Composition, form of production and packaging
Tablets of prolonged action, covered with a film shell of light orange color, biconvex, oval, with an embossed "500" or "GSI 500" on one side.
1 tab.
ranolazine 500 mg
[PRING] cellulose microcrystalline - 70.67 mg, a copolymer of methacrylic acid and ethyl acrylate (1: 1) - 66.67 mg, hypromellose - 13.33 mg, magnesium stearate - 13.33 mg, sodium hydroxide - 2.667 mg.
Composition of the film shell: opadrai II orange 85F93265 (macrogol 3350-4.04 mg, polyvinyl alcohol partially hydrolysed 8 mg, talc 2.96 mg, titanium dioxide 4.86 mg, iron oxide yellow oxide (E172) 0.118 mg, iron oxide red ( E172) - 0.022 mg, carnauba wax (trace amounts)).
10 pieces. - packings cellular planimetric (3) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
10 pieces. - packings cellular planimetric (10) - packs cardboard.
Tablets of prolonged action, covered with a film membrane of pale yellow color, biconvex, oval, embossed with "1000" or "GSI 1000" on one side.
1 tab.
ranolazine 1000 mg
[PRING] cellulose microcrystalline - 141.34 mg, copolymer of methacrylic acid and ethyl acrylate (1: 1) - 133.34 mg, hypromellose - 26.66 mg, magnesium stearate - 26.66 mg, sodium hydroxide - 5.334 mg.
The composition of the shell: opedrai II yellow 33G92144 (triacetin 2.4 mg, hypromellose 6cP 16 mg, lactose monohydrate 8.4 mg macrogol 3350 3.2 mg titanium dioxide 9.19 mg iron oxide yellow oxide (E172) 0.81 mg, carnauba wax (trace amounts)).
10 pieces. - packings cellular planimetric (3) - packs cardboard.
10 pieces. - packings cellular planimetric (6) - packs cardboard.
10 pieces. - packings cellular planimetric (10) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Antianginal drug. Ranolasin is an inhibitor of the late current of sodium ions into myocardial cells. Decreased intracellular accumulation of sodium leads to a decrease in the excess of intracellular calcium ions. This reduces intracellular ion imbalance in ischemia. Reducing the excess of intracellular calcium promotes relaxation of the myocardium and, thus, reduces the diastolic stress of the ventricular wall. Clinical evidence of inhibition of late sodium current under the action of ranolazine is a significant shortening of the QT c interval (QT c is the adjusted QT value with allowance for heart rate) and a positive effect on diastolic relaxation revealed in an open study involving patients with the QT prolonged interval syndrome (patients with LQT syndrome -3, having mutations of the gene SCN5A? KPQ). These effects of the drug do not depend on changes in heart rate, blood pressure, or the degree of vasodilation.
With the use of ranolazine, the incidence of angina attacks per week and the consumption of short-acting nitroglycerin significantly decrease compared with placebo, regardless of the sex of the patients. During the treatment, the development of tolerance to ranolazine does not occur. After a sharp discontinuation of the drug, the incidence of angina attacks does not increase.
Ranolazin has a significant advantage compared with placebo in increasing the time to the onset of an attack of angina and before the onset of depression of the ST segment by 1 mm with a dose of 500-1000 mg 2 times / day. The drug significantly improves the tolerance of exercise. For ranalazine, a dose-response relationship is fixed: when administered at a higher dose, the antianginal effect was higher than when administered at a lower dose.
When ranolazine was added (1500 mg or 2000 mg per day divided into 2 doses, compared to placebo for 12 weeks), 50 mg / day for atenolol, 5 mg / day for amlodipine or 180 mg / day for diltiazem, was proved the efficacy of Raneks В® , superior to placebo in terms of the duration of exercise for both study doses (24 seconds more than placebo). However, there was no difference in the duration of the exercise burden between the two doses of Raneks В® .
