Ranexa pills 500 mg 60 pcs
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Active ingredients
Ranolazine
Release form
Pills
Composition
Active ingredient: Ranolazin. Concentration of active ingredient (mg): 500
Pharmacological effect
Antianginal drug. Ranolazin is an inhibitor of late current of sodium ions in myocardial cells. Reduced intracellular accumulation of sodium leads to a decrease in excess intracellular calcium ions. This reduces intracellular ionic imbalance in ischemia. Reducing excess intracellular calcium contributes to the relaxation of the myocardium and, thus, reduces the diastolic tension of the ventricular wall. Clinical evidence of late sodium current inhibition under the action of ranolazine is a significant shortening of the QTc interval (QTc is the corrected QT value taking into account the heart rate) and a positive effect on diastolic relaxation found in an open study involving patients with prolonged QT syndrome (patients with LQT-3 syndrome) having mutations of the gene SCN5A ΔKPQ). These effects of the drug do not depend on changes in heart rate, blood pressure, or on the degree of vascular dilation. When using ranolazine, the incidence of angina attacks per week and the consumption of short-acting nitroglycerin are significantly reduced compared to placebo, regardless of the gender of the patients. During treatment, the development of tolerance to ranolazine does not occur. After abrupt discontinuation of the drug, the incidence of angina attacks does not increase. Ranolazine has a significant advantage over placebo in increasing the time before an attack of angina occurs and before the appearance of ST-segment depression by 1 mm when taken in a dose of 500-1000 mg 2 times / day. The drug significantly improves exercise tolerance. For ranolazine, a dose-response relationship was observed: when taken at a higher dose, the antianginal effect was higher than when taken at a lower dose. When ranolazine was added (1500 mg or 2000 mg per day, divided into 2 doses, compared with placebo). for 12 weeks) treatment with atenolol 50 mg / day, or amlodipine 5 mg / day, or diltiazem 180 mg / day, proved the effectiveness of the drug Ranexa, superior to placebo in terms of the duration of physical exertion for both studied doses of the drug (24 seconds more compare u with placebo).However, there were no differences in the duration of tolerable physical exertion between the two doses of Ranexa. Effects detected during ECG: in patients treated with Ranexa, a dose-dependent and plasma concentration-dependent, prolongation of the QTc interval was observed (about 6 ms when taking 1000 mg 2 times / day), a decrease in the amplitude of the T wave and, in some cases, double-humped teeth of T. The ECG parameters in patients taking ranolazine are the result of drug inhibition of the rate of rapidly rectifying potassium current, which prolongs the ventricular action potential and inhibits the late sodium current, which shortens the ventricular action potential. Population analysis showed that the use of ranolazine in patients with stable angina pectoris and in healthy volunteers leads to a prolongation of QTc relative to the initial level of 2.4 ms at an average plasma concentration of ranolazine 1000 ng / ml. In patients with clinically significant hepatic insufficiency, the QTc elongation rate was higher. Patients receiving ranolazine had a significantly lower incidence of arrhythmias compared with placebo, including ventricular tachycardia such as pirouette ≥8 contractions per episode. Effects on hemodynamics in patients treated with ranolazine as monotherapy or in combination with other antianginal agents, a slight decrease in heart rate (less than 2 beats / min) and a decrease in systolic blood pressure (less than 3 mm p) tst)
Pharmacokinetics
Absorption After taking ranolazine inside Cmax ranolazine in the blood plasma, as a rule, is achieved in 2-6 hours. The average absolute bioavailability of ranolazine after taking the drug inside is 35-50%, with a high degree of individual variability. With an increase in dose from 500 to 1000 mg 2 times / day, a 2.5–3 fold increase in AUC is observed in equilibrium. When taking ranolazine 2 times / day Css is usually achieved within 3 days. In healthy volunteers, Cssmax is approximately 1770 ng / ml, AUC0-12 in equilibrium, an average of 13 700 ng × h / ml after taking the drug in 500 mg 2 times / day. Food intake does not affect the rate and completeness of absorption of ranolazine. Distribution Approximately 62% of ranolazine is bound to plasma proteins, mainly alpha-1 acid glycoproteins, and only slightly to albumin. The average Vss is about 180 l. MetabolismRanolazine undergoes rapid and almost complete metabolism in the liver. The most important pathways of ranolazine metabolism are O-demethylation and N-dealkylation.Ranolazin is metabolized mainly by CYP3A4 isoenzyme, and also CYP2D6 isoenzyme. When taken in 500 mg 2 times / day in people with insufficient activity of the CYP2D6 isoenzyme, the AUC indicator exceeds the same value for people with a normal metabolic rate by 62%. The similar difference for the dose of 1000 mg 2 times / day was 25%. less than 5% of the received dose of ranolazine is excreted in urine and feces. The clearance of ranolazine depends on the dose, decreasing with its increase. T1 / 2 ranolazine in equilibrium after ingestion is about 7 hours. Pharmacokinetics in special clinical situations. In chronic heart failure (III-IV functional classes according to the NYHA