Ranexa - Instructions For Use, 500 And 1000 Mg, Price, Analogues, Reviews

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Ranexa

Ranexa: instructions for use and reviews

1. 1. Release form and composition
2. 2. Pharmacological properties
3. 3. Indications for use
4. 4. Contraindications
5. 5. Method of application and dosage
6. 6. Side effects
7. 7. Overdose
8. 8. Special instructions
9. 9. Application during pregnancy and lactation
10. 10. Use in childhood
11. 11. In case of impaired renal function
12. 12. For violations of liver function
13. 13. Use in the elderly
14. 14. Drug interactions
15. 15. Analogs
16. 16. Terms and conditions of storage
17. 17. Terms of dispensing from pharmacies
18. 18. Reviews
19. 19. Price in pharmacies

Latin name: Ranexa

ATX code: C01EB18

Active ingredient: ranolazine (Ranolazine)

Manufacturer: DSM Pharmaceuticals Inc. (DSM Pharmaceuticals Inc.) (USA, Italy); Menarini-Von Heyden, GmbH (Germany)

Description and photo update: 2019-04-12

Prices in pharmacies: from 2959 rubles.

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Ranexa is an antianginal agent.

Release form and composition

Ranexa is released in the form of tablets of prolonged action, film-coated: oval, biconvex, light orange (500 mg) or pale yellow (1000 mg); embossed on one side corresponding to the dosage: 500 mg - "500" or "GSI 500"; 1000 mg - "1000" or "GSI 1000" [package: 500 mg tablets - 10 pcs. in a contour acheikova packing (blister), in a cardboard box 3, 6 or 10 packages, 15 pcs. in a contour acheikova packing (blister), in a cardboard box 2 packages, 20 pcs. in a contour acheikova packing (blister), in a cardboard box 3 or 5 packages; tablets 1000 mg - 10 pcs. in a contour acheikova packing (blister), in a cardboard bundle 3, 6 or 10 packs, 15 pcs. in a contour acheikova packing (blister), in a cardboard box 2 or 4 packages. Each pack also contains instructions for the use of Ranexa].

1 tablet contains:

• active substance: ranolazine - 500 or 1000 mg;
• additional components: copolymer of methacrylic acid and ethyl acrylate (1 ÷ 1), microcrystalline cellulose, magnesium stearate, hypromellose, sodium hydroxide;
• film coat: 500 mg - Opadray II orange 85F93265 [partially hydrolyzed polyvinyl alcohol, macrogol 3350, titanium dioxide, talc, carnauba wax (trace amounts), iron dyes yellow oxide (E172) and red oxide (E172)]; 1000 mg - Opadry II yellow 33G92144 [hypromellose 6cP, titanium dioxide, lactose monohydrate, macrogol 3350, carnauba wax (trace amounts), triacetin, iron dye yellow oxide (E172)].

Pharmacological properties

Pharmacodynamics

Ranolazine has a complex mechanism of action, so far only partially established. The antianginal effect is based on the ability of the active substance to suppress the late flow of sodium ions into the cells of the heart muscle, which causes a decrease in intracellular sodium accumulation and leads to a decrease in the excess of intracellular calcium ions. The result of this process is a decrease in the intracellular ionic imbalance observed during ischemia. A decrease in excess intracellular calcium promotes relaxation of the myocardium and, in turn, reduces the diastolic tension of the ventricular wall. Clinically, the suppression of late sodium current by ranolazine is confirmed by a significant shortening of the QTc interval - a corrected QT value taking into account the heart rate (HR),and a positive effect on diastolic relaxation found in an open-label study in individuals with long QT syndrome (patients with LQT-3 syndrome and SCN5A ΔKPQ mutations). These drug effects are independent of changes in blood pressure (BP), heart rate, or vasodilation.

In the course of clinical studies, the safety and efficacy of ranolazine was demonstrated when used in patients with stable angina pectoris as a monotherapy drug, as well as as part of a combination treatment in case of insufficient effectiveness of other antianginal drugs.

