MRx Clinical Alert - August 2021

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DEPUTY EDITORS Jessica Czechowski PharmD Lara Frick PharmD, BCPS, BCPP Carole Kerzic RPh Leslie Pittman PharmD


TRENDING TOPICS HOT TOPIC: UPDATES TO ADUHELM™ LABEL The US FDA has approved a label update for Biogen’s amyloid beta-directed antibody, aducanumab-avwa (Aduhelm), for Alzheimer’s disease (AD); the indications and usage section has been updated to clarify the population of patients to be considered candidates for treatment. The indication is still for the treatment of AD; however, it is noted treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, as this was the population in which treatment was started in clinical studies. Furthermore, it is stated that data are not available on initiating therapy at earlier or later stages of the disease than were studied. The indication remains an Accelerated Approval based on reduction in amyloid beta plaques, and therefore, continued approval for this use may require demonstration of benefit in confirmatory clinical trials. Biogen submitted the label update to provide further clarification on the population of patients evaluated in the 3 clinical studies used for approval. The FDA has also released a new post-market drug safety information webpage providing FDA review documents for the product. ICER released a revised Evidence Report at the end of June, following aducanumab-avwa’s initial approval; the revised report was released before the most recent label update for aducanumab-avwa and was the subject of the July 15th independent evidence appraisal committee public meeting. The meeting included a discussion and vote on the net health benefit of aducanumab-avwa, other potential benefits and key considerations, and the long-term cost-effectiveness. The Final Evidence Report and Policy Recommendations are expected to be released by ICER on August 5, 2021.

COVID-19 NOTABLE DEVELOPMENTS The FDA has issued an EUA for commercially available tocilizumab (Actemra®) for the treatment of COVID-19 in hospitalized adults and pediatric patients (≥ 2 years of age) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive 2 | AUGUST 2021

mechanical ventilation, or ECMO. It is administered as a weight-based single 60-minute IV infusion (max dose 800 mg/infusion) by an HCP; if clinical signs/ symptoms worsen or do not improve after the first dose, 1 additional infusion may be given ≥ 8 hours after the initial infusion. The patient and provider fact sheets for the Moderna and Pfizer-BioNTech COVID-19 vaccines have been revised to include the suggested increased risks for myocarditis and pericarditis after vaccination, particularly after the second dose, with onset of symptoms (e.g., chest pain, shortness of breath, rapid or irregular heartbeat) within days of vaccination. The revisions were made after an extensive review and discussion by CDC’s ACIP. Although an increased risk for myocarditis has been seen following receipt of these mRNA COVID-19 vaccines, particularly in males 12 to 29 years old, ACIP has concluded the benefits of COVID-19 vaccination continue to outweigh the risks. The patient and provider fact sheets for the Janssen COVID-19 vaccine have been updated to include details about a potentially increased risk for Guillain-Barré Syndrome (GBS) after receipt of Janssen’s COVID-19 vaccine. GBS is a rare, neurological disorder that has been preliminarily reported in 100 recipients out of about 12.5 million doses. At this time, a causal relationship has not been established, and the agency has found the benefits outweigh risks. The FDA has accepted the BLA for the Pfizer-BioNTech COVID-19 vaccine for the prevention of COVID-19 in individuals ≥ 16 years old. The application has been granted Priority Review with a PDUFA goal date of January 2022. For more resources on COVID-19, visit the Magellan Rx Coronavirus Update webpage. For the most current information, visit the FDA, the CDC, the NIH, the NIH guidelines, and the 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.


HAPPENINGS & HIGHLIGHTS • Viona issued a retail level voluntary recall for 2 lots of metformin HCl ER tablets 750 mg due to detection of N-nitrosodimethylamine (NDMA) impurity above the acceptable limits. NDMA, a probable human carcinogen, is an environmental contaminant found in water and foods. • Pfizer has voluntarily recalled 12 lots of the smoking cessation drug, varenicline (Chantix®), to the patient level, as product contains a nitrosamine impurity, N-nitroso-varenicline, higher than the company established acceptable intake limit. Although the risk is not immediate, the impurity may be associated with the potential for an increased risk of cancer with long-term use. The FDA states the health benefits from quitting smoking outweigh the potential cancer risk from the impurity. The FDA is allowing for specific manufacturers’ temporary distribution of product containing levels of the impurity between 37 ng/day (FDA’s acceptable intake limit) and 185 ng/day (interim acceptable intake limit) until the impurity can be eliminated/reduced. Additionally, to minimize drug shortages, the FDA is allowing temporary importation of Apotex’s varenicline tartrate (Apo-Varenicline) from Canada.

