history of serious hypersensitivity reaction to guselkumab or to any of the excipients [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarket use of TREMFYA. Some cases required hospitalization. If a serious hypersensitivity reaction occurs, discontinue TREMFYA and initiate appropriate therapy. Infections: TREMFYA may increase the risk of infection. In clinical trials in subjects with plaque psoriasis, infections occurred in 23% of subjects in the TREMFYA group versus 21% of subjects in the placebo group through 16 weeks of treatment.

Upper respiratory tract infections, gastroenteritis, tinea infections, and herpes simplex infections occurred more frequently in the TREMFYA group than in the placebo group [see Adverse Reactions]. The rate of serious infections for the TREMFYA group and the placebo group was ≤ 0.2%. A similar risk of infection was seen in placebo-controlled trials in subjects with psoriatic arthritis.

Treatment with TREMFYA should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.

In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing TREMFYA. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and discontinue TREMFYA until the infection resolves. Pre-treatment Evaluation for Tuberculosis: Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TREMFYA. Initiate treatment of latent TB prior to administering TREMFYA. In clinical trials, 105 subjects with plaque psoriasis and 71 subjects with psoriatic arthritis with latent TB who were concurrently treated with TREMFYA and appropriate TB prophylaxis did not develop active TB. Monitor patients for signs and symptoms of active TB during and after TREMFYA treatment. Consider anti-TB therapy prior to initiating TREMFYA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer TREMFYA to patients with active TB infection. Immunizations: Prior to initiating therapy with TREMFYA, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with TREMFYA. No data are available on the response to live or inactive vaccines. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of labeling: • Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Contraindications and Warnings and Precautions] Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plaque Psoriasis: In clinical trials, a total of 1823 subjects with moderate-to-severe plaque psoriasis received TREMFYA. Of these, 1393 subjects were exposed to TREMFYA for at least 6 months and 728 subjects were exposed for at least 1 year. Data from two placebo- and active-controlled trials (PsO1 and PsO2) in 1441 subjects (mean age 44 years; 70% males; 82% white) were pooled to evaluate the safety of TREMFYA (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 8 weeks). Weeks 0 to 16: In the 16-week placebo-controlled period of the pooled clinical trials (PsO1 and PsO2), adverse events occurred in 49% of subjects in the TREMFYA group compared to 47% of subjects in the placebo group and 49% of subjects in the U.S. licensed adalimumab group. Serious adverse events occurred in 1.9% of subjects in the TREMFYA group (6.3 events per 100 subject-years of follow-up) compared to 1.4% of subjects in the placebo group (4.7 events per 100 subject-years of follow-up), and in 2.6% of subjects in U.S. licensed adalimumab group (9.9 events per 100 subject-years of follow-up). Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the TREMFYA group than in the placebo group during the 16-week placebo-controlled period.

Table 1: Adverse Reactions Occurring in ≥1% of Subjects through Week 16 in PsO1 and PsO2 TREMFYAa 100 mg Adalimumabb Placebo N=823 N=196 N=422 n (%) n (%) n (%) Upper respiratory infectionsc 118 (14.3) 21 (10.7) 54 (12.8) Headached 38 (4.6) 2 (1.0) 14 (3.3) Injection site reactionse 37 (4.5) 15 (7.7) 12 (2.8) Arthralgia 22 (2.7) 4 (2.0) 9 (2.1) Diarrhea 13 (1.6) 3 (1.5) 4 (0.9) Gastroenteritisf 11 (1.3) 4 (2.0) 4 (0.9) Tinea infectionsg 9 (1.1) 0 0 Herpes simplex infectionsh 9 (1.1) 0 2 (0.5)

TREMFYA® (guselkumab) injection

Subjects receiving 100 mg of TREMFYA at Week 0, Week 4, and every 8 weeks thereafter b U.S. licensed adalimumab c Upper respiratory infections include nasopharyngitis, upper respiratory tract infection (URTI), pharyngitis, and viral URTI. d Headache includes headache and tension headache. e Injection site reactions include injection site erythema, bruising, hematoma, hemorrhage, swelling, edema, pruritus, pain, discoloration, induration, inflammation, and urticaria. f Gastroenteritis includes gastroenteritis and viral gastroenteritis. g Tinea infections include tinea pedis, tinea cruris, tinea infection, and tinea manuum infections. h Herpes simplex infections include oral herpes, herpes simplex, genital herpes, genital herpes simplex, and nasal herpes simplex.

Adverse reactions that occurred in < 1% but > 0.1% of subjects in the TREMFYA group and at a higher rate than in the placebo group through Week 16 in PsO1 and PsO2 were migraine, candida infections, and urticaria.

Specific Adverse Reactions: Infections: Infections occurred in 23% of subjects in the TREMFYA group compared to 21% of subjects in the placebo group. The most common (≥ 1%) infections were upper respiratory infections, gastroenteritis, tinea infections, and herpes simplex infections; all cases were mild to moderate in severity and did not lead to discontinuation of TREMFYA. Elevated Liver Enzymes: Elevated liver enzymes were reported more frequently in the TREMFYA group (2.6%) than in the placebo group (1.9%). Of the 21 subjects who were reported to have elevated liver enzymes in the TREMFYA group, all events except one were mild to moderate in severity and none of the events led to discontinuation of TREMFYA. Safety through Week 48: Through Week 48, no new adverse reactions were identified with TREMFYA use and the frequency of the adverse reactions was similar to the safety profile observed during the first 16 weeks of treatment.

Psoriatic Arthritis: TREMFYA was studied in two placebo-controlled trials in subjects with psoriatic arthritis (748 subjects on TREMFYA and 372 subjects on placebo). Of the 748 subjects who received TREMFYA, 375 subjects received TREMFYA 100 mg at Week 0, Week 4, and every 8 weeks thereafter and 373 subjects received TREMFYA 100 mg every 4 weeks. The overall safety profile observed in subjects with psoriatic arthritis treated with TREMFYA is generally consistent with the safety profile in subjects with plaque psoriasis with the addition of bronchitis and neutrophil count decreased. In the 24week placebo-controlled period, combined across the two studies, bronchitis occurred in 1.6% of subjects in the TREMFYA q8w group and 2.9% of subjects in the TREMFYA q4w group compared to 1.1% of subjects in the placebo group. Neutrophil count decreased occurred in 0.3% of subjects in the TREMFYA q8w and 1.6% of subjects in the TREMFYA q4w group compared to 0% of subjects in the placebo group. The majority of events of neutrophil count decreased were mild, transient, not associated with infection and did not lead to discontinuation. Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity with TREMFYA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to guselkumab across indications or with the incidences of antibodies to other products may be misleading.

Plaque Psoriasis: Up to Week 52, approximately 6% of subjects treated with TREMFYA developed antidrug antibodies. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing antibodies. Among the 46 subjects who developed antibodies to guselkumab and had evaluable data, 21 subjects exhibited lower trough levels of guselkumab, including one subject who experienced loss of efficacy after developing high antibody titers. Up to Week 156, approximately 9% of subjects treated with TREMFYA developed antidrug antibodies and of these subjects approximately 6% were classified as neutralizing antibodies.

However, antibodies to guselkumab were generally not associated with changes in clinical response or development of injection-site reactions.

Psoriatic Arthritis: Up to Week 24, 2% (n=15) of subjects treated with TREMFYA developed antidrug antibodies. Of these subjects, 1 had antibodies that were classified as neutralizing antibodies. Overall, the small number of subjects who were positive for antibodies to guselkumab limits definitive conclusion of the effect of immunogenicity on the pharmacokinetics, efficacy and safety of guselkumab. Postmarketing Experience: The following adverse reactions have been reported during post-approval of TREMFYA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to TREMFYA exposure. Immune system disorders: Hypersensitivity, including anaphylaxis [see Warnings and Precautions] Skin and subcutaneous tissue disorders: Rash [see Warnings and Precautions] DRUG INTERACTIONS CYP450 Substrates: The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, interferon) during chronic inflammation. Results from an exploratory drug-drug interaction study in subjects with moderate-to-severe plaque a

TREMFYA® (guselkumab) injection

psoriasis suggested a low potential for clinically relevant drug interactions for drugs metabolized by CYP3A4, CYP2C9, CYP2C19 and CYP1A2 but the interaction potential cannot be ruled out for drugs metabolized by CYP2D6.

However, the results were highly variable because of the limited number of subjects in the study. Upon initiation of TREMFYA in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy registry that monitors pregnancy outcomes in women exposed to TREMFYA during pregnancy. Patients should be encouraged to enroll by calling 1-877-311-8972. Risk Summary: There are no available data on TREMFYA use in pregnant women to inform a drug associated risk of adverse developmental outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, TREMFYA may be transmitted from the mother to the developing fetus. In a combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD).

Neonatal deaths were observed at 6- to 30-times the MRHD (see Data). The clinical significance of these nonclinical findings is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data: Animal Data: In a combined embryofetal development and pre- and postnatal development study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of guselkumab up to 50 mg/kg (30 times the MRHD based on a mg/kg comparison) from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of one control monkey, three monkeys administered guselkumab at 10 mg/kg/week (6 times the MRHD based on a mg/kg comparison) and three monkeys administered guselkumab at 50 mg/kg/week (30 times the MRHD based on a mg/kg comparison). The clinical significance of these findings is unknown. No guselkumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age. Lactation: Risk Summary: There are no data on the presence of guselkumab in human milk, the effects on the breastfed infant, or the effects on milk production.

Guselkumab was not detected in the milk of lactating cynomolgus monkeys.

Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TREMFYA and any potential adverse effects on the breastfed infant from TREMFYA or from the underlying maternal condition. Pediatric Use: The safety and efficacy of TREMFYA in pediatric patients (less than 18 years of age) have not been established. Geriatric Use: Of the 3406 subjects with plaque psoriasis or psoriatic arthritis exposed to TREMFYA, a total of 185 subjects were 65 years or older, and 13 subjects were 75 years or older. No overall differences in safety or effectiveness were observed between older and younger subjects who received TREMFYA. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) in Full Prescribing Information]. OVERDOSAGE In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.

PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before starting TREMFYA therapy, and each time the prescription is renewed, as there may be new information they need to know. Hypersensitivity Reactions: Advise patients to discontinue TREMFYA and seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions]. Infections: Instruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection [see Warnings and Precautions]. Instruction on Injection Technique: Instruct patients or caregivers to perform the first selfinjection under the supervision and guidance of a qualified healthcare professional for proper training in subcutaneous injection technique. Instruct patients who are self-administering to inject the full dose of TREMFYA [see Medication Guide and Instructions for Use]. Instruct patients or caregivers in the technique of proper needle and syringe disposal. Needles and syringes should be disposed of in a puncture-resistant container. Advise patients and caregivers not to reuse needles or syringes. Remind patients if they forget to take their dose of TREMFYA to inject their dose as soon as they remember.

They should then take their next dose at the appropriate scheduled time.

Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044 US License No. 1864 © 2017 Janssen Pharmaceutical Companies cp-82992v3

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Revista Puertorriqueña de Medicina y Salud Pública

DISCAPACIDAD ENTRE ADULTOS CON DIAGNÓSTICO

DE VIH EN ESTADOS UNIDOS

Pranesh P. Chowdhurya, Linda Beera, Fengjue Shub, Jennifer Fagana and R. Luke Shousea a. Division of HIV/AIDS Prevention, CDC, Atlanta, GA, USA; b. ICF International, Atlanta, GA, USA Universidad Nacional de Colombia.

RESUMEN En los Estados Unidos, uno de cada cuatro adultos vive con una discapacidad. Los cambios relacionados con la edad, la patología relacionada con la enfermedad y los tratamientos pueden poner a una persona con VIH en riesgo de sufrir una discapacidad. Analizamos datos representativos a nivel nacional para describir el estado de discapacidad entre adultos ≥18 años con diagnóstico de VIH en los Estados Unidos y Puerto Rico por características demográficas, conductas de salud, calidad de la atención, resultados clínicos y estado de salud mental. Informamos porcentajes ponderados y razones de prevalencia con medias marginales predichas para evaluar diferencias significativas entre grupos (P < 0,05). En general, el 44,5% informó alguna discapacidad; las discapacidades reportadas con mayor frecuencia estaban relacionadas con la movilidad (24,8%) y la cognición (23,9%). Las personas que vivían en hogares en o por debajo del nivel de pobreza o que habían estado sin hogar en los últimos 12 meses informaron una mayor prevalencia de cualquier discapacidad que las personas que no eran pobres o no estaban sin hogar (60,2 % frente a 33,4 % y 61,8 % frente a 42,8 % , respectivamente). La prevalencia de depresión y ansiedad fue mayor entre las personas con alguna discapacidad en comparación con aquellas sin discapacidad (32,8 % y 26,6 % frente a 10,1 % y 7,0 %, respectivamente). Mejorar el apoyo de los médicos y proveedores auxiliares puede ayudar a optimizar los resultados de salud a largo plazo entre las personas con discapacidad que viven con el VIH.

ABSTRACT In the United States, one in four adults is living with a disability. Age-related changes, disease-related pathology and treatments can place a person with HIV at risk for a disability. We analyzed nationally representative data to describe disability status among adults ≥18 years with diagnosed HIV in the United States and Puerto Rico by demographic characteristics, health behaviors, quality of care, clinical outcomes and mental health status. We reported weighted percentages and prevalence ratios with predicted marginal means to evaluate significant differences between groups (P < .05).

Overall, 44.5% reported any disability; the most frequently reported disabilities were related to mobility (24.8%) and cognition (23.9%). Persons who lived in households at or below the poverty level or who experienced homelessness in the last 12 months reported a higher prevalence of any disability than persons who were not poor or not homeless (60.2% vs. 33.4%and 61.8% vs.

42.8%, respectively). Prevalence of depression and anxiety was higher among persons with any disability compared with those with no disability (32.8% and 26.6% versus 10.1% and 7.0%, respectively). Enhancing support from clinicians and ancillary providers may help optimize longterm health outcomes among HIV-positive persons with disabilities.

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INTRODUCTION The Centers for Disease Control and Prevention (CDC) defines a disability as a condition that makes it more difficult for a person to do certain activities and interact with the world around them.

In the United States, 61 million adults are living with some type of disability (Okoro et al., 2018) and the three most frequently reported disabilities were related to mobility (13.7%), cognition (10.8%) and independent living (6.8%).

Prevalence of disability increases with age (Courtney-Long et al., 2015). With the advances in antiretroviral therapy (ART) treatments, people with HIV are living longer (Antiretroviral Therapy Cohort Collaboration, 2008). Persons with HIV infection may be more likely to have disabilities because nearly half of the people with HIV are over 50 years (CDC, 2018) and many older adults with HIV experience health-related deterioration from aging (Pathai et al., 2014), HIV-related comorbidities (Leveille & Thapa, 2017), as well as negative long term effects of HIV treatments (Onen & Overton, 2011). It is important to know how disability can affect people with HIV and understanding who is disproportionately affected by disability may be helpful for public health prevention. The purpose of this analysis was to use Medical Monitoring Project (MMP) data to describe the prevalence of disability status overall and by selected characteristics, among adults with diagnosed HIV living in the United States and Puerto Rico.

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MATERIALS AND METHODS MMP is a surveillance system that produces nationally representative estimates of behavioral and clinical characteristics of adults aged ≥18 years with diagnosed HIV living in the United States and Puerto Rico. We used interview and medical record data collected from 4222 adults living with HIV collected from June 2017 through May 2018. Details about MMP sampling, data collection and weighting processes were described previously (Beer et al., 2019). All analyses were conducted using SAS callable SUDAAN version 11.03 (RTI International, Research Triangle Park, NC) to account for the complex survey design and weights. We estimated the weighted prevalence and 95% confidence interval (CI) of reporting at least one disability overall and by variables capturing socio demographics, any Ryan White HIV/ AIDS Program (RWHAP) assistance, unmet needs, quality of care, clinical outcomes, health behaviors and mental health. To compare groups, unadjusted prevalence ratios (PR) with CIs were calculated using logistic regression with predicted marginal means (Bieler et al., 2010).

MMP included six questions about disabilities related to hearing, vision, cognition, mobility, selfcare and independent living (HHS, 2011). Respondents were asked

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“Are you deaf or do you have serious difficulty hearing?” (hearing disability); “Are you blind or do you have serious difficulty seeing, even when wearing glasses?” (vision disability); “Because of a physical, mental, or emotional condition, do you have serious difficulty concentrating, remembering, or making decisions?” (cognition disability); “Do you have serious difficulty walking or climbing stairs?” (mobility disability); “Do you have difficulty dressing or bathing?” (self-care disability) and “Because of a physical, mental or emotional condition, do you have difficulty doing errands alone such as visiting a doctor’s office or shopping?” (indepen-dent living disability). Respondents could report more than one disability. Persons who responded “yes” to at least one of these questions were identified as having any disability and those who responded “no” to all six questions were identified as having no disability. Socio-demographics, RWHAP assistance, unmet needs, mental health, adherence to ART, and health behaviors were selfreported for the past 12 months unless otherwise indicated. Mental health status included symptoms of depression or anxiety in the past two weeks prior to the interview. ART prescription and viral suppression measures were abstracted from medical records.

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RESULTS Overall, 44.5% (CI 42.7–46.4) of adults with diagnosed HIV reported any disability; 13% reported three or more disabilities. The most frequently reported disability was difficulty related to mobility (24.8%, CI 23.2–26.4), followed by cognition (23.9%, CI 22.2–25.6), indepen-dent living (12.5%, CI 11.3–13.8), vision (12.5%, CI 11.0–14.1), hearing (9.7%, CI 8.5–11.1) and self-care (7.0%, CI 6.1–8.1) (not in tables). The prevalence of any disability differed across MMP project areas, ranging from 33.6% in Georgia to 57.0% in Puerto Rico (Table 1). Women reported a higher prevalence of any disability than men (53.6% vs.

41.3%) (Table 2). Among age groups, the prevalence of any disability was highest among adults aged 65 years or older (60.4%) and lowest among those aged 18–24 years (32.2%). Among racial/ ethnic groups, Hispanic/Latino adults reported the highest prevalence of any disability (48.9%). Persons who lived in households at or below the poverty level were 80% (PR = 1.80, CI 1.65–1.96) and who were homeless in the last 12 months were 44% (PR = 1.44, CI 1.31–1.59) more likely to report any disability than

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persons who were not poor or not homeless. Persons who went without food due to lack of money or who had at least one unmet ancillary service need were 76% (PR = 1.76, CI 1.65–1.89) and 66% (PR = 1.66, CI 1.51–1.81) more likely to report any disability than their counterparts, respectively.

There was no association between disability status and ART prescription, adherence to HIV medications, and viral suppression (Table 3). Persons with any dis-ability were 34% (PR = 1.34, CI 1.24–1.46) as likely to be current smoker than person with no disability. Simi-larly, compared with persons who did not have a disability, person with disability were over three times (PR = 3.27, CI 2.87– 3.27) as likely to report depression and nearly four times (PR = 3.81, CI 3.12– 4.65) as likely to report anxiety. When we stratified the analysis by num-ber of disabilities (data not presented in table), com-pared with persons who did not have a disability, persons with three or more disabilities were 10% (PR = 0.90, CI 0.83–0.98) less likely to be adherent to HIV medicine, 57% (PR = 1.57, CI 1.40– 1.75) more likely to be a current smoker, over four times (PR = 4.36, CI 3.73–5.11)

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as likely to report depression, and over five times (PR = 5.31, CI 4.08–6.91) as likely to report anxiety. There was no association between number of disabilities and ART prescription or viral suppression.

DISCUSSION The prevalence of any disability among adults with diagnosed HIV is higher than in the general population (44.5% vs. 25.7%) and is also higher among those aged 45–64 years (49.6% vs.

28.6%) and 65 or more years (60.4% vs. 41.7%) – indicating the substantial burden of disability among persons with HIV (Okoro et al., 2018). Like previous studies among the general popu-lation (Courtney-Long et al., 2015), the wide variation in the prevalence of disabilities among adults with diagnosed HIV across U.S. jurisdictions may reflect geo-graphic differences in demographic factors, health behaviors, health care access or combinations of these factors, and highlights the importance of monitoring of disability status in this population by area.

With advances in efficacy and tolerability of ART, people diagnosed with HIV are living longer; as the number of older persons living with HIV increases (Pathai

et al., 2014), the prevalence of disabilities may also increase. Similar to what has been found among the general population (Okoro et al., 2018), disabilities related to difficulties with mobility and cognition were the most frequently reported. The CDC-recommended self-management intervention, “Living Well with a Dis-ability” (Ravesloot et al., 2016), may be an effective tool to improve the health and quality of life among adults with HIV who are living with disabilities.

Our findings indicate that adults with HIV who are living with any disability may need enhanced access to ancillary services that can support their needs for hous-ing, food or nutrition, substance abuse and mental health services to improve their health outcomes (Con-viser & Pounds, 2002). We did not find any difference in RWHAP assistance between persons with and without disability, although persons with a disability may have a higher need for services available through Ryan White. The federally funded Ryan White HIV/AIDS Program provides access to medical and support ser-vices for nearly half a million persons living with HIV in the USA (Kaiser, 2019) and expanding its patient-centered medical home model may improve access to care for persons with disabilities (Pappas et al., 2014).

The findings of this analysis are subject to limitations. First, self-reported information may be subject to biases that may lead to measurement error. Second, disability measures were self-reported and are not official designa-tions for any Social Security benefit. However, self-report is the most commonly used method to assess disability for surveillance purposes. A strength of this analysis was the use of the Department of Health and Human Service’s standard self-reported six-question measure of any disability, which facilitates monitoring of disability status among people with HIV and enables comparisons of disability prevalence across different population-based studies.

Third, we cannot assess causality due to MMP’s cross-sectional design.

Successful treatment and management of HIV infec-tion have transformed HIV into a chronic disease. However, optimizing health outcomes among persons with HIV with a disability may require en-

hanced support from clinicians and ancillary providers.

ACKNOWLEDGEMENTS Participating Medical Monitoring Project respondents, advi-sory boards, and project areas.

DISCLOSURE STATEMENT No potential conflict of interest was reported by the authors.

FUNDING This work was supported by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.

DISCLAIMER The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

REFERENCES Antiretroviral Therapy Cohort Collaboration. (2008). Life expectancy of individuals on combination antiretroviral therapy in high-income countries: A collaborative analysis of 14 cohort studies. Lancet, 372(9635), 293–299. https://doi.org/10.1016/S01406736(08)61113-7 Beer, L., Johnson, C. H., Fagan, J. L., et al.

(2019). A national behavioral and clinical surveillance system of adults with diagnosed HIV (The Medical Monitoring Project): protocol for an annual cross-sectional interview and medical record abstraction survey. JMIR Research Protocols, 8(11), e15453. https://doi. org/10.2196/15453 Bieler, G. S., Brown, G. G., Williams, R. L., & Brogan, D. J.(2010). Estimating model-adjusted risks, risk differences, and risk ratios from complex survey data. American Journal of Epidemiology, 171(5), 618–623. https:// doi.org/ 10.1093/aje/kwp440 CDC, Centers for Disease Control and Prevention (2018). HIV Surveillance Report, 2017, vol. 29. https://www.cdc. gov/hiv/ pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2017-vol-29.pdf Conviser, R., & Pounds, M. B. (2002).

The role of ancillary services in client-centered systems of care. AIDS Care, 14 (sup1), 119–131. https://doi.org/10.1080/ 09540120220150018 Courtney-Long, E. A., Carroll, D. D., Zhang, Q. C., Stevens, A. C., Griffin-Blake, S., Armour, B. S., & Campbell, V. A.(2015). Prevalence of disability and disability type among adults–United States, 2013. MMWR Morbidity and Mortality Weekly Report, 64(29),

777–783. https://doi.org/ 10.15585/mmwr.

