February 2012 Clinical Advisor

THE CLINICAL ADVISOR • FEBRUARY 2012

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While there are many diabetes complications,

PAINFUL DPN IS ONE THEY CAN’T IGNORE Help manage your patients’ painful Diabetic Peripheral Neuropathy with LYRICA

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1

“If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved.

For full guideline, visit www.aan.com/guidelines.

Level A=Established as effective, based on at least 2 Class I studies.

Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria.

AAN=American Academy of Neurology.

LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia.

PBP01859A/291945-01

© 2011 Pfizer Inc.

Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.

There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of lifethreatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.

Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebotreated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA All rights reserved.

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention).

Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function.

Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema.

For Full Prescribing Information and Medication Guide, please visit www.LyricaHCP.com.

Please see the Brief Summary of Prescribing Information on adjacent pages.

Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.

September 2011

LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert.

INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week.

Neuropathic pain associated with diabetic peripheral neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)* ≥60 150 300 450 600 30–60

75

15–30 <15

Dose Regimen BID or TID

150

225

300

BID or TID

25–50

75

100–150

150

QD or BID

25

25–50

50–75

75

QD

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose.

CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy.

WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment.

Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing.

Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients

without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 31% of LYRICAtreated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treated patients compared to 7% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICAtreated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICAassociated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision).

Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICAtreated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events.

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

ADVERSE REACTIONS 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. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.

Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).

Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.

Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 1 0 1 3 2 0 Thinking abnormal† Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses 3 1 3 6 4 2 Blurry vision‡ Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia.

Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section.

Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation.

Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis.

Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men.

There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. 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. Nervous System Disorders – Headache.

Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement.

DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs.

Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.

When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for

rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. aedpregnancyregistry.org/. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.

LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment.

DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], suggestive of physical dependence.

OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalintreated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.

Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.

LAB-0294-21.0 June 2011

PBP01873/291898-01

© 2011 Pfizer Inc.

All rights reserved.

CONTENTS FEBRUARY 2012

NEWS AND COMMENT

DEPARTMENTS

14

62

Stat Consult Find out the most recent information on diagnosing and treating women with abmormal uterine bleeding.

67

CME/CE Dermatology Clinic

Newsline ■ Controlled BP levels keep patients alive ■ Hepatitis B vaccine for adults with diabetes ■ Higher resting heart rate may predict cardiovascular death ■ Doubts on HPV shots in men ■ Respiratory infections and asthma ■ Nicotine patch may improve cognitive function

■ One year after similar lesions on her arms had healed, a woman developed asymptomatic papules on her neck.

Normal BP reduces lifetime CVD risk 14

■ The parents of a boy noted a hairless area on his scalp shortly after birth that appeared to grow proportionately.

110 Commentary 84

Clinical Challenge A man with mildly diaphoretic skin complains of fatigue and an inability to tolerate food.

89

Derm Dx Read the clinical descriptions, view the images, and then make your diagnosis at ClinicalAdvisor.com.

90

Legal Advisor When a patient does not comply with medical reccomendations, how does a clinician protect herself?

FEATURES 27

39

Demystifying the liver and its diseases An understanding of the liver and its functions will provide the tools to perform a basic workup of patients suspected of having hepatic disease.

How to diagnose metabolic syndrome 39

CME/CE A practical guide to

metabolic syndrome With obesity on the rise, more and more patients are at risk for metabolic syndrome, a diagnosis given to a set of simultaneous disorders.

49

Getting young patients to take their medicine The problem is a challenging one, but there are steps primary-care clinicians can take to eliminate the barriers to medication adherence in children.

MAKING CONTACT

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Continues on page 8

SPECIAL FEATURE!

Picture This A pair of photo essays to break up the day 20, 78

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CONTENTS DEPARTMENTS, cont’d 95

■ Saw palmetto, even at high doses,

does not improve lower urinary symptoms in men with BPH

CME/CE Dermatologic

Look-Alikes Two cases of diffuse erythematous papules—one concentrated on a boy’s diaper area, axillae, palms, and soles, and the other on a man’s trunk and proximal extremities.

99

ADVISOR FORUM 54

Consultations ■ Vitamin D deficiency among Hispanics ■ Do proton pump inhibitors affect calcium absorption?

■ Primary-care hypothyroidism treatment ■ Raising vs. lowering bedtime insulin ■ What causes a metallic taste and burning tongue?

60

Clinical Pearls ■ A little birdie can facilitate pediatric ear exams ■ Ice down dyspnea ■ Check for flat feet in young patients with shin splints

61

Your Comments ■ Vancomycin dosing for MRSA infections

CME/CE Posttest

100 Alternative Meds Update Primarily used to treat menstrual pain and menopausal symptoms, the wild yam is considered by some to be an alternative to hormone therapy.

106 Evidence-Based Medicine ■ Early initiation of parenteral nutrition may increase complications and hospital stay compared with late initiation in critically ill patients ■ Benefits of salt restriction for cardiovascular disease prevention and treatment questioned ■ Cytisine for 25 days may increase smoking cessation rates at 12 months

Nonscaly pink pauples on the neck 67

Patient fails to follow up on breast lump 90

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EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com/web-only Web Exclusives

Slideshows

ClinicalAdvisor.com/WebExclusives

ClinicalAdvisor.com/Slideshows

U.S. health-care expenditure still unevenly distributed Approximately 1% of the U.S. population accounted for 20% percent of health-care spending in 2008 and 2009.

Fetal alcohol spectrum disorders (FASDs) The CDC estimates that 0.2 to 1.5 cases of FASD occur for every 1,000 live births in certain areas of the United States. Learn more about FASDs with this slideshow.

Access to quality primary care reduces mortality Greater access to high-quality primary medical care is associated with a reduced risk of death and supports the benefits of adopting aspects of the medical home model, data from the Medical Expenditure Panel Survey indicate.

Pediatric dosing errors common with IV acetaminophen Calculating IV acetaminophen in milligrams and administering the 10 mg/mL solution in milliliters without adjusting the volume may contribute to overdose in young children.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments.

ClinicalAdvisor.com/DermDx Hyper- and hypopigmented macules and patches Two patients present with hyper- and hypopigmented macules.

Both deny pain or itch but are embarrassed by the rashes.

MAKING CONTACT

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The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Robyn Carlisle, MSN, CNM, WHNP Encouraging a more collaborative medical culture Instead of viewing the new generation of health-care providers as a threat, seasoned clinicians should focus on shaping incoming nurses and physician assistants into colleagues they want working by their side.

Sharon M. O’Brien, MPAS, PA-C Watching the clock can worsen insomnia People who have trouble sleeping are more likely to keep track of the time that passes, creating a heightened sense of anxiety. These easy tips will make your patient’s insomnia disappear more quickly than counting sheep.

Julee B. Waldrop, DNP, PNP-BC, FNP Implementing standardized developmental screening in pediatrics Does your pediatric practice use standardized developmental screening tools for autism spectrum disorder? Research shows that developmental surveillance based on clinician experience alone is not good enough.

William B. Mosher, PA-C Evolution vs. extinction and the physician assistant profession Changing the name of physician assistants is just a starting point for broader redefinition of the profession.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 11

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. Brief Summary Retin-A Micro® (tretinoin gel) microsphere, 0.1% and 0.04% is a formulation containing 0.1% or 0.04%, by weight, tretinoin for topical treatment of acne vulgaris. This formulation uses patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel.

IMPORTANT NOTE: This information is a BRIEF SUMMARY of the complete prescribing information provided with the product and therefore should not be used as the basis for prescribing the product. This summary has been prepared by deleting information from the complete prescribing information such as certain text, tables, and references.

The physician should be thoroughly familiar with the complete prescribing information before prescribing the product.

INDICATIONS AND USAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the use of this product in the treatment of other disorders have not been established.

CONTRAINDICATIONS: This drug is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted.

PRECAUTIONS: General: • The skin of certain individuals may become excessively dry, red, swollen, or blistered. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established.

If a reaction suggesting sensitivity occurs, use of the medication should be discontinued.

Excessive skin dryness may also be experienced; if so, use of an appropriate emollient during the day may be helpful.

• Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products (SPF 15) and protective clothing over treated areas are recommended when exposure cannot be avoided.

• Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.

• Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes.

• Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition.

Information for Patients: A Patient Information Leaflet has been prepared and is included with each package of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%.

Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is begun.

Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of these clinical formulations (0.04% and 0.1%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose applied topically, when normalized for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, normalized for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose applied topically is defined as 1 gram of Retin-A Micro (tretinoin gel) microsphere, 0.1% applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).

Dermal carcinogenicity testing has not been performed with Retin-A Micro (tretinoin gel) microsphere, 0.04% or 0.1%.

Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photo­carcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.

The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.

The components of the microspheres have shown potential for genetic toxicity and teratogenesis.

EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, the HGPRT forward mutation assay, and the mouse micronucleus assay.

In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose applied topically, and normalized for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose applied topically and normalized for total body surface area) and above were observed. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (17 times the human topical dose normalized for total body surface area).

Dermal fertility and perinatal development studies with Retin-A Micro (tretinoin gel) micro­sphere, 0.1% or 0.04%, have not been performed in any species.

Pregnancy: Teratogenic Effects: Pregnancy Category C. In a study of pregnant rats treated with topical application of Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.5 to 1 mg/kg/day on gestation days 6-15 (4 to 8 times the maximum human systemic dose of tretinoin normalized for total body surface area after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%) some alterations were seen in vertebrae and ribs of offspring. In another study, pregnant

New Zealand white rabbits were treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.2, 0.5, and 1.0 mg/kg/day, administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. There appeared to be increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 3 times the maximum human systemic dose of tretinoin after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area. In a repeat study of the highest topical dose (1.0 mg/kg/day) in pregnant rabbits, these effects were not seen, but a few alterations that may be associated with tretinoin exposure were seen. Other pregnant rabbits exposed topically for six hours to 0.5 or 0.1 mg/ kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any teratogenic effects at doses up to 17 times (1.0 mg/kg/day) the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, adjusted for total body surface area, but fetal resorptions were increased at 0.5 mg/kg. In addition, topical tretinoin in non Retin-A Micro (tretinoin gel) microsphere formulations was not teratogenic in rats and rabbits when given in doses of 42 and 27 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively, (assuming a 50 kg adult applied a daily dose of 1.0 g of 0.1% gel topically).

At these topical doses, however, delayed ossification of several bones occurred in rabbits. In rats, a dose-dependent increase of supernumerary ribs was observed.

Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. Tretinoin was teratogenic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is more similar to humans than other species in its handling of tretinoin, fetal malformations were reported for doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose normalized for total body surface area), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques.

Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids.

There are no adequate and well-controlled studies in pregnant women. Retin-A Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of Retin-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.

Non-Teratogenic Effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose applied topically and normalized for total body surface area), resulting in fetal resorptions and variations in ossification. Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (21 times the maximum human systemic dose applied topically and normalized for total body surface area).

There are, however no adequate and well-controlled studies in pregnant women.

Animal Toxicity Studies: In male mice treated topically with Retin-A Micro (tretinoin gel) microsphere 0.1%, at 0.5, 2.0, or 5.0 mg/kg/day tretinoin (2, 8, or 21 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area) for 90 days, a reduction in testicular weight, but with no pathological changes were observed at the two highest doses. Similarly, in female mice there was a reduction in ovarian weights, but without any underlying pathological changes, at 5.0 mg/kg/day (21 times the maximum human dose). In this study there was a dose-related increase in the plasma concentration of tretinoin 4 hours after the first dose. A separate toxicokinetic study in mice indicates that systemic exposure is greater after topical application to unrestrained animals than to restrained animals, suggesting that the systemic toxicity observed is probably related to ingestion. Male and female dogs treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at 0.2, 0.5, or 1.0 mg/kg/day tretinoin (5, 12, or 25 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively) for 90 days showed no evidence of reduced testicular or ovarian weights or pathological changes.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Retin-A Micro (tretinoin gel) microsphere, 0.1% or 0.04%, is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established.

Geriatric Use: Safety and effectiveness in a geriatric population have not been established.

Clinical studies of Retin-A Micro did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

ADVERSE REACTIONS: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate.

However, efficacy has not been established for lower dosing frequencies.

True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin.

OVERDOSAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is intended for topical use only. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Rx only.

Distributed by: Ortho Dermatologics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Los Angeles, CA 90045 11DD0126 07/11 © OMP 2011 RETIN-A MICRO ® is a registered trademark of Ortho-McNeil Pharmaceutical, Inc. ® MICROSPONGE is a registered trademark of AMCOL International Corporation.

CME CE

PROGRAM OUTLINE FEBRUARY 2012

0.5 CREDITS

Page 39 FEATURE A practical guide to metabolic syndrome Jacinta Thomas, APRN-C, and Deborah K. Walker, DNP, CRNP, AOCN ■ LEARNING OBJECTIVES: • Identify the signs of dyslipidemia in obese individuals with metabolic syndrome.

• Describe the consequences of metabolic syndrome in pregnant women.

• Distinguish a normal-weight individual as defined by BMI. • Name the medication that reduces C-reactive protein and LDL cholesterol in patients with metabolic syndrome.

0.5 CREDITS

Page 67 DERMATOLOGY CLINIC Case #1: Nonscaly pink papules on the neck Ashley Brown and Julia R. Nunley, MD

Case #2: Asymptomatic scalp plaque since birth Kerri Robbins, MD ■ LEARNING OBJECTIVES: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 95 DERMATOLOGIC LOOK-ALIKES Diffuse erythematous papules Kerri Robbins, MD ■ Learning objective: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 99 POSTTEST

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of February 2012. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

12 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Newsline

Study casts doubt on male HPV vaccination page 19

Adult diabetics advised to get hep B vaccine page 16

F E B R U A R Y 2 0 12

Nicotine may help long-term memory page 19

© ISTOCKPHOTO.COM / DR. HEINZ LINKE

Controlled BP levels keep patients alive

Normal BP in middle age correlates with the lowest risk of CVD.

among patients aged 60 years and older with isolated systolic hypertension, antihypertensive therapy with chlorthalidone-based stepped-care therapy resulted in a lower rate of cardiovascular events than did placebo. However, at that time effects on mortality were not significant.

Recently, investigators reported on the gain in life expectancy at the 22-year follow-up of SHEP participants who had been randomized to active therapy ( JAMA. 2011; 306:2588-2593). By that point, life expectancy gain was 158 days for cardiovascular death and 105 days for death from all causes. This translated to approximately one day gained in life expectancy free from cardiovascular death per one month of treatment, and approximately half a day gained in life expectancy for all-cause mortality per one month of treatment.

Prevalence of current depression by age and sex Based on responses to the Patient Health Questionnaire, females have higher rates of depression than males in every age group.

12%

12

11%

Male

10 Percentage

CLINICIANS CAN commemorate American Heart Month by sharing with patients new findings that reinforce the importance of avoiding hypertension.

One recent study revealed that people who maintained or reduced their BP to normal levels during middle age have the lowest lifetime risk of cardiovascular disease (CVD), and those with an increase in BP have the highest risk (Circulation. 2012;125:37-44; available at circ.ahajournals.org/ content/125/1/37.long, accessed January 15, 2012).

Researchers recorded baseline BP readings for 61,585 men and women from an average of 14 years earlier, tracking changes in those measurements until the person reached age 55 years and then until the person experienced a MI or stroke, died, or reached age 95 years. The subjects who maintained BP at or reduced it

to normal levels by age 55 years had a CVD lifetime risk of 22%41%. Persons who had already developed hypertension by age 55 years had a CVD lifetime risk for of 42%-69%. To reduce patients’ CVD lifetime risk, prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension.

In another large, long-term trial—the Systolic Hypertension in the Elderly Program (SHEP)— 2,365 patients who underwent 4.5 years of treatment with the diuretic chlorthalidone exhibited significantly lower mortality and increased life expectancy free from cardiovascular death at nearly 22 years of follow-up than did 2,371 subjects taking a placebo.

When originally conducted between 1985 and 1990, the SHEP trial demonstrated that

Female 8%

8 6

7% 5%

7% 5%

5%

4 2

Source: National Health and Nutrition Examination Survey data, 2007–2010

0

12-17

14 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

18-39

40-59

Age group (yrs)

≥60

Newsline Hep B vaccine for adults with diabetes The ACIP put forth a categoryA recommendation advising the younger adults to be vaccinated against HBV as soon as possible after being diagnosed with diabetes. For the patients aged 60 years and older, however, data on the risk of hepatitis B were less robust, prompting a category-B recommendation that the decision to vaccinate should be made by the treating clinician based on an assessment of the patient’s risk and the likelihood of adequate immune response to vaccination.

The severity of HBV infection among adults ranges from asymptomatic to fulminant hepatitis. A total of 3,371 acute HBV infections were reported in 2009. Of the 2,126 infections for which information was available, nearly half (47%) resulted in hospitalization, and 1%

Hepatitis B virons (orange) are found in blood and other bodily fluids.

of the 1,900 infections for which information was available were fatal. Data from the nationwide Emerging Infections Program for the period of 2009-2010 indicated a higher case-fatality rate among acute-HBV–infected persons with diagnosed diabetes compared with those without diabetes (5% vs 2%), although the difference was not statistically significant.

Higher resting heart rate may predict CV death RESEARCHERS HAVE linked an increase in resting heart rate (RHR) over a 10-year period with a heightened risk of death from ischemic heart disease among men and women without known cardiovascular disease (CVD).

Investigators took two measurements of RHR, approximately 10 years apart, in 13,499 men and 15,826 women without known CVD. During a mean 12 years of follow-up, 3,038 people died, with 388 deaths caused by ischemic heart disease.

Compared with participants with an RHR of less than 70

A decrease in resting heart rate showed no mortality benefit.

beats per minute at both measurements (8.2 deaths per 10,000 person-years), the adjusted hazard ratio was 1.9 for participants with an RHR of less than 70 beats per minute at the fi rst measurement but greater than 85 beats per minute at the second measurement (17.2 deaths/10,000 person-years).

For those with an RHR of 70-85 beats per minute at the fi rst measurement and greater than 85 beats per minute at the second measurement, the adjusted hazard ratio was 1.8 (17.4 deaths/10,000 person-

16 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

years). The associations for total mortality were similar but generally weaker than those observed for ischemic heart disease mortality.

A decrease in RHR showed no general mortality benef it.

“Information on RHR and its time-related changes are easy to obtain and follow up and maybe useful in identifying asymptomatic people who could benefit from measures of primary prevention, but further study in this area is warranted,” the investigators concluded ( JAMA. 2011;306:2579-2587).

© TOP: CDC / DR. ERSKINE PALMER; BOTTOM: ISTOCKPHOTO.COM / ABEL MITJA VARELA

HEPATITIS B VIRUS (HBV) vaccination should be administered to all previously unvaccinated persons aged 19 through 59 years who have diabetes, and to those aged 60 years and older at the discretion of their clinicians.

The CDC’s Advisory Committee on Immunization Practices (ACIP) issued these recommendations (MMWR. 2011;60:1709-1711; available at www.cdc.gov/mmwr/ preview/mmwrhtml/mm6050a4. htm, accessed January 15, 2012) after a subcommittee found that diabetes patients aged 23 through 59 years had 2.1 times the odds of developing acute hepatitis B as those without diabetes. Diabetes patients aged 60 years and older were 1.5 times more likely than persons without diabetes to develop acute hepatitis B.

Everyone needs a break during the day. So relax with this photo essay, and pretend you’re someplace else.

© ISTOCKPHOTO.COM / PREDRAG MILORADOVIC

Picture this

20 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Subzero temperatures are no match for the waterfalls of Croatia’s Plitvice Lakes National Park, a UNESCO World Heritage site.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 21

Newsline Doubts on HPV shots in men Respiratory JUST DAYS before the CDC made official a recommendation to vaccinate boys and young men against human papillomavirus (HPV), an investigative team in the Netherlands announced that increasing HPV vaccine uptake among preadolescent girls is more effective in reducing HPV infection than including boys in existing vaccination programs would be (PLoS Med. 2011;8:e1001147; available at www.ncbi.nlm.nih. gov/pmc/articles/PMC3243713/, accessed January 15, 2012).

Investigators found that most existing HPV vaccination programs have achieved sufficient coverage to continue with femaleonly vaccination. “Once routine vaccination of one sex is in place, increasing the coverage in that sex is much more effective in bolstering herd immunity than switching to a policy that includes both sexes,” wrote the researchers.

The study noted that bisexuality often acts as a bridge for transmission between heterosexual

Increasing HPV vaccine uptake in girls is more effective in reducing infection.

and homosexual subpopulations.

“Female-only vaccination will never achieve the maximum possible reduction in HPV prevalence among [men who have sex with men], but the realized reductions could constitute a considerable health benefit.”