It was found that against the background of the use of Ranexa (when compared with placebo), the frequency of angina attacks per week significantly decreased, which reduced the need for taking short-acting nitroglycerin. During the period of therapy, the development of tolerance to the drug was not recorded, after its abrupt withdrawal, there was also no increase in the frequency of angina attacks.

The active substance, when used 2 times / day at a dose of 500–1000 mg, had a significant advantage over placebo in relation to an increase in the time before the onset of angina pectoris attack and before the onset of ST segment depression by 1 mm. Ranolazine has been shown to improve exercise tolerance. For Ranexa, a dose-effect relationship was established, since against the background of its administration in a higher dose, the antianginal effect of the drug was more intense than when it was used at a lower dose.

When Ranexa was added in daily doses of 1500 or 2000 mg, divided into 2 doses, to therapy with atenolol (50 mg / day), amlodipine (5 mg / day) or diltiazem (180 mg / day) for 12 weeks, the effectiveness of ranolazine was found to be superior to placebo (24 sec higher) for duration of exercise for both doses of the drug. At the same time, there were no differences in the duration of these loads between the two doses.

In patients receiving ranolazine therapy, during electrocardiography (ECG), dose-dependent and plasma level of the substance in the blood, lengthening of the QTc interval (approximately 6 ms when used 2 times / day at 1000 mg), decrease in the amplitude of the T wave and in some In cases, two-humped T waves. These effects, found on the ECG, are caused by the suppression of the speed of the rapidly rectifying potassium current by the drug, as well as the inhibition of the late sodium current, which in the first case provides an extension of the ventricular action potential, and in the second, the shortening of the latter.

Population analysis of the pooled data of patients with stable angina pectoris and healthy volunteers demonstrated that drug therapy caused an increase in QTc relative to the initial level by about 2.4 ms at a plasma ranolazine content of 1000 ng / ml. The rate of QTc prolongation was higher in the presence of clinically significant hepatic failure.

In patients using Ranexa, a significantly lower incidence of arrhythmias was recorded compared with placebo, including ventricular tachycardia of the pirouette type ≥ 8 contractions per episode.

When ranolazine was administered alone or in combination with other antianginal drugs, a slight decrease in heart rate (<2 beats / min) and a decrease in systolic blood pressure (<3 mm Hg) were observed.

Pharmacokinetics

After oral administration of ranolazine in blood plasma, its maximum concentration (C _max) is usually observed after 2–6 hours. When using Ranexa 2 times / day, the equilibrium concentration (Css) is usually reached within 3 days. After taking the immediate-release tablets, the average absolute bioavailability can be 35-50% with a high level of individual variability.

With an increase in the dose of the active substance from 500 to 1000 mg 2 times / day, there was a 2.5-3 fold increase in the area under the concentration-time curve (AUC) in the equilibrium state. In healthy volunteers using Ranexa 2 times / day at a dose of 500 mg in an equilibrium state, the average C _max was approximately 1770 ng / ml, the average AUC _0-12 was approximately 13 700 ng × h / ml. The speed and completeness of ranolazine absorption did not depend on food intake.

The active substance binds approximately 62% to plasma proteins, mostly to alpha-1 acid glycoproteins, and to a small extent to albumin. The average volume of distribution at steady state (Vss) is about 180 liters.

Ranolazine is rapidly and almost completely metabolized in the liver, mainly by O-demethylation and N-dealkylation. Responsible for the biotransformation of the drug is mainly the isoenzyme CYP3A4 and partially - CYP2D6. With insufficient activity of the latter, while taking a dose of Ranexa 500 mg 2 times / day, the AUC value exceeds that for persons with a normal metabolic rate by 62%. For a dose of Ranexa 1000 mg 2 times / day, a similar difference is 25%.

The kidneys and through the intestines are excreted unchanged in less than 5% of the dose taken. Clearance depends on the plasma concentration of ranolazine; with its increase, it decreases. In the equilibrium state, the half-life (T _1/2) after oral administration of Ranexa is approximately 7 hours.