MM6429a2 HHS, U.S Department of Health and Human Services. (2011). Implementation guidance on data collection standards for race, ethnicity, sex, primary language, and disability status. http://aspe.hhs.gov/datacncl/standards/ ACA/4302 Kaiser Family Foundation. (2019). The Ryan White HIV/ AIDS Program: The basics. https://www. kffi.org/hivaids/fact-sheet/the-ryan-whitehivaids-program-the-basics Leveille, S. G., & Thapa, S. (2017). Disability among persons aging with HIV/AIDS. In M. Brennan-Ing, & R. F. DeMarco (Eds.), HIV and aging. Interdisciplinary topics in gerontology and geriatrics, vol. 42 (pp. 101–118). Karger. doi:10.1159/000448547.

Okoro, C. A., Hollis, N. D., Cyrus, A. C., & Griffin-Blake, S. (2018). Prevalence of disabilities and health care access by disability status and type among adults – United States, 2016. MMWR Morbidity and Mortality Weekly Report, 67 (32), 882–887. https:// doi.org/10.15585/mmwr.mm6732a3 Onen, N. F., & Overton, E. T. (2011).

A review of premature frailty in HIV-infected persons; another manifestation of HIV-related accelerated aging. Current Aging Science, 4 (1), 33–41. https://doi. org/10.2174/1874609811104010033 Pappas, G., Yujiang, J., Seiler, N., Malcarney, M. B., Horton, K., Shaikh, I., … Hidalgo, J. (2014). Perspectives on the role of patient-centered medical homes in HIV care. American Journal of Public Health, 104(7), e49–e53. https://doi.org/10.2105/ AJPH.2014.302022 Pathai, S., Bajillan, H., Landay, A. L., & High, K. P. (2014). Is HIV a model of accelerated or accentuated aging? The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 69(7), 833–842. https://doi.org/10.1093/gerona/glt168 Ravesloot, C., Seekins, T., Traci, M., Boehm, T., White, G., ​​Witten, M. H., … Mayer, M. (2016). Living well with a dis-ability, a self-management program. MMWR Morbidity and Mortality Supplements, 65(01), 61–67. https://doi.org/ 10.15585/mmwr.su6501a10

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INVISIBLE. NO SOMOS INVISIBLES. WE ARE NOT “CRAZY.” NO SOMOS “LOCAS.”

no somos invisibles

WE ARE RESILIENT.

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RESILIENTES. Por servicios de SALUD MENTAL para todos enMENTAL cualquier JÓVENES LATINAS, LA SALUD Y LAS ESCUELAS DE FILADELFIA situación, en cualquier parte de Puerto Rico.

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WEIGH THE IMPORTANCE OF YOUR ARV DECISION

Lighten the HIV Treatment Burden Today Choose SYMTUZA® for1,2: • Sustained tolerability * • Proven efficacy • The protective resistance barrier of darunavir

ARV=antiretroviral.

INDICATION SYMTUZA® is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

IMPORTANT SAFETY INFORMATION BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B • Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of SYMTUZA®.

Action: Monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA®. If appropriate, anti-hepatitis B therapy may be warranted.

CONTRAINDICATIONS • Do not coadminister SYMTUZA® and the following drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect: alfuzosin, carbamazepine, colchicine (in patients with renal and/or hepatic impairment), dronedarone, elbasvir/ grazoprevir, ergot derivatives (such as: dihydroergotamine, ergotamine, methylergonovine), ivabradine, lomitapide, lovastatin, lurasidone, oral midazolam, naloxegol, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

WARNINGS AND PRECAUTIONS • Hepatotoxicity: Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and cases of liver injury, including some fatalities, have been reported in patients receiving darunavir, a component of SYMTUZA®. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

Action: Monitor liver function prior to initiating and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases. Patients with evidence of new or worsening liver function should consider discontinuing SYMTUZA®. SYMTUZA® is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING for SYMTUZA®, on the following pages.

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*≤3% of patients discontinued due to adverse events across pivotal trials through 48 weeks and 96 weeks (Week 96 was an open-label, single-arm extension, not the primary endpoint).1,2

IN TREATMENT-NAÏVE AND VIROLOGICALLY SUPPRESSED PATIENTS

Sustained Tolerability Through 48 and 96 Weeks*

≤ 3%

of patients discontinued due to adverse events among 1125 patients across pivotal trials, demonstrating tolerability through 48 and 96 weeks1,2*

Discontinuations across pivotal trials

2%

of treatment-naïve patients (n=362) discontinued due to adverse events at Week 483

1%

of virologically suppressed patients (n=763) discontinued due to adverse events at Week 484

- Compared to 4% (n=363) of patients in the control arm3

- 3% (n=362) of treatment-naïve patients taking SYMTUZA® discontinued at Week 961*

- Compared to 1% (n=378) of patients in the control arm4

- 2% (n=763) of virologically suppressed patients taking SYMTUZA® discontinued at Week 962*

*Week 96 was an open-label, single-arm extension, not a primary endpoint.1,2

Most common adverse events in AMBER and EMERALD at 48 weeks AMBER5 • The most common adverse reactions (all Grades) occurring in at least 2% of patients taking SYMTUZA® were diarrhea (9%), rash (8%),† nausea (6%), fatigue (4%), headache (3%), abdominal discomfort (2%), and flatulence (2%) • Most adverse reactions during treatment with SYMTUZA® were mild to moderate in severity (Grades 1 and 2)‡ - One Grade 3 reaction was reported and no Grade 4 adverse reactions were reported during treatment with SYMTUZA®

EMERALD4 • The most common treatment-related adverse events with SYMTUZA® were diarrhea (2%) and osteopenia (1%) • Most adverse events during treatment with SYMTUZA® were mild to moderate in severity (Grades 1 and 2) - The most common Grade 3 adverse event was pneumonia, which was reported for 3 (<1%) patients. No Grade 4 adverse events were reported in 2 or more patients in either group

This is not a complete list of all adverse reactions reported with the use of SYMTUZA®. Please refer to the full Prescribing Information for a complete list of adverse reactions.

AMBER study design: Phase 3, randomized, double-blind, active-controlled, international, multicenter, noninferiority study assessing the efficacy and safety of SYMTUZA® (n=362) vs DRV/c + FTC/TDF (n=363) in treatment-naïve adults (N=725).§ After Week 48, patients could continue on or switch to SYMTUZA® in an open-label, single-arm extension phase until Week 96. Primary endpoint: Proportion of patients with VL <50 copies/mL at 48 weeks (noninferiority margin 10% by FDA Snapshot).1,3,5 EMERALD study design: Phase 3, randomized, open-label, international, multicenter, noninferiority study that randomized 1141 treatment-experienced adults to SYMTUZA® (n=763) vs continuing on bPI + FTC/TDF (n=378). Patients had been on therapy for ≥6 months with no history of virologic failure on darunavir-based regimens and were virologically suppressed prior to and at screening. After Week 48, patients could continue on or switch to SYMTUZA® in an open-label extension phase until Week 96. Key endpoints: Proportion of patients with virologic rebound at Week 48 (noninferiority margin 4%); Proportion of patients with VL <50 copies/mL at 48 weeks (FDA Snapshot).2,4 Includes pooled reported terms: dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash pruritic, toxic skin eruption, and urticaria.5 Few treatment-naïve patients started a lipid-lowering medication (1.7% [n=6] in the SYMTUZA® arm and 0.6% [n=2] in the control arm).5 § Randomization was stratified by VL and CD4+ cell count.3 †

‡

bPI=boosted protease inhibitor; DRV/c=darunavir/cobicistat; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate; VL=viral load.

IMPORTANT SAFETY INFORMATION (CONTINUED) WARNINGS AND PRECAUTIONS (CONTINUED) • Severe Skin Reactions: In patients receiving darunavir, a component of SYMTUZA®, severe skin reactions may occur, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis. These include conditions accompanied by fever and/or elevations of transaminases.

Action: Discontinue SYMTUZA® immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING for SYMTUZA®, on the following pages.

Evaluate the Risks of ARV-Related Weight Gain

0

discontinuations due to weight gain across pivotal trials1,2,6

Median weight change from baseline at Weeks 48 and 96* in patients taking SYMTUZA®

3 2 1 0

1.5 kg

2.0 kg

0.0 kg Control (n=330)

SYMTUZA® (n=340)

Week 48

SYMTUZA® (n=318)

Virologically suppressed patients2,6 Median Weight Change From Baseline (kg)

Median Weight Change From Baseline (kg)

Treatment-naïve patients6 3

1.8 kg

2 1

0.5 kg

1.3 kg

0

Control (n=356)

Week 96*

SYMTUZA® (n=728)

Week 486

SYMTUZA® (n=701) Week 962*

*Week 96 was an open-label, single-arm extension, not a primary endpoint.1,2

Virologic suppression (<50 copies/mL) achieved at Week 48 and at Week 96* In treatment-naïve patients taking SYMTUZA®1: • 91% (n=362) achieved virologic suppression vs 88% (n=363) of control group patients at Week 48 - 4% virologic failure rate (≥50 copies/mL) in the SYMTUZA® arm vs 3% in the control arm - 4% of patients in the SYMTUZA® arm had no virologic data vs 8% in the control arm • 85% (n=362) achieved virologic suppression at Week 96 - 6% virologic failure rate - 9% of patients had no virologic data

In virologically suppressed patients taking SYMTUZA®2,4: • 95% (n=763) achieved virologic suppression vs 94% (n=378) of control group patients at Week 484 - 1% virologic failure rate (≥50 copies/mL) in the SYMTUZA® arm vs 1% in the control arm - 4% of patients in the SYMTUZA® arm had no virologic data vs 6% in the control arm • 91% (n=763) achieved virologic suppression at Week 962 - 1% virologic failure rate - 8% of patients had no virologic data available

ARV=antiretroviral.

IMPORTANT SAFETY INFORMATION (CONTINUED) WARNINGS AND PRECAUTIONS (CONTINUED) • Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Consult the full Prescribing Information prior to and during treatment for potential drug interactions.

• Immune Reconstitution Syndrome: Patients receiving SYMTUZA® may develop new onset or exacerbations of immune reconstitution syndrome.

• New Onset or Worsening Renal Impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events. SYMTUZA® is not recommended in patients with estimated creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Action: Prior to initiating or during treatment, on a clinically appropriate schedule, monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Discontinue SYMTUZA® in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

• Sulfa Allergy: Darunavir contains a sulfonamide moiety. The incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

Action: Monitor patients with a known sulfonamide allergy.

• Lactic Acidosis/Severe Hepatomegaly With Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA®, and tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals.

Action: Discontinue SYMTUZA® in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

• Diabetes Mellitus/Hyperglycemia: New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors.

Action: Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.

Please see additional Important Safety Information and Brief Summary, including Boxed WARNING for SYMTUZA®, on the following pages.

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Lighten the HIV Treatment Burden With Tolerability and Proven Resistance Protection

≤ 3%

0 Proven

of patients discontinued due to adverse events among 1125 patients across pivotal trials, demonstrating tolerability through 48 and 96 weeks1,2*

patients discontinued due to weight gain, nausea, vomiting, insomnia or anxiety related to SYMTUZA® across pivotal trials1,2,6

The protective barrier of darunavir was studied in >5500 patients in 14 clinical trials with data up to 192 weeks5,7-16†

*Week 96 was an open-label, single-arm extension, not a primary endpoint.1,2

AMBER (n=362); AMBER CONTROL (n=363); EMERALD (n=763); EMERALD CONTROL (n=266); DIAMOND (N=109); STUDY 130 (n=313); ARTEMIS (n=343); ODIN QD (n=294); ODIN BID (n=296); POWER 1 (n=65); POWER 2 (n=66); POWER 3 (n=336); METABOLIK (n=34); GRACE (n=429); DUET (n=599); DUET CONTROL (n=604); TITAN (n=298); PHASE 2 (n=103); PHASE 2 CONTROL (n=50)=5693. 5,7-16

†

BID=twice-daily; QD=once-daily.

IMPORTANT SAFETY INFORMATION (CONTINUED) WARNINGS AND PRECAUTIONS (CONTINUED) • Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy.

• Hemophilia: Patients with hemophilia may develop an increase in bleeding events.

USE IN SPECIFIC POPULATIONS • Pregnancy: SYMTUZA® is not recommended for use during pregnancy and should not be initiated in pregnant individuals because of substantially lower exposures of darunavir and cobicistat during pregnancy.

Lactation: The Centers for Disease Control and Prevention recommends that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

• Pediatric Use: The safety and effectiveness of SYMTUZA® have not been established and is not recommended in pediatric patients weighing less than 40 kg.

• Consult the full Prescribing Information for SYMTUZA® for additional information on the Uses in Specific Populations.

cp-62076v9

*Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash pruritic, toxic skin eruption, and urticaria.

Grade 2-4 laboratory abnormalities have been reported in patients receiving SYMTUZA®, including elevations in serum creatinine, liver function tests, triglycerides, total cholesterol, low-density lipoproteins, and glucose levels. This is not a complete list of all adverse reactions reported with the use of SYMTUZA®. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

Please see accompanying Brief Summary, including Boxed WARNING for SYMTUZA®, on the following pages.

References: 1. Orkin C, Eron JJ, Rockstroh J, et al; AMBER Study Group. Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2020;34(5):707-718. 2. Eron JJ, Orkin C, Cunningham D, et al; EMERALD Study Group. Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/ emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1. Antiviral Res. 2019;170:104543. 3. Eron JJ, Orkin C, Gallant J, et al; AMBER Study Group. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2018;32(11):14311442. 4. Orkin C, Molina JM, Negredo E, et al; EMERALD Study Group. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2018;5(1):e23-e34. 5. SYMTUZA® [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP. 6. Data on file.

Janssen Therapeutics, Division of Janssen Products, LP. 7. Huhn GD, Crofoot G, Ramgopal M, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in a rapid initiation model of care for HIV-1 infection: primary analysis of the DIAMOND study. Clin Infect Dis. Published online December 27, 2019. doi:10.1093/cid/ciz1213 8. Tashima K, Crofoot G, Tomaka FL, et al.

Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a phase IIIb, open-label single-arm trial. AIDS Res Ther. 2014;11:39. 9. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2013;14(1):4959. 10. Cahn P, Fourie J, Grinsztejn B, et al. Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS. 2011;25(7):929-939.

11. Arastéh K, Yeni P, Pozniak A, et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther.

2009;14(6):859-864. 12. Aberg JA, Tebas P, Overton ET, et al. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type-1 infected subjects over 48 weeks. AIDS Res Hum Retroviruses. 2012;28(10):1184-1195. 13. Currier J, Averitt Bridge D, Hagins D, et al; GRACE (Gender, Race, and Clinical Experience) Study Group. Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. Ann Intern Med. 2010;153(6):349-357. 14. Katlama C, Clotet B, Mills A, et al. Efficacy and safety of etravirine at week 96 in treatmentexperienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther. 2010;15(7):1045-1052. 15. Madruga JV, Berger D, McMurchie M, et al; TITAN Study Group. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007;370(9581):49-58. 16. Mills A, Crofoot G Jr, McDonald C, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2015;69(4):439-445.

Distributed by: Janssen Therapeutics, Division of Janssen Products, LP, Titusville, NJ 08560 © Janssen Therapeutics, Division of Janssen Products, LP 2021 08/21 cp-178680v3

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ADVERSE REACTIONS • The most common clinical adverse reactions (all grades) occurring in at least 2% of treatment-naïve patients were diarrhea, rash,* nausea, fatigue, headache, abdominal discomfort, and flatulence.

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SYMTUZA®

(darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use Brief Summary of Prescribing Information. For complete prescribing information, please consult official package insert.

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of SYMTUZA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions].

DOSAGE FORMS AND STRENGTHS Each SYMTUZA tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped, film-coated tablet is debossed with “8121” on one side and “JG” on the other side.

CONTRAINDICATIONS SYMTUZA is contraindicated with the following co-administered drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions].

• Alpha 1-adrenoreceptor antagonist: alfuzosin • Anticonvulsants: carbamazepine, phenobarbital, phenytoin • Anti-gout: colchicine, in patients with renal and/or hepatic impairment • Antimycobacterial: rifampin • Antipsychotics: lurasidone, pimozide • Cardiac Disorders: dronedarone, ivabradine, ranolazine • Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine • Herbal product: St. John’s wort (Hypericum perforatum) • Hepatitis C direct acting antiviral: elbasvir/grazoprevir • Lipid modifying agents: lomitapide, lovastatin, simvastatin

• Opioid Antagonist: naloxegol • PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension • Sedatives/hypnotics: orally administered midazolam, triazolam WARNINGS AND PRECAUTIONS Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy [see Dosage and Administration].

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate, and may occur with discontinuation of SYMTUZA. Patients coinfected with HIV-1 and HBV who discontinue SYMTUZA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Hepatotoxicity Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported in clinical trials with darunavir, a component of SYMTUZA. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse reactions.

Post-marketing cases of liver injury, including some fatalities, have been reported with darunavir. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with SYMTUZA and patients should be monitored during treatment as clinically appropriate. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of SYMTUZA treatment.

Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) should prompt consideration of interruption or discontinuation of SYMTUZA. Severe Skin Reactions In patients receiving darunavir, a component of SYMTUZA, severe skin reactions may occur. These include conditions accompanied by fever and/or elevations of transaminases. Stevens-Johnson syndrome was reported with darunavir co-administered with cobicistat in clinical trials at a rate of 0.1%. During darunavir post-marketing experience, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis have been reported.

Discontinue SYMTUZA immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.

Rash events of any cause and any grade occurred in 15% of subjects with no prior antiretroviral treatment history treated with SYMTUZA in the AMBER trial [see Adverse Reactions]. Rash events were mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using SYMTUZA was 2%.

Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of SYMTUZA and other drugs may result in known or potentially significant drug interactions which may lead to [see Contraindications and Drug Interactions]: • Clinically significant adverse reactions from greater exposures of concomitant drugs.

• Clinically significant adverse reactions from greater exposures of SYMTUZA. • Loss of therapeutic effect of the concomitant drugs from lower exposures of active metabolite(s).

• Loss of therapeutic effect of SYMTUZA and possible development of resistance from lower exposures of SYMTUZA.

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INDICATIONS AND USAGE SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg: • who have no prior antiretroviral treatment history or • who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.

DOSAGE AND ADMINISTRATION Testing Prior to Initiation of SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection [see Warnings and Precautions].

Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions].

Recommended Dosage SYMTUZA is a four-drug fixed-dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of SYMTUZA is one tablet taken orally once daily with food in adults and pediatric patients weighing at least 40 kg. For patients who are unable to swallow the whole tablet, SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Not Recommended in Patients with Severe Renal Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute [see Use in Specific Populations].

Not Recommended in Patients with Severe Hepatic Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations].

Not Recommended During Pregnancy SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy [see Use in Specific Populations and Clinical Pharmacology (12.3) in Full Prescribing Information].

SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA.

SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

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See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during SYMTUZA therapy; review concomitant medications during SYMTUZA therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications and Drug Interactions].

When used with concomitant medications, SYMTUZA, which contains darunavir boosted with cobicistat, may result in different drug interactions than those observed or expected with darunavir co-administered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with darunavir co-administered with ritonavir to certain SYMTUZA interactions [see Drug Interactions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, GuillainBarré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.

New Onset or Worsening Renal Impairment Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions]. SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL per minute.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Prior to or when initiating SYMTUZA and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Discontinue SYMTUZA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Cobicistat, a component of SYMTUZA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating SYMTUZA, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation.

Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.

Sulfa Allergy Darunavir contains a sulfonamide moiety. Monitor patients with a known sulfonamide allergy after initiating SYMTUZA. In clinical studies with darunavir co-administered with ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA, and TDF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with SYMTUZA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV infected patients receiving HIV protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between HIV PI therapy and these events have not been established.

Fat Redistribution Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with HIV protease inhibitors (PIs). In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued.

A causal relationship between PI therapy and these episodes has not been established.

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe acute exacerbations of hepatitis B [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Severe skin reactions [see Warnings and Precautions] • Immune reconstitution syndrome [see Warnings and Precautions] • New onset or worsening renal impairment [see Warnings and Precautions] • Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials in Adults Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF).

The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively.

An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX + FTC/TDF are presented in Table 3.

Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 adverse reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA PREZCOBIX+FTC/TDF (N=362) (N=363) All At least All At least Grades Grade 2 Grades Grade 2 Diarrhea 9% 2% 11% 2% Rasha 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% 4% <1% Flatulence 2% <1% 1% a Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria

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SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor (bPI) [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC/TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a bPI with FTC/TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history.

The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%.

Less Frequent Adverse Reactions The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir).

Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, StevensJohnson syndrome Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy Reproductive System and Breast Disorders: gynecomastia Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome Hepatobiliary Disorders: acute hepatitis Laboratory Abnormalities Table 2: Laboratory Abnormalities (Grade 2-4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) PREZCOBIX+ FTC/TDF N=363

Grade 2

>1.3 to 1.8 x ULN

4%

14%

Grade 4

≥3.5x ULN

<1%

0

Grade 2

301-500 mg/dL

7%

4%

Grade 3

501-1,000 mg/dL

1%

1%

Grade 4

>1,000 mg/dL

<1%

<1%

Grade 2

240-<300 mg/dL

17%

4%

Grade 3

≥300 mg/dL

2%

1%

Creatinine

Triglycerides

Total Cholesterol

Low-Density Lipoprotein Cholesterol Grade 2

160-189 mg/dL

9%

4%

Grade 3

≥190 mg/dL

5%

1%

Grade 2

126-250 mg/dL

6%

6%

Grade 3

251-500 mg/dL

<1%

0

Elevated Glucose Levels

ALT and/or AST elevations (Grade 2-4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF.

Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA PREZCOBIX+FTC/TDF N=362 N=363 Baseline Week 48 Baseline Week 48 Meana mg/dL Change mg/dL Change N=304c N=290 Nb Total cholesterol 168 +30 164 +11 HDL cholesterol 45 +6 44 +2 LDL cholesterol 100 +19 98 +5 Triglycerides 117 +34 112 +21 Total cholesterol to 4.1 0.2 4.0 0.1 HDL ratio a The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. b N corresponds to the number of subjects with paired values and not on a lipid-lowering agent at screening/baseline. Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/ TDF). Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). c One subject did not have a Week 48 result for LDL cholesterol (n=303).

The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively.

Renal Laboratory Tests In the AMBER trial, which enrolled 725 adults with no prior antiretroviral treatment history, subjects had a median baseline eGFR (estimated glomerular filtration rate) of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/ TDF). From baseline to Week 48, mean (SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) mg/dL in the PREZCOBIX + FTC/TDF group. Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/ dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable.

Median urine protein-to-creatinine ratio (UPCR) was 47 mg/g (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg/g (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48.

In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg/g (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg/g (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48.

Bone Mineral Density AMBER The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with PREZCOBIX + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/ TDF subjects. The long-term clinical significance of these BMD changes is not known.

EMERALD In EMERALD, bPI and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to

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Laboratory Parameter Grade

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Significant Drug Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs. The table includes potentially significant interactions but is not all inclusive.

Table 4: Significant Drug Interactions: Concomitant Drug Class: Drug Name, Clinical Comment Alpha 1-adrenoreceptor antagonist: alfuzosin. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension.

Antibacterials: clarithromycin, erythromycin, telithromycin. Consider alternative antibiotics with concomitant use of SYMTUZA. Anticancer agents: dasatinib, nilotinib. A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions. vinblastine, vincristine. For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when SYMTUZA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

Anticoagulants: Direct Oral Anticoagulants (DOACs). apixaban. Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with SYMTUZA depends on the apixaban dose. Refer to apixaban dosing instructions for co-administration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. rivaroxaban. Co-administration of rivaroxaban with SYMTUZA is not recommended because it may lead to an increased bleeding risk. betrixaban, dabigatran, edoxaban. No dose adjustment is needed when betrixaban, dabigatran, or edoxaban is co-administered with SYMTUZA. Other Anticoagulants: warfarin. Monitor international normalized ratio (INR) upon co-administration of SYMTUZA with warfarin.

