Clinical Alert - March 2023

MARCH

C LINICAL

ALERT

Your Monthly Source for Drug Information Highlights

EDITORIAL STAFF

EDITOR-IN-CHIEF

Maryam Tabatabai

PharmD

EXECUTIVE EDITOR

Anna Schreck Bird

PharmD

DEPUTY EDITORS

Jessica Czechowski PharmD

Carole Kerzic

RPh

Olivia Pane PharmD, CDCES

Leslie Pittman PharmD

Devon Trumbower PharmD, BCPS

TRENDING TOPICS

BEHAVIORAL HEALTH CORNER

COVID-19 NOTABLES

DRUG INFORMATION HAPPENINGS & HIGHLIGHTS

PIPELINE NEWS

RECENT FDA APPROVALS

TRENDING TOPICS

FDA APPROVES DAPRODUSTAT (JESDUVROQ™)

The FDA has approved the first oral treatment for anemia caused by CKD for adults who have been receiving dialysis for ≥ 4 months. Daprodustat is a hypoxiainducible factor prolyl hydroxylase (HIF PH) inhibitor which increases erythropoietin levels, thereby signaling production of red blood cells (RBCs). It is approved as 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg tablets; it is dosed once daily based on pre-treatment hemoglobin (Hb) levels or erythropoiesis stimulating agent (ESA) dosage if switching therapies. Prior to initiation, other causes of anemia should be excluded or corrected; liver testing should also be performed. Iron status must be assessed in case supplemental iron is needed during treatment. Dosage increases should be no more frequently than every 4 weeks, and therapy should be discontinued if a clinically meaningful increase in Hb is not seen after 24 weeks. Daprodustat carries a boxed warning for increased risk of death, MI, stroke, venous thromboembolism, and thrombosis of vascular access. Daprodustat is not indicated as a substitute for RBC transfusion in patients who require immediate correction of anemia. Further, it should not be used in patients who are not on dialysis. The drug has not been shown to improve quality of life, fatigue, or patient well-being.

Approval was based on the randomized, open-label, phase 3 ASCEND-D trial (n=2,964) which included adults with CKD who were on dialysis for ≥ 90 days and who had an Hb level between 8 to 11.5 g/dL. Patients were assigned to receive either daprodustat or an injectable ESA (darbepoetin alfa or epoetin alfa). The co-primary non-inferiority outcomes were mean change in Hb from baseline to weeks 28 through 52, and first occurrence of a major adverse cardiovascular event (MACE; composite of death from any cause, nonfatal MI, and nonfatal stroke). Results showed a mean change in Hb level from baseline to weeks 28 through 52 of 0.28 g/dL in the daprodustat group and 0.1 g/dL in the ESA group (difference, 0.18 g/dL, 95% CI, 0.12 to 0.24), which met the pre-specified non-inferiority margin. After a median follow-up of 2.5 years, MACE occurred in 25.2% of patients taking daprodustat and 26.7% of patients in the ESA group (HR, 0.93; 95% CI, 0.81 to 1.07), which met the pre-specified non-inferiority margin.

BEHAVIORAL HEALTH CORNER: NSDUH REPORT

Results from the 2021 National Survey on Drug Use and Health (NSDUH) by SAMHSA have been released. Overall, 14.1 million US adults (5.5%) had serious mental illness (SMI), with young adults ages 18 to 25 years and multiracial adults having the highest rates of SMI. Serious thoughts of suicide were reported by 4.8% of adults. For adolescents ages 12 to 17 years, 20.1% had a major depressive episode and 12.7% had serious thoughts of suicide. Among 133.1 million alcohol users ≥ 12 years of age, 45.1% were binge drinkers. There were 9.2 million people aged ≥ 12 years who misused opioids (heroin or prescription pain relievers), and 46.3 million people (16.5%) who had a substance use disorder (SUD), including alcohol use disorder (29.5 million), drug use disorder (24 million), and both alcohol and drug use disorders (7.3 million). The highest percentages of SUD were seen in American Indian or Alaska Natives, and multiracial people. Additional details are provided on use of mental health services, substance use treatments, and perceived recovery.

