💊 Medications 🩺 疾患・症状 ⚠ 相互作用 📚 ガイド
All Medications 薬効分類 疾患・症状 製造会社 副作用
ガイド 用語集 ツール タイムライン 今日の出来事
🇺🇸 English 🇰🇷 한국어 🇯🇵 日本語 🇨🇳 中文简体 🇪🇸 Español 🇧🇷 Português 🇮🇳 हिन्दी 🇸🇦 العربية 🇫🇷 Français 🇷🇺 Русский 🇩🇪 Deutsch 🇹🇷 Türkçe 🇻🇳 Tiếng Việt 🇮🇩 Bahasa Indonesia 🇹🇭 ไทย
この情報は教育目的のみに提供されています。必ず医療専門家にご相談ください。 詳しく見る

Xanomeline And Trospium Chloride

Prescription

商品名： Cobenfy

剤形
Capsule
投与経路
ORAL
製造会社
E.R. Squibb & Sons, L.L.C.

About This Medication

11 DESCRIPTION COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist. The chemical name of xanomeline tartrate is pyridine, 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methyl-, (2R,3R)-2,3-dihydroxybutanedioate (1:1). Its molecular formula is C 14 H 23 N 3 OS.C 4 H 6 O 6 and its molecular weight is 431.51 g/mol. Xanomeline tartrate is a white to slightly tan crystalline solid. Xanomeline tartrate is highly soluble in protic solvents, such as methanol and water, and in polar organic solvents such as DMF and dimethyl sulfoxide (DMSO). It is poorly soluble in lipophilic organic solvents, such as hexane or octanol. The chemical structure of xanomeline tartrate is: Trospium chloride is a quaternary ammonium compound with the chemical name of spiro[8-azoniabicyclo[3.2.1]octane-8,1′-pyrrolidinium], 3-[(2-hydroxy-2,2-diphenylacetyl)oxy]-, chloride (1:1), (1α,3β,5α). The molecular formula of trospium chloride is C 25 H 30 NO 3 .Cl and its molecular weight is 427.96 g/mol. Trospium chloride is a fine, colorless to slightly yellow, crystalline solid. Trospium chloride is highly soluble in water, freely soluble in methanol, and practically insoluble in methylene chloride. The chemical structure of trospium chloride is: COBENFY (xanomeline and trospium chloride) is for oral administration and is available in capsules in the following strengths: • 50 mg/20 mg (equivalent to 76.7 mg xanomeline tartrate and 18.3 mg trospium). • 100 mg/20 mg (equivalent to 153.3 mg xanomeline tartrate and 18.3 mg trospium). • 125 mg/30 mg (equivalent to 191.7 mg xanomeline tartrate and 27.5 mg trospium). COBENFY capsules contain a combination of pellets of xanomeline and pellets of trospium chloride. Inactive ingredients: The xanomeline tartrate pellets contain ascorbic acid, microcrystalline cellulose, and talc. The trospium chloride pellets contain lactose monohydrate, microcrystalline cellulose, and talc. The capsules, printed with black ink, contain black iron oxide (only 100 mg/20 mg), hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide (only 50 mg/20 mg and 100 mg/20 mg). Chemical Structure Chemical Structure

有効成分

成分 含有量
Trospium Chloride -
Xanomeline -

適応症と用法

1 INDICATIONS AND USAGE COBENFY is indicated for the treatment of schizophrenia in adults. COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, indicated for the treatment of schizophrenia in adults. ( 1 )

作用のしくみ

12.1 Mechanism of Action The mechanism of action of xanomeline in the treatment of schizophrenia is unclear; however, its efficacy is thought to be due to its agonist activity at M1 and M4 muscarinic acetylcholine receptors in the central nervous system. Trospium chloride is a muscarinic antagonist. Trospium chloride antagonizes the muscarinic receptors primarily in the peripheral tissues.

