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    Other Cardiovascular Products

    DEA CLASS

    Rx

    DESCRIPTION

    Hyperpolarization-activated cyclic nucleotide-gated channel blocker
    Used to reduce the risk of hospitalization for stable, symptomatic chronic heart failure who meet specified criteria for treatment
    Contraindicated when used in combination with strong CYP3A4 inhibitors

    COMMON BRAND NAMES

    Corlanor

    HOW SUPPLIED

    Corlanor Oral Tab: 5mg, 7.5mg

    DOSAGE & INDICATIONS

    For risk reduction of hospitalization for worsening heart failure (HF) in patients with stable, symptomatic chronic HF with left ventricular ejection fraction of 35% or less, who are in sinus rhythm with resting heart rate of 70 beats per minute or more and either are on maximally tolerated dose of beta-blocker or have a contraindication to beta-blocker use.
    Oral dosage
    Adults

    Initially, 5 mg PO twice daily. Initiate therapy at 2.5 mg PO twice daily in patients with a history of conduction defects, or in those whom bradycardia could lead to hemodynamic compromise. After 2 weeks, adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm). For a resting heart rate more than 60 bpm, increase the dose by 2.5 mg PO twice daily. For a resting heart rate of 50 to 60 bpm, maintain the current dose. For a resting heart rate less than 50 bpm, decrease the dose by 2.5 mg PO twice daily; if current dose is 2.5 mg PO twice daily, discontinue therapy. Additional dose adjustments should be made as needed based on resting heart rate and tolerability. Do not exceed 7.5 mg PO twice daily. Guidelines suggest ivabradine for reducing heart failure hospitalization for patients with symptomatic (NYHA class II or III) stable chronic reduced ejection fraction heart failure (HFrEF) who are receiving standard therapy, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a resting heart rate of 70 bpm or more at rest.

    MAXIMUM DOSAGE

    Adults

    7.5 mg PO twice daily.

    Geriatric

    7.5 mg PO twice daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Ivabradine has not been studied in patients with severe hepatic impairment (Child-Pugh C) as increased systemic exposure is anticipated. Therefore, ivabradine is contraindicated in this population. No dose adjustment is required in patients with mild to moderate hepatic impairment.

    Renal Impairment

    No dosage adjustment is needed in patients with CrCl 15—60 mL/min. No data are available for patients with CrCl < 15 mL/min.

    ADMINISTRATION

    Oral Administration

    Administer with meals.
    Patients should avoid ingestion of grapefruit juice.

    STORAGE

    Corlanor:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Acute heart failure, AV block, bradycardia, bundle-branch block, hypotension, sick sinus syndrome

    Ivabradine is contraindicated in pacemaker dependence (patients whose heart rate is maintained exclusively by a pacemaker). The dosing of ivabradine is based on a target heart rate reduction between 50 to 60 beats per minute (bpm); a target heart rate < 60 bpm cannot be achieved in patients with demand pacemakers set to >= 60 bpm. This population was excluded from clinical trials and therefore, use of ivabradine is not recommended in patients with demand pacemakers set to >= 60 bpm. Ivabradine is also contraindicated in patients with decompensated acute heart failure; hypotension (i.e. blood pressure < 90/50 mmHg); sick sinus syndrome, sinoatrial block, or third degree AV block, unless a functioning demand pacemaker is present; and bradycardia (i.e., resting heart rate < 60 bpm prior to treatment). Use of ivabradine has resulted in bradycardia, sinus arrest, and heart block. Bradycardia may increase the risk of QT prolongation which may cause severe ventricular arrhythmias, including torsades de pointes, especially in patients with risk factors such as use of QT prolonging drugs. The risk for bradycardia is increased in patients with sinus node dysfunction; ventricular dyssynchrony; use of other negative chronotropic agents like digoxin, diltiazem, verapamil, amiodarone; or conduction defects (e.g., first or second degree AV block, bundle-branch block). Avoid use of ivabradine in patients with second degree AV block unless a functioning pacemaker is present.

