Drug Information Center

Highlights of FDA Activities – 2/1/21 – 2/28/21

FDA Drug Safety Communications & Drug Information Updates:

Increased Risk of Heart‐related Problems and Cancer with Tofacitinib – Drug Safety Communication 2/4/21 The FDA alerted the public that preliminary results from a safety clinical trial found an increased risk serious heart‐ related problems and cancer were observed with the use of tofacitinib (Xeljanz, Xeljanz XR) compared with tumor necrosis factor (TNF) inhibitors. The benefits and risks should be considered when deciding to prescribe or continue this medication until final study results are available. Recommendations in the prescribing information should continue to be followed.

Risks Associated with Compounding Remdesivir Drug Products 2/4/21 Following approval of remdesivir (Veklury), the FDA cautioned against compounding remdesivir drug products due to complexities related to the quality and sourcing of the remdesivir active pharmaceutical ingredient. The structure is complex, with six stereocenters, and the pH of the formulation of the approved drug is critical to ensure stability. USP standards are not available.

Emergency Use Authorization for Monoclonal Antibodies for Treatment of COVID‐19 2/9/21 The FDA issued an emergency use authorization for bamlanivimab and etesevimab together for treatment of mild to moderate COVID‐19 in adults and pediatric patients, to reduce risk of hospitalization or death. The treatment is not authorized for use in hospitalized patients or patients who require oxygen due to COVID‐19.

Pulse Oximeter Accuracy and Limitations: FDA Safety Communication 2/19/21 The FDA has issued a safety communication to inform patients and health care providers that pulse oximeters have limitations and a risk of inaccuracy under certain circumstances. The safety communication provides recommendations for patients and providers regarding how to use pulse oximeters, and instructions for reporting problems with pulse oximeters to the FDA.

Flexible Storage, Transportation Conditions for Pfizer‐BioNTech COVID‐19 Vaccine 2/25/21 The FDA allowed undiluted frozen vials of the Pfizer‐BioNTech COVID‐19 vaccine to be transported and stored at conventional freezer temperatures for up to 2 weeks. Vials may be stored at ‐25°C to ‐15°C (‐13°F to 5°F) for up to 2 weeks. Vials stored at these temperatures may be returned one time to the recommended storage condition of ‐ 80°C to ‐60°C (‐112°F to ‐76°F); total time at the higher temperature should be tracked and should not exceed 2 weeks. See the EUA Fact Sheet for additional storage and transport conditions.

Emergency Use Authorization for Janssen COVID‐19 Vaccine 2/27/21 The FDA issued an emergency use authorization allowing for the use of the Janssen (Johnson & Johnson) COVID‐19 vaccine in individuals 18 years of age and older.

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

Enoxaparin Sodium Injection USP, Apotex: Recall – Mislabeled Syringe Barrel Measurement Markings 2/4/21 Apotex recalled 2 batches (CS008, CT003) of enoxaparin sodium injection USP due to a packaging error resulting in some syringe barrels containing 150 mg/mL markings instead of 100 mg/mL markings on the syringe barrel and vice versa.

Medfusion 3500 and 4000 Syringe Pumps, Smiths Medical: Recall – Risk of Medication Delivery Error 2/10/21 Smiths Medical recalled specific software versions of the Medfusion 3500 and 4000 Syringe Pumps because of a software error that may lead to over‐delivery or under‐delivery of fluids or medication. FDA Activity Newsletter WSU Drug Information Center February 2021 Page | 2

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 and/or tadalafil Capsule* Adam’s Secret Extra Strength 3000 Sexual Enhancement Sildenafil and/or tadalafil Capsule* ManukaGuard Allercleanse Nasal Spray* Clean nasal passages Yeast *recalled

New Product Shortages Date Initially Posted Calcium disodium versenate injection 2/2/21 Succimer capsules 2/26/21

Brand Name or Sole Source Product Discontinuations/Withdrawals Date Posted Efavirenz, emtricitabine, tenofovir disoproxil fumarate tablets (Atripla, Gilead Sciences) 2/4/21

