Ranex 500 mg tablet number 60

Ranexa (RANEXA) instructions for use

Composition

active ingredient: 1 tablet, coated, contains ranolazine 500 mg;
auxiliary substances: microcrystalline cellulose, methacrylic acid-ethyl acrylate copolymer (1: 1), hypromellose, magnesium stearate, sodium hydroxide, polyethylene glycol 3350, polyvinyl alcohol partially hydrolysed, talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E172), carnauba wax;

active ingredient: 1 tablet, coated, contains ranolazine 1000 mg;
auxiliary substances: microcrystalline cellulose, methacrylic acid-ethyl acrylate copolymer (1: 1), hypromellose, magnesium stearate, sodium hydroxide, lactose, glycerol triacetate, polyethylene glycol 400, polyethylene glycol 3350, titanium dioxide (E 171), iron oxide yellow (E172), carnauba wax.

Dosage form

Long-acting tablets.

Pharmacological group

Other means of the heart. Ranolasin. ATX Code C01E B18.

Indications

Treatment of stable angina pectoris.

Contraindications

Hypersensitivity to the active substance or to any auxiliary substance of the preparation.
Severe renal insufficiency (creatinine clearance <30 mL / min).
Liver failure medium or severe.
Simultaneous administration of potent inhibitors of CYP3A4 (eg, itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone).
Simultaneous administration of antiarrhythmic drugs of class Ia (quinidine) or class III (for example, dofetilide, sotalol), except for amiodarone.

Dosing and Administration

Tablets should be swallowed whole (without crushing, breaking, not chewing). The drug can be taken during meals or regardless of food intake.

Adults. The recommended initial dose of Ranex is 500 mg 2 times a day. After 2-4 weeks, the dose can be increased to 1000 mg twice a day if necessary. The maximum recommended dose is 1000 mg 2 times a day. If the patient has adverse reactions caused by the use of the drug (eg, dizziness, nausea, vomiting), the dose may be reduced to 500 mg.Treatment is discontinued if adverse reactions do not go away.

Simultaneous use with medium-power CYP3A4 inhibitors (eg, diltiazem, fluconazole, erythromycin) and P-gp inhibitors (eg, verapamil, cyclosporin). If patients receive these drugs, careful and careful dosing is recommended.

Renal failure. Patients with mild and moderate renal insufficiency (creatinine clearance ≥ 30-80 ml / min) are recommended to carefully and carefully select the dose.

Liver failure. Patients with mild hepatic insufficiency are advised to carefully and carefully select a dose.

Patients of advanced age. Selection of a dose of this category of patients should be carried out with care because in the elderly age there may be an age-related decrease in kidney function, and the action of ranolazine may increase. In elderly patients there is an increased incidence of adverse reactions.

Low body weight. An increased incidence of adverse reactions is characteristic for patients with a low body weight (≤ 60 kg), so the selection of a dose for this category of patients should be done with caution.

Congestive heart failure (CHF). The dose should be selected with caution in patients with moderate or severe CHF (classes NYHA III-IV).

Adverse Reactions

Adverse reactions are usually mild or moderate in severity and are often observed during the first 2 weeks of treatment.Below are the adverse reactions associated with the use of the drug, classified by body systems, organ classes and absolute frequency. The frequency was determined as follows: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1 / 1000), very rarely (<1/10000).

From the side of metabolism and nutrition.

Infrequent anorexia, decreased appetite, dehydration.

From the side of the psyche.

Infrequent anxiety, insomnia, confusion, hallucinations.

Rarely disorientation.

From the nervous system.

Often: dizziness, headache.

Infrequent inhibition, loss of consciousness, hypoesthesia, drowsiness, tremor, postural dizziness.

Rarely amnesia, turbidity, loss of consciousness, parosmia.

From the side of the organs of sight.

Infrequent blurred vision, visual disturbances.

From the organs of hearing and balance.

Infrequent: dizziness, noise in the ears.