Three days after the publication of the Dutch study, the CDC issued its Morbidity and Mortality Weekly Report (2011;60;1705-1708; available at www.cdc.gov/mmwr/ preview/mmwrhtml/mm6050a3. htm, accessed January 15, 2012) in which the agency made official the October 2011 recommendations on HPV vaccination for males in addition to females. These recommendations call for routine HPV vaccination for males aged 11 or 12 years (the three-dose vaccination series can be started beginning at age 9 years), and for males aged 13 through 21 years who were previously unvaccinated or who have not completed the three-dose series. Males aged 22 through 26 years may also be vaccinated.

© ISTOCKPHOTO.COM / ELENA ELISSEEVA

Nicotine patch may improve cognitive function Transdermal nicotine administered to nonsmokers with mild cognitive impairment (MCI) over a six-month period resulted in improved primary and secondary cognitive measures of attention, memory, and mental processing (Neurology. 2012;78:91-101).

Previous research has shown nicotine to improve cognitive performance in people who have stopped smoking and in people with Alzheimer disease. Although larger studies will be needed to determine whether the

positive effects of transdermal nicotine among nonsmoking patients with MCI, an initial trial involving 74 such individuals (mean age 76 years) demonstrated promising results.

In that study, half the participants received a nicotine patch (15 mg/day) for six months, and the other half received a placebo.By the six-month mark, the nicotine users regained 46% of normal performance for age on long-term memory, but the placebo users worsened by 26%.

infections and asthma REDUCING respiratory infections could prevent the onset of asthma in adulthood, suggest the findings of a population-based, case-control study conducted in Finland.

During a 2.5-year period, 521 persons aged 21 to 63 years with newly diagnosed asthma and 932 randomly selected controls from the same area were evaluated. Risk of asthma onset was strongly increased in subjects who had experienced lower respiratory tract infections in the preceding 12 months, including acute bronchitis and pneumonia, or upper respiratory tract infections, including the common cold, sinusitis, tonsillitis, and otitis media.

Asthma risk increased as the number of both lower and upper respiratory tract infections rose. A significant increase in asthma-onset risk was seen in association with all types of respiratory infections, with the exception of tonsillitis.

Persons who had allergies or who had a parent with allergies were more susceptible to the effects of respiratory infections on asthma onset than were nonatopic individuals.

“Our results suggest that reducing occurrence of respiratory infections could prevent onset of asthma, especially in individuals with atopic diseases or a hereditary propensity to it,” wrote the investigators (PLoS One. 2011;6:e27912; available at www.ncbi.nlm.nih. gov/pmc/articles/PMC3244385/, accessed January 15, 2012). ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 19

FEATURE: REBECCA DUKE, MSN, APN

Demystifying the liver and its diseases An understanding of the liver and its functions will provide the tools to perform a basic workup of patients suspected of having hepatic disease.

Hepatitis C virus (red) is an RNA virus that is transmitted through bodily fluids.

T

he liver has a multitude of functions, including protein synthesis, detoxification, and metabolic processes. Problems in the liver are often discovered incidentally through routine lab testing or screening blood tests that include liver enzyme determinations. Abnormal results can make any practitioner nervous. Liver disease is like a puzzle: You need to put the pieces together to see the whole picture.

© JAMES CAVALLINI / PHOTO RESEARCHERS, INC.

Liver function tests

A more descriptively accurate term for liver function tests (LFTs) might be “liver injury tests.”

Some tests in the hepatic profile can tell you how well the liver is functioning. The most common determinations are those for bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, and alkaline phosphatase levels. When an abnormal result is found, the clinician must figure out its origin.

One of the most common reasons for referral to a hepatologist is elevated results on the LFTs. The tests most often found to have abnormal results include those for AST and ALT. Hepatocyte injury. For AST and ALT to become elevated, there must be injury to the hepatic tissues rich in these enzymes. The injury results in changes in cell permeability and leakage of AST and ALT into the blood. The more damage there is to the hepatocytes, the greater the leakage. ALT is more specific for liver injury than AST. Elevations in AST can also be the result of cardiac and muscle disease.

Continues on page 28

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 27

LIVER DISEASE

Cholestasis. Patients with cholestasis will have elevations in their bilirubin, alkaline phosphatase (AP), and γ-glutamyltranspeptidase (GGT) levels. These elevations indicate damage to the bile ducts. AP is associated with the biliary tract but not specific to it. Elevations in AP can also be attributed to bone, placental, and intestinal sources. In the liver, AP is located in the hepatocyte membrane bordering the bile canaliculi. When this membrane is damaged, the enzyme is shed and AP levels in the blood become elevated.

To help determine the etiology of an elevated AP level, the test can be fractionated into its various sources. This test will provide the concentration of AP attributable to each source as well as its percentage of the total. Depending on the laboratory, a normal AP level is usually <120 units/L. GGT, like AP, is not specific to the liver. Alcohol intake can also cause elevations in the GGT. Sometimes the GGT can help differentiate the AP level with a hepatic etiology from other sources.

Bilirubin is a major breakdown product of hemoglobin and is derived from RBCs that have died and been removed by the spleen. During the degradation process, heme is separated out and the globin protein is transferred to the liver, where it is metabolized further in a process called conjugation. Bilirubin that has gone to the liver and undergone further metabolic process is called conjugated bilirubin. This form of bilirubin is water-soluble and goes into the bile.

The bilirubin that does not undergo this process is called unconjugated or indirect bilirubin. On laboratory reports, the most commonly reported level is the total bilirubin. A patient who develops jaundice will typically have a total bilirubin level that is at least two to three times the upper limit of normal (normal level being <1.0 mg/dL). The total AT A GLANCE ●

Functions of the liver include protein synthesis, detoxification, and metabolic processes.

●

Liver problems are often discovered incidentally through routine laboratory testing or screening blood tests.

●

Liver disease can have either an infectious or noninfectious etiology, such as hepatitis, nonalcoholic fatty liver disorders, and drug-induced injury.

●

Patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis whose liver enzymes normalize after modificaiton of risk factors can be monitored conservatively and may avoid a liver biopsy.

●

Imaging is becoming more sensitive to fatty infiltration in the liver. Both ultrasonography and MRI can be useful.

TABLE 1. Risk factors for hepatitis B and C Hepatitis B

Hepatitis C

• Blood transfusion • Hemodialysis • Nosocomial exposure • Perinatal exposure • Sexual contact • IV drug use • Occupational exposure • Unknown

• Blood transfusion • Hemodialysis • Nosocomial exposure • Perinatal exposure • Sexual contact • IV drug use • Piercing • Tattoo • Cocaine use • Unknown

bilirubin level must be fractionated to further differentiate the causes of any abnormality.

Synthetic function. The tests of synthetic function in the liver include prothrombin time (PT)/international normalized ratio (INR), platelet count, and albumin level. Abnormal results indicate disease that has caused loss of proteins or inability to synthesize proteins. If a patient presents with hypoalbuminemia, thrombocytopenia (platelet count <150,000/µL), and/or an elevated INR, the clinician should add advanced liver disease or cirrhosis to the list of differentials.

Other liver disorders. The last two liver tests worthy of mention are miscellaneous assays of the ammonia and the α-fetoprotein (AFP) levels. An ammonia level is usually measured when a patient presents with acute changes in mental status because ammonia can cross the blood-brain barrier and become toxic to the brain. In liver disease, ammonia may build up because the liver cannot process it quickly enough or because an enzyme that breaks down the ammonia is absent or is present only in insufficient quantities. This can lead to hepatic encephalopathy in the patient with cirrhosis. Ammonia levels, while useful, are primarily measured to rule out causes of changes in mental status. Ammonia levels are not always measured in hepatology practices. If the patient is mentating well, an elevated ammonia level may not mean anything. To use an old cliché, treat the patient, not the laboratory results.

AFP is a tumor marker for hepatocellular carcinoma (HCC) in patients with liver disease. The normal AFP level is <20 ng/mL. Most patients with hepatitis C have AFP levels that are <100 ng/mL. Any elevation in AFP warrants further investigation. Most concerning are elevated levels that continue to climb or levels found to be significantly elevated on first screening (i.e., in the several thousand range). The latest guidelines from the American Association for the Study of Liver Diseases do not recommend using AFP alone as a screening or diagnostic tool for HCC.1,2 Continues on page 31

28 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

LIVER DISEASE

TABLE 2. Interpretation of hepatitis B serologic testing HBsAg

Anti-HBs

Anti-HBc IgM

Anti-HBc IgG

HBeAg

Anti-HBe

HBV DNA

Interpretation

+

-

+

-

+

-

+

Acute infection, rarely acute flare of chronic disease

-

+/-

-

+

-

+/-

-

Previous infection with immunity Vaccinated with immunity

-

+

-

-

-

-

-

+

-

-

+

-

+

<105 IU/mL

Chronic HBV infection with replication (carrier status)

+

-

-

+

+

-

>105 IU/mL

Chronic HBV infection with replication

+

-

-

+

-

+

>105 IU/mL

HBeAg-negative chronic HBV (mutation strain)

Anti-HBc=antibody to hepatitis B core antigen, Anti-HBe=antibody to hepatitis Be, Anti-HBs=antibody to hepatitis B surface antigen, HBeAg=hepatitis Be antigen, HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, IgG=immunoglobulin G, IgM=immunoglobulin M.

Fibrosis markers. Blood tests that can estimate the degree of fibrosis in the liver are relatively new. Each test, or marker, utilizes various methods to determine the stage of fibrosis.

There are four stages of fibrosis in liver disease, so most test results will list four percentages. The F stage with the highest percentage is the one most likely in that particular patient.

Fibrosis marker determinations are primarily beneficial for patients with minimal disease or advanced liver disease; the test is not as specific for the middle stages of fibrosis.

There are several fibrosis markers on the market, and each takes into account multiple factors when determining F scores. The advantage to fibrosis markers is that they are blood tests and not an invasive liver biopsy. Fibrosis markers can be useful in those for whom a liver biopsy is contraindicated or when the patient refuses the invasive procedure.

Clinical scenarios

So now you have a patient with abnormal results on his or her liver function tests. Contrary to common belief, a basic workup can be done by any primary-care provider.

Begin by determining if the abnormality is new or if the patient has a history of the problem. Once the chronology of the event is determined, the abnormality can be further classified as hepatocellular, cholestatic, or a combination of both. The most common issues are mild elevations of the aminotransferases (usually <100 IU/L). These tend to be hepatocellular in etiology. While significant elevations of the aminotransferases (>1,000 IU/L) can also be hepatocellular in origin, the differential diagnosis list in that instance is usually limited to such acute disorders as drug-induced liver disease, shock liver, fulminant hepatic failure, autoimmune hepatitis, and acute hepatitis B.

In the patient with new-onset, mild AST/ALT elevations, the first step is to rule out alcohol ingestion and laboratory error, so rechecking the laboratory tests is indicated. How soon to repeat the tests depends on what the abnormality is. Most authorities recommend that testing be repeated anywhere from two to four weeks to three months later.

If repeat testing reveals persistent AST/ALT elevations, i.e., >50 IU/L but <100 IU/L, the next step is to rule out diseases that cause hepatocellular injury. These can include both infectious and noninfectious disorders, such as hepatitis, nonalcoholic fatty liver disorders, and druginduced injury.

Infectious hepatitis. One frequent cause of elevated AST/ ALT is infectious hepatitis, most commonly hepatitis A, B, or C. (Other forms of infectious hepatitis are less common and will not be discussed in this article.) Acute infectious hepatitis can present with both elevated liver enzymes and vague symptoms, including anorexia and abdominal pain.

Hepatitis A is always acute in its presentation, whereas hepatitis B and C can have both acute and chronic presentations. Most acute hepatitis manifests with significantly elevated aminotransferases (>1,000 IU/L). For the patient who presents with acute elevations of AST/ALT, infectious hepatitis should always be in the initial differential.

Infectious hepatitis is easily ruled in or out with serologic testing, which must take into consideration the patientâ&#x20AC;&#x2122;s risk factors. The risk factors for hepatitis A, B, and C are presented in Table 1. Whether the patient has risk factors or not, these diseases should always be considered in such applicable populations as those with history of IV drug use (for hepatitis C virus [HCV] and hepatitis B virus [HBV]), men who have had sex with men (HBV), children born to

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ FEBRUARY 2012 31

LIVER DISEASE

FIGURE 1. Evaluation of nonalcoholic fatty liver disease (NAFLD) Accidental discovery

ALT or

Screen those with risk factors

Symptomatic liver disease

1 Rule out coexistent or Alternate liver diseases

2

ALT Elevated normal 3

Ongoing alcohol abuse (>20-30 g/day)

Observation

4 abstinence

yes

no

Imaging study of liver

Echogenic liver or fat on CT scan 5 Evaluate need for biopsy

Biopsy

Observation/management

Need for histologic confirmation, grading/staging

Reprinted from Gastroenterology, Vol 123, No 5, American Gastroenterology Association Medical Position Statement: Nonalcoholic Fatty Liver Disease, p 1702-1704, copyright 2002, with permission from Elsevier.

a mother with HBV or HCV, and persons living in an area endemic for HBV. Therapy for acute hepatitis comprises rest, nutrition, and fluids. A few cases of acute hepatitis will progress to acute liver failure. Prompt referral to a specialist is warranted for acute hepatitis that is not improving. Prevention of infectious hepatitis via vaccination is always recommended for appropriate individuals, such as health-care workers, people

with liver disease or other chronic disease, and those traveling to endemic areas.

Chronic hepatitis presents with mild AST/ALT elevations.

According to the World Health Organization (WHO), approximately 350 million people live with chronic HBV infection,3 and approximately 3% of the world’s population has been infected with HCV.4 Hepatitis B. Patients who have chronic HBV infection may present with abnormal liver enzyme levels, fatigue, malaise, poor appetite, and right upper-quadrant abdominal pain.

Hepatitis B is diagnosed by serologic testing. The testing process is complex, and diagnosis relies on a number of assays, including those for hepatitis antigens (hepatitis B surface antigen [HBsAg] and hepatitis Be antigen [HBeAg]) and their respective antibodies (anti-HBsAg and anti-HBeAg), as well as antibodies to hepatitis B core antigen (anti-HBc immunoglobulin [Ig] M and IgG), and hepatitis B DNA. The combination of results from all these assays will determine the diagnosis. For example, a patient who tests positive for HBsAg may have an acute or a chronic infection; results of the other assays will help to differentiate acute from chronic disease and determine the patient’s immune status. Table 2 provides a summary of possible results and their interpretation.

Most adults clear HBV before it progresses to chronic infection. However, for the patient who develops chronic disease, several medical therapies are available, including both oral and subcutaneous injection treatments, such as pegylated interferon alpha 2a (Pegasys), entecavir (Baraclude), adefovir (Hespera), telbivudine (Tyzeka), and tenofovir (Viread).

Therapy should be started when the ALT elevation is more than two times the upper limit of normal, the patient has decompensated cirrhosis, or liver biopsy shows evidence of disease.5,6 Treatment of chronic hepatitis B requires the guidance of a specialist.

Hepatitis C. The diagnosis of HCV infection is also based on serologic testing. Although several tests can be involved, the testing process is less complex than it is for HBV infection.

Testing for HCV usually starts with an assay for the HCV antibody. This is only a screening test and is not diagnostic of HCV infection. The HCV recombinant strip immunoblot assay (RIBA) can help differentiate between exposure to HCV and actual infection. Patients who test positive for HCV antibody need to be tested for virus in the serum. HCV RNA polymerase chain reaction (PCR) quantitative or HCV RNA qualitative testing is usually done next. Results of the qualitative test will be positive if any virus is detected in the blood, and the quantitative test will report the actual viral content. Some tests can detect a result as low as 43 IU/mL.

32 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

A positive qualitative or quantitative test result is diagnostic for HCV infection. The actual viral count does not impact the severity of the disease. A patient with a viral load of 3 million copies/mL may not have more severe disease than the patient with a viral load of 1,000 copies/mL. Therapy for chronic HCV infection is more complex than for other forms of hepatitis. Currently approved therapies include either daily doses of interferon alfacon-1 (Infergen) or weekly administration of pegylated interferon (Pegasys, Peg-interferon) with ribavirin (Copegus, Rebetol, RibaTab, Ribasphere). Two new adjunct therapies—the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis)—were approved last year. These therapies are used in conjunction with pegylated interferon and ribavirin in treating HCV infection. They are currently approved for use in those with hepatitis C disease. Telaprevir and boceprevir can be used in a person with cirrhosis, but the individual must have well-compensated disease as evidenced by a Child-Turcotte-Pugh classification score of “A.” The protease inhibitors are not currently approved for use in the post-transplant population. The new triple therapy had doubled the rates of sustained viral response (SVR). The SVRs of therapies range from 20% to 80%, depending on the degree of fibrosis and the genotype of the disease.

Patients with a confirmed diagnosis of HCV infection must be referred to a specialist for further evaluation. The specialist may choose to treat the patient or to perform liver biopsy.

Because genotype 1 disease has the poorest rates of SVR, a liver biopsy is usually done to assess the extent of fibrosis.

Treatment is recommended in those with more advanced disease (stage 2+ fibrosis). Biopsy is not routinely done in patients with genotype 2 or 3 disease. Response to therapy is greatest in genotype 2 and 3 disease, and treatment is recommended in eligible patients regardless of disease severity.

Autoimmune hepatitis. This form of hepatitis primarily affects women. The age at diagnosis varies. Autoimmune hepatitis has links to other autoimmune diseases, such as thyroiditis, Sjögren syndrome, and diabetes mellitus. At presentation, the patient may have either mild or significant elevations of the aminotransferases. Autoimmune hepatitis is also ruled out or in with laboratory testing. The serum test for autoimmune hepatitis is the antinuclear antibody test. A liver biopsy is often done to further diagnose the disease as well as to stage the extent of inflammation and fibrosis.

Treatment of autoimmune hepatitis usually consists of high-dose prednisone (started at around 40 mg/day) and possibly another immunosuppressant medication, such as azathioprine (Azasan, Imuran). The prednisone can be

TABLE 3. Conditions associated with steatohepatitis 1. Alcoholism 2. Insulin resistance a. Syndrome X i. Obesity ii. Diabetes iii. Hypertriglyceridemia iv. Hypertension b. Lipoatrophy c. Mauriac syndrome 3. Disorders of lipid metabolism a. Abetalipoproteinemia b. Hypobetalipoproteinemia c. Andersen’s disease d. Weber-Christian syndrome 4. Total parenteral nutrition 5. Severe weight loss a. Jejunoileal bypass b. Gastric bypassa c. Severe starvation 6. Iatrogenic a. Amiodarone b. Diltiazem c. Tamoxifen d. Steroids e. Highly active antiretroviral therapy 7. Refeeding syndrome 8. Toxic exposure a. Environmental b. Workplace NOTE. All conditions except alcoholism are usually referred to as nonalcoholic steatohepatitis. a Much less common than after jejunoileal bypass.

Reprinted from Gastroenterology, Vol 123, No 5, American Gastroenterology Association Medical Position Statement: Nonalcoholic Fatty Liver Disease, p 1702-1704, copyright 2002, with permission from Elsevier.

slowly tapered in some patients. Management of this disease requires the supervision of a specialist.

NAFLD and NASH. Another common etiology of mild aminotransferase elevations is nonalcoholic fatty liver disease (NAFLD) or a more progressive form of obesity-related liver disease called nonalcoholic steatohepatitis (NASH).

NAFLD is an equal-opportunity disease, affecting 20% of adults and 5% of children.7 NASH results from fat deposition in the liver (steatosis).

Possible sequelae to this disorder include cirrhosis and HCC.2 We are still learning why patients progress from NAFLD to NASH. Elevations in fatty acids/triglycerides, obesity, and insulin resistance have all been associated with NASH. (See Table 3 for a more extensive list of associated conditions.) While

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LIVER DISEASE

some data have linked elevated triglycerides with NASH, the problem likely occurs when fatty acids accumulate because the fatty acid supply overwhelms triglyceride synthesis.2 NAFLD and NASH will likely not progress within the first few months of diagnosis. Many clinicians will monitor a patient after initial workup and make medical recommendations to lose weight or control diabetes mellitus (if applicable). Patients whose liver enzymes normalize after modifying their risk factors can be monitored conservatively and may avoid a liver biopsy. If the aminotransferase elevations persist, however, the patient requires referral to a specialist for a liver biopsy and further evaluation.

Ultrasonography and MRI have become more sensitive to fatty infiltration in the liver. The gold standard in diagnosing NAFLD and NASH is a liver biopsy. Liver biopsy carries risk factors and should be ordered only after other workup has been completed. Figure 1 is an algorithm for the evaluation of patients suspected of having NAFLD.

