What are the safety warnings, contraindications, and monitoring considerations for Cobenfy (xanomeline/trospium)?

Cobenfy (Xanomeline/Trospium) Safety Profile and Monitoring Requirements

Contraindications

Cobenfy is absolutely contraindicated in five specific clinical scenarios that must be ruled out before prescribing. 1

• Urinary retention (active or history of) 1
• Moderate or severe hepatic impairment 1
• Gastric retention 1
• History of hypersensitivity to Cobenfy or trospium chloride 1
• Untreated narrow-angle glaucoma 1

Critical Warnings and Precautions

Urinary Retention Risk

• Cobenfy can cause acute urinary retention, with geriatric patients and those with bladder outlet obstruction at highest risk 1
• Monitor all patients for symptoms of acute urinary retention throughout treatment 1

Hepatobiliary Toxicity

• Assess liver enzymes and bilirubin before starting Cobenfy and as clinically indicated during treatment 1
• Cobenfy is not recommended in patients with mild hepatic impairment 1
• Discontinue Cobenfy immediately if signs or symptoms of substantial liver injury develop 1

Gastrointestinal Effects

• Cobenfy decreases gastrointestinal motility and must be used with caution in patients with gastrointestinal obstructive disorders due to gastric retention risk 1
• The most common adverse events include constipation, nausea, dyspepsia, vomiting, abdominal pain, diarrhea, and gastroesophageal reflux disease (all occurring in ≥5% of patients at twice the placebo rate) 1
• Constipation, nausea, dry mouth, dyspepsia, and vomiting were the most frequently reported adverse events in clinical trials 2

Cardiovascular Monitoring

• Cobenfy increases heart rate—assess heart rate at baseline and as clinically indicated during treatment 1
• Hypertension and tachycardia occur in ≥5% of patients at twice the placebo rate 1
• Supine heart rate increases were observed in clinical trials 3

Angioedema Risk

• Angioedema of the face, lips, tongue, and/or larynx has been reported with Cobenfy 1

Narrow-Angle Glaucoma

• Use Cobenfy in treated narrow-angle glaucoma only if potential benefits outweigh risks and with careful monitoring 1

Renal Impairment Considerations

Cobenfy is not recommended for patients with moderate or severe renal impairment due to expected greater anticholinergic adverse reactions from trospium accumulation 1

Central Nervous System Effects

• Cobenfy may cause CNS effects including dizziness (≥5% incidence at twice placebo rate) 1
• Advise patients not to drive or operate heavy machinery until they know how Cobenfy affects them 1
• Notably, somnolence, restlessness, and extrapyramidal symptoms occurred at similar rates to placebo 2

Metabolic and Weight Effects

Cobenfy demonstrates a favorable metabolic profile compared to traditional antipsychotics:

• Risk of ≥7% weight gain is reduced (RR=0.46, NNT=19 to prevent one case) 3
• LDL-cholesterol and HDL-cholesterol levels are reduced 3
• Triglyceride levels may increase 3

Common Adverse Events Requiring Monitoring

The following adverse events occur in ≥5% of patients at twice the placebo rate 1:

• Nausea
• Dyspepsia
• Constipation
• Vomiting
• Hypertension
• Abdominal pain
• Diarrhea
• Tachycardia
• Dizziness
• Gastroesophageal reflux disease

Tolerability Profile

• Any adverse event occurs with NNH=6 3
• Cholinergic and anticholinergic side effects are typically mild-to-moderate and mostly transient 3
• All-cause discontinuation rates are not significantly increased compared to placebo 3
• Serious adverse events and severe adverse events do not occur at higher rates than placebo 3

Drug Interactions Requiring Monitoring

• Monitor for increased Cobenfy-related adverse reactions when co-administered with strong CYP2D6 inhibitors 1
• Monitor for increased adverse reactions from drugs eliminated by active tubular secretion (competition with trospium) 1
• Monitor for increased adverse reactions from sensitive substrates of CYP3A4 or P-glycoprotein 1
• Monitor for increased anticholinergic adverse reactions when combined with other antimuscarinic drugs 1

Special Population Warnings

Geriatric Patients

• Start at 50 mg/20 mg twice daily 1
• Consider slower titration 1
• Maximum dose is 100 mg/20 mg twice daily (lower than general adult population) 1
• Increased risk of urinary retention 1

Pregnancy and Lactation

The FDA label does not provide specific pregnancy category information, but this represents a novel mechanism requiring careful risk-benefit assessment 1

Baseline and Ongoing Monitoring Algorithm

Before initiating Cobenfy:

1. Liver enzymes and bilirubin 1
2. Heart rate 1
3. Renal function (to exclude moderate/severe impairment) 1
4. Screen for contraindications (urinary retention, gastric retention, untreated narrow-angle glaucoma, hepatic impairment) 1

During treatment:

1. Liver enzymes and bilirubin as clinically indicated 1
2. Heart rate as clinically indicated 1
3. Symptoms of urinary retention at each visit 1
4. Gastrointestinal symptoms 1
5. Signs of angioedema 1