classification), there is an increase in plasma concentration of ranolazine approximately 1.3 times. In patients with renal failure mild, moderate and severe severity, compared with volunteers with normal renal function, the rate of ranolazine AUC was on average 1.7-2 times higher. Significant individual variability of AUC in volunteers with renal insufficiency was noted. AUC of pharmacologically active metabolites increased 5-fold in patients with severe renal insufficiency. The duration of the presence of ranolazine in the blood plasma is increased by 1.2 times in patients with moderately severe renal insufficiency (CC 30-60 ml / min). In patients with severe renal insufficiency (CK less than 30 ml / min), an increase in the duration of the presence of ranolazine in the blood plasma by 1.3–1.8 times was found. Evaluation of the effect of dialysis on ranolazine pharmacokinetics was not carried out. Ranolazine AUC does not change in patients with mild hepatic insufficiency, but it increases 1.8 times in case of moderate hepatic insufficiency (7-9 points according to Child-Puy); in such patients, the prolongation of the QTc interval was more pronounced. Experience with the use of ranolazine in patients with severe hepatic insufficiency (more than 9 points according to the Child-Pugh classification) is absent.
Indications
Stable angina.
Contraindications
Hypersensitivity to the drug; severe renal failure (CC less than 30 ml / min); hepatic insufficiency of the average (7-9 points according to the Child-Pugh classification) or severe (more than 9 points according to the Child-Pugh classification) degree; simultaneous use with potent inhibitors of CYP3A4 isoenzyme (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin,nefazodone); simultaneous use with class I A antiarrhythmic drugs (eg, quinidine) or class III (eg, dofetilide), except for amiodarone; sotalol; children and adolescents under 18 years of age (efficacy and safety of the drug have not been established); pregnancy; breastfeeding period; lactase deficiency, hereditary lactose intolerance, glucose-galactose malabsorption syndrome (for 1000 mg only);
Precautionary measures
Do not exceed recommended doses.
Use during pregnancy and lactation
In connection with the lack of data, the use of the drug Ranexa during pregnancy and during breastfeeding is contraindicated. There are no data on the use of ranolazine in pregnant women. The penetration of ranolazine into breast milk has not been studied.
Dosage and administration
The recommended initial dose of the drug Raneks for adults is 500 mg 2 times a day. After 2-4 weeks, the dose, if necessary, can be increased to 1000 mg 2 times a day. The maximum daily dose is 2000 mg. If side effects caused by taking the drug Ranexa (for example, dizziness, nausea or vomiting) occur, a single dose should be reduced to 500 mg. If after this symptoms do not disappear, the use of the drug should be discontinued. For patients with chronic heart failure (III-IV functional classes according to NYHA classification), with mild to moderate renal insufficiency (CK 30-80 ml / min), mild hepatic insufficiency (5-6 points according to Child-Pugh ), as well as for patients with a body weight less than 60 kg and patients older than 75 years, it is recommended to titrate the dose of the drug. Eating does not affect the bioavailability of the drug, so it can be taken regardless of meals. Tablets should be swallowed whole, washed down with a sufficient amount of liquid, not grinding, not breaking and not chewing.
Side effects
On the part of the metabolism: infrequently - loss of appetite, anorexia, dehydration. On the part of the psyche: infrequently - anxiety, insomnia, clouding of consciousness, hallucinations; rarely disorientation. The nervous system: often - dizziness, headache; infrequently - lethargy, syncope, hypesthesia, drowsiness, tremor, postural dizziness; rarely - amnesia, confusion, loss of consciousness, parosmia. On the part of the organ of vision: infrequently - blurred vision, visual disorders. On the part of the hearing organs and labyrinth disorders: infrequently - vertigo, tinnitus; rarely - hearing loss.Since the cardiovascular system: infrequently - flushing, pronounced decrease in blood pressure; rarely - cold extremities, orthostatic hypotension. On the part of the respiratory system: infrequently - shortness of breath, cough, nosebleeds; rarely - a feeling of constriction in the throat. On the part of the digestive system: often - constipation, nausea, vomiting; infrequently - abdominal pain, dryness of the oral mucosa, dyspepsia, flatulence, discomfort in the stomach; rarely - pancreatitis, erosive duodenitis, oral hypoesthesia. On the part of the skin and subcutaneous tissues: infrequently - pruritus, hyperhidrosis; rarely, allergic dermatitis, urticaria, cold sweat, skin rash, angioedema. On the part of the musculoskeletal system: infrequently - pain in the limbs, muscle spasms, swelling of the joints. From the urinary system: infrequently - dysuria, hematuria, chromaturia; rarely acute renal failure. On the part of the reproductive system: rarely - erectile dysfunction. From the laboratory parameters: infrequently - an increase in the concentration of creatinine in the blood plasma, an increase in the concentration of urea in the blood plasma, a lengthening of the corrected QTc interval, thrombocytosis and leukocytosis, a decrease in body weight; rarely - increased activity of liver enzymes. General disorders: often - asthenia; infrequently - fatigue, peripheral edema.
