DECEMBER 2021
CLINICAL
ALERT YOUR MONTHLY SOURCE FOR DRUG INFORMATION HIGHLIGHTS
EDITORIAL STAFF EDITOR-IN-CHIEF Maryam Tabatabai PharmD EXECUTIVE EDITOR Anna Schreck Bird PharmD
TRENDING TOPICS
BEHAVIORAL HEALTH CORNER
COVID-19 UPDATE
DRUG INFORMATION HAPPENINGS & HIGHLIGHTS
PIPELINE NEWS
RECENT FDA APPROVALS
DEPUTY EDITORS Jessica Czechowski PharmD Lara Frick PharmD, BCPS, BCPP Carole Kerzic RPh Leslie Pittman PharmD
TRENDING TOPICS HOT TOPIC: ORAL ANTIVIRAL FOR COVID-19
BEHAVIORAL HEALTH CORNER: COVID-19
On November 30th, the US FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) reviewed Merck and Ridgeback’s EUA application for the investigational oral antiviral drug molnupiravir. The Advisory Committee voted 13 to 10 in favor of authorizing emergency use of molnupiravir for the treatment of mild-to-moderate COVID-19 in adults who have tested positive, are within 5 days of symptom onset, and are at high risk for severe COVID-19 including hospitalization or death. Molnupiravir is a potent ribonucleoside analog that acts to inhibit replication of SARS-CoV-2, the causative virus of COVID-19. Molnupiravir is a 200 mg capsule dosed as 800 mg (4 x 200 mg capsules) orally every 12 hours for 5 days (10 total doses; 40 total capsules for a course of treatment).
A randomized, placebo-controlled, adaptive platform trial was conducted in Brazil in adults with COVID-19 symptoms who were positive for SARS-CoV-2 and had a known risk factor for progression to severe disease. Patients were randomized 1:1 to fluvoxamine 100 mg twice daily (n=741) for 10 days or placebo (n=756). The primary composite endpoint was hospitalization (retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19) evaluated up to 28 days after randomization. Fewer patients in the fluvoxamine arm were hospitalized compared with placebo (11% versus 16%; relative risk, 0.68; 95% Bayesian credible interval, 0.52 to 0.88), and the probability of superiority was 99.8%, which was greater than the prespecified superiority threshold of 97.6%.
The EUA submission includes data from the analysis of the phase 3 MOVe-OUT study assessing molnupiravir in non-hospitalized adults with laboratory-confirmed mildto-moderate COVID-19 who are at risk of progressing to severe COVID-19 and/or hospitalization and had symptom onset within 5 days of randomization. The randomized, placebo-controlled, double-blind, multisite study enrolled patients with ≥ 1 risk factor associated with poor disease outcomes (e.g., obesity, age > 60 years, diabetes mellitus, or CVD). The primary efficacy endpoint was the proportion of patients who were hospitalized and/or died from randomization through day 29. At the planned interim analysis, molnupiravir decreased the risk of hospitalization or death by approximately 50% compared to placebo (28 out of 385 patients [7.3%] versus 53 out of 377 patients [14.1%], respectively; p=0.0012). In the full population analysis, all cause hospitalization or death through day 29 was reduced by 30% with molnupiravir compared to placebo (48 out of 709 patients [6.8%] versus 68 out of 699 patients [9.7%], respectively; p=0.0218). At the interim analysis, drug-related AEs occurred in a similar proportion of patients in each group (12.4% and 11.1%, respectively). Additionally, fewer patients in the molnupiravir arm discontinued study drug due to AEs (1.3% and 3.4%, respectively). 2 | DECEMBER 2021
COVID-19: NOTABLE DEVELOPMENTS The FDA has amended the EUAs for the Pfizer/Biontech and Moderna COVID-19 vaccines allowing a single booster dose for all persons ≥ 18 years old following primary vaccination with any FDA-authorized or approved COVID-19 vaccine. The CDC has endorsed ACIPs’ recommendations for booster shots for all adults ≥ 18 years old who received a Pfizer/Biontech or Moderna COVID-19 vaccine ≥ 6 months after their second dose. Additionally, the CDC has updated their Interim Clinical Considerations for select moderately and severely immunocompromised adults who have received a 2-dose mRNA primary series and an additional dose should receive a single COVID-19 booster dose ≥ 6 months after the third mRNA vaccine dose. The FDA has delayed a decision on EUA of Moderna’s COVID-19 vaccine in 12 to 17 years old until January 2022. 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.