In patients with chronic heart failure (CHF) of functional classes III – IV according to the classification of the New York Heart Association (NYHA), an increase in the plasma ranolazine content is approximately 1.3 times.

Gender has no clinically significant effect on Ranexa's pharmacokinetic parameters.

It was found that in persons with a body weight of 40 kg, the effect of ranolazine increased 1.4 times compared with that in persons with a body weight of 70 kg.

Indications for use

Ranexa is recommended for the treatment of stable angina pectoris.

The drug is used as part of a combination therapy for the symptomatic treatment of stable exertional angina with insufficient efficacy and / or intolerance to antianginal drugs of the first line, including such as slow calcium channel blockers and / or β-blockers.

Contraindications

Absolute:

• liver failure of moderate or severe severity;
• severe renal failure;
• pregnancy and lactation;
• age up to 18 years;
• syndrome of glucose-galactose malabsorption, hereditary lactose intolerance, lactase deficiency - for a dosage of Ranexa 1000 mg (the tablet shell contains lactose);
• combined treatment with class IA (quinidine) or class III (sotalol, dofetilide) antiarrhythmic drugs, excluding amiodarone; with potent inhibitors of the CYP3A4 isoenzyme (posaconazole, ketoconazole, itraconazole, HIV protease inhibitors, telithromycin, clarithromycin, nefazodone);
• hypersensitivity to any component of the drug.

Relative (caution should be exercised when using Ranexa, due to the possible increase in its action and aggravation of the risk of dose-dependent side effects; in the presence of several of the following factors, it is necessary to regularly monitor the patient's condition for early detection of adverse reactions in order to subsequently reduce the dose or discontinue the drug if necessary):

• renal impairment of mild / moderate severity;
• mild liver failure;
• diagnosed acquired lengthening of the QT interval; history of congenital long QT interval syndrome or family history;
• CHF (NYHA functional classes III – IV);
• weak activity of the isoenzyme CYP2D6;
• body weight less than 60 kg;
• age over 65;
• combination therapy with moderate-acting CYP3A4 isoenzyme inhibitors (erythromycin, fluconazole, diltiazem); inducers of the activity of the CYP3A4 isoenzyme (phenobarbital, phenytoin, carbamazepine, rifampicin, St. John's wort); inhibitors of P-glycoprotein (P-gp) (cyclosporin, verapamil).

Ranexa, instructions for use: method and dosage

Ranex tablets are taken orally, swallowing whole, without breaking, crushing or chewing, drinking plenty of liquid. The drug can be used regardless of food intake, since the latter does not affect the bioavailability of ranolazine.

At the beginning of treatment, it is recommended to take Ranex 500 mg 2 times / day, 2-4 weeks after the start of the course, if necessary, the dose can be increased to 1000 mg 2 times / day. The maximum daily dose is 2000 mg.

In the case of the development of side effects caused by the intake of the drug, such as nausea, vomiting, dizziness, it is necessary to reduce a single dose to 500 mg. If, after reducing the dose, it is not possible to stop unwanted symptoms, drug therapy should be discontinued.

Side effects

Adverse reactions recorded during therapy with Ranexa (as a rule, they are mild or moderately pronounced and occur mainly during the first 2 weeks of the course):

