Drug Information Center

Highlights of FDA Activities – 1/1/21 – 1/31/21

FDA Drug Safety Communications & Drug Information Updates:

Risk of False Results with the Curative SARS‐Cov‐2 Test for COVID‐19 1/7/2021 The Curative SARS‐Cov‐2 test is real‐time RT‐PCR test used to detect SARS‐Cov‐2. There are concerns that the test may yield false negatives. To reduce the risk of false negatives. Ensure that testing is done in accordance with the authorized labeling. Providers should consider retesting patients by using a different test if an inaccurate result is suspected. Health professionals and patients are encouraged to report problems with test performance or results to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program.

Vinca Alkaloid Labeling for Preparation in Intravenous Infusion Bags Only 1/15/21 The FDA alerted health care professionals to labeling updates for the preparation of vinca alkaloids including vincristine sulfate injection, vinblastine sulfate for injection, and vinorelbine tartrate injection. To avoid unintended intrathecal administration, labeling is being updated to remove instructions for preparation of these products in a syringe and to recommend preparation in intravenous infusion bags only.

Import Alert – All Alcohol‐Based Hand Sanitizers from Mexico 1/26/21 The FDA has placed all alcohol‐based hand sanitizers from Mexico on an import alert to prevent products contaminated with methanol from reaching the market. Inspections will determine if products have been manufactured according to U.S. current good manufacturing practice requirements before allowing entry.

Misbranded Active Pharmaceutical Ingredients – Drug Information Update 1/28/21 The FDA issued a warning to Professional Compounding Centers of America (PCCA) for receiving and distributing misbranded active pharmaceutical ingredients. The FDA recommends customers of PCCA contact PCCA to verify the identity of original API manufacturers for products purchased through PCCA and to ensure the products they received met regulatory standards.

Major Medication/Drug‐Related Product Recalls Announced Through MedWatch:

Metformin HCl Extended‐Release Tablets USP, 750 mg, Nostrum Laboratories: Recall – NDMA 1/4/21 Nostrum Laboratories, Inc. recalled one lot (MET200501, exp. 7/22) of metformin HCl extended‐release tablets, USP 750 mg (NDC 29033‐056‐01, generic equivalent to Glucophage) due to levels of nitrosamine impurities (N‐ nitrosodimethylamine, NDMA) exceeding levels above the FDA authorized acceptable daily intake limit.

Soho Fresh 70% Rubbing Alcohol, Essaar: Recall – Methanol Contamination 1/5/21 Essaar Inc. recalled one lot (#200528303) of Soho Fresh 70% Rubbing Alcohol in 33.81 oz due to contamination with methanol.

Ketorolac Tromethamine Injection, USP, Fresenius Kabi: Recall – Particulate Matter 1/8/21 Fresenius Kabi USA recalled one lot of ketorolac tromethamine injection, USP, 30 mg/mL 1 mL fill in 2 mL amber vial (NDC 63323‐162‐01, product code 160201, batch 6121083, exp 2/21) due to the presence of particulate matter detected in a reserve sample. The recalled lot was distributed nationwide between 3/28/19 and 9/3/19.

Cisatracurium Besylate Injection, USP, Meitheal Pharmaceuticals: Recall – Mislabeling 1/28/21 Meitheal Pharmaceuticals recalled one lot (C11507A, exp. October 2021) of cisatracurium besylate injection USP 10 mg/5 mL as a portion of the lot was mislabeled and contains cisatracurium besylate vials mis‐labeled as phenylephrine HCl injection 100 mg/10 mL. The cartons were distributed from 8/19/20 to 1/4/21.

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Dietary Supplement Recalls & Public Notifications Notifications were issued regarding undeclared active ingredients or contaminants in the following products. Patients are advised not to purchase or use these products. Product Promoted Use Undeclared Ingredient(s) or Contaminants Adam’s Secret Extra Strength 1500 Sexual enhancement Sildenafil, tadalafil Adam’s Secret Extra Strength 3000 Platinum Sexual enhancement Sildenafil, tadalafil

New Product Shortages No new shortages were reported by the FDA in January

Brand Name or Sole Source Product Discontinuations/Withdrawals Date Posted Ursodiol capsules (Actigall, Allergan); generic formulations remain available 1/15/21