“I think I deserve more than a stub on Wikipedia.”

Conclusion

Just as the liver has numerous functions, so does it have the potential for dysfunction. Primary-care clinicians with an understanding of basic liver function can begin the diagnostic process, recognizing that patients with more serious liver disorders may require the supervision of a hepatologist. ■ Ms. Duke is a transplant nurse practitioner at Northwestern Medical Faculty Foundation in Chicago.

References 1. Bruix J, Sherman M. Management of hepatocellular carcinoma: an

“I met somebody with a hut.” © The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

update. Hepatology. 2011;53:1020-1022. Available at www.ncbi.nlm.nih. gov/pmc/articles/PMC3084991/.

2. American Association for the Study of Liver Diseases Diagnosis and Management of Autoimmune Hepatitis Guidelines. Available at: www. aasld.org/practiceguidelines/Documents/AIH2010.pdf 3. World Health Organization. Hepatitis B. Available at www.who.int/ mediacentre/factsheets/fs204/en/index.html.

4. Holmberg S. Hepatitis C. Available at wwwnc.cdc.gov/travel /yellowbook/2010/chapter-5/hepatitis-c.aspx.

5. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225-1241.

6. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology.

2009;50:661-662.

7. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology.

2003;37:1202-1219.

All electronic documents accessed January 15, 2012

34 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

“Must be a celebrity inside!”

CME CE FEATURE

■ LEARNING OBJECTIVES : • Identify the signs of dyslipidemia in obese individuals with metabolic syndrome.

• Describe the consequences of metabolic syndrome in pregnant women.

• Distinguish a normal-weight individual as defined by BMI. • Name the medication that reduces C-reactive protein and LDL cholesterol in patients with metabolic syndrome.

■ COMPLETE THE POSTTEST: Page 99 ■ ADDITIONAL CME/CE: Pages 67, 95

JACINTA THOMAS, APRN-C, AND DEBORAH K. WALKER, DNP, CRNP, AOCN

A practical guide to metabolic syndrome With obesity on the rise, more patients are at risk for metabolic syndrome, a diagnosis given to a set of simultaneous disorders.

© BSIP / PHOTOTAKE

Adiposity is related to increased cardiovascular risk

T

he National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) report identified a constellation of factors that increased an individual’s risk of developing cardiovascular disease (CVD).1 Metabolic syndrome is a general diagnosis given to a set of disorders that a patient experiences simultaneously, including hyperglycemia, elevated BP, dyslipidemia, and abdominal obesity. In the United States, approximately 34% of adults carry the diagnosis of metabolic syndrome.2 As obesity rates increase, the incidence of metabolic syndrome is also expected to rise. The damaging effects of metabolic syndrome may place affected patients at a higher risk of developing CVD and type 2 diabetes mellitus (T2DM).3 The exact societal cost of the syndrome is unknown because the disorder can vary so much. However, given that the annual projected costs associated with hypertension, diabetes, cholesterol disorders, and obesity are escalating, one can expect that the annual cost associated with metabolic syndrome will be

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CME CE

METABOLIC SYNDROME

TABLE 1. Definitions of metabolic syndrome European Group for the Study of Insulin Resistance59

NCEP ATP III (2001)1

AHA/rATP III (2004)28

American Association of Clinical Endocrinologists (2003)60

International Diabetes Federation (2005)61

Metabolic risk factor

World Health Organization58

Insulin resistance

Required (IFG, IGT, T2DM) + two other risk factors

Required (Plasma insulin levels >75th percentile) + two other risk factors: places more emphasis on obesity than WHO; T2DM excluded

Not required; any three of the five risk factors

Not required; any three of the five risk factors

Required; any of the risk factors—no set number

Not required

Obesity

Waist-to-hip ratio >0.90 (males) or >0.85 (females), or BMI >30

WC >94 cm (males) or >80 cm (females

WC >102 cm (males) or >88 cm (females)

WC >102 cm (males) or >88 cm (females)

BMI >25

Required* + two other risk factors; WC >94 cm (males) or >80 cm (females) in United States

Triglycerides

≥150 mg/dL

≥177 mg/dL

≥150 mg/dL

≥150 mg/dL

≥150 mg/dL

≥150 mg/dL or on medication

HDL

<35 mg/dL (males) or <39 mg/dL (females)

<39 mg/dL (both males and females)

<40 mg/dL (male) or <50 mg/dL (females)

<40 mg/dL (males) or <50 mg/dL (females)

≤40 mg/dL (males) or ≤50 mg/dL (females)

≤40 mg/dL (males) or ≤50 mg/dL (females)

BP

>140/90 mm Hg

>140/90 mm Hg or on medication

>130/85 mm Hg

>130/85 mm Hg

≥130/85 mm Hg

≥130/85 mm Hg

Glucose

IFG, IGT, or T2DM

>110 mg/dL

>110 mg/dL

>100 mg/dL

Other

Albumin-to-creatinine ratio >30 mg/g

Diabetes excluded

Includes T2DM

Includes T2DM

Diabetes excluded; clinical judgment used for diagnosis; other factors considered: PCOS, family history, hyperuricemia

Ethnic cutoffs for WC

Key: BMI=body mass index, IFG=impaired fasting glucose, IGT=impaired glucose tolerance, PCOS=polycystic ovary syndrome, T2DM=type 2 diabetes mellitus; WC=waist cutoff. *Specific WC by population is presented in Alberti KG, et al, 2009.20

astronomical. Sullivan and colleagues estimated the loss in productivity resulting from metabolic risk factors was $17.3 billion annually.4 Boudreau et al studied the health-care utilization of patients with metabolic syndrome and found that the cost of care for patients with diabetes who were obese and had dyslipidemia and hypertension was almost twice that of patients with prediabetes who had the same risk factors ($8,067 compared with $4,638).5 Major organizations, such as the American Heart Association (AHA) and the American Diabetes Association (ADA), do not agree on the usefulness of metabolic syndrome in clinical practice. Several studies have testified to the significance of the syndrome as a diagnostic predictor of CVD.6,7 Yet many highly acclaimed scientists refute the validity of the syndrome

to predict cardiovascular or diabetes risk as postulated by others in the medical community.8,9 Reaven adamantly believes the syndrome is a “pathological process” and challenges the scientific world to stop “spinning” the notion that it is anything more.9 Despite the rather intense battles about the utility of a diagnosis of metabolic syndrome in clinical practice, most parties agree that the risk factors associated with the syndrome are problematic for the patient, public health, and health-care providers.10-12 Components of metabolic syndrome

While not all organizations agree on the requirements for a diagnosis of metabolic syndrome (Table 1), there is consensus about the factors that should be considered. These include

40 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

whether the patient is obese or overweight, lipid levels, BP, and the presence or absence of insulin resistance.

Obesity. In women, the metabolic syndrome affects 33.1% of overweight persons and 56.1% of obese and extremely obese individuals; slightly more than 10% of normal-weight and underweight persons have the syndrome.2 In men with metabolic syndrome, only 6% were in the normal-weight category, with more than 93% in the overweight or obese category. Metabolic syndrome is linked more to central visceral obesity than to overall obesity. Several studies cite central obesity as the pivotal component in development of the syndrome.13,14 The proposed connection between obesity and the risk factors for metabolic syndrome are complex. Increase in visceral fat leads to central obesity and has been linked to increased insulin resistance as a result of hormonal influences.15 Also, cortisol has been widely studied as a culprit in stimulating the appetite for high-carbohydrate, fatty foods that lead to increased deposition of fat around the abdomen. The hormones thought to play the greatest role in the development of obesity-related metabolic syndrome are the adipokines, leptin, and adiponectin.16 The hormone leptin helps regulate appetite and storage of fat and influences thermogenesis to burn calories. Sudden increase in weight or extreme weight gain disturbs the leptin regulation, thereby allowing deposition of fat in the visceral areas as well as inciting an increase in triglyceride storage in vital organs, such as the heart, muscles, and liver.13 Dyslipidemia. In obese patients with metabolic syndrome, deregulation of the hormonal system often leads to dyslipidemia. Levels of the hormone adiponectin were found to be inversely related to visceral fat and lower in patients with coronary artery disease.14 Adiponectin promotes insulin sensitivity and has an antiatherogenic effect.17 The patient with metabolic syndrome usually has normal levels of LDL, although the lipoproteins themselves are believed to be denser and smaller in nature, which makes them more atherogenic.

Levels of triglycerides and HDL are often elevated in the patient with metabolic syndrome.12 Insulin resistance. In insulin resistance, the body produces insulin, but it is not used properly. This cyclic dysfunction leads to higher glucose levels in the bloodstream, which causes more insulin production (hyperinsulinemia).

An increase in total body fat is independently related to insulin resistance. Scientists believe that adipose tissue releases additional adipokines that are insulin antagonists, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and resistin.17 These inflammatory factors are responsible

TABLE 2. 2009 Harmonious definition of metabolic syndrome20 Any three of the following is required for diagnosis Obesity

Population- and country-specific

Triglycerides

≥150mg/dL or on medication

HDL

<40 mg/dL in men or <50 mg/dL in women

BP

≥130/85 mm Hg or on medication

Fasting glucose

≥100 mg/dL or taking medication

for insulin resistance, the production of C-reactive protein (CRP), and increased adhesion of WBCs and molecules to endothelial cells.18 Hypertension. Hyperinsulinemia and obesity in metabolic syndrome raises patients’ risk for elevated BP. Elevated insulin levels increase the kidney’s absorption of sodium and water, which in turns increases blood volume and elevates the BP.19 Obese patients require a larger-than-normal cardiac output because of increased blood volume. In addition, sympathetic system in obese patients is overactive, leading to constriction of peripheral arteries, sodium retention, and vascular resistance. The presence of any of these actions, alone or synergistically, can lead to hypertension.

In 2009, a group of organizations released a set of diagnostic criteria on which they agreed (Table 2).20 The organizations involved were the International Diabetes Federation (IDF) Task Force on Epidemiology and Prevention; the National Heart, Lung, and Blood Institute; the AHA; the World Heart Federation; International Atherosclerosis Society; and the International Association for the Study of Obesity.

Consequences of metabolic syndrome

In many individuals with insulin resistance, hormonal imbalance and obesity are interrelated, resulting in even more devastating consequences of the metabolic syndrome.

Santos and Fonseca found that metabolic syndrome was more prevalent in patients with inflammatory disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.21 The researchers also discovered increased incidents of atherosclerosis in this same subset of patients. In a post hoc analysis of the Multiethnic Study of Atherosclerosis, Afonso et al discovered that of the four groups studied (no metabolic syndrome and no microalbuminuria, microalbuminuria only, metabolic syndrome only, and metabolic syndrome and microalbuminuria), the group with both metabolic syndrome and microalbuminuria had higher levels of inflammatory markers and more subclinical atherosclerosis than the other groups.22 Further studies have

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CME CE

METABOLIC SYNDROME

Metabolic syndrome has been linked to increased cardiovascular risk, polycystic ovary syndrome, sleep apnea, dementia, and fatty liver. shown that patients with metabolic syndrome demonstrate increased stiffness in precapillary vessels, which impedes subcutaneous microcirculation and makes cardiac events more likely.8 Investigators for the Strong Heart Study proved that patients with metabolic syndrome had a higher in-hospital death rate after acute ST-elevation MI.23 Zhao et al determined that in patients with metabolic syndrome, progression of coronary stenosis was increased by 50% and frequency of cardiovascular events was increased by 64% compared with those without the syndrome.24 In addition to increased cardiovascular risk, metabolic syndrome has been linked to polycystic ovary syndrome (PCOS), sleep apnea, dementia, and fatty liver.10 Moreover, recent studies have linked the metabolic factors of obesity, elevated glucose, and increased triglycerides to the development of macrosomia, obesity, and metabolic syndrome in the unborn child.25,26 Clinicians will have to rethink the care of the pregnant woman, insisting on lifestyle interventions to prevent the passage of unhealthy metabolic conditions to her child.

Tenenbaum and Fisman reported that patients with metabolic syndrome and hyperglycemia had higher mortality rates than patients with the same level of hyperglycemia and no metabolic syndrome; they also reported a 30-day mortality rate of 8.3% vs 2.5% (P <.05), respectively.27 Towfighi, Zheng, and Ovbiagele reported that the incidence of stroke has more than tripled for women in the past 20 years, and they attribute this increase to the rising incidence of obesity.28 In a meta-analysis that included 951,083 patients and 87 studies, Mottillo and colleagues found that metabolic syndrome was associated with a twofold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality.29 After analyzing the data from 22,719 individuals in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, Brown, Voeks, Bittner, and Safford found that 47% of the participants had metabolic syndrome.6 With such large numbers of patients falling into the metabolic syndrome category, the need for standardized diagnostic criteria and treatment protocols persists even in the midst of the controversy over the syndrome’s characteristics and utility.

Screening guidelines

The assessment of patients suspected of having metabolic syndrome should include a physical examination, a dietary history, and laboratory workup.

Physical examination. During the initial visit, measure the patient’s waist and calculate the BMI. Measurement of waist circumference is important because adiposity is related to cardiovascular risk.30 Obesity is defined as a BMI >30, and overweight is defined as a BMI of 25 to 29; a BMI of 18.5 to 24.9 indicates normal weight.31 However, a study of 32,024 participants revealed that the method used to define obesity—whether by body-fat percentage, truncal obesity measurements, or BMI—did not change the prevalence of metabolic syndrome, indicating that all measurements were equal.32 Coutinho et al analyzed 16,000 patients with coronary disease and found that increased waist circumference was associated with increased risk of death (hazard ratio [HR], 1.70; 95% confidence interval, 1.58-1.83).33 The study showed that central obesity was associated with an increased risk of death regardless of BMI. Thirty percent of all deaths in the study were attributed to central obesity independently,33 thereby confirming the need to measure both BMI and waist circumference to more adequately determine risk category and tailor treatment to the individual.

BMI can easily be calculated in adults once the height and current weight are plugged into the formula: weight (lb)÷height (in)2⫻703. The NIH classifications of obesity should be used only as a general guideline, as there are ethnicspecific considerations of obesity that should be applied to each patient.20 Rahman and Berenson found that increased percentage of body fat and obesity among Caucasian, African American, and Hispanic patients corresponded more with a BMI ≥25.5, 28.7, and 26.2, respectively.34 Therefore, counseling on ways to prevent obesity should begin long before the patient reaches a BMI of 30.

After the BMI has been determined, a screening waist circumference should be obtained with the provider standing on the patient’s right side. The patient’s right iliac crest is palpitated and marked, and then a vertical line is drawn from the mid-axillary line. The measuring tape is then placed in a horizontal plane at the level of the mark. The tape should be parallel to the floor and the measurement should be taken during normal respiration.31 According to guidelines in The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ( JNC 7), a screening BP measurement should be taken in the office while the patient is seated, with the arm at the level of the heart.35 Two separate readings are obtained, and elevated readings are confirmed

42 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Review of the diet history will give clues as to what dietary habits need improving and provide an estimate of the number of calories consumed. in the contralateral arm. Every office visit should include BP measurement and assessment of risk factors or other comorbidities. A systolic BP of 120 to 139 mm Hg and diastolic BP of 80 to 89 mm Hg is considered prehypertension.

BP readings >130/80 mm Hg in patients with diabetes or kidney disease are a risk factor for metabolic syndrome, and readings >130/85 mm Hg are a risk factor for those without chronic disease. BP readings >140/90 mm Hg require treatment, often with more than one antihypertensive. BP screenings are recommended every two years in patients aged 20 years and older.11 Diet and exercise history. The next step in the assessment for metabolic syndrome is to document a diet and exercise history. Overeating and inactivity are known risk factors for obesity.11 Discussion with patients should address barriers to exercise, support systems, and their readiness to change their current regimen. Open-ended, nonjudgmental questions, such as “How do feel about exercise?” rather than “Do you exercise?” will provide the clinician with more useful information to help determine the patient’s needs; unbiased comments will also help establish trust with the patient.36 Establishing a trusting relationship with the patient can help both patient and provider meet short- and long-term goals for weight loss. A careful food-consumption history should be taken on the first visit as well. Review of the diet history will give clues as to what dietary habits need improving and provide an estimate of the number of calories consumed.37 That information will be important when determining an appropriate caloric goal.31 Laboratory studies. Assessment for metabolic syndrome includes screening for lipids during normal stress levels, as acute illness, increased stress, and eating within nine hours of testing can produce falsely elevated results.30 A complete lipid profile should be obtained, including LDL (normal, <100 mg/dL), HDL (normal, >40 mg/dL), triglyceride (normal, AT A GLANCE ●

In the United States, approximately 34% of adults carry the diagnosis of metabolic syndrome.

●

Obesity, lipid levels, BP, and insulin resistance should be considered when diagnosing metabolic syndrome.

●

Screening should include a physical examination, a dietary history, and laboratory workup.

●

The goal of treatment is to delay or prevent CVD and diabetes.

<150 mg/dL), and total cholesterol (normal, <200 mg/dL) levels. Additional tests to rule out other differential diagnoses of elevated lipid levels include serum thyroid-stimulating hormone, blood urea nitrogen, creatinine, liver function tests, and urinalysis.

Once the lipid level is obtained, assess the risk of coronary heart disease. The Framingham risk assessment can be used to determine the patient’s risk factors for coronary heart disease or a cardiac event in the next 10 years.38 Diabetes, peripheral vascular disease, abdominal aortic aneurysm, and symptomatic carotid disease are considered risk equivalents for CVD in the Framingham risk calculations.12 Other Framingham risk predictors are age, total cholesterol, HDL, smoking, antihypertensive treatment, and BP. Points are assigned to each risk factor, and the total number of points determines LDL levels at which to begin therapeutic lifestyle changes and drug therapy.30 The risk factors are stratified separately for men and women.

Note that Framingham risk calculations underestimate cardiovascular risk in patients with T2DM, so be cautious about using them in that subset of patients.38 In addition, Sumner and colleagues have challenged the validity of the previously stated lipid classifications for metabolic syndrome as they relate to African Americans.39 The Triglyceride and Cardiovascular Risk in African Americans (TARA) study showed that even obese, insulin-resistant African American patients often have low triglyceride levels; 30% of the study participants were insulin-resistant, but only 2% had high triglyceride levels.39 The researchers stated that in comparative studies, 60% of whites with insulin resistance also had elevated triglycerides. Moreover, the researchers believe that both the IDF and the AHA criteria miss many African Americans who are at risk for metabolic syndrome.39 The oral glucose tolerance test (OGTT) is the most sensitive assay for detecting overt T2DM in patients with prediabetes; however, performing this test in the office setting is timeconsuming. Therefore, a fasting glucose determination is used more often. Patients with a history of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) should be screened every one to two years for T2DM.40 Balkau et al proved that serum glucose levels were more predictive of diabetes than was an HbA1c determination.41 In 2010, however, the ADA added an HbA1c determination to the tests for diabetes; levels >6.5% are diagnostic. The levels of

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CME CE

METABOLIC SYNDROME

Treatment of metabolic syndrome and its risk factors focuses on healthy lifestyle interventions, such as exercise and a nutritious diet. serum glucose and OGTT results diagnostic of diabetes were unchanged at ≥126 mg/dL and ≥200 mg/dL, respectively.

A random blood glucose >200 mg/dL that is accompanied by complaints of increased thirst, urination, hunger, and fatigue is considered a positive indicator of diabetes. IFG, which is a risk factor for metabolic syndrome, is defined as a blood glucose reading of 100 to 126 mg/dL.40 Treatment of metabolic syndrome

The goal of treatment for metabolic syndrome is to delay or prevent CVD and diabetes. Treatment of metabolic syndrome and its risk factors focuses on healthy lifestyle interventions, such as exercise and a nutritious diet. Patients whose metabolic syndrome persists may try behavior modification or pharmacotherapy.

Exercise. Vigorous activity for 45 to 60 minutes at least five times a week, but preferably daily, is recommended to aid in achieving and maintaining a healthy weight.42 The Diabetes Prevention Program study showed that for at-risk persons, a loss of approximately 10% of body weight could prevent or delay development of diabetes or other metabolic disorders.12 Resistance training in particular has received a great deal of attention in the treatment of metabolic syndrome. It was found to have a null effect on triglycerides, HDL, LDL, and diastolic BP, but resistance training has been shown to decrease systolic BP, HbA1c, and obesity.43 The AHA recommends resistance training two days a week in addition to behavioral changes in a physical-activity regimen.11 Using a pedometer to track exercise, taking the stairs, and reducing the amount of time spent in such sedentary activities as watching television can all be effective in reducing body weight.