Rarely hearing loss.

From the side of the vascular system.

Infrequent hot flashes, arterial hypotension.

Rarely cold extremities, orthostatic hypotension.

From the respiratory system.

Infrequent shortness of breath, cough, nosebleeds.

Rarely: a feeling of compression in the throat.

From the digestive system.

Often constipation, nausea, vomiting.

Infrequent: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.

Rarely pancreatitis, erosive duodenitis, oral hypoesthesia.

From the skin and subcutaneous fat.

Infrequent: itching, hyperhidrosis.

Rarely angioedema, allergic dermatitis, urticaria, cold sweat, rash.

From the side of the musculoskeletal system and connective tissue.

Infrequent: pain in the limbs, muscle spasms, swelling of the joints.

From the side of the kidneys and urinary tract.

Uncommon dysuria, hematuria, chromaturia.

From the reproductive system and mammary glands.

Rarely erectile dysfunction.

Systemic disorders.

Often asthenia.

Infrequent: fatigue, peripheral edema.

Data from additional research methods.

Infrequent: elevated serum creatinine levels, elevated blood urea levels, increased QT interval, increased platelet counts or white blood cells, weight loss.

Rarely: increased levels of liver enzymes in the blood.

Elderly age, renal insufficiency and low body weight.

In general, adverse reactions occurred more often among elderly patients and patients with kidney failure, but the types of phenomena in these subgroups were similar to those observed in the general group of patients. In elderly patients (≥ 75 years), compared with younger patients, adverse reactions such as constipation, nausea, arterial hypotension, and vomiting were more common with the drug.

In patients with mild or moderate renal insufficiency (creatinine clearance ≥ 30-80 ml / min) compared with patients with normal renal function (creatinine clearance> 80 ml / min), constipation, nausea and vomiting were more common with the drug.

Typically, the type and frequency of adverse reactions observed in patients with a low body weight (≤ 60 kg) were similar to similar reactions in patients with a higher body weight (≤ 60 kg), but in patients with a low body weight of placebo, the adjusted frequency was higher for such common phenomena as nausea, vomiting, arterial hypotension.

Laboratory methods of research.

In healthy volunteers and in patients receiving Ranex's preparation, there was a slight reversible increase in the level of serum creatinine, is not of clinical significance. With this phenomenon, renal failure was not associated. Study of kidneys in healthy volunteers showed a decrease in creatinine clearance in the absence of changes in glomerular filtration rate, which agrees with inhibition of renal tubular secretion of creatinine.

Postmarketing experience.

In the post-marketing experience, there were no reports of acute renal failure, including those with a previously existing decline in mild to moderate renal function, and / or those using concomitant drugs with ranalasin concomitantly with Ranex's drug.

Overdose

When studying the tolerability of increasing the dose of the drug used orally angina, the incidence of dizziness, nausea, vomiting increased in accordance with the dose. In case of an overdose, a patient should be closely monitored;symptomatic and supportive therapy is recommended. Since approximately 62% of ranolazine binds to plasma proteins, a complete inference in the hemodialysis process is unlikely.

Use during pregnancy and lactation

The necessary data on the use of ranolazine in pregnant women are not available, and the data obtained from animal experiments is not enough to assess the effect on pregnancy and embryo development. The potential risk to humans is unknown. Ranex should not be used during pregnancy, except in extreme cases.

It is unknown, ranolazine penetrates into breast milk. The withdrawal of ranolazine in mother's milk has not been studied in animals, so Ranex should not be used in women during lactation.

Children

It is not recommended to use Ranex's drug for children due to insufficient data on safety and efficacy.

Application features

One should be careful when applying or increasing the dose of ranolazine to patients for whom an increase in its effect may be expected, under such conditions:

• simultaneous administration of CYP3A4 inhibitors of moderate strength;

• simultaneous administration of P-gp inhibitors;

• hepatic insufficiency of mild degree;

• renal failure of mild or moderate severity (creatinine clearance 30-80 ml / min);

• old age of the patient;

• low body weight (≤ 60 kg);

• CHF of moderate or severe severity (classes NYHA III-IV).