COVID-19: NOTABLE DEVELOPMENTS

The Executive Office of the President of the US has announced that the COVID-19 public health emergency will be terminated on May 11, 2023. Vaccine reimbursement, COVID-19 treatments, OTC and pharmacist-provided testing, and controlled substances prescribing will be affected. The FDA has revised the EUA for molnupiravir (Lagevrio™) and nirmatrelvir/ritonavir (Paxlovid™) to remove the requirement for positive SARS-CoV-2 test results prior to prescribing these drugs. The CDC has issued an MMWR on early estimates of bivalent mRNA booster dose vaccine effectiveness in preventing symptomatic SARS-CoV-2 infection from Omicron XBB/ XBB.1.5 in immunocompetent US adults from December 2022 to January 2023. Results showed that a bivalent mRNA booster dose provided additional protection against symptomatic XBB/XBB.1.5 infection for at least the first 3 months after vaccination in persons who had previously received 2 to 4 monovalent vaccine doses. Please refer to the COVID-19 disclaimer at the end of the publication.

DRUG INFORMATION HAPPENINGS & HIGHLIGHTS

• An EUA has been issued for the “Lucira™ COVID-19 & Flu Home Test,” the first OTC at-home diagnostic test that detects both influenza and SARS-CoV-2 viruses. The single-use test kit analyzes a nasal swab sample in approximately 30 minutes. Samples can be selfcollected by individuals ≥ 14 years of age or collected by an adult for children ≥ 2 years of age.

• Global Pharma has issued a voluntary recall of all lots within expiry of OTC Artificial Tears lubricant eye drops, distributed by Ezricare and Delsam Pharma to the consumer level due to possible contamination. To date, there have been 55 reports of adverse events, including eye infections, permanent vision loss, and a death with a bloodstream infection, that are potentially associated with use of the product.

• The FDA has approved a 320 mg tablet of sotorasib (Lumakras®) in addition to the currently approved 120 mg strength tablet. Sotorasib is indicated for adults with KRAS G12C-mutated locally advanced or metastatic NSCLC after ≥ 1 prior systemic therapy.

• IBSA Pharma has initiated a voluntary recall of 27 lots of levothyroxine (Tirosint ®-Sol) oral solution to the consumer level due to product subpotency. Levothyroxine is indicated as a replacement therapy in hypothyroidism and in the management of thyrotropindependent thyroid cancer.

• Tezepelumab-ekko (Tezspire®) can now be administered by a patient or caregiver following FDA approval of a prefilled, fixed-dose, single-use, 210 mg/1.91 mL autoinjector pen. The product is also already approved in a prefilled syringe and vial for administration by an HCP. It is indicated as add-on maintenance treatment for patients ≥ 12 years old with severe asthma.

• Sanofi’s lixisenatide (Adlyxin®) has been permanently discontinued ; product will expire September 30, 2023. Lixisenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.

DRUG INFORMATION HAPPENINGS

• The American Academy of Dermatology (AAD) has released updated guidelines for the treatment of atopic dermatitis with topical therapies in adults.

• The American College of Physicians (ACP) has updated its living clinical guideline on treatment of adults in the acute phase of major depressive disorder.

• The ICER released its final evidence report on oral therapies and monoclonal antibodies for multiple sclerosis.

• The ICER published its final evidence report on fezolinetant (investigational) for vasomotor symptoms (VMS) associated with menopause.

• The US Department of Health and Human Services (HHS) has announced that the mpox Public Health Emergency has ended, effective January 31, 2023.