• Merck has announced plans for the voluntary withdrawal of pembrolizumab’s (Keytruda®) Accelerated Approval indication for treating patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1, as determined by an FDA-approved test, with disease progression on or after ≥ 2 prior lines of therapy including fluoropyrimidine- and platinumcontaining chemotherapy and if appropriate, HER2/ neu-targeted therapy. The indication in this setting of third-line treatment for gastric cancer will be withdrawn in 6 months as an overall survival benefit was not found in a phase 3 trial. Pembrolizumab remains FDAapproved for other uses, including in other settings for gastric cancer. • The FDA has granted full approval to enfortumab vedotin-ejfv (Padcev®) for the treatment of adults with locally advanced or metastatic urothelial cancer (UC) who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy. The agent received Accelerated Approval for this indication in 2019; full approval is based on Trial EV-301, required to confirm the clinical benefit.

DRUG INFORMATION HAPPENINGS • The American Diabetes Association (ADA) has issued updates to the following sections of the Standards of Medical Care in Diabetes – 2021: Classification and Diagnosis of Diabetes, Cardiovascular Disease (CVD) and Risk Management, and Microvascular Complications and Foot Care. • The American Gastroenterological Association (AGA) has published clinical practice guidelines on the medical management of moderate to severe luminal and perianal fistulizing Crohn’s disease. • The American Heart Association (AHA) has released a scientific statement on obstructive sleep apnea (OSA) and CVD. • ICER has released an Evidence Report on the comparative effectiveness and value of the following agents for atopic dermatitis: abrocitinib (investigational), tralokinumab (investigational), baricitinib (Olumiant®), upadacitinib (Rinvoq™), ruxolitinib (investigational), and dupilumab (Dupixent®).







tick-borne encephalitis vaccine Pfizer

• IM • Viral vaccine

Tick-borne encephalitis

August 2021

atogepant Abbvie

• Oral • CGRP inhibitor

Episodic migraine prevention

Aug-Sep 2021

dapivirine ring International Partnership for Microbicides/Janssen

• Intravaginal • NNRTI

HIV-1 infection prevention

Aug-Dec 2021

treosulfan Medac

• IV • Alkylating agent

Allogenic hematopoietic stem cell transplant conditioning


avalglucosidase alfa Sanofi

• IV • Lysosomal glycogen-specific enzyme

Pompe disease


oportuzumab monatox Sesen

• Intravesical • Anti-EpCAM antibody cytotoxic agent

Bladder cancer (BCGunresponsive, non-muscleinvasive)


dextromethorphan/ bupropion Axsome

• Oral • NMDA receptor antagonist/sigma-1 receptor agonist plus an NDRI

Major depressive disorder


vosoritide Biomarin

• SC • Natriuretic peptide



difelikefalin Cara

• IV • Opioid agonist

Pruritus (hemodialysisrelated)


paliperidone palmitate 6-month injectable Janssen

• IM • Atypical antipsychotic



BCG = Bacillus Calmette-Guérin; CGRP = calcitonin gene-related peptide; EpCAM = epithelial cell adhesion molecule; HIV-1 = human immunodeficiency virus-1; NMDA = N-Methyl-D-aspartate; NDRI = norepinephrine and dopamine reuptake inhibitor; NNRTI = non-nucleoside HIV-1 reverse-transcriptase inhibitor

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New Drugs azelastine HCl (Astepro® Allergy/ Children’s Astepro® Allergy) Bayer

• NDA approval 06/17/2021; Partial Rx to OTC switch • Used for the temporary relief of nasal congestion, runny nose, sneezing, and itchy nose due to hay fever or other upper respiratory allergies in patients ≥ 6 years old • Partial Rx to OTC switch as the 0.1% strength, which includes the perennial allergy indication for children 6 months to 6 years old and seasonal allergy indication for children 2 to 6 years old, will continue to require a Rx • Nasal antihistamine • Nasal spray: 0.15% • Recommended dosage is based on the patient’s age: » Adults and children ≥ 12 years of age: 2 sprays in each nostril once daily or 1 or 2 sprays in each nostril every 12 hours » Children 6 to 11 years old: 1 spray in each nostril every 12 hours • Product availability is expected in 1Q 2022

dabigatran etexilate (Pradaxa®) Boehringer Ingelheim

• NDA approval 06/21/2021; Priority Review • Indicated for the treatment of venous thromboembolic events (VTE) following treatment with a parenteral anticoagulant for ≥ 5 days and to reduce the risk of recurrence of VTE in pediatric patients ≥ 3 months old to < 12 years of age • Direct thrombin inhibitor • Oral pellet packets: 20 mg, 30 mg, 40 mg, 50 mg, 110 mg, and 150 mg; not substitutable on a mg-to-mg basis with other dabigatran etexilate dosage forms • Recommended dosage is dependent on the indication and is age-based and/or weight-based and ranges from 30 mg twice daily to 260 mg twice daily • Boxed warnings regarding increased risk of thrombotic events with premature discontinuation and spinal/epidural hematoma

cyclosporine ophthalmic emulsion (Verkazia®) Santen

• 505(b)(2) NDA approval 06/23/2021; Orphan Drug • Indicated for the treatment of vernal keratoconjunctivitis (VKC) in children and adults • Calcineurin inhibitor immunosuppressant • Ophthalmic emulsion: 0.1% (1 mg/mL); 0.3 mL SDV in packages of 30, 60, or 120 • Recommended dosage is instillation of 1 drop 4 times daily (morning, noon, afternoon, and evening) into each affected eye; therapy can be discontinued following resolution of signs/symptoms with reinitiation for recurrence

ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; H = Half; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.