用量と投与方法

2 DOSAGE AND ADMINISTRATION • Assess liver enzymes and bilirubin prior to initiating treatment with COBENFY and as clinically indicated during treatment. ( 2.1 ) • Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. ( 2.1 ) • Recommended starting dosage of COBENFY is 50 mg/20 mg orally twice daily for at least two days, then increase the dosage to 100 mg/20 mg twice daily for at least five days. ( 2.2 ) • Dosage may be increased to 125 mg/30 mg orally twice daily based on patient tolerability and response. ( 2.2 ) • See the full prescribing information for the recommended titration and maximum recommended dosage. ( 2.2 ) • Take at least 1 hour before a meal or at least 2 hours after a meal. Do not open capsules. ( 2.2 ) • Geriatric patients: Recommended starting dosage of COBENFY is 50 mg/20 mg orally twice daily. Consider a slower titration. The maximum recommended dosage is 100 mg/20 mg twice daily. ( 2.3 ) 2.1 Recommended Testing and Monitoring Prior to Initiation and During Treatment with COBENFY • Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment [see Contraindications (4) and Warnings and Precautions (5.2 , 5.3) ] . • Assess heart rate at baseline and as clinically indicated during treatment [see Warnings and Precautions (5.7) ] . 2.2 Recommended Dosage and Administration The recommended dosage of COBENFY is as follows: • The recommended starting dosage is one 50 mg/20 mg capsule (contains 50 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least two days. • Increase the dosage to one 100 mg/20 mg capsule (contains 100 mg of xanomeline and 20 mg of trospium chloride) orally twice daily for at least five days. • The dosage may be increased to one 125 mg/30 mg capsule (contains 125 mg of xanomeline and 30 mg of trospium chloride) orally twice daily based on patient tolerability and response [see Clinical Studies (14) ] . • Maximum recommended dosage is 125 mg/30 mg orally twice daily. Administer COBENFY orally at least one hour before a meal or at least two hours after a meal [see Clinical Pharmacology (12.3) ] . Do not open the capsules. 2.3 Dosage Recommendations in Geriatric Patients The recommended starting dosage of COBENFY in geriatric patients is one 50 mg/20 mg capsule orally twice daily. Consider a slower titration for geriatric patients. The maximum recommended dosage in geriatric patients is one 100 mg/20 mg capsule twice daily [see Warnings and Precautions (5.1 , 5.8) and Use in Specific Populations (8.5) ] .