Effects detected in ECG: patients who received Ranex В® treatment were noted, depending on the dose and concentration of the drug in the blood plasma, prolongation of the QT c interval (about 6 ms with 1000 mg bid 2 times / day), a decrease in the amplitude of the T wave and , in some cases, double-humped teeth T. ECG indices in patients taking ranolazin are the result of both inhibition by the drug of the rate of a rapidly rectifying potassium current that extends the ventricular action potential and inhibition of late sodium current, which shortens the same the action potential. Population analysis showed that the use of ranolazine in both patients with stable angina and in healthy volunteers leads to an elongation of QT c relative to the baseline level by an average of 2.4 ms with a ranolazine concentration in the plasma of 1000 ng / ml. In the case of clinically significant liver failure in patients, the rate of QTc extension was higher.
Patients treated with ranolazine showed a significantly lower incidence of arrhythmias compared with placebo, including ventricular pirouette tachycardia-8 reductions per episode.
Effects on hemodynamics in patients treated with ranolazine in the form of monotherapy or in combination with other antianginal agents showed a slight decrease in heart rate (<2 bpm) and a decrease in systolic blood pressure (<3 mm Hg).
PHARMACOKINETICS
Suction
After ingesting ranolazine inside C max, ranolazine in blood plasma is usually achieved in 2-6 hours. The average absolute bioavailability of ranolazine after oral administration is 35-50%, with a high degree of individual variability. When the dose is raised from 500 to 1000 mg twice a day, a 2.5-3 fold increase in the AUC in the equilibrium state is observed. When taking ranolazine 2 times / day, C ss is usually achieved within 3 days. In healthy volunteers C ss max is approximately 1770 ng / ml, AUC 0-12 in the equilibrium state averages 13 700 ng h / ml after taking the drug at 500 mg 2 times / day. Eating food does not affect the speed and completeness of absorption of ranolazine.
Distribution
Approximately 62% of ranolazine binds to blood plasma proteins, mainly with alpha-1 acidic glycoproteins, and slightly with albumin. The average V ss is about 180 liters.
Metabolism
Ranolazin undergoes rapid and almost complete metabolism in the liver. The most important ways of metabolizing ranolazine are O-demethylation and N-dealkylation. Ranolazine is metabolized mainly by the isoenzyme CYP3A4, as well as the isoenzyme CYP2D6. When taking 500 mg 2 times / day in people with inadequate activity of the isoenzyme CYP2D6, the AUC index exceeds the same value for people with a normal metabolic rate by 62%.
A similar difference for a dose of 1000 mg 2 times / day was 25%.
Excretion
Unchanged with urine and feces, less than 5% of the dose of ranolazine is released. The clearance of ranolazine depends on the dose, decreasing when it rises. T 1/2ranolazine in the equilibrium state after oral administration is about 7 hours.
Pharmacokinetics in special clinical cases
In chronic heart failure (III-IV functional classes according to the NYHA classification ) , an increase in the concentration of ranolazine in the blood plasma is approximately 1.3-fold.
In patients with mild, moderate and severe renal insufficiency, compared with volunteers with normal renal function, the ranolazine AUC was an average of 1.7-2 times higher. A significant individual variability in the magnitude 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 ranolazine in the blood plasma increases by 1.2 times in patients with moderate renal insufficiency (KK 30-60 ml / min). In patients with severe renal insufficiency (CC <30 ml / min), an increase in the duration of ranolazine in the blood plasma was found to be 1.3-1.8 times. Evaluation of the effect of dialysis on the pharmacokinetics of ranolazine was not carried out.
Ranolazine AUC does not change in patients with mild hepatic impairment, but increases 1.8-fold in the case of moderate-degree liver failure (7-9 Child-Pugh grade);In these patients, the QT interval was more pronounced. The experience with ranolazine in patients with hepatic insufficiency of severe severity (more than 9 points according to the Child-Pugh classification) is absent.
INDICATIONS
stable angina.
DOSING MODE
The recommended initial dose of Ranex В® for adults is 500 mg 2 times / day. After 2-4 weeks, the dose can be increased to 1000 mg 2 times / day if necessary. The maximum daily dose is 2000 mg.
If side effects caused by taking Raneks В® (eg, dizziness, nausea, or vomiting) occur, you should reduce the single dose to 500 mg.
If after this the symptoms do not disappear, the drug should be discontinued.
For patients with chronic heart failure (III-IV functional classes according to the NYHA classification), with mild and moderate renal insufficiency (KC 30-80 ml / min), mild liver failure (5-6 Child-Pugh grades ), and also for patients with a body weight of less than 60 kg and patients older than 75 years , titration of the dose is recommended.
