IVABRADINE tablet, film coated

Ivabradine by

Drug Labeling and Warnings

Ivabradine by is a Prescription medication manufactured, distributed, or labeled by American Health Packaging. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    1.1 Heart Failure in Adult Patients

    Ivabradine tablets are indicated to reduce the risk of hospitalization for worsening heart failure in adult 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.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Adults

    The recommended starting dose of ivabradine tablets is 5 mg twice daily with food. 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 adult patients unable to swallow tablets, ivabradine oral solution can be used [seeClinical Pharmacology (12.3)].

    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 [seeWarnings and Precautions (5.3)].

    Table 1. Dose Adjustment for Adults
  • * [see Warnings and Precautions (5.3)]
    		•

    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 to 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 *

  • 3 DOSAGE FORMS AND STRENGTHS

    Ivabradine Tablets 5 mg: White to off white-colored, oval-shaped, film-coated tablet, functionally scored on both edges, debossed with "V" on one side and "9" bisected "1" on other side.

    Ivabradine Tablets 7.5 mg: Tan colored, oval shaped, film-coated tablet debossed with "V" on one side and "92" on other side.

  • 4 CONTRAINDICATIONS

    Ivabradine tablets are contraindicated in patients with:

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Fetal Toxicity

    Ivabradine may cause fetal toxicity when administered to a pregnant woman based on findings in animal studies. Embryo-fetal toxicity and cardiac teratogenic effects were observed in fetuses of pregnant rats treated during organogenesis at exposures 1 to 3 times the human exposures (AUC 0 to 24hr) at the maximum recommended human dose (MRHD) [seeUse in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception when taking ivabradine [seeUse in Specific Populations (8.3)].

    5.2 Atrial Fibrillation

    Ivabradine increases the risk of atrial fibrillation. In the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT), the rate of atrial fibrillation was 5.0% per patient-year in patients treated with ivabradine and 3.9% per patient-year in patients treated with placebo [seeClinical Studies (14)]. Regularly monitor cardiac rhythm. Discontinue ivabradine if atrial fibrillation develops.

    5.3 Bradycardia and Conduction Disturbances

    Adult Patients
    Bradycardia, sinus arrest, and heart block have occurred with ivabradine. The rate of bradycardia was 6.0% per patient-year in patients treated with ivabradine (2.7% symptomatic; 3.4% asymptomatic) and 1.3% per patient-year in patients treated with placebo. Risk factors for bradycardia include sinus node dysfunction, conduction defects (e.g., 1 st or 2 nd degree atrioventricular block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (e.g., digoxin, diltiazem, verapamil, amiodarone). Bradycardia may increase the risk of QT prolongation which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors such as use of QTc prolonging drugs [seeAdverse Reactions (6.2)].

    Concurrent use of verapamil or diltiazem will increase ivabradine exposure, may themselves contribute to heart rate lowering, and should be avoided [seeClinical Pharmacology (12.3)]. Avoid use of ivabradine in patients with 2 nd degree atrioventricular block unless a functioning demand pacemaker is present [seeContraindications (4)].

  • 6 ADVERSE REACTIONS

    Clinically significant adverse reactions that appear in other sections of the labeling include:

    6.1 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.

    Adult Patients with Heart Failure
    In SHIFT, safety was evaluated in 3,260 patients treated with ivabradine and 3,278 patients given placebo. The median duration of ivabradine exposure was 21.5 months.

    The most common adverse drug reactions in the SHIFT trial are shown in Table 2 [seeWarnings and Precautions (5.2), ( 5.3)].

    Table 2 Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo occurring in > 1% on Ivabradine in SHIFT

    Ivabradine N=3,260

    Placebo N=3,278

    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. Ivabradine can cause phosphenes, thought to be mediated through ivabradine effects on retinal photoreceptors [seeClinical Pharmacology (12.1)]. 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.

    6.2 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 in adults during post-approval use of ivabradine: syncope, hypotension, torsade de pointes, ventricular fibrillation, ventricular tachycardia, angioedema, erythema, rash, pruritus, urticaria, vertigo, and diplopia, and visual impairment.

