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DECEMBER 2020

CLINICAL

ALERT YOUR MONTHLY SOURCE FOR DRUG INFORMATION HIGHLIGHTS

EDITORIAL STAFF EDITOR IN CHIEF Maryam Tabatabai PharmD

TRENDING TOPICS

BEHAVIORAL HEALTH CORNER

COVID-19 UPDATE

DRUG INFORMATION HAPPENINGS & HIGHLIGHTS

PIPELINE NEWS

RECENT FDA APPROVALS

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 EUAs FOR COVID-19 TREATMENTS The United States (US) Food and Drug Administration (FDA) has issued Emergency Use Authorizations (EUAs) for Lilly’s bamlanivimab and for Regeneron’s casirivimab and imdevimab for the treatment of mild to moderate coronavirus disease 2019 (COVID-19). All products are investigational monoclonal antibodies that bind to the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) spike protein and block the spike protein from attaching to the human angiotensin-converting enzyme 2 (ACE2) receptor. The EUAs allow for use of bamlanivimab or casirivimab and imdevimab (administered together) for patients with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19 and/or hospitalization. For bamlanivimab, the EUA authorizes use in adults and pediatric patients who are ≥ 12 years of age weighing ≥ 40 kg, whereas EUA for the combination of casirivimab and imdevimab authorizes for use in adults and pediatric patients (≥ 12 years of age weighing ≥ 40 kg). These agents share the same limitations of authorized use and are not authorized for use in the following patients: those who are hospitalized due to COVID-19, those who require oxygen therapy due to COVID-19, and those who require an increase in baseline oxygen flow rate due to COVID-19 in patients on chronic oxygen because of a non-COVID-19 related condition. Notably, a benefit with these agents has not been seen in patients hospitalized for COVID-19 infection. The authorized use of bamlanivimab is based on interim results from an ongoing, randomized, doubleblind, placebo-controlled, phase 2 study (BLAZE-1) performed in outpatients with mild to moderate COVID-19. Bamlanivimab decreased hospitalization or emergency room visits that were related to COVID-19 in high-risk patients within 28 days after administration compared to placebo. Similarly, the authorized use of casirivimab 2 | DECEMBER 2020

and imdevimab is based on phase 1 and 2 data from an ongoing, randomized, double-blind, placebo-controlled trial assessing the cocktail or placebo in non-hospitalized adults with mild to moderate COVID-19 symptoms. The combination decreased hospitalization or emergency room visits that were related to COVID-19 in highrisk patients within 28 days following administration compared to placebo. Bamlanivimab is administered as a single intravenous (IV) infusion of 700 mg over ≥ 60 minutes. For casirivimab and imdevimab, the optimal dosing regimen has not yet been established; therefore, the recommended dosing regimen may be updated as data emerges. The current recommended dosage is 1,200 mg of casirivimab and 1,200 mg of imdevimab administered together as a single IV infusion over ≥ 60 minutes. All 3 agents should be given as soon as possible following a positive viral test for SARS-CoV-2 and within 10 days of symptom onset. These drugs can only be administered in settings where healthcare professionals (HCPs) have immediate access to drugs for treating severe infusion reactions, including anaphylaxis. Additionally, the ability to activate the emergency medical system (EMS) is required. Patients should be monitored during the infusion and for ≥ 1 hour following completion. Following receipt, patients should continue to follow infection control measures and self-isolate. These products will be supplied by their respective manufacturers to authorized distributors for dispersal to healthcare facilities or HCPs, as determined by the US government. The FDA has also issued a separate EUA for the oral Janus kinase (JAK) inhibitor baricitinib (Olumiant®; FDAapproved for select patients with rheumatoid arthritis). Baricitinib is now authorized for use, in combination with IV remdesivir (Veklury®), for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized adults and pediatric patients ≥ 2 years of age that require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).


