ivabradine 7.5 mg Tablet, Film Coated, 60-count — NDC 69452-191-17 (Billing 69452-0191-17)

12. CLINICAL PHARMACOLOGY

12.1Mechanism 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 [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 )].

12.2Pharmacodynamics 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 pre-existing 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.

12.3Pharmacokinetics 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 B ioavailability 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

4.2L/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 co-administered 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 Co- a dministered Drugs on the Pharmacokinetics of Ivabradine Digoxin exposure did not change when concomitantly ad… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 [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 )].

12.3Pharmacokinetics 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 B ioavailability 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

4.2L/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 co-administered 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 Co- a dministered 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 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 [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 mL/min 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. figure 2

12.2Pharmacodynamics 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 pre-existing 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.

14. CLINICAL STUDIES

14.1Heart 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 bpm 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‑treated patients were taking 7.5 mg, 5 mg, 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 Ivabradine (N = 3,241) Placebo (N = 3,264) Endpoint n % % PY n % % PY Hazard Ratio [95% CI] p-value Primary composite endpoint: Time to first hospitalization for worsening heart failure or cardiovascular death a 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

12.5Cardiovascular death as first event 288 8.9 4.8 277 8.5

4.7Patients with events at any time Hospitalization for worsening heart failure b 514 15.9 9.4 672 20.6 12.7 0.74 [0.66, 0.83] Cardiovascular death b 449 13.9 7.5 491 15.0 8.3 0.91 [0.80, 1.03] a Patients who died on the same calendar day as their first hospitalization for worsening heart failure are counted under cardiovascular death. b Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity. N: number of patients at risk; n: number of patients having experienced the endpoint; %: incidence rate… [Excerpted — this section continues on DailyMed.]

13. NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 times to 133 times the human exposure (AUC 0-24hr ) at the MRHD.

13.2Animal Toxicology and/or Pharmacology Reversible changes in retinal function were observed in dogs administered oral ivabradine at total doses of 2 mg/kg/day, 7 mg/kg/day, or 24 mg/kg/day (approximately 0.6 times to 50 times the human exposure at the MRHD based on AUC 0- 24 hr ) 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.