New Drug Approvals: Description (See Attached Drug Summaries) Date Approved Vericiguat / Verquvo / Merck & Co., Inc. Guanylate cyclase stimulator indicated to reduce the risk of 1/19/21 cardiovascular death and heart failure hospitalization in select patients with symptomatic chronic heart failure Cabotegravir / Vocabria / ViiV In combination with rilpivirine for the short‐term treatment 1/21/21 Healthcare of HIV‐1 infection in adults who are virologically suppressed on a stable antiretroviral regimen Cabotegravir and rilpivirine / Cabenuva / Integrase inhibitor and non‐nucleoside reverse transcriptase 1/21/21 ViiV Healthcare inhibitor for use as a complete regimen for the treatment of HIV‐1 infection to replace Voclosporin / Lupkynis / Aurinia Calcineurin‐inhibitor immunosuppressant for use in 1/22/21 Pharmaceuticals combination with a background immunosuppressive regimen for the treatment of active lupus nephritis

New Indications: Description Date Approved Crizotinib / Xalkori / Pfizer Treatment of pediatric patients 1 year and older and young 1/14/21 adults with relapsed or refractory, systemic anaplastic large cell lymphoma that is ALK‐positive Daratumumab and hyaluronidase‐fihj / Use in combination with bortezomib, thalidomide, and 1/11/21 Darzalex Faspro / Janssen Biotech Inc. dexamethasone in newly diagnosed patients with multiple myeloma who are eligible for autologous stem cell transplant Fam‐trastuzumab deruxtecan‐nxki / Treatment of adult patients with locally advanced or 1/15/21 Enhertu / Daiichi Sankyo, Inc. metastatic HER2‐positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab‐based regimen Levetiracetam tablets for oral Treatment of partial onset seizures in patients 4 years of age 1/19/21 suspension / Spritam / Aprecia and older weighing more than 20 kg. Pharmaceuticals LLC Carglumic acid / Carbaglu / Recordati Use as an adjunctive therapy to standard of care for the 1/22/21 Rare Diseases treatment of acute hyperammonemia due to propionic acidemia or methylmalonic acidemia Nivolumab / Opdivo / Bristol Myers Treatment of patients with advanced renal cell carcinoma, as 1/22/21 Squibb Company a first‐line treatment in combination with cabozantinib Cabozantinib / Cabometyx / Exelixis Inc. Treatment of patients with advanced renal cell carcinoma, as 1/22/21 a first‐line treatment in combination with nivolumab Romiplostim / Nplate / Amgen Inc. To increase survival in adults and pediatric patients acutely 1/28/21 exposed to myelosuppressive doses of radiation

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New Dosage Forms or Formulation: Description Date Approved Rilpivirine / Edurant / Janssen In combination with cabotegravir for the short‐term 1/21/21 treatment of HIV‐1 infection in adults who are virologically suppressed on a stable antiretroviral regimen

Compiled by: Terri Levien, Pharm.D. Drug Information Center College of Pharmacy and Pharmaceutical Sciences Washington State University 412 E. Spokane Falls Blvd. Spokane, WA 99202‐2131 (509) 358‐7662 [email protected]

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Vericiguat / Verquvo / Merck & Co., Inc. Generic Name / Brand Name / Company Vericiguat / Verquvo / Merck & Co., Inc. Date of approval 1/19/21 Drug Class (Mechanism of Action if novel agent) Soluble guanylate cyclase stimulator; augments intracellular cGMP, leading to smooth muscle relaxation and vasodilation Indication To reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient intravenous diuretics in adults with symptomatic chronic heart failure and ejection fraction less than 45% Comparative agent – Therapeutic interchange? Vasodilators such as isosorbide dinitrate/hydralazine Dosage forms/strengths. Tablets: 2.5 mg, 5 mg, 10 mg Common Dose/sig Starting dose: 2.5 mg orally once daily; double dose approximately every 2 weeks to reach target maintenance dose of 10 mg once daily, if tolerated DEA Schedule None Date of market availability Mid‐February 2021 Similar Medication Names None identified Clinical Use Evaluation Common Adverse Effects >5% hypotension, anemia Severe Adverse Effects None reported Severe Drug‐Drug Interactions PDE‐5 inhibitors: concomitant use is not recommended Other soluble guanylate cyclase stimulators: contraindicated Severe Drug‐Food Interactions None; recommended to be taken with food Important Labs Values to assess prior to order entry Obtain a pregnancy test in females of reproductive potential prior to or at point of clinical follow up. initiating therapy. Used in Pediatric Areas Safety and effectiveness have not been established Renal or Hepatic Dosing No dosage adjustment in patients with mild to moderate hepatic impairment or with estimated glomerular filtration rate (eGFR) > 15 mL/min/1.73 m2 who are not on dialysis. It has not been studied in patients with severe hepatic impairment, with eGFR < 15 mL/min/1.73 m2 or on dialysis. Critical Issues (i.e., contraindications, warnings, etc) Contraindicated with concomitant use of other soluble guanylate cyclase that should be emphasized stimulators (riociguat) and in pregnancy. Embryofetal toxicity: exclude pregnancy before initiating treatment; females of reproductive potential must use effective contraception during treatment and for one month after stopping treatment. Special administration technique or considerations Administer with food. For patients unable to swallow whole tablets, crush and mix with water immediately prior to administration. Prepared by Terri Levien, PharmD Source Verquvo (vericiguat) [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc.; January 2021.