TRENDING TOPICS continued BEHAVIORAL HEALTH CORNER: COVID-19 AND PSYCHIATRIC DIAGNOSES A retrospective cohort study was conducted utilizing data from an electronic health record (EHR) network of more than 69 million patients across 54 US healthcare organizations. A total of 62,354 patients had received a diagnosis of COVID-19. It was evaluated as to whether a diagnosis of COVID-19 was associated with an increased likelihood of psychiatric diagnoses. Additionally, authors assessed if patients with a history of psychiatric conditions had a higher likelihood for a COVID-19 diagnosis. Propensity score matching was used to control for confounding variables such as risk factors for COVID-19. In this retrospective study of EHRs, a diagnosis of COVID-19 in patients (with no prior psychiatric history) was associated with an increased likelihood (p<0.0001 for all) of a first psychiatric diagnosis within 14 to 90 days as compared to 6 other health events (influenza, other respiratory tract infections, skin infection, cholelithiasis, urolithiasis, and large bone fracture). Furthermore, between 14 and 90 days following COVID-19 diagnosis, the estimated incidence for COVID-19 survivors having a first psychiatric diagnosis was 5.8% (95% confidence interval [CI], 5.2 to 6.4) as compared with 2.5% to 3.4% of patients in the other cohorts. Notably, a psychiatric diagnosis in the prior year was associated with a higher likelihood for COVID-19 diagnosis (relative risk, 1.65; 95% CI, 1.59 to 1.71; p<0.0001).

COVID-19: NOTABLE DEVELOPMENTS Pfizer and BioNTech have released study results from their phase 3 study evaluating their investigational vaccine, BNT162b2, for prevention of COVID-19. The vaccine utilizes a novel messenger RNA (mRNA) platform. The study is a multinational, randomized, placebo-controlled study in which participants receive 2 doses of the investigational vaccine or placebo with doses separated by 21 days. As the study was event-driven, it relied on the proportion of COVID-19 disease cases that were experienced by participants in the vaccine study arm compared to placebo. Based on the analysis of 170 confirmed cases with 162 cases occurring

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in placebo participants and 8 cases in those who received the vaccine, the primary efficacy analysis found BNT162b2 was 95% effective starting 7 days after the second dose (p<0.0001). This analysis was conducted in participants without prior evidence of SARS-CoV-2 infection. Furthermore, efficacy was demonstrated across various patient demographics (age, gender, race, ethnicity). Additionally, 9 of the 10 severe cases that occurred during the study were in the placebo group and 1 was in the vaccinated group. The Data Monitoring Committee (DMC) has not reported any serious safety concerns related to the vaccine, and the vaccine appears to be well tolerated. The manufacturers are planning to submit results from the completed phase 3 study (n=43,661) for publication in a peer-reviewed journal. Submission for EUA to the FDA was completed in November 2020. The FDA has planned a meeting of its Vaccines and Related Biological Products Advisory Committee (VRBPAC) for December 10, 2020 to review the request for EUA for this vaccine. Moderna has also released findings from the primary efficacy analysis of their mRNA-based COVID-19 vaccine candidate, mRNA-1273. The phase 3 COVE study has enrolled more than 30,000 US participants and has demonstrated a vaccine efficacy of 94.1%. This analysis was based on 196 COVID-19 cases (185 in the placebo group; 11 in the mRNA-1273 group). The analysis was of COVID-19 cases confirmed beginning 2 weeks after the second vaccine dose. Efficacy was similar across various demographic groups. Additionally, 30 severe cases, all of which occurred in the placebo arm, were reported. The vaccine was generally well tolerated and no serious safety issues have been found. The FDA’s VRBPAC will review Moderna’s EUA application on December 17, 2020. Study findings will be submitted for peerreviewed publication. For more resources on COVID-19, visit the Magellan Rx Coronavirus Update webpage. For the most current information, visit the FDA, the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the World Health Organization (WHO) websites. State and local health departments also provide valuable information regarding management in local communities.


DRUG INFORMATION

HAPPENINGS & HIGHLIGHTS • The FDA is requiring labeling changes for all prescription (Rx) and over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs) regarding the risk for rare but serious kidney problems in fetuses that can lead to low amniotic fluid levels. NSAID use should be avoided at 20 weeks or later in pregnancy; if determined to be necessary by an HCP, use should be limited (lowest dose, shortest duration) between 20 to 30 weeks of pregnancy due to this risk. Warnings to avoid NSAIDs after about 30 weeks of pregnancy are already included in the labeling due to the potential for fetal cardiac risks.

• The FDA has issued a communication to clarify the intent of the November 2019 revisions to labeling for insulin pens advising that insulin pens should be dispensed to a single patient in the original sealed carton. Sealed insulin pen cartons are designed to be dispensed to 1 patient, as each carton contains only 1 copy of the package insert (PI) and Instructions for Use. This results in insulin pens not being labeled for dispensing as individual units. However, the FDA notes there may be circumstances where HCPs may decide to dispense individual pens, and when this occurs, additional safety measures should be instituted.

