Clinical Alert April 2023

C LINICAL

ALERT

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

COVID-19 NOTABLES

BIOSIMILAR CORNER

DRUG INFORMATION HAPPENINGS & HIGHLIGHTS

PIPELINE NEWS

RECENT FDA APPROVALS

TRENDING TOPICS

HOT TOPIC – ORPHAN DRUG APPROVALS

The FDA has approved 2 novel therapies to treat rare diseases. Omaveloxolone (Skyclarys™), an oral capsule, received FDA approval as the first treatment for Friedreich’s ataxia, a degenerative, inherited disease of the nervous system leading to impaired coordination and walking. Trofinetide (Daybue™), an oral solution, is the first therapy approved for the neurological disorder, Rett syndrome. Both therapies received Priority Review, Orphan Drug, and Fast Track designations from the FDA.

Friedreich’s ataxia affects 1 in 50,000 individuals; it is the most common hereditary ataxia in the US. The condition leads to progressive damage to the CNS and peripheral nerves leading to challenges in walking, impaired speech and swallowing, and earlier mortality. Onset is often observed during childhood or adolescence. Omaveloxolone activates the Nrf2 pathway and is indicated for patients ≥ 16 years old. It is taken as 150 mg (3 capsules) orally once daily on an empty stomach. Aminotransferases (ALT, AST, and total bilirubin) as well as BNP and lipid levels should be assessed before starting and during therapy as it carries warnings for changes in these parameters. A 48-week randomized, double-blind study (n=103) assessed the change from baseline in the modified Friedreich’s ataxia rating scale (mFARS) score (assesses swallowing, speech, limb coordination, stability) and found omaveloxolone resulted in less impairment compared to placebo at week 48 (95% CI, -3.71 to -0.16; p=0.0331). Product availability is expected in 2Q 2023.

Rett syndrome is present primarily in females (1 in 10,000) and is characterized by frequent repetitive hand movements in babies 6 to 18 months of age who had previously exhibited normal development. The progressive disorder results in severe impairments in walking, eating, speaking, and breathing. Trofinetide oral solution (200 mg/mL) is indicated for patients ≥ 2 years old and is dosed twice daily based on body weight; it can be given orally or via G tube. Trofinetide carries warnings for diarrhea and weight loss. A randomized, double-blind, 12-week study (n=187) demonstrated significant improvements with trofinetide compared to placebo in coprimary efficacy endpoints evaluating signs/symptoms of Rett syndrome (p=0.018) and clinician-rated illness severity (p=0.003).

MAKENA® MARKET WITHDRAWAL

The FDA has withdrawn the approval of hydroxyprogesterone caproate (Makena). As of April 6, 2023, Makena and generic versions are no longer FDA approved and cannot be distributed in the US. Makena was previously approved to reduce the risk of preterm birth in pregnant women with a history of spontaneous preterm birth. Covis, the manufacturer, previously announced plans to voluntarily withdraw the NDA for Makena from the US market. This follows the October 2022 FDA advisory committee vote that the confirmatory trial did not demonstrate Makena’s benefit. For additional background details, view the December 2022 Clinical Alert.

COVID-19: NOTABLE DEVELOPMENTS

The FDA has authorized the bivalent Pfizer-Biontech COVID-19 vaccine as a booster dose for pediatric patients 6 months through 4 years of age. The FDA’s Antimicrobial Drugs Advisory Committee reviewed the NDA for nirmatrelvir co-packaged with ritonavir (Paxlovid™) and voted in favor of its safety and efficacy. The FDA issued a notice detailing guidance document changes after the expiration of the COVID-19 public health emergency on May 11, 2023. The CDC released the 2023 ACIP adult and child & adolescent immunization schedules that include new sections on COVID-19 vaccination. The FDA has issued an EUA for vilobelimab (Gohibic) injection for the treatment of COVID-19 in hospitalized adults when initiated within 48 hours of invasive mechanical ventilation or ECMO. Please refer to the COVID-19 disclaimer at the end of the publication.

BIOSIMILAR CORNER: NEW PRESENTATIONS

The FDA has approved a new 6 mg/0.6 mL prefilled autoinjector for Coherus’ pegfilgrastim-cbqv (Udenyca®), a biosimilar to Neulasta®. Udenyca was already available as a 6 mg/0.6 mL single-dose prefilled syringe for manual use only. The prefilled autoinjector is expected to launch in 2Q 2023. The agency has also approved a single-dose 40 mg/0.8 mL prefilled autoinjector pen of adalimumab-aqvh (Yusimry™), a biosimilar to Humira®. The product was previously approved as a prefilled syringe.