Eating does not affect the bioavailability of the drug, so it can be taken regardless of meals. Tablets should be swallowed whole, squeezed with a sufficient amount of liquid, not crushing, not breaking and not chewing.
SIDE EFFECT
The side effects observed in patients taking Raneks В® are generally mild or moderate and usually develop during the first 2 weeks of treatment. The following side effects are listed for which a possible association with the use of Raneks В® was recognized.
Determination of the frequency of side effects: very often (? 1/10), often (from? 1/100 to <1/10), infrequently (from? 1/1000 to <1/100), rarely (from? 1 / 10,000 up to <1/1000) and very rarely (<1/10 000).
From the side of metabolism: infrequently - decreased appetite, anorexia, dehydration.
From the side of the psyche: infrequently - anxiety, insomnia, blurred consciousness, hallucinations; rarely - disorientation.
From the nervous system: often - dizziness, headache; infrequently - retardation, fainting, hypoesthesia, drowsiness, tremor, postural dizziness; rarely - amnesia, confusion, loss of consciousness, parosmia.
From the side of the organ of vision: infrequently - blurred vision, visual disorders.
On the part of the hearing organs and labyrinthine disorders: infrequently - vertigo, tinnitus; rarely - hearing loss.
From the side of the cardiovascular system: infrequently - the flow of blood to the face, marked decrease in blood pressure; rarely - cold extremities, orthostatic hypotension.
On the part of the respiratory system: infrequently - dyspnea, cough, nosebleeds; rarely - a feeling of pressure in the throat.
From the digestive system: often - constipation, nausea, vomiting; infrequently - pain in the abdomen, dryness of the oral mucosa, dyspepsia, flatulence, discomfort in the stomach; rarely - pancreatitis, erosive duodenitis, hypoesthesia of the oral cavity.
From the skin and subcutaneous tissues: infrequently - skin itching, hyperhidrosis; rarely - allergic dermatitis, urticaria, cold sweat, skin rash, angioedema.
From 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.
On the part of laboratory indicators: infrequently - increase in the concentration of creatinine in the blood plasma, increased urea concentration in the blood plasma, prolongation of the corrected interval QT c , thrombocytosis and leukocytosis, weight loss; rarely - increased activity of liver enzymes.
General disorders: often - asthenia; infrequent - fatigue, peripheral edema.
CONTRAINDICATIONS
- renal failure of severe degree (CK <30 ml / min);
- Liver insufficiency average (7-9 points according to the Child-Pugh classification) or severe (more than 9 Child-Pugh grades) degree;
- simultaneous use with potent inhibitors of the isoenzyme CYP3A4 (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone);
- simultaneous use with class IA antiarrhythmics (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 are not established);
- Pregnancy;
- the period of breastfeeding;
- Lactase deficiency, hereditary lactose intolerance, glucose-galactose malabsorption syndrome (only for 1000 mg);
- Hypersensitivity to the components of the drug.
Carefully:
- Hepatic insufficiency of mild severity (5-6 points according to the Child-Pugh classification);
- renal failure of mild or moderate severity (CK 30-80 ml / min);
- age over 75 years;
- body weight less than 60 kg;
- Chronic heart failure (III-IV functional classes according to the NYHA classification);
- syndrome of congenital elongated QT interval in history, in family history; Diagnosed acquired QT interval elongation;
- Insufficiency of the isoenzyme CYP2D6;
- simultaneous application with inhibitors of the CYP3A4 isoenzyme of moderate strength (diltiazem, fluconazole, erythromycin);
- simultaneous use with inductors of the activity of the isoenzyme CYP3A4 (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort (Hypericum perforatum);
- simultaneous use with P-glycoprotein inhibitors (verapamil, cyclosporine).
PREGNANCY AND LACTATION
Due to the lack of data, the use of Ranex В® 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 investigated.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindication: severe renal insufficiency (CK <30 ml / min).
For patients with mild and moderate renal insufficiency (KK 30-80 ml / min) , titration of the dose is recommended.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindication: hepatic impairment of an average (7-9 points according to the Child-Pugh classification) or severe (more than 9 Child-Pugh grades) degree.