New Drug Approvals: Description (see attached drug summaries) Date Approved Tepotinib / Tepmetko / EMD Serono Inc Kinase inhibitor for the treatment of metastatic non‐small 2/3/21 cell lung cancer in patients harboring mesenchymal‐ epithelial transition (MET) exon 14 skipping alterations Lisocabtagene maraleucel / Breyanzi / Customized biologic cell‐based gene therapy, a chimeric 2/5/21 Juno Therapeutics antigen receptor (CAR) T cell therapy, to treat adults with diffuse large B‐cell lymphoma Umbralisib / Ukoniq / TG Therapeutics Kinase inhibitor for the treatment of relapsed or refractory 2/5/21 marginal zone lymphoma who have received one prior treatment with anti‐CD20‐based regimen and relapsed or refractory follicular lymphoma who received at least 3 prior systemic therapy Evinacumab‐dgnb / Evkeeza Regeneron Angiopoietin‐like 3 inhibitor indicated as adjunct to other 2/11/21 low‐density lipoprotein cholesterol lowering therapies in adults and pediatric patients 12 years and older with homozygous familial hypercholesterolemia (HoFH) Trilaciclib / Cosela / G1 Therapeutics Kinase inhibitor indicated to decrease incidence of 2/12/21 chemotherapy‐induced myelosuppression when administered prior to a platinum/etoposide‐containing regimen or topotecan‐containing regimen for extensive‐ stage small cell cancer Casimersen / Amondys 45 Sarepta Antisense oligonucleotide for the treatment of Duchenne 2/25/21 Therapeutics muscular dystrophy (DMD) in patients with confirmed mutation of the DMD gene amenable to exon 45 skipping Fosdenopterin / Nulibry / Origin To reduce the risk of death due to molybdenum cofactor 2/26/21 Biosciences deficiency type A, a rare genetic metabolic disorder

FDA Activity Newsletter WSU Drug Information Center February 2021 Page | 3

New Indications: Description Date Approved Amantadine hydrochloride ER / Adjunctive treatment to levodopa/carbidopa in patients with 2/1/21 Gocovri / Adamas Pharmaceuticals Parkinson’s disease experiencing “off” episodes. Cemiplimab‐rwlc / Libtayo / Regeneron Locally advanced basal cell carcinoma or metastatic basal cell 2/9/21 carcinoma, previously treated with a hedgehog pathway inhibitor, or for whom a hedgehog pathway inhibitor is not appropriate OnabotulinumtoxinA / Botox / Allergan Treatment of pediatric neurogenic detrusor overactivity in 2/9/21 patients greater than 5 years of age, who are intolerant or have an inadequate response to anticholinergic medication. Bevacizumab‐bvzr / Zirabev / Pfizer Treatment of epithelial ovarian, fallopian tube, or primary 2/9/21 peritoneal cancer Immune globulin intravenous (human)‐ Treatment of adults with chronic inflammatory demyelinating 2/11/21 ifas 10% / Panzyga / Octapharma polyneuropathy to improve neuromuscular disability and impairment Cemiplimab‐rwlc / Libtayo / Regeneron First‐line therapy in patients with non‐small lung cell cancer 2/22/21 whose tumors have PD‐L1 expression ≥50% and disease is locally advanced where the patient is not a candidate for surgical resection or metastatic

New Dosage Forms or Formulation: Description Date Approved Bupivacaine solution / Posimir / Durect Solution: 660 mg/5 mL; single‐dose administration into the 2/1/21 subacromial space under direct arthroscopic visualization to produce post‐surgical analgesia following arthroscopic subacromial decompression

Compiled by: Terri Levien, Pharm.D. Drug Information Center Brittany Craft, Pharm.D., PGY2 Drug Information Resident College of Pharmacy and Pharmaceutical Sciences David Tam, Doctor of Pharmacy Candidate 2021 Washington State University Brandon Tabor, Doctor of Pharmacy Candidate 2021 412 E. Spokane Falls Blvd. Spokane, WA 99202‐2131 (509) 358‐7662 [email protected]