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Cabotegravir and rilpivirine / Cabenuva / ViiV Healthcare Generic Name / Brand Name / Company Cabotegravir and rilpivirine / Cabenuva / ViiV Healthcare Date of approval 1/21/21 Drug Class (Mechanism of Action if novel agent) HIV‐1 integrase strand transfer inhibitor and HIV‐1 non‐nucleoside reverse transcriptase inhibitor Indication Complete regimen for the treatment of HIV‐1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to either agent Comparative agent – Therapeutic interchange? None Dosage forms/strengths. Extended‐release injectable suspension 400 mg/600 mg kit contains single‐dose vial of 400 mg/2 mL cabotegravir and single‐dose vial of 600 mg/2 mL rilpivirine 600 mg/900 mg kit contains single‐dose vial of 600 mg/3 mL cabotegravir and single‐dose vial of 900 mg/3 mL rilpivirine Common Dose/sig Following use of oral lead‐in dosing for approximately 1 month to establish tolerability, initiate with 600 mg cabotegravir and 900 mg rilpivirine on the last day of oral dosing, and continuing with injections of 400 mg cabotegravir and 600 mg rilpivirine every month thereafter DEA Schedule None Date of market availability February 2021 Similar Medication Names None identified Clinical Use Evaluation Common Adverse Effects >2%: injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, rash Severe Adverse Effects Depressive disorder, severe injection site reactions Severe Drug‐Drug Interactions Drugs that induce UGT1A1 or CYP3A4 (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, dexamethasone, St John’s wort) Drugs known to increase risk of Torsade de Pointes Severe Drug‐Food Interactions None Important Labs Values to assess prior to order entry Liver chemistries or at point of clinical follow up. Used in Pediatric Areas Safety and efficacy have not been established Renal or Hepatic Dosing No dosage adjustment is required in mild to moderate renal impairment; patients with severe renal impairment of end‐stage renal disease should receive increased monitoring for adverse effects. No dosage adjustment is required in mild or moderate hepatic impairment; there is no information on cabotegravir or rilpivirine in severe hepatic impairment. Critical Issues (i.e., contraindications, warnings, etc) Contraindications: that should be emphasized Previous hypersensitivity to cabotegravir or rilpivirine Coadministration with drugs that may reduce concentrations of cabotegravir or rilpivirine Warnings: Hypersensitivity reactions Serious post‐injection reactions with rilpivirine – observed patients for 10 minutes following injection Hepatotoxicity – monitor liver chemistries Depressive disorder Special administration technique or considerations Administer by intramuscular gluteal injection only; the ventrogluteal site is recommended. Each injection should be at a separate site on separate sides or 2 cm apart. The injection suspension should be FDA Activity Newsletter WSU Drug Information Center January 2021 Page | 6

allowed to come to room temperature prior to administration. Shake well prior to administration. Patients should be carefully selected who will be adherent. Prepared by Terri Levien, PharmD Source Cabenuva (cabotegravir extended‐release injectable suspension; rilpivirine extended‐release injectable suspension) [prescribing information]. Research Triangle Park, NC: ViiV Healthcare; January 2021.

Cabotegravir / Vocabria / ViiV Healthcare Generic Name / Brand Name / Company Cabotegravir / Vocabria / ViiV Healthcare Date of approval 1/21/21 Drug Class (Mechanism of Action if novel agent) HIV‐1 integrase strand transfer inhibitor Indication In combination with rilpivirine for short‐term treatment of HIV‐1 infection in adults who are virologically suppressed on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as ‐oral lead‐in to assess tolerability of cabotegravir prior to administration of cabotegravir and rilpivirine extended‐release injectable suspensions ‐oral therapy for patients who will miss planned injection dosing with cabotegravir and rilpivirine extended‐release injectable suspensions. Comparative agent – Therapeutic interchange? None Dosage forms/strengths. Tablets: 30 mg Common Dose/sig 30 mg orally once daily DEA Schedule None Date of market availability February 2021 Similar Medication Names Cabometyx, Cabozantinib, raltegravir Clinical Use Evaluation Common Adverse Effects Headache, nausea, abnormal dreams, anxiety, insomnia Severe Adverse Effects Suicidal depression Severe Drug‐Drug Interactions Contraindicated with strong inducers of UGT1A1 or 1A9 Coadministration with polyvalent cation‐containing products may lead to decreased cabotegravir absorption – administer antiacids 2 hours before or 4 hours after cabotegravir Severe Drug‐Food Interactions None known Important Labs Values to assess prior to order entry Liver chemistries or at point of clinical follow up. Used in Pediatric Areas Safety and efficacy have not been established Renal or Hepatic Dosing No dosage adjustment in mild to severe renal impairment and mild to moderate hepatic impairment. There is no information in end‐stage renal disease or severe hepatic impairment. Critical Issues (i.e., contraindications, warnings, etc) Contraindications: Hypersensitivity to cabotegravir that should be emphasized Use with UGT1A1 enzyme inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine Warnings: Hypersensitivity Hepatotoxicity – monitor Depressive disorders Consider all cautions for rilpivirine, which must be co‐administered. Special administration technique or considerations Administer at the same time each day with a meal. Prepared by Terri Levien, PharmD Source Vocabria (cabotegravir) [prescribing information]. Research Triangle Park, NC: ViiV Healthcare; January 2021.

