Instructions for Ranexa 1000 extended-release tablets 1000 mg blister No. 60
Composition
active ingredient: ranolazine;
1 film-coated tablet contains ranolazine 500 mg;
excipients: microcrystalline cellulose, methacrylic acid and ethyl acrylate copolymer (1:1), hypromellose, magnesium stearate, sodium hydroxide, polyethylene glycol 3350, partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), carnauba wax;
1 film-coated tablet contains ranolazine 1000 mg;
excipients: microcrystalline cellulose, methacrylic acid and ethyl acrylate copolymer (1:1), hypromellose, magnesium stearate, sodium hydroxide, glycerol triacetate, lactose monohydrate, polyethylene glycol 3350, titanium dioxide (E 171), iron oxide yellow (E 172), carnauba wax.
Dosage form
Extended-release tablets.
Main physicochemical properties:
500 mg tablets: light orange, film-coated, biconvex, oval tablets, embossed with "500" on one side, the other side is smooth;
1000 mg tablets: pale yellow, film-coated, biconvex, oval tablets, embossed with "1000" on one side, the other side is plain.
Pharmacotherapeutic group
Other cardiological agents. Ranolazine.
ATX code C01E B18.
Pharmacological properties
Pharmacodynamics.
Mechanism of action.
The mechanism of action of ranolazine remains largely unknown. Ranolazine may exert some antianginal effects by inhibiting the late influx of sodium ions into myocardial cells. This reduces intracellular sodium accumulation and, consequently, reduces the excess intracellular calcium ions. Ranolazine, by reducing the late influx of sodium ions, reduces the intracellular ion imbalance in ischemia. This reduction in the excess intracellular calcium will contribute to myocardial relaxation and, thus, reduce left ventricular diastolic stress. Clinical evidence of inhibition of the late influx of sodium by ranolazine was demonstrated by a significant shortening of the QTc interval and an improvement in diastolic relaxation, which was demonstrated in an open-label study in 5 patients with long QT syndrome (patients with LQT3 syndrome who have the SCN5A ΔKPQ gene mutation). These effects of the drug are independent of changes in heart rate, blood pressure, or blood vessel dilation.
Pharmacodynamic action.
Effect on hemodynamics.
Clinical studies have shown that patients who used ranolazine alone or in combination with other antianginal drugs experienced a decrease in mean heart rate (< 2 beats/min) and mean systolic blood pressure (< 3 mmHg).
Effects detected by electrocardiography (ECG).
In patients treated with Ranexa®, dose- and plasma concentration-dependent prolongation of the QTc interval (approximately 6 ms at 1000 mg twice daily), reduction in T wave amplitude, and, in some cases, double-humped T waves were observed. This effect of ranolazine on ECG characteristics is believed to be the result of inhibition of the fast rectifying potassium current, which prolongs the ventricular action potential, as well as inhibition of the late sodium current, which shortens the ventricular action potential. A population analysis of pooled data from 1308 patients and healthy volunteers showed a mean prolongation of QTc from baseline of 2.4 ms per 1000 ng/mL of ranolazine in plasma. This value is consistent with data from pivotal clinical studies, where the mean changes from baseline in QTcF (Friedrichian-corrected) after 500 and 750 mg twice daily were 1.9 and 4.9 ms, respectively. The slope of the line was higher in patients with clinically significant hepatic impairment.
In a large study (MERLIN-TIMI 36) of 6,560 patients with ACS (unstable angina/non-ST segment elevation myocardial infarction), there was no difference between Ranexa® and placebo in the risk of all-cause mortality (relative risk for ranolazine compared to placebo was 0.99), sudden cardiac death (relative risk for ranolazine compared to placebo was 0.87), or the incidence of reported symptomatic arrhythmias (3.0% vs. 3.1%).
In the MERLIN-TIMI 36 study, no proarrhythmic effects were observed in 3162 patients treated with Ranexa® during 7-day Holter monitoring. Patients treated with Ranexa® had a significantly lower incidence of arrhythmias compared to those treated with placebo (80% vs. 87%), including ventricular tachycardia ≥ 8 beats (5% vs. 8%).
Clinical efficacy and safety.
In the pivotal CARISA study, Ranexa® was added to atenolol 50 mg once daily, amlodipine 5 mg once daily, or diltiazem 180 mg once daily. 823 patients (23% women) were randomized to receive Ranexa® 750 mg twice daily, 1000 mg twice daily, or placebo for 12 weeks. Ranexa® was superior to placebo in increasing exercise time over 12 weeks at both doses studied as add-on therapy. However, there was no difference in exercise time between the two doses (24 seconds vs. placebo; p £ 0.03).