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Tepotinib / Tepmetko / EMD Serono, Inc. Generic Name / Brand Name / Company Tepotinib / Tepmetko / EMD Serono, Inc. Date of approval 2/3/21 Drug Class (Mechanism of Action if novel agent) Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits hepatocyte growth factor (HGF)‐ dependent and ‐independent MET phosphorylation and MET‐dependent downstream signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations. Indication Treatment of adult patients with metastatic non‐small cell lung cancer (NSCLC) harboring mesenchymal‐epithelial transition (MET) exon 14 skipping alterations. Comparative agent – Therapeutic interchange? Capmatinib Dosage forms/strengths. Tablet: 225 mg. Common Dose/sig Recommended dose: 450 mg taken orally once daily with food until disease progression or unacceptable toxicity DEA Schedule None Date of market availability Available Similar Medication Names Tepezza, Teprotumumab Clinical Use Evaluation Common Adverse Effects Adverse reactions (≥ 20%): Edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%): Decreased lymphocytes, decreased albumin, decreased sodium, increased gamma‐glutamyl transferase, increased amylase, increased ALT, increased AST, decreased hemoglobin. Severe Adverse Effects Pleural effusion (7%), pneumonia (5%), edema (3.9%), dyspnea (3.9%), general health deterioration (3.5%), pulmonary embolism (2%), musculoskeletal pain (2%), fatal pneumonitis, hepatic failure Severe Drug‐Drug Interactions Strong Inhibitors of CYP3A and P‐gp: May increase tepotinib exposure – avoid concomitant use. Strong Inducers of CYP3A: May decrease tepotinib exposure – avoid concomitant use. Severe Drug‐Food Interactions Tepotinib should be taken with food; peak concentration and exposure increased when administered with high‐fat, high‐calorie meal Important Labs Values to assess prior to order entry Liver function tests prior to initiating, every 2 weeks during first 3 months or at point of clinical follow up. and then monthly or as clinically indicated. Pregnancy test. Used in Pediatric Areas Safety and efficacy have not been established. Renal or Hepatic Dosing No dosing adjustment in mild or moderate renal or hepatic impairment; dosage not established for severe renal or hepatic impairment. Critical Issues (i.e., contraindications, warnings, etc) Interstitial Lung Disease (ILD)/Pneumonitis: Immediately withhold tepotinib that should be emphasized in patients with suspected ILD/pneumonitis. Permanently discontinue tepotinib in patients diagnosed with ILD/pneumonitis of any severity. Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue tepotinib based on severity. Embryo‐Fetal Toxicity: Advise males and females of reproductive potential that tepotinib can cause fetal harm and to use effective contraception. Special administration technique or considerations Tepotinib tablets should be taken with food, swallowed whole and at approximately the same time each day. Prepared by Brandon Tabor Source Tepmetko (tepotinib) [prescribing information]. Rockland, MA: EMD Serono, Inc.; February 2021.