• The Institute for Clinical and Economic Review (ICER) has announced the launch of the ICER Interactive Modeler™. This cloud-based program will allow international health technology assessment (HTA) agencies to use ICER’s economic models to assess the cost-effectiveness of various drug therapies. The modeler is a component of ICER Analytics™, a new cloud-based platform that allows for the use of ICER’s evidence reports. The initial model will focus on remdesivir and other COVID-19 therapies and will later be expanded to other areas. The assumptions and inputs used can be customized.

• Nostrum issued a voluntary recall of 2 lots of metformin hydrochloride (HCl) extended release (ER) tablets, USP 500 mg and 2 lots of metformin HCl ER tablets, USP 750 mg to the consumer level due to nitrosamine impurities (N-Nitrosodimethylamine [NDMA]) above the acceptable daily intake limit. • Sunstar Americas has issued a voluntary recall of specific lots of chlorhexidine gluconate oral rinse USP, 0.12% (Paroex®) with an expiration date of 6/30/22 to 9/30/22. The recall is to the consumer level and is because product may contain a bacterial contaminant, Burkholderia lata.

DRUG INFORMATION HAPPENINGS • The International Antiviral Society–USA Panel has published 2020 recommendations on the use of antiretroviral drugs for treatment and prevention of human immunodeficiency virus (HIV) infection in adults. • Kidney Disease: Improving Global Outcomes (KDIGO) has published a clinical practice guideline on the management of diabetes in chronic kidney disease (CKD). This is the first KDIGO guideline on this subject. • The FDA has issued final guidance for industry on the development of drugs for treating opioid use disorder (OUD) entitled, “Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Treatment.” • The Infectious Diseases Society of America (IDSA) has published clinical guidance on the treatment of antimicrobial resistant gram-negative bacterial infections.

4 | DECEMBER 2020


PIPELINE

NEWS

UPCOMING PRESCRIPTION DRUG/BIOSIMILAR USER FEE ACT (PDUFA/BsUFA) DATES DRUG NAME MANUFACTURER

FORMULATION THERAPEUTIC CLASS

PROPOSED CLINICAL USE

ANTICIPATED FDA APPROVAL

margetuximab Macrogenics

• IV • Anti-human epidermal growth factor receptor 2 (HER2) antibody

Breast cancer (HER2+)

12/18/2020

rituximab (biosimilar to Genentech’s Rituxan®) Amgen/Allergan

• IV • Anti-CD20 antibody

Inflammatory conditions; Specific cancers

12/18/2020

roxadustat AstraZeneca

• Oral • Hypoxia-inducible factor stabilizer

Anemia due to chronic renal failure

12/18/2020

relugolix Myovant

• Oral • Gonadotropin-releasing hormone (GnRH) antagonist

Prostate cancer

12/20/2020

ansofaxine Luye

• Oral • Norepinephrine-dopamine reuptake inhibitor/serotoninnorepinephrine reuptake inhibitor

Major depressive disorder

12/25/2020

bevacizumab (biosimilar to Genentech’s Avastin®) Mylan/Biocon

• IV • Vascular endothelial growth factor (VEGF) inhibitor

Brain cancer; Cervical cancer; Colorectal cancer; Non-small cell lung cancer; Ovarian cancer; Renal cell carcinoma

12/25/2020

vibegron Urovant

• Oral • Beta-adrenergic agonist

Overactive bladder

12/25/2020

arbaclofen extendedrelease Osmotica

• Oral • Gamma-aminobutyric acid (GABA) receptor agonist

Multiple sclerosis-related spasticity

12/29/2020

furosemide wearable pump scPharmaceuticals

• SC • Diuretic

Congestive heart failure

12/30/2020

tirbanibulin Almirall

• Topical • Tubulin and Src kinase inhibitor

Actinic keratoses

12/30/2020

IV = intravenous; SC = subcutaneous


RECENT FDA

APPROVALS DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs loteprednol etabonate (Eysuvis™) Kala