Side Effects Overview

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risk of Urinary Retention [see Warnings and Precautions (5.1) ] • Risk of Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.2) ] • Risk of Use in Patients with Biliary Disease [see Warnings and Precautions (5.3) ] • Decreased Gastrointestinal Motility [see Warnings and Precautions (5.4) ] • Risk of Angioedema [see Warnings and Precautions (5.5) ] • Risk of Use in Patients with Narrow-angle Glaucoma [see Warnings and Precautions (5.6) ] • Increases in Heart Rate [see Warnings and Precautions (5.7) ] • Anticholinergic Adverse Reactions in Patients with Renal Impairment [see Warnings and Precautions (5.8) ] • Central Nervous System Effects [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence ≥ 5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastrointestinal reflux disease. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. COBENFY was evaluated for safety in a total of 1,594 subjects exposed to one or more doses, including 1,135 adult patients with schizophrenia and 389 healthy subjects. A total of 347 COBENFY-treated patients had at least 6 months of exposure and 150 patients had at least 1 year of exposure (defined as ≥ 50 weeks) from open-label studies. The adverse reaction findings are based on two pooled 5-week, placebo-controlled, flexible-dose studies in 504 adult patients with schizophrenia in which COBENFY or placebo was started at an initial dose of 50 mg/20 mg twice daily for the first 2 days followed by 100 mg/20 mg twice daily for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated to 125 mg/30 mg twice daily unless the patient could not tolerate it. All patients had the option to return to 100 mg/20 mg twice daily for the remainder of the treatment period [see Clinical Studies (14) ] . In the 5-week placebo-controlled studies, 6% of patients treated with COBENFY and 4% of placebo-treated patients discontinued participation due to adverse reactions. Adverse reactions that led to study discontinuation in ≥1% of patients treated with COBENFY include nausea (2%) and vomiting (1%). The most common adverse reactions (≥5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease. Adverse reactions reported with COBENFY at an incidence of at least 2% in patients exposed to COBENFY and greater than the rate of placebo are shown in Table 1. Table 1: Adverse Reactions Reported in ≥2% of COBENFY-Treated Patients and Greater than Rate of Placebo in Two 5-week Schizophrenia Trials a Dyspepsia includes dyspepsia, esophageal discomfort b Hypertension includes hypertension, blood pressure increased, labile hypertension, orthostatic hypertension c Abdominal Pain includes abdominal discomfort, abdominal pain upper, abdominal pain, abdominal pain lower, abdominal tenderness d Tachycardia includes tachycardia, heart rate increased, sinus tachycardia e Cough: includes cough, productive cough f EPS (non-akathisia) includes dyskinesia, drooling, dystonia, extrapyramidal disorder, muscle contraction involuntary, muscle spasms COBENFY (N=251) Placebo (N=253) Nausea 19% 4% Dyspepsia a 18% 5% Constipation 17% 7% Vomiting 15% 1% Hypertension b 11% 2% Abdominal Pain c 8% 4% Diarrhea 6% 2% Tachycardia d 5% 2% Dizziness 5% 2% Gastroesophageal reflux disease 5% <1% Dry mouth 4% 2% Somnolence 3% 2% Vision blurred 3% 0% Salivary hypersecretion 2% 0% Orthostatic hypotension 2% 1% Cough e 2% 1% Extrapyramidal symptoms (EPS), non-akathisia f 2% <1% Increases in Heart Rate In a dedicated 8-week clinical study, 24-hour ambulatory blood pressure monitoring (ABPM) was conducted in 133 patients with schizophrenia. A total of 95 patients had acceptable ABPM recordings at both baseline and Week 8. In that group, there was a mean change in 24-hour heart rate of 9.8 beats per minute (bpm) (95% CI 7.5, 12.2) from baseline to Week 8. In the two placebo-controlled schizophrenia studies, COBENFY was associated with increases in heart rate compared to placebo, with peak elevation occurring on Day 8 of study treatment (13.5 bpm in the COBENFY group and 4.0 bpm in the placebo group), partially attenuating with continued dosing (11.4 bpm in the COBENFY group and 5.5 bpm in the placebo group at Week 5). Liver Enzyme Elevations In the 5-week, placebo-controlled schizophrenia studies, the proportions of patients with ALT or AST elevations of ≥3 times the upper limits of the normal reference range were 2.8% (6/214) for COBENFY-treated patients compared to 0.4% (1/224) of placebo-treated patients. Twenty-five (1.6%) of the total 1,594 subjects exposed to COBENFY had elevated liver enzymes. The majority of liver enzyme elevations occurred within the first month of treatment and resolved with continued COBENFY use, suggestive of liver adaptation; some cases required treatment interruption, and one was associated with an increase in bilirubin. Urinary Retention In the 5-week, placebo-controlled studies, urinary retention (urinary hesitation, dysuria, and urinary retention) was reported in 0.8% of COBENFY-treated patients and 0.4% on placebo. In the long-term, open-label studies, urinary retention was reported in 3.5% of COBENFY-treated patients. Urinary retention was more common in males, geriatric patients, and those with certain risk factors [see Warnings and Precautions (5.1) ] . Urinary retention occurred at all doses but was predominately observed at the maximum COBENFY dose. In the long-term, open-label studies, urinary tract infections were reported in 2.3% of COBENFY-treated patients and were more commonly reported in females than males. Of the total 1,594 subjects exposed to COBENFY (including healthy volunteers and patients with schizophrenia or other conditions), four subjects required a Foley catheter, including one with elevated serum creatinine and one with urinary tract infections. Four subjects with urinary retention required reduction of COBENFY dose, four discontinued COBENFY, and four received medications for the treatment of benign prostatic hyperplasia (BPH). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of trospium chloride, one of the components of COBENFY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Cardiovascular – chest pain, hypertensive crisis, palpitations, supraventricular tachycardia, syncope • Gastrointestinal – gastritis • General – rash • Musculoskeletal – rhabdomyolysis • Nervous System – confusion, delirium, dizziness, hallucinations, somnolence, vision abnormal • Skin and subcutaneous tissue disorders – angioedema, anaphylactic reaction, Stevens-Johnson syndrome

