Drug: Corlanor

Corlanor (ivabradine) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If current (If), resulting in heart rate reduction with no effect on ventricular repolarization and no effects on myocardial contractility. The chemical name for ivabradine is 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7yl)methyl] methyl amino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one, hydrochloride. The molecular formula is C27H36N2O5, HCl, and the molecular weight (free base + HCl) is 505.1 (468.6 + 36.5). The chemical structure of ivabradine is shown in Figure 1. Figure 1: Chemical Structure of Ivabradine
Corlanor tablets are formulated as salmon-colored, film-coated tablets for oral administration in strengths of 5 mg and 7.5 mg of ivabradine as the free base equivalent. Inactive Ingredients Core Lactose monohydrate, maize starch, maltodextrin, magnesium stearate, colloidal silicon dioxide Film Coating Hypromellose, titanium dioxide, glycerol, magnesium stearate, polyethylene glycol 6000, yellow iron oxide, red iron oxide Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

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Clinically significant adverse reactions that appear in other sections of the labeling include:
  • Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
  • Atrial Fibrillation [see WARNINGS AND PRECAUTIONS]
  • Bradycardia and Conduction Disturbances [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), safety was evaluated in 3260 patients treated with Corlanor and 3278 patients given placebo. The median duration of Corlanor exposure was 21.5 months. The most common adverse drug reactions in the SHIFT trial are shown in Table 2 [see also WARNINGS AND PRECAUTIONS]. Table 2: Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo occurring in > 1% on Ivabradine in SHIFT
  Ivabradine
N=3260 Placebo
N=3278 Bradycardia 10% 2.2% Hypertension, blood pressure increased 8.9% 7.8% Atrial fibrillation 8.3% 6.6% Phosphenes, visual brightness 2.8% 0.5% Luminous Phenomena (Phosphenes) Phosphenes are phenomena described as 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). Phosphenes are usually triggered by sudden variations in light intensity. Corlanor can cause phosphenes, thought to be mediated through Corlanor’s effects on retinal photoreceptors [see CLINICAL PHARMACOLOGY]. Onset is generally within the first 2 months of treatment, after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity and led to treatment discontinuation in < 1% of patients; most resolved during or after treatment. Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of Corlanor: syncope, hypotension, angioedema, erythema, rash, pruritus, urticaria, vertigo, diplopia, and visual impairment. Read the Corlanor (ivabradine tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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The recommended starting dose of Corlanor is 5 mg twice daily with meals. Assess patient after two weeks and adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm) as shown in Table 1. Thereafter, adjust dose as needed based on resting heart rate and tolerability. The maximum dose is 7.5 mg twice daily. In patients with a history of conduction defects, or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily before increasing the dose based on heart rate [see WARNINGS AND PRECAUTIONS]. Table 1: Dose Adjustment
Heart Rate Dose Adjustment > 60 bpm Increase dose by 2.5 mg (given twice daily) up to a maximum dose of 7.5 mg twice daily 50-60 bpm Maintain dose < 50 bpm or signs and symptoms of bradycardia Decrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg twice daily, discontinue therapy* *[see WARNINGS AND PRECAUTIONS]

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Cytochrome P450-Based Interactions Corlanor 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 [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. 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 Corlanor. Examples of moderate CYP3A4 inhibitors include diltiazem, verapamil, and grapefruit juice [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. Avoid concomitant use of CYP3A4 inducers when using Corlanor. Examples of CYP3A4 inducers include St. John’s wort, rifampicin, barbiturates, and phenytoin [see CLINICAL PHARMACOLOGY]. Negative Chronotropes Most patients receiving Corlanor 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 Corlanor with other negative chronotropes. Pacemakers Corlanor dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute [see DOSAGE AND ADMINISTRATION]. Patients with demand pacemakers set to a rate ≥ 60 beats per minute cannot achieve a target heart rate < 60 beats per minute, and these patients were excluded from clinical trials [see Clinical Studies]. The use of Corlanor is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute. Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Corlanor is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

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Corlanor is contraindicated in patients with:
  • Acute decompensated heart failure
  • Blood pressure less than 90/50 mmHg
  • Sick sinus syndrome, sinoatrial block, or 3rd degree AV block, unless a functioning demand pacemaker is present
  • Resting heart rate less than 60 bpm prior to treatment [see WARNINGS AND PRECAUTIONS]
  • Severe hepatic impairment [see Use in Specific Populations]
  • Pacemaker dependence (heart rate maintained exclusively by the pacemaker) [see DRUG INTERACTIONS]
  • Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors [see DRUG INTERACTIONS]
Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Overdose may lead to severe and prolonged bradycardia. In the event of bradycardia with poor hemodynamic tolerance, temporary cardiac pacing may be required. Supportive treatment, including intravenous (IV) fluids, atropine, and intravenous beta-stimulating agents such as isoproterenol, may be considered.