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Umbralisib / Ukoniq / TG Therapeutics Generic Name / Brand Name / Company Umbralisib / Ukoniq / TG Therapeutics Date of approval 2/5/21 Drug Class (Mechanism of Action if novel agent) Umbralisib is capable of inhibiting multiple kinases. It has been shown to inhibit PI3Kδ and casein kinase CK1ε. PI3Kδ is expressed in both normal and malignant B‐cells. CK1ε is thought to be involved in the pathogenesis of cancer cells, including lymphoid malignancies. Indication Treatment of adult patients with either relapsed or refractory marginal zone lymphoma (MZL) who received at least one prior anti‐CD20‐based regimen, or with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy. Comparative agent – Therapeutic interchange? PI3-kinase inhibitors (idelalisib, duvelisib, copanlisib) Dosage forms/strengths. Tablets: 200 mg Common Dose/sig 800 mg orally once daily with food DEA Schedule None Date of market availability Available Similar Medication Names Numbrino, Umbral Clinical Use Evaluation Common Adverse Effects (≥15% including laboratory abnormalities) increased creatinine, diarrhea‐ colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash Severe Adverse Effects Diarrhea‐colitis, pneumonia, sepsis, urinary tract infection, exfoliative dermatitis Severe Drug‐Drug Interactions None known Severe Drug‐Food Interactions None known Important Labs Values to assess prior to order entry Complete blood counts, liver function tests; pregnancy test or at point of clinical follow up. Used in Pediatric Areas Safety and efficacy have not been established in pediatric patients. Renal or Hepatic Dosing No dosage adjustments in mild to moderate renal impairment or mild hepatic impairment; has not been studied in severe renal impairment or moderate to severe hepatic impairment Critical Issues (i.e., contraindications, warnings, etc) Infections: Serious and fatal infections have occurred in patients treated with that should be emphasized umbralisib. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) should be provided during treatment with umbralisib. Prophylaxis for cytomegalovirus (CMV) infection should be considered and patients with a history of CMV infection should be monitored throughout treatment. Neutropenia: Neutrophil counts should be monitored at least every 2 weeks for the first 2 months of umbralisib, and more frequently if neutropenia occurs. Serious Diarrhea or Non-infectious colitis: Supportive care with antidiarrheal agents or enteric acting steroids should be used as appropriate. Hepatotoxicity: Monitor hepatic function at baseline and throughout treatment. Severe Cutaneous Reactions: monitor patients for new or worsening cutaneous reactions throughout therapy. Allergic Reactions: Sensitivity to FD&C Yellow No. 5 (tartrazine) may result in allergic-type reactions when taking umbralisib. Fetal Toxicity: During treatment and for one month following the last dose of umbralisib, female patients of reproductive potential and males with female partners of reproductive potential should be advised to use effective contraception. FDA Activity Newsletter WSU Drug Information Center February 2021 Page | 6

Special administration technique or considerations Umbralisib should be taken with food, swallowed whole, and at the same time each day. Prepared by Brandon Tabor Source Ukoniq (umbralisib) [prescribing information]. Edison, NJ: TG Therapeutics, Inc.; February 2021

Evinacumab‐dgnb / Evkeeza / Regeneron Generic Name / Brand Name / Company Evinacumab‐dgnb / Evkeeza / Regeneron Date of approval 2/11/21 Drug Class (Mechanism of Action if novel agent) Binds to angiopoietin‐like protein 3 (ANGPTL3) in the liver to help increase breakdown of lipids that lead to high cholesterol. Indication Indicated as adjunct to other low‐density lipoprotein cholesterol lowering therapies in adults and pediatric patients 12 years and older with homozygous familial hypercholesterolemia (HoFH). Comparative agent – Therapeutic interchange? None; PCSK9 inhibitors (alirocumab, evolocumab), lomitapide Dosage forms/strengths. Injection solution: 345 mg/2.3 mL and 1200 mg/8 mL (150 mg/mL) in single‐ dose vials Common Dose/sig 15 mg/kg by IV infusion over 60 minutes once monthly (or every 4 weeks) DEA Schedule None Date of market availability Available Similar Medication Names Evoxac, Evista, evolocumab Clinical Use Evaluation Common Adverse Effects ≥5%: nasopharyngitis, influenza‐like illness, dizziness, rhinorrhea, and nausea Severe Adverse Effects Infusion reactions, anaphylaxis Severe Drug‐Drug Interactions None known Severe Drug‐Food Interactions None Known Important Labs Values to assess prior to order entry Lipid panel, presence of HoFH; LDL‐C lowering effects may be measured at 2 or at point of clinical follow up. weeks after initiating treatment. Pregnancy test. Used in Pediatric Areas Safety and efficacy in patients less than 12 years has not been established Renal or Hepatic Dosing No dosage modification currently recommended. Evinacumab‐dgnb has not been studied in severe renal impairment or hepatic impairment. Critical Issues (i.e., contraindications, warnings, etc) Contraindications: History of serious hypersensitivity reactions to that should be emphasized evinacumab‐dgnb or any product ingredients. Warnings: Serious hypersensitivity reactions – discontinue infusion if occur. Embryo‐fetal toxicity – Evinacumab‐dgnb can cause fetal harm when administered to a pregnant patient. Advise females of reproductive potential to use effective contraception while receiving evinacumab‐dgnb and for at least 5 months after the last dose. Consider obtaining a pregnancy test prior to starting treatment. Special administration technique or considerations Administer the diluted solution via IV infusion immediately after preparation through an IV line containing sterile, in‐line or add‐on, 0.2‐to‐5‐micron filter; total infusion time should be 60 minutes. Slow, interrupt, or discontinue the rate of infusion if any signs of adverse reactions develop. Can be administered without regard to the timing of lipoprotein apheresis. Prepared by David Tam Source Evkeeza (evinacumab‐dgnb) [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals Inc; February 2021. FDA Activity Newsletter WSU Drug Information Center February 2021 Page | 7

