Version July 2025
Schizophrenia: Oral: Initial: Xanomeline 50 mg and trospium chloride 20 mg twice daily for ≥2 days, then increase to xanomeline 100 mg and trospium chloride 20 mg twice daily for ≥5 days. May increase further based on response and tolerability to xanomeline 125 mg and trospium chloride 30 mg twice daily. Maximum dose: Xanomeline 125 mg and trospium chloride 30 mg twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild impairment (eGFR 60 to <90 mL/minute): Refer to adult dosing.
Moderate impairment (eGFR 30 to <60 mL/minute): Use is not recommended.
Severe impairment (eGFR <30 mL/minute): Use is not recommended.
Mild impairment (Child-Turcotte-Pugh class A): Use is not recommended.
Moderate impairment (Child-Turcotte-Pugh class B): Use is contraindicated.
Severe impairment (Child-Turcotte-Pugh class C): Use is contraindicated.
Refer to adult dosing; consider titrating slower. Maximum dose: Xanomeline 100 mg and trospium chloride 20 mg twice daily.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Hypertension (11%)
Gastrointestinal: Constipation (17%), dyspepsia (18%), nausea (19%), vomiting (15%)
1% to 10%:
Cardiovascular: Orthostatic hypotension (2%), tachycardia (5%)
Gastrointestinal: Abdominal pain (8%), diarrhea (6%), gastroesophageal reflux disease (5%), sialorrhea (2%), xerostomia (4%)
Hepatic: Increased liver enzymes (3%; including increased serum alanine aminotransferase, increased serum aspartate aminotransferase)
Nervous system: Dizziness (5%), drowsiness (3%), extrapyramidal reaction (2%; non-akathisia)
Ophthalmic: Blurred vision (3%)
Respiratory: Cough (2%)
Frequency not defined:
Cardiovascular: Increased heart rate
Genitourinary: Urinary retention, urinary tract infection
Hepatic: Increased serum bilirubin
Renal: Increased serum creatinine
Postmarketing: Hypersensitivity: Angioedema
History of hypersensitivity (eg, angioedema) to xanomeline, trospium chloride, or any component of the formulation; urinary retention; moderate (Child-Pugh class B) or severe (Child-Pugh class C) liver impairment; gastric retention; untreated narrow-angle glaucoma.
Concerns related to adverse effects:
• Angioedema: Angioedema of the face, lips, tongue, and larynx have been reported, as early as the first dose, and may be life threatening in cases with upper airway swelling. Discontinue treatment if angioedema occurs.
• Anticholinergic adverse effects: May cause dizziness, confusion, hallucinations, and somnolence, particularly during initiation and dose changes. Patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• GI motility: Use with caution in patients with GI obstructive disorders, ulcerative colitis, intestinal atony, and myasthenia gravis due to risk of decreased GI motility.
• Liver impairment: If a patient develops signs or symptoms of liver injury during treatment (eg, jaundice, pruritus, alanine transaminase levels >5 × ULN or baseline values, discontinue treatment.
• Tachycardia: May cause tachycardia.
• Urinary retention: May cause urinary retention. Use with caution in older adults, those with clinically significant bladder obstruction and incomplete bladder emptying (eg, benign prostatic hyperplasia, diabetic cystopathy). Monitor for symptoms, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria.
Disease-related concerns:
• Biliary disease: Not recommended for those with active biliary disease (eg, symptomatic gallstones). Has been shown to cause transient increases in liver enzymes, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.
• Kidney impairment. Use is not recommended in patients with moderate or severe kidney impairment (eGFR <60 mL/minute) due to a higher systemic exposure to trospium chloride and risk for anticholinergic adverse reactions (eg, dry mouth, constipation, dyspepsia, urinary tract infection, urinary retention).
• Liver impairment: Use is not recommended in those with mild impairment and is contraindicated in moderate or severe impairment. Patients with liver impairment are at an increased risk of adverse reactions due to higher systemic exposure.
• Narrow-angle glaucoma: May cause pupillary dilation, which can trigger an acute angle closure attack in patients with anatomically narrow angles. In patients with anatomically narrow angle, use only if the potential benefits outweigh the risks and closely monitor.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Cobenfy: Xanomeline tartrate 50 mg and trospium chloride 20 mg, Xanomeline tartrate 100 mg and trospium chloride 20 mg, Xanomeline tartrate 125 mg and trospium chloride 30 mg
Capsule Therapy Pack, Oral:
Cobenfy Starter Pack: Xanomeline tartrate 50 mg and trospium chloride 20 mg (4s) and xanomeline tartrate 100 mg and trospium chloride 20 mg (52s) (56 ea)
No
Capsule Therapy Pack (Cobenfy Starter Pack Oral)
50-20 & 100-20 mg (per each): $37.00
Capsules (Cobenfy Oral)
50-20 mg (per each): $37.00
100-20 mg (per each): $37.00
125-30 mg (per each): $37.00
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Administer ≥1 hour before or ≥2 hours after a meal. Do not open capsules.
Schizophrenia: Treatment of schizophrenia in adults.