DRUG INFORMATION HAPPENINGS & HIGHLIGHTS

• The FDA is reporting albuterol sulfate 0.5% nebulizer solution from Akorn (20 mL) is not available and Nephron (0.5 mL) is on allocation. Akorn is reporting no new manufacturing of the product. The solution is indicated for the relief of bronchospasms in patients with reversible obstructive airway disease and acute attacks of bronchospasm.

• There is a shortage of erythromycin 0.5% ophthalmic ointment as Akorn currently does not have any product available and is not manufacturing any new product. Erythromycin ophthalmic ointment is indicated for treating superficial ocular infections and prophylaxis of ophthalmia neonatorum due to Neisseria gonorrhoeae or Chlamydia trachomatis

• Apotex has voluntarily recalled 6 lots of brimonidine tartrate 0.15% ophthalmic solution to the consumer level due to cracks in some of the bottle caps. A broken cap could affect product sterility.

• Global Pharma Healthcare has voluntarily recalled 1 batch (H29) of Artificial Eye Ointment, distributed by Delsam, to the consumer level, due to the potential for microbial contamination and packaging leaks.

• The FDA has approved Amphastar’s prescription naloxone 4 mg nasal spray formulation indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/ or CNS depression for adults and pediatric patients. The opioid antagonist is intended for immediate administration as emergency treatment in settings where opioids may be present and is not a substitute for emergency medical care. The product is supplied in unit-dose nasal spray devices; a single spray delivers 4 mg of naloxone HCl for intranasal administration. Other 4 mg intranasal naloxone sprays ( Narcan ® , generics) are available from other manufacturers.

• Pfizer’s rimegepant (Nurtec® ODT) 75 mg 8-unit dose blister packs have a recall due to packaging that is not child resistant. The packaging recall is in coordination with the US Consumer Product Safety Commission. Pfizer will provide child-resistant pouches to patients who request them. Pharmacies will place Nurtec ODT blister packages into vials with child-resistant lids when filling prescriptions until Pfizer develops new packaging. This notice only relates to the packaging, not the safety of the drug itself.

DRUG INFORMATION HAPPENINGS

• The FDA has updated shortage information on amphetamine aspartate/amphetamine sulfate/ dextroamphetamine saccharate/dextroamphetamine sulfate tablets (Adderall®) from certain manufacturers.

• A synopsis of the 2022 VA and DoD joint clinical practice guideline on the use of opioids for managing chronic pain has been published in the Annals of Internal Medicine.

• The FDA has announced that the Anesthetic and Analgesic Drug Products Advisory Committee will meet on April 19, 2023, to discuss a post-marketing requirement that was issued to NDA application holders for extended-release/long-acting opioid analgesics to evaluate the long-term efficacy of these agents and risk of opioid-induced hyperalgesia.

• The FDA has released a statement summarizing agency efforts for preventing drug overdoses and reducing related mortality; the statement coincides with the release of an external review of the agency’s regulation of opioid analgesics.

• The agency has published final guidance on compounding certain ibuprofen oral suspension products in outsourcing facilities for administration in hospitals and health systems to curtail the increased demand for pediatric antipyretic medications.

PIPELINE NEWS

UPCOMING PRESCRIPTION

• IM

• Bacterial vaccine

bimekizumab UCB

ritlecitinib Pfizer

• SC

• Interleukin 17 (IL-17) antagonist

• Oral

• Janus kinase 3 (JAK3) and tyrosine kinase expressed in hepatocellular carcinoma inhibitor (TEC) kinase dual inhibitor

• Intranasal

• Alpha/beta adrenergic agonist

psoriasis (moderate to severe)

adalimumab 100 mg/mL (biosimilar to Abbvie’s Humira®) Alvotech

rizatriptan film Gensco

quizartinib Daiichi Sankyo

tofersen Biogen

SER-109 Seres

aripiprazole

2-month

H. Lundbeck

mirikizumab

Eli Lilly

palopegteriparatide Ascendis

• SC

• Tumor necrosis factor-alpha (TNFα) inhibitor

Rheumatoid arthritis; Ankylosing spondylitis; Plaque psoriasis; Psoriatic arthritis; Juvenile idiopathic arthritis; Crohn’s disease; Ulcerative colitis