Trilaciclib / Cosela / G1 Therapeutics Generic Name / Brand Name / Company Trilaciclib / Cosela / G1 Therapeutics Date of approval 2/12/21 Drug Class (Mechanism of Action if novel agent) Antineoplastic Agent, Cyclin‐Dependent Kinase Inhibitor; induces transient G1 arrest of hematopoietic stem cells contributing to a myeloprotective effect during administration of chemotherapy Indication Chemotherapy‐induced myelosuppression: Decreases the incidence of chemotherapy‐induced myelosuppression when given before a platinum/etoposide containing regimen or topotecan‐ containing regiment for extensive‐stage small cell lung cancer in adults. Comparative agent – Therapeutic interchange? None Dosage forms/strengths. Injection: 300 mg Trilaciclib as a lyophilized cake in a single‐dose vial Common Dose/sig Recommended dose is 240 mg/m2 given as a 30‐minute IV infusion completed within 4 hours prior to the start of chemotherapy on each day chemotherapy is administered. DEA Schedule None Date of market availability Anticipated early March 2021 Similar Medication Names Triamcinolone, triamterene, Cozaar Clinical Use Evaluation Common Adverse Effects ≥10%: fatigue, hypocalcemia, hypokalemia, hypophosphatemia, aspartate aminotransferase increased, headache, and pneumonia. Severe Adverse Effects Infusion reactions, respiratory failure, hemorrhage, thrombosis, pneumonia, hemoptysis Severe Drug‐Drug Interactions Avoid concomitant use with OCT2, MATE1, and MATE‐2K substrates. Minimal substrate concentration changes may lead to serious or life‐ threatening toxicities. May increase serum concentration of cisplatin, dalfampridine, dofetilide, and metformin. Severe Drug‐Food Interactions None reported. Important Labs Values to assess prior to order entry Pregnancy test. or at point of clinical follow up. Used in Pediatric Areas Safety and effectiveness not established Renal or Hepatic Dosing Not recommended in patients with moderate or severe hepatic impairment. No dosage adjustment in mild hepatic impairment. No clinically significant differences in pharmacokinetics observed in patients with mild to moderate renal impairment. Critical Issues (i.e., contraindications, warnings, etc) Contraindications: history of serious hypersensitivity reactions to Trilaciclib. that should be emphasized Warnings: Injection site reactions including phlebitis and thrombophlebitis Acute hypersensitivity reactions Interstitial lung disease/pneumonitis Fetal harm Special administration technique or considerations Must be reconstituted before use and is only for IV administration. Administer with an infusion set including an in‐line filter (0.2 or 0.22 micron) and polyethylene sulfone, polyvinylidene fluoride, or cellulose acetate (not compatible with polytetrafluoroethylene in‐line filters). Following infusion, flush the line with at least 20 mL sterile 0.9% sodium chloride injection USP or 5% dextrose injection USP. Prepared by David Tam Source Cosela (trilaciclib) [prescribing information]. Durham, NC: G1 Therapeutics Inc; February 2021.

