MRx Clinical Alert - November 2020

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EXECUTIVE EDITOR Anna Schreck Bird PharmD DEPUTY EDITORS Jessica Czechowski PharmD Lara Frick PharmD, BCPS, BCPP Carole Kerzic RPh Leslie Pittman PharmD

TRENDING TOPICS HOT TOPIC: FDA ISSUES EUA GUIDANCE FOR COVID-19 VACCINES The United States (US) Food and Drug Administration (FDA) has issued guidance providing recommendations on the data and details in support of an Emergency Use Authorization (EUA) for an investigational vaccine for the prevention of novel coronavirus infection 2019 (COVID-19). The final guidance for industry contains nonbinding recommendations. The guidance addresses the criteria and considerations for issuance of a COVID-19 vaccine EUA and details recommendations on chemistry, manufacturing, regulatory information, nonclinical data, and clinical data to be included in an EUA request. In terms of safety and effectiveness, the EUA would need to meet the prespecified success criteria for the primary efficacy endpoint. The request should also include safety data from phase 1 and 2 studies to complement the data from the ongoing phase 3 studies. The phase 3 study data should have a median follow-up duration of ≥ 2 months following completion of the vaccine regimen. In order to assess vaccine safety and the benefits versus risks of the proposed vaccine, the agency has stated the following: local and systemic solicited adverse reactions should be collected; all safety data should be collected for > 3,000 vaccine recipients followed for serious adverse events and adverse events of special interest for ≥ 1 month following vaccine regimen completion; and a sufficient number of severe COVID-19 cases (≥ 5 severe cases in the placebo group) should occur to show a low potential for vaccine-induced enhanced respiratory disease (ERD). Additionally, the EUA request is recommended to include an approach for active safety follow-up (e.g., serious adverse events, hospitalizations, deaths) of individuals who receive the vaccine under an EUA as well as a plan for assessment of long-term safety and efficacy. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) intends to hold an open session 2 | NOVEMBER 2020

before the FDA issues any EUA for a COVID-19 vaccine. A VRBPAC public meeting was held on October 22, 2020, for discussion of COVID-19 vaccine development and authorization/licensure. No specific vaccine candidates were discussed at the meeting; however, the agency has reported they will schedule future VRBPAC meetings following receipt of biologics license applications (BLAs) or EUA requests. Additionally, the FDA has launched a new website to provide information on vaccines for COVID-19.

FDA PROPOSES WITHDRAWAL OF MAKENA® The FDA’s Center for Drug Evaluation and Research (CDER) has proposed hydroxyprogesterone caproate injection (Makena) be withdrawn from the US market as a post-marketing study did not show a clinical benefit. Currently, the evidence does not demonstrate the drug is effective for the approved use. The FDA provided a notice of opportunity for a hearing to the manufacturers of brand and generic formulations. Product will remain on the market until the manufacturers remove the drug or the FDA Commissioner mandates removal. The FDA Commissioner will decide on the need for a public hearing, if requested by the manufacturer; withdrawal of drug approval will be considered after a hearing. In 2011, the FDA granted Accelerated Approval of hydroxyprogesterone caproate for reducing the risk of preterm birth in women who previously had a spontaneous preterm birth (delivery prior to 37 weeks). As a condition of the Accelerated Approval, the FDA required a clinical trial to confirm the clinical benefit to newborns. The trial did not show hydroxyprogesterone caproate was effective at increasing the health of neonates born to women with a history of unexplained preterm birth and the risk for preterm birth was not decreased with hydroxyprogesterone caproate.


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The Institute for Clinical and Economic Review (ICER) has released an evidence report on targeted immune modulator (TIM) therapies for ulcerative colitis (UC). Agents included for review were adalimumab (Humira®), golimumab (Simponi®), infliximab (Remicade®), infliximab-abda (Renflexis ®), infliximab-dyyb (Inflectra®), tofacitinib (Xeljanz®), ustekinumab (Stelara®), and vedolizumab (Entyvio®).