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Dosage Forms And Strengths Corlanor 5 mg: salmon-colored, oval-shaped, film-coated tablet, scored on both edges, debossed with “5” on one face and bisected on the other face. The tablet is scored and can be divided into equal halves to provide a 2.5 mg dose. Corlanor 7.5 mg: salmon-colored, triangular-shaped, film-coated tablet debossed with “7.5” on one face and plain on the other face. Storage And Handling Corlanor 5 mg tablets are formulated as salmon-colored, oval-shaped, film-coated tablets scored on both edges, marked with “5” on one face and bisected on the other face. They are supplied as follows: Bottles of 60 tablets (NDC 55513-800-60)
Bottles of 180 tablets (NDC 55513-800-80) Corlanor 7.5 mg tablets are formulated as salmon-colored, triangular-shaped, film-coated tablets debossed with “7.5” on one face and plain on the other face. They are supplied as follows: Bottles of 60 tablets (NDC 55513-810-60)
Bottles of 180 tablets (NDC 55513-810-80) Storage Store at 25°C (77°F); excursions permitted to 15° -30°C (59° -86°F) [see USP Controlled Room Temperature]. Manufactured for: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799. Issued: 04/2015 Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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 (AUC0-24hr) at the maximum recommended human dose (MRHD) [see Use in Specific Populations]. Advise females to use effective contraception when taking Corlanor [see Use in Specific Populations]. Atrial Fibrillation Corlanor increases the risk of atrial fibrillation. In 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 [see Clinical Studies]. Regularly monitor cardiac rhythm. Discontinue Corlanor if atrial fibrillation develops. Bradycardia And Conduction Disturbances 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., 1st or 2nd degree atrioventricular block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (e.g., digoxin, diltiazem, verapamil, amiodarone). Concurrent use of verapamil or diltiazem will increase Corlanor exposure, may themselves contribute to heart rate lowering, and should be avoided [see CLINICAL PHARMACOLOGY]. Avoid use of Corlanor in patients with 2nd degree atrioventricular block, unless a functioning demand pacemaker is present [see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide).
  • Fetal Toxicity
    Advise pregnant women of the potential risks to a fetus.
    Advise females of reproductive potential to use effective contraception and to notify their healthcare provider with a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use in Specific Populations].
  • Low Heart Rate
    Advise patients to report significant decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension [see WARNINGS AND PRECAUTIONS].
  • Atrial fibrillation
    Advise patients to report symptoms of atrial fibrillation, such as heart palpitations or racing, chest pressure, or worsened shortness of breath [see WARNINGS AND PRECAUTIONS].
  • Phosphenes
    Advise patients about the possible occurrence of luminous phenomena (phosphenes). Advise patients to use caution if they are driving or using machines in situations where sudden changes in light intensity may occur, especially when driving at night. Advise patients that phosphenes may subside spontaneously during continued treatment with Corlanor [see ADVERSE REACTIONS].
  • Drug Interactions
    Advise patients to avoid ingestion of grapefruit juice and St. John's wort [see DRUG INTERACTIONS].
  • Intake with Food
    Advise patients to take Corlanor twice daily with meals [see DOSAGE AND ADMINISTRATION].
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility There was no evidence of carcinogenicity when mice and rats received ivabradine up to 104 weeks by dietary administration. High doses in these studies were associated with mean ivabradine exposures of at least 37 times higher than the human exposure (AUC0-24hr) at the MRHD. Ivabradine tested negative in the following assays: bacterial reverse mutation (Ames) assay, in vivo bone marrow micronucleus assay in both mouse and rat, in vivo chromosomal aberration assay in rats, and in vivo unscheduled DNA synthesis assay in rats. Results of the in vitro chromosomal aberration assay were equivocal at concentrations approximately 1,500 times the human Cmax at the MRHD. Ivabradine tested positive in the mouse lymphoma assays and in vitro unscheduled DNA synthesis assay in rat hepatocytes at concentrations greater than 1,500 times the human Cmax at the MRHD. Reproduction toxicity studies in animals demonstrated that ivabradine did not affect fertility in male or female rats at exposures 46 to 133 times the human exposure (AUC0-24hr) at the MRHD. Use In Specific Populations Pregnancy Risk Summary Based on findings in animals, Corlanor may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Corlanor in pregnant women to inform any drug-associated