• 505(b)(2) NDA approval 10/26/2020 • Indicated for the short-term (up to 2 weeks) treatment of the signs and symptoms of dry eye disease • Corticosteroid • Ophthalmic suspension: 0.25% (2.5 mg/mL) strength 8.3 mL in a 10 mL bottle • Recommended dosage is 1 to 2 drops instilled into each eye 4 times daily; shake for 2 to 3 seconds before using • Product availability is expected by the end of 4Q 2020

mannitol (Bronchitol®) Chiesi

• 505(b)(2) NDA approval 10/30/2020; Orphan Drug • Indicated for add-on maintenance therapy to improve pulmonary function in adults with cystic fibrosis; use only in adults who have passed the Bronchitol tolerance test • Sugar alcohol • Powder capsule for inhalation: 40 mg, supplied with inhaler that is discarded and replaced every 7 days • Recommended dosage is 400 mg (10 capsules) inhaled orally twice daily (morning and evening); administer evening dose 2 to 3 hours prior to bedtime • Product availability is expected in March 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.

6 | DECEMBER 2020


RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs continued fosphenytoin sodium (Sesquient™) Sedor

• 505(b)(2) NDA approval 11/05/2020 • Indicated for the treatment of tonic-clonic status epilepticus in adults, prevention and treatment of seizures occurring during neurosurgery in adults, and short-term substitution for oral phenytoin in patients ≥ 2 years of age when oral phenytoin administration is not possible • Hydantoin derivative • Solution for injection: 50 mg phenytoin sodium equivalents (PE)/mL in 2 mL and 100 mg single-dose vial (SDV); stable at room temperature • Recommended dosage is expressed as PE » Status epilepticus: loading dose of 15 to 20 mg PE/kg at a rate of 100 to 150 mg PE/minute » Non-emergent loading and initial maintenance doses: ₀ Adults – 10 to 20 mg PE/kg IV loading dose with maintenance of 4 to 6 mg PE/kg/day in divided doses ₀ Pediatrics – 10 to 15 mg PE/kg IV loading dose with maintenance of 2 to 4 mg PE/kg every 12 hours; do not exceed 0.4 mg PE/kg/minute due to betadex sulfobutyl ether sodium content • Boxed warning for cardiovascular risk associated with rapid infusion rates; therefore, administration should not exceed 150 mg PE/minute in adults

sodium sulfate, magnesium sulfate, potassium chloride (Sutab®) Braintree

• 505(b)(2) NDA approval 11/10/2020; Orphan Drug (pediatric population) • Indicated for cleansing of the colon in preparation for colonoscopy in adults • Osmotic laxative • Oral fixed-dose tablet: 1.479 g sodium sulfate, 0.225 g magnesium sulfate, 0.188 g potassium chloride • Recommended dosage is 2 oral doses of 12 tablets per dose; 1st dose taken the evening before the procedure and the 2nd dose taken the morning of the procedure; water must be consumed before and after each dose • Product availability is expected on January 1, 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.


RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs continued lonafarnib (Zokinvy™) Eiger

• NDA approval 11/20/2020; Breakthrough Therapy, Orphan Drug, Priority Review • Indicated in patients ≥ 12 months of age with a body surface area (BSA) of ≥ 0.39 m2: » To reduce the risk of mortality in Hutchinson-Gilford progeria syndrome (HGPS) » For the treatment of processing-deficient progeroid laminopathies with either: 1) heterozygous LMNA gene mutation with progerin-like protein accumulation or 2) homozygous or compound heterozygous ZMPSTE24 mutations • Not indicated for other progeroid syndromes or processing-proficient progeroid laminopathies as it would likely not be effective in these populations • Farnesyltransferase inhibitor • Capsules: 50 mg, 75 mg • Recommended dosage is initiated at 115 mg/m2 twice daily with morning and evening meals to decrease the risk of gastrointestinal (GI) adverse effects; following 4 months of treatment, increase to 150 mg/m2 twice daily with morning and evening meals; total daily doses should be rounded to the nearest 25 mg increment; if the patient cannot swallow whole capsules, the contents can be mixed with Ora Blend SF®, Ora-Plus®, orange juice, or applesauce and taken within 10 minutes of preparing