Anticonvulsants: carbamazepine, phenobarbital, phenytoin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine. Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If co-administration is necessary, monitor for lack or loss of virologic response.

Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam. Clinical monitoring of anticonvulsants is recommended.

Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., paroxetine, sertraline.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline.

Other antidepressants: trazodone. When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended.

Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole.

Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. Specific dosing recommendations are not available for co-administration with these antifungals. Monitor for increased itraconazole or ketoconazole adverse reactions. voriconazole. Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole.

Anti-gout: colchicine. Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or lifethreatening reactions. For patients without renal or hepatic impairment: • Treatment of gout flares – co-administration of colchicine: 0.6 mg (1 tablet) ×1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.

• Prophylaxis of gout flares – co-administration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

• Treatment of familial Mediterranean fever – co-administration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimalarial: artemether/lumefantrine. Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation.

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−0.6% with bPI + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of bPI + FTC/TDF subjects.

BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of bPI + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

Clinical Trials in Pediatric Patients Adverse Reactions in Pediatric Patients Weighing At Least 40 kg No clinical trials with SYMTUZA were performed in pediatric patients.

However, the safety of the components of SYMTUZA was evaluated in pediatric subjects of 12 to less than 18 years of age through clinical trials GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) for darunavir co-administered with cobicistat and other antiretroviral agents, and GS-US-292-0106 (treatment-naïve, N=50 with weight ≥35 kg) for a fixed-dose combination regimen containing cobicistat, emtricitabine, and tenofovir alafenamide together with elvitegravir. Safety analyses of the trials in these pediatric subjects did not identify new safety concerns compared to the known safety profile of SYMTUZA in adult subjects [see Clinical Studies (14.3) in Full Prescribing Information].

Postmarketing Experience The following additional adverse reactions that may occur in patients taking SYMTUZA have been identified during postmarketing experience in patients receiving a darunavir-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Metabolism and Nutrition Disorders: redistribution of body fat Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors) Skin and Subcutaneous Tissue Disorders: toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions] Renal and Urinary Disorders: acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome [see Warnings and Precautions] DRUG INTERACTIONS Not Recommended With Other Antiretroviral Medications SYMTUZA is a complete regimen for HIV-1 infection and co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drugdrug interactions with other antiretroviral medications is not provided.

Potential for SYMTUZA to Affect Other Drugs Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events. Co-administration of SYMTUZA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 4).

Potential for Other Drugs to Affect SYMTUZA Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4).

Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4).

Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions].

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Antimycobacterials: rifampin. Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. rifabutin. Co-administration of SYMTUZA with rifabutin is not recommended.

If the combination is needed, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis. rifapentine. Co-administration with rifapentine is not recommended.

Antipsychotics: lurasidone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. pimozide. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. other antipsychotics, e.g., perphenazine, risperidone, thioridazine. A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with SYMTUZA. quetiapine. Initiation of SYMTUZA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.

Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking SYMTUZA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. β-Blockers: e.g., carvedilol, metoprolol, timolol. Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized

by CYP2D6.

Calcium channel blockers: e.g., amlodipine, diltiazem, felodipine, nifedipine, verapamil. Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A. Cardiac Disorders: ranolazine, ivabradine. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. dronedarone. Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

Other antiarrhythmics e.g., amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine. Clinical monitoring is recommended upon co-administration with antiarrhythmics. digoxin. When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations.

Corticosteroids: dexamethasone (systemic). Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to SYMTUZA. Consider alternative corticosteroids.

Corticosteroids primarily metabolized by CYP3A: e.g., betamethasone, budesonide, ciclesonide, fluticasone, methylprednisolone, mometasone, triamcinolone. Co-administration with corticosteroids (all routes of administration) of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use.

Endothelin receptor antagonists: bosentan. Initiation of bosentan in patients taking SYMTUZA: In patients who have been receiving SYMTUZA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Initiation of SYMTUZA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of SYMTUZA. After at least 10 days following the initiation of SYMTUZA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Switching from darunavir co-administered with ritonavir to SYMTUZA in patients on bosentan: Maintain bosentan dose.

Ergot derivatives: e.g., dihydroergotamine, ergotamine, methylergonovine.

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir.

Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. glecaprevir/pibrentasvir. Co-administration of SYTMUZA with glecaprevir/ pibrentasvir is not recommended.

Herbal product: St. John’s wort (Hypericum perforatum). Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance.

Hormonal contraceptives: Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen based contraceptives are co-administered with SYMTUZA.

drosperinone/ethinylestradiol. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. other progestin/estrogen, contraceptives. No data are available to make recommendations on co-administration with oral or other hormonal contraceptives.

Immunosuppressants: cyclosporine, sirolimus, tacrolimus. These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended with concomitant use.

Immunosuppressant/neoplastic: everolimus. Co-administration of everolimus and SYMTUZA is not recommended. irinotecan. Discontinue SYMTUZA at least 1 week prior to starting irinotecan therapy. Do not administer SYMTUZA with irinotecan unless there are no therapeutic alternatives.

Inhaled beta agonist: salmeterol. Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

Lipid modifying agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin. Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. e.g., atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin. For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety.

Dosage recommendations with atorvastatin or rosuvastatin are as follows: • atorvastatin dosage should not exceed 20 mg/day • rosuvastatin dosage should not exceed 20 mg/day Other lipid modifying agents: lomitapide. Co-administration is contraindicated due to potential for markedly increased transaminases associated with increased plasma concentrations of lomitapide.

Narcotic analgesics metabolized by CYP3A: e.g., fentanyl, oxycodone.

Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. tramadol. A dose decrease may be needed for tramadol with concomitant use.

Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/naloxone, methadone. Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking SYMTUZA: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose.

Initiation of SYMTUZA in patients taking buprenorphine, buprenorphine/ naloxone, or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone, or methadone may be needed. Monitor clinical signs and symptoms.

Opioid Antagonist: naloxegol. Co-administration of SYMTUZA and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms.

Phosphodiesterase PDE-5 inhibitors: e.g., avanafil, sildenafil, tadalafil, vardenafil. Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established.

Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances, and priapism.

Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with SYMTUZA: • Initiation of tadalafil in patients taking SYMTUZA: In patients receiving SYMTUZA for at least one week, start tadalafil at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

• Initiation of SYMTUZA in patients taking tadalafil: Avoid use of tadalafil during the initiation of SYMTUZA. Stop tadalafil at least 24 hours prior to starting SYMTUZA. After at least one week following the initiation of SYMTUZA, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

• Patients switching from darunavir co-administered with ritonavir to SYMTUZA: Maintain tadalafil dose.

Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitorassociated adverse reactions.

Platelet aggregation inhibitor: ticagrelor. Co-administration of SYMTUZA and ticagrelor is not recommended. clopidogrel. Co-administration of SYMTUZA and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel.

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prasugrel. No dose adjustment is needed when prasugrel is co-administered with SYMTUZA. Sedatives/hypnotics: orally administered midazolam, triazolam.

Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. metabolized by CYP3A: e.g., buspirone, diazepam, estazolam, zolpidem.

With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions. parenterally administered midazolam. Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered.

Urinary antispasmodics: fesoterodine. When fesoterodine is co-administered with SYMTUZA, do not exceed a fesoterodine dose of 4 mg once daily. solifenacin. When solifenacin is co-administered with SYMTUZA, do not exceed a solifenacin dose of 5 mg once daily.

This table is not all inclusive

One out of 6 pregnant individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period.

There are no clinical data on the virologic response when darunavir and cobicistat are initiated during pregnancy.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of SYMTUZA are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

Darunavir: Based on prospective reports to the APR of over 960 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 640 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.7% (95% CI: 2.4% to 5.5%) with first trimester exposure to darunavir containing-regimens and 2.5% (95% CI: 1.1% to 4.9%) with second/third trimester exposure to darunavir-containing regimens.

Cobicistat: Based on prospective reports to the APR of over 560 exposures to cobicistat-containing regimens during pregnancy resulting in live births (including over 470 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.1% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester, respectively, to cobicistat-containing regimens.

Emtricitabine: Based on prospective reports to the APR of over 5400 exposures to emtricitabine-containing regimens during pregnancy resulting in live births (including over 3900 exposed in the first trimester and over 1500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) with first trimester exposure to emtricitabine-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) with the second/third trimester exposure to emtricitabinecontaining regimens.

Tenofovir alafenamide (TAF): Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) with first and second/third trimester exposure, respectively, to TAF-containing regimens.

Animal Data Darunavir: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (2.6-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended daily dose of darunavir in SYMTUZA. Cobicistat: Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6-17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.7 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7-20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 4.1 times higher than human exposures at the recommended daily dose of cobicistat in SYMTUZA. In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.1 times the human exposures at the recommended daily dose of cobicistat in SYMTUZA. Emtricitabine: Emtricitabine was administered orally to pregnant mice and rabbits (up to 1000 mg/kg/day) through organogenesis (on GD 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 88 times higher and in rabbits approximately 7.3 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA. In a pre/postnatal development study, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures of approximately 88 times higher than human exposures at the recommended daily dose of emtricitabine in SYMTUZA.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to SYMTUZA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.5)]. A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period (see Data) and [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir, cobicistat, emtricitabine, or tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, no adverse developmental effects were observed when the components of SYMTUZA were administered separately at darunavir exposures less than 1- (mice and rabbits) and 2.6-times (rats) higher, at cobicistat exposures 1.7- and 4.1-times higher (rats and rabbits respectively) at emtricitabine exposures 88- and 7.3- times higher (mice and rabbits, respectively), and tenofovir alafenamide exposures equal to or 85- times higher (rats and rabbits, respectively) than human exposures at the recommended daily dose of these components in SYMTUZA (see Data). No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.1 times the human exposure at the recommended therapeutic dose.

Clinical Considerations Not Recommended During Pregnancy SYMTUZA is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy (see Data) and [see Clinical Pharmacology (12.3) in Full Prescribing Information].

SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with SYMTUZA. Data Human Data Darunavir and cobicistat in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking darunavir and cobicistat prior to enrollment and who were willing to remain on darunavir and cobicistat throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial.

Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum [see Clinical Pharmacology (12.3) in Full Prescribing Information].

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SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

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SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

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SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

SYMTUZA® (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets

Tenofovir Alafenamide (TAF): TAF was administered orally to pregnant rats (up to 250 mg/kg/day) and rabbits (up to 100 mg/kg/day) through organogenesis (on GD 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures approximately similar to (rats) and 85 times higher (rabbits) than the exposure in humans at the recommended daily dose. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 51 (rats) and 80 (rabbits) times higher than human tenofovir exposures at the recommended daily dose of TAF in SYMTUZA. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF (another prodrug of tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on GD 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposure in humans at the recommended daily dose of TDF. Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIVinfected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Based on published data, emtricitabine has been shown to be present in human breast milk. There are no data on the presence of darunavir, cobicistat, or TAF in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir and cobicistat are present in the milk of lactating rats. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data).

Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving SYMTUZA. Data Animal Data Darunavir: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is excreted in milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 66% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir.

Cobicistat: During the pre/postnatal developmental toxicology study, at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.

Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is excreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating rhesus monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.

Pediatric Use The safety and effectiveness of SYMTUZA for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg was established through studies with components of SYMTUZA. Use of SYMTUZA in this group is supported by evidence from adequate and well-controlled studies of SYMTUZA in adults with additional pharmacokinetic, safety, and virologic data from studies of components of SYMTUZA (Trials GS-US-216-0128 and GS-US-292-0106) in pediatric subjects with HIV-1 infection aged 12 to less than 18 years [see Adverse Reactions, Clinical Pharmacology (12.3), and Clinical Studies (14.3) in Full Prescribing Information].

The safety and effectiveness of SYMTUZA have not been established in pediatric patients weighing less than 40 kg.

Darunavir, a component of SYMTUZA is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.

Juvenile Animal Toxicity Data Darunavir: In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on postnatal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.

Geriatric Use Clinical trials of SYMTUZA included 35 subjects aged above 65 years of which 26 received SYMTUZA. No differences in safety or efficacy have been observed between elderly subjects and those aged 65 years or less. In general, caution should be exercised in the administration and monitoring of SYMTUZA in elderly patients, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Renal Impairment SYMTUZA is not recommended in patients with severe renal impairment (creatinine clearance below 30 mL per minute). No dosage adjustment of SYMTUZA is required in patients with creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Cobicistat has been shown to decrease creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosage adjustment for renal impairment when used in combination with SYMTUZA [see Warnings and Precautions].

Hepatic Impairment No dosage adjustment of SYMTUZA is required in patients with mild (ChildPugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

SYMTUZA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and there are only limited data regarding the use of SYMTUZA components in this population. Therefore, SYMTUZA is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

OVERDOSAGE Human experience of acute overdose with SYMTUZA is limited. There is no specific antidote for overdose with SYMTUZA. Treatment of overdose with SYMTUZA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Manufactured by: Patheon Inc 2100 Syntex Ct Mississauga ON L5N 7K9, Canada Or Janssen Cilag SpA Latina, IT Manufactured for: Janssen Therapeutics, Division of Janssen Products, LP, Titusville NJ 08560 © 2020 Janssen Pharmaceutical Companies cp-62058v8

PREOCUPACIONES, USO DE ATENCIÓN MÉDICA E INTERRUPCIONES DE TRATAMIENTO en pacientes con enfermedades reumáticas autoinmunes comunes durante la pandemia de COVID-19 M.D. George, MD MSCE, Assistant Professor, University of Pennsylvania S. Venkatachalam, PhD MPH, Global Healthy Living Foundation S. Banerjee, MD, Assistant Professor, University of Pennsylvania J.F. Baker, MD MSCE, Assistant Professor, University of Pennsylvania P.A. Merkel, MD PMH, Professor, University of Pennsylvania K. Gavigan, MPH, Global Healthy Living Foundation D. Curtis, BA, Global Healthy Living Foundation M.I. Danila, MD MSc MSPH, Associate Professor, University of Alabama at Birmingham J. R. Curtis, MD MS MPH, Professor, University of Alabama at Birmingham W. B. Nowell, PhD MSW, Global Healthy Living Foundation

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RESUMEN Objetivo: Evaluar las preocupaciones y comportamientos relacionados con la atención de la salud de pacientes con enfermedades reumáticas autoinmunes durante la pandemia de COVID-19.

Métodos: Adultos de los Estados Unidos con artritis reumatoide (AR), artritis psoriásica (PsA), espondilitis anquilosante (AS) y lupus eritematoso sistémico (LES) de la red de investigación impulsada por pacientes de ArthritisPower y la comunidad de pacientes de CreakyJoints completaron encuestas. Se compararon las preocupaciones y los comportamientos entre pacientes con diferentes afecciones autoinmunes, uso de fármacos antirreumáticos modificadores de la enfermedad (DMARD) y medidas geo-

gráficas de estado urbano, ingresos, educación y actividad de COVID-19.

Resultados: Entre 1.517 participantes (925 RA, 299 PsA, 185 AS, 108 SLE), la edad media fue de 55,1 años, el 88,3 % eran mujeres y el 89,5 % blancos. Las preocupaciones por el COVID-19 fueron similares en todo el país y fueron más altas en los usuarios de productos biológicos (p < 0,001).

Evitar las visitas al consultorio médico (56,6 %) o las pruebas de laboratorio (42,3 %) y el uso de la telesalud (29,5 %) fueron más comunes en las áreas urbanas. Entre los participantes en DMARD sin COVID-19 u otra enfermedad respiratoria, el 14,9 % suspendió un DMARD, y el 78,7 % de las interrupciones de DMARD no fueron recomendadas por un médico. La suspensión de DMARD fue

más común en participantes con un nivel socioeconómico más bajo y en participantes que evitaron una visita al consultorio [OR 1.46 (1.04-2.04)] o informaron falta de disponibilidad de telesalud [OR 2.26 (1.25-4.08)].

Conclusión: en los primeros meses de la pandemia de COVID-19, los pacientes con AR, PsA, AS y SLE evitaban con frecuencia las visitas al consultorio y las pruebas de laboratorio. Las interrupciones de DMARD comúnmente ocurrieron sin el consejo de un médico y se asociaron con el nivel socioeconómico, las visitas al consultorio y la disponibilidad de telesalud, lo que destaca la necesidad de un acceso adecuado a la atención médica y atención a las poblaciones vulnerables durante la pandemia.

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ABSTRACT Objective: To assess concerns and healthcare-related behaviors of patients with autoimmune rheumatic diseases during the COVID-19 pandemic.

Methods: Adults from the United States with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE) from the ArthritisPower Patient-Powered Research Network and CreakyJoints patient community completed surveys. Concerns and behaviors were compared among patients with different autoimmune conditions, disease-modifying anti-rheumatic drug (DMARD) use, and geographic measures of urban status, income, education, and COVID-19 activity.

Results: Among 1,517 participants (925 RA, 299 PsA, 185 AS, 108 SLE), mean age was 55.1 years, 88.3% were female, and 89.5% white. COVID-19 concerns were similar across the country and were higher in biologic users (p < 0.001). Avoidance of doctor’s office visits (56.6%) or laboratory testing (42.3%) and use of telehealth (29.5%) were more common in urban areas.

Among participants on DMARDs without COVID-19 or other respiratory illness, 14.9% stopped a DMARD, with 78.7% of DMARD interruptions not recommended by a physician. DMARD stopping was more common participants with lower socioeconomic status and in participants who avoided an office visit [OR 1.46(1.04-2.04)] or reported lack of telehealth availability [OR 2.26(1.25-4.08)].

Conclusion: In the early months of the COVID-19 pandemic, patients with RA, PsA, AS, and SLE frequently avoided office visits and laboratory testing.

DMARD interruptions commonly occurred without the advice of a physician and were associated with socioeconomic status, office visits, and telehealth availability, highlighting the need for adequate healthcare access and attention to vulnerable populations during the pandemic.

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Figure 1: Location of participants and concerns about COVID-19. Number of participants by state/territory are shown. Colors represent median participant concern about COVID-19 in each state on a 5-point Likert scale, excluding states with <5 participants.

INTRODUCTION COVID-19, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)(1,2) may be of particular concern to patients with autoimmune rheumatic diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE). These patients are at increased risk of infections, with immunosuppression and common comorbidities further affecting infection risk.(3)(3,4) To better understand how the COVID-19 pandemic has affected these patients, the ArthritisPower Patient-Powered Research Network (PPRN) registry (www.ArthritisPower.org)(5) launched a study to capture patient experiences during the pandemic across the United States, hypothesizing that patients with autoimmune diseases would have high levels of concerns about COVID-19 and frequent disruptions in office visits, routine monitoring, and disease modifying anti-rheumatic drug (DMARD) use which would vary geographically.

METHODS Study population Adults >18 years-old in the ArthritisPower PPRN or CreakyJoints patient community were sent email invitations. The ArthritisPower PPRN(5,6) is a patient-led online registry of patients with inflammatory arthritis and other rheumatic conditions created as a joint venture of the patients and

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patient advocates of the Global Healthy Living Foundation, the CreakyJoints patient community, and researchers at the University of Alabama at Birmingham. Participants of partnering patient organizations were directed to a landing page (www. rheumcovid.com). Results are presented for surveys completed March 29-May 26, 2020 from participants in the United States with diagnoses of RA, PsA, SpA, or SLE. Participants provided consent and the protocol was approved by the Advarra Institutional Review Board (Protocol 00042873).

DATA COLLECTION Participants reported demographics, zip code, comorbidities, rheumatic conditions, and use of DMARDs. For participants indicating multiple autoimmune conditions, a hierarchical approach was taken (SLE > PsA > AS > RA) similar to previous studies.

(7) Participants were asked about their concerns about COVID-19 (5-point Likert scale), respiratory illnesses within the previous 2 weeks, COVID-19 testing/diagnoses, avoidance of office visits or laboratory/ diagnostic testing, use and availability of telehealth (“telephone or telehealth visit”) , and DMARD interruptions.

GEOGRAPHIC DATA County rural versus urban status was defined using National Center for Health

Statistics classification.(8) Tertiles of COVID-19 activity in the patient’s county relative to all other counties in the United States on the survey date were defined using the cumulative cases per capita on that date, weighting counties by population.(9) Zip-code-based median household income and education from the American Community Survey 2014-2018 5-year estimates were also divided into tertiles.(10) STATISTICAL ANALYSIS Median scores for concerns about COVID-19 were graphed among states/territories with ≥5 respondents. Kruskal-Wallis tests assessed for differences in concerns by geography (9 census divisions), autoimmune disease, biologic/Janus kinase inhibitor (JAKi) use, urban versus rural geography, and by tertiles of zip-code based median household income, education, and county-based COVID-19 cases per capita.

The proportions of participants who had avoided an office visit, avoided testing, had a telehealth visit, or who stopped medications were compared in the same subgroups of interest using univariate logistic regression to assess for statistical differences. DMARD stopping was assessed among participants reporting DMARD use, primarily evaluating patients without a respiratory illness or COVID-19 diagnosis to avoid participants who stopped DMARDs because of illness.

RESULTS Invitation emails were opened by 14,001 individuals, with 2,895 clicking to access the study and 1,935 completing the baseline survey as of May 26th.

Excluding 20 participants outside the United States and 398 without an autoimmune condition of interest left 1,517 participants representing all 50 states and Puerto Rico (Figure 1). Mean age was 55.1, 88.3% of participants were female, and 89.5% were white (Table 1).

A physician diagnosis of COVID-19 was reported by 11 participants (0.7%), with 243 (13.9%) reporting a respiratory illness without a diagnosis of COVID-19.

23.8% of participants who were not ill and 47.9% of participants reporting a respiratory illness wanted to be tested but were not. The most common barriers to testing were that the test was not available (43.0%) or not offered/recommended (36.8%) (Supplemental Table 1).

CONCERNS ABOUT COVID-19 Overall 698 (46.0%) participants were “extremely” and 515 (34.0%) “moderately” concerned about COVID-19, and 803 (52.9%) and 414 (27.3%) noted that their autoimmune disease “extremely” or “moderately” affected their concerns about COVID-19, respectively (Supplemental Figure 1). Levels of concern were high across the United States (Figure 1, Supplemental Figure 2), with no significant difference by geography, urban versus rural, median household income, or education level. Concerns were higher in participants receiving biologics/JAKi (p < 0.01, Supplemental Figure 1).

Participants receiving a biologic/JAKi, those in urban or higher COVID-19 activity counties, and participants with greater COVID-19 concerns were more likely to avoid office visits or testing (Table 2, Supplemental Table 2).

Telehealth visits were reported by 448 (29.5%) participants, more commonly by participants in urban locations (30.8% versus 22.4%, p=0.02) and in areas of higher COVID-19 activity (Table 2). Overall 951 (62.7%) participants reported that their doctor’s office offered telehealth, 474 (31.2%) did not know, and 92 (6.1%) reported that telehealth was not available.

IMPACTS ON HEALTHCARE Avoidance of doctor’s office visits, laboratory testing, and other testing was reported by 56.6%, 42.3%, and 36.0% of participants, respectively, with higher rates in participants with SLE (all p<0.05).

DMARD INTERRUPTIONS Among participants treated with DMARDs who did not report a respiratory illness or COVID-19 diagnosis, 169/1132 (14.9%) stopped a DMARD. More frequent stopping was associated with bioRevista Puertorriqueña de Medicina y Salud Pública

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COVID-19 (Supplemental Table 5). Healthcare providers were more commonly a source of information among participants reporting a telehealth visit (63.4% vs.

34.9%, p < 0.001).

logic/JAKi use, lower education, lower or higher median household income, and greater COVID-19 concerns (Table 2, Supplemental Table 2). Only 21.3% of these DMARD interruptions were recommended by a physician (Supplemental Table 3). Participants who avoided an office visit were more likely stop DMARDs [106/622(17.0%) versus 63/510(12.4%), OR 1.46(1.04-2.04), p=0.03)]. Telehealth use was not associated with stopping DMARDs [OR 1.04(0.72-1.49)], but DMARD stopping was more common among participants who reported that telehealth was not available [17/67(25.4%)] versus those reporting 62

telehealth availability [91/695(13.1%)], OR 2.26(1.25-4.08), p<0.01], with even stronger associations among patients who avoided office visits [OR 3.01(1.436.34), p<0.01, Supplemental Table 4].

