Carvedilol 3.125 mg, Ivabradine 5 mg Tablets

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 Ih. Ih is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of Ih 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)].

The peak concentration (Cmax) 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.

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 Cmax and AUCinf 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.

Age — No pharmacokinetic differences (AUC or Cmax) 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.

Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.

Carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food should minimize the risk of orthostatic hypotension.

Carvedilol is extensively metabolized. Following oral administration of radiolabeled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.

Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.

Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.

The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.

Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).

Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.