The FDA updated the Coronavirus Treatment Acceleration Program (CTAP) dashboard providing an overview of potential therapies for COVID-19. There are more than 550 drug development programs in the planning stages. In addition, more than 350 trials have been reviewed by the FDA as safe to proceed investigational new drugs (INDs). The data do not reflect vaccine development.

The panel concluded that all agents reviewed demonstrated superiority to placebo. A head-tohead study, supported by an indirect network metaanalysis, found vedolizumab resulted in higher rates of clinical response and remission than adalimumab in biologic-naïve and biologic-experienced patients. Other TIMs demonstrated net health benefits at least comparable to adalimumab; however, there were no apparent differences between the agents.

The agency has announced FDA approval of the antiviral drug remdesivir (Veklury®) for adults and pediatric patients (≥ 12 years of age and weighing ≥ 40 kg) for treating COVID-19 that requires hospitalization. Approval marks the first and only FDA-approved COVID-19 treatment. Additional details on the dosing and administration of remdesivir are provided in the FDA Approvals section. A corresponding new EUA has been issued for use of remdesivir in treating hospitalized pediatric patients < 12 years old weighing ≥ 3.5 kg or hospitalized pediatric patients weighing 3.5 kg to < 40 kg with suspected or laboratoryconfirmed COVID-19 for whom use of an intravenous (IV) product is appropriate.

BEHAVIORAL HEALTH CORNER: BOXED WARNING UPDATED FOR ANXIETY DRUGS The FDA has released a Drug Safety Communication regarding class-wide safety labeling changes for benzodiazepines (BZDs) to ensure their safe use. The FDA is requiring an update to the boxed warning for these products to include the potential for abuse, misuse, addiction, physical dependence, and withdrawal reactions. This class of medications is approved to treat a number of conditions, including generalized anxiety disorder, insomnia, seizures, social phobia, and panic disorder. The agency determined BZDs are commonly prescribed and frequently used for extended periods of time. Additionally, these agents are abused and misused, frequently with alcohol, prescription opioids, and illicit substances, further contributing to the potential for serious issues. Serious withdrawal reactions following rapid dose reduction or abrupt discontinuation have also occurred. Furthermore, patients have exhibited extended withdrawal symptoms for months. In conjunction with these updates, the FDA is also requiring additional labeling changes to the Warnings and Precautions subsection on drug abuse and dependence and the Patient Counseling Information section.

The National Academies of Sciences Engineering Medicine (NASEM) have released a final consensus study report on the “Framework for Equitable Allocation of COVID-19 Vaccine (2020).” Due to the likely high demand for the vaccine during the early stages, the Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) requested that NASEM, in partnership with the National Academy of Medicine (NAM), develop an ad hoc committee to provide a framework for allocation of the vaccine for policy makers domestically and globally. A 4-phased approach is recommended for equitable vaccine allocation. It is noted that within each phase, all groups are given equal priority. 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 treatment guidelines, and the World Health Organization (WHO) websites. State and local health departments also provide valuable information regarding management in local communities.


HAPPENINGS & HIGHLIGHTS • Perrigo has issued a voluntary recall of all unexpired albuterol sulfate inhalation aerosols manufactured by Catalent to the retail level. The recall is due to the potential for clogging of the inhaler leading to patients not receiving an adequate dose or any medication. The FDA has instructed patients to continue using the inhaler they have on hand, seek emergency medical care quickly if needed, have additional inhalers or another treatment in the event the Perrigo inhaler malfunctions, and contact a healthcare professional (HCP) with questions. • RLC Labs has announced a voluntary recall of all 483 lots of thyroid tablets, USP (Nature-Throid®, WP Thyroid®) in all strengths and all counts currently within expiration. The recall is to the consumer level due to the potential for product to contain as low as 87% of the labeled amount of levothyroxine (T4) or liothyronine (T3). Similarly, Acella has voluntarily recalled 1 lot of 15 mg and 1 lot of 120 mg thyroid tablets, USP (NP Thyroid®) to the consumer level due to the potential for sub-potent product containing as low as 87% of the labeled amount of T4.