Weight reduction results in improvement of all metabolic risk factors. Therefore, providers are encouraged to tailor an exercise regimen based on the patient’s individual characteristics and specific risk factors that predispose him or her to metabolic syndrome. Patients with metabolic syndrome who are at high risk for cardiovascular events should be medically supervised in their physical activity; some may require an exercise stress test to detect life-threatening abnormalities before initiating an exercise program.42 The Oslo Diet and Exercise Study revealed that diet and exercise together produced the greatest reduction in the incidence of metabolic syndrome. After one year, metabolic syndrome affected 32.6% of the diet-and-exercise group,

64.7% in the diet-only group, and 76.5% of the exerciseonly group.44 Similarly, Yassine et al found that exercise and caloric restriction versus exercise alone produced greater weight loss (6.8 kg ± 2.7 kg vs. 3.4 kg).45 After controlling for diet, increased physical activity was most associated with a decreased likelihood of developing metabolic syndrome in the Finnish Diabetes Prevention Study.46 Healthy diet. Treatment of metabolic syndrome also includes eating a proper diet. The Mediterranean diet consists of a lot of green leafy vegetables, fiber, fish, olive oil, and nuts; low intake of saturated fats, trans fats, and cholesterol has proven to be effective in aiding weight loss in patients with metabolic syndrome.40,47 Reducing daily caloric intake by 500 to 1,000 calories along with exercise will help place the body in a calorie-deficient state so that weight loss can occur.

A reduction in consumption of refined sugars, sodium, and high-glycemic food can aid in weight loss as well.48 Much attention has been given to studies showing that consumption of diet drinks leads to metabolic syndrome and increases weight gain.49 Scientists hypothesize that the artificial sugar increases cravings for other refined sugars, leading to weight gain and disruption of glucose metabolism. Also, patients with elevated lipid levels should keep fat intake in the range of 25% to 35% of calories. Fat intake >35% has the potential to increase LDL, whereas levels <25% will cause HDL to decrease and triglycerides to increase.30 A consultation with a dietitian can help the patient reach preset goals. Patients with a history of kidney disease should refrain from highprotein diets because reduced renal function can ultimately lead to insulin resistance.48 Behavior modification. Another important approach to maintaining weight loss is behavior modification. Providers should encourage patients to read all food labels, set goals for weight loss, keep food diaries or journals, and be active in their journey to a healthy weight.40 For patients who are unable to achieve weight loss after a reasonable time, such as six to 12 months of aggressive lifestyle interventions, a trial of oral weight-loss medications may be beneficial. Orlistat (Xenical) is the only drug approved by the FDA for weightloss maintenance. Bariatric surgery is another option for obese patients. Weight-loss surgery can be recommended for patients with a BMI >40 or a BMI >35 with comorbid conditions.50 Medications. Treatment of dyslipidemia in metabolic syndrome centers around the goal of reducing LDL with

44 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Concern over use of nicotinic acid in patients with metabolic syndrome continues because one of the side effects is possible elevation of blood glucose. lipid-lowering medications.28 The revised ATP III recommends an LDL of <70 mg/dL for high-risk patients and <100 mg/dL for those at moderate risk.30 The LDL for patients at low risk is <160 mg/dL, which is unchanged from the original 2001 guidelines. Once the primary goal of LDL reduction is reached, the secondary goal is to reduce elevated triglycerides. The tertiary goal is to increase HDL if levels are <40 mg/dL for men and <50 mg/dL for women.51 The 10-year risk of a first cardiovascular event averages 16% to 18% in metabolic syndrome patients.2 Recent studies have evaluated the positive effect of statins, which include reduction of LDL and the infl ammatory marker CRP, in metabolic syndrome patients.52 Statins combined with fibrates have the additive effect of reducing triglycerides and increasing HDL, but this combination has the potential to cause myopathy. Therefore, patients will have to be monitored closely. Other combinations, such as fenofibrate and nicotinic acid, can be considered.53 Great concern over the use of nicotinic acid in patients with metabolic syndrome continues because one of the side effects is possible elevation of blood glucose.52 Thus, providers are cautioned to use the smallest effective dose of nicotinic acid in patients with dyslipidemia and prediabetes.

More recently, the presumed positive effect of niacin combined with statins has been scarred by the discontinuation of the AIM-HIGH trial.54 The high-dose niacin-and-statin combination reduced triglyceride levels and raised HDL levels, but there was no reduction in heart attacks, strokes, or hospitalizations for acute coronary syndrome. There was a small increase in ischemic stroke with niacin use. The usefulness of raising HDL has been questioned with the discontinuation of this study, leaving many researchers searching for another marker of lipid control beyond LDL. Controlling blood sugar. IFG and IGT are also risk factors for metabolic syndrome that should be treated initially with lifestyle interventions. As previously stated, a weight loss of 7% to 10% of total body weight greatly reduces the patient’s potential to develop diabetes.11 Exercise improves

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

insulin sensitivity and aids in weight loss. Reducing caloric intake by 500 calories, avoiding refined sugars, and following a healthy diet will also be beneficial to the patient with IFG or IGT.42 The drug metformin has also been proven to slow down and impede the development of diabetes in patients with metabolic syndrome.55 The ADA does not routinely recommend treatment of insulin resistance in the absence of diabetes. Instead, the organization states that treatment can be “considered” in patients who have a BMI >35, are younger than age 60 years, or have IFG and IGT plus other risk factors.40 However, once T2DM develops, the recommendation is to use a combination of therapies, including lifestyle modifications and medications, to achieve an HbA1c <7% to reduce risk of CVD.40 Addressing BP. Lowering BP to <130/85 mm Hg is important in reducing the chance of cardiovascular events in patients at risk for metabolic syndrome. Lifestyle modifications are the starting point in any treatment related to hypertension control. The findings in the JNC 7 support use of the Dietary Approaches to Stop Hypertension (DASH) diet, weight loss, and moderate alcohol intake to reduce cardiovascular risk.35 Also, according to the guidelines, patients with a history of diabetes should aim for a BP ≤130/80 mm Hg. Several drug combinations for the treatment of hypertension and metabolic syndrome have been studied, but no one combination has supremacy over another. Researchers have supported the use of angiotensin-converting enzyme (ACE) inhibitors in patients with metabolic syndrome, especially those who also have IFG or IGT.30 Diuretics have been proven to reduce cardiovascular risk, but there is debate about progression to frank diabetes in those who have IFG or IGT. Hypertensive African Americans with metabolic syndrome respond better to thiazide diuretics than to ACE inhibitors as first-line therapy, based upon fi ndings of the ALLHAT trial.56 Thus, clinical judgment is required to produce results that will bring the patient’s BP to goal.

Other considerations. The prothrombotic state and the proinflammatory state in metabolic syndrome are also recognized as major risk factors for CVD.12 The proinflammatory state involves elevation of cytokines and CRP. Weight loss improves the inflammatory response. Coagulation factors increase in patients with metabolic syndrome. Aspirin is a low-cost medication that can help prevent the likelihood of stroke in women and MI in men. If there are no

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 45

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METABOLIC SYNDROME

contraindications, aspirin should be considered for women aged 55 to 79 years and men aged 45 to 79 for primary prevention of CVD. According to the US Preventive Services Task Force, the daily use of aspirin will reduce the relative risk of stroke in women by 17% and the relative risk of MI in men by 32%.57 There is no consensus on the aspirin dosage—either 81 mg or 325 mg can be considered; however, the higher dose is linked to GI bleeding.

3. Wu SH, Liu Z, Ho SC. Metabolic syndrome and all-cause mortality: a meta-analysis of prospective cohort studies. Eur J Epidemiol. 2010;25: 375-384.

4. Sullivan PW, Ghushchyan V, Wyatt HR, et al. Productivity costs associated with cardiometabolic risk factor clusters in the United States. Value Health. 2007;10:443-450.

5. Boudreau DM, Malone DC, Raebel MA, et al. Health care utilization and costs by metabolic syndrome risk factors. Metab Syndr Relat Disord.

2009;7:305-314.

Implications for practice

6. Brown TM, Voeks JH, Bittner V, Safford MM. Variations in prevalent car-

Health-care providers must suspect that patients with any one of the five metabolic risk factors can have other hidden risk factors that are silently working together to exacerbate the situation. This suspicion should lead to further inquiry into family and personal medical history. Consideration should be given to prescriptions for lifestyle modifications, investigative diagnostic procedures, and therapeutic medications, as deemed appropriate. The components that make up metabolic syndrome are at epidemic levels in the United States, and as waistlines are continuing to increase, solutions to this global problem are urgently needed.

This paper has provided a review of the metabolic syndrome and reported guidelines that can be utilized in the office setting. With continuing research, modifications in the recommendations for metabolic syndrome can be expected.

The turbulent atmosphere surrounding the syndrome may continue, but as long as the goal is improvement in patient outcome, the medical community will have to put aside differences and treat patient as a whole and not as a set of debatable numbers. ■

diovascular disease and future risk by metabolic syndrome classification in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Am Heart J. 2010;159:385-391.

7. de Simone G, Devereux RB, Chinali M, et al. Prognostic impact of metabolic syndrome by different definitions in a population with high prevalence of obesity and diabetes. Diabetes Care. 2007;30:1851-1856. Available at care.diabetesjournals.org/content/30/7/1851.long.

8. Bayturan O, Tuzcu EM, Lavoie A, et al. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med. 2010;170:478-484. Available at archinte.ama-assn.org/cgi/ content/full/170/5/478.

9. Reaven GM. The metabolic syndrome: time to get off the merry-goround? J Intern Med. 2011;269: 127-136.

10. National Heart, Lung, and Blood Institute. What is metabolic syndrome? Available at www.nhlbi.nih.gov/health/dci/Diseases/ms/ms_treatments.html.

11. American Heart Association. What is metabolic syndrome? Available at www.heart.org/HEARTORG/Conditions/More/MetabolicSyndrome/ Metabolic-Syndrome_UCM_002080_SubHomePage.jsp.

12. Rosenzweig JL, Ferrannini E, Grundy SM, et al. Primary prevention of cardiovascular disease and type 2 diabetes in patients at metabolic risk;

Ms. Thomas practices internal and family medicine in Atlanta, and is a student in the DNP Program at the University of Alabama, Birmingham, where Dr. Walker is an assistant professor. Neither author has any relationships to disclose relating to the content of this article.

an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab.

2009;93:3671-3689.

13. Gade W, Schmit J, Collins M, Gade J. Beyond obesity: the diagnosis and pathophysiology of the metabolic syndrome. Clin Lab Sci. 2010;23:51-61.

14. Whitmore C. Type 2 diabetes and obesity in adults. Br J Nurs.

2010;19:880-882.

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“We should make it past the rocks by nightfall, provided our luck holds.”

48 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

FEATURE: PAUL ZIMBECK, NP

Getting young patients to take their medicine The problem is a challenging one, but there are steps clinicians can take to eliminate the barriers to medication adherence in children.

Proper medication adherence can improve symptoms of chronic illness by almost 70%.

A

nyone who has seen a parent or other caregiver struggling to give medication to a child who has his or her lips tightly closed understands the challenge of medication adherence in the pediatric population.

Achieving full adherence in young patients requires not only the cooperation of the child but also a devoted, persistent, and adherent parent or caregiver. Additionally, as the child ages and becomes an adolescent, unique developmental, psychosocial, and lifestyle issues can create an even greater challenge.1 In children and adolescents with chronic health problems, medication adherence averages about 50%.2 Factors that affect medication adherence in children often revolve around family dynamics, including the hassles of daily living, stress, typical family confl ict, and the hectic schedules of patients from age 5 years to the early teens.1

© ISTOCKPHOTO.COM / CHAD THOMAS

Patient factors

Research on adherence has typically focused on the barriers patients face in taking medications.

However, the most common obstacles to adherence are under the patients’ control, so calling attention to modifiable barriers is a necessary and important step in improving outcomes.

Reasons most cited by parents who are coping with children and poor adherence include forgetfulness (30%), other priorities (16%), decision to omit doses (11%), lack of information (9%), and emotional factors (7%). The remaining 27% of parents were unable to provide a reason www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 49

MEDICATION ADHERENCE

POLL POSITION n=65

More than 60% of readers who responded to our poll report frequently encountering medication noncompliance among patients in their practice.

prescribed does work. Studies performed on individuals with such chronic illnesses as asthma and juvenile rheumatoid arthritis reveal an almost 70% improvement in symptoms and control of exacerbations with proper medication adherence.4 This finding reinforces the importance of educating the patient and continuing to work on eliminating barriers.

3%

Overcoming the challenge 35% 62%

Frequently Occasionally Seldom

For more polls, visit www.ClinicalAdvisor/polls

for poor adherence, although they acknowledged that the problem existed.3 Parents have voiced frustration with the current health-care system, in part blaming it for poor adherence. Barriers, such as limited access to health care; restrictive formularies; switching from one formulary to another; and prohibitively high costs for drugs, copayments, or both, pose obstacles to adherence.

The clinician’s role

Clinicians may also be responsible for some of the frustration felt by parents and caregivers. Among the factors thought to contribute to problems with medication adherence and attributable to clinicians are: • Prescribing complex medication regimens • Failing to provide adequate explanation of the benefits and side effects of a medication • Not giving consideration to the patient’s lifestyle • Not considering the cost of medications when prescribing • Having a poor therapeutic relationship with patients.4 Research on proper medication administration and adherence demonstrates that following a regimen exactly as

CLINICAL SLIDESHOW Up to 7% of U.S. school-age children have some form of ADHD, To learn about recommended treatments, go to ClinicalAdvisor.com/ADHDSlideshow.

How do clinicians overcome the challenge of poor adherence in children? Most of the interventions that have demonstrated success in children with chronic illnesses use behavioral interventions or a combination of behavioral and other interventions. The most frequently used intervention is the token-reinforcement system. This approach motivates adherence by awarding tokens to children who take their medications successfully. Tokens can be used to earn privileges, gain access to certain activities, or obtain other rewards.2 Additional tips clinicians may find useful for improving medication adherence in children and adolescents include the following: • Attitude regarding a medication’s benefit does affect children’s willingness to take it. Providing education to develop patients’ trust in the benefit and effectiveness of a drug regimen will assist in their understanding the necessity of taking the medication.

• Using the simplest regimen that has been proven effective is key to better adherence. Fewer pills taken fewer times each day will improve adherence in children and adults alike.

• The palatability of drugs can affect adherence. Masking the taste of medication by mixing liquid medicines in juice or other beverages will make them easier to take.

Another tip is to crush tablets and add them to foods like ice cream or pudding. The medication will taste better, and the child will not have to swallow a large pill. Check with your pharmacist before crushing any medicines.2 • Children who are old enough should be encouraged to participate in the medication process. Let them take their medications under the supervision of a parent, and be sure to provide education to ensure safety. As youngsters get older, instruct the parent to allow them a more active role in taking their medications each day.

• Getting additional family members, schools, and other social supports involved is a valuable strategy for maximizing the ability of school-age children to adhere to medication regimens.

• Research on interventions to improve communication, health behavior, and adherence in pediatric settings is sparse. Parents and families need education to understand

50 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

PEER PERSPECTIVES

“Many medications can be made more palatable by adding flavors or changing consistencies. Some can even be made into lollipops! A compounding pharmacist can be helpful in such cases. ” Julee B. Waldrop, DNP, PNP, FNP, Orlando, Fla. (via ClinicalAdvisor.com)

what they are being asked to do. In addition, they should be given the opportunity to provide feedback regarding their experience with their medication regimen. Sources of resistance need to be identified, and beliefs in the efficacy and benefits of treatment should be enhanced.5

in most clinical settings. In addition, electronic monitoring generally does not reveal whether or not the patient consumed the medicine, only that the container was opened. This is especially true when children have graduated to taking their own medication.3

Measuring adherence

The importance of persistence

Once a medication regimen has been established, ensuring that patients follow it is crucial. There are many ways to measure adherence, although some approaches are too costly and time-intensive. Direct methods include observed medication administration, measurement of the drug or its metabolite in blood, and assays for a biological marker in the urine. Although direct approaches are more accurate at assessing adherence, they are expensive and burdensome to the clinician, and they may be susceptible to distortion by the patient.6 Indirect methods, which are the most cost-effective and feasible, include the use of patient questionnaires and self-reports, pill counts, rates of prescription refills, assessment of clinical response, use of electronic medication monitors, measurement of physiologic markers, and patient diaries.2 Measurement of medication adherence in children largely relies on responses to questions (or questionnaires) by parents, caregivers, and sometimes teachers. The use of electronic monitoring is expensive and does not provide a useful solution

In conclusion, administering medication to children and adolescents is difficult and challenging. Be patient, and know that at times adherence is going to seem impossible. As the clinician, your role is to focus on education, simplification of medication regimens, and some old-fashioned common sense. With time, issues involving medication adherence will become much easier for you and your patients. ■ Mr. Zimbeck is a nurse practitioner specializing in cardiology at the Marshfield Clinic in Marshfield, Wis. References 1. Gardiner P, Dvorkin L. Promoting medication adherence in children. Am Fam Physician. 2006;74:793-798. Available at www.aafp.org/ afp/2006/0901/p793.html.

2. Lask B. Motivating children and adolescents to improve adherence. J Pediatr. 2003;143:430-433.

3. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

AT A GLANCE

4. Frush KS, Luo X, Hutchinson P, Higgins JN. Evaluation of a method to

●

In children and adolescents with chronic health problems, medication adherence averages about 50%.

reduce over-the-counter medication dosing error. Available at archpedi.

●

The token-reinforcement system is the most frequently used intervention to improve poor adherence in children.

5. Nevins TE. Non-compliance and its management in teenagers. Pediatr

●

Using the simplest regimen that has been proven effective is key to better adherence.

6. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed

●

Measurement of adherence in children relies on responses to questions by parents, caregivers, and teachers.

1990;150:1881-1884.

ama-assn.org/cgi/content/full/158/7/620.

Transplant. 2002:6:475-479. daily dose frequency on patient medication compliance. Arch Intern Med.

All electronic documents accessed January 15, 2012.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 51

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum FEBRUARY 2012

Consultations Vitamin D deficiency among Hispanics . . . . . . . . . . . . . . .54 Do PPIs affect calcium absorption? . . .54 Primary-care hypothyroidism treatment . . . . . . . . . . . . . . . . . . . .55 Raising vs. lowering bedtime insulin . .55 What causes a metallic taste and burning tongue? . . . . . . . . . . . . . . .60

Clinical Pearls A little birdie can facilitate pediatric ear exams . . . . . . . . . . . . . . . . . . . .60 Ice down dyspnea . . . . . . . . . . . . . . .61 Check for flat feet in young patients with shin splints. . . . . . . . . .61

Your Comments

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com.

If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter.

No anonymous contributions will be accepted.

Vancomycin dosing for MRSA infections. . . . . . . . . . . . . . .61

CONSULTATIONS VITAMIN D DEFICIENCY AMONG HISPANICS How prevalent is vitamin D deficiency in the Hispanic population? Should we routinely check vitamin D levels in Hispanic patients as we do in others?—BETH PRETTI, NP, Indianapolis In a 2009 national survey of adolescent health, vitamin D levels were consistent with the level of skin pigmentation (Pediatrics.

2009;123:797-803: available at pediatrics.aappublications.org/ content/123/3/797.long, accessed January 15, 2012). Since cutaneous formation of vitamin D (specifically from UVB light) is one of the most significant sources, it makes sense that, regardless of age, the amount of melanin in the skin, functioning as sun block, will have the greatest impact on vitamin D levels. Applying this logic to the Hispanic population, it would be difficult to make a blanket recommendation on screening given the wide variation in skin color among this group. Rather than focusing on patient ethnicity, it makes more sense to screen based on skin color.—Rebecca H. Bryan, APRN, CNP (160-1)

DO PPIS AFFECT CALCIUM ABSORPTION? Are there any studies that confirm effective calcium absorption when the patient is taking long-term proton pump

OUR CONSULTANTS

Bruce D. Askey, MSN, CRNP,

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

is a clinician in the Department of Hepatology/ Gastroenterology at the Guthrie Clinic in Sayre, Pa.

is a lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

54 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP program, University of Pennsylvania School of Nursing, Philadelphia.

inhibitors (PPIs) along with oral calcium? These patients should be on calcium citrate—not calcium carbonate—but my supervisor says there are no data to support this.—JO KILLENBECK, APRN, Billings, Mont.

The results of a recent small study showed impaired absorption of calcium carbonate but normal absorption of calcium citrate in achlorhydric subjects who were in a fasting state (J Bone Miner Res. 2010;25:2786-2795). In an older study, researchers found that the absorption from calcium carbonate was impaired in achlorhydria under fasting conditions, while absorption from calcium citrate in those with achlorhydria was higher (New Engl J Med. 1985;313: 70-73).—Eileen F. Campbell, MSN, CRNP (160-2)

PRIMARY-CARE HYPOTHYROIDISM TREATMENT Can a patient with new-onset hypothyroidism be started on levothyroxine 50 µg/day without endocrine referral?— MARIE LAGUERRE, NP, Weston, Fla. Most hypothyroidism is managed in primary care, and starting this patient on levothyroxine will certainly help him or her feel better.

