MRx Clinical Alert - May 2021

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MAY 2021










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

TRENDING TOPICS HOT TOPIC: JANSSEN COVID-19 VACCINE PAUSE LIFTED On April 13, 2021, the United States (US) Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) released a joint statement on 6 US cases of a rare and severe blood clot, cerebral venous sinus thrombosis (CVST), following administration of > 6.8 million doses of the Johnson & Johnson (Janssen) coronavirus disease 2019 (COVID-19) vaccine. These cases were reported to the Vaccine Adverse Event Reporting System (VAERS). The blood clots were observed in combination with thrombocytopenia in 6 women ranging in age from 18 to 48 years. The timeframe from receipt of the vaccine to onset of symptoms was a median of 9 days (range, 6 to 13 days). In some of these patients, blood clots also occurred in the large veins in the abdomen. One of the 6 patients died. At that time, the CDC and FDA recommended a pause in use of the Janssen COVID-19 vaccine to review and investigate these cases. The health authority also issued a Health Alert to ensure that healthcare providers (HCPs) are aware of these adverse events (AEs) and are able to provide appropriate management. HCPs should be aware of symptoms that are potentially related to thrombotic events or thrombocytopenia in patients who have recently received the Janssen vaccine. Furthermore, evaluation for autoimmune heparin-induced thrombocytopenia (HIT) should be conducted, and consultation with a hematologist is strongly recommended. Patients with these events should not receive heparin unless HIT testing is negative. Although these severe clots in combination with low platelets are extremely rare, patients who received the Janssen vaccine and experience any of the following are instructed to immediately contact their HCP: shortness of breath, chest pain, leg swelling, persistent abdominal pain, neurological symptoms (severe or persistent headaches, blurred vision), or petechiae (easy bruising 2 | MAY 2021

or tiny blood spots under the skin) outside the injection site. Notably, VAERS has not received any reports of CVST with thrombocytopenia in individuals who received either of the 2 messenger ribonucleic acid (mRNA)based COVID-19 vaccines (Pfizer-BioNTech or Moderna). The CDC convened 2 meetings of the Advisory Committee on Immunization Practices (ACIP) on April 14 and April 23 to review these cases plus additional new cases (total of 15 cases, including original 6 cases, all in women 18 to 59 years old with onset 6 to 15 days following vaccination). Following the ACIP’s vote to lift the pause, the FDA and CDC determined that use of the Janssen vaccine be resumed, and it is recommended under the Emergency Use Authorization (EUA) for all adults with a new warning on the risks of thrombosisthrombocytopenia syndrome (TTS). Almost all reports of TTS have been in women < 50 years old so they should be aware of this rare but serious AE and be aware of other COVID-19 vaccines options. The American Society of Hematology (ASH) has published guidance on the management of TTS.

BEHAVIORAL HEALTH CORNER: REPORT ON ANXIETY/DEPRESSION DURING COVID-19 The CDC has published a Morbidity and Mortality Weekly Report (MMWR) evaluating symptoms of anxiety or depression and the use of mental healthcare services in adults in the US during the COVID-19 pandemic. From August 19, 2020 to February 1, 2021, the proportion of adults who reported symptoms of an anxiety or a depressive disorder during the past 7 days increased from 36.4% to 41.5%. Similarly, the proportion of adults who reported that they needed mental health services in the prior 4 weeks but did not receive these services also increased from 9.2% to 11.7%. The greatest increases were observed in adults 18 to 29 years of age and in those with less than a high school education.

TRENDING TOPICS continued This data is based on the Household Pulse Survey (HPS) conducted by the CDC and US Census Bureau. The survey was a rapid-response online survey which utilized a probability-based sample design to assess the impact of the pandemic. Survey results are similar to data from prior surveys conducted earlier in the pandemic from March to June 2020 that demonstrated an increase in mental health symptoms, especially in young adults. Limitations of the survey data include reliance on selfreported data, lack of causal assessment of symptoms, potential impact of seasonal affective disorder, exclusion of survey participation in populations without internet access, and the potential for low response rates. A number of strategies have been implemented to mitigate potential mental health issues due to COVID-19, including expansion of telehealth services. These analyses can be used to evaluate the effects of various strategies and help to identify interventions for disproportionately impacted populations.

