Ranolazine (Ranolazine *)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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  • Ranex®
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    BERLIN-PHARMA, CJSC     Russia
    • АТХ:

    C.01.E.B   Other drugs for the treatment of heart disease

    C.01.E.B.18   Ranolazine

    Pharmacodynamics:

    Antianginal agent, inhibitor of 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 walls of the ventricles.

    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 reception, the incidence of angina attacks does not increase.

    Ranolazine 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 a day. 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.

    Patients treated with ranalazine showed a dose-dependent and active substance concentration in the blood plasma, an extension of the QTc interval (about 6 ms with 1000 mg bid 2 times a day), a decrease in the amplitude of the T wave and in some cases a double-humped tooth. patients receiving ranolazine, are the result of both inhibiting the potassium current rate, which extends the ventricular action potential and inhibition of late sodium current, which shortens the ventricular potential of the action. In the case of clinically significant liver failure in patients, the rate of QTc extension was higher.

    In patients who received ranolazine, there was a significantly lower incidence of arrhythmias compared with placebo, including ventricular pirouette tachycardia: ≥8 reductions per episode.

    In patients treated with ranolazine in the form of monotherapy or in combination with other antianginal agents, there was a slight decrease in the heart rate (<2 beats per minute) and a decrease in systolic blood pressure (<3 mmHg).

    Pharmacokinetics:

    After taking ranolazine, the maximum concentration 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 a day, the steady-state concentration is usually achieved within 3 days. In healthy volunteers, the maximum steady-state concentration is approximately 1770 ng / ml, AUC0-12 in the equilibrium state averages 13 700 ng × h / ml after administration of 500 mg twice a day. Eating food does not affect the speed and completeness of absorption of ranolazine.

    Binding to plasma proteins is about 62%, mainly with alpha-1 acidic glycoproteins, and slightly - with albumin. The average stationary volume of distribution is about 180 liters.

    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, and also by the isoenzyme CYP2D6.When taking 500 mg twice a day in people with inadequate activity of the isoenzyme CYP2D6, the AUC value exceeds the same value for people with a normal metabolic rate by 62%. A similar difference for a dose of 1000 mg twice a day was 25%.

    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. The half-life of ranolazine in the equilibrium state after oral administration is about 7 hours.

    Indications:Stable angina.
    ICD-10

    IX.I20-I25.I20   Angina pectoris [angina pectoris]

    Contraindications:Renal failure of severe degree (CK <30 ml / min); hepatic impairment of an average (7-9 points according to the Child-Pugh classification) or severe (more than 9 Child-Pugh grades) degree; simultaneous application with potent inhibitors of the isoenzyme CYP3A4 (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone); simultaneous use with antiarrhythmicand means of class I A (for example, quinidine) or class III (eg, dofetilide), other than amiodarone, with sotalol; children's andadolescence to 18 years (efficacy and safety of the drug not established); pregnancy; lactation period (breastfeeding); increased sensitivity to ranolazine.
    Carefully:For 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); in patients over the age of 75; in patients with a body weight of less than 60 kg; with chronic heart failure (III-IV functional classes according to the NYHA classification); syndrome of congenital prolongation of QT interval in history, in family history; diagnosedthe acquired interval elongation QT; insufficiency of the isoenzyme CYP2D6; simultaneously with inhibitors of the CYP3A4 isoenzyme of moderate strength of action (diltiazem, fluconazole, erythromycin); simultaneously with inducers of the activity of the isoenzyme CYP3A4 (rifampicin, phenytoin, phenobarbital, carbamazepineSt. John's wort (Hypericum perforatum); simultaneously with inhibitors of P-glycoprotein (verapamil, ciclosporin).
    Pregnancy and lactation:Recommendations for FDA - Category C. Contraindicated in pregnancy and lactation (breastfeeding).
    Dosing and Administration:

    Accepted inwards regardless of food intake.

    The recommended initial dose 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 daily dose is 2000 mg.

    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.

    Side effects:

    From the side of cardio-vascular system: a rush of blood to the face, a marked decrease in blood pressure; cold extremities, orthostatic hypotension.