DMARD interruptions were reported by 48/172 (27.9%) and 7/11 (63.6%) patients reporting respiratory illness or COVID-19 diagnosis, respectively; 56.4% of these interruptions were recommended by a physician (Supplemental Table 3).

SOURCES OF INFORMATION The news media (84.4%) and government websites (67.4%) were the most common sources for information about

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DISCUSSION This study of patients with common autoimmune rheumatic diseases across the United States during the early months of the COVID-19 pandemic found that participants had high levels of concern about COVID-19 and frequently avoided office visits and testing.

Of particular concern, approximately 15% had stopped one of their DMARDs, especially patients who avoided office visits and did not have telehealth available.

Most medication interruptions in patients without illnesses occurred without a physician recommendation, similar to previous findings.

(11) Although there are limited data on how immunosuppression affects the risk of severe COVID-19(12–14), medication interruptions can risk disease flares and glucocorticoid increases, both associated with infection risk.(15) The American College of Rheumatology recommends continuing DMARDs unless patients are exposed or infected,(16) but these recommendations may not reach or be accepted by patients. In this study, participants most frequently had obtained information about COVID-19 from news sources or government websites, which may not include information specific to patients with autoimmune disease.

Participants who had avoided office visits or who reported that telehealth was not available were the most likely to have stopped DMARDs. Higher rates of stopping DMARDs among participants with lower socioeconomic status are concerning and require further investigation.

Participants in urban areas more frequently avoided office visits or testing for their autoimmune condition, and these areas were also the areas with the most telehealth use. These observations could be due to increased concerns or restrictions around clinic office visits, greater availability of or access to healthcare providers, or greater availability of telehealth technology/infrastructure in these areas. Although socioeconomic status was not associated with telehealth use, participants tended to be of higher socioeconomic status and might be more likely to be telehealth users; continued assessment of inequities in access to care and the optimal use of telehealth are important as the pandemic continues.(17) Several limitations are important to note.

Patients who are members of online communities or networks and survey respondents may have different concerns and behaviors than the general population.

Respondents were primarily white, and results may differ in racial/ethnic minority populations. Participants self-reported autoimmune and COVID-19 diagnoses, although were specifically asked about physician diagnoses. We could not evaluate whether medication interruptions contributed to disease flares.

In conclusion, participants with autoimmune rheumatic disease across the United States were highly concerned about COVID-19 and frequently avoided office visits or tests. Participants often stopped medications without the advice of a physician, especially those who had missed office visits and did not have telehealth access. Physicians should ask patients about medication concerns and interruptions, proactively contact patients who have missed visits, and ensure patients are aware of available options for accessing care. Continued assessment of disruptions in care, with a particular focus on vulnerable populations, is of critical importance as the pandemic continues.

ACKNOWLEDGEMENTS We would like to recognize the partnering patient organizations that are disseminating this survey including Lupus Allied Disease Association (LADA), International Foundation for Autoimmune & Autoinflammatory Arthritis (IFAA), American Bone Health, and Myositis Support and Understanding, Jennifer Walker and Kristine Carandang for reviewing and

editing the survey, and the patients who have contributed and continue to participate in this ongoing project.

REFERENCES 1. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature Nature Publishing Group; 2020;579:270-3.

2. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention.

JAMA 2020; 3. Listing J, Gerhold K, Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatol Oxf Engl 2013;52:53-61.

4. Ogdie A, Maliha S, Shin D, Love TJ, Baker J, Jiang Y, et al. Cause-specific mortality in patients with psoriatic arthritis and rheumatoid arthritis. Rheumatol Oxf Engl 2017;56:907-11.

5. Patient-Centered Outcomes Research Institute. ArthritisPower (ARthritis Partnership with Comparative Effectiveness Researchers). Available at: https://www. pcori.org/research-results/2015/arthritispower-arthritis-partnership-comparative-effectiveness-researchers. Accessed May 28, 2020.

6. Nowell WB, Curtis D, Thai M, Wiedmeyer C, Gavigan K, Venkatachalam S, et al. Digital Interventions to Build a Patient Registry for Rheumatology Research. Rheum Dis Clin North Am 2019;45:173-86.

7. Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, et al. Risk of Major Cardiovascular Events in Patients with Psoriatic Arthritis, Psoriasis and Rheumatoid Arthritis: A population-based cohort study. Ann Rheum Dis 2015;74:326-32.

8. National Center for Health Statistics.

Urban Rural Classification Scheme for Counties. 2019. Available at: https:// www.cdc.gov/nchs/data_access/urban_ rural.htm. Accessed May 26, 2020.

9. USAFacts. US Coronavirus Cases by County. Available at: https://usafacts.org/visualizations/coronavirus-covid-19-spread-map/. Accessed May 26, 2020.

10. U.S. Census Bureau. American Community Survey 2014-2018 5-Year Estimates. Accessed through Social Explorer 2020 New York City, NY. Available at:

Accessed through http://www.socialexplorer.com/pub/ reportdata/HtmlResults.aspx?reportid=R12543316. Accessed May 5, 2020.

11. Michaud K, Wipfler K, Shaw Y, Simon TA, Cornish A, England BR, et al.

Experiences of Patients With Rheumatic Diseases in the United States During Early Days of the COVID-19 Pandemic. ACR Open Rheumatol 2020; 12. Haberman R, Axelrad J, Chen A, Castillo R, Yan D, Izmirly P, et al. Covid-19 in Immune-Mediated Inflammatory Diseases - Case Series from New York. N Engl J Med 2020; 13. Favalli EG, Ingegnoli F, De Lucia O, Cincinelli G, Cimaz R, Caporali R. COVID-19 infection and rheumatoid arthritis: Faraway, so close! Autoimmun Rev 2020;19:102523.

14. Gianfrancesco M, Hyrich KL, AlAdely S, Carmona L, Danila MI, Gossec L, et al. Characteristics associated with hospitalization for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 2020;79:859-66.

15. Au K, Reed G, Curtis JR, Kremer JM, Greenberg JD, Strand V, et al. High disease activity is associated with an increased risk of infection in patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:785-91.

16. Mikuls TR, Johnson SR, Fraenkel L, Arasaratnam RJ, Baden LR, Bermas BL, et al. American College of Rheumatology Guidance for the Management of Adult Patients with Rheumatic Disease During the COVID-19 Pandemic. Arthritis Rheumatol Hoboken NJ 2020; 17. Feldman CH, Ramsey-Goldman R. Widening Disparities Among Patients With Rheumatic Diseases in the COVID-19 Era: An Urgent Call to Action. Arthritis Rheumatol 2020;72:1409-11.

Sources of support: MG is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health (K23 AR073931-01). “The Arthritis and Rheumatic Disease COVID-19 Project” has received sponsorship support specifically from the Patient-Centered Outcomes Institute (PCORI), Eli Lilly and Company, and Janssen Pharmaceutical.

Revista Puertorriqueña de Medicina y Salud Pública

63

For moderate to severe rheumatoid arthritis (RA) in adult TNFi-IR patients1

EXPECTATIONS CHALLENGE TREATMENT GOALS IN RA WITH A ONCE-DAILY ORAL JAK INHIBITOR

RINVOQ met primary (ACR20 or ACR50 at Week 12 or 14) and ranked secondary endpoints in clinical trials, with some patients achieving ACR20 as early as Week 1 in SELECT-BEYOND1-3,a,b LONG-TERM REMISSION AND LOW DISEASE ACTIVITY DATA observed up to 84 weeks with or without MTX1,3-6 • DAS28-CRP<2.6* and DAS28-CRP≤3.2 evaluated at Week 12 or 14, with response rates from 60 to 84 weeks (in SELECT-BEYOND and SELECT-MONOTHERAPY, respectively) *Clinical remission does not mean drug-free remission or complete absence of disease activity.

LONG-TERM SAFETY DATA AEs observed in long-term analysis with ~4.5 years maximum and ~2.6 years median exposure to RINVOQ 15 mg as of 6/30/207,a,b • >4400 patients evaluated on upadacitinib,c with >7000 patientyears of long-term exposure to RINVOQ 15 mg as of 6/30/207,a,b

Discover our commitment to exceptional access and patient support at RinvoqHCPPR.com a SELECT-EARLY (RA-I; MTX-naïve) [primary endpoint at Week 12: ACR50 response vs MTX, select ranked secondary endpoint at Week 24: ΔmTSS vs MTX]; SELECT-MONOTHERAPY (RA-II; MTX-IR) [primary endpoint at Week 14: ACR20 response vs MTX, select ranked secondary endpoints at Week 14: DAS28-CRP<2.6 vs MTX, DAS28-CRP≤3.2 vs MTX]; SELECT-NEXT (RA-III; csDMARD-IR) [RINVOQ + csDMARD; primary endpoint at Week 12: ACR20 response vs placebo + csDMARD]; SELECT-COMPARE (RA-IV; MTX-IR) [RINVOQ + MTX; primary endpoint at Week 12: ACR20 response vs placebo + MTX, select ranked secondary endpoints at Week 26: ΔmTSS vs placebo + MTX]; SELECT-BEYOND (RA-V; bDMARD-IR) [RINVOQ + csDMARD; primary endpoint at Week 12: ACR20 response vs placebo + csDMARD, select ranked secondary endpoints at Week 12: DAS28-CRP≤3.2 vs placebo + csDMARD.] 1,2 bSELECT-CHOICE (bDMARD-IR) [RINVOQ + csDMARDs; primary endpoint at Week 12: ΔDAS28-CRP (noninferiority) vs active comparator + csDMARDs]. 8 c RINVOQ 15 mg; upadacitinib 30 mg; RINVOQ 15 mg is the approved dose.1,7

INDICATION1 RINVOQ is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

Limitation of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

Malignancies: Lymphoma and other malignancies have been observed in RINVOQ-treated patients. A higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]), lymphomas, and lung cancer (in current or past smokers) was observed with another JAK inhibitor when compared with TNF blockers in RA patients. Patients who are current or past smokers are at additional increased risk.

SAFETY CONSIDERATIONS1

Major Adverse Cardiovascular Events: A higher rate of CV death, myocardial infarction, and stroke was observed with a JAK inhibitor in a study comparing another JAK inhibitor with TNF blockers in RA patients ≥50 years of age with at least one CV risk factor. Current or past smokers are at additional increased risk.

Serious Infections: Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to opportunistic pathogens.

Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Thrombosis: Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions. A higher rate of thrombosis was observed with another JAK inhibitor when compared with TNF blockers in RA patients.

Mortality: A higher rate of all-cause mortality, including sudden cardiovascular (CV) death, was observed with a Janus kinase (JAK) inhibitor in a study comparing another JAK inhibitor with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years of age with at least one CV risk factor.

Hypersensitivity: RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients.

Other Serious Adverse Reactions: Hypersensitivity Reactions (anaphylaxis and angioedema), Gastrointestinal Perforations, Laboratory Abnormalities (neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations), and Embryo-Fetal Toxicity.

Please see additional Important Safety Information, including BOXED WARNING on Serious Infections, Mortality, Malignancies, Major Adverse Cardiovascular Events, and Thrombosis, on the previous page of this advertisement.

Please see Brief Summary of full Prescribing Information on previous pages of this advertisement.

ACR=American College of Rheumatology; AEs=adverse events; bDMARD=biologic DMARD; csDMARD=conventional synthetic DMARD; DAS28-CRP=Disease Activity Score 28 joints, C-reactive protein; DMARD=disease-modifying antirheumatic drug; HAQ-DI=Health Assessment Questionnaire Disability Index; IR=intolerance or inadequate response; JAK=Janus kinase; mTSS=modified total Sharp score; MTX=methotrexate; TNFi=tumor necrosis factor inhibitor.

1 1 1 IMPORTANT IMPORTANT IMPORTANT SAFETY SAFETY SAFETY INFORMATION INFORMATION INFORMATION SERIOUS SERIOUS INFECTIONS SERIOUS INFECTIONS INFECTIONS GASTROINTESTINAL GASTROINTESTINAL GASTROINTESTINAL PERFORATIONS PERFORATIONS PERFORATIONS Patients Patients treated Patients treated with treated with RINVOQ RINVOQ with are RINVOQ at are increased at increased are atrisk increased for riskdeveloping forrisk developing for developing serious seriousserious Gastrointestinal Gastrointestinal Gastrointestinal (GI) perforations (GI) perforations (GI) perforations havehave beenbeen reported havereported been in reported clinical in clinical trials in clinical trials with with RINVOQ. trials RINVOQ. with RINVOQ. infections infections that infections that may may lead that lead tomay hospitalization tolead hospitalization to hospitalization or death. or death.

Most or death.

Most patients patients Most who patients who developed developed who developed Monitor Monitor RINVOQ-treated Monitor RINVOQ-treated RINVOQ-treated patients patients who patients who may may bewho atbe risk may atfor risk begastrointestinal for at risk gastrointestinal for gastrointestinal perforation perforation perforation these these infections infections thesewere infections were taking taking were concomitant taking concomitant concomitant immunosuppressants, immunosuppressants, immunosuppressants, suchsuch as assuch as (e.g.,(e.g., patients patients (e.g., with patients with a history a history with of adiverticulitis history of diverticulitis of diverticulitis or taking or taking NSAIDs). or NSAIDs). taking Promptly NSAIDs).

Promptly evaluate Promptly evaluate evaluate methotrexate methotrexate methotrexate or corticosteroids. or corticosteroids. or corticosteroids.

If a serious If a serious If infection a serious infection develops, infection develops, interrupt develops, interrupt RINVOQ interrupt RINVOQ RINVOQ patients patients presenting patients presenting with presenting with new new onset with onset abdominal newabdominal onset pain abdominal pain for early forpain early identification foridentification early identification of GIof GI of GI untiluntil the infection the until infection the isinfection controlled. is controlled. is controlled. perforation. perforation. perforation.

Reported Reported infections Reported infections include: infections include: include: LABORATORY LABORATORY LABORATORY ABNORMALITIES ABNORMALITIES ABNORMALITIES • Active • Active tuberculosis • Active tuberculosis tuberculosis (TB),(TB), which which (TB), may may which present present may with present with pulmonary pulmonary with pulmonary or extrapulmonary or extrapulmonary or extrapulmonary Neutropenia Neutropenia Neutropenia disease. disease.

Test disease.

Test patients patients Test forpatients latent for latent TB for before TB latent before RINVOQ TB before RINVOQ use RINVOQ and use during and use during and therapy. during therapy. therapy. Treatment Treatment with Treatment with RINVOQ RINVOQ with was RINVOQ associated was associated was with associated with an increased anwith increased anincidence increased incidence ofincidence neutropenia of neutropenia of neutropenia 3 3 3 ). cells/mm Treatment ). Treatment ).with Treatment with RINVOQ RINVOQ with is not RINVOQ is not is not Consider Consider treatment Consider treatment for treatment latent for latent TB for infection TB latent infection TB prior infection prior to RINVOQ toprior RINVOQ to use.

RINVOQ use. use. (absolute (absolute neutrophil (absolute neutrophil count neutrophil count [ANC] [ANC] count <1000 <1000 [ANC] cells/mm <1000 cells/mm 3 3 3 recommended recommended in patients in patients with in patients with an ANC anwith ANC <1000 an <1000 ANC cells/mm <1000 cells/mm . Evaluate cells/mm . Evaluate neutrophil . Evaluate neutrophil counts neutrophil counts at counts at at • Invasive • Invasive fungal • Invasive fungal infections, fungal infections, infections, including including cryptococcosis including cryptococcosis cryptococcosis and pneumocystosis. and pneumocystosis. and pneumocystosis. recommended baseline baseline and baseline thereafter and thereafter andaccording thereafter according to according routine to routine patient to routine patient management. patient management. management.

• Bacterial, • Bacterial, •viral, Bacterial, viral, including including viral,herpes including herpes zoster, herpes zoster, andzoster, other and other infections andinfections otherdue infections to due opportunistic to due opportunistic to opportunistic pathogens. pathogens. pathogens.

Lymphopenia Lymphopenia Lymphopenia

Absolute lymphocyte Absolute lymphocyte lymphocyte counts counts (ALC) counts (ALC) <500<500 (ALC) cells/mm cells/mm <500were cells/mm were reported reported were inreported RINVOQin RINVOQin RINVOQCarefully Carefully consider Carefully consider the consider risks the risks and the benefits and risks benefits and of benefits treatment of treatment ofwith treatment with RINVOQ RINVOQ with prior RINVOQ prior to toprior to Absolute treated treated patients. treated patients.

Treatment patients.

Treatment with Treatment with RINVOQ RINVOQ with is not RINVOQ is recommended not recommended is not recommended in patients in patients in with patients with with initiating initiating therapy initiating therapy in patients therapy in patients in with patients with chronic chronic with or recurrent chronic or recurrent orinfection. recurrent infection.

Monitor infection.

Monitor patients Monitor patients patients 3 3 3 an ALC an ALC <500 an <500 cells/mm ALCcells/mm <500 . Evaluate cells/mm . Evaluate at . Evaluate baseline at baseline at and baseline thereafter and thereafter and according thereafter according to according routine to routine to routine closely closely for the closely fordevelopment thefor development the development of signs of signs and ofsymptoms and signs symptoms and of symptoms infection of infection of during infection during and during after and after and after patient management. patient management. management. treatment treatment with treatment with RINVOQ, RINVOQ, with including RINVOQ, including the including possible the possible the development possible development development of TBofinTB patients inofpatients TB in who patients who patient who Anemia Anemia Anemia tested tested negative tested negative for negative latent for latent TB for infection TB latent infection TB prior infection prior to initiating toprior initiating to therapy. initiating therapy. therapy.

Decreases Decreases in Decreases hemoglobin in hemoglobin in hemoglobin levels levels to <8to levels g/dL <8 g/dL were to <8 were reported g/dLreported were in reported RINVOQ-treated in RINVOQ-treated in RINVOQ-treated MORTALITY MORTALITY MORTALITY patients. patients.

Treatment patients.

Treatment should Treatment should not be should notinitiated be not initiated be or should initiated or should be orinterrupted should be interrupted be interrupted in patients in patients with in patients with with In a large, In a large, randomized, In arandomized, large, randomized, postmarketing postmarketing postmarketing safety safety study safety study comparing comparing study comparing another another Janus another Janus Janushemoglobin hemoglobin hemoglobin levels levels <8 g/dL. <8 levels g/dL. Evaluate <8Evaluate g/dL. at Evaluate baseline at baseline and at baseline thereafter and thereafter andaccording thereafter according to according routine to routine to routine kinase kinase (JAK) kinase (JAK) inhibitor inhibitor (JAK) with inhibitor with tumor tumor with necrosis necrosis tumor factor necrosis factor (TNF) (TNF) factor blockers blockers (TNF) inblockers rheumatoid in rheumatoid in rheumatoid patient patient management. patient management. management. arthritis arthritis (RA) arthritis (RA) patients patients (RA) ≥50 patients years ≥50 years old ≥50 with old years with at least old atwith least oneat cardiovascular one least cardiovascular one cardiovascular (CV)(CV) risk risk (CV) risk Lipids Lipids factor, factor, a higher factor, a higher rate a higher rate of all-cause ofrate all-cause ofmortality, all-cause mortality, including mortality, including sudden including sudden CVsudden death, CV death, was CV death, was was Lipids Treatment Treatment with Treatment with RINVOQ RINVOQ with was RINVOQ associated was associated was with associated with increases increases withinincreases lipid in lipid parameters, in parameters, lipid parameters, including including including observed observed with observed with the JAK the with inhibitor.

JAK the inhibitor.

JAKConsider inhibitor.

Consider the Consider benefits the benefits the andbenefits risks and risks forand the forrisks individual the for individual the individual totaltotal cholesterol, cholesterol, total cholesterol, low-density low-density low-density lipoprotein lipoprotein lipoprotein (LDL)(LDL) cholesterol, cholesterol, (LDL) cholesterol, and high-density and high-density and high-density patient patient priorpatient prior to initiating toprior initiating to orinitiating continuing or continuing or therapy continuing therapy with therapy with RINVOQ. RINVOQ. with RINVOQ. lipoprotein lipoprotein lipoprotein (HDL)(HDL) cholesterol. cholesterol.

(HDL) cholesterol.

Manage Manage patients Manage patients according patients according to according clinical to clinical guidelines to clinical guidelines for guidelines the for the for the MALIGNANCIES MALIGNANCIES MALIGNANCIES management management management of hyperlipidemia. of hyperlipidemia. of hyperlipidemia.

Evaluate Evaluate patients Evaluate patients 12 weeks patients 12 weeks after 12 after weeks initiation initiation after of initiation treatment of treatment of treatment Lymphoma Lymphoma Lymphoma and other and other malignancies andmalignancies other malignancies havehave beenbeen observed haveobserved beenin observed patients in patients in treated patients treated with treated with and withthereafter and thereafter andaccording thereafter according to according the toclinical the clinical to the guidelines clinical guidelines for guidelines hyperlipidemia. for hyperlipidemia. for hyperlipidemia.

RINVOQ. RINVOQ. RINVOQ. LiverLiver enzyme enzyme Liver elevations enzyme elevations elevations 3

3

3

Treatment with Treatment with RINVOQ RINVOQ with was RINVOQ associated was associated was with associated with increased increased withincidence increased incidence ofincidence liver of liver enzyme of enzyme liver enzyme In a large, In a large, randomized, In arandomized, large, randomized, postmarketing postmarketing postmarketing safety safety study safety study comparing comparing study comparing another another JAK another JAK JAK Treatment elevation elevation compared elevation compared to compared placebo. to placebo. to Evaluate placebo.

Evaluate at Evaluate baseline at baseline and at baseline thereafter and thereafter andaccording thereafter according to according to to inhibitor inhibitor with inhibitor with TNF TNF blockers with blockers TNF inblockers RAinpatients, RA patients, in RA a higher patients, a higher rate a higher rate of malignancies ofrate malignancies of malignancies (excluding (excluding (excluding routine patient routine patient management. patient management. management.

Prompt Prompt investigation Prompt investigation investigation of the ofcause the cause ofofthe liver of cause liver enzyme of enzyme liver enzyme non-melanoma non-melanoma non-melanoma skin skin cancer cancer skin [NMSC]), cancer [NMSC]), lymphomas, [NMSC]), lymphomas, lymphomas, and lung and lung cancer and cancer lung (in current cancer (in current (in or current or or routine elevation elevation is elevation recommended is recommended is recommended to identify to identify potential to identify potential cases potential cases of drug-induced of cases drug-induced of drug-induced liver liver injury. injury. liver injury. pastpast smokers) smokers) pastwas smokers) observed was observed waswith observed with the JAK the with inhibitor.

JAK the inhibitor.

JAKPatients inhibitor.

