MRx Clinical Alert - April 2022

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APRIL 2022










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



The American Academy of Neurology (AAN) has published an Evidence in Focus report on the use of aducanumab-avwa (Aduhelm™) in symptomatic Alzheimer’s disease (AD). In June 2021, the FDA granted Accelerated Approval to the anti-amyloid therapy for treating patients with AD. Accelerated Approval was based on a surrogate endpoint of reduction in amyloid beta plaques. In July 2021, the indication for use was revised to specify that treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease. The amyloid betadirected antibody is administered every 4 weeks as a weight-based 10 mg/kg IV infusion following titration. Although the agent targets neuropathologic changes seen in AD, it has not yet shown clinically significant decline in cognitive function.

The FDA has released an alert to HCPs on the potential risks of compounded ketamine nasal spray. From April 2011 to January 2022, five cases of psychiatric events (delusion, dissociation, hallucination, panic attack, abuse/misuse) were identified after use of compounded ketamine nasal spray. Although ketamine is not FDAapproved for treating any psychiatric disorders, the “S” form of ketamine (esketamine [Spravato®]) received FDA-approval in 2019 as a nasal spray formulation for certain adult patients with depression. Due to serious risks, esketamine carries a Boxed Warning and is only available through the Spravato REMS. The intent of the FDA’s alert is to raise awareness regarding the risks of compounded ketamine nasal spray for home use, especially because a safe and effective dosage regimen for psychiatric use has not been determined.

AAN identified four clinical studies: one Class I level evidence (low risk of bias) and three Class II level evidence (moderate risk of bias). The Class I study was an ascendingdose study and demonstrated that single doses of up to 30 mg/kg were safe and well tolerated. Although the 3 Class II studies showed that aducanumab-avwa reduced amyloid deposition compared to placebo based on brain PET at 1 year, data evaluating clinical efficacy were mixed depending on the dose and the endpoint. Compared to placebo, aducanumab-avwa showed no change or a slower decline in CDR Sum-of-Boxes score that was of uncertain clinical significance. Furthermore, the agent carries a Warning/Precaution for amyloid-related imaging abnormalities (ARIA) that were observed in about 40% of aducanumab-treated patients, compared with 10% of patients receiving placebo. The evidence report details the populations indicated for use compared to the patients enrolled in the clinical studies. There are no contraindications to use on the FDA-approved label but a number of exclusions in the clinical studies (e.g., bleeding disorders, past brain hemorrhage, antiplatelets other than daily aspirin). Other concerns covered in the report include infrastructure demand, as well as duration of therapy. Notably, CMS will announce its final coverage determination for aducanumab-avwa by April 11, 2022.


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The FDA has authorized a second booster dose of either mRNA COVID-19 vaccine, Pfizer-Biontech or Moderna, for people ≥ 50 years old and certain immunocompromised individuals. The White House has announced the launch of a “One-Stop-Shop” website to find where to access vaccines, tests, treatments, and high-quality masks. The website also includes a tool to locate > 2,000 test-to-treat sites (e.g., pharmacy-based clinics) for outpatient testing and treatment. The CDC has added considerations for an 8-week interval between the primary doses of an mRNA vaccine for those 12 to 64 years old, especially for males 12 to 39 years old. The risk of myocarditis is higher for males this age and may be decreased by extending the interval between the first 2 doses. The FDA has revised the EUA for the pre-exposure prophylaxis combination of tixagevimab co-packaged with cilgavimab (Evusheld™) to update the initial dose to 300 mg IM of each component due to the potential for decreased activity against certain Omicron subvariants. Previously, the initial dose was 150 mg of each component; those who received this dose should receive an additional 150 mg dose of each component as soon as possible. Please refer to the COVID-19 disclaimer at the end of the publication.