Obtaining a careful history would help determine the need for an endocrine referral. According to the American Association of Clinical Endocrinologists, age younger than 18 years, pregnancy, history of cardiac disease, lack of response to thyroid hormone (as evidenced by lack of improvement or change in thyroid labs), or presence of thyroid nodules or goiter are all indications for referral to an endocrinologist (Endocr Pract. 2002;8:457-469). The starting dose for treating hypothyroidism can be 50 µg/day, and dose requirements can be as much as 1.6 µg/kg/day. Checking labs (thyroid-stimulating hormone and free thyroxine) six to eight weeks later will help determine if the dose needs to be adjusted.—Kathy Pereira, MSN, FNP-BC,

assistant professor, co-coordinator, Family Nurse Practitioner Program, Duke University School of Nursing, Durham, N.C. (160-3)

RAISING VS. LOWERING BEDTIME INSULIN I am treating a middle-aged patient with a seven-year history of insulin-dependent type 2 diabetes mellitus. He is having increasing difficulty controlling morning glucose levels. How does one determine whether to raise or lower bedtime insulin?—ZIEV MOSES, Hanover, N.H. Fasting hyperglycemia can be caused by several problems: • The “dawn phenomenon,” described as a rise in glucose levels in the predawn hours, is caused by abnormal hepatic glucose output at night (attributable to increased production of growth hormone and cortisol at night).

• Nighttime hypoglycemia with subsequent rebound hyperglycemia, sometimes called “Somogyi effect.” This can occur when a patient has autonomic neuropathy (usually from long-standing diabetes) and sleeps through low blood glucose. Secretion of counterregulatory hormones (i.e., epinephrine, norepinephrine, cortisol, and growth hormone) occurs during the low, which will raise the blood glucose hours later. In patients on insulin, more than half of all hypoglycemia occurs at night.

• Insufficient nighttime insulin dosing.

• Eating supper late at night.

• Eating a high-fat dinner the night before. Large amounts of fat in a meal slow the absorption of glucose from meals, resulting in morning hyperglycemia.

To help sort this out, obtain a few days’ worth of middle-of-thenight glucose readings (2:00 AM or 3:00 AM), which requires asking the patient to set an alarm clock. Careful questioning about eating habits and meal composition is also helpful. If the patient is having

Maria Kidner, DNP, FNP-C,

Debra August King, PHD, PA,

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

is a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

is senior physician assistant of the Department of Cardiothoracic Surgery, Lenox Hill Hospital, New York City.

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

is a primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

teaches at the University of North Carolina School of Nursing in Chapel Hill and practices pediatrics at UNC Hospitals.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 55

Advisor Forum middle-of-the-night lows, decrease the bedtime basal insulin. If glucose is normal at bedtime but rises throughout the night, increase the basal insulin at bedtime (Beaser RS. Joslin’s Diabetes Deskbook. 2nd ed. Boston, Mass.: Joslin Diabetes Center; 2010:157-158). – Kathy Pereira, MSN, FNP-BC, assistant professor, co-coordinator, Family Nurse Practitioner Program, Duke University School of Nursing, Durham, N.C. (160-4)

“And just where did that extra vowel come from?”

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

“I rearrange the furniture—he doesn’t notice.”

WHAT CAUSES A METALLIC TASTE AND BURNING TONGUE? What are the differential diagnoses for a woman aged 60 years with a metallic taste in her mouth and the sensation of a burning tongue? Objective findings of the head and neck are benign, with a normal MRI.—VERONICA R. WIZES, MSN, FNP, Arcata, Calif.

The differential diagnosis for altered taste and burning tongue includes nutritional deficiencies (e.g., folate, zinc, and vitamins B, E, and C), pernicious anemia, and iron-deficiency anemia. Diabetes, thyroid disorders, nerve damage, glossitis, allergies, systemic lupus, herpes simplex, herpes zoster, Parkinson disease, side effects of medications, local infection, dental-alveolar diseases, salivary disorders, hormonal changes, gastroesophageal reflux, oral cancer, and burning mouth syndrome (BMS) are also included in the differential.

BMS is a chronic disorder that is most common in postmenopausal women, although younger men and women are affected. The etiology is unknown, and no systemic or underlying causes are identified in patients. Symptoms include burning sensation of the tongue and other soft tissue of the oral cavity. Patients may also complain of altered taste, including metallic or bitter sensations, and dry mouth.

Coexisting anxiety or other psychological conditions are often seen in cases of BMS. Primary BMS is a diagnosis of exclusion once other causes have been ruled out.—Eileen F. Campbell, MSN, CRNP (160-5)

CLINICAL PEARLS A LITTLE BIRDIE CAN FACILITATE PEDIATRIC EAR EXAMS When checking the ears of an infant or small child, I tell him or her that I am searching for a rare and beautiful bird.

I get very close to the ear and make a soft whistling noise before gently putting the otoscope into the ear canal. The patients love it and remain still and quiet as I whistle for the birdie.—PATRICIA A. OUELLETTE, FNP, Scotts Valley, Calif. (160-6) 60 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

ICE DOWN DYSNPEA One of the easiest ways to treat shortness of breath in any situation is to ice the facial nerve. This reduces the sensation of dyspnea. Fully explaining this treatment is essential to its success. This may indicate that there is some placebo effect at work.—JAN MORGAN, ARNP, FAAPM, Bremerton, Wash. (160-7)

CHECK FOR FLAT FEET IN YOUNG PATIENTS WITH SHIN SPLINTS In younger patients complaining of shin splints or knee, back, or hip pain, examine the feet to rule out pes planus or its variants before ordering pain medicine or referring to physical therapy or orthopedics.—ROBERT KAPPEL, PA-C, Downers Grove, Ill. (160-8)

YOUR COMMENTS VANCOMYCIN DOSING FOR MRSA INFECTIONS I am a podiatrist and a fellow of the Infectious Diseases Society of America (IDSA). Your December 2011 article,

“Updated information on MRSA infections,” presented interesting clinical information. However, the dosing recommendation provided for vancomycin (Vanocin) is incorrect. According to the most recent IDSA guidelines (Clin Infect Dis. 2011;52:e18-55; available at cid.oxfordjournals.org/content/52/3/e18.long, accessed January 15, 2012), the recommendations for systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA) is 15-20 mg/kg every 8-12 hours, not to exceed 2 g per dose (not per 24 hours as stated in the article). It is not uncommon to use vancomycin at 1.5-2.0 g every 12 hours, especially for overweight patients. The idea is to maintain an AUC/MIC ratio of >400. The dose is then adjusted at steady state to maintain a trough level of 15-20 μg/mL (although I feel this is too high for skin and skin structure and will aim for a trough of only 10-15 mcg/mL to minimize renal toxicity).

MRSA is a significant clinical problem encountered by all health-care providers. I would like to applaud the author and The Clinical Advisor for reviewing this important topic. However, it is important to base antibiotic recommendations on the best available medical evidence and sound science.—WARREN S. JOSEPH, DPM, FIDSA, Philadelphia (160-9) ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 61

Stat Consult

A quick review of common conditions, using the best global evidence

Description

Abnormal uterine bleeding

• Abnormal uterine bleeding (AUB) is infrequent, unpredictable, irregular bleeding variable in amount, duration, and character (anovulatory bleeding).

• Heavy menstrual bleeding (HMB) is flow >80 mL with menses that last ≥7 days or have intervals ≤21 days.

Also called

BY ALAN DRABKIN, MD

Dr. Drabkin is a clinical editor for DynaMed (www.ebscohost.com /dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and A Assistant Clinical Professor of Population Medicine at Harvard Medical School.

A magnified view of the uterine endometrium during menses, which shows hemorrhage and exfoliation of the surface epithelium.

• There is extensive disagreement worldwide in the use of terminology describing symptoms, signs, and causes of AUB. Common terms include: — Abnormal vaginal bleeding — Dysfunctional uterine bleeding (DUB) — Functional uterine bleeding — Irregular menstrual bleeding — Prolonged menstrual bleeding ICD-9 codes

• • • • • • •

626.2 excessive or frequent menstruation 626.3 puberty bleeding 626.4 irregular menstrual cycle 626.5 ovulation bleeding 626.6 metrorrhagia 626.7 postcoital bleeding 626.8 other disorders of menstruation and other abnormal bleeding from female genital tract • 626.9 unspecified disorders of menstruation and other abnormal bleeding from female genital tract Incidence/prevalence

© VETPATHOLOGIST / SHUTTERSTOCK

• Occurs in 10% -30% of women who are of reproductive age Causes

• Pregnancy-related — Pregnancy/ectopic pregnancy — Miscarriage • Hormonal — Physiologic anovulatory cycles Continues on page 65

62 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Stat Consult Within two years of menarche (secondary to immature hypothalamic-pituitary-ovarian axis) ■ Perimenopause — Hypo- or hyperthyroidism — Hyperprolactinemia — Polycystic ovary syndrome (PCOS) and other hyperandrogenic conditions — Premature ovarian failure (hypothalamic dysfunction) including that due to anorexia nervosa — Oral contraceptives — Medroxyprogesterone acetate • Medications — Anticoagulants — Phenytoin (Di-Phen, Dilantin, Phenytek) — Antipsychotics — Tricyclic antidepressants — Corticosteroids — Tamoxifen — Herbal supplements with estrogenic activity • Gynecologic lesions — Vaginal ulcers or carcinoma — Cervical ulcer, polyp, or carcinoma — Uterine leiomyoma (fibroids—most common uterine cause) — Other endometrial pathology including adenocarcinoma, sarcoma, hyperplasia, endometritis, adenomyomata, polyps — Genital trauma resulting from foreign bodies, including intrauterine device • Bleeding disorders (including von Willebrand disease) ■

Complications

• Iron-deficiency anemia History

• Structured history recommended for women with HMB — Positive screen defined as any of the following ■ HMB since menarche ■ Postpartum hemorrhage ■ Surgery-related bleeding ■ Bleeding associated with dental work ■ Two or more of the following » Family history of bleeding symptoms » Bruising or epistaxis one to two times a month » Frequent gum bleeding — If positive screening, consider further evaluation including consultation with hematologist and/or testing for von Willebrand disease

• Determine ovulatory function (reliably confi rmed if history of predictable, cyclic menses with cycle length of every 22 to 35 days).

• Determine pattern of bleeding.

— Severe acute bleeding requiring more than one pad or tampon per hour or vital signs indicating hypovolemia — Irregular bleeding includes metrorrhagia, menometrorrhagia, oligomenorrhea, prolonged bleeding, intermenstrual bleeding, prolonged bleeding for more than 12 days or other irregular pattern.

— HMB (menorrhagia) is heavy but regular cyclic bleeding plus more than seven days of bleeding or clots or iron-deficiency anemia • Ask about — Symptoms of anemia — Weight change — History or symptoms of thyroid disorder — Medication use Physical Examination

• Check for signs of — Pregnancy — Anemia — Endocrine disorders ■ Hyperandrogenism ■ Hypo- or hyperthyroidism — Abdominal mass — Gynecologic lesions Diagnostics

• Testing to consider — For all women with chronic AUB ■ Pregnancy test (urine or blood) ■ Complete blood count — Additional testing per patient history ■ Thyroid-stimulating hormone ■ Prolactin ■ Test for PCOS or any other hyperandrogenic state ■ Test for bleeding disorder ■ Imaging ■ Endometrial sampling » Indicated if increased risk of endometrial hyperplasia or neoplasia » If indicated and cannot be obtained or inadequate, repeat sampling should be attempted, if necessary with dilation and curettage (D&C) Continues on page 66

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 65

Stat Consult • Indications for imaging — Persistent AUB despite normal and satisfactory endometrial sampling — Irregular endometrial thickening on ultrasound — Incomplete evaluation of endometrial cavity — Suspected polyps or fibroids • Imaging studies — Transvaginal ultrasound, sonohysterography, and hysteroscopy may be similarly effective in detection of intrauterine pathology in premenopausal women with AUB. — No consensus on normal upper limit of endometrial thickness in premenopausal women Treatment

• For acute, severe bleeding — Blood transfusion if severely anemic — Estrogen ■ Use often recommended, but evidence for efficacy is limited ■ Management plans include intravenous or oral conjugated equine estrogens followed by a tapered plan of combination oral contraceptive.

— Oral medroxyprogesterone acetate and combination oral contraceptives appear to be equally effective in terminating acute uterine bleeding.

— D&C or intrauterine Foley bulb placement if ■ Hemodynamic instability and acute bleeding ■ Lack of response to initial therapy • For irregular menses — Lifestyle changes including stress reduction and weight loss — Medical therapy for presumed anovulatory irregular bleeding ■ Withdrawal bleeding induced by progestin ■ Progesterones used alone or in combination with estrogens have shown limited evidence for management ■ Metformin and other insulin-sensitizing drugs may reduce menstrual abnormalities in women with PCOS ■ Gonadotropin-releasing hormone agonists — Surgical therapy ■ Indicated only for women not interested in future fertility ■ Hysterectomy is more effective than endometrial ablation for symptom resolution, but it has more adverse perioperative events.

■

If AUB due to leiomyomas

» Surgical management determined by size, location, and number

» Abdominal myomectomy preferred procedure if resectoscopic removal unsuitable and patient wishes to retain her uterus ■ Remove symptomatic endometrial polyps completely with hysteroscopy.

• For HMB — Improvement in quality of life should be the clinician’s primary goal.

— Clarifying values and patient preferences may reduce hysterectomy rates.

— Medications ■ Levonorgestrel intrauterine system (LNG-IUS) treatment of choice if » Hormonal treatments are acceptable » At least 12 months’ use anticipated ■ Other options » Combined oral contraceptives (second-line) » NSAID or tranexamic acid (preferred treatment options if hormonal treatments not acceptable) » Progestins (oral or injected long-acting) (third-line) » Danazol (Danocrine) — Surgery/procedures ■ Surgery reduces menstrual bleeding at one year more than does medical therapy.

■ LNG-IUS improves quality of life as effectively as does surgery.

■ Endometrial ablation preferred to hysterectomy in HMB when uterus ≤10-week-pregnancy size ■ Surgery and uterine artery embolization are fi rstline treatments recommended for women with large fibroids, HMB, and other significant symptoms.

■ Vaginal hysterectomy preferred over abdominal hysterectomy Other management

• Iron therapy (assess individualized need) • Chinese herbal medication has insufficient evidence for evaluation of use for DUB. ■

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

66 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Test your clinical acumen with our monthly quiz

CME Dermatology Clinic CE

■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment.

■ COMPLETE THE POSTTEST: Page 99

■ ADDITIONAL CME/CE: Pages 39, 95

CASE #1

Nonscaly pink papules on the neck ASHLEY BROWN AND JULIA R. NUNLEY, MD

A woman aged 28 years presented with asymptomatic lesions on her neck. Similar lesions noted on her arms the year before had healed without scarring. The woman admitted to sun sensitivity but denied fevers, chills, myalgias, or arthralgias. Examination revealed six to seven variably sized, nonscaly, pink papules and plaques on the left side of the neck. Biopsy demonstrated an interface dermatitis with a lymphocytic perivascular and periadnexal infi ltrate. Special stains showed an increase in dermal mucin with negative immunofluorescent staining. Laboratory data demonstrated a low titer anti-nuclear antibody (1:80) with a negative anti-Smith antibody.

What is your diagnosis? Turn to page 68

CASE #2

Asymptomatic scalp plaque since birth KERRI ROBBINS, MD

A boy aged 3 years was brought to the pediatric dermatology clinic with a lesion on his scalp that was first noted shortly after birth. The lesion was originally thought to be attributable to a scalp electrode that had been placed during delivery. The lesion was asymptomatic and seemed to be growing proportionately with the boy. The child’s parents were concerned that no hair grew within the area and asked about treatment options to improve the cosmetic appearance of the lesion. On physical examination, a large salmon-colored plaque was appreciated on the vertex of the scalp.

What is your diagnosis? Turn to page 69 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 67

CME CE

CASE #1

Dermatology Clinic

Tumid lupus erythematosus

The clinical, laboratory, and histologic findings of this case are diagnostic for tumid lupus erythematosus (TLE). Lupus erythematosus (LE) encompasses a wide range of autoimmune diseases, for which the exact pathogenic mechanisms are unknown. The spectrum of LE ranges from various cutaneous disorders without visceral organ involvement to a multiorgan systemic disease with or without cutaneous changes.

For most individuals, TLE is a purely cutaneous disease.

TLE was first reported in 1909.1 Since then, various distinct subtypes of chronic cutaneous lupus erythematosus (CLE) have been described and characterized; these include chronic cutaneous (discoid) LE (CCLE), subacute cutaneous LE (SCLE), lupus panniculitis, and nonbullous neutrophilic dermatosis of LE, as well as TLE. Furthermore, TLE also has clinical or histologic features that resemble a number of such non-LE cutaneous diseases as polymorphous light eruption (PMLE), pseudolymphoma, reticular erythematous mucinosis (REM), and Jessner lymphocytic infiltrate of the skin (JLI).2 Without complete histologic and immunologic data, it is highly likely that TLE could be confused with any of these other conditions. Fortunately, the diagnosis of TLE is easier to make with modern technology; serologic, immunohistochemical, and histopathologic features have been have been identified, defining TLE as a distinct entity.3 TLE typically develops as innocuous papules, plaques, and/or nodules; although most patients are asymptomatic, a minority may note mild pruritus. Lesions are often annular in shape and range from mild pink to a more violaceous color. Unlike most subtypes of cutaneous lupus, the lesional surface of TLE is characteristically smooth, lacking scale, follicular plugging, scarring, telangiectasia, or atrophy.4-6 Sun-exposed areas including the face, upper back, chest, and upper extremities are most commonly affected; rarely are lesions found on the lower extremities or inner aspect of the arms. Consistent with a photoactivated process, there is a higher incidence of TLE in the summer months.5 When multiple lesions are present, they tend to develop in a bilaterally symmetric distribution similar to other subtypes of cutaneous lupus. Although TLE can affect individuals of any age, the mean age of onset is the third or fourth decade of life;5 there appears to be no gender predominance.

A skin biopsy using special stains is necessary to confirm the diagnosis of TLE. Histologically, one finds a moderateto-dense, superficial, and deep lymphocytic infiltrate affecting the perivascular and periadnexal areas.3-5 An increased amount of interstitial dermal mucin can be demonstrated with such stains as colloidal iron.6 The mucin deposition of TLE resembles that of REM but is distinct from DLE and JLI. Whereas REM classically has a greater amount of mucin and fewer inflammatory cells than does TLE, both DLE and JLI have minimal mucin deposition.2 Inflammation of the dermoepidermal junction is a frequent finding in most subtypes of CLE, but this interface dermatitis is less consistently observed in TLE, comparatively.2,4 When observed, involvement is typically focal, demonstrating vacuolar alteration with necrotic keratinocytes.4 Pseudolymphoma and PMLE can be differentiated from TLE through immunohistologic staining for lymphocyte markers. The infi ltrate in TLE is composed predominantly of T-lymphocytes that are CD3-positive and CD4-positive; the typical CD4-to-CD8 ratio is 3:1.2,4 Pseudolymphoma has more variable B and T cells, and PMLE has a predominance of CD8-positive cells.2 Serologic studies are nondiagnostic, since most individuals with true TLE have negative test results for lupus autoantibodies (i.e., antinuclear antibody [ANA], anti-Ro, anti-La, anti-dsDNA, and anti-Sm).4-6 However, some may have a low-positive ANA titer. Cases in which patients have high auto-antibody titers most likely represent patients with an overlap of TLE and systemic lupus erythematosus

A skin biopsy using special stains is necessary to confirm the diagnosis of tumid lupus erythematosus.

(SLE).2,4 Because of this rare association, it is critical that all patients with TLE—or any of the subtypes of cutaneous lupus—be evaluated for SLE.2 The clinical course of TLE is usually benign with a favorable prognosis: Complete resolution of skin lesions occurs in the majority of cases, sometimes spontaneously without treatment. All patients need to be told of the photosensitive nature of the condition and educated appropriately about sun protection and sun avoidance. Broad-spectrum sunscreens should be recommended. Both UVA and visible light can pass through glass, so protection is needed in sunlit rooms

68 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

and cars. Inorganic sunblocks and sun-protective clothing may provide more effective types of sun protection.

For mild and limited disease, a topical corticosteroid may be effective monotherapy. Steroid class is dictated by anatomic location. For example, a class 1 steroid may be used short-term on extremities, neck, and torso; a class 5 steroid would be more appropriate on the face.