• The VRBPAC met on February 28, 2023 to make recommendations on the safety and efficacy of Pfizer’s investigational respiratory syncytial virus (RSV) vaccine, seeking an indication for active immunization for the prevention of acute respiratory disease and lower respiratory tract disease (LRTD) caused by RSV in adults ≥ 60 years of age. The panel also met on March 1, 2023 to make recommendations on the safety and efficacy of GlaxoSmithKline’s pipeline RSV vaccine, seeking an indication for active immunization for the prevention of LRTD caused by RSV-A and RSV-B subtypes in adults ≥ 60 years of age.

RECENT FDA APPROVALS

DRUG NAME MANUFACTURER

elacestrant (Orserdu™)

Stemline Therapeutics

pirtobrutinib (Jaypirca™) Loxo Oncology

DESCRIPTION

New Drugs

• NDA approval 01/27/2023; Assessment Aid, Fast Track, Priority Review

• Indicated for treatment of postmenopausal women or adult men with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following ≥ 1 line of endocrine therapy; select patients for treatment based on the presence of ESR1 mutations

• Estrogen receptor antagonist

• Oral tablet: 86 mg, 345 mg

• Recommended dosage is 345 mg once daily with food; dose modifications, including interruption of therapy, reduction, or permanent discontinuation, may be required depending on adverse event severity

• NDA approval 01/27/2023; Accelerated Approval, Orphan Drug, Priority Review

• Indicated for the treatment of adults with relapsed or refractory mantle cell lymphoma after ≥ 2 lines of systemic therapy, including a BTK inhibitor; continued approval for this use may require demonstration of benefit in confirmatory clinical trials

• Kinase inhibitor

• Oral tablet: 50 mg, 100 mg

• Recommended dosage is 200 mg once daily; dose modifications, including interruption of therapy, reduction, or permanent discontinuation, may be required depending on adverse event severity

RECENT FDA APPROVALS continued

DRUG NAME MANUFACTURER

atorvastatin calcium (Atorvaliq®) CMP

velmanase alfa-tycv (Lamzede®) Chiesi

pegcetacoplan (Syfovre™) Apellis

DESCRIPTION

New Drugs continued

• 505(b)(2) NDA approval 02/01/2023; Standard Review

• Indicated:

- To reduce the risk of (1) MI, stroke, revascularization procedures, and angina in adults with multiple risk factors for CHD but without clinically evident CHD; (2) MI and stroke in adults with T2DM with multiple risk factors for CHD but without clinically evident CHD; and (3) non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in adults with clinically evident CHD

- As an adjunct to diet to reduce LDL-C in (1) adults with primary hyperlipidemia and (2) patients ≥ 10 years old with heterozygous familial hypercholesterolemia (HeFH)

- As an adjunct to other LDL-C lowering therapies to reduce LDL-C in patients ≥ 10 years old with homozygous familial hypercholesterolemia (HoFH)

- As an adjunct to diet for the treatment of adults with (1) primary dysbetalipoproteinemia and (2) hypertriglyceridemia

• HMG-CoA reductase inhibitor

• Oral suspension: 20 mg/5 mL

• Recommended starting dosage in adults is 10 mg to 20 mg once daily; maximum dose is 80 mg once daily; recommended starting dose in pediatric patients is 10 mg to 20 mg once daily; maximum dose in pediatric patients with HoFH is 80 mg daily

• BLA approval 02/16/2023; Orphan Drug

• Indicated for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients

• Recombinant human lysosomal alpha-mannosidase enzyme replacement therapy

• For injection: 10 mg lyophilized powder in an SDV for reconstitution

• Recommended dosage is 1 mg/kg, using actual body weight, administered IV once weekly by an HCP; pre-treatment with antihistamines, antipyretics, and/or corticosteroids should be considered

• Boxed warning for severe hypersensitivity reactions

• NDA approval 02/17/2023; Priority Review

• Indicated for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD)

• Complement inhibitor

• For injection: 150 mg/mL solution in an SDV

• Recommended dosage is 15 mg (0.1 mL) administered via intravitreal injection by a qualified physician into each affected eye once every 25 to 60 days