Patients who Patients who are current are who current are or past current or pastor past If increases If increases Ifinincreases aspartate in aspartate inaminotransferase aspartate aminotransferase aminotransferase (AST)(AST) or alanine or (AST) alanine aminotransferase or alanine aminotransferase aminotransferase (ALT)(ALT) (ALT) smokers smokers are smokers at are additional at additional are atincreased additional increased risk. increased risk. risk. are observed are observed areduring observed during routine during routine patient routine patient management patient management management and drug-induced and drug-induced and drug-induced liver liver injuryinjury is liverisinjury is WithWith RINVOQ, RINVOQ, With consider RINVOQ, consider the consider benefits the benefits the andbenefits risks and risks forand the forrisks individual the for individual thepatient individual patient priorpatient prior to toprior to suspected, suspected, suspected, RINVOQ RINVOQ should RINVOQ should be interrupted should be interrupted be interrupted until until this diagnosis this until diagnosis thisisdiagnosis excluded. is excluded. is excluded. initiating initiating orinitiating continuing or continuing or therapy, continuing therapy, particularly therapy, particularly particularly in patients in patients with in patients with a known a known with malignancy a known malignancy malignancy EMBRYO-FETAL EMBRYO-FETAL EMBRYO-FETAL TOXICITY TOXICITY TOXICITY (other (other than than (other a successfully a successfully than a successfully treated treated NMSC), treated NMSC), patients NMSC), patients who patients who develop develop who a malignancy develop a malignancy a malignancy whenwhen when Based on findings on Based findings on in animal findings in animal studies, in animal studies, RINVOQ studies, RINVOQ may RINVOQ may cause cause fetal may fetal harm cause harm when fetalwhen harm administered administered when administered on treatment, on treatment, on and treatment, patients and patients and who patients who are current are who current are or past current or past smokers. or smokers. past NMSCs smokers.

NMSCs have NMSCs have beenbeen have been Based to a pregnant to a pregnant to a woman. pregnant woman.

Advise woman.

Advise pregnant Advise pregnant women pregnant women of the women ofpotential the potential of the risk potential to risk a fetus. to arisk fetus.

Advise to aAdvise fetus. Advise reported reported in reported patients in patients treated in patients treated withtreated with RINVOQ. RINVOQ. with Periodic RINVOQ. Periodic skin Periodic examination skin examination skin examination is recommended is recommended is recommended females females of reproductive females of reproductive of reproductive potential potential topotential use to effective use effective to use contraception effective contraception contraception during during treatment during treatment with treatment with with for patients for patients for who patients who are atare increased who at increased are atrisk increased for riskskin forrisk cancer. skinfor cancer. skin Advise cancer.

Advise patients Advise patients to limit patients to limit sunlight to sunlight limit sunlight RINVOQ RINVOQ and RINVOQ for and4for weeks and 4 weeks for after 4 after weeks the final the after final dose. the dose.

Verify finalVerify dose. pregnancy pregnancy Verify status pregnancy status of females of status females of of females of of exposure exposure byexposure wearing by wearing by protective wearing protective clothing protective clothing and clothing using and using sunscreen. andsunscreen. using sunscreen. reproductive reproductive reproductive potential potential prior potential prior to starting toprior starting treatment to starting treatment with treatment with RINVOQ. RINVOQ. with RINVOQ. MAJOR MAJOR ADVERSE MAJOR ADVERSE CARDIOVASCULAR ADVERSE CARDIOVASCULAR CARDIOVASCULAR EVENTS EVENTS EVENTS VACCINATION VACCINATION VACCINATION In a large, In a large, randomized, In a randomized, large, randomized, postmarketing postmarketing postmarketing study study comparing comparing study comparing another another JAK another JAK inhibitor inhibitor JAK inhibitor Avoid Avoid use of use Avoid live ofvaccines live use vaccines of live during, vaccines during, or immediately during, or immediately or immediately priorprior to, RINVOQ to, prior RINVOQ to, therapy.

RINVOQ therapy.

Prior therapy.

Prior Prior withwith TNF TNF blockers with blockers TNF inblockers RAinpatients RA patients in RA ≥50 patients years ≥50 years old ≥50with old years with at old least atwith least oneatCV one least risk CVone factor, riskCV factor, risk factor, to initiating to RINVOQ, initiating RINVOQ, patients RINVOQ, patients should patients should be brought should be brought be up brought toup date to date on upall to on immunizations, date all immunizations, on all immunizations, a higher a higher rate a higher rate of major ofrate major adverse of adverse major cardiovascular adverse cardiovascular cardiovascular events events (MACE) events (MACE) (defined (MACE) (defined as(defined as as to initiating including varicella including varicella zoster varicella zoster or prophylactic or zoster prophylactic or prophylactic herpes herpes zoster herpes zoster vaccinations, vaccinations, zoster vaccinations, in agreement in agreement in agreement cardiovascular cardiovascular cardiovascular death, death, myocardial death, myocardial myocardial infarction, infarction, infarction, and stroke) and stroke) and wasstroke) was observed observed waswith observed with withincluding current current with immunization current immunization immunization guidelines. guidelines. guidelines. the JAK the JAK inhibitor. the inhibitor.

JAKPatients inhibitor.

Patients who Patients who are current are who current are or past current or past smokers or smokers past are smokers at are additional at additional are at additionalwith with increased increased risk. increased risk.

Discontinue Discontinue risk. Discontinue RINVOQ RINVOQ inRINVOQ patients in patients in that patients that havehave experienced thatexperienced have experienced a a a myocardial myocardial myocardial infarction infarction or infarction stroke. or stroke. or stroke.

LACTATION LACTATION LACTATION There There are no are There data no are data on the no ondata presence the on presence theofpresence RINVOQ of RINVOQ of in human RINVOQ in human milk, in human milk, the effects the milk, effects on thethe effects on the on the breastfed breastfed infant, breastfed infant, or the infant, oreffects the effects or on themilk effects on milk production. on production. milk production.

Available Available data Available data in animals indata animals have in animals have have Consider Consider the Consider benefits the benefits the andbenefits risks and risks forand the forrisks individual the for individual thepatient individual patient priorpatient prior to initiating toprior initiating to orinitiating or or shown the excretion shown the excretion theofexcretion RINVOQ of RINVOQ of in milk.

RINVOQ in milk.

Advise inAdvise milk. patients Advise patients that patients breastfeeding that breastfeeding that breastfeeding is notis not is not continuing continuing therapy continuing therapy with therapy with RINVOQ, RINVOQ, with particularly RINVOQ, particularly particularly in patients in patients who in patients who are current are who current are or past current or pastor pastshown recommended recommended recommended during during treatment during treatment with treatment with RINVOQ RINVOQ with and RINVOQ for and6for days and 6 days after for 6 after the days last the after dose. lastthe dose. last dose. smokers smokers and smokers patients and patients and with patients with otherother CV with risk CV other factors. riskCV factors. risk Patients factors.

Patients should Patients should be informed should be informed be about informed about about the symptoms the symptoms the of symptoms serious of serious CV of events serious CV events and CV events the andsteps theand steps tothe take to steps take if they to if they take occur. occur. if they occur.

HEPATIC HEPATIC IMPAIRMENT HEPATIC IMPAIRMENT IMPAIRMENT

RINVOQ RINVOQ is not RINVOQ isrecommended not recommended is not recommended for use for in use patients for in patients use with in patients with severe severe with hepatic severe hepatic impairment. hepatic impairment. impairment.

THROMBOSIS THROMBOSIS THROMBOSIS Thrombosis, Thrombosis, Thrombosis, including including deep including deep venous venous deep thrombosis, venous thrombosis, thrombosis, pulmonary pulmonary pulmonary embolism, embolism, and embolism, arterial and arterial and arterial ADVERSE ADVERSE REACTIONS ADVERSE REACTIONS REACTIONS thrombosis thrombosis thrombosis havehave occurred occurred haveinoccurred patients in patients in treated patients treated with treated with JAK inhibitors JAK with inhibitors JAKused inhibitors used to treat toused treatto treat The most The most common Thecommon most adverse common adverse reactions adverse reactions inreactions RINVOQ in RINVOQ clinical in RINVOQ clinical trialsclinical trials werewere upper trialsupper were respiratory respiratory upper respiratory inflammatory inflammatory inflammatory conditions. conditions. conditions.

Many Many of these of Many these adverse ofadverse these events adverse events were events were serious serious were andserious some and some and some tracttract infections, infections, tract herpes infections, herpes zoster, herpes zoster, herpes zoster, herpes simplex, herpes simplex, bronchitis, simplex, bronchitis, nausea, bronchitis, nausea, cough, nausea, cough, pyrexia, cough, pyrexia,pyrexia, resulted resulted in resulted death. in death. in death. acne,acne, headache, headache, acne, increased headache, increased blood increased blood creatine creatine blood phosphokinase, creatine phosphokinase, phosphokinase, hypersensitivity, hypersensitivity, hypersensitivity, folliculitis, folliculitis, folliculitis, abdominal pain, abdominal pain, increased increased pain,weight, increased weight, influenza, weight, influenza, fatigue, influenza, fatigue, neutropenia, fatigue, neutropenia, neutropenia, myalgia, myalgia, influenzamyalgia, influenzainfluenzaIn a large, In a large, randomized, In arandomized, large, randomized, postmarketing postmarketing postmarketing study study comparing comparing study comparing another another JAK another inhibitor JAK inhibitor JAK toinhibitor to to abdominal like illness, like illness, elevated like illness, elevated liver elevated liver enzymes, enzymes, liverand enzymes, rash. and rash. and rash.

TNF TNF blockers blockers TNF inblockers RAinpatients RA patients in RA ≥50 patients years ≥50 years old ≥50 with old years with at least old atwith least oneat CV one least risk CVone factor, riskCV factor, risk a higher factor, a higher a higher rate rate of thrombosis ofrate thrombosis of thrombosis was observed was observed waswith observed with the JAK the with inhibitor.

JAK the inhibitor.

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Dosage Dosage Forms Dosage Forms and Strengths: Forms and Strengths: and Strengths: RINVOQ RINVOQ is available RINVOQ is available is in available 15in mg, 15 30 mg, inmg, 15 30mg, and mg,30 45 and mg, mg 45and mg 45 mg RINVOQ RINVOQ is contraindicated RINVOQ is contraindicated is contraindicated in patients in patients with in patients with known known with hypersensitivity known hypersensitivity hypersensitivity to upadacitinib to upadacitinib to upadacitinib extended-release extended-release extended-release tablets. tablets.tablets. or any or of any itsof or excipients. its anyexcipients. of its Serious excipients.

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If a clinically Iftrials. a clinically If a clinically significant significant hypersensitivity significant hypersensitivity hypersensitivity reaction reaction occurs, reaction occurs, discontinue occurs, discontinue discontinue RINVOQ RINVOQ and RINVOQ institute and institute and institute appropriate appropriate appropriate therapy. therapy. therapy.

References: References: 1.

References: RINVOQ 1. RINVOQ [package 1. RINVOQ [package insert]. [package insert].

NorthNorth insert].

Chicago, Chicago, North IL: AbbVie Chicago, IL: AbbVie Inc; IL:2022.

Inc; AbbVie 2022.

2. Data Inc; 2.2022. on Data file, on 2.AbbVie Data file, AbbVie onInc. file,ABVRRTI68885.

Inc. AbbVie ABVRRTI68885.

Inc. ABVRRTI68885.

3. Genovese 3. Genovese MC, 3. Genovese Fleischmann MC, Fleischmann MC, R, Fleischmann Combe R, Combe B, et R, al.

B, Combe et Safety al. Safety B,and et al. efficacy and Safety efficacy of and upadacitinib efficacy of upadacitinib of upadacitinib in patients in patients with in patients active with active rheumatoid withrheumatoid activearthritis rheumatoid arthritis refractory arthritis refractory to biologic refractory to biologic disease-modifying to biologic disease-modifying disease-modifying anti-rheumatic anti-rheumatic anti-rheumatic drugsdrugs (SELECT-BEYOND): (SELECT-BEYOND): drugs (SELECT-BEYOND): a double-blind, a double-blind, a double-blind, randomised randomised controlled randomised controlled phase controlled phase 3 trial.3 phase Lancet. trial. Lancet.

3 2018;391(10139): trial. 2018;391(10139): Lancet. 2018;391(10139): 2513-2524.

2513-2524.

4.2513-2524.

Smolen 4. Smolen JS,4.

Emery Smolen JS, Emery P, Rigby JS,P,Emery Rigby W, etP, W, al.Rigby et Upadacitinib al. W, Upadacitinib et al. Upadacitinib as monotherapy as monotherapy as monotherapy in patients in patients with in patients rheumatoid with rheumatoid witharthritis rheumatoid arthritis and prior arthritis and prior inadequate and inadequate priorresponse inadequate response to methotrexate: response to methotrexate: to methotrexate: results results at 84 at weeks results 84 weeks from at 84the from weeks SELECTthefrom SELECTthe SELECTMONOTHERAPY MONOTHERAPY MONOTHERAPY study.study.

PosterPoster study. presented presented Poster at:presented The at:European The European at: The Congress European Congress of Rheumatology; Congress of Rheumatology; of Rheumatology; June 3-6, June2020; 3-6, June 2020; E-Congress.

3-6,E-Congress.

2020;5.

E-Congress.

Smolen 5. Smolen JS,5.

Pangan Smolen JS, Pangan AL, JS,Emery Pangan AL, Emery P, et AL, al.

P,Emery et Upadacitinib al. Upadacitinib P, et al. Upadacitinib as monotherapy as monotherapy as monotherapy in patients in patients with in patients with with activeactive rheumatoid rheumatoid activearthritis rheumatoid arthritis and inadequate arthritis and inadequate andresponse inadequate response to methotrexate response to methotrexate to methotrexate (SELECT-MONOTHERAPY): (SELECT-MONOTHERAPY): (SELECT-MONOTHERAPY): a randomised, a randomised, a placebo-controlled, randomised, placebo-controlled, placebo-controlled, double-blind double-blind double-blind phasephase 3 study.

3 phase study.

Lancet.

3Lancet. study.

2019;393(10188):2303-2311.

2019;393(10188):2303-2311.

Lancet. 2019;393(10188):2303-2311.

Erratum Erratum Erratum in: Lancet. in: Lancet.

2019;393(10191):2590. in: 2019;393(10191):2590.

Lancet. 2019;393(10191):2590.

6. Genovese 6. Genovese MC, 6. Genovese Combe MC, Combe B, MC, HallB, Combe S,Hall et al.

S,B,et Upadacitinib Hall al. Upadacitinib S, et al. Upadacitinib in patients in patients with in patients rheumatoid with rheumatoid witharthritis rheumatoid arthritis and inadequate arthritis and inadequate andresponse inadequate response or intolerance response or intolerance ortointolerance biological to biological DMARDs: to biological DMARDs: Results DMARDs: Results at 60 at Results 60 at 60 weeksweeks from the from weeks SELECT-BEYOND thefrom SELECT-BEYOND the SELECT-BEYOND study.study.

PosterPoster study. presented presented Poster at:presented The at:American The American at: The College American College of Rheumatology; College of Rheumatology; of Rheumatology; November November 8-13, November 8-13, 2019.2019.

7. 8-13, Cohen 7. 2019.

Cohen SB, van 7.SB, Cohen Vollenhoven van Vollenhoven SB, van R, Vollenhoven Curtis R, Curtis JR, et R,JR, al.

Curtis et Integrated al.JR, Integrated et al. safety Integrated safety profile profile safety of of profile of upadacitinib upadacitinib with upadacitinib up with to up 4.5to with years 4.5up years oftoexposure 4.5 of years exposure inofpatients exposure in patients with in patients rheumatoid with rheumatoid witharthritis. rheumatoid arthritis.

Poster arthritis.

Poster presented presented Poster at:presented The at:European The European at: The Congress European Congress of Rheumatology; Congress of Rheumatology; of Rheumatology; June 2-5, June2021; 2-5,June 2021; E-Congress.

2-5, E-Congress.

2021;8.

E-Congress.

Rubbert-Roth 8. Rubbert-Roth 8. Rubbert-Roth A, Enejosa A, Enejosa J, A, Enejosa J, J, Pangan Pangan AL, etPangan AL, al. et Trial al.AL, of Trial upadacitinib et of al.upadacitinib Trial of or upadacitinib abatacept or abatacept or in rheumatoid abatacept in rheumatoid inarthritis. rheumatoid arthritis.

N Engl arthritis.

N JEngl Med. JN Med. 2020;383(16):1511-1521.

Engl2020;383(16):1511-1521.

J Med. 2020;383(16):1511-1521.

Please Please see Please see Brief Brief see Summary Brief Summary Summary of full of full Prescribing of Prescribing full Prescribing Information Information Information on previous on previous on previous pages pages of pages this of this advertisement. ofadvertisement. this advertisement.

RINVOQ® RINVOQ® and RINVOQ® its and design its design and are itsregistered are design registered aretrademarks registered trademarks of trademarks AbbVie of AbbVie Biotechnology of AbbVie Biotechnology Biotechnology Ltd. Ltd. Ltd. ©2022 ©2022 AbbVie ©2022 AbbVie Inc. AbbVie Inc. NorthNorth Chicago, Inc. Chicago, North IL 60064 Chicago, IL 60064 US-RNQR-220149 IL 60064 US-RNQR-220149 US-RNQR-220149 April April 20222022 April Printed Printed 2022 in Puerto Printed in Puerto Rico in Rico Puerto Rico

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RINVOQ® (RIN-VOKE) (upadacitinib) extended-release tablets, for oral use WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS SERIOUS INFECTIONS Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions, Adverse Reactions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before RINVOQ use and during therapy. Treatment for latent infection should be considered prior to RINVOQ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with RINVOQ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions].

MORTALITY In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another Janus kinase (JAK) inhibitor to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor [see Warnings and Precautions].

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with RINVOQ. In RA patients treated with another JAK inhibitor, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk [see Warnings and Precautions].

MAJOR ADVERSE CARDIOVASCULAR EVENTS In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions].

THROMBOSIS Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid RINVOQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ and be promptly evaluated [see Warnings and Precautions].

INDICATIONS AND USAGE Rheumatoid Arthritis RINVOQ® is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

Psoriatic Arthritis RINVOQ is indicated for the treatment of adults with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

Atopic Dermatitis RINVOQ is indicated for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable.

• Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.

Ulcerative Colitis RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for ulcerative colitis, or with potent immunosuppressants such as azathioprine and cyclosporine.

Ankylosing Spondylitis RINVOQ is indicated for the treatment of adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

20071734 Rinvoq PB-7.625 x 10.5(3.5).indd 1

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

CONTRAINDICATIONS RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections have been reported in patients receiving RINVOQ. The most frequent serious infections reported with RINVOQ included pneumonia and cellulitis [see Adverse Reactions]. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis, were reported with RINVOQ. Avoid use of RINVOQ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating RINVOQ in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ. Interrupt RINVOQ if a patient develops a serious or opportunistic infection.

A patient who develops a new infection during treatment with RINVOQ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and RINVOQ should be interrupted if the patient is not responding to antimicrobial therapy. RINVOQ may be resumed once the infection is controlled.

Tuberculosis Evaluate and test patients for latent and active tuberculosis (TB) infection prior to administration of RINVOQ. Patients with latent TB should be treated with standard antimycobacterial therapy before initiating RINVOQ. RINVOQ should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of RINVOQ in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

During RINVOQ use, monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, were reported in clinical trials with RINVOQ [see Adverse Reactions]. The risk of herpes zoster appears to be higher in patients treated with RINVOQ in Japan. If a patient develops herpes zoster, consider temporarily interrupting RINVOQ until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed in accordance with clinical guidelines before starting and during therapy with RINVOQ. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA, were excluded from clinical trials. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical trials. However, cases of hepatitis B reactivation were still reported in patients enrolled in the Phase 3 trials of RINVOQ. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted.

Mortality In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ. Malignancy and Lymphoproliferative Disorders Malignancies, including lymphomas, were observed in clinical trials of RINVOQ [see Adverse Reactions].

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

Non-Melanoma Skin Cancer NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen.

Major Adverse Cardiovascular Events In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients

should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Thrombosis Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.

If symptoms of thrombosis occur, patients should discontinue RINVOQ and be evaluated promptly and treated appropriately. Avoid RINVOQ in patients that may be at increased risk of thrombosis.

Hypersensitivity Reactions Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy [see Adverse Reactions].

Gastrointestinal Perforations Gastrointestinal perforations have been reported in clinical trials with RINVOQ. Monitor RINVOQ-treated patients who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).

Evaluate promptly patients presenting with new onset abdominal pain for early identification of gastrointestinal perforation.

Laboratory Abnormalities Neutropenia Treatment with RINVOQ was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3).

Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation and interrupt RINVOQ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3).

Lymphopenia ALC less than 500 cells/mm3 were reported in RINVOQ-treated patients in clinical trials.

Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation or interrupt RINVOQ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3).

Anemia Decreases in hemoglobin levels to less than 8 g/dL were reported in RINVOQ-treated patients in clinical trials.

Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation or interrupt RINVOQ treatment in patients with a low hemoglobin level (i.e., less than 8 g/dL).

Lipids Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol [see Adverse Reactions].

Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assess lipid parameters approximately 12 weeks after initiation of treatment, and thereafter according to the clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for the management of hyperlipidemia.

Liver Enzyme Elevations Treatment with RINVOQ was associated with increased incidence of liver enzyme elevations compared to treatment with placebo.

Evaluate liver enzymes at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury.

If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

Embryo-Fetal Toxicity Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in fetal malformations.

Verify the pregnancy status of patients of reproductive potential prior to starting treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with RINVOQ and for 4 weeks following completion of therapy [see Use in Specific Populations].

Vaccinations Avoid use of live vaccines during, or immediately prior to, RINVOQ therapy.

Prior to initiating RINVOQ, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions] • Mortality [see Warnings and Precautions] • Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions] • Major Adverse Cardiovascular Events [see Warnings and Precautions] • Thrombosis [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Gastrointestinal Perforations [see Warnings and Precautions] • Laboratory Abnormalities [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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Adverse Reactions in Patients with Rheumatoid Arthritis A total of 3833 patients with rheumatoid arthritis were treated with upadacitinib in the Phase 3 clinical trials of whom 2806 were exposed for at least one year.

Patients could advance or switch to RINVOQ 15 mg from placebo, or be rescued to RINVOQ from active comparator or placebo from as early as Week 12 depending on the trial design.

A total of 2630 patients received at least 1 dose of RINVOQ 15 mg, of whom 1860 were exposed for at least one year. In trials RA-I, RA-II, RA-III and RA-V, 1213 patients received at least 1 dose of RINVOQ 15 mg, of which 986 patients were exposed for at least one year, and 1203 patients received at least 1 dose of upadacitinib 30 mg, of which 946 were exposed for at least one year.

Table 1: Adverse Reactions Reported in ≥ 1% of Rheumatoid Arthritis Patients Treated with RINVOQ 15 mg in Placebo-controlled Trials Adverse Reaction

Placebo

RINVOQ 15 mg

n=1042 (%)

n=1035 (%)

Upper respiratory tract infection (URTI)*

9.5

13.5

Nausea

2.2

3.5

Cough

1.0

2.2

Pyrexia

0

1.2

*URTI includes: acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, viral upper respiratory tract infection Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg group and at a higher rate than in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (includes oral herpes), and oral candidiasis.

Four integrated datasets are presented in the Specific Adverse Reaction section: Placebo-controlled Trials: Trials RA-III, RA-IV, and RA-V were integrated to represent safety through 12/14 weeks for placebo (n=1042) and RINVOQ 15 mg (n=1035). Trials RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), RINVOQ 15 mg (n=385), and upadacitinib 30 mg (n=384). Trial RA-IV did not include the 30 mg dose and, therefore, safety data for upadacitinib 30 mg can only be compared with placebo and RINVOQ 15 mg rates from pooling trials RA-III and RA-V. MTX-controlled Trials: Trials RA-I and RA-II were integrated to represent safety through 12/14 weeks for MTX (n=530), RINVOQ 15 mg (n=534), and upadacitinib 30 mg (n=529).

12-Month Exposure Dataset: Trials RA-I, II, III, and V were integrated to represent the long-term safety of RINVOQ 15 mg (n=1213) and upadacitinib 30 mg (n=1203).

Exposure adjusted incidence rates were adjusted by trial for all the adverse events reported in this section.