    From the side digestive system: constipation, nausea, vomiting; pain in the abdomen, dryness of the oral mucosa, dyspepsia, flatulence, discomfort in the stomach; pancreatitis, erosive duodenitis, hypoesthesia of the oral cavity.

    From the side nervous system: dizziness, headache; inhibition, fainting, hypoesthesia, drowsiness, tremor, postural dizziness; amnesia, confusion, loss of consciousness, parosmia.

    From the side mentality: anxiety, insomnia, confusion, hallucinations; disorientation.

    From the side organ of vision: blurred vision, visual disorders.

    From the side organs of hearing and labyrinthine disorders: vertigo, noise in the ears; hearing loss.

    From the side respiratory system: shortness of breath, cough, nosebleeds; sensation of compression in the throat.

    From the side metabolism: decreased appetite, anorexia, dehydration.

    From the side skin and subcutaneous tissues: infrequently - itchy skin, hyperhidrosis; cold sweat, skin rash.

    Allergic reactions: Allergic dermatitis, urticaria, angioedema.

    From the side musculoskeletal system: pain in the extremities, muscle spasms, swelling of the joints.

    From the side urinary system: dysuria, hematuria, chromaturia; acute renal failure.

    From the side reproductive system: erectile disfunction.

    From the side laboratory indicators: an increase in the concentration of creatinine in the blood plasma, an increase in the concentration of urea in the blood plasma, prolongation of the corrected interval QTc, thrombocytosis and leukocytosis, weight loss; increased activity of hepatic enzymes.

    Common reactions: asthenia; fatigue, peripheral edema.

    Overdose:

    Symptoms: dizziness, nausea and vomiting, diplopia, retardation, fainting. Symptoms may increase with increasing doses.

    Treatment: symptomatic therapy. Within 30 min. after taking the drug, you can take measures to prevent its absorption from the gastrointestinal tract (gastric lavage, the use of activated charcoal). Hemodialysis is ineffective.

    Interaction:

    Amitriptyline. There is a theoretical likelihood that with the simultaneous use of ranolazine and amitriptyline, a tricyclic antidepressant that prolongs the QT interval, pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Care must be taken when treating patients receiving amitriptyline.

    Astemizole. There is a theoretical likelihood that with the simultaneous use of ranolazine and astemizole - an antihistamine drug that prolongs the QT interval - pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Care must be taken when treating patients receiving astemizole.

    Bupropion. The potential for inhibition of the CYP2B6 isoenzyme is not established. While prescribing ranolazine together with the substrate of the isoenzyme CYP2B6-bupropion, caution is recommended.

    Verapamil. Ranolasin is a substrate of P-glycoprotein. P-glycoprotein inhibitors increase the concentration of ranolazine in the blood plasma. Verapamil (120 mg three times a day) increases the Css of ranolazine by a factor of 2.2. Caution should be exercised while using ranolazine with a P-glycoprotein inhibitor verapamil. Patients receiving treatment with verapamil, an inhibitor of P-glycoprotein, are recommended to titrate the dose of ranolazine. It may be necessary to reduce the dose of ranolazine.

    Voriconazole. Ranolazine is a substrate of cytochrome CYP3A4. Simultaneous application of CYP3A4 isozyme activity with inhibitors increases the concentration of ranolazine in blood plasma. With an increase in the concentration of ranolazine in the blood plasma, potential dose-dependent side effects can also increase (for example, nausea, dizziness). The simultaneous use of ranolazine and a strong inhibitor of the CYP3A4 isoenzyme voriconazole is contraindicated.

    Digoxin. There is evidence of an increase in the concentration of digoxin in the blood plasma by an average of 1.5 times with the simultaneous use of digoxin and ranolazin. Therefore, it is necessary to monitor the level of digoxin at the beginning and after the end of therapy with the use of ranolazine.

    Dizopyramide. There is a theoretical likelihood that with the simultaneous use of ranolazine and an antiarrhythmic agent of disopyramide extending the QT interval, pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Care must be taken when treating patients receiving disopyramide.

