ivabradine (Rx)

Brand and Other Names:Corlanor
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 5mg (scored and can be divided into equal halves to provide a 2.5-mg dose)
  • 7.5mg

oral solution

  • 5mg/5mL

Heart Failure

Indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with resting heart rate ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use

Initial: 5 mg PO BID with meals

After 2 weeks, assess patient and adjust dose to achieve a resting heart rate of 50-60 bpm (see dose adjustment section below)

Thereafter, adjust dose as needed based on resting heart rate and tolerability; not to exceed 7.5 mg BID

Dose adjustment

  • HR >60 bpm: Increase dose by 2.5 mg (given BID) up to a maximum dose of 7.5 mg BID
  • HR 50-60 bpm: Maintain dose
  • HR <50 bpm or signs and symptoms of bradycardia: Decrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg BID, discontinue therapy

Dosage Modifications

History of conduction defects or adults in whom bradycardia could lead to hemodynamic compromise: Decrease initial dose to 2.5 mg PO BID; may increase dose based on heart rate

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dose adjustment required
  • Severe (Child-Pugh C): Contraindicated

Renal impairment

  • CrCl 15-60 mL/min: No dose adjustment required
  • CrCl <15 mL/min: No data available

Heart Dysfunction (Orphan)

Designated for treatment of postcardiac transplant heart dysfunction

Orphan sponsor

  • Amgen, Inc; 1 Amgen Center Drive; Thousand Oaks, CA

Dosage Forms & Strengths

tablet

  • 5mg (scored and can be divided into equal halves to provide a 2.5-mg dose)
  • 7.5mg

oral solution

  • 5mg/5mL

Heart Failure

Indicated for treatment of stable symptomatic heart failure due to dilated cardiomyopathy (DCM) in children aged ≥6 months, who are in sinus rhythm with an elevated heart rate

<6 months: Safety and efficacy not established

≥6 months

  • <40 kg (oral solution)
    • Initial: 0.05 mg/kg PO BID with meals
    • Assess patient at 2-week intervals and adjust dose by 0.05 mg/kg to target HR reduction of at least 20%, based on tolerability
    • Maximum dose aged 6 months to <1 year: Not to exceed 0.2 mg/kg BID
    • Maximum dose aged ≥1 year: 0.3 mg/kg BID; not to exceed 7.5 mg BID
  • ≥40 kg (oral tablets)
    • Initial: 2.5 mg PO BID with meals
    • Assess patient at 2-week intervals and adjust dose by 2.5 mg to target HR reduction of at least 20%, based on tolerability; not to exceed 7.5 mg BID

Dose reduction for bradycardia

  • If bradycardia develops, reduce dose to the previous titration step
  • In patients who develop bradycardia at recommended initial dosage, consider reducing dose to 0.02 mg/kg BID

Dosage Modifications

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dose adjustment required
  • Severe (Child-Pugh C): Contraindicated

Renal impairment

  • CrCl 15-60 mL/min: No dose adjustment required
  • CrCl <15 mL/min: No data available
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Interactions

Interaction Checker

and ivabradine

No Results

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            1-10%

            Bradycardia (10%)

            Hypertension or increased blood pressure (8.9%)

            Atrial fibrillation (8.3%)

            Luminous phenomena (phosphenes) or visual brightness (2.8%)

            Postmarketing Reports

            Syncope, hypotension

            Angioedema, erythema, rash, pruritus, urticaria

            Vertigo, diplopia, visual impairment

            Torsade de pointes, ventricular fibrillation, ventricular tachycardia

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            Warnings

            Contraindications

            Acute decompensated heart failure

            Clinically significant hypotension

            Sick sinus syndrome, sinoatrial block, or third-degree AV block (unless a functioning demand pacemaker is present)

            Clinically significant bradycardia

            Severe hepatic impairment

            Pacemaker dependence (heart rate maintained exclusively by the pacemaker)

            Concomitant use of strong CYP3A4 inhibitors

            Cautions

            Increases the risk of atrial fibrillation; regularly monitor cardiac rhythm and discontinue drug if atrial fibrillation develops

            May cause fetal toxicity when administered to a pregnant woman; inform women of childbearing potential to use effective contraception

