MRx Clinical Alert - October 2021

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



The CDC has issued an official health advisory on increases in ivermectin prescriptions and reports of severe illness with use for prevention or treatment of COVID-19. Ivermectin is FDA-approved for treating certain parasitic infections and is generally well tolerated when used as indicated. However, during the COVID-19 pandemic there has been a 24-fold increase in the dispensing of prescription ivermectin as well as human use of OTC veterinary ivermectin. Compared to before the pandemic, a five-fold increase in calls to poison control centers related to adverse effects associated with misuse and overdose of these products has been reported. Ivermectin is not FDA-approved or authorized for preventing or treating COVID-19, and the NIH guidelines have found data are insufficient to recommend the product as a COVID-19 treatment.

The FDA has announced a public workshop will be held for reconsideration of mandatory opioid education for prescribers. The upcoming October 2021 workshop will facilitate discussion with stakeholders on components of the opioid crisis that could be improved through requiring prescriber education as part of the Opioid Analgesic REMS. The benefits of a single source for education to address use and risks of opioids and treatment of OUD will also be discussed.

FDA-approved oral formulations are indicated for treating onchocerciasis (river blindness) and intestinal strongyloidiasis; topical formulations are indicated for treating head lice and rosacea. Before the pandemic, the average prescriptions per week being dispensed from retail pharmacies in the US was 3,600; prescriptions rose to 39,000 per week in January 2021 and to > 88,000 prescriptions per week in August 2021. Relatedly, in January 2021, calls to poison control centers for exposure to ivermectin increased to levels three-times greater than before the pandemic, and in July 2021, calls increased to five-times more than pre-pandemic baseline levels. Animal formulations of ivermectin are available for prevention and treatment of parasitic infection in animals; however, people have ingested these products, some of which are intended for use in large animals and contain highly concentrated amounts leading to overdose levels. Additionally, these veterinary formulations can contain inactive ingredients not assessed in humans. Overdose symptoms include GI toxicity, hypotension, and neurologic changes (e.g., confusion, hallucinations, seizures, coma, death) which may be further exacerbated by other CNS depressants (e.g., benzodiazepines and barbiturates). 2 | OCTOBER 2021

COVID-19: NOTABLE DEVELOPMENTS The FDA has amended the EUA for the Pfizer-Biontech COVID-19 vaccine authorizing a single booster dose, ≥ 6 months following completion of the primary 2-dose series, for the following individuals: 1) ≥ 65 years old, 2) 18 to 64 years old at high risk of severe COVID-19, and 3) 18 to 64 years old with institutional/ occupational exposure to SARS-CoV-2 resulting in a high risk of serious complications from COVID-19. This EUA update follows the FDA’s VRBPAC September 17th meeting; the booster was not recommended for all ≥ 16 years old, primarily due to insufficient safety data and the risk of myocarditis in young men. Interim CDC guidance recommends that certain populations should (e.g., ≥ 65 years old) receive a booster of the Pfizer-Biontech vaccine while other populations may (e.g., high risk occupational/institutional settings) receive the booster. The FDA issued a statement on COVID-19 vaccination in children that aligns with a release from the AAP cautioning against off-label use of COVID-19 vaccines in those < 12 years old. For more resources on COVID-19, visit the Magellan Rx Coronavirus Update webpage. For the most current 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.


HAPPENINGS & HIGHLIGHTS • Pfizer has expanded the voluntary recall of varenicline (Chantix®) 0.5 mg and 1 mg tablets to include all remaining lots due to N-nitroso-varenicline at or above the FDA’s interim acceptable limit. The precautionary recall is to the consumer level and follows the approval of alternative suppliers’ product. Although the health benefits from quitting smoking outweigh the theoretical cancer risk, long-term exposure may be associated with a potential increased risk for cancer. • Jacobus has voluntarily recalled 3 lots of amifampridine (Ruzurgi®) 10 mg tablets to the consumer level due to contamination with yeast, mold, and aerobic bacteria. Drug product with substantial contamination has the potential to lead to serious and life-threatening infections. • Azurity has issued a voluntary recall of 1 lot of vancomycin HCl for oral solution (Firvanq®) 50 mg/mL kit to the consumer level, as some products contain the incorrect diluent (incorrectly contain a First® Omeprazole [FIRST®-PPI] diluent). This may result in incomplete solubilization impacting the overall dose administered, potentially leading to persistent infection.