    Hepatic disease

    Ivabradine was not studied in patients with severe hepatic impairment. Because increased systemic exposure is anticipated in patients with severe hepatic disease (Child-Pugh C), ivabradine is contraindicated in this population. No dosage adjustments are necessary in patients with mild to moderate hepatic impairment.

    Pregnancy

    There are no adequate and well-controlled studies of ivabradine in pregnant women to inform any drug-associated risks. Based on animal studies, ivabradine may cause fetal harm if administered during human pregnancy. Doses providing 1 to 3 times the human exposure at the maximum recommended human dose (MRHD) resulted in embryo-fetal toxicity and teratogenicity manifested as abnormal shape of the heart, interventricular septal defect, and complex anomalies of primary arteries with associated postnatal mortality in animal reproduction studies. At doses 5 times the human exposure at the MRHD, there was an increased rate of post-implantation loss. During pregnancy, stroke volume and heart rate increase, resulting in increased cardiac output, particularly during the first trimester. Pregnant patients with left ventricular ejection fraction less than 35% on maximally tolerated doses of beta-blockers may be particularly heart-rate dependent for augmenting cardiac output. Closely follow pregnant patients started on ivabradine, especially in the first trimester, for destabilization of congestive heart failure that could result in slowing of the heart rate. Pregnant women with chronic heart failure should be monitored for pre-term birth in the third trimester.

    Contraception requirements, reproductive risk

    Discuss reproductive risk and contraception requirements with female patients of childbearing potential. Because there is a potential for fetal harm with use of ivabradine, advise females of child-bearing potential to utilize effective contraception during therapy.

    Breast-feeding

    There is no information about the presence of ivabradine in human milk or the effects of ivabradine on the breast-fed infant or milk production. Animal studies found ivabradine was present in rat milk. Because of the potential risk to breast-fed infants from exposure to ivabradine, breast-feeding is not recommended.

    Driving or operating machinery

    Advise patients to use caution when driving or operating machinery when sudden changes in light intensity may occur, especially while driving at night. Ivabradine has been associated with visual impairment presenting as luminous phenomena (phosphenes). Patients may experience a transiently enhanced brightness in a limited area of the visual field, halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency) that is usually triggered by sudden variations in light intensity (e.g., night driving). Phosphenes may subside spontaneously during continued treatment with ivabradine.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 8.3-8.3
    torsade de pointes / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    visual impairment / Early / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    hypertension / Early / 8.9-8.9
    hypotension / Rapid / Incidence not known
    erythema / Early / Incidence not known