  • 7 DRUG INTERACTIONS

    7.1 Cytochrome P450-Based Interactions

    Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases them. Increased plasma concentrations may exacerbate bradycardia and conduction disturbances.

    The concomitant use of strong CYP3A4 inhibitors is contraindicated [seeContraindications (4)andClinical Pharmacology (12.3)]. Examples of strong CYP3A4 inhibitors include azole antifungals (e.g., itraconazole), macrolide antibiotics (e.g., clarithromycin, telithromycin), HIV protease inhibitors (e.g., nelfinavir), and nefazodone.

    Avoid concomitant use of moderate CYP3A4 inhibitors when using ivabradine. Examples of moderate CYP3A4 inhibitors include diltiazem, verapamil, and grapefruit juice [seeWarnings and Precautions (5.3)andClinical Pharmacology (12.3)].

    Avoid concomitant use of CYP3A4 inducers when using ivabradine. Examples of CYP3A4 inducers include St. John's wort, rifampicin, barbiturates, and phenytoin [seeClinical Pharmacology (12.3)].

    7.2 Negative Chronotropes

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

    7.3 Pacemakers in Adults

    Ivabradine dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute in adults [seeDosage and Administration (2.1)]. 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 [seeClinical Studies (14.1)]. The use of ivabradine is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary
    Based on findings in animals, ivabradine may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of ivabradine 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 (AUC 0 to 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 post-natal mortality was associated with these teratogenic effects in rats. In pregnant rabbits, increased post-implantation loss was noted at an exposure (AUC 0 to 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 ivabradine, 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 3 rd trimester of pregnancy for preterm birth.

    Data
    Animal Data
    In pregnant rats, oral administration of ivabradine during the period of organogenesis (gestation day 6 to 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 AUC 0 to 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 AUC 0 to 24hr).

    In pregnant rabbits, oral administration of ivabradine during the period of organogenesis (gestation day 6 to 18) 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 AUC 0 to 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 AUC 0 to 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 post-natal 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 post-natal 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 AUC 0 to 24hr).

    8.2 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 ivabradine, 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.

    8.3 Females and Males of Reproductive Potential

    Contraception
    Females
    Ivabradine may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during ivabradine treatment [seeUse in Specific Populations (8.1)].

    8.4 Pediatric Use

    The safety and efficacy of ivabradine have not been established in patients less than 6 months of age.

    8.5 Geriatric Use

    No pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population. However, ivabradine has only been studied in a limited number of patients ≥ 75 years of age.

    8.6 Hepatic Impairment

    No dose adjustment is required in patients with mild or moderate hepatic impairment. Ivabradine 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 [seeContraindications (4)andClinical Pharmacology (12.3)].

    8.7 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 [seeClinical Pharmacology (12.3)].

  • 10 OVERDOSAGE

    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.

  • 11 DESCRIPTION

    Ivabradine tablets contains ivabradine as the active pharmaceutical ingredient. 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 I f current, resulting in heart rate reduction with no effect on ventricular repolarization and no effects on myocardial contractility.

    The chemical name for ivabradine hydrochloride is 3-(3-{[((7 S)-3,4-Dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl)methyl] methyl amino} propyl) -1,3,4,5-tetrahydro-7,8-dimethoxy-2 H-3-benzazepin-2-one, hydrochloride. The molecular formula is C 27H 36N 2O 5. 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
    chemical structure

    Ivabradine tablets are supplied in 5 mg and 7.5 mg tablets for oral administration. The tablets contain 5 mg and 7.5 mg of ivabradine, as the active ingredient, equivalent to 5.39 mg and 8.09 mg of ivabradine hydrochloride, respectively.

    Inactive Ingredients
    Colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate and maltodextrin. The film coating contains glycerin, hypromellose, magnesium stearate, polyethylene glycol, titanium dioxide. In addition, 7.5 mg contains black iron oxide, iron oxide yellow and iron oxide red.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Ivabradine blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I f 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 as has PR interval prolongation. There was no effect on ventricular repolarization and no effects on myocardial contractility [seeClinical Pharmacology (12.2)].

