Ivabradine

Ivabradine tablets are a hyperpolarization-activated cyclic nucleotide-gated channel blocker indicated: To reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with reduced left ventricular ejection fraction. ( 1.1 )

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.

Adult patients Starting dose is 2.5 (vulnerable adults) or 5 mg twice daily with food. After 2 weeks of treatment, adjust dose based on heart rate. The maximum dose is 7.5 mg twice daily. ( 2.1 )

2.1 Adults The recommended starting dose of ivabradine tablets are 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 [see Clinical 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 [see Warnings and Precautions (5.3)] . Table 1. Dose Adjustment for Adults Heart Rate Dose Adjustment > 60 bpm Increase dose by 2.5 mg (given twice daily) up to 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 (5.3)]

Ivabradine tablets 5 mg: orange colored, capsule shaped, film-coated tablets, functionally scored with debossing "M" & "I" on one side and "2" on other side. The tablet is scored and can be divided into equal halves to provide a 2.5 mg dose. 7.5 mg: orange colored, round shaped, film-coated tablets debossed with “MI” on one side and “1” on the other side. Tablets: 5 mg, 7.5 mg ( 3 )

Ivabradine is contraindicated in patients with:

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

5 WARNINGS AND PRECAUTIONS

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

5.1 Fetal Toxicity 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 0-24hr ) at the maximum recommended human dose (MRHD) [ see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception when taking ivabradine [ see Use in Specific Populations (8.3) ] .

5.2 Atrial Fibrillation Ivabradine increases the risk of atrial fibrillation. In the Systolic Heart Failure Treatment with the If 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 [ see Clinical 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 [see Adverse Reactions (6.2)] . Concurrent use of verapamil or diltiazem will increase ivabradine exposure, may themselves contribute to heart rate lowering, and should be avoided [see Clinical Pharmacology (12.3)] . Avoid use of ivabradine in patients with 2 nd degree atrioventricular block unless a functioning demand pacemaker is present [see Contraindications (4)] .

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

7.1 Cytochrome P450-Based Interactions Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases them. Increased plasma concentrations may exacerbate bradycardia and conduction disturbances. The concomitant use of strong CYP3A4 inhibitors is contraindicated [ see Contraindications (4) and Clinical 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 [ see Warnings and Precautions (5.3) and Clinical 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 [ see Clinical 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 [ see Dosage 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 [ see Clinical Studies (14.1) ] . The use of ivabradine is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

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

• Atrial Fibrillation [ see Warnings and Precautions (5.2) ]
• Bradycardia and Conduction Disturbances [ see Warnings and Precautions (5.3) ] Most common adverse reactions occurring in ≥ 1% of patients are bradycardia, hypertension, atrial fibrillation and luminous phenomena (phosphenes). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Northstar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 [ see Warnings 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's effects on retinal photoreceptors [ see Clinical 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, diplopia, and visual impairment.

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.

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 0-24hr ) 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 0-24hr ) 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 6-15) 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 0-24hr ). 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 0-24hr ). In pregnant rabbits, oral administration of ivabradine during the period of organogenesis (gestation day 6-18) 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 0-24hr ) 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 0-24hr ), 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 0-24hr ).

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 [ see Use in Specific Populations (8.1) ] .

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

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.

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-2H-3-benzazepin-2-one, hydrochloride. The molecular formula is C 27 H 36 N 2 O 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 Tablets 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. The tablets contain the following inactive ingredients: colloidal silicon dioxide, glycerin, hypromellose, lactose monohydrate, magnesium stearate, maize starch, maltodextrin, polyethylene glycol, FD&C yellow#6, iron oxide red, iron oxide yellow, and titanium dioxide. ivabradine-figure-1

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 [ see Clinical 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 [ see Adverse Reactions (6.1) ] .

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.

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 [ see Dosage 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 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 [0.83-1.15] and 1.02 [0.86-1.22], 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 [ see Use 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) [ see Contraindications (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. ivabradine-figure-2

, 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 0-24hr ) 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 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 0-24hr ) at the MRHD.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling [see Medication Guide and Instructions for Use] .

• 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 (5.1) and Use 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 [ see Warnings 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 [ see Warnings 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 [ see Adverse Reactions (6.1) ] .
• Drug Interactions Advise patients to avoid ingestion of grapefruit juice and St. John's wort [ see Drug Interactions (7.1) ] .
• Intake with Food Advise patients to take ivabradine twice daily with food [ see Dosage and Administration (2) ] . Medication Guides available at www.northstarrxllc.com/products or call 1-800-206-7821 Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA. Issued: 04/2026