For patients with mild hepatic insufficiency (5-6 points according to the Child-Pugh classification) , titration of the dose is recommended.
APPLICATION FOR CHILDREN
Contraindicated in children and adolescents under 18 years.
APPLICATION IN ELDERLY PATIENTS
Use with caution in patients over 75 years of age (titration is recommended).
SPECIAL INSTRUCTIONS
Raneks В® is intended for permanent therapy.
For patients with mild or moderate renal failure (CK 30-80 ml / min), dose titration is recommended. Raneks В® is contraindicated in patients with severe renal insufficiency (CK <30 ml / min).
For patients with mild hepatic insufficiency (5-6 points according to the Child-Pugh classification), titration of the dose is recommended. Raneks В® is contraindicated in patients with moderate hepatic insufficiency (7-9 points according to the Child-Pugh classification) or severe (more than 9 Child-Pugh grades) severity.
In elderly patients, there may be an increase in the effect of Ranex В® because of the age-related decline in kidney function. There is an increased incidence of side effects.
Dose selection for patients with a body weight of less than 60 kg should be done with caution, since cases of side effects in these patients were observed more often.
Chronic heart failure
Dose selection for patients with chronic heart failure of moderate to severe severity (NYHA class III-IV functional class) should be conducted with caution. It is necessary to carry out frequent monitoring of the development of side effects, if necessary, the dose of the drug should be reduced or canceled treatment.
QT interval extension
A population-based analysis of pooled data from a study of patients and healthy volunteers showed that the dependence of the duration of the QT interval c on the plasma concentration can be estimated as 2.4 ms per 1000 ng / ml, which is approximately equivalent to an increase from 2 to 7 ms for the concentration range in blood plasma, corresponding to a dose of 500 to 1000 mg of ranolazine, taken 2 times / day. Therefore, caution should be exercised in the treatment of patients with a history of QT history of congenital prolongation of the QT interval, the presence of an extended QT interval in the family history, patients with known acquired QT interval prolongation, and also patients receiving treatment with drugs that affect the QT interval.
Insufficient activity of the isoenzyme CYP2D6
The risk of an increased 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 a normal metabolic rate of the CYP2D6 isoenzyme (patients with "fast" metabolism). Precautions are designed taking 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 the CYP2D6 isoenzyme, there is no need for such precautions. In patients who have been identified (for example, by genotyping) or known to have an intense metabolic status of the isoenzyme CYP2D6, Raneks В® should be used with caution if the patient has a combination of several of the above listed risk factors.
Impact on the ability to drive vehicles and mechanisms
Studies on the effect of ranolazine on ability to drive vehicles and management mechanisms are not carried out. Given the possibility of side effects such as dizziness, blurred vision, confusion and hallucinations, caution should be exercised in the management of vehicles and mechanisms, as well as classes of potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
Symptoms: dizziness, nausea and vomiting, diplopia, lethargy, fainting. Symptoms may increase with increasing dose.
Treatment: symptomatic therapy. Within 30 minutes after administration of the drug can take measures to prevent its absorption from the gastrointestinal (gastric lavage, administration of activated charcoal). Hemodialysis is ineffective.
DRUG INTERACTION
The simultaneous use is contraindicated
powerful inhibitors of CYP3A4 isoenzyme
Ranolazine is a substrate of cytochrome CYP3A4. The simultaneous use of inhibitors of CYP3A4 isoenzyme activity increases the concentration of ranolazine in the blood plasma. Potential dose-related side effects (e.g., nausea, dizziness) may increase With the rise in blood plasma concentration of the drug as well. Simultaneous treatment with ketoconazole 200 mg of 2 times / day increases the AUC of ranolazine 3-3.9 times.
The simultaneous 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 CYP3A4 isoenzyme.
Concomitant use with caution
Inhibitors of CYP3A4 isoenzyme average potency of
diltiazem (180-360 mg 1 time / day), an inhibitor of isozyme CYP3A4 average force action, causes a dose dependent increase in the mean C ss ranolazine plasma levels in the 1.5-2.4 times. For patients receiving diltiazem and other inhibitors of CYP3A4 isoenzyme average force action (e.g., erythromycin, fluconazole) recommended dose titration ranolazine. It may be necessary to reduce the dose of ranolazine.