    Ivabradine can also inhibit the retinal current I h. I h is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of I h by ivabradine may underlie the luminous phenomena experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field [seeAdverse Reactions (6.1)].

    12.2 Pharmacodynamics

    Ivabradine causes a dose-dependent reduction in heart rate. The size of the effect is dependent on the baseline heart rate (i.e., greater heart rate reduction occurs in patients with higher baseline heart rate). At recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. Analysis of heart rate reduction vs. dose indicates a plateau effect at doses > 20 mg twice daily. In a study of patients with preexisting conduction system disease (first- or second-degree AV block or left or right bundle branch block) requiring electrophysiologic study, IV ivabradine (0.20 mg/kg) administration slowed the overall heart rate by approximately 15 bpm, increased the PR interval (29 msec), and increased the AH interval (27 msec).

    Ivabradine does not have negative inotropic effects. Ivabradine increases the uncorrected QT interval with heart rate slowing but does not cause rate-corrected prolongation of QT.

    12.3 Pharmacokinetics

    The peak concentration (C max) and area under the plasma concentration time curve (AUC) are similar for ivabradine and S 18982 between oral solution and tablets for the same dose.

    Absorption and Bioavailability
    Following oral administration, peak plasma ivabradine concentrations are reached in approximately 1 hour under fasting conditions. The absolute oral bioavailability of ivabradine is approximately 40% because of first-pass elimination in the gut and liver.

    Food delays absorption by approximately 1 hour and increases plasma exposure by 20% to 40%. Ivabradine should be taken with food [seeDosage and Administration (2)].

    Ivabradine is approximately 70% plasma protein bound, and the volume of distribution at steady state is approximately 100 L.

    Metabolism and Excretion
    The pharmacokinetics of ivabradine are linear over an oral dose range of 0.5 mg to 24 mg. Ivabradine is extensively metabolized in the liver and intestines by CYP3A4-mediated oxidation. The major metabolite is the N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations approximately 40% that of ivabradine. The N-desmethylated derivative is also metabolized by CYP3A4. Ivabradine plasma levels decline with a distribution half-life of 2 hours and an effective half-life of approximately 6 hours.

    The total clearance of ivabradine is 24 L/h, and renal clearance is approximately 4.2 L/h, with ~ 4% of an oral dose excreted unchanged in urine. The excretion of metabolites occurs to a similar extent via feces and urine.

    Drug Interactions
    The effects of coadministered drugs (CYP3A4 inhibitors, substrates, inducers, and other concomitantly administered drugs) on the pharmacokinetics of ivabradine were studied in several single- and multiple-dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 2.

    Figure 2. Impact of Coadministered Drugs on the Pharmacokinetics of Ivabradine

    Figure 2

    Digoxin exposure did not change when concomitantly administered with ivabradine. No dose adjustment is required when ivabradine is concomitantly administered with digoxin.

    Effect of Ivabradine on Metformin Pharmacokinetics
    Ivabradine, dosed at 10 mg twice daily to steady state, did not affect the pharmacokinetics of metformin (an organic cation transporter [OCT2] sensitive substrate). The geometric mean (90% confidence interval [CI]) ratios of C max and AUC inf of metformin, with and without ivabradine were 0.98 [0.83 to 1.15] and 1.02 [0.86 to 1.22], respectively. No dose adjustment is required for metformin when administered with ivabradine.

    Specific Populations
    Age
    No pharmacokinetic differences (AUC or C max) have been observed between elderly (≥ 65 years) or very elderly (≥ 75 years) patients and the overall patient population [seeUse in Specific Populations (8.5)].

    Hepatic Impairment
    In patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of ivabradine were similar to that in patients with normal hepatic function. No data are available in patients with severe hepatic impairment (Child-Pugh C) [seeContraindications (4)].