Beers Criteria: Trospium is identified in the Beers Criteria as a potentially inappropriate medication in patients ≥65 years of age due to its strong anticholinergic properties (Beers Criteria [AGS 2023]).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Acetylcholinesterase Inhibitors. Risk C: Monitor
Aclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Acrivastine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Agents with Clinically Relevant Anticholinergic Effects: May increase anticholinergic effects of Trospium. Risk C: Monitor
Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Alcohol (Ethyl): May increase CNS depressant effects of Trospium. Management: Avoid consuming any alcohol within 2 hours of taking a dose of trospium XR. Alcohol may increase sedation and CNS depressant effects of trospium XR. Risk D: Consider Therapy Modification
Amantadine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Benperidol: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Benperidol. Risk C: Monitor
Benztropine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Benztropine. Risk C: Monitor
Biperiden: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Biperiden. Risk C: Monitor
Bornaprine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Bornaprine. Risk C: Monitor
Botulinum Toxin-Containing Products: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Bromperidol: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Bromperidol. Risk C: Monitor
Buclizine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Buclizine. Risk C: Monitor
Cannabinoid-Containing Products: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of Cannabinoid-Containing Products. Risk C: Monitor
Chlorprothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Chlorprothixene. Risk C: Monitor
Cimetropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Cimetropium. Risk X: Avoid
CloZAPine: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider Therapy Modification
Cyclizine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
CYP2D6 Inhibitors (Strong): May increase serum concentration of Xanomeline. Risk C: Monitor
CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Xanomeline may increase serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Darifenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Darifenacin. Risk C: Monitor
Dicyclomine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dicyclomine. Risk C: Monitor
Dimethindene (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Dimethindene (Systemic). Risk C: Monitor
DroNABinol: Agents with Clinically Relevant Anticholinergic Effects may increase tachycardic effects of DroNABinol. Risk X: Avoid
Eluxadoline: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Eluxadoline. Risk X: Avoid
Fesoterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Fesoterodine. Risk C: Monitor
FluPHENAZine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Gastrointestinal Agents (Prokinetic): Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Gepotidacin: May decrease anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Glucagon: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor
Glycopyrrolate (Oral Inhalation): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Oral Inhalation). Risk X: Avoid
Glycopyrrolate (Systemic): Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Glycopyrrolate (Systemic). Risk C: Monitor
Glycopyrronium (Topical): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Ipratropium (Nasal): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Ipratropium (Oral Inhalation): May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Itopride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Itopride. Risk C: Monitor
Levosulpiride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Levosulpiride. Risk X: Avoid
Maprotiline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Maprotiline. Risk C: Monitor
Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid
Melperone: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Methotrimeprazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methotrimeprazine. Risk C: Monitor
Methscopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Methscopolamine. Risk C: Monitor
Mirabegron: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Mirabegron. Risk C: Monitor
Nitroglycerin: Agents with Clinically Relevant Anticholinergic Effects may decrease absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor
OLANZapine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OLANZapine. Risk C: Monitor
Opioid Agonists: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor
Opipramol: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Oxatomide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
OxyBUTYnin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of OxyBUTYnin. Risk C: Monitor
P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Xanomeline may increase serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Perazine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Perphenazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Perphenazine. Risk C: Monitor
Potassium Chloride: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid
Potassium Citrate: Agents with Clinically Relevant Anticholinergic Effects may increase ulcerogenic effects of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid
Pramlintide: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. These effects are specific to the GI tract. Risk X: Avoid
Promethazine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Promethazine. Risk C: Monitor
Propantheline: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Propantheline. Risk C: Monitor
Propiverine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
QuiNIDine: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk C: Monitor
Ramosetron: Agents with Clinically Relevant Anticholinergic Effects may increase constipating effects of Ramosetron. Risk C: Monitor
Revefenacin: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Revefenacin. Risk X: Avoid
Rivastigmine: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Rivastigmine. Rivastigmine may decrease therapeutic effects of Agents with Clinically Relevant Anticholinergic Effects. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider Therapy Modification
Scopolamine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Scopolamine. Risk C: Monitor
Secretin: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider Therapy Modification
Sofpironium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Sofpironium. Risk X: Avoid
Thiazide and Thiazide-Like Diuretics: Agents with Clinically Relevant Anticholinergic Effects may increase serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor
Thiothixene: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Thiothixene. Risk C: Monitor
Tiapride: Agents with Clinically Relevant Anticholinergic Effects may decrease therapeutic effects of Tiapride. Risk C: Monitor
Tiotropium: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tiotropium. Risk X: Avoid
Tolterodine: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Tolterodine. Risk C: Monitor
Topiramate: Agents with Clinically Relevant Anticholinergic Effects may increase adverse/toxic effects of Topiramate. Risk C: Monitor
Trimethobenzamide: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Trimethobenzamide. Risk C: Monitor
Umeclidinium: May increase anticholinergic effects of Agents with Clinically Relevant Anticholinergic Effects. Risk X: Avoid
Zuclopenthixol: Agents with Clinically Relevant Anticholinergic Effects may increase anticholinergic effects of Zuclopenthixol. Risk C: Monitor
High-fat meals (800 to 1,000 calories, 50% from fat) increase absorption of xanomeline and reduce absorption of trospium. Low-fat meals (400 to 500 calories, 25% from fat) reduce absorption of trospium. Management: Administer at least 1 hour before a meal and at least 2 hours after a meal.