DRUG INFORMATION
HAPPENINGS & HIGHLIGHTS • Oncopeptides has announced withdrawal of the alkylating drug melphalan flufenamide (Pepaxto®) from commercialization in the US. In July 2021, the FDA communicated to patients and HCPs that the OCEAN study showed an increased risk of death with melphalan flufenamide compared to pomalidomide. The withdrawal is based on findings from this phase 3 study, a post-approval requirement, that found a hazard ratio of 1.104 for overall survival. Melphalan flufenamide received Accelerated Approval in February of 2021, in combination with dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma (MM) who had received ≥ 4 prior lines of therapy and whose disease was refractory to ≥ 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. The manufacturer plans to collaborate with the FDA to allow the agent to be available for patients currently taking it.
• The FDA has approved the first generic versions to Celgene’s Revlimid®, lenalidomide. Dr. Reddy’s received approval for the strengths of 2.5 mg and 20 mg, and Watson received approval in May 2021 for the 5 mg, 10 mg, 15 mg, and 25 mg strengths. Revlimid is a thalidomide analogue indicated for certain patients with the following: MM, transfusion-dependent anemia due to myelodysplastic syndromes, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma.
• The FDA has reported that brand-name meloxicam (Mobic®) will be discontinued by the manufacturer, Boehringer Ingelheim. Generic versions of the NSAID will remain available.
• Pancrelipase (Pancreaze®) has received FDA-approval in the strength of 37,000 USP lipase units; the drug is indicated for exocrine pancreatic insufficiency due to CF or other conditions.
• The first generic to Recordati Rare Diseases’ Carbaglu®, carglumic acid, from Novitium has received FDA-approval.Carglumic acid is a tablet for oral suspension indicated as acute adjunctive therapy and chronic maintenance therapy for hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency. It is also indicated as adjunctive therapy for acute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA).
DRUG INFORMATION HAPPENINGS • The American Academy of Neurology (AAN) has published a practice guideline on the use of dopaminergic therapy for motor symptoms in early-stage Parkinson disease. • The American Gastroenterological Association (AGA) assembled a multidisciplinary task force and published a Clinical Care Pathway on risk stratification of patients with nonalcoholic fatty liver disease (NAFLD) and appropriate management strategies. • The US Preventive Services Task Force (USPSTF) has published a report describing the USPSTF’s approach and methods for addressing sex and gender in clinical preventive services recommendations; the report expands on prior methods used for the development of evidence-based recommendations in diverse populations.
PIPELINE
NEWS
UPCOMING PRESCRIPTION DRUG/BIOSIMILAR USER FEE ACT (PDUFA/BsUFA) DATES DRUG NAME MANUFACTURER
FORMULATION THERAPEUTIC CLASS
PROPOSED CLINICAL USE
ANTICIPATED FDA APPROVAL
adalimumab (biosimilar for Abbvie’s Humira®) Coherus
• SC • TNF-α inhibitor
AS; CD; JIA; PSO; PsA; RA
December 2021
clindamycin phosphate gel Daré
• Intravaginal • Lincosamide antibiotic
Bacterial vaginosis
12/07/2021
budesonide, long-acting Calliditas
• Oral • Glucocorticosteroid
Immunoglobulin A nephropathy (Berger’s disease)
12/15/2021
efgartigimod Argenx
• IV • Neonatal Fc receptor antagonist
Myasthenia gravis
12/17/2021
diazepam film Aquestive
• Oral transmucosal • Benzodiazepine
Seizure clusters
12/23/2021
tadalafil/finasteride Veru
• Oral • PDE-5 inhibitor/5α-reductase inhibitor
Benign prostatic hyperplasia
12/23/2021
inclisiran Novartis
• SC • Small interfering RNA (siRNA) cholesterol lowering therapy
Hypercholesterolemia (2nd-line)
12/31/2021
levoketoconazole Xeris
• Oral • Steroidogenesis inhibitor
Cushing’s syndrome
12/31/2021
dexmedetomidine Bioxcel
• Oral • Selective alpha-2 adrenoreceptor agonist sedative
Agitation associated with bipolar disorder or schizophrenia
01/05/2022
carbetocin Levo
• Intranasal • Oxytocic
Prader-Willi syndrome-related hyperphagia and behavioral distress
01/06/2022
daridorexant Idorsia
• Oral • Dual orexin receptor (OX1R and OX2R) antagonist
Insomnia
01/07/2022
4 | DECEMBER 2021
RECENT FDA
APPROVALS DRUG NAME MANUFACTURER
DESCRIPTION
New Drugs pilocarpine HCl (Vuity™) Allergan
asciminib (Scemblix®) Novartis
• • • • • •
505(b)(2) NDA approval 10/28/2021; Standard Review Indicated for the treatment of presbyopia in adults Cholinergic muscarinic receptor agonist Ophthalmic solution: 1.25% Recommended dosage is 1 drop instilled into each eye once daily Product availability is expected by the end of 2021
• NDA approval 10/29/2021; Accelerated Approval, Assessment Aid, Breakthrough Therapy, Fast Track, Orphan Drug, Priority Review, Real-Time Oncology Review (RTOR) • Indicated for the treatment of adults with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with ≥ 2 tyrosine kinase inhibitors (TKIs) (Accelerated Approval based on major molecular response [MMR]; continued approval may require demonstration of benefit in confirmatory clinical trials); and Ph+ CML in CP with the T315I mutation • ABL/BCR-ABL1 tyrosine kinase inhibitor (STAMP inhibitor) • Film-coated oral tablet: 20 mg and 40 mg • Recommended dosage for Ph+ CML in CP is based on the presence of T315I mutation, and all doses should be swallowed whole, avoiding food ≥ 2 hours before and 1 hour after taking asciminib: » Ph+ CML in CP: 80 mg once daily or 40 mg twice daily » Ph+ CML in CP with T315I mutation: 200 mg twice daily
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.
RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER
DESCRIPTION
New Drugs continued amphetamine (Dyanavel® XR) Tris
• 505(b)(2) NDA approval 11/04/2021; Standard Review • Indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients ≥ 6 years of age • CNS stimulant • Extended-release oral tablet: 5 mg (functionally scored), 10 mg, 15 mg, and 20 mg; already available as a 2.5 mg/mL oral suspension • Recommended dosage is 2.5 mg or 5 mg once daily in the morning with or without food, titrated as needed in 2.5 mg to 10 mg daily increments every 4 to 7 days to a maximum daily dose of 20 mg • Boxed warning for abuse and dependence • Product availability is expected in 1Q 2022
topiramate (Eprontia™) Azurity
• 505(b)(2) NDA approval 11/05/2021; Standard Review • Indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients ≥ 2 years of age; adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome in patients ≥ 2 years of age; and for the preventive treatment of migraine in patients ≥ 12 years of age • Anticonvulsant • Oral solution: 25 mg/mL • Recommended dosage varies by indication, renal function, and age; see full product labeling for details » Epilepsy monotherapy in patients ≥ 10 years of age: 400 mg/day in 2 divided doses following a 6-week titration beginning at 25 mg twice daily and increasing by 25 to 50 mg/day in weekly intervals » Epilepsy monotherapy in patients 2 to 9 years of age: weight-based maintenance dose target range of 150 to 400 mg/day in 2 equally divided doses following a titration beginning at 25 mg once in the evening and increasing by 25 to 50 mg/day in weekly intervals over 5 to 7 weeks » Adjunctive epilepsy therapy in patients ≥ 17 years of age: target dosing varies by epilepsy type, with a range of 200 to 400 mg/day in 2 divided doses following a titration beginning at 25 to 50 mg/day and increasing by 25 to 50 mg/day in weekly intervals » Adjunctive epilepsy therapy in patients 2 to 16 years of age: weight-based maintenance dose target range of approximately 5 to 9 mg/kg/day in 2 divided doses following a titration beginning at 25 mg/day (or less with range of 1 to 3 mg/kg/day) nightly and increasing by 1 to 3 mg/kg/day in 1 or 2 week intervals » Preventive treatment of migraine: maintenance dose of 100 mg/day in 2 divided doses following a 4-week titration beginning at 25 mg once in the evening and increasing by 25 mg/day in weekly intervals
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 | DECEMBER 2021
RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER
DESCRIPTION
New Drugs continued carbidopa/levodopa (Dhivy) Riverside
• 505(b)(2) NDA approval 11/12/2021; Standard Review • Indicated for the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication in adults • Decarboxylase inhibitor/dopamine precursor • Oral tablet: 25 mg/100 mg (functionally scored into 6.25 mg/25 mg increments) • Recommended dosage is 1 tablet (25 mg/100 mg) 3 times a day with or without food; may be increased by 1 tablet per day or every other day to a maximum dose of 8 tablets/day, as needed
ropeginterferon alfa2b-njft (Besremi®) PharmaEssentia
• • • • •
vosoritide (Voxzogo™) Biomarin
BLA approval 11/12/2021; Orphan Drug Indicated for the treatment of adults with polycythemia vera Interferon alfa-2b SC injection: 500 mcg/mL solution in a single-dose prefilled syringe Recommended dosage is 100 mcg by SC injection every 2 weeks (50 mcg if receiving hydroxyurea) initially, increasing the dose by 50 mcg every 2 weeks up to a maximum of 500 mcg until hematological parameters are stabilized; can be administered by an HCP or a patient/caregiver, if determined appropriate, following proper training; CBCs should be monitored every 2 weeks during the titration and dose modification phases; phlebotomy may be needed as rescue treatment to normalize blood hyperviscosity • Boxed warning for risk of serious disorders (e.g., neuropsychiatric, autoimmune, ischemic, infectious disorders) • NDA approval 11/19/2021; Accelerated Approval, Orphan Drug, Priority Review, Rare Pediatric Disease Priority Review designation • Indicated to increase linear growth in pediatric