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Voclosporin / Lupkynis / Aurinia Pharmaceuticals Generic Name / Brand Name / Company Voclosporin / Lupkynis / Aurinia Pharmaceuticals Date of approval 1/22/21 Drug Class (Mechanism of Action if novel agent) Calcineurin‐inhibitor immunosuppressant Indication Use in combination with background immunosuppressive therapy regimen (mycophenolate mofetil and corticosteroids) for the treatment of adult patients with active lupus nephritis Comparative agent – Therapeutic interchange? None Dosage forms/strengths. Capsules: 7.9 mg Common Dose/sig Starting dose: 23.7 mg orally twice a day DEA Schedule None Date of market availability Available Similar Medication Names Cyclosporin, voxelotor Clinical Use Evaluation Common Adverse Effects >3%: glomerular filtration rate decreased, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain, dyspepsia, alopecia, renal impairment, mouth ulceration, fatigue, tremor, acute kidney injury, decreased appetite Severe Adverse Effects Infection, acute kidney injury, renal impairment, hypertension, headache, migraine, seizure, posterior reversible encephalopathy syndrome, malignancy, Severe Drug‐Drug Interactions Moderate CYP3A4 inhibitors: reduce voclosporin dose Strong and moderate CYP3A4 inducers: avoid co‐administration P‐glycoprotein substrates with narrow therapeutic index: reduce dose of these agents. Avoid use with cyclophosphamide. Severe Drug‐Food Interactions Avoid grapefruit or grapefruit juice. Important Labs Values to assess prior to order entry Establish an accurate baseline eGFR before initiating and assess every 2 or at point of clinical follow up. weeks for the first month, and every 4 weeks thereafter. Used in Pediatric Areas Safety and efficacy have not been established Renal or Hepatic Dosing Modify dose based on eGFR. The Recommended dose is 15.8 mg twice daily in patients with severe renal impairment. Use is not recommended in patients with eGFR < 45 mL/min/1.73 m2 unless benefit exceeds risk. Recommended dose is 15.8 mg twice daily in mild and moderate hepatic impairment. Avoid use in severe hepatic impairment. Critical Issues (i.e., contraindications, warnings, etc) Contraindicated in patients on strong CYP3A4 inhibitors (eg, ketoconazole, that should be emphasized itraconazole, clarithromycin) and with known serious or severe hypersensitivity reactions to any product ingredients. Warnings: Increases risk of serious infections Increases risk of lymphoma and other malignancies, particularly of the skin. Nephrotoxicity – monitor renal function and consider dosage adjustment Hypertension – may require antihypertensive therapy; do not initiate if baseline blood pressure is greater than 165/105 mmHg or with hypertensive emergency. Monitor blood pressure every 2 weeks for the first month and as clinically indicated thereafter. Discontinue if blood pressure exceeds 165/105 mmHg and initiate antihypertensive therapy. Neurotoxicity ‐ monitor Hyperkalemia – monitor serum potassium

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QT prolongation – obtain electrocardiogram and monitor electrolytes in patients at high risk Immunizations – avoid live vaccines Pure red cell aplasia – consider discontinuation if occurs Consider discontinuation of therapy if benefit not observed by 24 weeks. Special administration technique or considerations Swallow whole on an empty stomach. Administer as close to a 12‐ hour schedule as possible, with at least 8 hours between doses. Prepared by Terri Levien, PharmD Source Lupkynis (voclosporin) [prescribing information]. Rockville, MD: Aurinia Pharma U.S., Inc.; January 2021.

FDA Activity Newsletter WSU Drug Information Center January 2021