Evaluate pregnancy status and provide preconception counseling prior to initiating treatment in patients who could become pregnant (Ref). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment and the risks of discontinuing antipsychotic therapy (Ref).
Adverse events were observed in animal reproduction studies following oral doses equivalent to <10 times the maximum recommended human dose (based on BSA) of this combination; maternal toxicity was also observed.
Management of mental health conditions should be made as part of a shared decision-making process (Ref).
Data collection to monitor pregnancy and infant outcomes following exposure to psychiatric medications is ongoing. Encourage pregnant patients ≤45 years of age with a history of psychiatric illness to enroll in the National Pregnancy Registry for Psychiatric Mediations (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/).
It is not known if xanomeline or trospium are present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Liver enzymes and bilirubin (baseline, periodically, and as clinically indicated), heart rate (baseline and as clinically indicated).
Xanomeline is an agonist at M1 and M4 muscarinic acetylcholine receptors in the central nervous system. The reason for its efficacy in schizophrenia is unclear.
Trospium chloride is a muscarinic antagonist. It is a highly polarized tertiary amine, and this prevents it from entering the CNS. As a result, trospium chloride antagonizes the muscarinic receptors primarily in the peripheral tissues (Ref).
Absorption: High-fat meals (800 to 1,000 calories, 50% from fat) increase AUC of xanomeline by 30% with no change in Cmax. High-fat meals reduced Cmax of trospium by 70% to 75% and AUC of trospium by 85% to 90%; low-fat meals (400 to 500 calories, 25% from fat) had no effect on AUC or Cmax of xanomeline, but reduced Cmax of trospium by 70% to 75% and AUC of trospium by 85% to 90%.
Distribution: Vd: Xanomeline: 10,800 L; Trospium: 531 L.
Protein binding: Xanomeline: ~95%; Trospium: ~80%.
Metabolism: Xanomeline is metabolized by CYP2D6, CYP2B6, CYP1A2, CYP2C9, CYP2C19, and flavin monooxygenases (FM01 and FM03). Trospium is metabolized by ester hydrolysis and glucuronic acid conjugation.
Half-life elimination: Xanomeline: 5 hours; Trospium: 6 hours.
Time to peak: Xanomeline: 2 hours; Trospium: 1 hour.
Excretion: Xanomeline: Urine: 78% (<0.01% as unchanged drug); feces: 12%. Trospium: Urine: 85% to 90% unchanged.
Altered kidney function:
Xanomeline:
Mild kidney impairment (eGFR 60 to <90 mL/minute): Steady-state Cmax and AUC0-12h were 2.1 and 1.9 times higher than those with eGFR ≥90 mL/minute.
Moderate kidney impairment (eGFR 30 to <60 mL/minute): Steady-state Cmax and AUC0-12h were 2.4 and 2.1 times higher than those with eGFR ≥90 mL/minute.
Severe kidney impairment (eGFR <30 mL/minute): Steady-state Cmax and AUC0-12h were 2.6 and 2.4 times higher than those with eGFR ≥90 mL/minute.
Trospium:
Mild kidney impairment (eGFR 60 to <90 mL/minute): Steady-state Cmax and AUC0-12h were 1.6 and 1.6 times higher than those with eGFR ≥90 mL/minute.
Moderate kidney impairment (eGFR 30 to <60 mL/minute): Steady-state Cmax and AUC0-12h were 2.7 and 2.2 times higher than those with eGFR ≥90 mL/minute.
Severe kidney impairment (eGFR <30 mL/minute): Steady-state Cmax and AUC0-12h were 2.9 and 2.9 times higher than those with eGFR ≥90 mL/minute.
Hepatic function impairment:
Xanomeline:
Mild liver impairment (Child-Turcotte-Pugh class A): Steady-state Cmax and AUC0-12h were 2.8 and 2.6 times higher than those with normal liver function.
Moderate liver impairment (Child-Turcotte-Pugh class B): Steady-state Cmax and AUC0-12h were ≥7 times that in subjects with normal liver impairment.
Severe liver impairment (Child-Turcotte-Pugh class C): Has not been evaluated.
Trospium:
Mild liver impairment (Child-Turcotte-Pugh class A): No impact on trospium exposure.
Moderate liver impairment (Child-Turcotte-Pugh class B): No impact on trospium exposure.
Severe liver impairment (Child-Turcotte-Pugh class C): Has not been evaluated.
Older adult: AUC0-12h and Cmax of trospium were 60% and 36% higher, respectively, compared to adults <65 years of age.
Molecular Weight: Trospium chloride: 427.96 g/mol; Xanomeline tartrate: 431.51 g/mol.