警告と注意事項

禁忌

薬物動態

12.3 Pharmacokinetics Following COBENFY administration, xanomeline area under the plasma concentration-time curve during a 12-hour dosing interval (AUC 0-12 ) at steady state and maximum concentration (C max ) increased 50% when the COBENFY dose increased from 100 mg/20 mg twice daily to 125 mg/30 mg twice daily. Trospium exposures increase dose-proportionally over the COBENFY dosage range of 100 mg/20 mg twice daily to 125 mg/30 mg twice daily. Pharmacokinetic properties of COBENFY are provided in Table 3. Table 3: Pharmacokinetic Properties of COBENFY Parameter Xanomeline Trospium General Information Dose proportionality Greater than proportional Proportional Accumulation a 2 to 3-fold 2 to 3-fold Time to steady state 3 to 5 days 3 to 5 days Absorption T max 2 hours 1 hour Effect of food: PK in fed state (compared to fasted state) High fat meal b C max Unchanged Reduced 70% to 75% AUC Increased 30% Reduced 85% to 90% Low fat meal b C max Unchanged Reduced 70% to 75% AUC Unchanged Reduced 85% to 90% Distribution Central volume of distribution (oral) 10,800 Liters 531 Liters Plasma protein binding Approximately 95% Approximately 80% Elimination Half-life (t 1/2 ) 5 hours 6 hours Apparent clearance 1950 Liters/hour 796 Liters/hour Renal clearance 0.085 Liters/hour 21 Liters/hour Metabolism Primary metabolic pathways CYP450 2D6, 2B6, 1A2, 2C9, and 2C19 Unlikely Other Flavin monooxygenases (FMO1 and FMO3) Ester hydrolysis and glucuronic acid conjugation (not fully characterized) Excretion Urine Total 78% Unknown Unchanged Less than 0.01% 85-90% Tubular secretion Unknown Yes Feces Total 12% Unknown Unchanged Unknown Unknown Abbreviations: AUC = Area under the time-concentration curve; C max = Maximum concentration; T max =Time to C max a Dose-normalized accumulation at steady state b High-fat high-calorie meal is 800-1000 calories, 50% from fat; a low-fat meal is 400-500 calories, 25% from fat Specific Populations Geriatric Patients Population pharmacokinetic analysis suggests that AUC 0-12h and C max of trospium at steady state were 60% higher and 36% higher, respectively, in subjects 65 years and older compared to subjects younger than 65 years old. The exposures (AUC 0-12h and C max ) of xanomeline at steady state were not different between subjects 65 years and older and subjects younger than 65 years old [see Dosage and Administration (2.3) and Use in Specific Populations (8.5) ] . Male and Female Patients Plasma concentrations of xanomeline and trospium are similar between females and males. Racial or Ethnic Groups Most subjects in clinical studies were Black. Xanomeline and trospium exposure did not differ between Black and non-Black subjects. Studies have included too few subjects of Asian descent to evaluate comparisons. Patients with Renal Impairment The effect of renal impairment on xanomeline and trospium exposure was assessed in a dedicated study that enrolled healthy subjects and subjects with mild, moderate, or severe renal impairment. Estimated glomerular filtration rate (eGFR) was determined by the MDRD equation. Plasma concentrations of xanomeline and trospium increased with increasing renal dysfunction [see Use in Specific Populations (8.6) ] . For xanomeline, compared to subjects with normal renal function (eGFR: ≥90 mL/min), the steady-state C max and AUC 0-12h were 2.1 and 1.9 times higher in subjects with mild renal impairment (eGFR: 60 to <90 mL/min), 2.4 and 2.1 times higher in subjects with moderate renal impairment (eGFR: 30 to <60 mL/min), and 2.6 and 2.4 times higher in subjects with severe renal impairment (eGFR: <30 mL/min). For trospium, compared to subjects with normal renal function, the steady-state C max and AUC 0-12h were 1.6 and 1.6 times higher in subjects with mild renal impairment, 2.7 and 2.2 times higher in subjects with moderate renal impairment, and 2.9 and 2.9 times higher in subjects with severe renal impairment. Patients with Hepatic Impairment The effect of hepatic impairment on xanomeline and trospium in combination was assessed in a dedicated study that enrolled healthy subjects and subjects with mild or moderate hepatic impairment as determined by their Child-Pugh score. Plasma concentrations of xanomeline increased with increasing hepatic dysfunction [see Use in Specific Populations (8.7) ] . In subjects with mild hepatic impairment (Child-Pugh Class A), the steady-state C max and AUC 0-12h of xanomeline was 2.8 and 2.6 times that in subjects with normal hepatic function. Mild and moderate hepatic impairment did not substantially affect trospium exposure, but significantly impacted xanomeline exposures. In subjects with moderate hepatic impairment (Child-Pugh Class B), the steady-state C max and AUC 0-12h of xanomeline was at least 7 times that in subjects with normal hepatic function [see Contraindications (4) and Warnings and Precautions (5.2) ] . The effect of severe hepatic impairment on xanomeline and trospium exposure was not evaluated. Body Weight Compared to subjects weighing 70 kg, xanomeline exposures were 30 to 35% lower and trospium exposures were 20 to 35% lower in subjects weighing 120 kg. The lower exposures observed in subjects weighing 120 kg are expected to be clinically not meaningful. Drug Interaction Studies Drugs Eliminated by Active Tubular Secretion Active tubular excretion is a major elimination pathway for trospium. Trospium has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion. Coadministration of COBENFY with these drugs may increase plasma concentrations of trospium and/or the coadministered drug due to competition for this elimination pathway [see Drug Interactions (7.1) ] . Metformin A drug interaction study was conducted in which extended-release trospium chloride 60 mg once daily was coadministered with metformin hydrochloride 500 mg twice daily under steady-state conditions in 44 healthy subjects. Co-administration of 500 mg metformin immediate-release tablets twice daily reduced the steady-state systemic exposure of trospium by approximately 29% for mean AUC 0-24 and by 34% for mean C max . The steady-state pharmacokinetics of metformin were comparable when administered with or without 60 mg extended-release trospium chloride once daily under fasted conditions. The effect of metformin at higher doses on trospium pharmacokinetics is unknown. Drugs That Inhibit CYP2D6 CYP2D6 is a significant contributor to the metabolism of xanomeline. Drugs that are inhibitors of CYP2D6 may increase xanomeline concentrations in plasma [see Drug Interactions (7.1) ] . Drugs That Are Substrates of P-glycoprotein In vitro data suggest that xanomeline does not inhibit P-glycoprotein systemically, but it may transiently inhibit P-glycoprotein locally in the intestine after dosing. COBENFY may increase plasma concentrations of coadministered P-gp substrates [see Drug Interactions (7.1) ] . Drugs That Are Substrates of CYP3A4 In vitro data suggest that xanomeline does not inhibit CYP3A4 systemically, but it may transiently inhibit CYP3A4 locally in the intestine after dosing. COBENFY may increase plasma concentrations of coadministered CYP3A4 substrates [see Drug Interactions (7.1) ] .