    Renal Impairment
    Renal impairment (creatinine clearance from 15 to 60 mL/min) has minimal effect on the pharmacokinetics of ivabradine. No data are available for patients with creatinine clearance below 15 mL/min.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 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 (AUC 0 to 24 hr) 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 C max 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 C max 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 (AUC 0 to 24hr) at the MRHD.

    13.2 Animal Toxicology and/or Pharmacology

    Reversible changes in retinal function were observed in dogs administered oral ivabradine at total doses of 2, 7, or 24 mg/kg/day (approximately 0.6 to 50 times the human exposure at the MRHD based on (AUC 0 to 24hr) for 52 weeks. Retinal function assessed by electroretinography demonstrated reductions in cone system responses, which reversed within a week post-dosing, and were not associated with damage to ocular structures as evaluated by light microscopy. These data are consistent with the pharmacological effect of ivabradine related to its interaction with hyperpolarization-activated I h currents in the retina, which share homology with the cardiac pacemaker I f current.

  • 14 CLINICAL STUDIES

    14.1 Heart Failure in Adult Patients

    SHIFT
    The Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT) was a randomized, double-blind trial comparing ivabradine and placebo in 6,558 adult patients with stable New York Heart Association (NYHA) class II to IV heart failure, left ventricular ejection fraction ≤ 35%, and resting heart rate ≥ 70 bpm. Patients had to have been clinically stable for at least 4 weeks on an optimized and stable clinical regimen, which included maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and diuretics, with fluid retention and symptoms of congestion minimized. Patients had to have been hospitalized for heart failure within 12 months prior to study entry.

    The underlying cause of CHF was coronary artery disease in 68% of patients. At baseline, approximately 49% of randomized patients were NYHA class II, 50% were NYHA class III, and 2% were NYHA class IV. The mean left ventricular ejection fraction was 29%. All patients were initiated on ivabradine 5 mg (or matching placebo) twice daily and the dose was increased to 7.5 mg twice daily or decreased to 2.5 mg twice daily to maintain the resting heart rate between 50 and 60 bpm, as tolerated. The primary endpoint was a composite of the first occurrence of either hospitalization for worsening heart failure or cardiovascular death.

    Most patients (89%) were taking beta-blockers, with 26% on guideline-defined target daily doses. The main reasons for not receiving the target beta-blocker doses at baseline were hypotension (45% of patients not at target), fatigue (32%), dyspnea (14%), dizziness (12%), history of cardiac decompensation (9%), and bradycardia (6%). For the 11% of patients not receiving any beta-blocker at baseline, the main reasons were chronic obstructive pulmonary disease, hypotension, and asthma. Most patients were also taking ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). Few patients had an implantable cardioverter-defibrillator (ICD) (3.2%) or a cardiac resynchronization therapy (CRT) device (1.1%). Median follow-up was 22.9 months. At 1 month, 63%, 26%, and 8% of ivabradinetreated patients were taking 7.5, 5, and 2.5 mg BID, whereas 3% had withdrawn from the drug, primarily for bradycardia.

    SHIFT demonstrated that ivabradine reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis (hazard ratio: 0.82, 95% confidence interval [CI]: 0.75, 0.90, p < 0.0001) (Table 3). The treatment effect reflected only a reduction in the risk of hospitalization for worsening heart failure; there was no favorable effect on the mortality component of the primary endpoint. In the overall treatment population, ivabradine had no statistically significant benefit on cardiovascular death.

    Table 3. SHIFT – Incidence of the Primary Composite Endpoint and Components
  • * Subjects who died on the same calendar day as their first hospitalization for worsening heart failure are counted under cardiovascular death.
  • † Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity.
    		•

    Endpoint

    Ivabradine (N = 3,241) %

    Placebo (N = 3,264) %

    n

    %

    PY

    n

    %

    PY

    Hazard Ratio

    [95% Cl]

    p-value

    Primary composite endpoint: Time to first hospitalization for worsening heart failure or cardiovascular death *

    793

    24.5

    14.5

    937

    28.7

    17.7

    0.82

    [0.75, 0.90]