In patients who have several of the above factors, one can expect an additional increase in action. Possible the occurrence of adverse reactions, depend on the dose. When ranolazine is used in patients with a combination of several of the above factors, frequent monitoring of adverse reactions should be carried out, and if necessary, the dose of ranolazine should be reduced or discontinued.

The risk of increasing the effect of ranolazine, which leads to an increase in the incidence of adverse reactions in the above groups, is increased in patients with insufficient activity of CYP2D6 (patients with reduced metabolism) compared to patients with normal activity of CYP2D6 (patients with intensive metabolism). The above warnings are designed taking into account the possible risk for patients with a decreased metabolism of CYP2D6 and should be considered in the case where the metabolic status of CYP2D6 is unknown. For patients with an intensive metabolism of CYP2D6, such reservations are of lesser importance. In patients for whom it has been determined (for example, by genotyping) or the normal status of the metabolism of CYP2D6 was previously known, ranolazine can be used with caution in cases where the patient needs several of the above risk factors.

Elongation of the QT interval.

One should be cautious in treating patients with the QT history of congenital extension of the QT history in the anamnesis or with the hereditary extension of the QT interval in the family history or with the known acquired QT interval prolongation, as well as patients receiving treatment with drugs affecting the QT interval duration (see Sections "Interaction with other drugs and other types of interactions "and" Pharmacological properties ").

Renal failure.

The function of the kidneys decreases with age, so it is important to carry out a regular check when applying ranolazine.

Lactose. This drug contains lactose, therefore it should not be used in patients with a rare congenital intolerance to galactose, lactase deficiency, or impaired absorption of glucose and galactose.

The ability to influence the reaction rate when driving vehicles or other mechanisms

Ranolazin can cause dizziness and blurred vision, which can adversely affect the ability to drive vehicles or work with other mechanisms.

Interaction with other drugs and other interactions

Effect of other drugs on ranolazine.

Inhibitors of CYP3A4 and P-gp.

Ranolasin is a substrate of CYP3A4, so CYP3A4 inhibitors increase the concentration of ranolazine in the blood plasma.As the plasma concentration increases, the manifestation of potential adverse reactions that depend on the dose (eg, nausea, dizziness) can be exacerbated. Simultaneous use of ketoconazole at a dose of 200 mg twice a day increases the AUC (area under the "concentration-time" curve) of ranolazine by 3-3.9 times. Also, a powerful inhibitor of CYP3A4 is grapefruit juice.

Diltiazem (180-360 mg once a day), CYP3A4 inhibitor of average power, raises depending on the dose, average equilibrium concentrations of ranolazine in 1,5-2,4 times. For patients who use diltiazem and other CYP3A4 medium power (for example, erythromycin, fluconazole), careful and careful selection of a Raneks dose is recommended. It may be necessary to reduce the dose of the drug.

Ranolasin is a substrate of P-gp. P-gp inhibitors (eg, cyclosporine, verapamil) increase the concentration of ranolazine in the blood plasma. Verapamil (120 mg 3 times a day) raises equilibrium concentrations of ranolazine in blood plasma by a factor of 2.2. For patients taking P-gp inhibitors, careful and careful selection of a dose of Ranex is recommended. It may be necessary to reduce the dose of the drug.

Inductors CYP3A4

Rifampicin (600 mg once a day) reduces the equilibrium concentrations of ranolazine by approximately 95%. Do not start treatment with Ranex with CYP3A4 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort).

Inhibitors of CYP2D6.