• The FDA is requiring revisions to the Boxed Warning of the labels for tofacitinib (Xeljanz®/Xeljanz XR®), baricitinib (Olumiant®), and upadacitinib (Rinvoq™) to include information about increased risks for serious CV events, cancer, blood clots, and death. While this change is based on data from a large, randomized, safety clinical trial of tofacitinib in RA patients, baricitinib and upadacitinib are included in the action based on their shared mechanism of action with tofacitinib. This update by the FDA does not apply to other JAK inhibitors, ruxolitinib (Jakafi®) and fedratinib (Inrebic®), which are used in the oncology setting. The agency is also limiting all approved uses of tofacitinib, baricitinib, and upadacitinib to certain patients who have not responded or cannot tolerate ≥ 1 TNF blocker. • The FDA has granted full approval of pembrolizumab (Keytruda®) in patients with locally advanced or metastatic urothelial carcinoma (UC) who are not eligible for any platinum-containing chemotherapy (regardless of PD-L1 status); previously this indication was an Accelerated Approval. Dosage for UC is 200 mg every 3 weeks or 400 mg every 6 weeks via IV infusion.

DRUG INFORMATION HAPPENINGS • The CDC has published ACIP’s recommendations on prevention and control of seasonal influenza with vaccines in the US for the upcoming influenza season; the AAP has also released recommendations for influenza prevention. • ICER has published the final evidence report and policy recommendations for atopic dermatitis therapies. • The ADA convened an international expert group and has published a consensus report on defining and interpreting remission in T2DM. • The NAMS has published a 2021 position statement on managing osteoporosis in postmenopausal women. • The USPSTF has issued a final recommendation statement on screening for prediabetes and T2DM. In asymptomatic adults 35 to 70 years old who are overweight or obese, it is recommended to screen for these conditions, and HCPs should offer/refer those with prediabetes to receive interventions for preventing progression to diabetes (Grade B).







avacopan Chemocentryx

• Oral • Complement inhibitor

Antineutrophil cytoplasmic antibodies-associated vasculitis


RVT-802 (cultured human thymus tissue) Enzyvant

• Surgical implant • Tissue-based regenerative therapy

DiGeorge syndrome (congenital athymia)


bimekizumab UCB

• SC • Interleukin-17 antagonist

Plaque psoriasis


narsoplimab Omeros

• IV, SC • Mannan-binding lectinassociated serine protease-2 (MAPS-2) inhibitor

Hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA)


sodium oxybate Avadel

• Oral • CNS depressant

Narcolepsy-related excessive daytime sleepiness and cataplexy


varenicline Oyster Point

• Intranasal • Nicotinic acetylcholine receptor (nAchR) agonist

Dry eye syndrome


treprostinil dry powder (Tyvaso® DPI) United/Mannkind

• Inhalation • Prostaglandin vasodilator

Pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease


ranibizumab Genentech

• Intravitreal implant • Vascular endothelial growth factor (VEGF) inhibitor

Wet age-related macular degeneration (wet AMD)


phenylephrine/tropicamide Eyenovia

• Ophthalmic • Alpha adrenergic agonist/ anticholinergic

Pharmacologic mydriasis


triamcinolone acetonide Bausch

• Suprachoroidal injection • Glucocorticosteroid

Uveitis-associated macular edema


4 | OCTOBER 2021




New Drugs lorazepam extended-release (ER) capsule (Loreev XR®) Almatica

• 505(b)(2) NDA approval 08/27/2021; Standard Review • Indicated for the treatment of anxiety disorders in adults who are receiving stable, evenly divided, 3-times daily dosing with lorazepam tablets • Benzodiazepine • ER oral capsule: 1 mg, 2 mg, and 3 mg • Recommended dosage is equal to the total daily dose of lorazepam tablets (at the previous 3-times daily dosage) taken once daily in the morning • Boxed warnings regarding risks from concomitant use with opioids; abuse, misuse, and addiction; dependence and withdrawal reactions

paliperidone palmitate ER (Invega Hafyera™) Janssen

• sNDA approval 08/30/2021; Standard Review • Indicated for the treatment of schizophrenia in adults after they have been adequately treated with once monthly paliperidone palmitate ER (Invega Sustenna®) for ≥ 4 months or every-3-month paliperidone palmitate ER (Invega Trinza®) for at least one 3-month cycle • Atypical antipsychotic • Injectable suspension: 1,092 mg/3.5 mL and 1,560 mg/5 mL single-dose prefilled syringes • Recommended dosage is based on the previous once-a-month or every-3-month paliperidone palmitate product; dosage is administered by gluteal injection by an HCP every 6 months • Boxed warning regarding increased mortality in elderly patients with dementia-related psychosis

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 dihydroergotamine mesylate (Trudhesa™) Impel