Specific Adverse Reactions Infections Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, infections were reported in 218 patients (95.7 per 100 patient-years) treated with placebo and 284 patients (127.8 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, infections were reported in 99 patients (136.5 per 100 patient-years) treated with placebo, 118 patients (164.5 per 100 patient-years) treated with RINVOQ 15 mg, and 126 patients (180.3 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Infections were reported in 127 patients (119.5 per 100 patient-years) treated with MTX monotherapy, 104 patients (91.8 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 128 patients (115.1 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Infections were reported in 615 patients (83.8 per 100 patient-years) treated with RINVOQ 15 mg and 674 patients (99.7 per 100 patient-years) treated with upadacitinib 30 mg.

Serious Infections Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, serious infections were reported in 6 patients (2.3 per 100 patient-years) treated with placebo, and 12 patients (4.6 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, serious infections were reported in 1 patient (1.2 per 100 patientyears) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 7 patients (8.2 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Serious infections were reported in 2 patients (1.6 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 8 patients (6.4 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Serious infections were reported in 38 patients (3.5 per 100 patient-years) treated with RINVOQ 15 mg and 59 patients (5.6 per 100 patient-years) treated with upadacitinib 30 mg.

The most frequently reported serious infections were pneumonia and cellulitis.

Tuberculosis Placebo-controlled Trials and MTX-controlled Trials: In the placebo-controlled period, there were no active cases of tuberculosis reported in the placebo, RINVOQ 15 mg, and upadacitinib 30 mg groups.

In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, RINVOQ 15 mg monotherapy, and upadacitinib 30 mg monotherapy groups.

12-Month Exposure Dataset: Active tuberculosis was reported for 2 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg.

Cases of extra-pulmonary tuberculosis were reported.

Opportunistic Infections (excluding tuberculosis) Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, opportunistic infections were reported in 3 patients (1.2 per 100 patient-years) treated with placebo, and 5 patients (1.9 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, opportunistic infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 6 patients (7.1 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Opportunistic infections were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 0 patients

20071734 Rinvoq PB-7.625 x 10.5(3.5).indd 2

treated with RINVOQ 15 mg monotherapy, and 4 patients (3.2 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Opportunistic infections were reported in 7 patients (0.6 per 100 patient-years) treated with RINVOQ 15 mg and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg.

Malignancies Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, malignancies excluding NMSC were reported in 1 patient (0.4 per 100 patient-years) treated with placebo, and 1 patient (0.4 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, malignancies excluding NMSC were reported in 0 patients treated with placebo, 1 patient (1.1 per 100 patient-years) treated with RINVOQ 15 mg, and 3 patients (3.5 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Malignancies excluding NMSC were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 0 patients treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Malignancies excluding NMSC were reported in 13 patients (1.2 per 100 patient-years) treated with RINVOQ 15 mg and 14 patients (1.3 per 100 patient-years) treated with upadacitinib 30 mg.

Gastrointestinal Perforations Placebo-controlled Trials: There were no gastrointestinal perforations (based on medical review) reported in patients treated with placebo, RINVOQ 15 mg, and upadacitinib 30 mg.

MTX-controlled Trials: There were no cases of gastrointestinal perforations reported in the MTX and RINVOQ 15 mg group through 12/14 weeks. Two cases of gastrointestinal perforations were observed in the upadacitinib 30 mg group.

12-Month Exposure Dataset: Gastrointestinal perforations were reported in 1 patient treated with RINVOQ 15 mg and 4 patients treated with upadacitinib 30 mg.

Thrombosis Placebo-controlled Trials: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in 1 patient treated with placebo and 1 patient treated with RINVOQ 15 mg. In RA-V, venous thrombosis was observed in 1 patient treated with RINVOQ 15 mg. There were no observed cases of venous thrombosis reported in RA-III. No cases of arterial thrombosis were observed through 12/14 weeks.

MTX-controlled Trials: In RA-II, venous thrombosis was observed in 0 patients treated with MTX monotherapy, 1 patient treated with RINVOQ 15 mg monotherapy and 0 patients treated with upadacitinib 30 mg monotherapy through Week 14. In RA-II, no cases of arterial thrombosis were observed through 12/14 weeks. In RA-I, venous thrombosis was observed in 1 patient treated with MTX, 0 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg through Week 24. In RA-I, arterial thrombosis was observed in 1 patient treated with upadacitinib 30 mg through Week 24.

12-Month Exposure Dataset: Venous thrombosis events were reported in 5 patients (0.5 per 100 patient-years) treated with RINVOQ 15 mg and 4 patients (0.4 per 100 patient-years) treated with upadacitinib 30 mg.

Arterial thrombosis events were reported in 0 patients treated with RINVOQ 15 mg and 2 patients (0.2 per 100 patient-years) treated with upadacitinib 30 mg.

Laboratory Abnormalities Hepatic Transaminase Elevations In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ 15 mg, and in 1.5% and 0.7% of patients treated with placebo, respectively. In RA-III and RA-V, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 1.0% of patients treated with RINVOQ 15 mg, 1.0% and 0% of patients treated with upadacitinib 30 mg and in 1.3% and 1.0% of patients treated with placebo, respectively.

In MTX-controlled trials, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with RINVOQ 15 mg, 1.7% and 1.3% of patients treated with upadacitinib 30 mg and in 1.9% and 0.9% of patients treated with MTX, respectively.

Lipid Elevations Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Elevations in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In controlled trials, for up to 12/14 weeks, changes from baseline in lipid parameters in patients treated with RINVOQ 15 mg and upadacitinib 30 mg, respectively, are summarized below: • Mean LDL cholesterol increased by 14.81 mg/dL and 17.17 mg/dL. • Mean HDL cholesterol increased by 8.16 mg/dL and 9.01 mg/dL. • The mean LDL/HDL ratio remained stable.

• Mean triglycerides increased by 13.55 mg/dL and 14.44 mg/dL. Creatine Phosphokinase Elevations In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the RINVOQ 15 mg and placebo groups, respectively. Most elevations >5 x ULN were transient and did not require treatment discontinuation. In RA-III and RA-V, CPK elevations > 5 x ULN were observed in 0.3% of patients treated with placebo, 1.6% of patients treated with RINVOQ 15 mg, and none in patients treated with upadacitinib 30 mg.

Neutropenia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in neutrophil counts, below 1000 cells/mm3 in at least one measurement occurred in 1.1% and <0.1% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in neutrophil counts below 1000 cells/mm3 in at least one measurement occurred in 0.3% of patients treated with placebo, 1.3% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical trials, treatment was interrupted in response to ANC less than 1000 cells/mm3.

Lymphopenia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.9%

and 0.7% of patients in the RINVOQ 15 mg and placebo groups, respectively.

In RA-III and RA-V, decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.5% of patients treated with placebo, 0.5% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg.

Anemia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in <0.1% of patients in both the RINVOQ 15 mg and placebo groups. In RA-III and RA-V, hemoglobin decreases below 8 g/dL in at least one measurement were observed in 0.3% of patients treated with placebo, and none in patients treated with RINVOQ 15 mg and upadacitinib 30 mg.

Adverse Reactions in Patients with Psoriatic Arthritis A total of 1827 patients with psoriatic arthritis were treated with upadacitinib in clinical trials representing 1639.2 patient-years of exposure, of whom 722 were exposed to upadacitinib for at least one year. In the two Phase 3 trials, 907 patients received at least 1 dose of RINVOQ 15 mg, of whom 359 were exposed for at least one year.

Two placebo-controlled trials were integrated (640 patients on RINVOQ 15 mg once daily and 635 patients on placebo) to evaluate the safety of RINVOQ 15 mg in comparison to placebo for up to 24 weeks after treatment initiation.

Overall, the safety profile observed in patients with active psoriatic arthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequencies of herpes zoster and herpes simplex were ≥1% (1.1% and 1.4%, respectively) with RINVOQ 15 mg and 0.8% and 1.3%, respectively with placebo. A higher incidence of acne and bronchitis was also observed in patients treated with RINVOQ 15 mg (1.3% and 3.9%, respectively) compared to placebo (0.3% and 2.7%, respectively).

Adverse Reactions in Patients with Atopic Dermatitis Three Phase 3 (AD-1, AD-2, and AD-3) and one Phase 2b (AD-4) randomized, double-blind, placebo-controlled, multicenter trials evaluated the safety of RINVOQ in patients with moderate-to-severe atopic dermatitis.

The majority of patients were White (68%) and male (57%). The mean age was 34 years (ranged from 12 to 75 years) and 13% of the patients were 12 to less than 18 years. In these 4 trials, 2612 patients were treated with RINVOQ 15 mg or 30 mg orally once daily, with or without concomitant topical corticosteroids (TCS).

In the Phase 3 clinical trials (AD-1, AD-2, and AD-3), a total of 1239 patients received RINVOQ 15 mg, of whom 791 were exposed for at least one year and 1246 patients received RINVOQ 30 mg, of whom 826 were exposed for at least one year.

Trials AD-1, AD-2, and AD-4 compared the safety of RINVOQ monotherapy to placebo through Week 16. Trial AD-3 compared the safety of RINVOQ + TCS to placebo + TCS through Week 16.

Weeks 0 to 16 (Trials AD-1 to AD-4) In RINVOQ trials with and without TCS (Trials AD-1, 2, 3 and 4) through Week 16, the proportion of patients who discontinued treatment because of adverse reactions in the RINVOQ 15 mg, 30 mg and placebo groups were 2.3%, 2.9% and 3.8%, respectively. Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% in the RINVOQ 15 mg or 30 mg groups during the first 16 weeks of treatment.

Table 2: Adverse Reactions Reported in ≥ 1% of Patients with Atopic Dermatitis Treated with RINVOQ 15 mg or 30 mg Placebo Adverse Reaction Upper respiratory tract infection (URTI)* Acne** Herpes simplex*** Headache Increased blood creatine phosphokinase Cough Hypersensitivity**** Folliculitis Nausea Abdominal pain***** Pyrexia Increased Weight Herpes zoster****** Influenza Fatigue Neutropenia Myalgia Influenza like illness

n=902 (%) 17 2 2 4

RINVOQ 15 mg n=899 (%) 23 10 4 6

RINVOQ 30 mg n=906 (%) 25 16 8 6

2 1 2 1 1 1 1 1 1 <1 1 <1 1 1

5 3 2 2 3 3 2 2 2 2 1 1 1 1

6 3 3 3 3 2 2 2 2 2 2 2 2 2

* Includes: laryngitis, laryngitis viral, nasopharyngitis, oropharyngeal pain, pharyngeal abscess, pharyngitis, pharyngitis streptococcal, pharyngotonsillitis, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinolaryngitis, sinusitis, tonsillitis, tonsillitis bacterial, upper respiratory tract infection, viral pharyngitis, viral upper respiratory tract infection ** Includes: acne and dermatitis acneiform *** Includes: genital herpes, genital herpes simplex, herpes dermatitis, herpes ophthalmic, herpes simplex, nasal herpes, ophthalmic herpes simplex, herpes virus infection, oral herpes **** Includes anaphylactic reaction, anaphylactic shock, angioedema, dermatitis exfoliative generalized, drug hypersensitivity, eyelid oedema, face oedema, hypersensitivity, periorbital swelling, pharyngeal swelling, swelling face, toxic skin eruption, type I hypersensitivity, urticaria ***** Includes abdominal pain and abdominal pain upper ****** Includes herpes zoster and varicella

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Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg and/or 30 mg group and at a higher rate than in the placebo group through Week 16 included anemia, oral candidiasis, pneumonia, and the adverse event of retinal detachment.

The safety profile of RINVOQ through Week 52 was generally consistent with the safety profile observed at Week 16.

Overall, the safety profile observed in patients with AD treated with RINVOQ was similar to the safety profile in patients with RA. Other specific adverse reactions that were reported in patients with AD included eczema herpeticum/Kaposi’s varicelliform eruption.

Eczema Herpeticum/Kaposi’s Varicelliform Eruption Placebo-controlled Period (16 weeks): Eczema herpeticum was reported in 4 patients (1.6 per 100 patient-years) treated with placebo, 6 patients (2.2 per 100 patient-years) treated with RINVOQ 15 mg and 7 patients (2.6 per 100 patient-years) treated with RINVOQ 30 mg.

12-Month Exposure (Weeks 0 to 52): Eczema herpeticum was reported in 18 patients (1.6 per 100 patient-years) treated with RINVOQ 15 mg and 17 patients (1.5 per 100 patient-years) treated with RINVOQ 30 mg.

Adverse Reactions in Patients with Ulcerative Colitis RINVOQ was studied up to 8 weeks in patients with moderately to severely active ulcerative colitis in two randomized, double-blind, placebo-controlled induction studies (UC-1, UC-2) and a randomized, double-blind, placebo controlled, dose-finding study (UC-4; NCT02819635). Long term safety up to 52-weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (UC-3) and a long-term extension study.

In the two induction studies (UC-1, UC-2) and a dose finding study (UC-4), 1097 patients were enrolled of whom 719 patients received RINVOQ 45 mg once daily.

In the maintenance study (UC-3), 746 patients were enrolled of whom 250 patients received RINVOQ 15 mg once daily and 251 patients received RINVOQ 30 mg once daily.

Adverse reactions reported in ≥2% of patients in any treatment arm in the induction and maintenance studies are shown in Tables 3 and 4, respectively.

Table 3. Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with RINVOQ 45 mg in Placebo-Controlled Induction Studies (UC-1, UC-2 and UC-4) Adverse Reaction

Placebo

RINVOQ 45 mg Once Daily

N= 378 (%)

N = 719 (%)

Upper respiratory tract infection*

7

9

Acne*

1

6

Increased blood creatine phosphokinase

1

5

Neutropenia*

<1

5

Rash*

1

4

Elevated liver enzymes**

2

3

Lymphopenia*

1

3

Folliculitis

1

2

Herpes simplex*

<1

2

* Composed of several similar terms ** Elevated liver enzymes composed of elevated ALT, AST, GGT, ALP, liver transaminases, hepatic enzymes, bilirubin, drug-induced liver injury and cholestasis.

Other adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 8 included herpes zoster and pneumonia.

Table 4. Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with RINVOQ 15 mg or 30 mg in the Placebo-Controlled Maintenance Study (UC-3)1 Adverse Reaction

RINVOQ RINVOQ 15 mg 30 mg Placebo Once Daily Once Daily n = 245 (%)

n = 250 (%)

n = 251 (%)

Upper respiratory tract infection*

18

16

20

Increased blood creatine phosphokinase

2

6

8

Neutropenia*

2

3

6

Elevated liver enzymes**

1

6

4

Rash*

4

5

5

Herpes zoster

0

4

4

Folliculitis

2

2

4

Hypercholesterolemia*

1

2

4

Influenza

1

3

3

Herpes simplex*

1

2

3

Lymphopenia*

2

3

2

Hyperlipidemia*

0

2

2

1

Patients who were responders to 8 weeks induction therapy with RINVOQ 45 mg once daily * Composed of several similar terms ** Elevated liver enzymes composed of elevated ALT, AST, GGT, ALP, liver transaminases, hepatic enzymes, bilirubin, drug-induced liver injury, and cholestasis.

The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods.

Overall, the safety profile observed in patients with ulcerative colitis treated with RINVOQ was generally similar to the safety profile in patients with RA and AD.

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Specific Adverse Reactions Serious Infections Induction Studies: In UC-1, UC-2, and UC-4, serious infections were reported in 5 patients (8.4 per 100 patient-years) treated with placebo and 9 patients (8.4 per 100 patient-years) treated with RINVOQ 45 mg through 8 weeks.

Placebo-controlled Maintenance Study: In UC-3, serious infections were reported in 8 patients (6.3 per 100 patient-years) treated with placebo, 8 patients (4.5 per 100 patient-years) treated with RINVOQ 15 mg, and 6 patients (3.1 per 100 patient-years) treated with RINVOQ 30 mg through 52 weeks.

Laboratory Abnormalities Hepatic Transaminase Elevations In studies UC-1, UC-2, and UC-4, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 1.5% of patients treated with RINVOQ 45 mg, and 0% of patients treated with placebo for 8 weeks. AST elevations to ≥ 3 x ULN occurred in 1.5% of patients treated with RINVOQ 45 mg, and 0.3% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN occurred in 0.4% of patients treated with RINVOQ 45 mg and 0% of patients treated with placebo.

In UC-3, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 4% of patients treated with RINVOQ 30 mg, 2% of patients treated with RINVOQ 15 mg, and 0.8% of patients treated with placebo for 52 weeks. Elevations of AST to ≥ 3 x ULN in at least one measurement were observed in 2% of patients treated with RINVOQ 30 mg, 1.6% of patients treated with RINVOQ 15 mg and 0.4% of patients treated with placebo.

Elevations of ALT to ≥ 5 x ULN were observed in 0.8% of patients treated with 30 mg, 0.4% of patients treated with 15 mg, and 0.4% of patients treated with placebo.

Overall, laboratory abnormalities observed in patients with ulcerative colitis treated with RINVOQ were similar to those described in patients with RA. Adverse Reactions in Patients with Ankylosing Spondylitis A total of 596 patients with ankylosing spondylitis were treated with RINVOQ 15 mg in the two clinical trials representing 577.3 patient-years of exposure, of whom 228 were exposed to RINVOQ 15 mg for at least one year.

Overall, the safety profile observed in patients with active ankylosing spondylitis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis and psoriatic arthritis.

During the 14-week placebo-controlled period in Trial AS-I, the frequency of headache was 5.4% with RINVOQ 15 mg and 2.1% with placebo. During the 14-week placebo-controlled period in Trial AS-II, the frequency of headache was 3.3% with RINVOQ 15 mg and 1.4% with placebo.

DRUG INTERACTIONS Strong CYP3A4 Inhibitors Upadacitinib exposure is increased when RINVOQ is co-administered with a strong CYP3A4 inhibitor (such as ketoconazole and clarithromycin), which may increase the risk of RINVOQ adverse reactions. Monitor patients closely for adverse reactions when co-administering RINVOQ 15 mg once daily with strong CYP3A4 inhibitors.

For patients with atopic dermatitis, coadministration of RINVOQ 30 mg once daily with strong CYP3A4 inhibitors is not recommended.

For patients with ulcerative colitis taking strong CYP3A4 inhibitors, reduce the RINVOQ induction dosage to 30 mg once daily. The recommended maintenance dosage is 15 mg once daily.

Strong CYP3A4 Inducers Upadacitinib exposure is decreased when RINVOQ is co-administered with strong CYP3A4 inducers (such as rifampin), which may lead to reduced therapeutic effect of RINVOQ. Coadministration of RINVOQ with strong CYP3A4 inducers is not recommended.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Available data from the pharmacovigilance safety database and postmarketing case reports on use of RINVOQ in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. Based on animal studies, RINVOQ has the potential to adversely affect a developing fetus. Advise patients of reproductive potential and pregnant patients of the potential risk to the fetus.

In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the 15 mg dose, 0.8 and 7.6 times the 30 mg dose, and 0.6 and 5.6 times the maximum recommended human dose (MRHD) of 45 mg (on an AUC basis) resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib during organogenesis at exposures approximately 0.29 and 2.2 times the 15 mg dose, 0.15 times and 1.1 times the 30 mg dose, and at 0.11 and 0.82 times the MHRD (on an AUC basis).

In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 3 times the 15 mg dose, 1.4 times the 30 mg dose, and the same as the MRHD (on an AUC basis) resulted in no maternal or developmental toxicity (see Data).

The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages are 2-4% and 15-20%, respectively.

Report pregnancies to the AbbVie Inc.’s Adverse Event reporting line at 1-888-633-9110, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data Animal Data In an oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 5, 25, and 75 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that consisted of misshapen humerus and bent scapula) at exposures equal to or greater than approximately 1.7 times the

15 mg dose, 0.9 times the 30 mg dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 5 mg/kg/day and higher). Additional skeletal malformations (bent forelimbs/hindlimbs and rib/vertebral defects) and decreased fetal body weights were observed in the absence of maternal toxicity at an exposure approximately 84 times the 15 mg dose, 43 times the 30 mg dose, and 31 times the MRHD (on an AUC basis at a maternal oral dose of 75 mg/kg/day).

In a second oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 1.5 and 4 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that included bent humerus and scapula) at exposures approximately 1.6 times the 15 mg dose, 0.8 times the 30 mg dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 4 mg/kg/day). No developmental toxicity was observed in rats at an exposure approximately 0.29 times the 15 mg dose, 0.15 times the 30 mg dose, and 0.11 times the MRHD (on an AUC basis at a maternal oral dose of 1.5 mg/kg/day).

In an oral embryo-fetal developmental study, pregnant rabbits received upadacitinib at doses of 2.5, 10, and 25 mg/kg/day during the period of organogenesis from gestation day 7 to 19. Embryolethality, decreased fetal body weights, and cardiovascular malformations were observed in the presence of maternal toxicity at an exposure approximately 15 times the 15 mg dose, 7.6 times the 30 mg dose, and 5.6 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both total and early resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 2.2 times the 15 mg dose, 1.1 times the 30 mg dose, and 0.82 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

In an oral pre- and post-natal development study, pregnant female rats received upadacitinib at doses of 2.5, 5, and 10 mg/kg/day from gestation day 6 through lactation day 20. No maternal or developmental toxicity was observed in either mothers or offspring, respectively, at an exposure approximately 3 times the 15 mg dose, 1.4 times the 30 mg dose, and at approximately the same exposure as the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

Lactation Risk Summary There are no data on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with RINVOQ, and for 6 days (approximately 10 half-lives) after the last dose.

Data A single oral dose of 10 mg/kg radiolabeled upadacitinib was administered to lactating female Sprague-Dawley rats on post-partum days 7-8. Drug exposure was approximately 30-fold greater in milk than in maternal plasma based on AUC0-t values. Approximately 97% of drug-related material in milk was parent drug.

Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ [see Use in Specific Populations].

Contraception Females Based on animal studies, upadacitinib may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations]. Advise female patients of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose.

Pediatric Use Juvenile Idiopathic Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The safety and effectiveness of RINVOQ in pediatric patients with juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis have not been established.

Atopic Dermatitis The safety and effectiveness of RINVOQ in pediatric patients 12 years of age and older weighing at least 40 kg with atopic dermatitis have been established. A total of 344 pediatric patients aged 12 to 17 years with moderate to severe atopic dermatitis were randomized across three trials (AD-1, AD-2 and AD-3) to receive either RINVOQ 15 mg (N=114) or 30 mg (N=114) or matching placebo (N=116) in monotherapy or combination with topical corticosteroids. Efficacy was consistent between the pediatric patients and adults. The adverse reaction profile in the pediatric patients was similar to the adults [see Adverse Reactions].

The safety and effectiveness of RINVOQ in pediatric patients less than 12 years of age with atopic dermatitis have not been established.

Ulcerative Colitis The safety and effectiveness of RINVOQ in pediatric patients with ulcerative colitis have not been established.

Geriatric Use Rheumatoid Arthritis and Psoriatic Arthritis Of the 4381 patients treated in the five clinical trials, a total of 906 rheumatoid arthritis patients were 65 years of age or older, including 146 patients 75 years and older. Of the 1827 patients treated in the two psoriatic arthritis Phase 3 clinical trials, a total of 274 patients were 65 years of age or older, including 34 patients 75 years and older. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of overall adverse events, including serious infections, in patients 65 years of age and older.

Atopic Dermatitis Of the 2583 patients treated in the three Phase 3 clinical trials, a total of 120 patients with atopic dermatitis were 65 years of age or older, including 6 patients 75 years of age. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of serious infections and malignancies in those patients 65 years of age or older in the 30 mg dosing group in the long-term trials.

Ulcerative Colitis Of the 1097 patients treated in the controlled clinical trials, a total of 95 patients with ulcerative colitis were 65 years and older. Clinical studies of RINVOQ did not include sufficient numbers of patients 65 years of age and older with ulcerative colitis to determine whether they respond differently from younger adult patients.

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Renal Impairment For patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no dosage adjustment is needed in patients with mild (eGFR 60 to < 90 mL/min/1.73 m2), moderate (eGFR 30 to < 60 mL/min/1.73 m2), or severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2).

