After receiving the highest concentration of ranolazine inside ranolazine plasma , usually reached in 2 – 6 hours When receiving ranolazine 2 times a day equilibrium concentration is usually achieved within 3 days.. The mean absolute bioavailability of ranolazine after oral administration is 35-50%, with a high degree of individual variability. At higher oral primobolan doses of 500 to 1000 mg per day, 2 times a 2.5-3 fold increase observed AUC (area under the curve “concentration-time”) in an equilibrium state. In healthy volunteers, C max at steady state is about 1770 ng / ml at steady state AUC 0-12 on average equal to 13700 hr x ng / mL after administration of 500 mg two times a day. Food does not affect the speed and completeness of absorption of ranolazine. Distribution: Approximately 62% of ranolazine binds to plasma proteins, mainly alpha-1 acid glycoprotein and albumin slightly. The mean volume of distribution at steady state is about 180 l. Metabolism: Ranolazine undergoes rapid and almost complete metabolism predominantly in the liver. The most important metabolic pathways are ranolazine O-demethylation and N-dealkylation. Ranolazine is metabolized mainly isoenzyme CYP3A4, and isoenzyme CYP2D6. Upon receiving 500 mg 2 times a day for people with insufficient activity of the isoenzyme CYP2D6, AUC indicator exceeds the same amount for people with a normal metabolic rate by 62%. A similar difference for a dose of 1000 mg 2 times per day was 25%.
Excretion: unchanged to the kidneys and the bowel is allocated less than 5% of the dose of ranolazine. Clearance of ranolazine is dose-dependent, decreasing with the increase it. The half-life of ranolazine in an equilibrium state after oral administration is about 7 hours.
Oral primobolanactive metabolites increased 5 times in patients with severe renal failure severity. Duration finding ranolazine plasma increases 1.2 times in patients with moderate renal impairment (creatinine clearance of 30-60 ml / min). In patients with severe renal failure severity (creatinine clearance <30 mL / min) increasing the length of stay in the blood plasma ranolazine was found to 1.3-1.8 times. Effect of dialysis on the pharmacokinetics of ranolazine has not been evaluated. Hepatic impairment the AUC of ranolazine is not changed in patients with hepatic insufficiency mild, but increased by 1.8 times in the case of hepatic failure, moderate (7-9 points on a scale Child-Pugh); in these patients was more pronounced elongation of the QTc interval. Experience in the use of ranolazine in patients with hepatic insufficiency, severe gravity (more than 9 points on a scale Child-Pugh) is absent. Advanced age is clinically significant changes in pharmacokinetic parameters of ranolazine as a function of age was observed. Older patients due to age-related decrease in renal function may increase ranolazine actions. Body weight The patients weighing 40 kg, it was noted that the effect of ranolazine 1.4 times greater than its effect in patients with a body weight of 70 kg.
- Hypersensitivity to the active substance or to any of the excipients (see section. Composition );
- lactase deficiency, hereditary lactose intolerance, glucose-galactose malabsorption (for 1000 mg);
- severe renal insufficiency (creatinine clearance <30 mL / min);
- liver failure secondary (7-9 points on a scale Child-Pugh) or severe (more than 9 points on a scale Child-Pugh) severity;
- simultaneous application of potent inhibitors isoenzyme CYP3A4 (itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone);
- simultaneous application of antiarrhythmics of class IA (e.g., quinidine) or a class III (e.g., dofetilide) except amiodarone; with sotalol.
- children under 18 years of age (efficacy and safety have not been established);
- during breastfeeding.Carefully
- liver failure, mild ;
- renal failure mild or moderate (creatinine clearance 30-80 ml / min);
- age over 65 years;
- patient body weight less than 60 kg;
- Chronic heart failure (III-IV functional class NYHA classification);
- syndrome of congenital long history, family history; diagnosed acquired prolongation of the interval ;
- failure isozyme;
- simultaneous use with moderate inhibitors of isoenzyme (diltiazem, fluconazole, erythromycin);
- simultaneous use with inducers isoenzyme (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort (Hypericum perforatum));
- simultaneous oral primobolan application of inhibitors of P-gp (P-glycoprotein) (verapamil, cyclosporin).
In patients with a combination of several of the above conditions may increase the action of ranolazine, includingIt increases the risk of side effects.In this case, requires regular monitoring of the state for the purpose of early detection of adverse effects, if necessary, may require dose reduction or withdrawal of the drug.