Pharmacy Update

March 2025

Clozapine REMS Practice Update

John Hoffman, PharmD Candidate

Previously, clozapine required monitoring and enrollment in a Risk Evaluation and Mitigation Strategies (REMS) program, due to a risk of severe neutropenia that could be potentially life-threatening.  According to the package insert, the incidence of leukopenia, decreased WBC, and neutropenia was 3% across all clozapine studies with the highest rates of clozapine-related neutropenia occurring in the first 18 weeks of treatment. The goal of the REMS program was early detection and prevention by monitoring the absolute neutrophil count (ANC) regularly.

In 2015, a unified clozapine REMS program was created to standardize monitoring across all clozapine products. This program required prescribers and pharmacies to enroll in the program, and patients’ ANC levels had to be reported to continue clozapine dispensing. In 2021, significant program modifications were implemented requiring real-time ANC reporting and authorization for clozapine dispensing. These changes led to delays in clozapine access, resulting in concerns from healthcare professionals about patient care interruptions. In February 2025, the FDA eliminated the REMS for clozapine3, no longer requiring mandatory patient registration or ANC reporting.

There were many factors leading to the decision to remove the REMS requirement; one of the more informative reasons was looking at the rates of neutropenia of clozapine compared to other antipsychotic medications. The FDA concluded that the incidence of neutropenia was not significant enough to warrant the use of a REMS program, citing a 2023 observational analysis:

“Glocker et al. (2023) analyzed data from an observational pharmacovigilance program in Germany, Austria, and Switzerland from 1993 to 2016, which included 333,175 psychiatric inpatients treated with antipsychotic drugs. They identified 124 cases of antipsychotic-induced neutropenia (ANC <1500/µL) and 48 cases of severe neutropenia (ANC <500/µL), corresponding to a cumulative incident rate of 0.37 and 0.14 per 1000 in patients treated with antipsychotic drugs, respectively. Inpatients who were exposed to clozapine had the highest incidence rate of neutropenia of 1.57% (95% CI 1.2-2.0) across 60 cases, followed by perazine 0.52% (95% CI 0.24-1.0) across 8 cases, quetiapine 0.23% (95% CI 0.12-0.4) across 15 cases, olanzapine 0.13% (95% CI 0.06-0.25) across 7 cases, aripiprazole 0.13% (95% CI 0.05-0.45) across 2 cases, risperidone 0.11% (95%CI 0.07-0.25) across 6 cases, prothipendyl 0.06% (95% CI 0-0.32) in 1 case, promethazine 0.06% (95%CI 0-0.3) in 1 case, and haloperidol 0.03% (95% CI 0-0.13) in 1 case.”1,2

The FDA concluded that the REMS program was no longer necessary to ensure patient safety and that removing it would improve access while maintaining monitoring recommendations. The FDA still recommends that prescribers monitor patients’ ANC according to the monitoring frequencies described in the prescribing information. Information about severe neutropenia will remain in the prescribing information, including in the existing boxed warning.

References:

1. FDA Briefing Document. Risk Evaluation and Mitigation Strategy (REMS) for Clozapine Products. Division of Risk Management/Office of Medication Error Prevention and Risk Management and Division of Psychiatry/Office of Neuroscience. November 19, 2024. Page 37-38. Accessed March 16, 2025 from: https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-meeting-time-and-public-participation-information-november-19-2024-joint-meeting-drug-safety#event-information

2. Glocker, C, R Grohmann, G Burkhardt, J Seifert, S Bleich, T Held, S Toto, S Stübner, and C Schüle, 2023, Antipsychotic drug-induced neutropenia: results from the AMSP drug surveillance program between 1993 and 2016, J Neural Transm (Vienna), 130(2):153-163.

3.     Research C for DE and. Frequently Asked Questions | Clozapine REMS Modification. FDA. Published online February 25, 2025. Accessed March 16, 2025. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/frequently-asked-questions-clozapine-rems-modification

4.     UPDATED MEETING TIME AND PUBLIC PARTICIPATION INFORMATION: November 19, 2024: Joint Meeting of the Drug Safety and Risk Management Advisory Committee and Psychopharmacologic Drugs Advisory Committee Meeting Announcement - 11/19/2024. FDA. February 4, 2025. Accessed March 16, 2025. https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-meeting-time-and-public-participation-information-november-19-2024-joint-meeting-drug-safety

December 2024

Cobenfy (Xanomeline/Trospium)

Erin Isaacson, PharmD Candidate

Cobenfy (xanomeline/trospium) is a dual muscarinic agonist (xanomeline) and antagonist (trospium) used to treat schizophrenia in adults. Xanomeline treats schizophrenia through agonist activity at the M1 and M4 receptors in the central nervous system. Trospium antagonizes muscarinic receptors primarily in the peripheral tissues. Xanomeline/trospium does not have any direct inhibition of dopamine 2 receptors, making it a first in class medication for schizophrenia that is not associated with the same side effect profile of other antipsychotic agents (such as movement disorders and metabolic effects).1