    Diltiazem (180-360 mg once daily) - an inhibitor of the CYP3A4 isoenzyme of moderate strength, causes a dose increase of 1.5-2.4 times the average Css of ranolazine depending on the dose. Caution should be exercised while using ranolazine with diltiazem. Patients receiving diltiazem treatment are recommended to titrate the dose of ranolazine. It may be necessary to reduce the dose of ranolazine.

    Doxepine. There is a theoretical likelihood that with the simultaneous use of ranolazine and the tricyclic antidepressant doxepin, extending the QT interval,pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Care must be taken when treating patients receiving doxepin.

    Imipramine. There is a theoretical likelihood that with the simultaneous use of ranolazine and imipramine, a tricyclic antidepressant that prolongs the QT interval, pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Care must be taken when treating patients receiving imipramine.

    Itraconazole. Ranolazine is a substrate of cytochrome CYP3A4. Simultaneous application of CYP3A4 isozyme activity with inhibitors increases the concentration of ranolazine in blood plasma. With an increase in the concentration of ranolazine in the blood plasma, potential dose-dependent side effects can also increase (for example, nausea, dizziness). The simultaneous use of ranolazine and itraconazole, a potent inhibitor of the CYP3A4 isoenzyme, is contraindicated.

    Carbamazepine. The simultaneous use of ranolazine with carbamazepine, an inducer of the activity of the CYP3A4 isoenzyme, may lead to a decrease in its effectiveness.Therefore, do not begin the use of ranolazine in patients receiving carbamazepine. Caution should be exercised while using ranolazine with carbamazepine.

    Ketoconazole. Ranolazine is a substrate of cytochrome CYP3A4. Simultaneous application of CYP3A4 isozyme activity with inhibitors increases the concentration of ranolazine in blood plasma. With an increase in the concentration of ranolazine in the blood plasma, potential dose-dependent side effects can also increase (for example, nausea, dizziness). Simultaneous treatment with ketoconazole 200 mg 2 times a day increases the ARL of ranalazine by 3-3.9 times. The simultaneous use of ranolazine and ketoconazole, a potent inhibitor of the isoenzyme CYP3A4, is contraindicated.

    Clarithromycin. With an increase in the concentration of ranolazine in the blood plasma, potential dose-dependent side effects can also increase (for example, nausea, dizziness). The simultaneous use of ranolazine and clarithromycin, a potent inhibitor of the CYP3A4 isoenzyme, is contraindicated.

    Lovastatin. Ranolasin is a weak inhibitor of the isoenzyme CYP3A4, which can lead to an increase in the concentration of lovastatin, a sensitive substrate of the isoenzyme CYP3A4, in the blood plasma and require correction of its dose.

    Metoprolol. There is evidence that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. The use of ranolazine 750 mg twice a day increases the concentration of metoprolol in blood plasma by 1.8 times. Therefore, with simultaneous application with ranolazine, the effect of metoprolol, the substrate of the isoenzyme CYP2D6, can be increased, which may require a reduction in the dose of this drug.

    Posaconazole. Ranolazine is a substrate of cytochrome CYP3A4. Simultaneous application of CYP3A4 isozyme activity with inhibitors increases the concentration of ranolazine in blood plasma. With an increase in the concentration of ranolazine in the blood plasma, potential dose-dependent side effects can also increase (for example, nausea, dizziness). The simultaneous use of ranolazine and a strong inhibitor of the CYP3A4 isozyme, posaconazole, is contraindicated.

    Procainamide. There is a theoretical likelihood that with the simultaneous use of ranolazine and procainamide - an antiarrhythmic drug that prolongs the QT interval, pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Care should be taken when treating patients receiving treatment with procainamide.

    Propaphenone. There is evidence that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme.With simultaneous application with ranolasin, the action of propafenone, the substrate of the isoenzyme CYP2D6, can be intensified, which may require a reduction in the dose of this drug.

    Rifampicin. The simultaneous use of ranolazine with rifampicin, an inducer of the activity of the isoenzyme CYP3A4, may lead to a decrease in its effectiveness. For example, rifampicin (600 mg once daily) reduces the equilibrium concentration of ranolazine in the blood plasma by approximately 95%. Therefore, do not begin the use of ranolazine in patients receiving rifampicin. Caution should be exercised while using ranolampine with rifampicin.