• nervous system: often - headache, dizziness; infrequently - drowsiness, lethargy, hypesthesia, tremors, fainting, postural dizziness; rarely - parosmia, gait disturbances, impaired coordination of movements, confusion, amnesia, loss of consciousness;
• cardiovascular system: infrequently - flushing of the face, a significant decrease in blood pressure; rarely - coldness of the extremities, orthostatic hypotension;
• psyche: infrequently - insomnia, anxiety, hallucinations, clouding of consciousness; rarely - disorientation;
• respiratory system, chest and mediastinal organs: infrequently - cough, shortness of breath, nosebleeds; rarely - a feeling of squeezing in the throat;
• metabolism and nutrition: infrequently - loss of appetite, dehydration, anorexia; rarely, hyponatremia;
• organ of vision: infrequently - blurred vision, diplopia, visual disturbances;
• organ of hearing and labyrinthine disorders: infrequently - tinnitus, vertigo; rarely - hearing loss;
• digestive system: often - nausea, constipation, vomiting; infrequently - dryness of the oral mucosa, flatulence, dyspepsia, discomfort in the stomach, abdominal pain; rarely - oral hypoesthesia, erosive duodenitis, pancreatitis;
• musculoskeletal system: infrequently - joint swelling, muscle spasms, pain in the limbs; rarely - muscle weakness;
• skin and subcutaneous fat: infrequently - hyperhidrosis, pruritus; rarely - cold sweat, urticaria, skin rash, allergic dermatitis, angioedema;
• general disorders: often - asthenia; infrequently - increased fatigue, peripheral edema;
• reproductive system: rarely - erectile dysfunction;
• urinary system: infrequently - hematuria, chromaturia, dysuria; rarely - urinary retention, acute renal failure;
• others: infrequently - an increase in the plasma level of creatinine in the blood, a decrease in body weight, an increase in the content of urea in the blood plasma, thrombocytosis, leukocytosis, prolongation of the corrected QTc interval; rarely - increased activity of liver enzymes.

In persons with an increased risk of side effects, including patients with diabetes mellitus, obstructive airway diseases, CHF I – II functional class according to NYHA, during treatment with other antianginal drugs, the same frequency of adverse reactions was recorded.

Overdose

Symptoms of ranolazine overdose may include the following reactions, aggravated by increasing the dose of Ranexa: diplopia, nausea, vomiting, dizziness, lethargy, fainting.

In this condition, symptomatic therapy is recommended. Within 30 minutes after taking Ranexa, it is advisable to perform gastric lavage and the use of enterosorbent - activated carbon. Hemodialysis is ineffective.

special instructions

For patients with a body weight of less than 60 kg or with moderate / severe CHF (NYHA functional classes III – IV), the dose of Ranexa should be selected with caution because of the increased risk of side effects.

Based on a population analysis of pooled data from a study of patients and healthy volunteers, the dependence of QTc interval duration on plasma level can be estimated as 2.4 ms per 1000 ng / ml, which is approximately equivalent to an increase from 2 to 7 ms for a range of levels in blood plasma corresponding to the received dose of ranolazine 500-1000 mg 2 times / day. Therefore, caution is required when treating persons with a history of congenital lengthening of the QT interval, family history of lengthening of this interval, diagnosed acquired lengthening of the QT interval, or in patients receiving concomitant treatment with drugs that affect the duration of the QT interval.

The threat of an increase in the concentration of the drug and an increase in the frequency of development of side reactions also increases in the presence of insufficient activity of the isoenzyme CYP2D6 (slow metabolism) when compared with the normal ability to metabolize this isoenzyme. Patients with a slow metabolism or an unknown metabolic status of the CYP2D6 isoenzyme should be treated with Ranexa with caution. In persons with a detected (for example, by means of genotyping) or previously known intensive metabolic status of the aforementioned isoenzyme, the drug must also be used with extreme caution in the presence of a combination of several of the above risk factors.

Influence on the ability to drive vehicles and complex mechanisms

Studies of the effect of the antianginal drug Ranex on the ability to drive vehicles and control other complex mechanisms have not been conducted. However, in view of the fact that during the period of therapy, side effects such as dizziness, diplopia, blurred vision, impaired coordination of movements and confusion may occur, caution must be exercised when performing any potentially dangerous types of work (including driving).

Application during pregnancy and lactation

There are no data on the use of ranolazine in pregnant women. The penetration of the drug into breast milk has not been studied. As a result, during pregnancy and lactation, Ranexa is contraindicated.