• Sun has issued a voluntary nationwide recall of 1 lot of metformin hydrochloride (HCl) extended-release (ER) oral suspension (Riomet ER™) in the strength of 500 mg/5 mL to the consumer level due to N-Nitrosodimethylamine (NDMA) levels greater than the acceptable daily intake (ADI) limit. Marksans has expanded their previously issued voluntary nationwide recall of metformin HCl ER tablets, USP 500 mg and 750 mg to include an additional 76 unexpired lots. The previous June 2020 recall is being expanded because testing showed the NDMA content in some lots was greater than the ADI limit. For additional updates on NDMA in metformin-containing products, visit the FDA’s website. • ICER has published a White Paper on the cornerstones of fair patient access and drug coverage, providing an analysis of ethical and practical considerations for insurance drug coverage. The White Paper includes criteria for assessment of cost-sharing and utilization management policies. A new initiative is also being launched by ICER evaluating US insurers’ policies for appropriateness and fairness.

DRUG INFORMATION HAPPENINGS • The American College of Cardiology (ACC) published an Expert Consensus Decision Pathway on the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for cardiovascular (CV) risk reduction in patients with type 2 diabetes. • The American Heart Association (AHA) has issued a scientific statement on drugs that can cause or worsen arrhythmias. • The CDC’s Advisory Committee on Immunization Practices (ACIP) has issued recommendations on the use of meningococcal vaccination in the US, including new information on appropriate candidates for booster doses. • The North American Menopause Society (NAMS) has released a 2020 position statement on genitourinary syndrome of menopause.

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naloxone prefilled syringe US WorldMeds

• IM • Opioid antagonist

Opioid overdose

November 2020

viloxazine HCl Supernus

• Oral • Serotonin norepinephrine modulating agent

Attention deficit hyperactivity disorder (ADHD)


amphetamine sulfate (immediate-release, tamper-resistant) Arbor

• Oral • Central nervous system (CNS) stimulant



samidorphan/olanzapine Alkermes

• Oral • Opioid antagonist/atypical antipsychotic

Bipolar disorder; Schizophrenia


sutimlimab Sanofi

• IV • Complement inhibitor

Cold agglutinin disease


lisocabtagene maraleucel Bristol-Myers Squibb

• IV • Chimeric antigen receptor T cell (CAR-T) immunotherapy

Diffuse large B cell lymphoma (relapsed/refractory)


lonafarnib Eiger

• Oral • Farnesyl transferase inhibitor

Hutchinson–Gilford progeria syndrome


setmelanotide Rhythm

• SC • Melanocortin-4 receptor agonist

Leptin receptor (LEPR) deficiency obesity; Proopiomelanocortin (POMC) deficiency obesity


naxitamab Y-mAbs

• IV • Anti-GD2 monoclonal antibody

Neuroblastoma (high-risk, relapsed/refractory)


tasimelteon (Hetlioz®) Vanda

• Oral • Melatonin receptor agonist

Smith-Magenis syndrome


berotralstat Biocryst

• Oral • Plasma kallikrein inhibitor

Hereditary angioedema (attack prevention)


lumasiran Alnylam

• SC • Antisense oligonucleotide



IM = intramuscular; IV = intravenous; SC = subcutaneous




New Drugs ketotifen fumarate (Alaway®) Bausch

• ANDA approval 09/24/2020; new over-the-counter (OTC) preservative-free formulation; product is currently available in an OTC formulation with the preservative benzalkonium chloride • Indicated for the temporary relief of itchy eyes due to pollen, ragweed, grass, animal hair, and dander in patients ≥ 3 years old • Antihistamine • Ophthalmic solution: 0.035% strength in single-dose vial (SDV) • Recommended dosage is 1 drop in the affected eye(s) twice daily, every 8 to 12 hours; do not administer more than twice per day • Product availability is expected in Spring 2021

tofacitinib citrate (Xeljanz®) Pfizer

• NDA approval 09/25/2020; Priority Review • Indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients ≥ 2 years; Xeljanz tablets also received FDA approval for this use • Janus kinase (JAK) inhibitor • Oral solution: 1 mg/mL; not interchangeable or substitutable for Xeljanz XR • Recommended dosage is 5 mg (or a weight-based equivalent with recommendations for body weight as low as 10 kg) orally twice daily with or without food; use in combination with biologic disease-modifying anti-rheumatic drugs (DMARDs) or potent immunosuppressants (e.g., azathioprine, cyclosporine) is not recommended • Boxed warning for serious infections, mortality, malignancy, and thrombosis • Product availability is expected in 1Q 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.