    <0.0001

    Hospitalization for worsening heart failure

    505

    15.6

    9.2

    660

    20.2

    12.5

    Cardiovascular death as first event

    288

    8.9

    4.8

    277

    8.5

    4.7

    Patients with events at any time

    Hospitalization for worsening heart failure †

    514

    15.9

    9.4

    672

    20.6

    12.7

    0.74

    [0.66, 0.83]

    Cardiovascular death †

    449

    13.9

    7.5

    491

    15.0

    8.3

    0.91

    [0.80, 1.03]

    N: number of patients at risk; n: number of patients having experienced the endpoint; %: incidence rate = (n/N) x 100; % PY: annual incidence rate = (n/number of patient-years) x 100; CI: confidence interval

    The hazard ratio between treatment groups (ivabradine/placebo) was estimated based on an adjusted Cox proportional hazards model with beta-blocker intake at randomization (yes/no) as a covariate; p-value: Wald test

    The Kaplan-Meier curve (Figure 3) shows time to first occurrence of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death in the overall study.

    Figure 3. SHIFT: Time to First Event of Primary Composite Endpoint

    Figure 3

    Most of the results show effects consistent with the overall study result. Ivabradine benefit on the primary endpoint in SHIFT appeared to decrease as the dose of beta-blockers increased, with little if any benefit demonstrated in patients taking guideline-defined target doses of beta-blockers.

    Figure 4. Effect of Treatment on Primary Composite Endpoint in Subgroups

    Figure 4

    Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

    BEAUTIFUL and SIGNIFY: No benefit in stable coronary artery disease with or without stable heart failure
    The Morbidity-mortality Evaluation of the I f Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction Trial (BEAUTIFUL) was a randomized, double-blind, placebo-controlled trial in 10,917 adult patients with coronary artery disease, impaired left ventricular systolic function (ejection fraction < 40%) and resting heart rate ≥ 60 bpm. Patients had stable symptoms of heart failure and/or angina for at least 3 months and were receiving conventional cardiovascular medications at stable doses for at least 1 month. Beta-blocker therapy was not required, nor was there a protocol mandate to achieve any specific dosing targets for patients who were taking beta-blockers. Patients were randomized 1:1 to ivabradine or placebo at an initial dose of 5 mg twice daily with the dose increased to 7.5 mg twice daily depending on resting heart rate and tolerability. The primary endpoint was the composite of time to first cardiovascular death, hospitalization for acute myocardial infarction, or hospitalization for new-onset or worsening heart failure. Most patients were NYHA class II (61.4%) or class III (23.2%) - none were class IV. Through a median follow-up of 19 months, ivabradine did not significantly affect the primary composite endpoint (HR 1.00, 95% CI = 0.91, 1.10).

    The Study Assessing the Morbi-mortality Benefits of the I f Inhibitor Ivabradine in Patients with Coronary Artery Disease Trial (SIGNIFY) was a randomized, double-blind trial administering ivabradine or placebo to 19,102 adult patients with stable coronary artery disease but without clinically evident heart failure (NYHA class I). Beta-blocker therapy was not required. Ivabradine was initiated at a dose of 7.5 mg twice daily and the dose could be increased to as high as 10 mg twice daily or down-titrated to 5 mg twice daily to achieve a target heart rate of 55 to 60 bpm. The primary endpoint was a composite of the first occurrence of either cardiovascular death or myocardial infarction. Through a median follow-up of 24.1 months, ivabradine did not significantly affect the primary composite endpoint (HR 1.08, 95% CI = 0.96, 1.20).

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Ivabradine 5 mg tablets are formulated as white to off white-colored, oval-shaped, film-coated tablet, functionally scored on both edges, debossed with "V" on one side and "9" bisected "1" on other side. They are supplied as follows:

    Unit dose packages of 30 (3 x 10) NDC: 60687-862-21

    Storage
    Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

    FOR YOUR PROTECTION: Do not use if blister is torn or broken.