Pediatric use

For patients under 18 years of age, the drug is contraindicated due to the lack of studies of the safety profile of Ranexa in children and adolescents.

With impaired renal function

In patients with impaired renal function of mild, moderate or severe severity, the value of ranolazine AUC was approximately 1.7–2 times higher than in patients with normal renal function. With concomitant renal failure of moderate (CC 30-60 ml / min) and severe (CC <30 ml / min) severity, an increase in the duration of the drug's presence in plasma was revealed by 1.2 times and 1.3-1.8 times, respectively … Also, in severe renal dysfunction, the AUC of active metabolites of the active substance increased by 5 times. The effect of dialysis on the pharmacokinetic parameters of ranolazine has not been evaluated.

Ranexa is contraindicated in patients with severe renal failure. With mild to moderate (CC 30–80 ml / min) renal dysfunction, treatment is possible only with careful titration of the ranolazine dose. During therapy, it is required to regularly monitor kidney activity.

For violations of liver function

Individuals with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale) have no experience with ranolazine. If patients have mild severity (5-6 points on the Child-Pugh scale) hepatic failure, the AUC value of the drug does not change, but with a moderate degree (7-9 points on the Child-Pugh scale), it increases 1.8 times. Also, in patients from this group, an increase in the QT interval is more pronounced.

Ranexa treatment is contraindicated in patients with severe and moderate hepatic insufficiency. In case of mild liver dysfunction, careful and careful titration of the dose of the drug is recommended.

Use in the elderly

Patient age does not have a clinically significant effect on Ranexa's pharmacokinetics. At the same time, in elderly patients, as a result of age-related decline in renal function, the effect of ranolazine may increase and, as a result, the development of side effects may become more frequent. Elderly people need an individual selection of the dose of the drug.