Ranolasin is partially metabolized by CYP2D6, so CYP2D6 inhibitors can increase the concentration of ranolazine in the blood plasma. A powerful inhibitor of CYP2D6 paroxetine (20 mg once a day) increases the average equilibrium concentrations of ranolazine in blood plasma by 1.2 times (with ranolazine 1000 mg bid 2 times a day). Correction of the dose is not required. With a dose of ranolazine 500 mg twice a day, simultaneous application of a powerful inhibitor of CYP2D6 can lead to an increase in AUC of ranolazine by about 62%.

Effect of ranolazine on other medicines.

Ranolasin is an inhibitor of P-gp (moderate to severe potency) and a weak inhibitor of CYP3A4, so it can increase the substrate concentrations of these enzymes in the blood plasma. The distribution of drugs transported by P-gp may also increase. The available data indicate that ranolazine is a weak inhibitor of CYP2D6. The use of ranolazine 750 mg twice a day increases the concentration of metoprolol in blood plasma by 1.8 times, so when they are used simultaneously, the effect of metoprolol or other substrates of CYP2D6 (for example, propafenone, flecainide, to a lesser extent, tricyclic antidepressants and antipsychotics ), so you may need to reduce the dose of these drugs. The potential for inhibition of CYP2B6 is not established. When administering ranolazine simultaneously with the substrates CYP2B6 (eg, bupropion, efavirenz, cyclophosphamide), caution should be exercised.

Digoxin.

There is evidence of an increase in the concentration of digoxin in the blood plasma by an average of 1.5 times with simultaneous application with the Ranex drug, so it is necessary to monitor the level of digoxin at the beginning and at the completion of the Raneks drug.

Simvastatin.

Metabolism and clearance of simvastatin largely depend on CYP3A4. The use of Ranex 1000 mg twice a day increases the concentration of lactone simvastatin, simvastatinic acid and inhibitor reductase activity HMG-CoA in the blood plasma by 1.4-1.6 times.

With the simultaneous use of ranolazine and other drugs that extend the QT interval, pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. These drugs include some antihistamines (for example, terfenadine, astemizole, misolastine), some antiarrhythmic drugs (eg, quinidine, disopyramide, procainamide), erythromycin and cyclic antidepressant drugs (eg, imipramine, doxepin, amitriptyline).

Pharmacological properties

Pharmacodynamics. Until now, the mechanism of action of ranolazine has remained largely unknown. Ranolazin can have some antianginal effect by inhibiting the late current of sodium ions in myocardial cells, reduces intracellular accumulation of sodium, and, accordingly, reduces the excess of intracellular calcium ions. It is believed that ranolazine due to a decrease in the late current of sodium ions reduces intracellular ion imbalance in ischemia. It can be expected that such a reduction in excess intracellular calcium will promote relaxation of the myocardium and, thus, reduce gastric diastolic tension. Clinical evidence of inhibition of late sodium current under the action of ranolazine is a significant reduction in the QT interval and a positive effect on diastolic relaxation in patients with the QT prolonged interval syndrome. These drug effects do not depend on a decrease in heart rate, from blood pressure or vasodilation.

Influence on hemodynamics.The clinical study showed that patients treated with ranolazine alone or in combination with other drugs designed to treat angina, was observed decrease in the mean heart rate (<2 beats / min) and average systolic blood pressure (<3 mm Hg. Art. ).

The effects are manifested by electrocardiography (ECG). Patients treated with this drug, the observed elongation of the QTc interval, which depended on the dose and plasma concentration (approximately 6 msec when using 1000 mg 2 times a day), decrease in T wave amplitude and, in some cases, double-humped tine believed T. that this influence on the characteristics of the ECG ranolazine is a result of rapid braking potassium current which prolongs the action potential schlunochkovy, but also inhibits late sodium current which shortens the ventricular action potential. Studies showed QT interval elongation dependence on a concentration equal to 2.4 ms at 1000 ng / ml in plasma ranolazine, which is approximately equal to the elongation of 2 to 7 milliseconds to dose concentration range respectively from 500 to 1000 mg twice a day.elongation rate was higher in patients with clinically significant hepatic impairment.