Overdose
Symptoms: dizziness, nausea and vomiting, diplopia, lethargy, syncope. Symptoms may increase with increasing dose. Treatment: symptomatic therapy. Within 30 minutes after taking the drug, you can take measures to prevent its absorption from the gastrointestinal tract (gastric lavage, the use of activated carbon). Hemodialysis is ineffective.
Interaction with other drugs
Simultaneous use is contraindicated. Powerful inhibitors of the isoenzyme CYP3A4Ranolazine is a substrate of cytochrome CYP3A4. Simultaneous use with CYP3A4 isoenzyme activity inhibitors increases the concentration of ranolazine in the blood plasma. With increasing plasma concentrations of the drug, potential dose-dependent side effects (such as nausea, dizziness) may also increase. Simultaneous treatment with ketoconazole 200 mg of 2 times / day increases the AUC of ranolazine 3-3.9 raz.Odnovremennoe use of ranolazine and potent inhibitors of isoenzyme CYP3A4 (e.g., itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin.Nefazodone) is contraindicated. Grapefruit juice is also a potent inhibitor of the CYP3A4 isoenzyme. Simultaneous use with caution Inhibitors of the isoenzyme CYP3A4 of moderate potency Diltiazem (180-360 mg 1 time / day), an inhibitor of the isoenzyme CYP3A4 of moderate potency, causes a dose-dependent increase in the mean in blood plasma 1.5-2.4 times. For patients receiving diltiazem and other inhibitors of the isoenzyme CYP3A4 of moderate potency (for example, erythromycin, fluconazole), titration of the dose of ranolazine is recommended. It may be necessary to reduce the dose of ranolazine. CYP3A4 isoenzyme activity inducers Simultaneous use of ranolazine with inducers of CYP3A4 isoenzyme activity (rifampicin, phenytoin, phenobarbital, carbamazepine, Hypericum perforatum) can reduce the effect For example, rifampicin (600 mg 1 time / day) reduces Css ranolazine in the blood plasma by about 95%. Therefore, you should not start the use of ranolazine in patients receiving treatment with CYP3A4 isoenzyme inducers. P-glycoprotein inhibitorsRanolazine is a substrate of P-glycoprotein (P-gp). P-gp inhibitors (for example, cyclosporine, verapamil) increase the concentration of ranolazine in the blood plasma. Verapamil (120 mg 3 times / day) increases the Css of ranolazine 2.2 times. For patients receiving treatment with P-gp inhibitors, titration of ranolazine dose is recommended. It may be necessary to reduce the dose of ranolazine. On the other hand, ranolazine is a medium-strength P-gp inhibitor and a weak inhibitor of the CYP3A4 isoenzyme and may increase the plasma concentration of the substrates P-gp or the isoenzyme CYP3A4. The tissue distribution of drugs that are transported using P-gp may be increased. CYP2D6 isoenzyme substrates There is evidence that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. The administration of ranolazine 750 mg 2 times / day increases the plasma concentration of metoprolol 1.8 times. Therefore, with simultaneous use with ranolazine, it is possible to enhance the action of metoprolol or other substrates of the CYP2D6 isoenzyme (for example, propafenone and flecainide, to a lesser extent, tricyclic antidepressants and neuroleptics), as a result, a reduction in the dose of these drugs may be needed. The substrates of CYP2B6 isoenzyme. CYP2B6 is not installed.It is recommended to take caution during administration in conjunction with CYP2B6 isoenzyme substrates (for example, bupropion, efavirenz, cyclophosphamide). Digoxin There is an average increase in plasma concentration of digoxin 1.5 times while using digoxin and ranolazine. It is therefore necessary monitoring digoxin level at the beginning and after the end of therapy ranolazinom.Substaraty CYP3A4Ranolazin isozyme is a weak inhibitor of isozyme CYP3A4, which may lead to increased concentrations of isoenzyme CYP3A4 substrates in plasma and require dose adjustments sensitive substrates isoenzyme CYP3A4 (for example, simvastatin, lovastatin) and substrates of isoenzyme CYP3A4 with a narrow therapeutic range (for example, cyclosporine, tacrolimus, sirolimus, everolimus). SimvastatinMetabolism and clearance imvastatina highly dependent isoenzyme CYP3A4. Taking ranolazine 1000 mg 2 times / day increases the concentration of simvastatin lactone, simvastatinic acid, which increases the inhibition of HMG-CoA reductase 1.4-1.6 times. High doses of simvastatin are associated with the development of rhabdomyolysis, and cases of the development of rhabdomyolysis with simultaneous use of ranolazine and simvastatin