Consider antimalarial medications, preferably hydroxychloroquine (HCQ) (Plaquenil, Quineprox), for people who have more widespread lesions or cannot tolerate or are unresponsive to topical steroids.4,5 Pretesting and laboratory monitoring are necessary with HCQ therapy. Periodic ophthalmologic examinations are also essential because of the potential risk (though low) of retinal toxicity.5 Once in remission, taper treatment if possible; recurrences are not uncommon and typically respond to the same regimen.

This patient was treated with clobetasol cream. HCQ 200 mg twice daily was added because of her concern for cutaneous atrophy from use of the topical steroid. The woman was advised to use an adequate form of birth control; HCQ is a pregnancy-prescribing category C medication.

Ms. Brown is a fourth-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is professor of dermatology. Neither author has any relationship to disclose relating to the content of this article.

References 1. Hoffman E, Demonstrationen A. Isolierter lupus erythematodes tumidus der gesichtshaut. Derm Zeitschr. 1909;16:159–60.

2. Stead J, Headley C, Ioffreda M, et al. Coexistence of tumid lupus erythematosus with systemic lupus erythematosus and discoid lupus erythematosus: a report of two cases of tumid lupus. J Clin Rheumatol. 2008;14:338-341.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2829660/.

3. Kuhn A, Sonntag M, Ruzicka T, et al. Histopathologic finding in lupus erythematosus tumidus: review of 80 patients. J Am Acad Dermatol 2003; 48:901-908.

4. Alexiades-Armenakas MR, Baldassano M, Bince B, et al. Tumid lupus erythematosus: Criteria for classification with immunohistochemical analysis. Arthritis Rheum. 2003;49: 494-500.

5. Kuhn A, Richter-Hintz D, Oslislo C, et al. Lupus erythematosus tumidus—a neglected subset of cutaneous lupus erythematosus: report of 40 cases. Arch Dermatol. 2000;136:1033-1041. Available at archderm .ama-assn.org/cgi/content/full/136/8/1033.

6. Alexiades-Armenakas M. Tumid lupus erythematosus. Dermatol Online J. 2001;7:14. Available at dermatology.cdlib.org/DOJvol7num2/nyu2/4/4.html.

All electronic documents accessed January 15, 2012.

CASE #2

Nevus sebaceus

First described in 1895, nevus sebaceus is often thought of as a sebaceous malformation.

However, the condition is better described as a circumscribed hamartomatous lesion that has follicular, sebaceous, and apocrine malformation to varying degrees.1 A hamartoma is defined as a benign, focal malformation that resembles a neoplasm in the tissue of its origin.

Nevus sebaceus is also referred to as “organoid nevus.” Today, the lesion is known to be a congenital malformation and presents as a solitary hairless plaque found mainly on the face and scalp.

Nearly all lesions of nevus sebaceus are present at birth. As the infant grows into a child, the lesions will also grow and become more apparent. The probability of developing a nevus sebaceus seems to be random among the patient population.

There are a few forms that do run in families, but these are uncommon. Approximately 0.3% of newborns will be affected by a nevus sebaceus.2,3 There is no evidence to suggest that the disorder favors a particular sex or race. There is no involvement of any other organ system. The disorder stems from a principal malformation of individual folliculosebaceous entities. Research shows postzygotic somatic mutations result in the various clinical expressions of mosaicism (i.e., cells with a different genetic makeup). The pluripotent cells give rise to harmartomas with multiple cell lines.4 Extensive nevus sebaceus may be associated with multiple systemic abnormalities, in which case it is referred to as “nevus sebaceus syndrome,” defined as the combination of extensive sebaceous nevi with systemic abnormalities that affect the central nervous system, bone, and eye. This may manifest as epilepsy, mental retardation, or other neurologic defects. Also seen are such skeletal deformities as spina bifida or bone hypertrophy and such ocular abnormalities as ptosis, nystagmus, and oculomotor dysfunction.

At birth, a nevus sebaceus may be very subtle. Lesions begin as thin, salmon-colored plaques on the scalp or face.

However, there have been cases in which the neck or trunk was affected. At puberty, hormonal changes cause the sebaceous glands to become more active, and the surface of the nevus sebaceus often becomes greasier and thicker and develops a verrucous surface.3,4 The lesions are distributed in a linear configuration that follows the lines of Blaschko.3 This may be difficult to appreciate if lesions are small.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 69

CME CE

Dermatology Clinic

Histologically, the sebaceous glands are well developed during infancy due to maternal hormonal influences. In childhood, the sebaceous glands are reduced in number and size, and the diagnosis may be missed when examining the skin microscopically. The hair structures must be carefully analyzed, because there will often be undifferentiated cells mimicking the embryonic stage of hair follicles,5,6 which may provide a clue to the diagnosis. At puberty, hormonal influences allow the lesion to assume its diagnostic histologic appearance. An abundance of mature sebaceous glands will be found underneath a papillomatous hyperplasia of the epidermis. These sebaceous glands are often unassociated with mature hair shafts.5 Ectopic apocrine glands will develop in about two thirds of patients at puberty.6 The apocrine glands are located deep in the dermis below the abundant sebaceous glands. Often, there are malformed hair germs that appear as buds of undifferentiated cells that resemble foci of basal cell carcinoma (BCC).

During adulthood, various tumors may develop secondarily within the nevus sebaceus. The most commonly associated

Consider excision during childhood when facial lesions are small and have not developed secondary verrucous changes. tumor was once thought to be BCC. However, reevaluation has led researchers to believe that these were actually misdiagnosed cases of trichoblastoma. Currently, trichoblastoma is thought to be the most commonly associated tumor, with BCC occurring only rarely. Syringocystadenoma papilliferum has been found in 8% -19% of nevus sebaceus lesions.6 Other tumors that may develop—but are much less commonly seen—include nodular hidradenoma, syringoma, sebaceous epithelioma, chondroid syringoma, trichilemmoma, trichoadenoma, sebaceous carcinoma, squamous cell carcinoma, eccrine poroma, and proliferating trichilemmal cyst.

Similar lesions that may be mistaken for nevus sebaceus include epidermal nevi, congenital nevi, sebaceous adenoma, sebaceous carcinoma, aplasia cutis congenita, seborrheic keratoses, and verruca vulgaris. When considering the diagnosis of epidermal nevus, keep in mind that although both may appear similar clinically, epidermal nevi are found mainly on the extremities and trunk of the body. Histologically, there is no proliferation of sebaceous or apocrine glands.6

It was previously thought that approximately 10% of nevus sebaceus lesions would undergo malignant transformation into BCC (or other types of carcinoma).7 Complete surgical excision was recommended because of this risk. However, new research shows that the only about 1% of the lesions may develop into a malignant carcinoma.3 Most patients desire removal for cosmetic reasons. The excision needs to be conservative but still reach the adipose tissue or galea. Complete excision of the lesion will prevent the development of secondary neoplasms.8 For facial lesions, consider excision during childhood while the lesions are small and have not developed secondary verrucous changes.

Early excision will help minimize scarring. Treatment with shaving and laser ablation has been attempted but with minimal success.3 The prognosis for those who are diagnosed with nevus sebaceus is excellent. Most lesions may be monitored over time for malignant progression. If it is cosmetically undesirable or in an area where monitoring may be difficult, complete surgical excision is curative.

In this case, extensive education and anticipatory guidance regarding the diagnosis of nevus sebaceus was given to the child’s parents. Given the lesion’s large size and concern for cosmesis, a referral was made to plastic surgery to discuss options for removal. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. The author has no relationships to disclose relating to the content of this article.

References 1. Prioleau PG, Santa Cruz DJ. Sebaceous gland neoplasia. J Cutan Pathol.

1984;11:396-414.

2. Habif, TP. Skin Disease: Diagnosis and Treatment. 2nd ed. St. Louis, Mo: Mosby/Elsevier; 2005:408-411.

3. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, 2nd ed., St. Louis, Mo.: Elsevier-Mosby; 2008:1695-1696.

4. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed.

Philadelphia, Pa.: Elsevier Saunders; 2006:221-222.

5. Rapini RP. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:281-282.

6. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin. 10th ed., Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:870-874.

7. Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: A study of 596 cases. J Am Acad Dermatol. 2000;42:263-268.

8. Chun K, Vázquez M, Sánchez JL. Nevus sebaceus: clinical outcome and considerations for prophylactic excision. Int J Dermatol. 1995;34:538-541.

70 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

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www.tradjenta.com Copyright © 2011, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

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Please see brief summary of full Prescribing Information on the following page.

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Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com

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USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

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ADVERSE REACTIONS Adverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (eg, rifampin).

Therefore, use of alternative treatments is strongly recommended.

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WARNINGS AND PRECAUTIONS Use With Medications Known To Cause Hypoglycemia Insulin secretagogues (eg, sulfonylurea) are known to cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

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Important Safety Information CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus zero in 433 person-years for comparator).

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Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA has not been studied in combination with insulin.

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The only DPP-4 inhibitor approved at 1 dose for adult patients with type 2 diabetes

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FOR ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS

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Tradjenta™ (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

INDICATIONS AND USAGE TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

TRADJENTA has not been studied in combination with insulin.

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

OVERDOSAGE During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis.

Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Monotherapy* n (%)

Nasopharyngitis Hyperlipidemia Cough Hypertriglyceridemia† Weight increased

Combination with SU n (%)

TRADJENTA Placebo n = 765 n = 458

Combination with Metformin# n (%) TRADJENTA Placebo n = 590 n = 248

– – – – –

– – – – –

7 (4.3) – – 4 (2.4) –

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– – – – –

TRADJENTA Placebo n = 161 n = 84 1 (1.2) – – 0 (0.0) –

Combination with Metformin + SU n (%) TRADJENTA Placebo n = 791 n = 263

Combination with Pioglitazone n (%) TRADJENTA Placebo n = 259 n = 130

– – 19 (2.4)

– 7 (2.7) – – 6 (2.3)

–

– – 3 (1.1) – –

– 1 (0.8) – – 1 (0.8)

SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)

Copyright © 2011 Boehringer Ingelheim Pharmaceuticals, Inc. Revised: July 2011

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USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

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Table 1

DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp or CYP3A4 inducer.

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ADVERSE REACTIONS 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 linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with pioglitazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in ≥5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyngitis (5.8% vs 5.5%). Adverse reactions reported in ≥2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥ 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).

Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.

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QUESTIONS 1. What percentage of women aged 18-39 years currently suffer from depression? (p. 14) 2. According to the World Health Organization, approximately how many people live with chronic hepatitis B infection? (p. 32) 3. Approximately what percentage of adults carry the diagnosis of metabolic syndrome? (p. 39) 4. What phrase is sometimes used to describe nighttime hypoglycemia with subsequent rebound hyperglycemia? (p. 55) 5. In what patient population is burning mouth syndrome most common? (p. 60) 6. What is a potential complication of abnormal uterine bleeding? (p. 65) 7. What is the mean age of onset for tumid lupus erythematosus? (p. 68) 8. What findings make up the “classic pentad” of thrombotic thrombocytopenic purpura? (p. 87) 9. What is the life span of a scabies mite? (p. 96) 10. What is the recommended dose of topical wild yam cream? (p. 102)

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Clinical Challenge Symptoms suggesting urolithiasis mask a life-threatening ailment MICHELE D. TINGE, MPAS, PA-C

Two days after onset, the patient’s skin is still mildly diaphoretic, he complains of fatigue, and he cannot tolerate food.

Initially, the clinical support team suspected that the young man may have a kidney stone.

Mr. R, a 30-year-old black man, presented to our clinic noting that he had experienced fever, chills, and sweats accompanied by nausea and vomiting, all of which started two days earlier. Mr. R had no diarrhea or abdominal pain, but he did complain of fatigue. He also mentioned a steady, dull pain in his back. When asked, Mr. R noted no dysuria or urinary frequency or urgency. His urine was darker than normal, and he noted occasional gross hematuria (but no nocturia). He reported no headache, confusion, cough, shortness of breath, and palpitations. No recent weight changes were reported. Mr. R’s vomiting was significant enough that he could only tolerate popsicles and small sips of water, but there was no hematemesis.

CASE

1. HISTORY Mr. R’s history is questionable for nephrolithiasis. He has no incidence of renal, bladder, or prostate disease, and until this episode, he had been healthy except for periodic migraine headaches. His family history is significant for nephrolithiasis. Mr. R is married with one daughter. In his job as a mortician, he routinely uses embalming chemicals. He admits to occasional marijuana use and smokes cigarettes but does not consume alcohol.

2. EXAMINATION

© ANDERSEN ROSS / GETTY IMAGES

Upon presentation, the patient was afebrile and had a BP of 142/82 mm Hg. He was at a healthy weight. Mr. R’s head and neck exam was unremarkable; his lung sounds were normal, and his heart rhythm was regular, expressing no click, murmur, or rub. The patient’s abdomen showed no scarring, exhibited normoactive bowel sounds, and was tympanic to percussion. The abdomen was nontender and soft throughout without organomegaly. There were no hernias or costovertebral angle tenderness. In addition, Mr. R had no evident edema about the extremities, and his 84 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Clinical Challenge

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skin was mildly diaphoretic but without rash, ecchymosis, or petechiae. Mr. R exhibited no focal neurologic deficits.

3. LABORATORY DATA AND DIAGNOSIS A urinalysis dip exhibited blood and protein but was otherwise normal. Mr. R was sent for a CT scan with renal stone protocol to rule out nephrolithiasis. Because of the fever and vomiting, a basic metabolic panel and complete blood count were obtained: glucose 118 mg/dL; blood urea nitrogen and creatinine 33.4 mg/dL and 1.8 mg/dL, respectively; sodium 135 mEq/L; potassium 3.5 mEq/L; chloride 98 mEq/L. Bicarbonate and calcium were normal. His white blood cell count was 6.84 103/µL, hemoglobin 11.1 g/dL, and hematocrit 31.5%, and platelets were verified to be 14.8 103/µL. The severe thrombocytopenia prompted an immediate hospital admission. To complete the workup, the following tests were performed: a lactate dehydrogenase (LDH) and antinuclear antibody test with reflex; prothrombin time; partial thromboplastin time; international normalized ratio; lupus anticoagulant, and anticardiolipin panel. The LDH returned >1,000 U/L (reference range 80-230). The remaining labs were normal. Hepatitis and HIV panels were later found to be negative. A STAT pathology review of Mr. R’s peripheral smear revealed normochromic, normocytic anemia, thrombocytopenia, and a moderate amount of schistocytes. Thrombotic thrombocytopenic purpura (TTP) was diagnosed.

4. TREATMENT Hematology was consulted and plasmapheresis was immediately scheduled. A Quinton catheter was placed in the internal jugular vein under ultrasound guidance. Mr. R underwent plasmapheresis daily while hospitalized, in addition to prednisone therapy. On day 3 in-hospital, Mr. R’s LDH dropped dramatically to 358 U/L, and his platelets rose slowly to 65.

On day 5, his LDH and platelet count normalized to 165 U/L and 301, respectively. After six plasmapheresis treatments, Mr. R’s platelet count stablilized and the gross hematuria cleared. He was discharged on 60 mg of prednisone, with instructions to taper down by 20 mg every four days. The

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In this patient, blood clots formed in the small vessels (as seen here in a pancreatic artery) throughout the body.

catheter was removed nine days after initial presentation. At his two-week outpatient follow-up, Mr. R was back to full health. He was no longer smoking cigarettes or marijuana, he was back at work, and he felt more energetic. In addition, he started a light workout regime. He did not have any complications from the TTP or treatment. He continues to follow up with hematology as an outpatient.

5. DISCUSSION TTP is a rare, most often idiopathic, acute hematologic state, traditionally described in a “classic pentad:” Hemolytic anemia, thrombocytopenia, renal insufficiency, neurologic abnormalities, and fever are the representative findings. With modern medicine and plasmapheresis available, all five components are rarely present in one individual.1 Mr. R did exhibit four of the five signs, but did not have any neurologic deficits.

TTP is often seen in conjunction with hemolytic uremic syndrome (HUC). The incidence of suspected TTP-HUS is 11 cases/million/year. There is a greater propensity for the disease in women and blacks.

In cases that are not idiopathic, etiology may be related to use of quinine, chemotherapeutic agents, immunosuppressive agents (e.g., cyclosporine,) and antiplatelet agents (e.g., clopidogrel and ticlopidine).2-4 Infectious causes are also noted to yieldTTP-HUS. Shiga toxin released from E. coli can lead to HUS, especially in children.5 Thrombotic microangiopathy has been seen in HIV infection, and pneumococcal infection can also cause HUS in rare instances.6 TTP-HUS can be related to pregnancy or can be induced by oral contraceptives,7 and incidence has been linked to pancreatitis8 and to surgery.9

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Everyone needs a break during the day. So relax with this photo essay, and pretend you’re someplace else.

© ISTOCKPHOTO.COM / LESLEY JACQUES

Picture this

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A Tuscan sunrise lights up the Val d’Orcia between the Italian cities of Pienza and San Quirico d’Orcia.

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Clinical Challenge 6. SUMMARY Left untreated, TTP-HUS can progress to renal failure, neurologic deterioration, cardiac ischemia, and death. With the advent of plasma exchange, the mortality rate for this disorder has decreased from 90% to 20% in modern times.

Mr. R received immediate plasmapheresis, which dramatically increased his platelet count. In patients with idiopathic TTP, as here, treatment with immunosuppressive agents such as prednisone is also recommended.1 After resolution of the acute TTP event, patients should be monitored with CBCs and LDH levels. In a study involving 63 subjects, the estimated 10-year relapse rate was 36%.10 ■ Ms. Tinge is a physician assistant at Alton Internal Medicine in Alton, Ill. References 1. George JN. How I treat patients with thrombotic thrombocytopenic purpura. Blood. 2010;116:4060-4069.

2. Kojouri K, Vesely SK, George JN. Quinine-associated thrombotic thrombocytopenic purpura–hemolytic uremic syndrome: frequency, clinical features, and long term outcomes. Ann Intern Med. 2001;135:1037-1041.

3. Lesesne JB, Rothschild N, Erickson B, et al. Cancer-associated hemolytic uremic syndrome: analysis of 85 cases from a national registry. J Clin Oncol.

1989;7:781-789.

4. Walfe JA, McCann RL, Sanfilippo F. Cyclosporine-associated micro-

“This one has the most friends.”

angiopathy in renal transplantation: a severe but potentially reversible form of early graft injury. Transplantation. 1986;41:541-544.

5. Boyce TG, Swerdlow DL, Griffin PM. Escherichia coli 0157:H7 and the hemolytic uremic syndrome. N Engl J Med. 1995;333:364-368. angiopathy in patients with acquired immunodeficiency syndrome before and during the era of introduction of highly active antiretroviral therapy.

Clin Infect Dis. 2002;35:1534-1540.

7. Hauglustaine D, Van Damme B, Vanrenterghem Y, Michielsen P. Recurrent hemolytic uremic syndrome during oral contraception. Clin Nephrol. 1981;15:148-153.

8. Boyer A, Chadda K, Salah A, Bonmarchand G. Thrombotic microangiopathy: an atypical cause of acute renal failure in patients with acute pancreatitis. Intensive Care Med. 2004;30:1235-1239.

9. Chang JC, Shipstone A, Llenado-Lee MA. Postoperative thrombotic thrombocytopenic purpura following cardiovascular surgeries. Am J Hematol. 1996;53:11-19.

10. Ruggenenti P, Galbusera M, Cornejo RP, et al. Thrombotic thrombocytopenic purpura: evidence that infusion rather than removal of plasma induces remission of the disease. Am J Kidney Dis. 1993;21:314-318.

88 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

6. Gervasoni C, Ridolfo AL, Vaccarezza M, et al. Thrombotic micro-

Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Hyperpigmented macules and patches A man presented with brown patches on his trunk and abdomen. The patches were present all year long but significantly more noticeable in the summer.

No pain or pruritus was reported.

WHAT IS YOUR DIAGNOSIS?

• • • •

Tinea versicolor Ichthyosis vulgaris Lichen planus Pityriasis rosea

● See the full case at ClinicalAdvisor.com/DermDx0212A

Pus blisters on the leg evolve into ulcers A 56-year-old woman presented complaining of painful and foul-smelling crusted ulcers on her leg and thigh. Read the full case and make the diagnosis.

WHAT IS YOUR DIAGNOSIS?

• • • • •

Ecthyma gangrenosum Pyoderma gangrenosum Ecthyma Bullous impetigo Cellulitis

● See the full case at ClinicalAdvisor.com/DermDx0212B

Have you missed any recent Derm Dx cases? Go to ClinicalAdvisor.com/DermDx for a complete archive of past quizzes as well as additional images of last month’s other cases.