Inducers of CYP3A4 isoenzyme activity
Simultaneous use of inducers ranolazine isoenzyme activity CYP3A4 (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort (Hypericum perforatum)) may reduce the effectiveness of the drug. For example, rifampicin (600 mg 1 time / day) decreases the C ss ranolazine plasma by about 95%. Therefore, you should not start the use of ranolazine in patients being treated with inducers of CYP3A4 isoenzyme.
Inhibitors of P-glycoprotein
Ranolazine is a substrate of P-glycoprotein (P-gp). Inhibitors of P-gp (e.g., cyclosporine, verapamil) increase the concentration of ranolazine in the blood plasma. Verapamil (120 mg 3 times / day) enhances C ssranolazine by 2.2 times. For patients treated with inhibitors of P-gp, titration is recommended dose of ranolazine. It may be necessary to reduce the dose of ranolazine. On the other hand, ranolazine is an inhibitor of P-gp average force action and a weak inhibitor of isozyme CYP3A4 and can increase the concentration in plasma substrates P-gp or isoenzyme CYP3A4. Tissue distribution of drugs that are transported by means of P-gp, may be increased.
Substrates of CYP2D6 isoenzyme
There is evidence that ranolazine is a weak inhibitor of the isoenzyme CYP2D6. Receiving ranolazine 750 mg of 2 times / day improves blood plasma concentration of metoprolol in 1.8 times. Therefore, while the use of ranolazine may potentiation of metoprolol or other substrates isoenzyme CYP2D6 (e.g., flecainide, propafenone, and to a lesser extent, tricyclic antidepressants and neuroleptics), therefore may require dose reduction of these drugs.
Substrates isoenzyme CYP2B6
The potential for inhibition of CYP2B6 isoenzyme is not installed. During the destination together with the substrates isoenzyme CYP2B6 (eg bupropion, efavirenz, cyclophosphamide) caution is recommended.
Digoxin
There is evidence of increasing the concentration of digoxin in the blood plasma of on average 1.5 times, while the use of digoxin and ranolazine. Therefore, the need to monitor the level of digoxin at the beginning and after the end of therapy ranolazine.
Substaraty isoenzyme CYP3A4
Ranolazine is a weak inhibitor of isozyme CYP3A4, which may lead to increased concentrations of substrates isoenzyme CYP3A4 in plasma and require dose adjustments sensitive substrates isoenzyme CYP3A4 (for example, simvastatin, lovastatin) and substrates isoenzyme CYP3A4 with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus, everolimus).
simvastatin
Metabolism and simvastatin clearance highly dependent isoenzyme CYP3A4. Receiving ranolazine 1000 mg of 2 times / day simvastatin lactone concentration increases, simvastatinovoy acid, which increases the inhibition of HMG-CoA reductase 1.4-1.6 times. Simvastatin in high doses associated with the development of rhabdomyolysis, also cases of rhabdomyolysis while the use of ranolazine and simvastatin have been described. The maximum dose of simvastatin for patients receiving simultaneously ranolazine, should not exceed 20 mg / day. For other statins metabolized with the participation of isoenzyme CYP3A4 (lovastatin), may limit the dose.
Tacrolimus, cyclosporine, sirolimus, everolimus
The increase in the plasma concentration of tacrolimus substrate isoenzyme CYP3A4, was observed in patients on treatment with ranolazine. With simultaneous use of ranolazine and tacrolimus is recommended to monitor the plasma concentration of tacrolimus and, if necessary, to carry out dose correction. This approach is not recommended for other isoenzyme CYP3A4 substrates with a narrow therapeutic range (e.g., cyclosporine, sirolimus, everolimus).
Drugs prolonging QT interval
There is a theoretical possibility that, while the use of ranolazine and other drugs prolonging the QT interval, may be pharmacodynamic interaction and increase the risk of ventricular arrhythmias. Among such drugs include certain antihistamines (e.g., terfenadine, astemizole, mizolastine), certain antiarrhythmic agents (e.g., quinidine, disopyramide, procainamide) and erythromycin, and tricyclic antidepressants (e.g., imipramine, doxepin, amitriptyline).
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 4 years.