For patients with atopic dermatitis, the maximum recommended dosage is 15 mg once daily for patients with severe renal impairment. No dosage adjustment is needed in patients with mild or moderate renal impairment.

For patients with ulcerative colitis, the recommended dosage for severe renal impairment is 30 mg once daily for induction and 15 mg once daily for maintenance. No dosage adjustment is needed in patients with mild or moderate renal impairment.

RINVOQ has not been studied in patients with end stage renal disease (eGFR <15 mL/min/1.73m2). Use in patients with atopic dermatitis or ulcerative colitis with end stage renal disease is not recommended.

Hepatic Impairment The use of RINVOQ has not been studied in patients with severe hepatic impairment (Child Pugh C), and therefore not recommended for use in patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, or ankylosing spondylitis.

For patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis, no dosage adjustment is needed in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment.

For patients with ulcerative colitis, the recommended dosage for mild to moderate hepatic impairment is 30 mg once daily for induction and 15 mg once daily for maintenance.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Infections Inform patients that they may be more likely to develop infections when taking RINVOQ. Instruct patients to contact their healthcare provider immediately during treatment if they develop any signs or symptoms of an infection [see Warnings and Precautions].

Advise patients that the risk of herpes zoster is increased in patients taking RINVOQ and in some cases can be serious [see Warnings and Precautions].

Malignancies Inform patients that RINVOQ may increase their risk of certain cancers and that periodic skin examinations should be performed while using RINVOQ. Advise patients that exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen [see Warnings and Precautions].

Major Adverse Cardiovascular Events Inform patients that RINVOQ may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke,

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and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions].

Thrombosis Inform patients that events of deep venous thrombosis and pulmonary embolism have been reported in clinical trials with RINVOQ. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions].

Hypersensitivity Reactions Advise patients to discontinue RINVOQ and seek immediate medical attention if they develop any signs and symptoms of allergic reactions [see Warnings and Precautions].

Gastrointestinal Perforations Inform patients that gastrointestinal perforations have been reported in clinical trials with RINVOQ and that risk factors include the use of NSAIDS or history of diverticulitis. Instruct patients to seek medical care immediately if they experience new onset of abdominal pain, fever, chills, nausea, or vomiting [see Warnings and Precautions].

Retinal Detachment Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ [see Adverse Reactions].

Laboratory Abnormalities Inform patients that RINVOQ may affect certain lab tests, and that blood tests are required before and during RINVOQ treatment [see Warnings and Precautions].

Vaccinations Advise patients to avoid use of live vaccines with RINVOQ. Instruct patients to inform their healthcare practitioner that they are taking RINVOQ prior to a potential vaccination [see Warnings and Precautions].

Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential that exposure to RINVOQ during pregnancy may result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions and Use in Specific Populations].

Advise females of reproductive potential that effective contraception should be used during treatment and for 4 weeks following the final dose of upadacitinib [see Use in Specific Populations].

Advise females patients who are exposed to RINVOQ during pregnancy to contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Lactation Advise women not to breastfeed during treatment with RINVOQ and for 6 days after the last dose [see Use in Specific Populations].

Administration Advise patients not to chew, crush, or split RINVOQ tablets.

Manufactured by: AbbVie Inc., North Chicago, IL 60064, USA RINVOQ® is a registered trademark of AbbVie Biotechnology Ltd. ©2019-2022 AbbVie Inc. Ref: 20071734

Revised: April 2022

LAB-7082 MASTER US-RNQR-220149

04 May 2022 9:00 AM

EL ESTRÉS

Y LA INTELIGENCIA EMOCIONAL EN MÉDICOS PUERTORRIQUEÑOS Ivette S. Rivera Martínez Ph.D. Psicología Industrial Organizacional Pontificia Universidad Católica de Puerto Rico, Ponce

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Revista Puertorriqueña de Medicina y Salud Pública

PALABRAS CLAVE Estrés, Inteligencia Emocional, Médicos KEYWORDS Stress, Emotional Intelligence, Physicians Revista Puertorriqueña de Medicina y Salud Pública

71

RESUMEN Esta investigación pretendió analizar la relación entre el estrés y la inteligencia emocional en una muestra de médicos de la región sur de Puerto Rico. La investigación cuantitativa quedó constituida por 115 participantes. Se encontró una relación estadísticamente significativa entre la inteligencia emocional y el estrés. Igualmente se encontró diferencia estadísticamente significativa entre los médicos de ambos géneros y el estrés. Contrario a lo esperado, no se halló diferencia estadísticamente significativa entre los médicos de ambos géneros y la inteligencia emocional. Se estableció un nivel de significancia de .05, encontrándose niveles de correlación rho de Spearman en .001. El valor obtenido producto de la correlación fue de -.335. El estudio sirve como herramienta para poder comprender mejor las variables estudiadas en la población médica puertorriqueña. Se evidencia la importancia de un buen control de las emociones para mantener reducidos los niveles de estrés percibido. Para futuras investigaciones se recomienda entre otras cosas, proveer una mayor representatividad de la muestra.

ABSTRACT This research aimed to analyze the relationship between stress and emotional intelligence in a sample of physicians from the southern region of Puerto Rico. The quantitative research was made up of 115 participants. A statistically significant relationship was found between emotional intelligence and stress. Likewise, a statistically significant difference was between the physicians of both genders and stress. Contrary to expectations, no statistically significant difference was found between physicians of both genders and emotional intelligence. A significance level of .05 was established, finding Spearman’s rho correlation levels at .001. The value obtained as a product of the correlation was -.335. The study serves as a tool to better understand the variables studied in the Puerto Rican medical population. The importance of good control of emotions to keep levels of perceived stress low is evidenced. For future research it is recommended among other things, to provide a greater representativeness of the sample.

INTRODUCCIÓN El propósito de esta investigación fue analizar la relación entre el estrés y la inteligencia emocional en una muestra de médicos. El estudio conllevó la oportunidad de que los individuos pudiesen identificar con qué frecuencia se han sentido estresados, particularmente durante el último mes. Igualmente, permitió conocer la frecuencia con la cual el individuo siente que ha sido capaz de afrontar sus problemas.

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METODOLOGÍA La investigación cuantitativa, contó con la participación de 115 médicos afiliados a una organización sin fines de lucro de la región sur de Puerto Rico que brinda educación continua a médicos con licencia vigente. Los criterios de inclusión fueron: ser mayor de 21 años, de ambos géneros y llevar al menos tres meses o más ejerciendo la profesión de la Medicina en Puerto Rico entre los cuales podían encontrarse médicos/médicos residentes.

Recibida la aprobación de la Junta de Revisión Institucional (Institutional Review Board, IRB), se inició la investigación.

El proceso fue realizado de manera vir-

Revista Puertorriqueña de Medicina y Salud Pública

tual entre octubre de 2020 a febrero de 2021 utilizando la plataforma PsychData. En primer lugar, se encontraba la Hoja de Consentimiento Informado, documento que explicaba a los posibles participantes el propósito de la investigación, la voluntariedad de su participación y la garantía de su anonimato a tenor con el Código de Ética que rige la profesión de la Psicología en Puerto Rico.

Igualmente, se informó a los participantes acerca del respeto a la dignidad y la confidencialidad que se mantendría durante el estudio y posterior al mismo.

Luego se encontraba la Hoja de Datos Sociodemográficos, donde se recopiló

información de variables relacionadas con los participantes en el estudio. A este instrumento le seguía la Escala de Estrés Percibido (Versión Adaptada, EEP-14) de Cohen et al. en 1983 y traducida al español por Remor en 2006. Por último, se encontraba el Inventario de Inteligencia Emocional (Versión Corta, IIE-20) de Andújar en 2005.

Para el análisis estadístico de resultados se utilizó la base de datos IBM SPSS Statistics versión 27. Los resultados de esta investigación están disponibles en la Biblioteca Encarnación Valdés de la Pontificia Universidad Católica, Ponce.

RESULTADOS Análisis Sociodemográfico. Los hallazgos reflejaron que 61 (53%) de los participantes fueron mujeres, mientras 54 (47%) fueron hombres. Además, 69 (60%) de los participantes tienen más de 51 años. Un total de 83 (72%) de los participantes indicó estar casado (a). De los cuales, 85 (74%) de los participantes opinó tener hijo (a) o dependientes. En cuanto a la especialidad de los participantes, se obtuvo que 38 (33%) de los médicos que participaron de la investigación ejercen la medicina general. De igual manera 58 (50%) de los médicos reportaron poseen otra especialidad. Según los hallazgos 78 (68%) de los participantes tienen más de 18 años de servicio en la Medicina. Además, 67 (58%) de los participantes cuenta con oficina privada para ejercer sus funciones en Medicina.

Finalmente, se encuestó si es catedrático en la universidad. El resultado fue que 71 (62%) de los médicos opinó que no.

Escala de Estrés Percibido. Con relación a las preguntas de la 1 a la 7, se observó que el resultado de mayor porcentaje ante muy a menudo fue: en el último mes, ¿con qué frecuencia se ha sentido nervioso o estresado? (12%, ƒ = 13). Sin embargo, hay que resaltar que los participantes presentaron nunca estar estresado en cuanto en el último mes, ¿con qué frecuencia ha estado seguro sobre su capacidad para manejar sus problemas personales? (66%, ƒ = 61). Las preguntas 8 a la 14 completaron con la indagación sobre el estrés percibido que presentaron los participantes. Entre los resultados de

mayor porcentaje se destacan, en el último mes, ¿con que frecuencia ha pensado sobre las cosas que le quedan por hacer? (44%, ƒ = 47). Además, se observó que los médicos nunca perciben estrés en el último mes en la frecuencia para controlar las dificultades de su vida (49%, ƒ = 53).

Inventario de Inteligencia Emocional.

Con relación a los resultados relacionados con la escala de Autoconocimiento, la premisa de mayor porcentaje en totalmente de acuerdo fue las personas deben ser capaces de conocer sus emociones (68%, ƒ = 70). Sobre la escala de Automanejo, la premisa de mayor porcentaje en totalmente de acuerdo fue uno debe tratar de dar el máximo en lo que hace (87%, ƒ = 90). En cuanto a la escala de Conciencia Emocional, los resultados reflejaron que la premisa de mayor porcentaje en totalmente de acuerdo fue disfruto ayudar a que otros crezcan (86%, ƒ = 89). Los resultados relacionados a la escala de Manejo de las Relaciones, mostraron que la premisa de mayor porcentaje en totalmente de acuerdo fue un líder respeta a su gente y NO abusa de su poder (91%, ƒ = 94).

Preguntas de Investigación. La primera pregunta tuvo como propósito discutir la relación entre el estrés y la inteligencia emocional. De acuerdo con los resultados de la prueba estadística, Spearman (N = 108) = -.335, p = .001. Este valor de p, si se compara a un nivel de significancia de 0.05 (p < 0.05) establece que se rechaza la hipótesis nula. Por tanto, existe relación estadísticamente significativa entre el estrés y la inteligencia emocional. Con relación a la segunda pregunta de investigación, la misma tuvo como propósito discutir la diferencia entre los médicos de ambos géneros y el estrés que perciben de las situaciones de la vida cotidiana, mediante la prueba no paramétrica Mann-Whitney. Los resultados indicaron un rango promedio en los masculinos de 45.52 y en las féminas un rango promedio de 62.24. El valor de la significancia de la prueba fue de p = .006 < 0.05, por lo tanto, se determinó rechazar la hipótesis nula, y se encontró que existe diferencia estadísticamente significativa entre los médicos de ambos

géneros y el estrés que perciben de las situaciones de la vida cotidiana a un nivel de .05 de significancia. Por último, la tercera pregunta de investigación, tuvo como propósito discutir la diferencia entre los médicos de ambos géneros y las competencias de inteligencia emocional (autoconocimiento, automanejo, conciencia emocional y manejo de las relaciones) que poseen, mediante la prueba no paramétrica de Mann-Whitney. Los resultados indicaron que los rangos promedios en las competencias de inteligencia emocional no difieren significativamente.

El valor de la significancia de la prueba en las cuatro competencias fue > 0.05, por lo tanto, se determinó no rechazar la hipótesis nula, y se encontró que no existe diferencia estadísticamente significativa entre los médicos de ambos géneros y las competencias de inteligencia emocional que poseen a un nivel de .05 de significancia.

DISCUSIÓN Y CONCLUSIÓN Se encontró que mientras más fortalecida está la inteligencia emocional existe mayor probabilidad de que los niveles de estrés sean bajos. Esto evidencia la importancia de que las organizaciones puedan establecer programas de control de emociones que vayan dirigidos a fomentar una buena salud mental entre sus empleados, en este caso en particular, los médicos. Para esto, se pueden establecer protocolos que vayan dirigidos a crear alianzas con entidades que trabajen el aspecto de la salud mental y creen una línea de apoyo 24/7 con la intención de que los médicos puedan manifestar incomodidades ante situaciones que le provoquen estrés. Lo anterior pudiese representar una apertura para que desde la disciplina de la Psicología Industrial Organizacional se pueda ayudar a atender la complicada situación del éxodo de médicos fuera del País, buscando alternativas que colaboren a retener el talento médico puertorriqueño en las organizaciones.

Revista Puertorriqueña de Medicina y Salud Pública

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LA SALUD ORAL ES PIEZA CLAVE EN EL CUIDADO INTEGRAL DE LA DIABETES Por: Wanda Nazario, Dentista Directora Administrativa de Servicios Dentales de MCS

H

oy en día contamos con estudios que revelan la estrecha e importante relación de la diabetes y la salud oral. Todos aprendimos desde pequeños lo importante que es cepillarse los dientes dos veces al día y evitar comer dulces. Podríamos pensar que estos consejos de prevención son una fórmula sencilla y simple para disfrutar de una vida saludable.

Pese al progreso en conocimiento científico en los temas de salud, el número de adultos que enfrentan condiciones crónicas como la enfermedad periodontal y la diabetes continua en aumento. Múltiples factores, incluyendo genética y estilos de vida son las mismas causas principales para ambas condiciones. Estudios como el del Dr. Casanova et al 1 establecen que la relación de estas condiciones es bidireccional: la diabetes aumenta el riesgo de periodontitis y la periodontitis afecta el control glicémico de los pacientes.

Esta relación bidireccional ha sido tópico de una amplia literatura que se esfuerza por concientizar a todas las partes sobre el impacto directo que tiene cada condición en la otra.2 Por ejemplo, el tratamiento de condiciones periodontales, según reportado, lleva a la reducción de HbA1c de aproximadamente 0.4%. Esto es similar al progreso que se puede esperar con cambios en el manejo farmacéutico al añadir un segundo medicamento para un

REFERENCIAS

paciente diabético con dificultad para controlar la hiperglicemia, pero a un menor costo para el paciente y sin efectos secundarios permanentes.

Otra interacción importante es el mantenimiento de los dientes en boca. Si el paciente no tiene dientes, se limita la dieta, por lo que se altera la nutrición y esto podría llevar a pobre control de la glucosa o azúcar en sangre. La prevención y el tratamiento de las condiciones orales se ha convertido en una de las herramientas importantes para poder manejar la condición de diabetes.

El manejo interdisciplinario de estas condiciones se convierte en una necesidad para poder alcanzar la salud óptima en los pacientes de diabetes. Es por esto por lo que la Asociación Americana de Diabetes incluye en los estándares de cuidado médico del 2021 un referido al dentista como parte del manejo de cuidado médico inicial.3 El tratamiento efectivo de las condiciones de salud oral en pacientes con diabetes incluye el manejo, no tan solo de la periodontitis, sino también de boca seca, candidiasis, caries y pérdida de dientes, entre otras. Estas condiciones afectan la calidad de vida del paciente significativamente. Los médicos, al detectar complicaciones de naturaleza oral, deben poder orientar al paciente sobre la importancia de mantener los hábitos de higiene y visitar al dentista para el

manejo apropiado. Por otro lado, al detectar condiciones periodontales avanzadas, los dentistas pueden ayudar a identificar pacientes prediabéticos o pacientes que desconocen su condición de diabetes, refiriéndolos a su médico para evaluación.

Aunque un equipo multidisciplinario es esencial para manejar adecuadamente esta condición crónica, las personas con diabetes también tienen un rol protagónico para alcanzar una mejor calidad de vida. Esto se logra: •Controlando su ingesta de azúcares: este hábito saludable ayuda tanto al índice glicémico como a la prevención de caries.

•Manteniendo su higiene oral a diario: esto ayuda a combatir la enfermedad periodontal.

•Reconociendo signos de pobre control de salud oral: los cambios orales como el sangrado de las encías, sequedad de la boca y cambios en sabor pueden ayudar a identificar problemas en el control de la diabetes.

•Asistiendo a las citas de prevención: se logra una comunicación entre los diferentes profesionales de la salud.

En ocasiones, el cuidado de los dientes y encías pasa a segundo plano cuando se habla de diabetes y sus complicaciones. Visitemos al dentista según recomendado para cumplir con los procedimientos de rutina y alcanzar Salud Completa.

1.Casanova L. Hughes FJ. Preshaw PM. Diabetes and periodontal disease: a two-way relationship. British Dental Journal 2014; 217(8): 433-7.

2.Borgnakke WS and Poudel P (2021)- Diabetes and oral health: summary of current scientific evidence for why transdisciplinary collaboration is needed. Frontiers in Dental Medicine. 2:709831.2021 3.American Diabetes Association, Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Medical Care in Diabetes – 2021. Diabetes Care 2021: 44(S1): S40.S52

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Revista Puertorriqueña de Medicina y Salud Pública

Dr. Eric Adler

Dr. Álvarez Romagosa

Cirujano Plástico Facial

Ginecólogo/Obstetra

SALUD QUE TE CUIDA Salud completa es un equilibrio entre tu salud física, mental y emocional.

Con MCS cuentas con una amplia red de médicos y hospitales para atender tus necesidades de salud y con beneficios innovadores que transforman tu calidad de vida.

787.758.2500 | mcs.com.pr

@MCSPuertoRico

AGENDA MÉDICA 2022 EVENTOS Y CONVENCIONES www.medicinaysaludpublica.com

Puerto Rico TIPO DE EVENTO

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Actividad

Lugar

Contacto

23 al 25 de junio de 2022

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Graduaciones 2022

Lucy M. Studemeister (Estudiante en el centro) | A mano izquierda el Rector el Dr. José A Torres Ruiz y a la derecha la Decana de la Escuela de Medicina la Dra. Olga Rodríguez De Arzola Reconocimiento Academia Médica del Sur (Promedio mas alto en medicina)

Dra. Jacqueline Barrientos (Oradora Principal) Directora de la Unidad de Cáncer Hematológico en el Mount Sinai Medical Center in Miami Directora del Programa de Investigación en Oncología de esa institución

Fotos de izquierda a derecha: Luis K. Hernández Muñiz, (Estudiante Doctorado en Psicología Clínica) junto al Presidente y CEO David Lenihan de Ponce Health Sciences University.

Premio Presidencial a la Diversidad Reconocimiento por Departamento del Programa Doctoral en Psicología Clínica Reconocimiento de Honor Académico (Promedio 3.90 a 4.0) Karen L. Ocasio Rivera (Maestría en Salud Pública) junto al Presidente y CEO David Lenihan de Ponce Health Sciences University.

Reconocimiento de Honor Académico (Promedio 3.90 a 4.0) Reconocimiento Academia Médica del Sur Premio Presidencial a la Diversidad Daniela N. Martir (Graduanda del Doctorado en Medicina) a su lado Izquierdo Dr. David Lenihan Presidente y CEO de Ponce Health Sciences University.

Recibe Premio Presidencial a la Diversidad

Graduaciones 2022

El Dr. José Seguinot, Decano de la Facultad de Ciencias Biosociales y Escuela Graduada de Salud Pública recibiendo un reconocimiento junto a la Dra. Mayra Olavarría Cruz, Presidenta de la Universidad de Puerto Rico y la Dra. Ilka C. Ríos Reyes, Rectora del Recinto de Ciencias Médicas.

Estudiantes recibiendo su diploma.

Graduaciones 2022

Estudiante recibiendo su diploma junto a la Dra. Yocasta Brugal, Presidenta y Rectora de la Escuela de Medicina San Juan Bautista y con miembros de la Junta de Síndicos.

Estudiante recibiendo su diploma junto a miembros de la Junta de Síndicos.

Estudiante recibiendo su diploma junto a la Dra. Yocasta Brugal Presidenta y Rectora de la Escuela de Medicina San Juan Bautista.

La estudiante de Medicina Evian Pérez y la Dra. Michelle Santiago, recibiendo la dedicatoria de los actos de graduación del programa de Medicina.

De izquierda a derecha): Evian Pérez, Presidenta Programa de Medicina, Yarelis Colorado, Presidenta Programa de Salud Pública, Amneris Andujar, Presidenta Programa de Enfermería.

Estudiantes en el proceso de juramentación como Profesionales de la Salud.

Graduaciones 2022

Dra. Waleska Crespo Rivera_Presidenta de la Universidad Central del Caribe

Alejandro Santiago Nazario - Estudiante de Medicina de la Universidad Central del Caribe, Summa Cum Laude.

Momento De La Investidura Doctoral De La Dra. Ana Judith Román, Primera Neuróloga De Puerto Rico.

Estudiantes recibiendo su diploma.

Primera clase graduada de Doctores en Quiropráctica

Erica Ventura - Presidenta de la Clase de Quiropráctica de la Universidad Central del Caribe, Summa Cum Laude.

La Dra. Ana Judith Román durante su mensaje a los graduandos

MSP SERVICIO PÚBLICO

FDA APPROVES LILLY AND INCYTE’S OLUMIANT® (BARICITINIB) AS FIRST AND ONLY SYSTEMIC MEDICINE FOR ADULTS WITH SEVERE ALOPECIA AREATA

Eli Lilly and Company (NYSE: LLY) and Incyte (NASDAQ:INCY) announced today that the U.S. Food and Drug Administration (FDA) has approved OLUMIANT® (baricitinib), a once-daily pill, as a first-in-disease systemic treatment for adults with severe alopecia areata (AA), available as 4-mg, 2-mg and 1-mg tablets. The recommended dose is OLUMIANT 2- mg/day, with an increase to 4-mg/day if treatment response

is inadequate. For patients with nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider treating with 4- mg/day.

Once an adequate response is achieved on 4-mg/day, the dosage is to be decreased to 2-mg/day.

OLUMIANT is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants.

SKYRIZI® (RISANKIZUMAB-RZAA) RECIBE APROBACIÓN DE LA FDA COMO LA PRIMERA Y ÚNICA INTERLEUCINA-23 (IL_23) ESPECÍFICA PARA TRATAR LA ENFERMEDAD DE CROHN ACTIVA DE MODERADA A SEVERA EN ADULTOS

AbbVie (NYSE: ABBV) hoy anunció que la Administración Federal de Drogas y Alimentos (FDA, por sus siglas en inglés) de los Estados Unidos aprobó SKYRIZI® (risankizumab-rzaa) como el primer y único inhibidor de interleucina-23 (IL-23) específico para el tratamiento de adultos con enfermedad de Crohn (EC) activa de moderada a severa. En dos estudios clínicos de inducción y uno de mantenimiento, SKYRIZI demostró mejoras significativas en la respuesta endoscópica

(definida como una disminución de más del 50% del Puntaje Endoscópico Simple en EC [SES-CD, por sus siglas en inglés] inicial o en pacientes con enfermedad ileal aislada y SES-CD de 4, una reducción de al menos 2 puntos desde el inicio) y en la remisión clínica (definida como un Índice de Actividad de la Enfermedad de Crohn [CDAI, por su siglas en inglés] de menos de 150) en comparación con placebo, tanto en terapia de inducción como de mantenimiento.