Facial edema, fevers, and rash

Itchy brown patches on the groin

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 89

LEGAL ADVISOR CASE

© LARRY MULVEHILL / PHOTO RESEARCHERS, INC.

A suspicious lump is of real concern When a patient does not comply with medical recommendations, how do you protect yourself ?

BY ANN W. LATNER, JD

As a nurse practitioner in a breast clinic affiliated with a large hospital, Ms. F, 51, was accustomed to getting referrals. A high percentage of the clinic’s traffic was comprised of in-network referrals as well as routine screenings. More often than not patients were referred with an accompanying phone call, but sometimes a note from the referring clinician would filter down. Nevertheless, Ms. F was always careful to take detailed notes on new cases and conduct comprehensive interviews with patients.

On this particular afternoon, 21-year-old Ms. K, who had been seen in the hospital’s family planning clinic, was sent to the breast center. A lump had been detected in her left breast. Ms. K had a family history of breast cancer that made the lump a cause for concern.

Notes from the initial exam confirmed a “soft, nontender, 2 ⫻ 3 cm, cystic mass in the left breast.” The referring nurse wanted the mass evaluated, explaining that the patient’s mother had died of breast cancer.

Before examination, Ms. F reviewed the personal medical history Ms. K provided and then chatted

The patient’s positive left axillary lymph node moved freely, and there was no nipple discharge from either breast.

90 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

with her young patient at length about her family history. According to Ms. K, her mother had developed breast cancer in her early 50s and died just before reaching age 60 years. Ms. K had no aunts on her mother’s side and did not know her maternal grandmother’s cause of death. There was no history of breast cancer on her father’s side. Other than the appearance of this lump, Ms. K’s medical history was normal, with only minor illnesses reported.

Ms. F carefully added the information to the patient’s chart and then conducted a thorough physical exam. She noted that Ms. K’s breast condition was a bilateral nodularity with no definite masses or nodes. Furthermore, the positive left axillary lymph node moved freely. There was no nipple discharge from either breast. Ms. F recorded that the patient denied having any breast pain or noticing any recent changes to her Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

LEGAL ADVISOR breasts. After the examination, Ms. F consulted with one of the clinic physicians, per established policy. Despite the negative findings, the patient’s maternal history suggested the need for follow-up to monitor the mass. The physician read Ms. F’s notes and agreed with her assessment.

“While it’s not uncommon for women to have lumps in their breasts,” Ms. F told the patient, “in a situation where there is a family history, this is worrisome. It is extremely important that you routinely examine your breasts for changes. You will need to come back, as we need to monitor the situation.

There is a very high correlation between family history and the development of breast cancer.”

Grief can sometimes propel families to lash out and sue clinicians, even when documented facts show no malpractice.

Ms. F then showed Ms. K how to conduct a breast self-exam and gave her appropriate literature, with explicit instructions to return for a follow-up evaluation in three months.

Ms. F again stressed the importance of not ignoring family history. Ms. K said that she would return for her follow-up appointment, but she never came back.

Three years later, while pregnant with her fi rst child and seeking prenatal care, Ms. K told her obstetrician, Dr. H, that she had been experiencing some breast pain.

Dr. H asked about her family history. Once he learned that Ms. K’s mother had died of breast cancer and that a lump had been previously detected in her own breast, he ordered a mammogram following the birth. The mammogram results were suspicious, and a subsequent biopsy revealed that Ms. K had breast cancer that had metastasized to her neck and arm. A mastectomy was performed and followed by a course of radiation and chemotherapy. The treatment was unsuccessful, however, and Ms. K died within the year at the age of 25 years.

Her distraught family remembered that Ms. K had gone to the breast clinic for an evaluation. They contacted a plaintiff’s attorney, who took on the case. A lawsuit was subsequently initiated against Ms. F and the clinic physician who signed off on Ms. K’s case.

Ms. F was stunned when she was notified of the lawsuit.

At this point, she barely remembered the patient, but a quick perusal of the records showed that Ms. K had never returned after the initial visit. Ms. F met with the defense attorney provided by her insurance company.

“It’s an unfortunate situation,” remarked the attorney.

“You clearly did nothing wrong here, but the plaintiff ’s attorney probably believes that a jury would be sympathetic in this case considering the age of Ms. K at the time of her death—and the fact that she left a baby behind.”

The counselor assured Ms. F, however, that his plan was to file a motion for summary judgment—in other words, to ask the judge to dismiss the case before it went to trial.

“With any luck,” said the attorney, “this case will never reach a jury and we won’t have to worry about the sympathy issue.”

The case went through the discovery process and Ms. F took time off from work to give a deposition. Once the discovery process was complete, the defense attorney fi led a motion to dismiss, and the judge granted it.

Legal background

In order for a judge to consider a motion for summary judgment, the issue has to be one of law, not one of fact. In this case, both sides agreed on the facts of what had happened.

The question left to be decided was whether Ms. F and her supervising physician had been negligent in their treatment of the patient. After reviewing the facts—and Ms. F’s especially well-documented notes—the judge declared that no malpractice had occurred and the case was dismissed.

Protecting yourself

This case serves as a reminder that protecting yourself from liability doesn’t always mean protecting yourself from being sued. Ms. F acted appropriately in her treatment of the patient and thoroughly documented all in the patient’s chart. But even this could not protect her from being subjected to a lawsuit and the accompanying stress. Had Ms. F not had solid malpractice insurance provided by the hospital, she could have been responsible for her legal fees. Frivolous lawsuits are an unfortunate reality in the medical profession. Although you might not be able to avoid them, you can protect yourself from being found liable by documenting everything and keeping meticulous notes about interactions with patients, as Ms. F did.

In this case, Ms. F recorded her instructions to the patient to follow up in three months time. She further advised Ms. K that careful monitoring of her breasts was a necessity. Finally, she warned Ms. K about the connection between family history and propensity for breast cancer. And because Ms. F had documented everything, she was not held liable. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

94 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations.

■ COMPLETE THE POSTTEST: Page 99

■ ADDITIONAL CME/CE: Pages 39, 67

Diffuse erythematous papules KERRI ROBBINS, MD

CASE #1

CASE #2

A boy aged 3 years presented to the dermatology clinic with a pruritic rash. The boy’s mother stated that the rash had been present for approximately one month. OTC hydrocortisone cream provided no relief of symptoms or resolution of the rash. On clinical examination, erythematous papules, linear papules, and pustules were seen diffusely, with the greatest concentration in the interdigital web spaces, diaper area, axillae, palms, and soles. No other household contacts had a similar rash. No use of new medications or skin-care products was reported.

A man aged 46 years presented complaining of a rash that had been present for one month. The rash began on his trunk and had spread to the extremities. No treatment was sought before this time because the man believed some of the lesions were resolving. However, he recently noticed that new lesions appear as the others resolve. The man is asymptomatic and has not had any prior treatment. On physical examination, erythematous papules and nodules—some with a hemorrhagic crust—were appreciated on the trunk and proximal extremities.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 95

CME CE

CASE #1

Dermatologic Look-Alikes

Scabies

Scabies mites have been found on the human body for millennia.1 The severe pruritus associated with these microscopic organisms has caused countless sleepless nights all over the world. Today, they exist in every country, socioeconomic class, race, gender, and age group. Scabies are a large-scale epidemic in some countries, with 100% of the population suffering from infestation.1,2 Because of the highly contagious nature of scabies, their rampant spread is hastened by overcrowding, which is seen during disasters or war, in refugee camps, and during economic depressions. If one family member has scabies, there is a very high probability that the entire family will have it as well.2 Other factors that make scabies highly contagious are the delay until the time of treatment and the lack of public education on the condition. Crusted scabies is a form of scabies that primarily affects such immunocompromised individuals as the elderly, HIV-infected individuals, and people who have had medical transplants. Crusted scabies has less severe pruritus and a very thick crust.3 Sarcoptes scabiei var. hominis, or simply S. scabiei, is a tiny, hostspecific, eight-legged mite. This mite is an obligate human parasite that burrows tunnels through the epidermis. Its size is too small for human eyes, measuring a mere 0.35mm by 0.3mm.4 Although they only have a life span of 30 days, the female mites lay anywhere from 60 to 90 eggs (one to four eggs per day).3 The eggs take approximately three to four days to hatch in the burrows.5 An infestation requires approximately 100 mites to be living on the skin. For crusted scabies, mites may number in the thousands. Once scabies infest the epidermis, the incubation period can be anywhere from days to months.6 If the individual has never been infested with scabies before, it takes two to six weeks before the hosts’s immune system becomes sensitized to the mite or its feces. At this time, the initial symptom of scabies—pruritic skin—will start to

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

occur. The pruritus will worsen at night, and infants and young children will become increasingly irritable. Contrary to popular belief, hot showers or baths will only make the pruritus worse. About 24 to 48 hours after the initial signs, the infestation will become apparent.7 Adults may harbor the mite without having clinical symptoms; they are considered a carrier and are still highly contagious.

Scabies mites rely on the epidermis for survival. The skin will show papules, nodules, burrows, and vesciculopustules.

The lesions will be symmetrical in nature and found on various parts of the body. The most commonly infested areas include the ankles, wrists, webbing of digits, axillae, buttocks, and waistline.6 Males may have lesions on the scrotum and penis, and women may have lesions on the nipples and genital area. The scalp and face may be affected, especially in patients who are immunocompromised.1,2 Female mites will excavate and burrow out tunnels within the epidermis while laying their eggs. The burrows are grayish-white or erythematous, wavy or S-shaped, and slightly elevated, and

The areas most commonly infested with scabies include the ankles, wrists, webbing of digits, axillae, buttocks, and waistline. may be 1 mm to 2 mm wide and 1 mm to 10 mm long.8 If the infected individual currently lives in or is from a warm climate, the burrows are usually not clinically obvious.

The diagnosis of scabies is often a clinical one. However, since the mites are not visible to the naked eye, it is sometimes necessary to examine a skin sample or scraping under a microscope for proper diagnosis. The skin surface may be scraped with a scalpel and placed on a slide with mineral oil to visualize the mites, eggs, or feces using light microscopy.9 Skin biopsy will reveal a patchy or diffuse infi ltrate with eosinophils in the reticular dermis. Mites, eggs, or scybala may be found within the epidermis, and pink pigtail-like structures attached to the stratum corneum may be seen as remnants of the exoskeleton.10 While scabies often can be clinically diagnosed based on the presence of burrows and the distribution of the lesions, many diseases that are associated with pruritus or infection must also be considered in the differential. These disorders include atopic dermatitis, contact dermatitis, pyoderma, dermatitis herpetiformis, bullous pemhigoid, autosensitization, and other insect bites.

96 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Plenty of treatment options exist for individuals with scabies. Clinicians generally recommend 5% permethrin (Elimite) cream as the main treatment. The cream should be applied in a thin and even coat, from the neck down only. For infants and the elderly, the cream should be applied to the entire body, including the head. In all patients, the medication should be left to take effect for eight to 14 hours, after which it should be thoroughly rinsed. All household contacts should be treated once. Those household contacts who are pruritic and/or have a rash should be treated with the full two courses.

Permethrin is an excellent scabicide and has low toxicity to humans. Lindane 1% (Kwell) lotion used to be the primary treatment option, but the risk it poses for central nervous system toxicity, its poor efficacy, and increasing resistance have made it an inferior treatment choice to the medication permethrin. Other treatments include sulfur ointment, crotamiton (Eurax) cream, benzyl benzoate, and oral ivermectin (Mectizan, Stromectol).6 Eczematous dermatitis and secondary bacterial infections are the chief problems that may arise due to scabies.

Secondary infection is primarily attributable to Staphylococcus aureus or group A beta-hemolytic streptococci. Even when the appropriate scabicide is used, scabies will not be defeated without proper decontamination of the environment.

Decontamination of linens and clothes is essential. Wash all such items in hot water and dry with high heat.9 Items that cannot be washed should be stored in plastic bags for a week (to assure suffocation of any mites) or dry-cleaned if possible.

To ensure that proper treatment and decontamination are achieved, extensive education must be provided to the individuals diagnosed with scabies and their families.

Patients may still be pruritic and have lesions for one to two months after treatment. This is referred to as postscabietic pruritus and is caused by the body’s response to the dead mites in tandem with natural epidermal exfoliation.

If the patient’s condition still has not improved after this time period, consider treating again or broadening your differential diagnosis.

The boy in this case was treated from the neck down with two courses of permethrin 5% cream. All household contacts were treated once. No other family members had complaints of pruritus or a rash. Linens and clothes were washed in hot water and dried on high heat. Those that could not be washed were placed in a sealed garbage bag for one week. The scabies infestation resolved without any recurrence or complications.

CASE #2

Lymphomatoid papulosis

The term lymphomatoid papulosis (LyP) was first used in 1968 to illustrate a clinically benign but histologically malignant, chronic, self-healing, recurrent eruption. Previously, it was thought that LyP was a pseuodolymphomatous inflammatory process; however, it has been classified among the indolent cutaneous T-cell lymphomas (CTCLs). This is because of the overlapping clinical and histological features between LyP and cutaneous anaplastic large-cell lymphoma, including the presence of an aberrant T-cell phenotype, clonally rearranged TCR genes in the majority of patients, and identical T-cell clones in LyP lesions and associated lymphomas.7,11 LyP accounts for approximately 15% of the cases of all CTCLs.7 The average age of onset is between 35 and 45 years, but cases involving patients as young as age 8 months and as old as age 84 years have been noted.

Little is known about the mechanisms involved in LyP. In the past, it has been suggested that a virus is the initiating event. The mechanism for tumor progression is now believed to involve a mutation in the transforming growth factor-beta type 1 (TGF-beta) receptor on the CD30+ tumor cells.7 This mutation causes unresponsiveness to the growth inhibitory effect of TGF-beta, thus allowing extensive reproduction and growth of cells.12 LyP is a disorder that forms papular or nodular lesions that are reddish-brown in color. The papules and nodules may develop hemorrhage, necrosis, and crusting. Characteristically, all lesions will be in different stages of healing and are known to regress spontaneously within three to eight weeks.7 On occasion, lesions may leave transient hypopigmented or hyperpigmented macules and superficial atrophic scars. Lesions are most commonly found on the trunk and proximal extremities and are occasionally seen on the hands, feet, scalp, and genitalia.13 Lesions may appear in a localized, generalized, or clustered pattern and contain a few to hundreds of papules.

The eruption is asymptomatic in nature.

The histologic findings of LyP are complex and variable. Not only does LyP differ histologically with age of the lesion, but there are also three different histological types of LyP: type A, type B, and type C. The three types of LyP do not differ clinically. The different histologic types serve as a tool for researchers to understand the relationship between LyP and

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 97

CME CE

Dermatologic Look-Alikes

other CTCLs. LyP type A is characterized by a wedge-shaped infiltrate that is extensively interspersed with an inflammatory infiltrate composed of lymphocytes, neutrophils, and eosinophils.10 Within the infiltrate are scattered or small clusters of large atypical CD30+ cells that are few in number in early lesions and more numerous in established lesions. LyP type B lesions occur less than 10% of the time and contain a superficial perivascular or lichenoid lymphocytic infiltrate, which may infiltrate the basal and parabasal layers of the epidermis.7 The infiltrate is composed of small to medium-sized atypical cells with cerebriform nuclei that are similar to those found in mycosis fungoides. These cells express CD3+ and CD4+ but are negative for CD30+. Some LyP lesions may have type A and type B histological findings at the same time. LyP type C lesions have a population of large clusters of CD30+ cells intermixed with few inflammatory cells.9,14 Lesions on the trunk can be mistaken for folliculitis or arthropod bites. The presence of CD30+ cells that appear similar to those in large-cell lymphoma may confuse a clinician unfamiliar with LyP. This often leads to unnecessary multiagent chemotherapy. To an experienced clinician, the two disorders are easy to distinguish based on their clinical features. Mucha-Habermann disease, also known as pityriasis lichenoides, is clinically very similar to LyP in that both have clonal T-cell populations. However, pityriasis lichenoides does not develop nodular lesions and is generally a short-lived disease that occurs mainly in younger patients.

Treatment of LyP is usually unnecessary and generally ineffective. Although systemic chemotherapy or total skin electron beam irradiation has been known to produce complete remission, the lesions reappear after discontinuing therapy. LyP will run its natural course regardless of treatment, so carefully consider the risks and benefits prior to initiating any regimen. The lesions can become very large or lead to scarring, so treatment may be desired for cosmetic reasons. In this subset of patients, a low-dose of oral methotrexate (Rheumatrex, Trexall) is best used to reduce the amount of lesions present.2 Large lesions that do not resolve spontaneously may be surgically excised or treated with radiotherapy. Such treatments as psoralen and ultraviolet A (PUVA) radiation, low-dose etoposide (VePesid), and topical nitrogen mustard have shown some beneficial effect.2 The prognosis for those with LyP is excellent. While the lesions tend to resolve within three to eight weeks, the disease can linger from several months to as long as 40 years. In 10% -20% of cases, another malignant cutaneous lymphoma may develop before, during, or after diagnosis of LyP.7 Because of the possible risk of the development of systemic lymphoma, long-term follow up is advised.

Extensive education and anticipatory guidance were provided to the patient in this case. No treatment was necessary given the asymptomatic nature of his disease, but long-term follow up was encouraged. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. The author has no relationships to disclose relating to the content of this article.

References 1. Meinking TL, Burkhart CG, Burkhart CN. Ectoparasitic disease in dermatology: reassessment of scabies and pediculosis. In: James W (ed.).

Advances in Dermatology Vol. 15. St. Louis, Mo.: Mosby; 1999:67-108.

2. Burkhart CG. Scabies: an epidemiologic reassessment. Ann Intern Med. 1983;98:498-503.

3. Burkhart CG, Burkhart CN. An epidemiological and therapeutic reassessment of scabies. Cutis. 2000;65:233-240.

4. Peterson CM, Eichenfield LF. Scabies. Pediatr Ann. 1996;25:97-100.

5. Wendel K, Rompalo A. Scabies and pediculosis pubis: An update of treatment regimens and general review. Clin Infect Dis. 2002;35(Suppl 2):S146-151. Available at cid.oxfordjournals.org/content/35/ Supplement_2/S146.long.

6. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed.

Philadelphia, Pa.: Elsevier Saunders; 2006:479-484.

7. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:1291-1294, 1880-1882.

8. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, N.Y.: McGraw-Hill; 2005:853-860.

9. Habif TP. Skin Disease: Diagnosis and Treatment. 2nd ed., Philadelphia, Pa.: Elsevier Mosby; 2005:134, 304-307.

10. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin.

10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:626-627, 945-947.

11. Bekkenk MW, Geelen FA, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood. 2000;95:3653-3661.

Available at bloodjournal.hematologylibrary.org/content/95/12/3653.long.

12. Schiemann WP, Pfeifer WM, Levi E, et al. A deletion in the gene for transforming growth factor beta type I receptor abolishes growth regulation by transforming growth factor beta in a cutaneous T-cell lymphoma.

Blood. 1999;94:2854-2861. Available at bloodjournal.hematologylibrary. org/content/94/8/2854.long.

13. Thomas GJ, Conejo-Mir JS, Ruiz AP, et al. Lymphomatoid papulosis in childhood with exclusive acral involvment. Pediatr Dermatol. 1998;15:146-147.

14. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:314-316.

All electronic documents accessed January 15, 2012.

98 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

CE

POSTTEST Expiration date: February 2013

The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC).