New Drugs continued asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze™) Jazz

• BLA approval 06/30/2021; Assessment Aid, Fast Track, Orphan Drug, Project Orbis, Real-Time Oncology Review (RTOR) • Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients ≥ 1 month of age who have developed hypersensitivity to Escherichia coli-derived asparaginase • Asparagine specific enzyme • Injection: 10 mg/0.5 mL solution in SDV • Recommended dosage is 25 mg/m2 administered via IM injection every 48 hours to replace a long-acting asparaginase product; administer in a setting that can manage anaphylaxis and has resuscitation equipment

finerenone (Kerendia®) Bayer

• NDA approval 07/09/2021; Priority Review • Indicated to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adults with chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM) • Non-steroidal mineralocorticoid receptor antagonist (MRA) • Oral tablets: 10 mg and 20 mg • Recommended starting dosage is 10 mg or 20 mg once daily with or without food, based on eGFR and serum potassium levels; the dose can be increased after 4 weeks to the target dose of 20 mg once daily

belumosudil (Rezurock™) Kadmon

• NDA approval 07/16/2021; Assessment Aid, Breakthrough Therapy, Priority Review, Project Orbis, RTOR • Indicated for the treatment of patients ≥ 12 years old with chronic graft-versus-host disease (GVHD) after failure of ≥ 2 prior lines of systemic therapy • Kinase inhibitor • Oral tablets: 200 mg • Recommended dosage is 200 mg once daily with food until progression of chronic GVHD that requires new systemic therapy

odevixibat (Bylvay™) Albireo

• NDA approval 07/20/2021; Orphan Drug, Priority Review • Indicated for the treatment of pruritus in patients ≥ 3 months of age with progressive familial intrahepatic cholestasis (PFIC); it may not be effective in PFIC type 2 patients with ABCB11 variants resulting in non-functional or complete absence of bile salt export pump protein (BSEP-3) • Ileal bile acid transporter (IBAT) inhibitor • Oral capsules: 400 mcg and 1,200 mcg; oral pellets: 200 mcg and 600 mcg • Recommended dosage is 40 mcg/kg once daily in the morning with a meal; if no improvement in pruritus within 3 months, can increase the dose in 40 mcg/kg increments up to 120 mcg/kg once daily; maximum daily dose is 6 mg

ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; H = Half; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

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New Drugs continued tretinoin/benzoyl peroxide (Twyneo®) Sol-Gel Technologies

• 505(b)(2) NDA approval 07/26/2021; Standard Review • Indicated for the topical treatment of acne vulgaris in adults and pediatric patients ≥ 9 years old • Combination of tretinoin (a retinoid) and benzoyl peroxide • Topical cream: 0.1% tretinoin/3% benzoyl peroxide in a 50 g bottle • Recommended dosage is to apply a thin layer to the affected area(s) once daily while avoiding contact with eyes, lips, paranasal creases, and mucous membranes

insulin glargine-yfgn (Semglee®) Mylan

• BLA approval 07/28/2021; interchangeable biosimilar to insulin glargine (Lantus®); an interchangeable biosimilar product may be substituted for the reference product without the intervention of the prescriber, at the pharmacy, depending on state pharmacy substitution laws • Indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus (T1DM) and in adults with T2DM; it is not recommended for treating diabetic ketoacidosis • Long-acting human insulin analog • Injection: 100 units/mL (U-100) available as 10 mL multiple-dose vial and 3 mL single-patient-use prefilled pen • Recommended dosage is individualized based on metabolic needs, blood glucose (BG) monitoring, glycemic control, diabetes type, and previous insulin use with SC administration into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day; careful monitoring of BG is recommended when switching to Semglee and during the first weeks after switching • Product availability is expected before the end of 2021

ANDA = Abbreviated New Drug Application; BLA = Biologics License Application; H = Half; NDA = New Drug Application; Q = Quarter; sBLA = Supplemental Biologics License Application; sNDA = Supplemental New Drug Application; 505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

Glossary: ACIP Advisory Committee on Immunization Practices

ER extended-release

ICER Institute for Clinical and Economic Review

PDUFA Prescription Drug User Fee Act

IM intramuscular

Rx prescription

BLA Biologics License Application

EUA Emergency Use Authorization

CDC Centers for Disease Control and Prevention

FDA Food and Drug Administration

IV intravenous

COVID-19 Coronavirus Disease 2019

HCl hydrochloride

NIH National Institutes of Health

ECMO extracorporeal membrane oxygenation

HER2 human epidermal growth factor receptor 2


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HCP healthcare professional

mRNA messenger ribonucleic acid OTC over-the-counter PD-L1 programmed death-ligand 1 © 2021, Magellan Health. All rights reserved.

PD-1 programmed death receptor-1 SC subcutaneous SDV single dose vial US United States WHO World Health Organization