DEPARTAMENTO DE SALUD ANUNCIA JORNADAS DE VACUNACIÓN PARA NIÑOS DE 6 MESES A 4 AÑOS CONTRA EL COVID-19

A través de un comunicado, el Departamento de Salud informó que se prepara para vacunar a los niños de seis meses a cuatro años con las vacunas de Pfizer y Moderna. El proceso de inoculación debe comenzar la próxima semana, una vez, se reciban las recomendaciones puntuales por parte de los científicos asesores de los Centros para el Control y Prevención de Enfermedades (CDC, siglas en inglés).

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En ese contexto, la agencia, estableció un plan de trabajo que incluye adiestrar a los más de 200 proveedores pediátricos de la vacuna contra el COVID-19.

En Puerto Rico fueron asignadas 22,000 vacunas para atender esa población. _____

Dr. Carlos Mellado, secretario del Departamento de Salud. Foto: Revista de Medicina y Salud Pública.

De izquierda a derecha: Dr. Gino Natalicchio, Rector, Dra. Lorna Martínez, Vicerrectora UAGM Cupey, Dra. Lilliam Rodríguez Capó, Honoris Causa, José F. Méndez Méndez, Presidente y Dr. José E. Maldonado, VP Asuntos Académicos.

Confieren doctorado HONORIS CAUSA a Lilliam Rodríguez Capó de VOCES

Lilliam Rodríguez Capó durante su mensaje a las graduandos.

Momento de la investidura doctoral.

La Universidad Ana G. Méndez (UAGM) confirió un total de 2,015 grados académicos en la segunda ceremonia de graduación realizada hoy en el Centro de Convenciones de Puerto Rico.

“Apuesto cien por ciento a su talento y a sus ganas de crecer. A su determinación de hacer las cosas de manera distinta. Estoy convencido de que se destacarán en sus respectivas profesiones y que seremos testigos de sus grandes aportaciones al país”, expresó José F. Méndez Méndez, presidente de UAGM, en su mensaje a los graduandos.

Durante los actos, la universidad le otorgó un doctorado honoris causa en Salud a Lilliam Rodríguez Capó, principal oficial ejecutivo y fundadora de VOCES, Coalición de Inmunización y Promoción de la Salud de Puerto Rico, por su excelente liderato para articular de forma exitosa los esfuerzos de vacunación y orientación a la población en tiempos de pandemia.

En su mensaje, Rodríguez destacó, entre otras cosas, la importancia de ser salubristas. “Todos debemos ser salubristas, no importa la carrera en que nos desempeñemos o estemos a punto de emprender. Esta pandemia, que nos ha tocado vivir tan duramente estos dos años, nos debe hacer reflexionar que no podemos vivir una vida de manera individual, sino pensando en el colectivo, en el bien común”, expresó.

Es la primera vez que la institución celebra una graduación integrada con sus tres recintos de Carolina, Cupey y Gurabo y sus ocho centros universitarios. Los recién graduados que obtuvieron sus grados en la ceremonia de hoy jueves, 16 de junio pertenecen a las divisiones académicas de: Ciencias y Tecnología, Negocios, Turismo y Emprendimiento, Ingeniería, Diseño y Arquitectura, Medicina Naturopática, Medicina Veterinaria y Dental. Se otorgaron 59 certificados técnicos,

297 grados asociados, 1,071 bachilleratos, 567 maestrías y 21 doctorados.

Lilliam Rodríguez: Siempre lista para ayudar al país El 2021 trajo para ella y su organización distintos retos que ha sabido proyectar y llevar adelante junto con un equipo de personas que solo trabaja para ser útil a la sociedad en la que viven.

Conoce la trayectoria de esta ilustre dama que se convirtió en la heroína contra el Covid-19.

VOCES es una coalición multisectorial, centrada en la comunidad, dedicada a la promoción de la salud y prevención de enfermedades mediante la inmunización con estrategias diversas basadas en evidencia. Fue fundada en el 2013 por Lilliam Rodríguez Capó.

Cuenta con la colaboración de sobre 100 entidades e individuos en el campo de la salud en P.R. Actualmente, es reconocida como una organización con certificación 501c3 y en cumplimiento con las regulaciones del Estado libre Asociado de Puerto Rico.

Desde su creación, VOCES ha tenido un impacto significativo en la educación y promoción de la inmunización a través de iniciativas diversas, campañas educativas y eventos nacionales en colaboración con asociaciones profesionales, el Departamento de Salud de Puerto Rico y entidades no gubernamentales.

Estos esfuerzos de concienciación integral han dado lugar a darle un tema de la actualidad, a la inmunización, a la aprobación de política pública, mejor cobertura y regulaciones innovadoras que han acercado a Puerto Rico a garantizar un acceso adecuado a las vacunas para un segmento amplio de la población.

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MSP celebra y honra a profesionales en el Día Internacional de Acción por la Salud de las Mujeres

Isbelia Farías Periodista

A propósito del Día Internacional de Acción por la Salud de las Mujeres, Pedro Lugo, vicepresidente del Grupo Editorial Mundo y de la Revista Medicina y Salud Pública, destacó la labor de los médicos y profesionales quienes se esfuerzan por brindar su apoyo a favor de la salud de las féminas puertorriqueñas, agradeciendo a las mujeres que han encaminado su vida, como su madre, y otras que lideran en el campo de la ciencia, salud y la política.

El doctor Oscar Soto Raíces, reumatólogo y asesor editorial de la Revista Medicina y Salud Pública, resaltó que el camino a transitar ha sido más difícil para la mujer que para el hombre, por lo que se reconoce la contribución histórica que han hecho al pueblo a través del apoyo que han dado a la salud de la mujer en Puerto Rico. Las mujeres han roto patrones y han superado obstáculos, por lo que merecen ser celebradas.

Por su parte, el médico y editor de la Revista Medicina y Salud Pública, Dr. Alberto Santiago Cornier, felicitó a quienes se han dedicado a la investigación y el manejo de las enfermedades en la mujer puertorriqueña La senadora Ana Irma Rivera Lassén, enfatizó que hablar de la salud de la mujer,

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del cuerpo femenino, es un tabú: “parecería que todo el mundo tiene derecho de hablar del cuerpo de las mujeres, menos las mujeres mismas. Todos se creen con derecho de controlar el cuerpo de las mujeres, hasta el Estado. Hablar de persona gestante parece darles pánico a algunas personas, porque ello significa hablar de diversidad, reconocer que hay mujeres que en sus cuerpos tienen capacidad de gestación, aunque su identidad de género sea otra”, afirmó, añadiendo que hablar de los derechos de las mujeres y de sus embarazos atañe a las mujeres y a las personas gestantes, así que se deben normalizar las conversaciones entre las mujeres, para las mujeres y por las mujeres.

La senadora Migdalia González Arroyo, presidenta de la comisión de asuntos de la mujer del Senado de Puerto Rico, felicitó a las profesionales como salubristas y por sus aportes en el ámbito de la salud de las mujeres. Libia Méndez, la vicepresidenta de la Cámara de Representantes, recordó que su madre era ama de casa y su papá agricultor, por lo que los pequeños iban a la escuela para aprender y luego enseñar a la madre. Desde el 97 ocupa el cargo como representante, pero su camino no fue fácil, pues, venía de la pobreza. Hace énfasis

Revista Puertorriqueña de Medicina y Salud Pública

en la importancia que tiene la lactancia materna, calificándolo como un acto de amor y de ternura.

La mujer es la fuerza unificadora de la familia y la sociedad, por lo que se debe promover su bienestar, el cual es, más que una necesidad, es un deber que implica retos, ya que, por ser mujer, los números no siempre están a favor, basándose en el hecho de que la depresión es más alta en la mujer, las muertes por enfermedades cardiovasculares son más elevadas en la mujer, las discapacidades son más frecuentes en las mujeres, las infecciones por VIH son más altas en la mujer, quienes, además, padecen de cáncer uterino y seno, endometriosis, síndrome de ovario poliquístico, lupus, artritis, entre otras condiciones que arriesgan su salud, en Puerto Rico y en el mundo.

En este sentido, se destaca la labor de: Lilliam Rodríguez, principal oficial y fundadora de VOCES; Dra. María Ramos, cardióloga y presidenta de la sociedad de cardiología; Dra. Leticia Hernánez, endocrinóloga y presidenta de la sociedad puertorriqueña de endocrinología y diabetología; Dra. Idhaliz Flores, Investigadora en endometriosis; Dra. Esther Torres, gastroenteróloga, directora del centro de

Lilliam Rodríguez, primera oficial y CEO de VOCES, recibe su condecoración. Foto: Senado de Puerto Rico.

enfermedades inflamatorias del intestino de la UPR, presidenta de la fundación Esther A. Torres; Dra. Carmen Zorrilla, catedrática del recinto de ciencias médicas y miembro de la coalición científica de Puerto Rico; Dr. Nabal Bracero, ginecólogo, presidente de Progyn, especialista en infertilidad y endocrinología reproductiva; Dra. Damaris Torres Paoli, presidenta de la sociedad dermatológica de Puerto Rico; Dra. Eva Cruz, radióloga, especialista en imágenes de la mujer; Dr. Bolívar Arboleda, director médico y director del Instituto de Seno, del Hospital HIMA, San Pablo, Caguas; Dra. Franchesca Fiorito, neuróloga especialista en cefaleas; Dra. Ángeles Rodríguez, infectóloga y exepidemióloga del Estado; Dra. Bárbara Rosado, gastroenteróloga hepatóloga; Dra. Elivette Zambrana, reumatóloga pediátrica y presidenta de la Asociación de Reumatólogos de Puerto Rico; Lcda. Linette Sánchez, directora del programa de vacunación del colegio de médicos cirujanos de Puerto Rico; Adria García, enfermera oncóloga.

La Revista Medicina y Salud Pública agradece y reconoce el valor y contribución para la salud de todas las mujeres puertorriqueñas, por parte de los profesionales mencionados.

Los profesionales homenajeados recibieron un premio en el marco del Día Internacional de Acción por la Salud de las Mujeres, destacando que todos cuentan con una preparación académica y una experiencia laboral formidable. En el caso

Dra. Elivette Zambrana, presidenta de la Asociación de Reumatólogos de Puerto Rico, recibe su condecoración. Foto: Senado de Puerto Rico.

de la doctora Carmen Zorrilla, ella se mantiene activa en varios proyectos, pues actualmente, está trabajando en respuesta a la pandemia de COVID-19 en PR, con un centro de pruebas diagnósticas moleculares, el estudio de la vacuna Novavax para COVID, un centro de vacunación de COVID en el RCM y futuros estudios de estrategias de vacunación de COVID en embarazadas.

Zorrilla, al recibir su premio, señaló que falta que la Organización Mundial de la Salud reconozca que Puerto Rico fue el primer país en eliminar la infección perinatal del VIH desde 1994.

La doctora Elivette Zambrana indicó que es necesario trabajar de la mano en políticas públicas que promuevan un estilo de vida saludable para paliar muchas condiciones que están asociadas a la obesidad y que afectan a las mujeres. El Dr. Nabal Bracero también resaltó la preocupación que existe sobre la educación reproductiva, que esta sea de calidad, tangible y que permite defender a la mujer de la violencia sexual o reproductiva.

El doctor Bolívar Arboleda mencionó lo importante que ha sido la Revista y Salud Pública en la difusión de temas científicos que permiten la actualización de conocimientos, acotando que el cáncer de seno continúa siendo la primera causa de mortalidad por cáncer en la mujer, por lo que queda mucho trabajo para avanzar.

La doctora Esther Torres reconoce que su inspiración han sido sus pacientes, por

Dra. Esther Torres, catedrática en medicina, en el Recinto de Ciencias Médicas, recibe su condecoración. Foto: Senado de Puerto Rico.

lo que aboga por el derecho y el acceso a la salud, felicitando a la Revista Medicina y Salud Pública por los años que han dedicado a la educación.

La doctora María Ramos es cardióloga y la primera presidenta de la Sociedad Puertorriqueña de Cardiología, en 72 años, lo cual la hace sentir honrada. La gastroenteróloga Bárbara Rosado se pronunció sobre el honor que significa servir a su país.

Finalmente, se honró la labor que realizan las enfermeras 7 enfermeros, quienes cumplen un rol importante como enlace entre los médicos y pacientes, en especial a la licenciada Adria García.

Finalmente, Belinda Z. Burgos González, gerente de proyectos, indicó que “a nivel editorial reconocemos la importancia que ha tenido para nosotros el poder ser testigo del trabajo de mujeres científicas desde los laboratorios del País, precisamente en estudios que pudieran beneficiar a otras mujeres en un futuro, como lo es el caso de enfermedades como el cáncer triple negativo y otros tipos de enfermedades. Igualmente hemos sido testigos de la empatía de distintas profesionales de la salud que dan la milla extra por esas mujeres trabajadoras y jefas de familia, quienes en muchas ocasiones se tienen como última prioridad. Expresamos nuestro agradecimiento a este selecto grupo de profesionales de la salud que se han hecho eco de las atenciones necesarias hacia las mujeres puertorriqueñas”.

Dra. Leticia Hernández, presidenta de la Sociedad Puertorriqueña de Endocrinología y Diabetología, recibe su condecoración. Foto: Senado de Puerto Rico.

Dra. María Ramos, cardióloga y presidenta de la Sociedad Puertorriqueña de Cardiología.

Foto: Senado de Puerto Rico.

Dra. Damaris Torres Paoli, presidenta de la Sociedad Dermatológica de Puerto Rico, recibe su condecoración. Foto: Senado de Puerto Rico.

Dra. Carmen Zorrilla, catedrática e investigadora del RCM, recibe su condecoración. Foto: Senado de Puerto Rico.

Linette Sánchez, directora del programa de vacunación del Colegio de Médicos Cirujanos de Puerto Rico, recibe su condecoración. Foto: Senado de Puerto Rico.

Adria García Rodríguez, enfermera oncóloga, recibe su condecoración.

Foto: Senado de Puerto Rico.

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Dra. Alma Cruz1

Dr. Gabriel Arias2

Dra. Adriana Figueroa3

Adeline Pagán López5

Dr. John Sánchez6

Lcda. Catherine Pimentel 7

Sully Díaz4

Dra. Olga Pereira8

Visibilizando la Hidradenitis:

Primer encuentro de pacientes en Puerto Rico Yolimarian Torres Periodista

Con el objetivo de educar y concientizar acerca de la Hidradenitis Supurativa, desde el año 2020 la Asamblea Legislativa de Puerto Rico, en vista de que esta condición crónica de la piel, dolorosa, no contagiosa, necesitaba más visibilización por el impacto en la vida de los pacientes, declaró la primera semana de junio como la “Semana de la Concienciación de la Hidradenitis Supurativa”.

Motivados por el objetivo de educar y dar voz a los pacientes, la Revista de Medicina y Salud Pública, junto al grupo Hidradenitis Supurativa Golondrinos, serán parte del primer encuentro presencial de esta comunidad de pacientes y especialistas para conocer los avances en tratamientos y diagnóstico en el País.

Vale la pena mencionar que la condición no incapacita, pero sí genera incomodidad, porque la persona afectada comúnmente puede sentir vergüenza y rehusarse a salir en público, debido a la ubicación de estos abscesos, a la supuración y al mal olor, lo cual puede provocar tristeza o incluso, depresión. Aunque no existe cura para esta condición, el diagnóstico y tratamiento temprano pueden controlar el dolor, promover la 90

cicatrización de las heridas y prevenir complicaciones.

Al respecto, la Lic. Janice Marrero Irizarry, presidenta de Vocational and Transition Services, y Consejera de Rehabilitación, indicó que es muy común que se presenten situaciones de empresas que no garantizan los derechos de los pacientes con esos limitantes. “Muchas veces las personas tienen miedo y se quedan callados porque pueden que los despidan si piden un acomodo razonable. A veces sufren atropellos y no hacen valer sus derechos”.

La Licenciada, quien también cita las leyes federales, American with disability (ADA), Acta de Rehabilitación, Sección 504 y la Individual with Disability Education Act (IDEA), que protegen a las personas con discapacidades en el área laboral y educativa, es enfática en precisar que un paciente con Hidradenitis no necesariamente es una persona con discapacidad, ya que no depende de la condición misma, sino las limitaciones que trae consigo esa condición.

Por esa razón, esta Ley contempla la exhortación a todos los organismos públicos y entidades privadas, así como

Revista Puertorriqueña de Medicina y Salud Pública

la ciudadanía en general, a unirse a ser parte de la educación de esta afección para concienciar sobre esta enfermedad autoinmune.

La misma Ley 29, indica que el Departamento de Salud, así como los municipios y cualesquiera otras entidades sin fines de lucro interesadas, deberán adoptar las medidas necesarias para la consecución de los objetivos de esta Ley, mediante la organización y realización de actividades que promuevan la educación a la ciudadanía puertorriqueña sobre esta condición.

REFERENCIAS 1 Dermatóloga y fundadora del Programa de Ciencias Clínicas Externas de hidradenitis supurativa del Recinto de Ciencias Médicas de la Universidad de Puerto Rico. 2Residente del Departamento de Dermatología del Recinto de Ciencias Médicas 3Residente del Departamento de Dermatología del Recinto de Ciencias Médicas 4Veterana actriz puertorriqueña 5 Fundadora de HS Golondrinos Puerto Rico 6Residente del Departamento d e Psiquiatría del RCM 7MS RDN LND 8 Ginecóloga obstetra.

Socializar es saludable, Socializar es saludable, háblalo háblalocon contu tupaciente. paciente.

Déjale saber saberaatus tuspacientes pacientesque que Déjale correr bicicleta bicicletacuida cuidalalaespalda espalday ylas las correr articulaciones,pero perosisiademás ademáslolo articulaciones, hacen con con amigos, amigos,ayuda ayudaaafortalecer fortalecer hacen el sistema sistema inmunológico inmunológicoyya areducir reducirelel riesgo riesgo de de sufrir sufrirenfermedades enfermedades cardiovasculares. cardiovasculares.

Tener vida Teneruna una vida social que los haga social que los haga sentir acompañados sentir acompañados es importante para es importante para la salud. la salud. ¡Háblalo con tus ¡Háblalo con tus pacientes! pacientes!

Visita: grupotriples.com/socializaressaludable Visita: grupotriples.com/socializaressaludable

EN SUS MANOS EL RESPIRO DE LA VIDA:

DR. JOSÉ RODRÍGUEZ SANTANA

DR. JOSÉ RODRÍGUEZ SANTANA Neumólogo Pediátrico

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Muchos son los testimonios de cómo ha salvado a los niños de las garras de una enfermedad respiratoria. Su práctica enfocada en el área de neumología y cuidado crítico ha sido el bálsamo que precisamente han devuelto a su vez la vida a esos padres que han desesperado por la vida de sus hijos ante la amenaza de un virus pulmonar y el cuidado crítico de sus vástagos.

Se trata de una humilde síntesis de la vida del Dr. José Rodríguez Santana, neumólogo pediátrico puertorriqueño, quien ha sumergido su carrera en la investigación clínica y científica del asma pediátrica en Puerto Rico, y en atender a los cientos de pacientes que como comuna, le esperan día a día en su oficina médica para probar la fuerza de ese suspiro de vida.

Luego de estudiar biología y ciencias naturales en la Universidad de Puerto Rico, Rodríguez descubrió que su verdadera vocación era la medicina, así que la estudió en la Universidad Pedro Henríquez Ureña, en la República Dominicana; su especialidad en pediatría la cursó en Puerto Rico. Su interés estuvo orientado hacia el cuidado crítico pediátrico y las enfermedades respiratorias, tal cual lo ejerce hoy día desde los hospitales Hima San Pablo de Caguas y Auxilio Mutuo.

Ha sido testigo de cómo el manejo de los pacientes con asma se hacía de forma muy rudimentaria, sin computación ni toda la sofisticación con la que se cuenta en la actualidad, lo cual representó un reto para el consagrado galeno.

Desde el año 2000 inició unos proyectos de investigación, conocidos como el análisis genético de los latinos con asma, el cual se hizo de manera colaborativa con la Universidad de

California, San Francisco y otros entes.

El interés de estudiar esta población se debe a que es la más propensa, sobre todo cuando hay exposición a cierto tipo de ambiente.

Su equipo ha sido pionero promoviendo la necesidad de que esta condición sea vista y tratada como una enfermedad crónica, a base de esteroides. Todos estos descubrimientos hicieron que los pacientes ganaran buena calidad de vida.

La muerte por asma, en latinos y en puertorriqueños, era mayor que lo que se describía en la raza caucásica en Puerto Rico, incluso más que otras razas denominadas hispanas, como los mexicanos.

La respuesta al albuterol, en mexicanos y puertorriqueños, era diferente. Los puertorriqueños no respondían tan bien. Esto hizo pensar que había algo genético en la población de Puerto Rico.

Fueron estos los primeros estudios que esclarecieron muchas dudas sobre la condición del asma.

Rodríguez y su equipo hicieron cultivos de las células nasales y cómo estas responden a las infecciones virales para conocer la relación entre el asma e infecciones virales.

Hoy día, ellos hacen un seguimiento a los niños cada vez que se exponen a una infección viral, esto lo hacen en laboratorios especializados, analizando no solo los factores ambientales, sino también genéticos. Ya no se necesita recurrir a estudios invasivos para tratar a los niños.

Precisamente por todas las contribuciones de la carrera en medicina contra el asma, este A Ciencia Cierta se lo dedicamos al Dr. José Rodríguez Santana, neumólogo pediátrico.

¿PODRÍA ESTAR EXPERIMENTANDO MIGRAÑA? ¿Experimenta ataques de dolor de cabeza que duran entre 4 y 72 horas? ¿Su dolor de cabeza se concentra en un lado de la cabeza, de manera pulsante y se agrava con la actividad? ¿Experimenta sensibilidad a la luz o al sonido cuando sufre un dolor de cabeza?

Cuando sufre un dolor de cabeza, ¿experimenta náuseas o vómitos?1

ES POSIBLE QUE SUFRA DE MIGRAÑA La migraña es la segunda causa principal de discapacidad en todo el mundo a partir del 2016.2 Según el estudio American Migraine Prevalence and Prevention (Prevalencia y prevención de la migraña en Estados Unidos), más del 35 % de las personas con migraña eran candidatos para un tratamiento preventivo, pero solo el 10 % de esas personas estaban en un tratamiento preventivo.3 13 % de los puertorriqueños experimentan migraña.4

La migraña afecta la capacidad de las personas para funcionar y realizar las actividades diarias de su vida personal y profesional. Para las personas con migraña, un día de dolor de cabeza por semana podría significar una posibilidad de más de 50 días al año afectados por la migraña.3 Converse con su médico sobre sus opciones

Referencias: 1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition.

Cephalalgia. 2018;38(1):1-211. 2. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

Lancet. 2017;390:1211-1259. 3. Lipton RB, Bigal ME, Diamond M, et al; on behalf of the AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-349. 4. Miranda H, Ortiz G, Figueroa S., et al. Prevalence of headache in Puerto Rico. Headache. 2003;43:774-778.

PP-LU-US-0514 07/2020 ©Lilly USA, LLC 2020. Todos los derechos reservados.

It’s time to fill in the gaps in our understanding of alopecia areata (AA).

AA is an autoimmune disease driven by an attack at the hair follicle, leading to hair loss.1,2 AA can have a considerable impact on the quality of life and emotional well-being of patients. 3-7

Pfizer is a leader in immuno-inflammation and is working to gain a deeper understanding of AA—its pathophysiology and the role of the JAK/STAT pathway.

References: 1. Simakou T, Butcher JP, Reid S, Henriquez FL. Alopecia areata: a multifactorial autoimmune condition. J Autoimmun. 2019;98:74-85.

2. Meah N, Wall D, York K, et al. The Alopecia Areata Consensus of Experts (ACE) study: results of an international expert opinion on treatments for alopecia areata. J Am Acad Dermatol. 2020;83(1):123-130. 3. Aldhouse NVJ, Kitchen H, Knight S, et al. “‘You lose your hair, what’s the big deal?’ I was so embarrassed, I was so self-conscious, I was so depressed:” a qualitative interview study to understand the psychosocial burden of alopecia areata.

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