    Mild

    syncope / Early / Incidence not known
    diplopia / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    vertigo / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Acetaminophen; Butalbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Aldesleukin, IL-2: (Moderate) Use caution during coadministration of ivabradine and aldesleukin, IL-2 as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is an inhibitor of the hepatic isoenzyme CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Amiodarone: (Major) Avoid coadministration of ivarbadine and amiodarone as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; amiodarone is a moderate CYP3A4 inhibitor. In addition, coadministration of ivabradine with other negative chronotropes like amiodarone increases the risk for bradycardia. Increased ivabradine concentrations may further increase the risk of bradycardia exacerbation and conduction disturbances.
    Amobarbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Amoxicillin; Clarithromycin; Lansoprazole: (Severe) Coadministration of ivabradine and clarithromycin is contraindicated. Ivabradine is primarily metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Amoxicillin; Clarithromycin; Omeprazole: (Severe) Coadministration of ivabradine and clarithromycin is contraindicated. Ivabradine is primarily metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Apalutamide: (Major) Avoid coadministration of ivabradine and apalutamide due to decreased plasma concentrations of ivabradine. Ivabradine is a CYP3A4 substrate and apalutamide is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ivabradine exposure by approximately half.
    Aprepitant, Fosaprepitant: (Major) Use caution if ivabradine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ivabradine-related adverse effects, including bradycardia exacerbation and conduction disturbances, for several days after administration of a multi-day aprepitant regimen. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ivabradine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Atazanavir: (Severe) Coadministration of ivabradine and atazanvir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; atazanavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Atazanavir; Cobicistat: (Severe) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold. (Severe) Coadministration of ivabradine and atazanvir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; atazanavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Atenolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Atenolol; Chlorthalidone: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Barbiturates: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Bendroflumethiazide; Nadolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Beta-blockers: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Betaxolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Bexarotene: (Major) Avoid coadministration of ivabradine and bexarotene. Ivabradine is primarily metabolized by CYP3A4; bexarotene induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Bisoprolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Boceprevir: (Severe) Coadministration of ivabradine and boceprevir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; boceprevir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Bosentan: (Major) Avoid coadministration of ivabradine and bosentan. Ivabradine is primarily metabolized by CYP3A4; bosentan induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Brigatinib: (Major) Avoid coadministration of brigatinib with ivabradine due to decreased plasma exposure to ivabradine which may result in decreased efficacy. Ivabradine is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer in vitro.
    Brimonidine; Timolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Butabarbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Carbamazepine: (Major) Avoid coadministration of ivabradine and carbamazepine. Ivabradine is primarily metabolized by CYP3A4; carbamazepine induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Carteolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Carvedilol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Ceritinib: (Major) Avoid coadministration of ceritinib with ivabradine due to increased ivabradine exposure, which may exacerbate bradycardia and conduction disturbances. Ceritinib is a CYP3A4 inhibitor and ivabradine is metabolized by CYP3A4. Coadministration of ivabradine with a strong CYP3A4 inhibitor is contraindicated, while the manufacturer recommends avoiding coadministration with moderate CYP3A4 inhibitors. Coadministration with a strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold, while concomitant use of moderate CYP3A4 inhibitors increased exposure of ivabradine by 2-fold to 3-fold. The degree of CYP3A4 inhibition with ceritinib is unknown.
    Chloramphenicol: (Severe) Coadministration of ivabradine and chloramphenicol is contraindicated. Ivabradine is primarily metabolized by CYP3A4; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Cimetidine: (Moderate) Use caution during coadministration of ivabradine and cimetidine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; cimetidine inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ciprofloxacin: (Major) Avoid coadministration of ivabradine and ciprofloxacin as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; ciprofloxacin inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Clarithromycin: (Severe) Coadministration of ivabradine and clarithromycin is contraindicated. Ivabradine is primarily metabolized by CYP3A4; clarithromycin is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Cobicistat: (Severe) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Severe) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Cocaine: (Moderate) Use caution during coadministration of ivabradine and cocaine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; cocaine is a weak inhibitor or CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Conivaptan: (Severe) Coadministration of ivabradine and conivaptan is contraindicated. Ivabradine is primarily metabolized by CYP3A4; conivaptan is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Crizotinib: (Major) Avoid coadministration of ivabradine and crizotinib as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased the AUC of ivabradine by 2- to 3-fold.