Frequently Asked Questions

1 INDICATIONS AND USAGE COBENFY is indicated for the treatment of schizophrenia in adults. COBENFY is a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, indicated for the treatment of schizophrenia in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION • Assess liver enzymes and bilirubin prior to initiating treatment with COBENFY and as clinically indicated during treatment. ( 2.1 ) • Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. ( 2.1 ) • Recommended starting dosage of COBENFY is 50 mg/20 mg orally twice daily for at least two days, then increase the dosage to 100 mg/20 mg twice daily for at least five days. ( 2.2 ) • Dosage …

5 WARNINGS AND PRECAUTIONS • Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with bladder outlet obstruction and incomplete bladder emptying are at increased risk. Monitor patients for symptoms of acute urinary retention. ( 5.1 ) • Risk of Use in Patients with Hepatic Impairment: COBENFY is contraindicated in patients with moderate to severe hepatic impairment and is not recommended in patients with mild hepatic impairment. ( 5.2 ) • Risk of Use in Patients …

4 CONTRAINDICATIONS COBENFY is contraindicated in patients with: • urinary retention [see Warnings and Precautions (5.1) ] . • moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment [see Warnings and Precautions (5.2) ] . • gastric retention [see Warnings and Precautions (5.4) ] . • history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride [see Warnings and Precautions (5.5) ] . • untreated narrow-angle glaucoma [see Warnings and Precautions …

Xanomeline And Trospium Chloride is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Similar Capsule Products

Migalastat Hydrochloride Capsule pillfyi.com

Migalastat Hydrochloride
Atazanavir Capsule pillfyi.com

Atazanavir
Sodium Iodide I 131 Capsule pillfyi.com

Sodium Iodide I 131
Pirfenidone Capsule pillfyi.com

Pirfenidone
Ensartinib Capsule pillfyi.com

Ensartinib
Tizanidne Hydrochloride Capsule pillfyi.com

Tizanidne Hydrochloride
Browse all Capsule products →

References & Data Sources

医療免責事項

このページの情報は教育目的のみを意図しており、専門家による医療アドバイス、診断、または治療の代替として使用すべきではありません。

疾患や医薬品に関するご質問がある場合は、必ず担当医またはその他の資格を持つ医療専門家にご相談ください。

データソース： DailyMed (NLM), openFDA, MFDS

Medical Disclaimer

This content is for educational and informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider before making medication decisions.

Data sources: ChEMBL, PubChem, DailyMed.