COVID-19 NOTABLE DEVELOPMENTS The FDA has revoked the EUA for the investigational drug bamlanivimab. The EUA for Eli Lilly’s monoclonal antibody was originally issued in November 2020 based on the scientific evidence available and authorized the agent as monotherapy for the treatment of mild to moderate COVID-19 in adults and pediatric patients (≥ 12 years old weighing ≥ 40 kg) with positive results from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral test who were at high risk for progressing to severe COVID-19 and/or hospitalization. Although the EUA for bamlanivimab monotherapy has been revoked, the EUAs for the combination therapies of casirivimab + imdevimab (Regen-cov™) and bamlanivimab + etesevimab remain in place. The bamlanivimab monotherapy EUA was revoked due to emerging data showing an increase in SARSCoV-2 viral variants with resistance to monotherapy. The CDC’s national genomic surveillance program has shown that about 20% of sequenced US viruses were anticipated to be resistant to bamlanivimab monotherapy as of mid-March 2021, compared with 5% observed in mid-January 2021.

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The FDA has revised the Moderna COVID-19 vaccine EUA to clarify the maximum number of extractable doses per vial is 11 (range, 10 to 11 doses). Also, an additional multi-dose vial (MDV) with a maximum number of 15 doses (range, 13 to 15 doses) has now been authorized. As the vaccine does not contain preservative, remaining product that does not result in a full dose should not be pooled from multiple vials. Additionally, Moderna has announced publication of data from an ongoing phase 1 trial on the persistence of COVID-19 vaccine antibodies for 6 months following the second dose in 33 healthy adults. Pfizer-BioNTech has released data from a US phase 3 study on the efficacy of their COVID-19 vaccine (BNT162b2) in adolescents 12 to 15 years old (n=2,260) that shows 100% efficacy in those with or without prior evidence of SARS-CoV-2 infection. The vaccine was well-tolerated with AEs similar to those seen in individuals 16 to 25 years old. Additionally, the manufacturers have requested amendments to the EUA to expand vaccine use for ages 12 to 15 years old. Pfizer-BioNTech has also released 6-month data on efficacy and safety that demonstrates vaccine efficacy of 91.3% from 7 days following the second dose through 6 months. Efficacy in preventing severe disease was 95.3% and 100%, respectively, according to the FDA’s and CDC’s definitions. Furthermore, ≥ 6 months of safety data are now available for > 12,000 individuals and demonstrate results similar to prior study findings with no serious safety concerns. The National Institutes of Health (NIH) has updated their COVID-19 Treatment Guidelines to include a new section on the outpatient management of acute COVID-19; this section addresses patients with mild to moderate illness not requiring hospitalization. New subsections were also added to provide information on SARS-CoV-2 variants of concern and details on SARSCoV-2 reinfection in those with a prior documented COVID-19 infection. For more resources on COVID-19, visit the Magellan Rx Coronavirus Update webpage. For the most current information, visit the FDA, the CDC, NIH, and World Health Organization (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.


HAPPENINGS & HIGHLIGHTS • The FDA has issued a Drug Safety Communication for the antiepileptic agent lamotrigine (Lamictal®, generics) regarding a potential increased risk of arrhythmias, based on reports of abnormal electrocardiograms (ECGs), in patients with heart disease. Chest pain, loss of consciousness, and cardiac arrest were also reported. The agency will continue to evaluate and inform the public and HCPs of their findings as more data from required in vitro studies are available. HCPs should evaluate whether the potential benefits of lamotrigine outweigh the potential risk of arrhythmias for individual patients. Additionally, the FDA has approved associated updates to relevant prescribing information (PI). • The FDA has approved updated labeling for pembrolizumab (Keytruda ® ) for the voluntary withdrawal of its indication for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and ≥ 1 other prior line of therapy. The original June 2019 Accelerated Approval of pembrolizumab was based on results of the KEYNOTE-158 and KEYNOTE-028 trials; however, subsequent results of the KEYNOTE-604 trial did not demonstrate statistically significant improvements in overall survival. Pembrolizumab continues to be FDA-approved for other specific types of cancer.