    Cyclosporine: (Major) Avoid coadministration of ivabradine and cyclosporine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; cyclosporine inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Dabrafenib: (Major) Avoid coadministration of ivabradine and dabrafenib. Ivabradine is primarily metabolized by CYP3A4; dabrafenib is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Danazol: (Major) Avoid coadminsitration of ivabradine and danazol as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; danazol inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Darunavir: (Severe) Coadministration of ivabradine and darunavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Darunavir; Cobicistat: (Severe) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold. (Severe) Coadministration of ivabradine and darunavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Severe) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold. (Severe) Coadministration of ivabradine and darunavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of ivabradine and ritonavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Deferasirox: (Major) Avoid coadministration of ivabradine and deferasirox. Ivabradine is primarily metabolized by CYP3A4; deferasirox is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Delavirdine: (Severe) Coadministration of ivabradine and delavirdine is contraindicated. Ivabradine is primarily metabolized by CYP3A4; delavirdine is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Dexamethasone: (Major) Avoid coadministration of ivabradine and dexamethasone. Ivabradine is primarily metabolized by CYP3A4; dexamethasone is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Digoxin: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like digoxin. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Diltiazem: (Major) Avoid coadministration of ivabradine and diltiazem. Both ivabradine and diltiazem may cause bradycardia. In addition, ivabradine is primarily metabolized by CYP3A4; diltiazem inhibits CYP3A4. Coadministration may increase the plasma concentrations of ivabradine further increasing the risk for bradycardia exacerbation and conduction disturbances.
    Dorzolamide; Timolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Dronedarone: (Major) Avoid coadministration of ivabradine and dronedarone as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; dronedarone inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Efavirenz: (Major) Avoid coadministration of ivabradine and efavirenz. Ivabradine is primarily metabolized by CYP3A4; efavirenz is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of ivabradine and efavirenz. Ivabradine is primarily metabolized by CYP3A4; efavirenz is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ivabradine and efavirenz. Ivabradine is primarily metabolized by CYP3A4; efavirenz is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Elagolix: (Major) Avoid coadministration of ivabradine and elagolix. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure. Ivabradine is primarily metabolized by CYP3A4; elagolix is a weak to moderate inducer of CYP3A4.
    Elbasvir; Grazoprevir: (Moderate) Administering ivabradine with elbasvir; grazoprevir may result in elevated ivabradine plasma concentrations. Ivabradine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Enzalutamide: (Major) Avoid coadministration of ivabradine and enzalutamide due to decreased plasma concentrations of ivabradine. Ivabradine is a CYP3A4 substrate and enzalutamide is a CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ivabradine exposure by approximately half.
    Erythromycin: (Major) Avoid coadministration of ivabradine and erythromycin as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; erythromycin inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of ivabradine and erythromycin as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; erythromycin inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Eslicarbazepine: (Major) Avoid coadministration of ivabradine and eslicarbazepine. Ivabradine is primarily metabolized by CYP3A4; eslicarbazepine is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Esmolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Etravirine: (Major) Avoid coadministration of ivabradine and etravirine. Ivabradine is primarily metabolized by CYP3A4; etravirine is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Felbamate: (Major) Avoid coadministration of ivabradine and felbamate. Ivabradine is primarily metabolized by CYP3A4; felbamate is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Fluconazole: (Major) Avoid coadministration of ivabradine and fluconazole as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; fluconazole inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Fluoxetine: (Moderate) Use caution during coadministration of ivabradine and fluoxetine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; norfluoxetine, the active metabolite of fluoxetine, inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Fluoxetine; Olanzapine: (Moderate) Use caution during coadministration of ivabradine and fluoxetine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; norfluoxetine, the active metabolite of fluoxetine, inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Fluvoxamine: (Moderate) Coadministration may increase the plasma concentrations of ivabradine, potentially increasing the risk for bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and fluvoxamine is a moderate CYP3A4 inhibitor.
    Fosamprenavir: (Severe) Coadministration of ivabradine and fosamprenavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Fosphenytoin: (Major) Avoid coadministration of ivabradine and phenytoin or fosphenytoin. Ivabradine is primarily metabolized by CYP3A4; phenytoin induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Grapefruit juice: (Major) Avoid consuming grapefruit juice during ivabradine therapy. Ivabradine is primarily metabolized by CYP3A4; grapefruit juice inhibits CYP3A4. Coadministration may increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Idelalisib: (Severe) Coadministration of ivabradine and idelalisib is contraindicated. Ivabradine is primarily metabolized by CYP3A4; idelalisib is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Imatinib: (Major) Avoid coadministration of ivabradine and imatinib, STI-571 as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; imatinib inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Indinavir: (Severe) Coadministration of ivabradine and indinavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; indinavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Isavuconazonium: (Major) Avoid coadministration of ivabradine and isavuconazonium. Ivabradine is primarily metabolized by CYP3A4; isavuconazonium is a moderate CYP3A4 inhibitor. Coadministration may increase the plasma concentrations of ivabradine further increasing the risk for bradycardia exacerbation and conduction disturbances.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ivabradine and rifampin. Ivabradine is primarily metabolized by CYP3A4; rifampin induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ivabradine and rifampin. Ivabradine is primarily metabolized by CYP3A4; rifampin induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Itraconazole: (Severe) Ivabradine is contraindicated for use during and for 2 weeks after itraconazole therapy. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; itraconazole is a strong CYP3A4 inhibitor.