HAPPENINGS & HIGHLIGHTS • The FDA has approved Mylan’s first generic version of budesonide and formoterol fumarate dihydrate (AstraZeneca’s Symbicort®) inhalation aerosol. The product is indicated for treating asthma in patients ≥ 6 years old as well as for the maintenance treatment of airflow obstruction and decreasing exacerbations in patients with COPD, including chronic bronchitis and/or emphysema. The drug-device combination metered-dose inhaler will be marketed under the trade name Breyna™. It is dosed as 2 inhalations 2 times a day (about 12 hours apart). Breyna is expected to be available in 2 strengths: 160 mcg/4.5 mcg per actuation and 80 mcg/4.5 mcg per actuation. • Product labeling for pembrolizumab (Keytruda®) has been updated to withdraw the indication for use in the third-line gastric cancer setting. This indication was granted Accelerated Approval in 2017 as a single agent 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 fluoropyrimidineand platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy). Withdrawal of this indication was announced in July 2021.

• The FDA has approved the first generic (drug cartridges only) of MDD’s Apokyn® (apomorphine HCl) from Sage Chemical. The drug cartridges are compatible with the Apokyn Pen (brand-name pen injector). Apomorphine is indicated for the acute, intermittent treatment of hypomobility, “off” episodes in patients with advanced Parkinson’s disease. • The agency has granted approval to the first generic version of Viiv’s Selzentry® (maraviroc) tablets from Hetero Labs. Product is available in 150 mg and 300 mg tablets and is indicated in combination with other antiretroviral agents for the treatment of only CCR5tropic HIV-1 infection in adult and pediatric patients ≥ 2 years old weighing ≥ 10 kg. • A generic version of Almirall’s topical acne agent, Veltin™ (clindamycin phosphate/tretinoin), has received FDA approval. The topical clindamycin phosphate/tretinoin gel, 1.2%/0.025%, is indicated for the treatment of acne vulgaris in patients ≥ 12 years old and is from Solaris. • Obinutuzumab (Gazyva®) has received a new dosing regimen allowing for administration as an approximately 90-minute infusion in patients with follicular lymphoma who have received 3 obinutuzumab administrations at the standard infusion rate and not experienced any grade 3 or greater infusion related reactions.

DRUG INFORMATION HAPPENINGS • The American College of Rheumatology has published updated guidelines on the treatment of juvenile idiopathic arthritis (JIA), including treatment strategies for oligoarthritis, temporomandibular joint arthritis, and systemic JIA. • The CDC has released the 2022 Adult Immunization Schedule for individuals ≥ 19 years old as well as the 2022 Child and Adolescent Immunization Schedule for those ≤ 18 years of age. • The FDA has released final guidance on voluntary recalls urging companies to be proactive and “recall ready.” • The FDA has published 3 final guidance documents, to industry, on advancing the development of cancer therapies. The FDA has also released the second in a series of 4 patient-focused drug development guidance documents.






dexmedetomidine Bioxcel

• SL • Selective α2-adrenoreceptor agonist sedative

Bipolar disorder-related acute agitation; Schizophreniarelated acute agitation


casirivimab/imdevimab Regeneron

• IM, IV, SC • Antiviral antibodies

COVID-19 treatment (outpatient setting); COVID-19 post-exposure prophylaxis


mavacamten Bristol-Myers Squibb

• Oral • Cardiac muscle myosin inhibitor

Obstructive hypertrophic cardiomyopathy


meloxicam/rizatriptan Axsome

• Oral • COX2 inhibitor/selective 5-HT1 serotonin agonist (triptan)

Migraine treatment


surufatinib Hutchmed

• Oral • Tyrosine kinase inhibitor

Neuroendocrine tumors


toripalimab Coherus/AstraZeneca

• IV • PD-1 inhibitor

Nasopharyngeal carcinoma


vonoprazan Phathom

• Oral • Potassium-competitive acid blocker

Helicobacter pylori infection (in combination with amoxicillin ± clarithromycin)


edaravone Mitsubishi Tanabe

• Oral • Neuroprotective agent

Amyotrophic lateral sclerosis


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New Drugs amlodipine besylate (Norliqva®) CMP Pharma

• 505(b)(2) NDA approval 02/24/2022; Standard Review • Indicated for the treatment of: » Hypertension in adults and children ≥ 6 years old, to lower blood pressure » Coronary artery disease, including chronic stable angina, vasospastic