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Casimersen / Amondys 45 / Sarepta Therapeutics Generic Name / Brand Name / Company Casimersen / Amondys 45 / Sarepta Therapeutics Date of approval 2/25/21 Drug Class (Mechanism of Action if novel agent) Antisense oligonucleotide; increases dystrophin production Indication Treatment of Duchenne muscular dystrophy (DMD) in patients who have confirmed mutation of the DMD gene amenable to exon 45 skipping. Comparative agent – Therapeutic interchange? None Dosage forms/strengths. Injection: 100 mg/2 mL in single‐dose vial Common Dose/sig 30 mg/kg as an IV infusion once weekly DEA Schedule None Date of market availability Available Similar Medication Names Casirivimab, Exondys 51 Clinical Use Evaluation Common Adverse Effects >20%: upper respiratory tract infection, cough, pyrexia, headache, arthralgia, oropharyngeal pain Severe Adverse Effects None reported Severe Drug‐Drug Interactions None known Severe Drug‐Food Interactions None known Important Labs Values to assess prior to order entry Serum cystatin C, urine dipstick, urine protein‐to‐creatinine ratio, or at point of clinical follow up. glomerular filtration rate Used in Pediatric Areas Indication includes pediatric patients. Renal or Hepatic Dosing No specific dosage adjustments; monitor patients with renal function impairment closely. Critical Issues (i.e., contraindications, warnings, etc) Warnings: that should be emphasized Kidney toxicity: monitor renal function Special administration technique or considerations Application of a topical anesthetic cream to infusion site prior to administration may be considered. Administer as IV infusion over 35 to 60 minutes via an infusion set with in‐line 0.2‐micron filter. Flush with 0.9% sodium chloride injection USP before and after infusion. Prepared by Terri Levien Source Amondys 45 (casimersen) [prescribing information]. Cambridge, MA: Sarepta Therapeutics, Inc.; February 2021.

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Fosdenopterin / Nulibry / Origin Biosciences Generic Name / Brand Name / Company Fosdenopterin / Nulibry / Origin Biosciences Date of approval 2/26/21 Drug Class (Mechanism of Action if novel agent) Cyclic pyranopterin monophosphate (cPMP); substrate replacement Indication Reduce the risk of mortality in patients with molybdenum cofactor deficiency type A; may be initiated with diagnosis or presumptive diagnosis, but must be confirmed by genetic testing Comparative agent – Therapeutic interchange? None Dosage forms/strengths. Injection: 9.5 mg as a lyophilized powder/cake in singe‐dose vial Common Dose/sig Administer once daily as an IV infusion; dose varies by age (see prescribing information) DEA Schedule None Date of market availability Available Similar Medication Names Fosaprepitant, Nulytely Clinical Use Evaluation Common Adverse Effects >25%: catheter‐related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, diarrhea Severe Adverse Effects None reported Severe Drug‐Drug Interactions None known Severe Drug‐Food Interactions None known Important Labs Values to assess prior to order entry Confirmation of diagnosis by genetic testing or at point of clinical follow up. Used in Pediatric Areas Indicated in pediatric patients from birth Renal or Hepatic Dosing No dosage adjustments: effects of impairment on fosdenopterin pharmacokinetics are not known. Critical Issues (i.e., contraindications, warnings, etc) Warnings: that should be emphasized Photosensitivity – avoid exposure to sunlight Special administration technique or considerations Administered as an IV infusion through an infusion pump at a rate of 1.5 mL/minute using non‐DEHP tubing with a 0.2‐micron filter. Prepared by Terri Levien Source Nulibry (fosdenopterin) [prescribing information]. Boston, MA: Origin Biosciences, Inc.; February 2021.

FDA Activity Newsletter WSU Drug Information Center February 2021