    Ketoconazole: (Severe) Coadministration of ivabradine and ketoconazole is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Labetalol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Lapatinib: (Moderate) Use caution during coadministration of ivabradine and lapatinib as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; in vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ivabradine; monitor for potential reduction in efficacy. Ivabradine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ivabradine; monitor for potential reduction in efficacy. Ivabradine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Major) Avoid concurrent use of ivabradine and letermovir as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Ivabradine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold, while concomitant use of moderate CYP3A4 inhibitors increased exposure of ivabradine by 2-fold to 3-fold.
    Levobetaxolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Levobunolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Lopinavir; Ritonavir: (Severe) Coadministration of ivabradine and lopinavir; ritonavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances. (Severe) Coadministration of ivabradine and ritonavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Lorlatinib: (Major) Avoid coadministration of ivabradine and lorlatinib due to decreased plasma concentrations of ivabradine. Ivabradine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of ivabradine; avoid concurrent use. Ivabradine is primarily metabolized by CYP3A4. Lumacaftor is a strong CYP3A inducer.
    Mephobarbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Methohexital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Metoprolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Mifepristone: (Major) Avoid coadministration of ivabradine and mifepristone as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; mifepristone inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances. Due to the slow elimination of mifepristone from the body, drug interactions may be prolonged.
    Mitotane: (Major) Avoid the concomitant use of mitotane with ivabradine; if coadministration cannot be avoided, monitor for decreased efficacy of ivabradine. Mitotane is a strong CYP3A4 inducer and ivabradine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ivabradine.
    Modafinil: (Major) Avoid coadministration of ivabradine and modafinil. Ivabradine is primarily metabolized by CYP3A4; modafinil is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Nadolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Nebivolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Nebivolol; Valsartan: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Nefazodone: (Severe) Coadministration of ivabradine and nefazodone is contraindicated. Ivabradine is primarily metabolized by CYP3A4; nefazodone is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Nelfinavir: (Severe) Coadministration of ivabradine and nelfinavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; nelfinavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of ivabradine and netupitant; palonosetron as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; netupitant is a moderate CYP3A4 inhibitor. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Nevirapine: (Major) Avoid coadministration of ivabradine and nevirapine. Ivabradine is primarily metabolized by CYP3A4; nevirapine is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Nicardipine: (Major) Avoid coadministration of ivabradine and nicardipine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; nicardipine inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Nilotinib: (Major) Avoid coadministration of ivabradine and nilotinib as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; nilotinib inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Octreotide: (Moderate) Use caution during coadministration of ivabradine and octreotide as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; octreotide suppresses growth hormone secretion, which may cause a decrease in the metabolic clearance of drugs metabolized by CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Coadministration of ivabradine and ritonavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Oritavancin: (Major) Avoid coadministration of ivabradine and oritavancin. Ivabradine is primarily metabolized by CYP3A4; oritavancin is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Oxcarbazepine: (Major) Avoid coadministration of ivabradine and oxcarbazepine. Ivabradine is primarily metabolized by CYP3A4; oxcarbazepine is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Pazopanib: (Moderate) Use caution during coadministration of ivabradine and pazopanib as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; pazopanib is a weak inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Penbutolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Pentobarbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Perampanel: (Major) Avoid coadministration of ivabradine and perampanel. Ivabradine is primarily metabolized by CYP3A4; peramapanel is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Phenobarbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Phentermine; Topiramate: (Major) Avoid coadministration of ivabradine and topiramate. Ivabradine is primarily metabolized by CYP3A4; topiramte is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Phenytoin: (Major) Avoid coadministration of ivabradine and phenytoin or fosphenytoin. Ivabradine is primarily metabolized by CYP3A4; phenytoin induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Pindolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Pirfenidone: (Moderate) Use caution during coadministration of ivabradine and pirfenidone as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; pirfenidone is a weak inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Posaconazole: (Severe) Coadministration of ivabradine and posaconazole is contraindicated. Ivabradine is primarily metabolized by CYP3A4; posaconazole is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Primidone: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Propranolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Quinine: (Major) Avoid coadministration of ivabradine and quinine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; quinine is an inhibitor of CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ranolazine: (Moderate) Use caution during coadministration of ivabradine and ranolazine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; ranolazine is a weak inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ribociclib: (Severe) Coadministration of ribociclib with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Ribociclib; Letrozole: (Severe) Coadministration of ribociclib with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Rifabutin: (Major) Avoid coadministration of ivabradine and rifabutin. Ivabradine is primarily metabolized by CYP3A4; rifabutin is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Rifampin: (Major) Avoid coadministration of ivabradine and rifampin. Ivabradine is primarily metabolized by CYP3A4; rifampin induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Rifapentine: (Major) Avoid coadministration of ivabradine and rifapentine. Ivabradine is primarily metabolized by CYP3A4; rifapentine is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ritonavir: (Severe) Coadministration of ivabradine and ritonavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Saquinavir: (Severe) Coadministration of ivabradine and saquinavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; saquinavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Secobarbital: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Simeprevir: (Moderate) Use caution during coadministration of ivabradine and simeprevir as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; simeprevir is a mild inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Sotalol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of ivabradine and St. John's wort. Ivabradine is primarily metabolized by CYP3A4; St. John's wort induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for reduced efficacy of ivabradine.
    Streptogramins: (Severe) Coadministration of ivabradine and dalfopristin; quinupristin is contraindicated. Ivabradine is primarily metabolized by CYP3A4; dalfopristin; quinupristin is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Telithromycin: (Severe) Coadministration of ivabradine and telithromycin is contraindicated. Ivabradine is primarily metabolized by CYP3A4; telithromycin is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Telotristat Ethyl: (Major) Avoid coadministration of telotristat ethyl with ivabradine, as the systemic exposure of ivabradine may be decreased resulting in reduced efficacy. Ivabradine is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Thiopental: (Major) Avoid coadministration of ivabradine and barbiturates including primidone. Ivabradine is primarily metabolized by CYP3A4; barbiturates induce CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ticagrelor: (Moderate) Use caution during coadministration of ivabradine and ticagrelor as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; ticagrelor is a weak inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Timolol: (Moderate) Monitor heart rate if ivabradine is coadministered with other negative chronotropes like beta-blockers. Most patients receiving ivabradine will receive concomitant beta-blocker therapy. Coadministration of drugs that slow heart rate increases the risk for bradycardia.
    Tipranavir: (Severe) Coadministration of ivabradine and tipranavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; tipranavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Topiramate: (Major) Avoid coadministration of ivabradine and topiramate. Ivabradine is primarily metabolized by CYP3A4; topiramte is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Trandolapril; Verapamil: (Major) Avoid coadministration of ivabradine and verapamil. Both ivabradine and verapamil may cause bradycardia. In addition, ivabradine is primarily metabolized by CYP3A4; verapamil inhibits CYP3A4. Coadministration may increase the plasma concentrations of ivabradine further increasing the risk for bradycardia exacerbation and conduction disturbances.
    Vemurafenib: (Major) Avoid coadministration of ivabradine and vemurafenib. Ivabradine is primarily metabolized by CYP3A4; vemurafenib is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Verapamil: (Major) Avoid coadministration of ivabradine and verapamil. Both ivabradine and verapamil may cause bradycardia. In addition, ivabradine is primarily metabolized by CYP3A4; verapamil inhibits CYP3A4. Coadministration may increase the plasma concentrations of ivabradine further increasing the risk for bradycardia exacerbation and conduction disturbances.
    Voriconazole: (Severe) Coadministration of voriconazole with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
    Zafirlukast: (Moderate) Use caution during coadministration of ivabradine and zafirlukast as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; zafirlukast is a minor inhibitor of CYP3A, in vitro. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies of ivabradine in pregnant women to inform any drug-associated risks. Based on animal studies, ivabradine may cause fetal harm if administered during human pregnancy. Doses providing 1 to 3 times the human exposure at the maximum recommended human dose (MRHD) resulted in embryo-fetal toxicity and teratogenicity manifested as abnormal shape of the heart, interventricular septal defect, and complex anomalies of primary arteries with associated postnatal mortality in animal reproduction studies. At doses 5 times the human exposure at the MRHD, there was an increased rate of post-implantation loss. During pregnancy, stroke volume and heart rate increase, resulting in increased cardiac output, particularly during the first trimester. Pregnant patients with left ventricular ejection fraction less than 35% on maximally tolerated doses of beta-blockers may be particularly heart-rate dependent for augmenting cardiac output. Closely follow pregnant patients started on ivabradine, especially in the first trimester, for destabilization of congestive heart failure that could result in slowing of the heart rate. Pregnant women with chronic heart failure should be monitored for pre-term birth in the third trimester.