• 505(b)(2) NDA approval 09/02/2021; Standard Review • Indicated for the acute treatment of migraine with or without aura in adults • Not indicated for the preventive treatment of migraine or for the management of hemiplegic or basilar migraine • Ergotamine derivative • Nasal spray: 4 mg/mL (package of 4 SDVs and 1 nasal spray device) • Recommended dosage is 1.45 mg, administered as 1 spray into each nostril; the dose may be repeated once, if needed, administered ≥ 1 hour later (maximum of 2 doses per 24 hours or 3 doses per 7 days) • Boxed warning regarding peripheral ischemia following coadministration with potent cytochrome P450 3A4 (CYP3A4) inhibitors; concomitant use is contraindicated; CV evaluation is recommended prior to initiation

mobocertinib (Exkivity™) Takeda

• NDA approval 09/15/2021; Accelerated Approval; Assessment Aid; Breakthrough Therapy; Fast Track; Orphan Drug; Priority Review; Project Orbis • Indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy • Kinase inhibitor • Oral capsule: 40 mg • Recommended dosage is 160 mg once daily, with or without food, until disease progression or unacceptable toxicity • Boxed warning regarding QTc prolongation and torsades de pointes

ranibizumab-nuna (Byooviz™) Biogen

• BLA approval 09/17/2021; biosimilar to Genentech’s ranibizumab (Lucentis®) • Indicated for the treatment of patients with neovascular wet AMD, macular edema following retinal vein occlusion (RVO), or myopic choroidal neovascularization (mCNV) • Lucentis also carries indications for diabetic retinopathy and diabetic macular edema; Byooviz was not approved for these indications • VEGF inhibitor • Solution for intravitreal injection: 10 mg/mL in a SDV • Recommended dosage is 0.5 mg (0.05 mL) administered via intravitreal injection by an HCP once monthly (approximately 28 days); although not as effective, for wet AMD, can be given as 3 monthly doses followed by less frequent dosing or 1 dose every 3 months after 4 monthly doses, both with regular assessment; duration of therapy for mCNV is up to 3 months with retreatment, if necessary • Availability is expected in June 2022

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.

6 | OCTOBER 2021



New Drugs continued tisotumab vedotin-tftv (Tivdak™) Seagen

• BLA approval 09/20/2021; Accelerated Approval, Assessment Aid, Priority Review • Indicated for the treatment of adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy • Tissue factor-directed antibody and microtubule inhibitor conjugate • Injection: 40 mg as a lyophilized cake or powder in a SDV for reconstitution • Recommended dosage is 2 mg/kg (up to a maximum of 200 mg) administered IV over 30 minutes every 3 weeks by an HCP until disease progression or unacceptable toxicity • Boxed warding regarding ocular toxicity

ruxolitinib (Opzelura™) Incyte

• NDA approval 09/21/2021; Priority Review • Indicated for short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis (AD) in non-immunocompromised patients ≥ 12 years old whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advised • Use in combination with therapeutic biologics, other JAK inhibitors, or potent immunosuppressants (e.g., azathioprine or cyclosporine) is not recommended • JAK inhibitor • Topical cream: 1.5% • Recommended dosage is to apply a thin layer twice daily to affected areas of up to 20% of body surface area (maximum of 60 grams per week) • Boxed warning for serious infections, mortality, malignancy, major adverse CV events, and thrombosis

atogepant (Qulipta™) Abbvie

• NDA approval 09/28/2021; Priority Review • Indicated for the preventive treatment of episodic migraine in adults • Calcitonin gene-related peptide (CGRP) receptor antagonist • Oral tablet: 10 mg, 30 mg, and 60 mg • Recommended dosage is 10 mg, 30 mg, or 60 mg once daily with or without food; PI details dose modifications due to drug interactions or renal insufficiency

maralixibat (Livmarli™) Mirum

• NDA approval 09/29/2021; Breakthrough Therapy, Orphan Drug, Priority Review • Indicated for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) ≥ 1 year of age • Ileal bile acid transporter (IBAT) inhibitor • Oral solution: 9.5 mg/mL • Recommended dosage is 380 mcg/kg once daily, taken 30 minutes prior to the 1st meal of the day, following an initial dose of 190 mcg/kg once daily for 1 week; maximum of 3 mL or 28.5 mg/day for patients > 70 kg

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.

7 | OCTOBER 2021

Glossary: AAP American Academy of Pediatrics

EUA Emergency Use Authorization

NIH National Institutes of Health

SDV single dose vial

ACIP Advisory Committee on Immunization Practices

FDA Food and Drug Administration

OTC over-the-counter

T2DM type 2 diabetes mellitus

GI gastrointestinal

OUD opioid use disorder

TNF tumor necrosis factor

HCl hydrochloride

PD-L1 programmed death-ligand 1

US United States

HCP healthcare professional

PI prescribing information

ICER Institute for Clinical and Economic Review

RA rheumatoid arthritis

USPSTF US Preventive Services Task Force

ADA American Diabetes Association CDC Centers for Disease Control and Prevention CNS central nervous system COVID-19 Coronavirus Disease 2019 CV cardiovascular


8 | OCTOBER 2021

IV intravenous JAK Janus kinase NAMS North American Menopause Society

REMS Risk Evaluation and Mitigation Strategy

VRBPAC Vaccines and Related Biological Products Advisory Committee

SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 WHO World Health Organization SC subcutaneous

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