TROSPIUM Drug Interactions: What You Need to Know

INTERACTIONS

• Drugs Eliminated by Active Tubular Secretion: Monitor for increased frequency and/or severity of adverse reactions related to COBENFY and to drugs eliminated by active tubular secretion. ( 7.1 )
• Strong CYP2D6 Inhibitors: Monitor for increased frequency and/or severity of COBENFY-related adverse reactions. ( 7.1 )
• Sensitive Substrates of CYP3A4 or P-glycoprotein: Monitor for increased frequency and/or severity of adverse reactions from these substrates. ( 7.1 )
• Antimuscarinic Drugs: Monitor for increased frequency or severity of anticholinergic adverse reactions. ( 7.2 )

7.1 Clinically Significant Drug Interactions with COBENFY Table 2 displays clinically significant drug interactions with COBENFY.

Table

2: Clinically Significant Drug Interactions with COBENFY Strong Inhibitors of CYP2D6 Clinical Implication: CYP2D6 contributes significantly to the metabolism of xanomeline, a component of COBENFY. Concomitant use of COBENFY with strong CYP2D6 inhibitors may increase plasma concentrations of xanomeline, which may increase the frequency and/or severity of adverse reactions from COBENFY [see Clinical Pharmacology (12.3)] . Prevention or Management: Monitor patients for increased frequency and/or severity of adverse reactions related to COBENFY in patients taking COBENFY with strong inhibitors of CYP2D6.

Drugs

Eliminated by Active Tubular Secretion Clinical Implication: Concomitant use of COBENFY with drugs that are eliminated by active tubular secretion may increase plasma concentrations of trospium a component of COBENFY, and/or the concomitantly used drug due to competition for this elimination pathway, which may increase the frequency and/or severity of adverse reactions from COBENFY or the drug eliminated by active tubular secretion [see Clinical Pharmacology (12.3)] . Prevention or Management: Monitor patients for increased frequency and/or severity of adverse reactions related to COBENFY and adverse reactions related to drugs eliminated by active tubular secretion in patients concomitantly receiving such drugs.

Oral Drugs That Are Sensitive

Substrates of CYP3A4 Clinical Implication: Xanomeline, a component of COBENFY, transiently inhibits CYP3A4 locally in the gut but not systemically. Concomitant use of COBENFY with oral drugs that are sensitive substrates of CYP3A4 may result in increased plasma concentrations of the oral drugs that are sensitive substrates of CYP3A4. This may increase the frequency and/or severity of adverse reactions from such substrates [see Clinical Pharmacology (12.3)] . Prevention or Management: Monitor patients for increased frequency and/or severity of adverse reactions related to oral drugs that are sensitive substrates of CYP3A4 in patients taking COBENFY with such substrates.

Oral Drugs That Are

Substrates of P-glycoprotein Clinical Implication: Xanomeline, a component of COBENFY, transiently inhibits P-glycoprotein locally in the gut but not systemically. Concomitant use of COBENFY with oral drugs that are substrates of P-glycoprotein may result in increased plasma concentrations of the oral drugs that are substrates of P-glycoprotein, which may increase the frequency and/or severity of adverse reactions from such substrates [see Clinical Pharmacology (12.3)] . Prevention or Management: Monitor patients for increased frequency and/or severity of adverse reactions related to oral drugs that are narrow therapeutic index substrates of P-glycoprotein in patients taking COBENFY with such substrates.

7.2 Other Antimuscarinic Drugs Concomitant use of COBENFY with other antimuscarinic drugs that produce anticholinergic adverse reactions (e.g., dry mouth, constipation) may increase the frequency and/or severity of such effects. Monitor patients for increased frequency and/or severity of anticholinergic adverse reactions when COBENFY is used concomitantly with other antimuscarinic drugs.

7.3 Effects on Absorption of Drugs COBENFY may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Dosage adjustment of concomitant medications may be necessary based on clinical response and tolerability.

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 (5.6) ] . COBENFY is contraindicated in:
• urinary retention ( 4 )
• moderate or severe hepatic impairment ( 4 )
• gastric retention ( 4 )
• history of hypersensitivity to COBENFY or trospium chloride ( 4 )
• untreated narrow-angle glaucoma ( 4 )

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 with Biliary Disease: Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated. Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury. ( 5.3 )
• Decreased Gastrointestinal Motility: COBENFY may decrease gastrointestinal motility. Use with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. ( 5.4 )
• Risk of Angioedema: Angioedema of the face, lips, tongue and/or larynx has been reported with COBENFY. ( 5.5 )
• Risk of Use in Patients with Narrow-angle Glaucoma: Use COBENFY only if the potential benefits outweigh the risks and with careful monitoring. ( 5.6 )
• Increases in Heart Rate: COBENFY may increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. ( 5.7 )
• Anticholinergic Adverse Reactions in Patients with Renal Impairment: COBENFY is not recommended for use in patients with moderate and severe renal impairment. Anticholinergic adverse reactions are expected to be greater in these patients. ( 5.8 )
• Central Nervous System Effects: COBENFY may be associated with CNS effects. Advise patients not drive or operate heavy machinery until they know how COBENFY affects them. ( 5.9 )

5.1 Risk of Urinary Retention COBENFY can cause urinary retention <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 )]</span> . Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), diabetic cystopathy) may be at increased risk of urinary retention <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span> . COBENFY is contraindicated in patients with pre-existing urinary retention <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> and is not recommended in patients with moderate or severe renal impairment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span> . In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated.

5.2 Risk of Use in Patients with Hepatic Impairment Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . COBENFY is contraindicated in patients with moderate or severe hepatic impairment <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . COBENFY is not recommended in patients with mild hepatic impairment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]</span> . Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment.

5.3 Risk of Use in Patients with Biliary Disease In clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones. Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated. Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values.

5.4 Decreased Gastrointestinal Motility COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.

5.5 Risk of Angioedema Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway. COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride.

5.6 Risk of Use in Patients with Narrow-angle Glaucoma Pupillary dilation may occur due to the anticholinergic effects of COBENFY. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.7 Increases in Heart Rate COBENFY can increase heart rate <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Assess heart rate at baseline and as clinically indicated during treatment with COBENFY <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> .

5.8 Anticholinergic Adverse Reactions in Patients with Renal Impairment Trospium chloride, a component of COBENFY, is substantially excreted by the kidney. COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) &lt;60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span> . Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment.

5.9 Central Nervous System Effects Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients 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 COBENFY affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.