Xanomeline/trospium requires a dose titration, based on patient response:1

Initial dose: xanomeline 50 mg/trospium 20 mg BID for >2 days

Increased to: xanomeline 100 mg/trospium 20 mg BID for > 5 days

Maximum dose: xanomeline 125 mg/trospium 30 mg twice a day

The EMERGENT 1 through 3 clinical trials 2–4 studied the safety and efficacy of this first in class medication.  EMERGENT-1 showed a significant decrease in the Positive and Negative Syndrome Scale (PANSS) as compared to placebo (-11.6 point difference between groups, p<0.001.)2  EMERGENT-2 also showed a significant decrease in the PANSS as compared to placebo (-9.6 point different between groups, p<0.0001).3  Similarly, EMERGENT-3 showed a significant decrease in the PANSS as compared to placebo (-8.4 point difference between groups, p<0.001)4 The most common adverse event during these trials were nausea (19%), dyspepsia (18%), constipation (17%), vomiting (15%), and hypertension (11%).

References

1.       Xanomeline and Trospium (Lexi-Drugs) - UpToDate® LexidrugTM. Accessed Dec. 5, 2024.

2.       Brannan, S. K. et al. Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. N. Engl. J. Med. 384, 717–726 (2021).

3.       Kaul, I. et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet Lond. Engl. 403, 160–170 (2024).

4.       Kaul, I. et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry 81, 749–756 (2024).

September 2023

Adult RSV Vaccine Recommendations

Nicole Shattuck, PharmD Candidate

Respiratory syncytial virus (RSV) is associated with increased morbidity and mortality in older adults aged ³ 60 years. Certain patients with health conditions such as COPD, congestive heart failure, diabetes mellitus, chronic kidney disease, and other cardiovascular diseases are also at increased risk of RSV-associated hospitalization.

There are two FDA approved RSV vaccines available as of May 2023:

RSVPreF3 (Arexvy, GSK): 1-dose, 0.5 ml adjuvanted recombinant RSV vaccine

RSVpreF (Abrysvo, Pfizer): 1-dose, 0.5 ml recombinant RSV vaccine

The RSV vaccine may be given simultaneously with other vaccines (such as influenza and COVID) to increase convenience of vaccination.

In clinical trials the GSK and Pfizer vaccines demonstrated 74.5% and 84.4% effectiveness respectively at preventing RSV over two seasons.1  (The studies did not have enough power to estimate efficacy at preventing severe RSV and associated hospitalization.)  Serious adverse effects did not differ between either of the vaccine formulations and placebo.  However, there were 6 cases of inflammatory neurologic events reported after RSV vaccination in the various trials.  Due to the low number of events, it is unknown if they were caused by the vaccines or due to chance.1

In June 2023, the ACIP recommended that adults aged ³ 60 years may receive a single dose of RSV vaccine, using shared clinical decision-making with their vaccine provider.1  It is important to note that the recommendation for this vaccine is that patients may receive a dose and not patients should receive a dose.  Shared clinical decision-making is key to this recommendation, as all patients may not benefit from the vaccine.  Patients at highest risk of severe disease will likely gain the most benefit from this vaccine.

Reference:

1. Melgar M, Britton A, Roper LE, et al. Use of Respiratory Syncytial Virus Vaccines in Older Adults: Recommendations of the Advisory Committee on Immunization Practices — United States, 2023. MMWR. 2023;72:793–801.

June 2023

Nurtec (Rimegepant)

Aaron Christian, PharmD Candidate 2023

Rimegepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist. Currently, we don’t have a good understanding of how CGRP might act in migraine pathophysiology, but we do know that levels of CGRP are increased during acute migraine episodes and decrease with treatment.  There are currently several migraine treatments that target CGRP, however, rimegepant is currently the only CGRP antagonist that is approved for both acute treatment and prevention.

Dosing:

Acute Migraine: 75 mg ODT single dose (max dose 75 mg/24 hours)

Prevention: 75 mg ODT every other day

When used for treatment of an acute migraine episode, 81% of patients reported freedom from pain or pain relief at 2 hours and 86% of patients did not take another rescue medication within 24 hours after their dose.1  When used for prevention of migraine episodes, patients had an average of 4.3 fewer migraine days per month and 49% of patients reduced their migraine days by at least 50%.2

Rimegepant was well tolerated by patients being treated with both acute and preventive therapy.  The most common side effect was nausea in 2-3% of patients and only 2% of patients discontinued treatment due to adverse effects.

Currently, treatment with rimegepant is recommended for patients who do not tolerate or respond to other acute or preventative migraine treatments.