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New Drugs continued hydrocortisone (Alkindi® Sprinkle) Eton

• 505(b)(2) NDA approval 09/29/2020; Orphan Drug • Indicated as replacement therapy in pediatric patients with adrenocortical insufficiency • Corticosteroid • Oral granules within capsules: 0.5 mg, 1 mg, 2 mg, and 5 mg • Recommended starting dose is 8 to 10 mg/m2 daily, rounded to the nearest 0.5 mg or 1 mg and divided into 3 doses to be administered 3 times daily (twice daily may be used in older patients); dose should be individualized, using the lowest possible dose » For administration, the capsule should not be swallowed; capsules are opened and granules poured directly onto the patient’s tongue, spoon, or spoonful of cold or room temperature soft food (yogurt, fruit puree) and swallowed within 5 minutes to avoid a bitter taste • Product availability is expected in 4Q 2020

atoltivimab/maftivimab/ odesivimab-ebgn (Inmazeb®) Regeneron

• BLA approval 10/14/2020; Breakthrough Therapy, Orphan Drug • Indicated for the treatment of infection caused by Zaire ebolavirus in adult and pediatric patients, including neonates born to a mother who is reverse transcriptionpolymerase chain reaction (RT-PCR) positive for Zaire ebolavirus infection; efficacy has not been established for other species of the Ebolavirus and Marburgvirus genera • Antiviral drug combination of 3 glycoprotein-directed human monoclonal antibodies • Solution for injection: 241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab-ebgn per 14.5 mL in SDV • Recommended dosage is 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab-ebgn per kg administered as an IV infusion by an HCP; the infusion duration (2 to 4 hours) is based on the patient’s body weight and prepared infusion volume • Product will be delivered, as a set number of treatment doses over 6 years, to the Biomedical Advanced Research and Development Authority (BARDA), as a component of the US Department of Health and Human Services’ preparation for public health emergencies

remdesivir (Veklury®) Gilead

• NDA approval 10/22/2020; Fast Track, Priority Review • Indicated for adults and pediatric patients (≥ 12 years of age and weighing ≥ 40 kg) for the treatment of COVID-19 requiring hospitalization; should only be administered in a hospital or a healthcare facility that can provide acute care similar to an inpatient hospital • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleotide analog ribonucleic acid (RNA) polymerase inhibitor • For injection: 100 mg lyophilized powder in SDV for reconstitution and 100 mg/20 mL solution in SDV for further dilution • Recommended dosage is 200 mg on day 1, followed by maintenance doses of 100 mg once daily; administered via IV infusion over 30 to 120 minutes for a duration of 5 days for patients not requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) with an extension of up to 10 days if no clinical improvement or if the patient requires invasive mechanical ventilation and/or ECMO

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 ivermectin (Sklice®) Arbor

• Prescription (Rx) to OTC switch 10/27/2020; product will no longer be available as a prescription drug • Indicated for adults and children ≥ 6 months of age for treating head lice • Pediculicide • Topical lotion: 0.5% in a 117 g tube • Recommended dosage is the amount required to cover hair and scalp completely, up to 1 tube » Product is applied directly to dry hair and scalp covering the scalp and hair closest to the scalp, and then applied outwards towards the ends of hair; rub lotion throughout hair; after 10 minutes, rinse completely from hair and scalp using only water (wait 24 hours before using shampoo) » Following completion of treatment, evaluate everyone in the household for lice after 1 week; consider treatment for those who have lice; this product should not be used again on the same person and same lice infestation without discussing with an HCP

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.


8 | NOVEMBER 2020 © 2020, Magellan Health. All rights reserved.

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