• Oral transmucosal

• Selective 5-HT1 serotonin agonist

• Oral

• FMS-like tyrosine kinase 3 (FLT3) inhibitor

• Intrathecal

• Antisense oligonucleotide

• Oral

• Microbiome therapy

• IM

• Atypical antipsychotic

• IV, SC

• Interleukin 23 (IL-23) antagonist

• SC

• Parathyroid hormone prodrug

Treatment of acute migraine

Acute myelogenous leukemia (AML) 04/24/2023

Amyotrophic lateral sclerosis (ALS) (superoxide dismutase 1) 04/25/2023

Prevention of Clostridioides difficileassociated diarrhea recurrence

Bipolar disorder; Schizophrenia 04/27/2023

Ulcerative colitis (moderate to severe) 04/28/2023

Hypoparathyroidism (adults)

RECENT FDA APPROVALS

DRUG NAME MANUFACTURER

acetaminophen/ ibuprofen (Combogesic®) Catalent

zavegepant (Zavzpret™)

Pfizer

retifanlimab-dlwr (Zynyz™) Incyte

leniolisib (Joenja®)

Pharming

DESCRIPTION

New Drugs

• 505(b)(2) NDA approval 03/01/2023; Standard Review

• Indicated for the short-term management of mild to moderate acute pain in adults

• Combination of a non-opioid, non-salicylate analgesic, and an NSAID

• Film-coated tablet: 325 mg acetaminophen/97.5 mg ibuprofen

• Recommended dosage is 3 tablets every 6 hours as needed for pain relief; maximum of 12 tablets per day

• Boxed warnings for hepatotoxicity, cardiovascular risk, and gastrointestinal risk

• NDA approval 03/09/2023; Standard Review

• Indicated for the acute treatment of migraine with or without aura in adults

• Not indicated for migraine prevention

• Calcitonin gene-related peptide (CGRP) receptor antagonist

• Nasal spray: 10 mg ready-to-use, unit-dose disposable device

• Recommended dosage is 10 mg, as a single spray, in 1 nostril, as needed; maximum dose in 24 hours is 10 mg (1 spray); safety of treating > 8 migraines in 30 days has not been established

• Product availability is expected in July 2023

• BLA approval 03/22/2023; Accelerated Approval, Assessment Aid, Fast Track, Orphan Drug, Priority Review

• Indicated for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma; continued approval for this use may require a demonstration of benefit in confirmatory clinical trials

• Programmed death receptor-1 (PD-1)–blocking antibody

• Injection: 500 mg/20 mL solution in an SDV

• Recommended dosage is 500 mg IV infusion over 30 minutes every 4 weeks administered by an HCP; withholding therapy or permanent discontinuation may be required depending on the type and severity of the adverse reaction

• NDA approval 03/24/2023; Orphan Drug, Priority Review, Rare Pediatric Disease designation

• Indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients ≥ 12 years old

• Kinase inhibitor

• Oral tablet: 70 mg

• Recommended dosage is 70 mg twice daily approximately 12 hours apart, with or without food, in patients weighing ≥ 45 kg

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

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.

Glossary:

ACIP Advisory Committee on Immunization Practices

ALT alanine aminotransferase

AST aspartate aminotransferase

BLA Biologics License Application

BNP B-type natriuretic peptide

CDC Centers for Disease Control and Prevention

CI confidence interval

CNS central nervous system

COVID-19 Coronavirus Disease 2019

DoD US Department of Defense

ECMO extracorporeal membrane oxygenation

EUA Emergency Use Authorization

FDA Food and Drug Administration

G gastrostomy

HCl hydrochloride

HCP healthcare professional

IM intramuscular

IV intravenous

NDA New Drug Application

NIH National Institutes of Health

References: cdc.gov fda.gov federalregister.gov acpjournals.org

Nrf2 Nuclear factor (erythroid-derived 2)-like 2

NSAID nonsteroidal anti-inflammatory drug

ODT orally disintegrating tablet

Q quarter

SC subcutaneous

SDV single-dose vial

US United States

VA US Department of Veterans Affairs

WHO World Health Organization