baloxavir marboxil (Xofluza®) Genentech

• NDA approval 11/23/2020; new oral suspension formulation; product is currently available as an oral tablet • Indicated for the treatment of acute uncomplicated influenza in patients ≥ 12 years old who have been symptomatic for no more than 48 hours and who are otherwise healthy, or at high risk of developing influenza-related complications; baloxavir marboxil is also indicated for post-exposure prophylaxis of influenza in persons ≥ 12 years old following contact with an individual who has influenza • Influenza virus polymerase acidic (PA) endonuclease inhibitor • Granules for oral suspension: 40 mg/20 mL, requires constitution prior to dispensing • Recommended dosage for oral suspension for both indications is based on the patient’s body weight (< 80 kg: 40 mg/20 mL [1 bottle]; ≥ 80 kg: 80 mg/40 mL [2 bottles]) taken as a single dose as soon as possible and within 48 hours of influenza symptom onset or exposure to influenza; may be taken with or without food; administration of the suspension should occur within 10 hours after constitution as the product does not contain a preservative

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 2020


RECENT FDA APPROVALS continued DRUG NAME MANUFACTURER

DESCRIPTION

New Drugs continued lumasiran (Oxlumo™) Alnylam

• NDA approval 11/23/2020; Breakthrough Therapy, Orphan Drug, Priority Review, Rare Pediatric Disease Designation • Indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients • Hydroxyacid oxidase 1 (HAO1)-directed small interfering ribonucleic acid (siRNA) • Injection: 94.5 mg/0.5 mL in a SDV • Recommended dosage is based on actual body weight administered as a SC injection by an HCP; maintenance doses are started 1 month following the last loading dose » weight < 10 kg: loading dose of 6 mg/kg once monthly for 3 doses, followed by maintenance doses of 3 mg/kg once monthly » weight 10 kg to < 20 kg: loading dose of 6 mg/kg once monthly for 3 doses, followed by maintenance doses of 6 mg/kg once every 3 months » weight ≥ 20 kg: loading dose of 3 mg/kg once monthly for 3 doses, followed by maintenance doses of 3 mg/kg once every 3 months • Product availability is expected by end of 2020

naxitamab-gqgk (Danyelza®) Y-mAbs Therapeutics

• BLA approval 11/25/2020; Accelerated Approval, Assessment Aid, Breakthrough Therapy, Orphan Drug, Priority Review, Rare Pediatric Disease Designation, Real-Time Oncology Review (RTOR) • Indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients ≥ 1 year old and adults with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response (PR), minor response, or stable disease to prior therapy; continued approval may require demonstration of benefit in confirmatory clinical trials • GD2-binding monoclonal antibody • Injection: 40 mg/10 mL (4 mg/mL) solution in a SDV • Recommended dosage is 3 mg/kg/day (up to 150 mg/day) on days 1, 3, and 5 of each treatment cycle via IV infusion by an HCP; given in combination with SC GM-CSF (dosing regimen detailed in the PI) with treatment cycles repeated every 4 weeks until complete response or PR, followed by 5 additional cycles every 4 weeks; subsequent cycles can be repeated every 8 weeks; discontinue naxitamab-gqgk and GM-CSF for disease progression or unacceptable toxicity; pre-infusion medications and supportive treatment during the infusion should be given, as appropriate • Boxed warning for serious infusion-related reactions and neurotoxicity • Product availability is expected in the coming weeks

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 setmelanotide (Imcivree™) Rhythm

• NDA approval 11/25/2020; Breakthrough Therapy, Orphan Drug, Priority Review • Indicated for chronic weight management in adult and pediatric patients ≥ 6 years old with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/ kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in these genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance • Not indicated for the treatment of patients with the following conditions as it would not be expected to be effective: » Obesity due to suspected POMC-, PCSK1-, or LEPR-deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign » Other types of obesity not related to these deficiencies, including obesity associated with other genetic syndromes and general (polygenic) obesity • Melanocortin 4 (MC4) receptor agonist • Injection: 10 mg/mL solution in a 1 mL multiple-dose vial • Recommended dosage is initially 2 mg SC once daily for 2 weeks for adults and pediatric patients ≥ 12 years old (maintenance dose range, 1 mg to 3 mg once daily) and 1 mg SC once daily for 2 weeks for pediatric patients 6 years to < 12 years old (maintenance dose range, 0.5 mg to 3 mg once daily); monitor for GI adverse effects, and titrate the dose based on tolerability and desired weight loss • 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.

References:

fda.gov

10 | DECEMBER 2020

lancet.com

lilly.com

modernatx.com

pfizer.com

regeneron.com

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