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling [see 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 [seeWarnings and Precautions (5.1)andUse in Specific Populations (8.1), ( 8.3)].
    • Low Heart Rate
      Advise patients to report significant decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension [seeWarnings and Precautions (5.3)].
    • Atrial Fibrillation
      Advise patients to report symptoms of atrial fibrillation, such as heart palpitations or racing, chest pressure, or worsened shortness of breath [seeWarnings and Precautions (5.2)].
    • 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 ivabradine tablets [seeAdverse Reactions (6.1)].
    • Drug Interactions
      Advise patients to avoid ingestion of grapefruit juice and St. John's wort [seeDrug Interactions (7.1)].
    • Intake with Food
      Advise patients to take ivabradine tablets twice daily with food [seeDosage and Administration (2)].

    PACKAGING INFORMATION
    American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Camber Pharmaceuticals, Inc. as follows:
    (5 mg / 30 UD) NDC: 60687-862-21 packaged from NDC: 31722-053

    Distributed by:
    American Health Packaging
    Columbus, OH 43217

    8486221/0924F

  • Medication Guide

    8486221/0924F

    Ivabradine (eye VAB ra deen)

    Tablets

    What is the most important information I should know about ivabradine tablets?

    Ivabradine tablets may cause serious side effects in adults including:

    • Harm to an unborn baby. Females who are able to get pregnant:
      • Must use effective birth control during treatment with ivabradine tablets.
      • Tell your doctor right away if you become pregnant during treatment with ivabradine tablets.
    • Increased risk of irregular or rapid heartbeat (atrial fibrillation or heart rhythm problems). Tell your doctor if you feel any of the following symptoms of an irregular or rapid heartbeat:
      • heart is pounding or racing (palpitations).
      • chest pressure.
      • worsened shortness of breath.
      • near fainting or fainting.
    • Slower than normal heart rate (bradycardia). Tell your doctor if you have:
      • a slowing of heart rate, or
      • symptoms of a slow heart rate such as dizziness, fatigue, lack of energy. In young children signs and symptoms of slow heart rate may include: poor feeding, difficulty breathing or turning blue.

    What are ivabradine tablets?

    Ivabradine tablets are a prescription medicine used:

    • to treat adults who have chronic (lasting a long time) heart failure, with symptoms, to reduce their risk of hospitalization for worsening heart failure.

    Who should not take ivabradine tablets?

    Do not take ivabradine tablets if you have:

    • symptoms of heart failure that recently worsened
    • very low blood pressure (hypotension)
    • certain heart conditions: sick sinus syndrome, sinoatrial block, or 3 rd degree atrioventricular block
    • a slow resting heart rate before treatment with ivabradine tablets. Ask your doctor what a slow
    • resting heart rate is for you.
    • certain liver problems
    • been prescribed any medicines that can increase the effects of ivabradine tablets.

    Ask your doctor if you are not sure if you have any of the medical conditions listed above.

    What should I tell my doctor before taking ivabradine tablets?

    Before you take ivabradine tablets, tell your doctor about all of your medical conditions, including if you:

    • have any other heart problems, including heart rhythm problems, a slow heart rate, or a heart conduction problem.
    • are breastfeeding or planning to breastfeed. It is not known if ivabradine passes into breast milk. You and your doctor should decide if you will take ivabradine tablets or breastfeed; do not do both.
    • are pregnant or planning to become pregnant. See “What is the most important information I should know about ivabradine tablets? - Harm to an unborn baby” section.

    Tell your doctor about all the medicines you take, including prescription and over the counter

    medicines, vitamins, and herbal supplements. Ivabradine tablets may affect the way other medicines

    work, and other medicines may affect how ivabradine tablets work. This could cause serious side

    effects.

    How should you take ivabradine tablets?

    • Take ivabradine tablets exactly as your doctor tells you.
    • Do not stop taking ivabradine tablets without talking with your doctor.
    • Ivabradine comes as a tablet.
      • Tell your doctor if you have trouble swallowing tablets.
      • Your doctor may change your dose of ivabradine tablets during treatment
    • Take ivabradine tablets 2 times each day with food.
    • If you miss a dose of ivabradine tablets, do not give another dose. Give the next dose at the usual time.
    • If you or your child take too much ivabradine, call your doctor or go to the nearest emergency room right away.

