IVABRADINE Drug Interactions: What You Need to Know

INTERACTIONS Avoid CYP3A4 inhibitors or inducers. ( 7.1 ) Negative chronotropes increase risk of bradycardia; monitor heart rate. ( 7.2 )

7.1 Cytochrome P450-Based Interactions Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases them. Increased plasma concentrations may exacerbate bradycardia and conduction disturbances. The concomitant use of strong CYP3A4 inhibitors is contraindicated <span class="opacity-50 text-xs">[see Contraindications (4) and Clinical Pharmacology (12.3) ]</span>. Examples of strong CYP3A4 inhibitors include azole antifungals (e.g.,itraconazole), macrolide antibiotics (e.g., clarithromycin, telithromycin), HIV protease inhibitors (e.g.nelfinavir), and nefazodone. Avoid concomitant use of moderate CYP3A4 inhibitors when using ivabradine tablets. Examples of moderate CYP3A4 inhibitors include diltiazem, verapamil, and grapefruit juice <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ]</span>. Avoid concomitant use of CYP3A4 inducers when using ivabradine tablets. Examples of CYP3A4 inducers include St. John&apos;s wort, rifampicin, barbiturates, and phenytoin <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

7.2 Negative Chronotropes Most patients receiving ivabradine tablets will also be treated with a beta-blocker. The risk of bradycardia increases with concomitant administration of drugs that slow heart rate (e.g., digoxin, amiodarone, beta-blockers). Monitor heart rate in patients taking ivabradine tablets with other negative chronotropes.

7.3 Pacemakers in Adults Ivabradine tablets dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute in adults <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span>. Patients with demand pacemakers set to a rate ≥ 60 beats per minute cannot achieve a target heart rate &lt; 60 beats per minute, and these patients were excluded from clinical trials <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>. The use of ivabradine tablets is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

Ivabradine tablets are contraindicated in patients with:

• Acute decompensated heart failure
• Clinically significant hypotension
• Sick sinus syndrome, sinoatrial block or 3 rd degree AV block, unless a functioning demand pacemaker is present
• Clinically significant bradycardia [see Warnings and Precautions ( 5.3 )]
• Severe hepatic impairment [see Use in Specific Populations ( 8.6 )]
• Pacemaker dependence (heart rate maintained exclusively by the pacemaker) [see Drug Interactions ( 7.3 )]
• Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors [see Drug Interactions ( 7.1 )]
• Acute decompensated heart failure ( 4 )
• Clinically significant hypotension ( 4 )
• Sick sinus syndrome, sinoatrial block or 3 rd degree AV block, unless a functioning demand pacemaker is present ( 4 )
• Clinically significant bradycardia ( 4 )
• Severe hepatic impairment ( 4 )
• Heart rate maintained exclusively by the pacemaker ( 4 )
• In combination with strong cytochrome CYP3A4 inhibitors ( 4 )

5.

Warnings And Precautions

Fetal toxicity: Females should use effective contraception. ( 5.1 ) Monitor patients for atrial fibrillation. ( 5.2 ) Monitor heart rate decreases and bradycardia symptoms during treatment. ( 5.3 ) Not recommended in patients with 2 nd degree AV block. ( 5.3 )

5.1 Fetal Toxicity Corlanor may cause fetal toxicity when administered to a pregnant woman based on findings in animal studies. Embryo-fetal toxicity and cardiac teratogenic effects were observed in fetuses of pregnant rats treated during organogenesis at exposures 1 to 3 times the human exposures (AUC 0-24hr ) at the maximum recommended human dose (MRHD) <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Advise females of reproductive potential to use effective contraception when taking Corlanor <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span> .

5.2 Atrial Fibrillation Corlanor increases the risk of atrial fibrillation. In the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT), the rate of atrial fibrillation was 5.0% per patient-year in patients treated with Corlanor and 3.9% per patient-year in patients treated with placebo <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . Regularly monitor cardiac rhythm.

Discontinue

Corlanor if atrial fibrillation develops.

5.3 Bradycardia and Conduction Disturbances Adult Patients Bradycardia, sinus arrest, and heart block have occurred with Corlanor. The rate of bradycardia was 6.0% per patient-year in patients treated with Corlanor (2.7% symptomatic; 3.4% asymptomatic) and 1.3% per patient-year in patients treated with placebo. Risk factors for bradycardia include sinus node dysfunction, conduction defects (e.g., 1 st or 2 nd degree atrioventricular block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (e.g., digoxin, diltiazem, verapamil, amiodarone). Bradycardia may increase the risk of QT prolongation which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors such as use of QTc prolonging drugs <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Concurrent use of verapamil or diltiazem will increase Corlanor exposure, may themselves contribute to heart rate lowering, and should be avoided <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Avoid use of Corlanor in patients with 2 nd degree atrioventricular block unless a functioning demand pacemaker is present <span class="opacity-50 text-xs">[see Contraindications ( 4 ) ]</span>.

Pediatric Patients

Bradycardia and first-degree heart block were observed in pediatric patients treated with Corlanor. Asymptomatic and symptomatic bradycardia were observed in 6.8% and 4.1% of pediatric patients treated with Corlanor, respectively. In the placebo treatment arm, 2.4% of pediatric patients had asymptomatic bradycardia, but none had symptomatic bradycardia. Bradycardia was managed through dose titration but did not result in study drug discontinuation [see Dosage and Administration ( 2.2 )] .