References

1.       Croop R, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet 2019; 394: 737–45.

2.       Croop R, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomized, double-blind, placebo-controlled trial. Lancet 2021; 397: 51–60.

February 2023

Tirzepatide (Mounjaro): What's All the Fuss About?

Jennifer King, PharmD Candidate

Tirzepatide is the newest glucose-dependent insulinotropic polypeptide (GIP) AND glucagon-like peptide (GLP-1) receptor agonist. It is indicated as an adjunct to diet and exercise in patients with type 2 diabetes. 1,2

Initial dosing is 2.5 mg subcutaneously once weekly titrated up by 2.5 mg every 4 weeks to a max of 15 mg once weekly.  Reduction of current insulin doses should be considered on initiation of terzepatide to decrease the incidence of hypoglycemia. 1,2

The mechanism of action for this first in class medication is similar to the GLP-1’s:1,2

-          Decreasing food intake

-          Delaying gastric emptying

-          Reducing inappropriate glucagon secretion

-          Increasing insulin sensitivity

-          Enhancing first and second phase insulin secretion

The most common reported adverse reactions are nausea (12-18%), vomiting (5-9%), diarrhea (12-17%), decreased appetite (5-11%), constipation (6-7%), indigestion (5-8%), and abdominal pain (5-6%), increased pancreatic enzymes (31-42%).2

Clinical trials3 found an average reduction in A1c of up to 2.3% and an average weight reduction of 12.4 kg with tirzepatide 15 mg.  Eighty percent of patient’s were able to achieve a 5% weight loss, 57% of patients were able to achieve a 10% weight loss and 36% of patients were able to achieve a 15% weight loss on tirzepatide 15 mg.

References:

1.      Mounjaro [package insert]. Indianapolis, IN: Lilly; 2022.

2.      Lexicomp: Mounjaro (Lexi-drugs) [database online]. NY, New York: Wolters Kluwer; February 1, 2023.

3.      Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). N Engl J Med 2021;385:503-15.

November 2022

Updated Adult* COVID Vaccine Recommendations Fall 2022 

McKayla Schafsnitz, PharmD Candidate

Updated mRNA bivalent COVID vaccines have been available since September of 2022. Patients are eligible for the updated bivalent vaccine if they meet the following requirements:

• Completed the primary series of the original monovalent vaccine (2 doses of Moderna or Pfizer or 1 dose of Janssen in most patients*)

• At least 2 months have passed since the most recent COVID vaccination (regardless of primary series or a booster)

• At least 12 years old for the bivalent Pfizer vaccine or 18 years old for the bivalent Moderna vaccine.

Patients who have not yet completed their primary vaccine series must do so prior to receiving the updated bivalent vaccine per ACIP guidance.  Booster doses of the original monovalent mRNA COVID vaccines are no longer recommended in patients 12 years or older. Instead, these patients should receive a single dose of the updated bivalent mRNA vaccine.

The updated bivalent vaccine contains components of the original Wuhan variant plus BA.4 and BA.5 Omicron subvariants.  It can be coadministered with other common immunizations, such as influenza, pneumococcal, hepatitis A, and Tdap vaccines.

*These recent updates from the ACIP are intended for patients 12 and older.

October 2022

Paxlovid and Oral Contraceptives

Brenda Rosebrugh, PharmD Candidate

Paxlovid is an investigational packaged combination of nirmatrelvir, a second-generation protease inhibitor, and ritonavir, commonly used to boost plasma concentrations of protease inhibitors, for the treatment of severe acute respiratory syndrome caused by coronavirus-2 infection (COVID-19). Paxlovid does have a significant direct interaction with most oral contraceptives that pharmacists should be aware of.

In numerous pharmacokinetic studies1,2, it is demonstrated that protease inhibitors can decrease ethinyl estradiol AUC anywhere from 19% to 55%. The package insert states that "an additional, non-hormonal method of contraception should be considered during the 5 days of PAXLOVID treatment and until one menstrual cycle after stopping PAXLOVID”. While there is limited and conflicting data if there is a statistically significant difference in contraceptive failure with the use of protease inhibitors, the potential risk of unplanned pregnancy would still warrant basic mitigation measures.

Every patient who is receiving an oral contraception containing estrogen should be counselled on the importance of using a non-hormonal back up protection, not only for the duration of Paxlovid therapy, but also for one menstrual cycle after stopping therapy.

1.       Scarsi KK, Cramer YS, Rosenkranz SL, et al. Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study. Lancet HIV. 2019;6(9):e601-e612. [PubMed 31498109]

2.       5. Vogler MA, Patterson K, Kamemoto L, et al. Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188. J Acquir Immune Defic Syndr. 2010;55(4):473-482. [PubMed 20842042]

3.       PAXLOVID package insert; https://www.fda.gov/media/155050/download