    Simvastatin. Ranolasin is a weak inhibitor of the CYP3A4 isoenzyme, which can lead to an increase in the concentration of simvastatin, a sensitive substrate of the CYP3A4 isoenzyme, in the blood plasma and require correction of its dose. The metabolism and clearance of simvastatin are highly dependent on the isoenzyme CYP3A4. The use of ranolazine 1000 mg twice a day increases the concentration of lactone, simvastatin, simvastatin acid, which increases the inhibition of HMG-CoA reductase by 1.4-1.6 times. The use of simvastatin in high doses is associated with the development of rhabdomyolysis,The cases of development of rhabdomyolysis with simultaneous application of ranolazine and simvastatin have also been described. The maximum dose of simvastatin for patients concomitantly taking ranolazine, should not exceed 20 mg / day.

    Sirolimus. With simultaneous application of sirolimus and ranolazine, it is recommended to monitor the concentration of sirolimus in the blood plasma and, if necessary, adjust the dose.

    Sotalol. The simultaneous use of ranolazine with sotalol is contraindicated.

    Tacrolimus. Ranolazine is a weak inhibitor of the isoenzyme CYP3A4, which can lead to an increase in the concentration of tacrolimus - the substrate of the isoenzyme CYP3A4 with a narrow therapeutic range, in the blood plasma and require correction of its dose. With simultaneous application of tacrolimus and ranolazine, it is recommended to monitor the concentration of tacrolimus in the blood plasma and, if necessary, to adjust the dose.

    Terfenadine. There is a theoretical likelihood that with the simultaneous use of ranolazine and terfenadine, an antihistamine drug that prolongs the QT interval, pharmacodynamic interaction may occur and the risk of developingventricular arrhythmias. Care must be taken when treating patients receiving terfenadine.

    Phenytoin, phenobarbital. The simultaneous use of ranolazine with phenobarbital or phenytoin, an inducer of the activity of the isoenzyme CYP3A4, may lead to a decrease in its effectiveness. Therefore, do not begin the use of ranolazine in patients receiving these drugs. Care must be taken when applying simultaneously.

    Fluconazole. Patients receiving fluconazole - an inhibitor of the CYP3A4 isoenzyme of moderate strength, a titration of the dose of ranolazine is recommended. It may be necessary to reduce the dose of ranolazine. Caution should be exercised while using ranolazine with fluconazole.

    Quinidine. There is a theoretical likelihood that with the simultaneous use of ranolazine and quinidine, an antiarrhythmic drug that prolongs the QT interval, pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. The simultaneous use of ranolazine with quinidine, an antiarrhythmic agent of class IA, is contraindicated.

    Cyclosporine. Ranolazine is a weak inhibitor of the isoenzyme CYP3A4, which can lead to an increase in the concentration of cyclosporin-substrate isoenzyme CYP3A4 with a narrow therapeutic range in the blood plasma and require correction of its dose.

    Cyclophosphamide. The potential for inhibition of the CYP2B6 isoenzyme is not established. When ranolazine is administered together with cyclophosphamide, a substrate of the CYP2B6 isoenzyme, caution is recommended.

    Everolimus. With simultaneous application of everolimus and ranolazin, it is recommended to monitor the concentration of everolimus in the blood plasma and, if necessary, adjust the dose.

    Erythromycin. Patients receiving erythromycin - an inhibitor of the CYP3A4 isoenzyme of moderate strength, a titration of the dose of ranolazine is recommended. It may be necessary to reduce the dose of ranolazine. Caution should be exercised while using ranolazine with erythromycin.

    Efavirenz. The potential for inhibition of the CYP2B6 isoenzyme is not established. While prescribing ranolazine together with efavirenz-a substrate of the CYP2B6 isoenzyme, caution is recommended.

    Special instructions:

    Dose selection for patients with a body weight of less than 60 kg should be carried out with caution, as the incidence of side effects in these patients were more frequent.

    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.

    Impact on the ability to drive vehicles and mechanisms

    Given the potential for the development of side effects such as dizziness, blurred vision, confusion and hallucinations, patients should be careful when driving vehicles and mechanisms, and when engaging in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

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