            Bradycardia and conduction disturbances

            • Bradycardia, sinus arrest, and heart block reported
            • Bradycardia may increase risk of QT prolongation which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors
            • Risk factors for bradycardia include sinus node dysfunction, conduction defects (eg, first or second degree AV block, bundle-branch block), ventricular dyssynchrony, and use of other negative chronotropes (eg, beta-blockers, clonidine, digoxin, diltiazem, verapamil, amiodarone)
            • Bradycardia and first-degree heart block were observed in pediatric patients; bradycardia was managed through dose titration, but did not result in study drug discontinuation
            • Avoid use in patients with second-degree AV block unless a functioning demand pacemaker is present

            Pacemakers

            • Dosing is based on heart rate reduction, targeting a heart rate of 50-60 bpm
            • Patients with demand pacemakers set to a rate ≥60 bpm cannot achieve a target heart rate <60 bpm, and these patients were excluded from clinical trials
            • Not recommended in patients with demand pacemakers set to rates ≥60 bpm

            Drug interactions overview

            • Coadministration of verapamil or diltiazem with ivabradine increases ivabradine systemic exposure and should be avoided
            • Concomitant use with negative chronotropes (eg, digoxin, amiodarone, beta-blockers) may increase the risk of bradycardia; monitor heart rate in patients taking ivabradine with other negative chronotropes
            • Coadministration with CYP3A4 inhibitors and inducers
              • Primarily metabolized by CYP3A4
              • Coadministration of CYP3A4 inhibitors increases ivabradine plasma concentrations
              • Increased plasma concentrations may exacerbate bradycardia and conduction disturbances
              • Contraindicated with strong CYP3A4 inhibitors
              • Avoid use with moderate CYP3A4 inhibitors
              • Avoid use with CYP3A4 inducers; coadministration may decrease ivabradine plasma concentrations
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            Pregnancy & Lactation

            Pregnancy

            May cause fetal toxicity when administered to a pregnant woman, based on findings in animal studies

            There are no adequate and well-controlled studies in pregnant women to inform any drug-associated risks

            Advise females of childbearing potential to use effective contraception

            Animal data

            • In animal reproduction studies, embryo-fetal toxicity and teratogenic effects (eg, abnormal shape of the heart, interventricular septal defect, complex anomalies of primary arteries) were observed
            • Increased postnatal mortality was associated with these teratogenic effects in rats
            • In pregnant rabbits, increased postimplantation loss was noted at an exposure 5 times the human exposure at the MRHD; lower doses were not tested in rabbits

            Clinical considerations

            • Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester
            • Pregnant patients with LVEF <35% on maximally tolerated doses of beta-blockers may be particularly heart rate dependent for augmenting cardiac output
            • Therefore, closely follow pregnant patients starting treatment, especially during the first trimester, for destabilization of their congestive heart failure; monitor pregnant women with chronic heart failure in 3rd trimester of pregnancy for preterm birth

            Lactation

            Unknown if distributed in human breast milk

            Animal studies have shown, however, that ivabradine is present in rat milk

            Because of potential risk to breastfed infants, breastfeeding is not recommended

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I(f) ‘funny’ current, which regulates heart rate

            In clinical electrophysiology studies, the cardiac effects were most pronounced in the sinoatrial (SA) node, but prolongation of the AH interval has occurred on the surface ECG, as has PR interval prolongation

            There was no effect on ventricular repolarization and no effects on myocardial contractility

            Absorption

            Bioavailability: ~40% (because of first-pass elimination in the gut and liver)

            Peak plasma time: 1 hr (fasting)

            Food delays absorption by ~1 hr and increases plasma exposure by 20-40%

            Ivabradine should be taken with meals

            Distribution

            Protein bound: 70%

            Vd: 100 L

            Metabolism

            Extensively metabolized in the liver and intestines by CYP3A4-mediated oxidation

            Major metabolite: N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations ~40% that of ivabradine

            The N-desmethylated derivative is also metabolized by CYP3A4

            Elimination

            Distribution half-life: 2 hr

            Effective half-life: ~6 hr

            Total clearance: 24 L/hr

            Renal clearance: 4.2 L/hr

            Excretion: 4% unchanged in urine; excretion of metabolites occurs to a similar extent via feces and urine

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            Administration

            Oral Administration

            Take BID with meals

            Oral solution

            • Empty entire contents of the ampule(s) into a medication cup
            • With a calibrated oral syringe, measure prescribed dose from the medication cup and administer
            • Oral solution is sterile and preservative-free
            • Discard the unused oral solution; do not store or reuse any oral solution left in either the medication cup or an ampule

            Missed dose

            • If patient misses a dose, do not give another dose; give next dose at scheduled time

            Storage

            Tablets: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

            Oral solution: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); protect ampule from light by storing in the foil pouch until use

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.