• • •

filgrastim-ayow (Releuko®) Amneal

• •

• • •

angina (Prinzmetal’s or variant angina), and angiographically documented coronary artery disease in patients without heart failure or an ejection fraction < 40% Calcium channel blocker Oral solution: 1 mg/mL (peppermint flavor) Recommended dosage is 5 mg once daily (maximum 10 mg once daily) in adults and 2.5 mg to 5 mg once daily in children (≥ 6 years of age) BLA approval 02/25/2022; biosimilar to Amgen’s Neupogen® (filgrastim) Indicated to reduce: » The incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; » The time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML); » The duration of neutropenia and neutropenia-related clinical sequelae (e.g.‚ febrile neutropenia), in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation; » The incidence and duration of sequelae of severe neutropenia‚ (e.g., fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia Leukocyte growth factor Injectable preservative-free solution: 300 mcg/mL and 480 mcg/1.6 mL in an SDV; 300 mcg/0.5 mL and 480 mcg/0.8 mL in single-dose prefilled syringes Recommended dosage regimen and route of administration are dependent on indication for use and patient body weight; SC injections may be administered by the patient or caregiver following proper instruction; the prefilled syringe should not be used for direct administration of < 0.3 mL (180 mcg) due to the potential for dosing errors



New Drugs continued ciltacabtagene autoleucel (Carvykti™) Janssen Biotech

• BLA approval 02/28/2022; Assessment Aid, Breakthrough Therapy, Orphan Drug, Priority Review • Indicated for the treatment of adults with relapsed or refractory multiple myeloma after ≥ 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody • BCMA-directed genetically modified autologous T cell immunotherapy • Cell suspension for IV infusion: 30 mL or 70 mL infusion bag and metal cassette for autologous use • Recommended dosage range is 0.5 to 1 x 106 (maximum, 1 x 108) CAR-positive viable T cells per kg body weight in a single IV infusion administered by an HCP; administer after lymphodepleting chemotherapy • Boxed warnings for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and recurrent cytopenia • Product availability is expected by late 2022 or early 2023 only through the restricted Carvykti REMS program

pacritinib (Vonjo™) CTI BioPharma

• NDA approval 02/28/2022; Accelerated Approval, Fast Track, Orphan Drug, Priority Review • Indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count < 50 x 109/L • Kinase inhibitor with specificity for JAK2 and FMS-like tyrosine kinase 3 (FLT3) • Oral capsule: 100 mg • Recommended dosage is 200 mg orally twice daily with or without food

ranolazine (Aspruzyo Sprinkle™) Sun

• 505(b)(2) NDA approval 02/28/2022; Standard Review • Indicated for the treatment of chronic angina; may be used in conjunction with other therapies such as beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and ARBs • Antianginal • Extended-release oral granules: 500 mg, 1,000 mg • Recommended dosage is 500 mg twice daily; may increase to 1,000 mg twice daily based on clinical symptoms; sprinkle granules on 1 tablespoonful of soft food and consume immediately or add to 30 mL or 50 mL of water and administer promptly via gastric or nasogastric tube, respectively

donepezil (Adlarity®) Corium

• 505(b)(2) NDA approval 03/11/2022; Standard Review • Indicated for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type • Acetylcholinesterase inhibitor • Transdermal system: 5 mg/day, 10 mg/day • Recommended starting dosage is 5 mg/day; may increase to a maximum of 10 mg/day after 4 to 6 weeks; for patients on oral donepezil 5 mg/day for ≥ 4 to 6 weeks or 10 mg/day orally, the recommended starting dosage is 10 mg/day; apply 1 transdermal system to the skin once weekly • Product availability is expected in early Fall 2022

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New Drugs continued ganaxolone (Ztalmy®) Marinus

• NDA approval 03/18/2022; Orphan Drug, Priority Review, Rare Pediatric Disease • Indicated for the treatment of seizures associated with cyclin-dependent kinaselike 5 (CDKL5) deficiency disorder (CDD) in patients ≥ 2 years of age • Neuroactive steroid GABA A receptor positive modulator • Oral suspension: 50 mg/mL • Recommended dosage in patients weighing ≤ 28 kg is 6 mg/kg three times daily and titrate to a maximum of 21 mg/kg three times daily; in patients weighing > 28 kg, the initial dose is 150 mg three times daily and titrate to a maximum of 600 mg three times daily; administer with food and increase the dosage based on tolerability, no more often than every 7 days • Product availability is expected in July 2022 through limited specialty pharmacy distribution following scheduling by the DEA