patients with achondroplasia who are ≥ 5 years old with open epiphyses; Accelerated Approval was based on an improvement in annualized growth velocity; therefore, continued approval may require demonstration of benefit in confirmatory clinical trials • C type natriuretic peptide (CNP) analog • SC injection: 0.4 mg, 0.56 mg, or 1.2 mg of lyophilized powder in a SDV for reconstitution • Recommended dosage is based on the patient’s actual body weight and is administered via SC injection once daily by caregivers following proper training from an HCP; to decrease the potential for low blood pressure, the patient should have adequate food intake before administration and drink 240 to 300 mL of fluid in the hour before administration; body weight, growth, and physical development should be evaluated every 3 to 6 months with adjustments of the dose based on actual body weight; therapy should be permanently discontinued once closure of epiphyses occurs
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 | DECEMBER 2021
RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER
DESCRIPTION
New Drugs continued baclofen (Lyvispah™) Saol
• 505(b)(2) NDA approval 11/22/2021; Standard Review • Indicated for the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity; it may also be of some value in patients with spinal cord injuries and other spinal cord diseases • It is not indicated for the treatment of skeletal muscle spasm resulting from rheumatic disorders • Gamma-aminobutyric acid (GABA)-ergic agonist • Oral granules: 5 mg, 10 mg, or 20 mg in packets • Recommended dosage is to initiate therapy with a low dosage, preferably in divided doses; the dose can be increased gradually based on clinical response and tolerability to a maximum dosage of 80 mg daily (20 mg four times a day); the granules can be mixed with soft food for administration within 2 hours or can be administered via enteral feeding tubes and can be taken with or without water; when treatment is discontinued, slowly decrease the dose
sirolimus proteinbound particles (Fyarro™) Aadi
• 505(b)(2) NDA approval 11/22/2021; Orphan Drug, Priority Review • Indicated for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa) • Mechanistic target of rapamycin kinase (mTOR) inhibitor • Injectable suspension: lyophilized powder containing 100 mg of sirolimus formulated as albumin-bound particles in a SDV for reconstitution • Recommended dosage is 100 mg/m2 IV over 30 minutes by an HCP on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity • Product availability is expected in 1Q 2022
maribavir (Livtencity™) Takeda
• NDA approval 11/23/2021; Breakthrough Therapy, Orphan Drug, Priority Review • Indicated for the treatment of adults and pediatric patients (≥ 12 years old and weighing ≥ 35 kg) with post-transplant cytomegalovirus (CMV) infection/ disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet • CMV pUL97 kinase inhibitor, antiviral drug against human CMV • Oral tablet: 200 mg • Recommended dosage is 400 mg (two 200 mg tablets) twice daily with or without food
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 | DECEMBER 2021
Glossary: ACIP Advisory Committee on Immunization Practices
COVID-19 Coronavirus Disease 2019
mRNA messenger ribonucleic acid
AE adverse event
CVD cardiovascular disease
NIH National Institutes of Health
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 SC subcutaneous
AS ankylosing spondylitis
EUA Emergency Use Authorization
NSAID nonsteroidal antiinflammatory drug
SDV single-dose vial
CBC complete blood count
FDA Food and Drug Administration
PDE-5 phosphodiesterase 5
TNF tumor necrosis factor
CD Crohn’s disease
HCl hydrochloride
PSO plaque psoriasis
US United States
CDC Centers for Disease Control and Prevention
HCP healthcare professional
PsA psoriatic arthritis
USP United States Pharmacopeia
CF cystic fibrosis
IV intravenous
RA rheumatoid arthritis
WHO World Health Organization
JIA juvenile idiopathic arthritis
RNA ribonucleic acid
CNS central nervous system
References:
cdc.gov
9 | DECEMBER 2021
clinicaltrials.gov
fda.gov
thelancet.com
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