• Apotex has issued a voluntary recall of 3 lots of guanfacine extended-release (ER) tablets 2 mg to the consumer level due to trace amounts of quetiapine fumarate in 1 lot (RX1663). Out of caution, 2 other lots are also being recalled: RX1662 and RX1664. No adverse effects related to this recall have been reported, but exposure in trace amounts could result in a hypersensitivity reaction. In addition, exposure to quetiapine could result in additive effects in reducing blood pressure, sleepiness/sedation, and dizziness. • Alembic has issued a voluntary recall of 1 lot of telmisartan tablets, USP, 20 mg, packaged in 30-count bottles to the consumer level due to a complaint stating that 1 bottle labeled as 20 mg incorrectly contained 40 mg tablets. Too high of a dose could lead to hypotension, worsened renal function, or elevated potassium, which could be life threatening. No AEs have been reported related to the recall. • The FDA issued a Safety Communication and is requiring a new warning be added to the PI for zoster vaccine recombinant, adjuvanted (Shingrix) regarding the risk for Guillain-Barré syndrome (GBS) following administration. This new warning is based on a postmarketing observational study. The vaccine is indicated for prevention of herpes zoster (shingles) in adults ≥ 50 years old.

DRUG INFORMATION HAPPENINGS • The American College of Physicians (ACP) has published Best Practice Advice on the use of short-course antibiotics for common bacterial infections (e.g., acute bronchitis with chronic obstructive pulmonary disease [COPD] exacerbation, community-acquired pneumonia [CAP], urinary tract infections [UTIs], cellulitis). • The FDA has published its inaugural issue of the quarterly Sentinel Newsletter. Sentinel was developed in 2008 and provides innovative methods for evaluating the safety of medical products. • The US Preventive Services Task Force (USPSTF) has published a final recommendation on screening for vitamin D deficiency in adults. Currently, evidence is inadequate to determine the benefits versus harms for screening for vitamin D deficiency in asymptomatic, community-dwelling, non-pregnant adults (Grade I). • The FDA has launched a new webpage that includes all the reviews for EUAs for COVID-19 drugs and biologics.







eflapegrastim Spectrum

• SC • Granulocyte colony-stimulating factor (G-CSF)


May 2021

bupivacaine/meloxicam Heron

• Instillation • Amide anesthetic/nonsteroidal antiinflammatory drug (NSAID)

Postsurgical pain


pegcetacoplan Apellis

• SC • Complement inhibitor

Paroxysmal nocturnal hemoglobinuria


avalglucosidase alfa Sanofi

• IV • Lysosomal glycogen-specific enzyme

Pompe disease


filgrastim (biosimilar to Amgen’s Neupogen®) Tanvex

• SC • G-CSF



leuprolide mesylate (ready-to-use, 6-month depot) Intas

• SC • Gonadotropin-releasing hormone (GnRH) agonist

Prostate cancer


ozanimod (Zeposia®) Bristol-Myers Squibb

• Oral • Sphingosine 1-phosphate (S1P) receptor modulator

Ulcerative colitis


zonisamide oral suspension Azurity

• Oral • Antiepileptic agent

Partial seizures


ibrexafungerp Scynexis

• Oral • Glucan synthase inhibitor

Vulvovaginal candidiasis


relugolix/estradiol/ norethindrone Myovant

• Oral • GnRH antagonist/estrogen/progestin

Uterine fibroids


samidorphan/olanzapine Alkermes

• Oral • Opioid antagonist/atypical antipsychotic

Bipolar disorder; Schizophrenia


IV = intravenous; SC = subcutaneous

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New Drugs rosuvastatin/ezetimibe (Roszet®) Althera

• 505(b)(2) NDA approval 03/23/2021; Standard Review • Indicated as an adjunct to diet in adults with primary non-familial hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C), and indicated alone or as an adjunct to other LDL-C-lowering therapies in adults with homozygous familial hypercholesterolemia (HoFH) to reduce LDL-C • Combination of a 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA)-reductase inhibitor (statin) and dietary cholesterol absorption inhibitor • Oral tablets: 5 mg/10 mg, 10 mg/10 mg, 20 mg/10 mg, and 40 mg/10 mg • Recommended dosage is dependent on a patient’s indication for usage, LDL-C, and risk for cardiovascular (CV) events; the dosage range is 5 mg/10 mg to 40 mg/10 mg once daily, swallowed whole at any time of day, with or without food; initial dose for patients switching from co-administration of a statin and ezetimibe is based on the equivalent dose of rosuvastatin and 10 mg ezetimibe; evaluate LDL-C as clinically indicated, as early as 2 weeks following initiation, and adjust the dose if needed; dose adjustments are required for Asian patients, patients with severe renal impairment, and due to certain drug interactions • Product availability is expected in June 2021