nivolumab/relatlimabrmbw (Opdualag™) Bristol-Myers Squibb

• BLA approval 03/18/2022; Orphan Drug, Project Orbis, Real-Time Oncology Review • Indicated for the treatment of adult and pediatric patients ≥ 12 years of age with unresectable or metastatic melanoma • Combination of PD-1 blocking antibody (nivolumab) and LAG-3 blocking antibody (relatlimab-rmbw) • Solution for injection: nivolumab 240 mg/relatlimab-rmbw 80 mg in a 20 mL SDV • Recommended dosage in adults and pediatric patients ≥ 12 years of age weighing ≥ 40 kg is 480 mg nivolumab and 160 mg relatlimab-rmbw via IV infusion over 30 minutes every 4 weeks until disease progression or unacceptable toxicity; recommended dosage for pediatric patients ≥ 12 years of age weighing < 40 kg has not been established

dextroamphetamine (Xelstrym™) Noven

• 505(b)(2) NDA approval 03/22/2022; Standard Review • Indicated for the treatment of ADHD in adults and pediatric patients ≥ 6 years old • Pediatric patients with ADHD < 6 years of age experienced more long-term weight loss than those ≥ 6 years old • CNS stimulant • Transdermal system: 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, 18 mg/ 9 hours; not substitutable with other amphetamine products on a mg-per-mg basis due to differences in the amphetamine base composition and PK profiles • Recommended starting dosage is dependent on the patient’s age and is applied to the hip, upper arm, chest, upper back, or flank 2 hours before efficacy is needed and removed within 9 hours; the site of application should be changed when a new transdermal system is applied; clinical response and tolerability should be used to individualize dose titration and final dosage » Patients 6 to 17 years: 4.5 mg/9 hours; titrate dosage in weekly increments of 4.5 mg (maximum dose of 18 mg/9 hours) » Adults: 9 mg/9 hours (maximum dose of 18 mg/9 hours) • Boxed Warnings for abuse and dependence • Schedule II controlled substance • Product availability is expected as early as 2H 2022

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New Drugs continued sirolimus (Hyftor™) Nobelpharma

• 505(b)(2) NDA approval 03/22/2022; Orphan Drug, Priority Review • Indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients ≥ 6 years old • mTOR inhibitor immunosuppressant • Topical gel: 2 mg per gram (0.2%) • Recommended dosage is to apply to the skin of the face with the angiofibroma twice daily; the maximum daily dosage for patients 6 to 11 years of age is 600 mg (2 cm) and 800 mg (2.5 cm) for patients ≥ 12 years of age; if improvement is not noted within 12 weeks, reassess if therapy should be continued

505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

COVID-19 Disclaimer: 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. Glossary: CNS central nervous system

HCP healthcare professional

NIH National Institutes of Health

COPD chronic obstructive pulmonary disease

HER2 human epidermal growth factor receptor 2

PD-1 programmed cell death 1

ARB angiotensin receptor blocker

COVID-19 Coronavirus Disease 2019

HIV-1 human immunodeficiency virus type 1

PET positron emission tomography

BCMA B-cell maturation antigen

COX2 cyclooxygenase-2

IM intramuscular

BLA Biologics License Application

DEA Drug Enforcement Administration

IV intravenous

EUA Emergency Use Authorization

ACE angiotensin-converting enzyme ADHD attention deficit hyperactivity disorder

CAR chimeric antigen receptor

JAK2 Janus associated kinase 2

CDC Centers for Disease Control and Prevention

FDA Food and Drug Administration

LAG-3 lymphocyte activation gene-3

GABA gamma-aminobutyric acid

mRNA messenger ribonucleic acid

CDR Clinical Dementia Rating

H half

CMS Centers for Medicare & Medicaid Services

HCl hydrochloride

mTOR mammalian target of rapamycin

CCR5 CC chemokine receptor 5

NDA New Drug Application


8 | APRIL 2022

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PD-L1 programmed death ligand 1 PK pharmacokinetic REMS Risk Evaluation and Mitigation Strategy SC subcutaneous SDV single-dose vial SL sublingual WHO World Health Organization

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