    There is no information about the presence of ivabradine in human milk or the effects of ivabradine on the breast-fed infant or milk production. Animal studies found ivabradine was present in rat milk. Because of the potential risk to breast-fed infants from exposure to ivabradine, breast-feeding is not recommended.

    MECHANISM OF ACTION

    Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker. Ivabradine selectively and specifically inhibits the cardiac pacemaker If current in the sinoatrial node resulting in a dose-dependent reduction in heart rate. Studies in healthy hearts suggest ivabradine does not affect other channels in the heart or vascular system. Unlike beta-blockers, ivabradine has no effect on myocardial contractility and intracardiac conduction, even in patients with impaired systolic function. The magnitude of heart rate reduction is proportional to the baseline heart rate with a plateau effect at doses > 20 mg twice daily. Because ivabradine also inhibits h-channels, which carry the Ih current in the retina, some patients have experienced luminous phenomena (phosphenes).
     
    In clinical studies, ivabradine was associated with a dose-dependent increase of 18—30 ms in the uncorrected QT interval with heart rate reduction. However, the rate-corrected increase in QT interval did not exceed 2 ms which is below the limit of 5 ms for torsadogenicity.

    PHARMACOKINETICS

    Ivabradine is administered orally. Plasma protein binding is approximately 70% with a steady state volume of distrubution of about 100 L. Ivabradine undergoes extensive metabolism in the liver and intestines via CYP3A4-mediated oxidation. The N-desmethylated derivative (S 18982) is the major metabolite and is equipotent to ivabradine. S 18982 circulates at concentrations approximately 40% that of ivabradine and is also metabolized by CYP3A4. The effective half-life of ivabradine is approximately 6 hours. Approximately 4% of an oral dose is excreted unchanged in the urine; the metabolites are excreted to a similar extent in the feces and urine.
     
    Affected cytochrome P450 isoenzymes and drug transporter: CYP3A4
    Ivabradine is primarily metabolized by CYP3A4. The plasma concentrations of ivabradine are altered by coadministration of CYP3A4 inhibitors and inducers.

    Oral Route

    The absolute oral bioavailability of ivabradine is 40%. Ivabradine undergoes extensive first-pass elimination in the gut and liver. The maximum plasma concentration (Cmax) occurs 1 hour after administration in the fasted state. Food delays the time to Cmax by approximately 1 hour and increases plasma exposure by 20—40%.