mirabegron (Myrbetriq® Granules) Astellas

• NDA approval 03/25/2021; Priority Review • Indicated for the treatment of neurogenic detrusor overactivity (NDO) in pediatric patients ≥ 3 years of age • Beta-3 adrenergic agonist • Oral granules for suspension: 8 mg/mL ER oral suspension after reconstitution; not substitutable on a mg-per-mg basis with the ER tablets; the granules should be used for pediatric patients < 35 kg; for pediatric patients ≥ 35 kg, the granules or tablets can be used • Recommended dosage is weight-based, administered orally once daily » Body weight < 35 kg: starting dose range is 3 mL (24 mg) to 4 mL (32 mg), depending on body weight, to a maximum of 6 mL (48 mg) to 8 mL (64 mg) » Body weight ≥ 35 kg: starting dosage is 6 mL (48 mg) orally once daily, maximum 10 mL (80 mg) orally once daily after 4 to 8 weeks • Product availability is expected by the end of 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.



New Drugs continued idecabtagene vicleucel (Abecma®) Celgene

• BLA approval 03/26/2021; Breakthrough Therapy; Orphan Drug • Indicated for treatment of adults with relapsed or refractory multiple myeloma after ≥ 4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody • B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy • Cell suspension for injection: chimeric antigen receptor (CAR)-positive T cells in 1 or more infusion bags for autologous use • Recommended dosage is 300 to 460 x 106 CAR-positive T cells given via IV infusion • Only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program and must be administered by an HCP at a certified healthcare facility • Boxed warnings for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), and prolonged cytopenia

viloxazine (Qelbree™) Supernus

• NDA approval 04/02/2021; Standard Review • Indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients 6 to 17 years of age • Selective norepinephrine reuptake inhibitor (SNRI) • Oral ER capsules: 100 mg, 150 mg, and 200 mg • Recommended dosage based on patient’s age; capsules can be swallowed whole or opened and the contents sprinkled onto applesauce; dosage adjustment is recommended for severe renal impairment » Age 6 to 11 years: starting dose is 100 mg once daily, titrated in increments of 100 mg weekly to a maximum of 400 mg once daily » Age 12 to 17 years: starting dose is 200 mg once daily, titrated in increments of 200 mg to a maximum of 400 mg once daily • Boxed warning for suicidal thoughts and behaviors

drospirenone/estetrol (Nextstellis®) Mayne

• 505(b)(2) NDA approval 04/15/2021; Standard Review • Indicated for use by females of reproductive potential to prevent pregnancy • May be less effective in females with a body mass index (BMI) ≥ 30 kg/m2; in these patients, decreasing efficacy may be associated with increasing BMI • Combination of a progestin and an estrogen • Oral tablets: 28-tablet blister card with 24 pink active drospirenone 3 mg/estetrol 14.2 mg tablets and 4 white inert tablets • Recommended dosage is 1 tablet by mouth at the same time every day, with or without food, in the order directed on the blister pack • Boxed warning for cigarette smoking and serious CV events

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.

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New Drugs continued dostarlimab-gxly (Jemperli) GlaxoSmithKline

• BLA approval 04/22/2021; Accelerated Approval, Breakthrough Therapy, Priority Review, Real-Time Oncology Review • Indicated for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen; continued approval may require demonstration of benefit in confirmatory clinical trials • Programmed death receptor-1 (PD-1)-blocking antibody • Solution for injection: 500 mg/10 mL (50 mg/mL) in a single-dose vial (SDV) • Recommended dosage is 500 mg every 3 weeks for 4 doses, with subsequent doses beginning 3 weeks after dose 4 as 1,000 mg every 6 weeks; administered as an IV infusion over 30 minutes by an HCP; continue therapy until disease progression or unacceptable toxicity; dosage modifications are recommended for certain adverse reactions, depending on the type and severity

loncastuximab tesirinelpyl (Zynlonta™) ADC Therapeutics

• BLA approval 04/23/2021; Accelerated Approval, Assessment Aid, Orphan Drug, Priority Review • Indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma after ≥ 2 lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma; continued approval may require demonstration of benefit in confirmatory clinical trials • CD19-directed antibody and alkylating agent conjugate • Powder for injection: 10 mg as a lyophilized powder in an SDV for reconstitution and further dilution • Recommended dosage is 0.15 mg/kg every 3 weeks for 2 cycles, followed by 0.075 mg/kg every 3 weeks for subsequent cycles; administered by an HCP as an IV infusion over 30 minutes on day 1 of each 3-week cycle; dosage delays and modifications are recommended for certain adverse reactions, depending on the type and severity

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: © 2021, Magellan Health. All rights reserved.