Cobenfy From Bristol Myers Squibb

The FDA has approved xanomeline and trospium chloride oral capsules (Cobenfy; Bristol Myers Squibb) for the treatment of schizophrenia in adults.¹ Schizophrenia affects approximately 2.8 million individuals in the US and 24 million people around the globe, with initial symptoms usually occurring in early adulthood. It is among the top 15 leading causes of disability worldwide.²

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PHARMACOLOGY AND PHARMACOKINETICS

Xanomeline is an M1 and M4 muscarinic acetylcholine receptor agonist. It reaches maximum plasma concentrations 2 hours after oral administration and steady-state concentrations after 3 to 5 days. It has an elimination half-life of 5 hours. Trospium chloride is a muscarinic receptor antagonist that acts primarily in the peripheral tissues. Maximum plasma concentrations are achieved 1 hour after oral administration, and steady-state concentrations are observed after 3 to 5 days. Trospium chloride has an elimination half-life of 6 hours.¹

DOSING AND ADMINISTRATION

Before beginning treatment, bilirubin, liver enzymes, and heart rate should be assessed. The xanomeline and trospium chloride dose is 50 mg/20 mg orally twice daily for at least 2 days, followed by 100 mg/20 mg twice daily for at least 5 days. The dose may be increased to a maximum of 125 mg/30 mg twice daily if required for clinical response and tolerated. Older patients should begin treatment with 50 mg/20 mg twice daily and titrate slowly to the maximum dose of 100 mg/20 mg twice daily. The medication should be taken at least 1 hour before a meal or at least 2 hours afterward. The capsules should not be opened.¹

CLINICAL TRIALS

The efficacy of xanomeline and trospium chloride was evaluated in the phase 3 EMERGENT-2 (NCT04659161) and EMERGENT-3 (NCT04738123) clinical trials, consisting of adults with a diagnosis of schizophrenia. In both double-blind, multicenter, placebo-controlled, randomized studies, patients received either placebo or xanomeline and trospium chloride 50 mg/20 mg orally twice daily for 2 days, followed by 100 mg/20 mg orally twice daily for 5 days, with an increase to 125 mg/30 mg orally twice daily on day 8 if tolerated.

The primary efficacy measure was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 5. In both studies, patients using xanomeline and trospium chloride demonstrated a statistically significant reduction in the PANSS total score compared with placebo, with a 9.6-point reduction in EMERGENT-2 and an 8.4-point reduction in EMERGENT-3. The EMERGENT-2 trial met a secondary end point: the change from baseline to week 5 in the Clinical Global Impression–Severity score, a validated clinician-rated scale that measures current illness state and overall clinical state.^1,2

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS

Treatment with xanomeline and trospium chloride is contraindicated in patients with gastric retention, moderate or severe hepatic impairment, untreated narrow-angle glaucoma, urinary retention, or a history of hypersensitivity to any component of the medication.

Patients should be monitored for symptoms of acute urinary retention. Xanomeline and trospium chloride should not be used in patients with mild hepatic impairment or moderate or severe renal impairment. The medication should be discontinued if signs or symptoms of substantial liver injury occur. Xanomeline and trospium chloride may decrease gastrointestinal motility. Angioedema of the face, lips, larynx, and/ or tongue has been reported during treatment. Xanomeline and trospium chloride should only be used in patients with narrow-angle glaucoma if the benefits outweigh the risks, and these patients should be monitored carefully. Treatment with xanomeline and trospium chloride may increase heart rate. Patients should not drive or operate heavy machinery until they know how the medication affects them.

Additional monitoring is warranted when using xanomeline and trospium chloride concomitantly with agents eliminated by active tubular secretion, antimuscarinic drugs, sensitive substrates of cytochrome P450 (CYP) 3A4 or P-glycoprotein, or strong CYP2D6 inhibitors.

The most common adverse reactions are abdominal pain, constipation, diarrhea, dizziness, dyspepsia, gastrointestinal reflux disease, hypertension, nausea, tachycardia, and vomiting.¹

REFERENCES

1. Cobenfy. Prescribing information. Bristol Myers Squibb; 2024. Accessed October 23, 2024. https://packageinserts.bms.com/pi/pi_cobenfy.pdf

2. U.S. Food and Drug Administration approves Bristol Myers Squibb’s Cobenfy (xanomeline and trospium chloride), a first-in-class muscarinic agonist for the treatment of schizophrenia in adults. News release. Bristol Myers Squibb. September 26, 2024. Accessed October 23, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx