Xanomeline-Trospium

Xanomeline-Trospium is a prescription medication indicated for the treatment of schizophrenia in adults.

• Xanomeline-Trospium is available under the following different brand names: Cobenfy.

Common side effects of Xanomeline-Trospium include:

• nausea
• stomach upset or burning (dyspepsia)
• constipation
• vomiting
• high blood pressure
• stomach (abdominal) pain
• diarrhea
• increased heart rate
• dizziness
• heartburn (gastrointestinal reflux disease) 

Serious side effects of Xanomeline-Trospium include:

• urinary retention symptoms include difficulty urinating, urination in a weak stream or drips, urinating frequently, full bladder difficulty emptying your bladder, pain when you urinate
• liver problem symptoms include yellowing of your skin or the white part of your eyes, dark urine, pain and swelling in the upper right part of your stomach (abdomen), stomach pain that spreads to your back or to below your right shoulder, itching, nausea or vomiting, loss of appetite, fever, chills, light-colored stools, tiredness
• biliary disease symptoms include stomach upset or burning (dyspepsia), nausea, vomiting, pain in the upper right part of your stomach
• decreased gastrointestinal motility symptoms include constipation, vomiting, nausea, stomach (abdominal) bloating, stomach (abdominal) pain, a feeling of fullness after eating just a few bites, acid reflux
• risk of angioedema symptoms include hives, swelling of your face, lips, mouth, or tongue, swelling of your throat, hoarseness or difficulty speaking, breathing problems
• patients with narrow-angle glaucoma symptoms include red eyes, blurred vision, seeing halos or bright colors around lights, eye pain or discomfort, nausea or vomiting, severe headache
•  increases in heart rate
• kidney problems such as increased risk of getting dry mouth, constipation, stomach upset or burning, urinary tract infection, and urinary retention

Rare side effects of Xanomeline-Trospium include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Capsule

• 50 mg/20 mg
• 100 mg/20 mg
• 125 mg/30 mg

Schizophrenia

Adult dosage

• Administer at least 1 hour before a meal or at least 2 hours after a meal
• Initiate at 50 mg/20 mg orally two times a day for at least 2 days, and then
• Increase to 100 mg/20 mg orally two times a day for at least 5 days
• May further increase to 125 mg/30 mg two times a day based on the patient’s tolerability and response
• Not to exceed 125 mg/30 mg two times a day

Geriatric dosage

• Slower titration and lower maximum dose recommended
• Controlled clinical studies did not include patients aged greater than 65 years to determine whether they respond differently from younger adults
• Because Xanomeline-Trospium can increase the risk of urinary retention in geriatric patients, including older males with bladder outlet obstruction due to benign prostatic hyperplasia, a slower titration and lower maximum dosage is recommended in geriatric patients

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Xanomeline-Trospium has no noted severe interactions with any other drugs
• Xanomeline-Trospium has no noted serious interactions with any other drugs
• Xanomeline-Trospium has no noted moderate interactions with any other drugs
• Xanomeline-Trospium has no noted minor interactions with any other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Urinary retention
• Moderate or severe hepatic impairment (Child-Pugh B or C)
• Gastric retention
• History of hypersensitivity to Xanomeline or trospium
• Untreated narrow-angle glaucoma

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Xanomeline-Trospium?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Xanomeline-Trospium?”

Cautions

• Urinary retention
  • Can cause urinary retention
  • Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., Benign prostatic hypertrophy (BPH), diabetic cystopathy) may be at increased risk
  • Contraindicated with pre-existing urinary retention
  • Monitor for symptoms, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria
  • Instruct patients to be aware of the risk and promptly report symptoms to their healthcare provider
  • Urinary retention is a known risk factor for urinary tract infections
  • If urinary retention occurs, consider reducing the dose, discontinuing the drug, or referring patients for urologic evaluation as clinically indicated
• Hepatic impairment
  • Patients with hepatic impairment have higher systemic exposures to xanomeline
  • Contraindicated with moderate or severe hepatic impairment
  • Not recommended with mild hepatic impairment
  • Assess liver enzymes before initiating and as clinically indicated during treatment
• Biliary disease
  • Transient increased liver enzymes with rapid decline occurred during clinical trials, which is consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage
  • Not recommended for patients with active biliary disease (e.g., symptomatic gallstones)
  • Assess liver enzymes and bilirubin before initiating and as clinically indicated during treatment
  • Assess for gallbladder disorders, biliary disorders, and pancreatitis if symptoms occur (e.g., dyspepsia, nausea, vomiting, upper abdominal pain), as clinically indicated
  • Discontinue if signs or symptoms of substantial liver injury (e.g., jaundice, pruritus, alanine aminotransferase levels above 5 times the upper limit of norma (ULN) or 5x baseline values)
• Decreased GI mobility
  • Trospium, like other antimuscarinic agents, may decrease gastrointestinal (GI) motility
  • Caution in patients with GI obstructive disorders owing to the risk of gastric retention
  • Caution with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis
• Angioedema
  • Angioedema of the face, lips, tongue, and/or larynx reported, including 1 case after the first dose
  • Angioedema associated with upper airway swelling may be life-threatening
  • If involvement of the tongue, hypopharynx, or larynx occurs, discontinue the drug and initiate appropriate therapy and/or measures necessary to ensure a patent airway
  • Contraindicated with a history of hypersensitivity
• Narrow-angle glaucoma
  • Pupillary dilation may occur owing to anticholinergic effects
  • This may trigger an acute angle closure attack in patients with anatomically narrow angles
  • Consider if potential benefits outweigh risks in patients known to have anatomically narrow angles; if prescribed, careful monitoring recommended
  • Increased heart rate
  • Can increase heart rate
  • Assess heart rate at baseline and as clinically indicated during treatment
  • Anticholinergic effects with renal impairment
  • The kidney substantially excretes trospium
  • Not recommended with moderate or severe renal impairment (eGFR below 60 mL/min)
  • Systemic exposure of trospium is higher in patients with moderate and severe renal impairment; therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater with moderate and severe renal impairment
• CNS effects
  • Trospium associated with anticholinergic CNS
  • A variety of CNS anticholinergic effects were reported, including dizziness, confusion, hallucinations, and somnolence
  • Monitor for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose
  • Advise patients not to drive or operate heavy machinery until they know how the drug affects them
  • If anticholinergic CNS effects occur, consider dose reduction or drug discontinuation
• Drug interaction overview
  • Substrate of CYP2D6
  • Weak inhibitor of CYP3A4 and P-gp
  • Strong CYP2D6 inhibitors
    • Monitor for increased frequency and/or severity of adverse effects
    • Coadministration of Xanomeline-Trospium with strong CYP2D6 inhibitors may increase xanomeline plasma concentrations
  • Drug eliminated by active tubular secretion
    • Monitor for increased frequency and/or severity of adverse effects
    • Coadministration of Xanomeline-Trospium with drugs that are eliminated by active tubular secretion may increase plasma concentrations of trospium and/or the concomitantly used drug due to competition for this elimination pathway
  • Oral drugs that are sensitive to CYP3A4 substrates
    • Monitor for increased frequency and/or severity of adverse effects
    • Xanomeline transiently inhibits CYP3A4 locally in the gut, but not systemically
    • Coadministration with oral drugs that are sensitive CYP3A4 substrates may increase plasma concentrations of oral sensitive CYP3A4 substrates
  • Oral drugs that are P-gp substrates
    • Monitor for increased frequency and/or severity of adverse effects
    • Xanomeline transiently inhibits P-gp locally in the gut, but not systemically
    • Coadministration with oral drugs that are sensitive P-gp substrates may increase plasma concentrations of oral sensitive P-gp substrates
  • Other antimuscarinic drugs
    • Monitor for increased frequency and/or severity of anticholinergic adverse effects
    • Coadministration may increase anticholinergic effects (e.g., dry mouth, constipation)
• Effects on the absorption of drugs
  • Xanomeline-Trospium may alter the absorption of some concomitantly administered drugs due to anticholinergic effects on GI motility
  • Dosage adjustment of concomitant medications may be necessary based on clinical response and tolerability

Pregnancy and Lactation

• Data are not available regarding use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes
• There are risks to the mother associated with untreated schizophrenia
• Pregnancy registry
  • There is a pregnancy exposure registry that monitors outcomes in women exposed to psychiatric medications during pregnancy
    • Advise patients to register by calling 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/atypicalantipsychotic/
    • Clinical considerations
    • There is a risk of untreated schizophrenia during pregnancy, including an increased risk of relapse, hospitalization, and suicide
    • Schizophrenia is associated with adverse perinatal outcomes, including preterm birth
    • Unknown if this is a direct result of the illness or other comorbid factors
• Lactation
  • Data are unavailable regarding the presence of the drug in human milk, its effects on breastfed infants, or milk production
  • Xanomeline and trospium are present in animal milk; when a drug is present in animal milk, it is likely to be present in human milk
  • Consider the developmental and health benefits of breastfeeding along with the clinical need for the drug and any potential adverse effects on breastfed infants or from the underlying maternal condition