have also been described. The maximum dose of simvastatin for patients simultaneously taking ranolazine should not exceed 20 mg / day. Tacrolimus, cyclosporine, sirolimus, everolimus. Increased plasma concentrations of tacrolimus, a substrate of the isoenzyme CYP3A4, have been observed in patients with the use of ranolazine. With simultaneous use of tacrolimus and ranolazine, it is recommended to monitor the concentration of tacrolimus in the blood plasma and, if necessary, to adjust the dose. This approach is also recommended for other CYP3A4 isoenzyme substrates with a narrow therapeutic range (for example, cyclosporin, sirolimus, everolimus). Preparations that extend the QTC interval there is a theoretical probability that with simultaneous use of ranolazine and other drugs that extend the QT interval, pharmacodynamic interaction may occur and increase the risk of developing ventricular arrhythmias.These drugs include certain antihistamines (for example, terfenadine, astemizole, mizolastine), certain antiarrhythmic drugs (for example, quinidine, disopyramide, procainamide), and also erythromycin and tricyclic antidepressants (for example, imipramine, doxepine, amitriptyline).
special instructions
The drug Raneksa is intended for continuous therapy. For patients with mild to moderate renal insufficiency (CK 30-80 ml / min), dose titration is recommended. The drug Ranexa is contraindicated in patients with severe renal insufficiency (CC less than 30 ml / min). For patients with mild hepatic insufficiency (5-6 points according to Child-Pugh classification), dose titration is recommended. The drug Ranexa is contraindicated in patients with moderate liver failure (7-9 points according to Child-Pugh classification) or severe (more than 9 points according to Child-Pugh classification) severity. Elderly patients may experience an increase in the effect of the Ranexa drug due to age-related decline in function the kidneys. There is an increased incidence of side effects. Selection of the dose for patients with a body weight less than 60 kg should be carried out with caution, because cases of side effects in these patients were observed more often. Chronic heart failure Selection of the dose for patients with moderate-to-severe chronic heart failure (NYHA classification III-IV functional class) should be carried out with caution. It is necessary to conduct frequent monitoring of the development of side effects; if necessary, the dose of the drug should be reduced or canceled. Extending the QTP interval Population analysis of pooled data obtained from patients and healthy volunteers showed that the dependence of the QTc interval on plasma concentration can be estimated as 2.4 ms per 1000 ng / ml, which is approximately equal to the increase from 2 to 7 ms for a range of plasma concentrations corresponding to a dose from 500 to 1000 mg of ranolazine taken 2 times per day Therefore, care must be taken in treating patients with a syndrome of congenital lengthening of the QT interval in history, the presence of a lengthening of the QT interval in a family history,patients with known acquired lengthening of the QT interval, as well as patients receiving treatment with drugs that affect the QT interval. Insufficient activity of the CYP2D6 isoenzyme The risk of an increase in the incidence of side effects in these groups is increased in patients with insufficient activity of the CYP2D6 isoenzyme (patients with slow metabolism) compared to patients with normal ability to metabolize CYP2D6 isoenzyme (patients with rapid metabolism). Precautions are designed to take into account the risk for patients with a slow metabolism of the CYP2D6 isoenzyme and are necessary if the metabolic status of the CYP2D6 isoenzyme is unknown. For patients with a fast metabolism of an isoenzyme CYP2D6 there is no need for such precautions. In patients with identified (for example, by genotyping) or the previously known intensive metabolic status of the CYP2D6 isoenzyme, Ranexa should be used with caution if the patient has a combination of several risk factors listed above. The effect on the ability to drive vehicles and mechanisms influence of ranolazine on the ability to drive vehicles and control mechanisms was not carried out. Considering the possibility of such side effects as dizziness, blurred vision, confusion and hallucinations, care should be taken when driving vehicles and mechanisms, as well as when engaging in potentially hazardous activities that require increased concentration and psychomotor reactions.