Pharmacokinetics. After oral administration of the drug Raneksa maximum concentration in plasma ranolazine usually observed after 2-6 hours. Annex 2 times a day equilibrium state is usually achieved within 3 days. Suction.Average bioavailability of ranolazine after oral application of tablets with immediate release is 35-50%, with a high degree of individual variance. Action Raneksa drug increases depending on the dose. By increasing the dose from 500 to 1000 mg 2 times a day, one-time increase observed 2,5-3- AUC at steady state. meal time does not affect the speed and completeness of absorption.

Distribution.Approximately 62% of ranolazine is bound to plasma proteins. The mean volume of distribution at steady state (V ss) of approximately 180 liters.

Conclusion. Ranolazine is derived mainly pathway. Less than 5% of the dose excreted in the urine and feces in unmodified form. After oral administration of a single dose of 500 mg labeled with radioactive carbon [14 C] ranolazine healthy person 73% of the radioactivity is determined in urine and 25% - in the feces. Clearance of ranolazine is dose-dependent, decreasing with increasing it. The half-life is approximately 2-3 hours after administration. The terminal half-life at steady state after oral ranolazine is approximately 7:00, which is caused by restriction of the output speed of fast absorption.

Metabolism.Ranolazine undergoes emergency and scale metabolism. In young healthy volunteers after single oral administration of 500 mg of ranolazine labeled with radioactive carbon 13% of the radioactivity detected in plasma. A large number of metabolites has been detected in human plasma (47 metabolites), urine (> 100 metabolites), and faeces (25 metabolites). 14 major metabolic pathways were determined, including O-demethylation, N-dealkylation and are essential. Studies conducted in vitro using human liver microsomes revealed that ranolazine CYRZA4 metabolized, and CYP2D6. In applying ranolazine 500 mg 2 times a day in humans with lack CYP2D6 activity indicator exceeds a similar AUC value in humans with normal CYP2D6 activity by 62%.The corresponding difference for a dose of 1000 mg two times a day was 25%.

Special patient groups.

Influence of gender. Sex has no clinical significance on pharmacokinetic parameters.

Patients of advanced age. Advanced age also has no clinical effect on the pharmacokinetic parameters, however, elderly patients may be observed enhanced effect of ranolazine due to age-related decrease in renal function.

Body mass. In patients with a body weight of 40 kg the effect of ranolazine is about 1.4 times higher than in patients with a body weight of 70 kg.

Congestive heart failure (CHF). CHF (NYHA III-IV classes) leads to an increase in plasma concentrations of ranolazine 1.3 times.

Renal failure.Studies have shown that in patients with mild, moderate or severe renal insufficiency, the AUC was on average 1.7-2 times higher than in patients with normal renal function. There was also a considerable individual variation AUC values in patients with renal insufficiency persons. AUC metabolites increased with a decrease in kidney function. Studies have revealed the increasing influence of ranolazine 1.2 times in patients with moderate renal impairment (creatinine clearance of 40 ml / min) and 1.3-1.8 times in patients with severe renal failure (creatinine clearance of 10-30 ml / min).

Liver failure.Experience in the use of ranolazine in patients with severe hepatic impairment is not. In patients with hepatic insufficiency mild ranolazine AUC value does not change, and in patients with hepatic insufficiency of moderate severity AUC value is increased by 1.8 times. These patients had a more pronounced increase in the QT interval.

Basic physical and chemical properties

Tablets of 500 mg of a light orange, film-coated, biconvex tablets oval embossed "500" on one side and the other side is smooth;
Tablets of 1000 mg of a pale yellow film-coated, biconvex tablets oval embossed "1000" on the one side, the other side is smooth.

Shelf life

4 years. Do not use after the expiration date printed on the package.

Storage conditions

Special storage conditions are required. Keep out of the reach of children.

Packaging

10 tablets in a blister, the blister 6 in a carton.

Category of leave

On prescription.