Ivabradine 5 Mg (as Ivabradine Hcl 5.39 Mg) Oral Tablet

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)] .

Bradycardia, sinus arrest, and heart block have occurred with ivabradine tablets. The rate of bradycardia was 6.0% per patient-year in patients treated with ivabradine tablets (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 ^stor 2 ^nddegree 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 tablets exposure, may themselves contribute to heart rate lowering, and should be avoided [see Clinical Pharmacology (12.3)] . Avoid use of ivabradine tablets in patients with 2 ^nddegree atrioventricular block unless a functioning demand pacemaker is present [see Contraindications (4)].

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 tablets. 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 tablets. Examples of CYP3A4 inducers include St. John's wort, rifampicin, barbiturates, and phenytoin [see Clinical Pharmacology (12.3)].

Based on findings in animals, ivabradine tablets may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of ivabradine tablets 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 tablets, 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 ^rdtrimester 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 ≥ 4.6mg/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).

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 tablets, 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 radio activity 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

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

Ivabradine tablets can also inhibit the retinal current I _h. I _his involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of I _hby ivabradine tablets 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 tablets 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.

Absorption and Bioavailability

Following oral administration, peak plasma ivabradine concentrations are reached in approximately1 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 tablets 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 tablets 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 tablets

Ivabradine tested negative in the following assays: bacterial reverse mutation (Ames) assay, in vivobone marrow micronucleus assay in both mouse and rat, in vivochromosomal aberration assay in rats, and in vivounscheduled DNA synthesis assay in rats. Results of the in vitrochromosomal aberration assay were equivocal at concentrations approximately 1,500 times the human C _maxat the MRHD. Ivabradine tested positive in the mouse lymphoma assays and in vitrounscheduled DNA synthesis assay in rat hepatocytes at concentrations greater than 1,500 times the human C _maxat 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.

The Systolic Heart failure treatment with the I _finhibitor ivabradine Trial (SHIFT) was a randomized, double-blind trial comparing ivabradine tablets and placebo in 6558 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 subjects were NYHA class II, 50% were NYHA class III, and 2% were NYHA class IV. The mean left ventricular ejection fraction was 29%. All subjects were initiated on ivabradine tablets 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 ivabradine tablets -treated 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 tablets 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 tablets had no statistically significant benefit on cardiovascular death.