RECENT FDA APPROVALS continued

DRUG NAME MANUFACTURER

sparsentan (Filspari™) Travere

antihemophilic

Bioverativ

DESCRIPTION

New Drugs continued

• NDA approval 02/17/2023; Accelerated Approval, Orphan Drug, Priority Review

• Indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine proteinto-creatinine ratio (UPCR) ≥ 1.5 g/g

• Accelerated Approval based on reduction in proteinuria; the effect of sparsentan on kidney function decline is unknown; continued approval for this use may require demonstration of benefit in confirmatory clinical trials

• Endothelin and angiotensin II receptor antagonist

• Oral tablet: 200 mg, 400 mg

• Recommended starting dosage is 200 mg once daily; after 14 days, the dose should be increased to 400 mg once daily, if tolerated; swallow whole with water before the morning or evening meal; measure aminotransferase levels and total bilirubin prior to initiating therapy and monitor monthly for the first 12 months, then every 3 months; dosage adjustments may be required due to aminotransferase elevations

• Boxed warnings for hepatotoxicity and embryo-fetal toxicity; only available through a REMS program

• BLA approval 02/22/2023; Breakthrough Therapy, Fast Track, Orphan Drug, Priority Review

• Indicated for use in adults and pediatric patients with hemophilia A (congenital factor VIII deficiency) for (1) routine prophylaxis to reduce the frequency of bleeding episodes; (2) on-demand treatment and control of bleeding episodes; and (3) perioperative management of bleeding

• Not indicated for the treatment of von Willebrand disease

• Recombinant DNA-derived, factor VIII concentrate

• For injection: 250 IU, 500 IU, 750 IU, 1,000 IU, 2,000 IU, 3,000 IU, or 4,000 IU of lyophilized powder in an SDV for reconstitution

• Recommended dosage is 50 IU/kg IV once weekly for routine prophylaxis and 50 IU/kg once, followed by 30 or 50 IU/kg doses, if needed, every 2 to 3 days depending on severity of bleeding (on-demand indication) or type of surgery; patient or caregiver can administer following proper training

• Product availability is expected in April 2023

COVID-19 Disclaimer: For the most current COVID-19 information, visit the FDA, CDC, NIH, NIH guidelines, and WHO websites. State and local health departments also provide valuable information regarding management in local communities. As the COVID-19 landscape is fluid, assumptions are subject to change.

505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

Glossary:

BLA Biologics License Application

BTK Bruton’s tyrosine kinase

CDC Centers for Disease Control and Prevention

CHD coronary heart disease

CHF congestive heart failure

CI confidence interval

CKD chronic kidney disease

COVID-19 Coronavirus Disease 2019

DNA deoxyribonucleic acid

ER+ estrogen receptor positive

ESR1 estrogen receptor 1

EUA Emergency Use Authorization

FDA Food and Drug Administration

HCP healthcare professional

HER2- human epidermal growth factor receptor 2 negative

HMG-CoA hydroxymethylglutaryl-coenzyme A

HR hazard ratio

ICER Institute for Clinical and Economic Review

IM intramuscular

IV intravenous

KRAS Kirsten rat sarcoma viral oncogene homolog

LDL-C low-density lipoprotein cholesterol

MI myocardial infarction

MMWR Morbidity and Mortality Weekly Report

mpox monkeypox

mRNA messenger ribonucleic acid

NDA New Drug Application

NIH National Institutes of Health

References: cdc.gov fda.gov nejm.org samhsa.gov whitehouse.gov

NSCLC non-small cell lung cancer

OTC over-the-counter

REMS Risk Evaluation and Mitigation

Strategies

SAMHSA Substance Abuse and Mental Health Services Administration

SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

SC subcutaneous

SDV single-dose vial

T2DM type 2 diabetes mellitus

US United States

VRBPAC Vaccines and Related Biological Products Advisory Committee

WHO World Health Organization