The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at www.myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 39

page 67

page 95

A practical guide to metabolic syndrome

Case #1: Tumid lupus erythematosus

Case #1: Scabies

1. The patient with metabolic syndrome usually has normal levels of a. Total cholesterol b. LDL cholesterol c. HDL cholesterol d. Triglycerides

1. The lesions of tumid lupus erythematosus (TLE) are rarely found on the a. Lower extremities b. Upper extremities c. Face d. Chest

5. Crusted scabies primarily affects a. HIV-infected individuals b. Transplant recipients c. The elderly d. All of the above

2. Recent studies have linked the metabolic factors of obesity, elevated glucose, and increased triglycerides with the development of which of the following in the unborn child? a. Obesity b. Metabolic syndrome c. Macrosomia d. All of the above

2. In the treatment of TLE, what is a side effect associated with hydroxychloroquine (Plaquenil, Quineprox)? a. Vasculitis b. Dyspepsia c. Retinal toxicity d. Syncope

3. As defined by BMI, normal weight is a. 16–18.4 b. 18.5–24.9 c. 25.0–27.5 d. 27.6–30

Case #2: Nevus sebaceus

4. Which medication reduces the inflammatory marker C-reactive protein and LDL in metabolic syndrome patients? a. Nicotinic acid (Niaspan) b. Fenofibrate (Antara, Fenoglide, Fibricor, Lipofen, Lofibra, Tricor, Triglide, Trilipix) c. Statins d. Niacin

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureFeb2012

3. Which abnormality is associated with nevus sebaceus syndrome? a. Epilepsy b. Spina bifida c. Nystagmus d. All of the above 4. What is the treatment for nevus sebaceus? a. Surgical excision b. Laser ablation c. Cryotherapy d. Topical steroids

6. What is the recommended main treatment for scabies? a. Oral ivermectin (Mectizan, Stromectol) b. 1% lindane lotion (Kwell) c. 5% permethrin cream (Elimite) d. Sulfur ointment Case #2: Lymphomatoid papulosis 7. The lesions of lymphomatoid papulosis (LyP) are most commonly found on the a. Feet b. Trunk c. Scalp d. Genitalia 8. What is the treatment for LyP? a. Watchful waiting b. High-dose oral methotrexate (Rheumatrex, Trexall) c. Cryotherapy d. Wide surgical excision

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermFeb2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 99

CME

POSTTEST Expiration date: February 2013

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of February 2012. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 39

page 67

page 95

A practical guide to metabolic syndrome

Case #1: Tumid lupus erythematosus

Case #1: Scabies

1. The patient with metabolic syndrome usually has normal levels of a. Total cholesterol b. LDL cholesterol c. HDL cholesterol d. Triglycerides

1. The lesions of tumid lupus erythematosus (TLE) are rarely found on the a. Lower extremities b. Upper extremities c. Face d. Chest

5. Crusted scabies primarily affects a. HIV-infected individuals b. Transplant recipients c. The elderly d. All of the above

2. Recent studies have linked the metabolic factors of obesity, elevated glucose, and increased triglycerides with the development of which of the following in the unborn child? a. Obesity b. Metabolic syndrome c. Macrosomia d. All of the above

2. In the treatment of TLE, what is a side effect associated with hydroxychloroquine (Plaquenil, Quineprox)? a. Vasculitis b. Dyspepsia c. Retinal toxicity d. Syncope

3. As defined by BMI, normal weight is a. 16–18.4 b. 18.5–24.9 c. 25.0–27.5 d. 27.6–30

Case #2: Nevus sebaceus

4. Which medication reduces the inflammatory marker C-reactive protein and LDL in metabolic syndrome patients? a. Nicotinic acid (Niaspan) b. Fenofibrate (Antara, Fenoglide, Fibricor, Lipofen, Lofibra, Tricor, Triglide, Trilipix) c. Statins d. Niacin

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureFeb2012

3. Which abnormality is associated with nevus sebaceus syndrome? a. Epilepsy b. Spina bifida c. Nystagmus d. All of the above 4. What is the treatment for nevus sebaceus? a. Surgical excision b. Laser ablation c. Cryotherapy d. Topical steroids

6. What is the recommended main treatment for scabies? a. Oral ivermectin (Mectizan, Stromectol) b. 1% lindane lotion (Kwell) c. 5% permethrin cream (Elimite) d. Sulfur ointment Case #2: Lymphomatoid papulosis 7. The lesions of lymphomatoid papulosis (LyP) are most commonly found on the a. Feet b. Trunk c. Scalp d. Genitalia 8. What is the treatment for LyP? a. Watchful waiting b. High-dose oral methotrexate (Rheumatrex, Trexall) c. Cryotherapy d. Wide surgical excision

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermFeb2012

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2012 99

ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Wild Yam

© GERRY BISHOP / VISUALS UNLIMITED, INC.

It should be stated upfront that the wild yam is not the same as the common American “sweet potato.”1 More than 600 species of wild yam have been identified, but only 12 are known to be edible.2 In some areas of the world, these edible species are grown as dietary staples. One, Dioscorea villosa—otherwise known as the Mexican wild yam—is a tuberous plant that produces a thick, starchy underground rhizome. It is this root that is used in many herbal remedies—in both nutritional and medicinal products.2

Background The wild yam is marketed as an herbal remedy for menstrual discomfort and menopausal symptoms, and is typically promoted as an alternative to hormone replacement therapy (HRT).

In the two years since the publication of the Women’s Health Initiative (WHI)—a study designed to address the most common causes of death, disability, and impaired quality of life in postmenopausal women—women have increasingly turned to natural alternatives to patented estrogens.3 Survey findings recently released by the Stanford School of Medicine indicated that the number of prescriptions written for HRT in postmenopausal women dropped by more than 50% from pre-WHI levels.4,5 This suggests that a very large number of postmenopausal women are now seeking alternative methods for controlling hormonal decline.

The wild yam seems like a natural solution, as it contains diosgenin, a steroid that can be used to synthesize various hormones— estrogen, dehydroepiandrosterone (DHEA), and progesterone—in

the laboratory.6 Yet while a small number of animal studies have demonstrated in vivo synthesis and hormone surge, studies in humans have not successfully replicated this process.6 Diosgenin, extracted from the tubers of Dioscorea villosa, has been promoted as a natural form of DHEA, yet the chemical reaction needed to convert diosgenin into DHEA is not known to occur in the human body. Ingesting the yam extract has not been found to increase DHEA levels in humans.

Science A standardized, evidence-based rating system showed poor efficacy scores for the wild yam, indicating fair scientific evidence against its use for alleviating menopausal symptoms.7 In a small, double-blind, placebo-controlled trial, researchers studied 23 healthy women with postmenopausal symptoms.After a four-week baseline period, each subject was given topical wild yam extract (a cream typically used to ameliorate hot flashes) and matching placebo for three months in random order.8 Diaries

100 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

Evolving anticoagulation in patients with NVAF, including those at increased stroke risk...

HELP INTERCEPT STROKE RISK

...combining proven protection, a demonstrated safety profile, and convenient once-daily dosing XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

IMPORTANT SAFETY INFORMATION WARNING A. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO® discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS 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 clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. 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.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS 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 clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. 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.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort).

Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban.

NSAIDs/Aspirin: In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. In a singledose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.

Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions].

Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)]. XARELTO should be used in patients with CrCL 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Use in Specific Populations].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions].

Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.

Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.

Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information].

Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.

Table 2: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study Renal Impairment Class [CrCl (mL/min)] Parameter Mild Moderate Severe [50 to 79] [30 to 49] [15 to 29] N=8 N=8 N=8 Exposure AUC 44 52 64 28 12 26 (% increase relative to normal) Cmax FXa Inhibition AUC 50 86 100 9 10 12 (% increase relative to normal) Emax PT Prolongation AUC 33 116 144 4 17 20 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1) in full Prescribing Information].

Hepatic Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed.

Table 3: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study Hepatic Impairment Class (Child-Pugh Class) Parameter Mild Moderate (Child-Pugh A) (Child-Pugh B) N=8 N=8 Exposure AUC 15 127 0 27 (% increase relative to normal) Cmax FXa Inhibition AUC 8 159 0 24 (% increase relative to normal) Emax PT Prolongation AUC 6 114 2 41 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions].

OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

© Janssen Pharmaceuticals, Inc. 2011 10185201 02X11309BBA

Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

ALTERNATIVE MEDS UPDATE were completed for the baseline period and for one week each month thereafter. Blood and saliva samples were collected at baseline and at three and six months to measure lipid and hormone levels.8 The diaries showed no significant difference between the two groups, with no real change from baseline for either group.8 This suggests that shortterm treatment with topical wild yam extract has little effect on menopausal symptoms.

A study examining hormone levels in Taiwanese postmenopausal women after yam extract ingestion did not show appreciable changes in serum concentrations.2 In this trial, 24 women replaced their daily dietary staple of rice with a wild yam supplement for thirty days.2 At one month, serum concentrations of estrone (a weak form of estrogen) increased 26% in the cohort, with sex-hormonebinding globulin levels up nearly 10%, and data showed a lesser increase in serum estradiol (the principal form of estrogen produced by the ovaries).2 It should be noted that estrone is typically seen in postmenopausal women who are not on HRT, and its potency is far less than estradiol.9

Safety, interactions Trials of topical and oral preparations showed no significant adverse effects. However, large doses of wild yam extract can cause nausea, vomiting, and diarrhea.Women who are pregnant or breastfeeding should not use wild yam derivatives. Allergic reactions, although rare, can occur; they typically include rash and respiratory distress.10 Many manufacturers add synthetic progesterones to wild yam products. Although not advertised as having additives, consumers should be cautious since many products may be adulterated.

Summary The use of wild yam as a substitute for commercially available HRT is not evidence-based, but it is relatively benign. Patients wanting to try wild yam can be counseled that it is safe but not proven to be efficacious. In patients with other clinical conditions and/or additional circumstances involving estrogen levels, a more involved discussion should take place. ■ References 1. Tufts Medical Center resources page: Wild Yam. Tufts

Wild yam supplements are available in powder-filled capsules.

Medical Center website. Available at www.tufts-nemc.org/ apps/HealthGate/Article.aspx?chunkiid=21816.

2. Wu WH, Liu LY, Chung CJ, et al. Estrogenic effect of

The use of wild yam as a substitute for commercially available HRT is not evidencebased, but it is relatively benign.

yam ingestion in healthy postmenopausal women. J Am Coll Nutr. 2005;24:235-243.

3. Women’s Health Initiative page. National Institutes of Health website. Available at www.nhlbi.nih.gov/whi.

4. School of Medicine news release. Stanford School of Medicine website. Available at med.stanford.edu/news_ releases/2004/january/prescrip.html.

5. Wegienka G, Havstad S, Kelsey J. Menopausal hormone therapy in a health maintenance organization before and after Women’s Health Initiative hormone trials termination. J Womens Health. 2006;15:369-378.

6. About Herbs, Botanicals, & Other Products page.

Memorial Sloan-Kettering Cancer Center website.

Available at www.mskcc.org/print/cancer-care/herb /wild-yam.

7. Ulbricht C, Basch E, Sollars D, et al. Wild yam (Dioscoreaceae). J Herb Pharmacother. 2003;3:77-91.

8. Komesaroff PA, Black CV, Cable V, Sudhir, K. Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women. Climacteric.

2001;4:144-150.

Comprehensive Database website. Available at naturaldatabase.therapeuticresearch.com/nd/PrintVersion.

Wild yam is available in a variety of forms, but topical creams and powder-filled capsules are the most commonly used. Depending on the concentration of the product, the recommended dose is one teaspoonful of cream applied twice daily or 250 mg of wild yam powder, taken one to three times daily.11 Cost varies depending on the source and formulation.

102 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

aspx?cs=CP&s=ND&id=970.

10. Herbs, Vitamins, and Minerals information page.

American Cancer Society website. Available at www.cancer.org/Treatment/index.

11. Professional review: Wild Yam. Available at www.camline .ca/professionalreview/pr_print.php?NHPID=49.

All electronic documents accessed on January 15, 2012.

© WAVEBREAKMEDIA LTD / SHUTTERSTOCK

9. Therapeutic Research page. Natural Medicines

Dosage and cost

Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,200 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

EARLY INITIATION OF PARENTERAL NUTRITION MAY INCREASE COMPLICATIONS AND HOSPITAL STAY COMPARED WITH LATE INITIATION IN CRITICALLY ILL PATIENTS Level 2: Mid-level evidence The optimal time to initiate parenteral nutrition in critically ill patients unable to get adequate enteral nutrition is a subject of ongoing debate.

European guidelines recommend parenteral nutrition in these patients within 24 to 48 hours of admission to an intensive care unit (ICU) (Clin Nutr. 2009;28:387-400), while AmericanCanadian guidelines recommend waiting for at least seven days ( JPEN J Parenter Enteral Nutr.

2009;33:277-316; available at pen.sagepub.com/ content/33/3/277.long, accessed January 15, 2012). The two strategies were compared in a new unblinded trial (N Engl J Med. 2011;365:506517). A total of 4,640 intensive-care patients were randomized to parenteral nutrition initiated early (48 hours after ICU admission) vs. late (on day 8 after admission). All patients were classified as being at nutritional risk (risk score of 3 or more on 7-point scale), as determined by assessment of disease severity, age, extent of weight loss within previous three months, and extent of food intake within previous week. Underlying conditions included sepsis in 22%, cancer in 19%, and diabetes in 17%.

Comparing early vs. late initiation of parenteral nutrition, the median ICU stay was four days vs. three days (p=0.02), and the median hospital stay was 16 days vs. 14 days (p=0.004). New infections occurred in 26% vs. 23% (p=0.008, NNH 25), and mechanical ventilation was required for more than two days in 40% vs.

36% (p=0.006, NNH 25). Early initiation was

also associated with increased duration of renal replacement therapy (10 days vs. seven days, p=0.008). There were no significant differences in mortality during ICU or hospital stays. There was also no mortality difference at 90 days.

At trial end (up to three years), reduced dietary salt was associated with a trend toward reduced allcause mortality.

106 THE CLINICAL ADVISOR â&#x20AC;˘ FEBRUARY 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

BENEFITS OF SALT RESTRICTION FOR CARDIOVASCULAR DISEASE PREVENTION AND TREATMENT QUESTIONED Level 2: Mid-level evidence Observational data have long suggested that higher dietary salt intake is associated with increased risk of cardiovascular disease. Results from randomized trials on the effects of restricting salt intake have been less consistent, and the clinical benefits of reduced sodium remain unclear. A recent Cochrane review examined seven randomized trials evaluating interventions to reduce dietary salt intake (including either active salt restriction or advice to reduce salt use) in 6,489 adults, the largest collection of data to date (Cochrane Database Syst Rev. 2011;7:CD009217). Trial durations ranged from seven to 36 months, and the longest follow-up was 12.7 years.

In normotensive adults, reduced dietary salt was associated with a trend toward reduced allcause mortality at trial end (up to three years) (relative risk [RR] 0.67, 95% CI 0.4-1.12), but not at longest follow-up (up to 12.7 years), in an analysis of three trials with 3,518 participants.

Additionally, no significant differences in cardiovascular morbidity were found in an analysis The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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Evidence-Based Medicine

CYTISINE FOR 25 DAYS MAY INCREASE SMOKING CESSATION RATES AT 12 MONTHS Level 2: Mid-level evidence Cytisine is a nicotine partial agonist that has been available for smoking cessation in Eastern Europe for several decades (as Tabex), but has not been approved in Western countries.

Derived from an extract of golden rain acacia seeds, cytisine may have potential as a low-cost treatment for smoking cessation. A recent trial in Poland evaluated cytisine (1.5 mg oral tablets) in 740 adults who smoked ≥10 cigarettes/day and were willing to attempt to stop smoking permanently (N Engl J Med. 2011;365:1193-1200). Patients were randomized to cytisine vs. placebo for 25 days. The dose was six tablets for the first three days, followed by five tablets/day on days 4-12, four tablets/day on days 13-16, three tablets/day on days 17-20, and finally two tablets/day on days 21-25. All patients received minimal counseling during four clinical visits and three telephone calls over 12 months.

Follow-up at 12 months after the end of treatment included 73% of the randomized patients. The sustained abstinence rate was 8.4% for cytisine vs. 2.4% for placebo (p=0.001, NNT 17). The cytisine group also had higher seven-day point prevalence for abstinence (13.2% vs. 7.3%, p=0.01, NNT 17). Gastrointestinal adverse events (most commonly upper abdominal pain and nausea) were significantly increased for cytisine (13.8% vs. 8.1%, p <0.05, NNH 17). Cytisine is currently available in Russia and Poland (at the equivalent of $6 to $15 per course).

SAW PALMETTO, EVEN AT HIGH DOSE, DOES NOT IMPROVE LOWER URINARY SYMPTOMS IN MEN WITH BPH Level 1: Likely reliable evidence Lower urinary tract symptoms are common in men with benign prostatic hypertrophy (BPH) and are frequently treated with natural plant extracts. Saw palmetto, at a dose of 320 mg/day, has been a popular choice, although data supporting its efficacy has been inconsistent (Cochrane Database Syst Rev. 2009;2:CD001423). A new randomized trial has evaluated saw palmetto at three times the standard dose in 369 men with BPH and lower urinary tract symptoms and has found no evidence for any benefits from the extract ( JAMA. 2011;306:1344-1351).

Men age 45 years or older with peak urinary flow rate ≥4 mL/second were randomized to oral saw palmetto vs. placebo for 72 weeks. The saw palmetto dose started at 320 mg/day, increasing to 640 mg/day at 24 weeks, and to 960 mg/day at 48 weeks. All participants had a score of 8-24 on the American Urological Association Symptom Index (AUASI), which measures frequency of urinary symptoms on a scale of 0 to 35. A reduction of three points on the AUASI was considered clinically important.

At 72 weeks, there were no significant differences between groups in nocturia, patient global assessments, indices of sexual function, continence, sleep quality, or prostatitis symptoms.

The mean reduction in AUASI score was 2.2 points for saw palmetto vs. 2.99 points for placebo (not significant). AUASI scores fell by at least three points in 42.6% vs. 44.2% (not significant). Additionally, there were no significant differences in change in peak flow rate or postvoid residual. ■

108 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

of two trials with 2,505 participants at longest follow-up.

Salt restriction significantly reduced diastolic BP and trended toward reduced systolic pressure.

In hypertensive adults, reduced dietary salt was associated with a trend toward reduced cardiovascular mortality at trial end in an analysis of two studies with 2,058 patients (RR 0.69, 95% CI 0.45-1.05). However, there were no significant differences in all-cause mortality at any time point or in cardiovascular morbidity at longest follow-up in this population. Salt restriction significantly reduced systolic but not diastolic BP. One trial compared low-sodium vs. standard diets for six months in 232 patients with heart failure. In this population, reduced salt was associated with increased all-cause mortality (13.2% vs. 5.1%, p=0.041, NNH 12).

Despite the large numbers of patients analyzed, there remains insufficient statistical power to confidently exclude the possibility of benefit from salt restriction for cardiovascular health.

COMMENTARY Debra Clements Coats, RN, BSN, CRNP, is an oncology nurse and FNP student in Pennsylvania. She plans to work in internal medicine upon graduation.

Prescribing pain meds the right way As I journey toward my goal of nurse practitioner, I am becoming increasingly aware of the number of patients living with chronic pain. My clinical rotations have given me a front-row view of the lack of monitoring of patients living with chronic pain who are prescribed pain medications.

In some cases prescriptions for pain medications were simply written out and no urine testing was ever ordered. No contract was signed between the patient and provider to help the patient manage his or her pain-medication compliance. Joanna L. Starrels, MD, an assistant professor of medicine at Albert Einstein College of Medicine of Yeshiva University in Bronx, New York, headed

Patients who are given pain meds are often not tracked by the prescribing primary-care physicians.

a study investigating the tracking of patients prescribed pain medications by primary-care providers. The researchers followed 1,612 patients from eight primary-care practices who had been prescribed pain medications from January 2004 through April 2008.

Starrels and colleagues found that patients who are given pain medications are often not tracked by the primary-care physicians who prescribed the drugs. Just 8% of the study participants underwent urine testing, only half made regular visits to their prescribers, and 23% received more than one early opioid refi ll. Patients at highest risk of opioid misuse were more likely to receive more than one early refi ll, but their office-based monitoring was no greater than for persons without any risk factors for opioid misuse.

The investigators concluded that primary-care physicians’ adoption of opioid risk-reduction strategies is limited, even among patients at increased risk of misuse ( J Gen Intern Med. 2011; 26:958-964; available at www.springerlink .com/content/n380t884p57g3887/fulltext.pdf, accessed January 15, 2012).

Another report, this one from Linda Garufi Clark, MD, and Carole C. Upshur, EdD, both with the family medicine and community health department at the University of Massachusetts Medical School in Worcester, sought to determine family-practitioners’ views

110 THE CLINICAL ADVISOR • FEBRUARY 2012 • www.ClinicalAdvisor.com

of how to improve chronic nonmalignant pain (CNMP) management in primary care ( J Am Board Fam Med. 2007;20:479-482; available at www.jabfm.org/content/20/5/479.long, accessed January 15, 2012).

Among 14 family physicians from six community practice sites, three community health centers, a rural health center, and two hospitalowned practices, four overarching themes emerged across all groups and respondents: 1. The need for a physician practice guideline toolkit with a range of information, but particularly around opioid prescribing 2. The need for changes in the way patients obtain monthly medications 3. The need for improvements in patient selfmanagement education and increased access to both providers and alternative interventions 4. The importance of a nurse care manager to collaborate with both providers and patients.

As the dynamics of our health-care system evolve, nurse practitioners and physician assistants will be called upon to manage the diverse needs of our patients, and some of those patients will be living with chronic pain. The clinical management of chronic pain will be complex and time-consuming. It will be important to maintain ongoing collaborations with physicians and coordinate care with specialists in order to promote safe and effective pain management for our patients. ■

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