Drug interactions

• ketoconazole, posaconazole, itraconazole, voriconazole, HIV protease inhibitors, nefazodone, telithromycin, clarithromycin, as well as grapefruit juice (strong inhibitors of the CYP3A4 isoenzyme): increase the plasma concentration of ranolazine, since it is a CYP3A-dependent cytochrome substratum, undesirable effects (nausea, dizziness); these combinations are contraindicated;
• diltiazem (in a daily dose of 180-360 mg), fluconazole, erythromycin and other inhibitors of the CYP3A4 isoenzyme of medium action: there is a dose-dependent increase in the average plasma Css of ranolazine (in combination with diltiazem - by 1.5-2.4 times); careful selection of the Ranexa dose is recommended, if necessary, its reduction may be required;
• carbamazepine, phenytoin, rifampicin, phenobarbital, St. John's wort (Hypericum perforatum) and other inducers of the CYP3A4 isoenzyme: a decrease in the effectiveness of Ranexa is possible; when combined with rifampicin (600 mg 1 time / day), the plasma Css of ranolazine decreases by approximately 95%; the simultaneous use of ranolazine with these funds is not recommended;
• inhibitors of the CYP2D6 isoenzyme (paroxetine): there is an increase in the plasma level of ranolazine in the blood, since the latter is partially metabolized by the CYP2D6 isoenzyme; when combined with ranolazine at a dose of 1000 mg 2 times / day with paroxetine at a dose of 20 mg 1 time / day, the Css of ranolazine increases by an average of 1.2 times; dose changes are not required; with the appointment of a powerful inhibitor of the isoenzyme CYP2D6 simultaneously with Ranexa 2 times / day at 500 mg, the AUC of ranolazine may increase by about 62%;
• metoprolol, flecainide, propafenone, antipsychotics, tricyclic antidepressants (substrates of the isoenzyme CYP2D6): an increase of 1.8 times in the concentration of metoprolol in the blood is recorded when combined with ranolazine (a weak inhibitor of the isoenzyme CYP2D6) at a dose of 750 mg 2 times / day; when combined with Ranexa, the aggravation of the action of these drugs is likely, as a result of which a decrease in their doses may be necessary;
• verapamil, cyclosporine (P-gp inhibitors): increase the content of ranolazine in the blood: when taken simultaneously with verapamil 120 mg 3 times / day, the Css of ranolazine increases 2.2 times, as a result of this, careful titration or, if necessary, a decrease in its dose is required;
• P-gp substrates: an increase in the plasma concentration of these substances is likely; there may be an increase in tissue distribution of drugs transported by P-gp;
• cyclophosphamide, bupropion, efavirenz (substrates of the isoenzyme CYP2B6): it is recommended to combine with Ranexa, being careful, since the potential of the drug to suppress CYP2B6 has not been evaluated;
• lovastatin simvastatin, tacrolimus, cyclosporine, everolimus, sirolimus (substrates of the isoenzyme CYP3A4): an increase in the plasma level of these agents is likely, since ranolazine is a member of the group of weak inhibitors of the isoenzyme CYP3A4; with the combined use of Ranexa with substrates of the CYP3A4 isoenzyme with a narrow therapeutic range, it is required to control the level of the latter in the blood and, if necessary, adjust their dose;
• digoxin: there is information about an increase in its content in the blood by about 1.5 times, as a result, the concentration of this substance should be monitored at the beginning of the course of combined treatment and after its completion;
• simvastatin: there is an increase in blood levels of simvastatin acid, simvastatin lactone, on average, 2 times when combined with ranolazine at a dose of 1000 mg 2 times / day; isoenzyme CYP3A4 significantly affects the metabolism and clearance of simvastatin, the use of this substance in high doses causes the development of rhabdomyolysis, there are also descriptions of cases of rhabdomyolysis when ranolazine and simvastatin are combined; in combination therapy with any dose of simultaneously received ranolazine, the maximum daily dose of simvastatin should not be higher than 20 mg;
• atorvastatin: an increase in C _max and AUC of this substance is recorded, respectively, by 1.4 and 1.3 times when it is combined at a dose of 80 mg 1 time / day with ranolazine at a dose of 1000 mg 2 times / day; change in C _max and AUC of atorvastatin metabolites is less than 35%; dose reduction of atorvastatin may be necessary;
• other statins metabolized with the participation of the isoenzyme CYP3A4 (lovastatin): dose reduction may be required;
• some antihistamines (astemizole, terfenadine, mizolastine), certain antiarrhythmics (procainamide, disopyramide, quinidine), tricyclic antidepressants (amitriptyline, doxepin, imipramine), erythromycin and other drugs that lengthen the QT-inactivity interval, possibly pharmacological ventricular arrhythmias.

Analogs

Analogs of Ranexa are Bravadin, Vivaroxan, Ivabradin Canon, Ivabradin Medisorb, Coraksan, Karniland, Preductal OD, Renesin, etc.

Terms and conditions of storage

Store out of the reach of children at a temperature not exceeding 25 ° C.

Shelf life is 4 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Ranex

According to the few reviews about Ranex, left by patients on specialized sites, the drug has positively proven itself in the treatment of stable angina pectoris both in monotherapy mode and in combination with other antianginal drugs in case of insufficient effectiveness. It helped to reduce the frequency of attacks and improve the general condition.

At the same time, patients note the development of undesirable side reactions, due to which in some cases they had to abandon therapy. The disadvantages of Ranexa also include its high cost.

Price for Ranexa in pharmacies

The price of Ranexa, prolonged-release film-coated tablets, can be per package containing 60 pieces: dosage of 500 mg - 2900-3300 rubles, dosage of 1000 mg - 3100-3700 rubles.

Ranexa: prices in online pharmacies

Drug name Price Pharmacy

Ranexa 500 mg film-coated tablets of prolonged action 60 pcs. 2959 RUB Buy

Ranexa 1000 mg film-coated tablets of prolonged action 60 pcs. 3348 RUB Buy

Ranexa tab.prolong.p.o. 1000mg n60 3472 RUB Buy

Ranexa tab.prolong.p.o. 500mg n60 3536 RUB Buy

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!