risks. In animal reproduction studies, oral administration of ivabradine to pregnant rats during organogenesis at a dosage providing 1 to 3 times the human exposure (AUC0-24hr) at the MRHD resulted in embryo-fetal toxicity and teratogenicity manifested as abnormal shape of the heart, interventricular septal defect, and complex anomalies of primary arteries. Increased postnatal mortality was associated with these teratogenic effects in rats. In pregnant rabbits, increased post-implantation loss was noted at an exposure (AUC0-24hr) 5 times the human exposure at the MRHD. Lower doses were not tested in rabbits. The background risk of major birth defects for the indicated population is unknown. The estimated background risk of major birth defects in the U.S. general population is 2 to 4%, however, and the estimated risk of miscarriage is 15 to 20% in clinically recognized pregnancies. Advise a pregnant woman of the potential risk to the fetus. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially 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. Therefore, pregnant patients who are started on Corlanor, especially during the first trimester, should be followed closely for destabilization of their congestive heart failure that could result from heart rate slowing. Monitor pregnant women with chronic heart failure in 3rd trimester of pregnancy for preterm birth. Data Animal Data In pregnant rats, oral administration of ivabradine during the period of organogenesis (gestation day 6-15) at doses of 2.3, 4.6, 9.3, or 19 mg/kg/day resulted in fetal toxicity and teratogenic effects. Increased intrauterine and post-natal mortality and cardiac malformations were observed at doses ≥ 2.3 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC0-24hr). Teratogenic effects including interventricular septal defect and complex anomalies of major arteries were observed at doses ≥ 4.6 mg/kg/day (approximately 3 times the human exposure at the MRHD based on AUC0-24hr). In pregnant rabbits, oral administration of ivabradine during the period of organogenesis (gestation day 618) at doses of 7, 14, or 28 mg/kg/day resulted in fetal toxicity and teratogenicity. Treatment with all doses ≥ 7 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC0-24hr) caused an increase in post-implantation loss. At the high dose of 28 mg/kg/day (approximately 15 times the human exposure at the MRHD based on AUC0-24hr), reduced fetal and placental weights were observed, and evidence of teratogenicity (ectrodactylia observed in 2 of 148 fetuses from 2 of 18 litters) was demonstrated. In the pre-and postnatal study, pregnant rats received oral administration of ivabradine at doses of 2.5, 7, or 20 mg/kg/day from gestation day 6 to lactation day 20. Increased postnatal mortality associated with cardiac teratogenic findings was observed in the F1 pups delivered by dams treated at the high dose (approximately 15 times the human exposure at the MRHD based on AUC0-24hr). Lactation Risk Summary There is no information regarding the presence of ivabradine in human milk, the effects of ivabradine on the breastfed infant, or the effects of the drug on milk production. Animal studies have shown, however, that ivabradine is present in rat milk [see Data]. Because of the potential risk to breastfed infants from exposure to Corlanor, breastfeeding is not recommended. Data Lactating rats received daily oral doses of [14C]-ivabradine (7 mg/kg) on post-parturition days 10 to 14; milk and maternal plasma were collected at 0.5 and 2.5 hours post-dose on day 14. The ratios of total radioactivity associated with [14C]-ivabradine or its metabolites in milk vs. plasma were 1.5 and 1.8, respectively, indicating that ivabradine is transferred to milk after oral administration. Females And Males Of Reproductive Potential Contraception Females Corlanor may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Corlanor treatment [see Use In Specific Populations]. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use No pharmacokinetic differences have been observed in elderly ( ≥ 65 years) or very elderly ( ≥ 75 years) patients compared to the overall population. However, Corlanor has only been studied in a limited number of patients ≥ 75 years of age. Hepatic Impairment No dose adjustment is required in patients with mild or moderate hepatic impairment. Corlanor is contraindicated in patients with severe hepatic impairment (Child-Pugh C) as it has not been studied in this population and an increase in systemic exposure is anticipated [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY]. Renal Impairment No dosage adjustment is required for patients with creatinine clearance 15 to 60 mL/min. No data are available for patients with creatinine clearance below 15 mL/min [see CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 4/27/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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