    What should you avoid while taking ivabradine tablets?

    • Avoid drinking grapefruit juice and taking St. John's wort during treatment with ivabradine tablets. These can affect the way ivabradine tablets work and may cause serious side effects.

    What are the possible side effects of ivabradine tablets?

    Ivabradine tablets may cause serious side effects. See “What is the most important information I should know about ivabradine tablets?”

    The most common side effects of ivabradine tablets are:

    • increased blood pressure
    • temporary brightness in part of your field of vision. This is usually caused by sudden changes in light (luminous phenomena). This brightness usually happens within the first 2 months of treatment with ivabradine tablets and may go away during or after treatment with ivabradine tablets. Be careful when driving or operating machinery where sudden changes in light can happen, especially when driving at night.

    These are not all the side effects of ivabradine tablets. Ask your doctor or pharmacist for more

    information.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at

    1-800-FDA-1088.

    How should I store ivabradine tablets?

    • Store ivabradine tablets at room temperature between 68°F to 77°F (20°C to 25°C).

    Keep ivabradine tablets and all medicines out of the reach of children.

    General information about the safe and effective use of ivabradine tablets.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ivabradine tablets for a condition for which it was not prescribed. Do not give ivabradine tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about ivabradine tablets that is written for health professionals.

    What are the ingredients in ivabradine tablets?

    Active ingredient: ivabradine

    Inactive ingredients:

    Colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate and maltodextrin.

    The film coating contains glycerin, hypromellose, magnesium stearate, polyethylene glycol, titanium

    dioxide. In addition, 7.5 mg contains black iron oxide, iron oxide yellow and iron oxide red.
    To order more Medication Guides call American Health Packaging at 1‐800‐707‐4621.

    Distributed by:
    American Health Packaging
    Columbus, OH 43217

    8486221/0924F

    For more information about the drug product, call the supplier at 1-866-495-1995.

    For more information about the packaging or labeling, call American Health Packaging at 1‐800‐707‐4621.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

  • Package/Label Display Panel

    5 mg Ivabradine Tablets Carton.jpg

    NDC 60687- 862-21

    Ivabradine
    Tablets

    5 mg

    30 Tablets (3 x 10)               Rx Only

    PHARMACIST: Dispense with Medication Guide to each patient.

    Each Film-coated Tablet Contains
    5 mg ivabradine equivalent to 5.39 mg ivabradine as hydrochloride.

    Oral Use.

    Usual Dosage: See full prescribing information.

    Store at 20° to 25°C (68° to 77°F); excursions permitted between
    15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

    FOR YOUR PROTECTION: Do not use if blister is torn or broken.

    The drug product contained in this package is from
    NDC # 31722-053, Camber Pharmaceuticals, Inc.

    Distributed by: American Health Packaging, Columbus, Ohio 43217

    786221
    0486221/0924

  • Package/Label Display Panel

    5 mg Ivabradine Tablet Blister.jpg

    Ivabradine
    Tablet

    5 mg

  • INGREDIENTS AND APPEARANCE
    IVABRADINE 
    ivabradine tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 60687-862(NDC:31722-053)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    IVABRADINE HYDROCHLORIDE (UNII: TP19837BZK) (IVABRADINE - UNII:3H48L0LPZQ) IVABRADINE5 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MALTODEXTRIN (UNII: 7CVR7L4A2D)  
    GLYCERIN (UNII: PDC6A3C0OX)  
    HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
    POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    Colorwhite (white to off white) Score2 pieces
    ShapeOVALSize8mm
    FlavorImprint Code V;9;1
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 60687-862-2130 in 1 CARTON06/21/2025
    1NDC: 60687-862-111 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21336606/21/2025
    Labeler - American Health Packaging (929561009)
    Establishment
    NameAddressID/FEIBusiness Operations
    American Health Packaging929561009repack(60687-862)
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