Ranexa® significantly reduced the number of angina attacks per week and the need for short-acting nitroglycerin compared with placebo. Tolerance to ranolazine did not develop during treatment, and there was no increase in angina attacks after abrupt discontinuation of the drug. The improvement in exercise capacity in women was approximately 33% of that observed in men at 1000 mg twice daily. However, both men and women experienced similar reductions in angina attacks and nitroglycerin use. Given the dose-related side effects and similar efficacy at 750 and 1000 mg twice daily, the recommended maximum dose is 750 mg twice daily.
In the second ERICA study, Ranexa® was added to amlodipine 10 mg once daily (the maximum recommended dose). 565 patients were randomized to receive Ranexa® at an initial dose of 500 mg twice daily or placebo for 1 week, followed by 1000 mg twice daily or placebo for 6 weeks in addition to concomitant amlodipine 10 mg once daily. In addition, 45% of the study population was also taking long-acting nitrates. Ranexa® significantly reduced the number of angina attacks per week (p = 0.028) and the need for short-acting nitroglycerin (p = 0.014) compared with placebo. Both the average number of angina attacks and the number of nitroglycerin tablets taken decreased by approximately 1 unit per week.
In the MARISA study, a pivotal dose-finding study, ranolazine was used as monotherapy. 191 patients were randomized to receive Ranexa® 500 mg twice daily, 1000 mg twice daily, 1500 mg twice daily, or placebo, each for 1 week in a crossover design. Ranexa® demonstrated significant improvements over placebo in exercise tolerance, time to angina attack, and time to 1 mm ST-segment depression at all doses studied; a dose-response relationship was observed. Compared with placebo, the increase in exercise duration was statistically significant with ranolazine at all three doses and ranged from 24 seconds at 500 mg twice daily to 46 seconds at 1500 mg twice daily, demonstrating a dose-dependent effect. In this study, exercise duration was greatest in the 1500 mg dose group; however, a disproportionate increase in adverse events was observed. Therefore, the 1500 mg twice daily dose was excluded from further study.
In a large, hard-endpoint study (MERLIN-TIMI 36) of 6,560 patients with ACS (unstable angina/non-ST-segment elevation myocardial infarction), there was no difference between Ranexa® and placebo in the risk of all-cause mortality (ratio of risk for ranolazine to placebo was 0.99), sudden cardiac death (ratio of risk for ranolazine to placebo was 0.87), or the incidence of documented symptomatic arrhythmias (3.0% vs. 3.1%) when added to standard medical therapy (including beta-blockers, calcium channel blockers, nitrates, antiplatelet agents, lipid-lowering agents, and ACE inhibitors). Approximately half of the patients in the MERLIN-TIMI 36 trial had a history of angina. Results showed that the duration of exercise tolerance increased by 31 seconds in patients taking ranolazine compared with patients taking placebo (p = 0.002). The Seattle Angina Questionnaire showed a significant effect of ranolazine on several parameters, including angina attack frequency (p < 0.001), compared with placebo.
In a phase 3, double-blind, placebo-controlled, endpoint-oriented clinical trial (RIVER-PCI) in 2604 patients ≥ 18 years of age with a history of chronic angina and incomplete revascularization after percutaneous coronary intervention (PCI), the dose was increased to 1000 mg twice daily. The primary endpoint (time to first evidence of ischemia-induced revascularization or ischemia-related hospitalization not associated with revascularization) was not statistically different between the ranolazine group (26.2%) and the placebo group (28.3%), hazard ratio 0.95, 95% CI 0.82–1.10, p = 0.48. The risk of all-cause mortality, cardiovascular death, serious adverse cardiovascular events (SACEs), and hospitalization for heart failure was similar in all groups; however, serious adverse cardiovascular events were more common in patients ≥ 75 years of age treated with ranolazine compared with placebo (17.0% vs. 11.3%, respectively); in addition, there was a significant increase in all-cause mortality in patients ≥ 75 years of age (9.2% vs. 5.1%, p = 0.074).
Pharmacokinetics.
Following oral administration of Ranexa®, peak plasma concentrations (Cmax) of ranolazine are typically achieved within 2–6 hours. Steady state is typically achieved within 3 days when administered twice daily.
Absorption.
The mean absolute bioavailability of ranolazine after oral administration of immediate-release tablets is 35–50% with a high degree of individual variability. The effect of Ranexa® is dose-dependent. When the dose is increased from 500 to 1000 mg twice daily, a 2.5–3-fold increase in AUC at steady state is observed. In a pharmacokinetic study in healthy volunteers, the steady-state Cmax concentration averaged approximately 1770 (SD 1040) ng/mL, and the steady-state AUC0–12 averaged 13700 (SD 8290) ng × h/mL after administration of the drug at 500 mg twice daily. Food intake does not affect the rate and completeness of absorption of ranolazine.
Distribution.
Ranolazine is approximately 62% bound to plasma proteins, primarily alpha-1 acid glycoprotein and weakly bound to albumin. The mean volume of distribution at steady state (Vss) is approximately 180 L.
Breeding.
Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excreted unchanged in the urine and feces. After a single oral dose of 500 mg of [14C]-labeled ranolazine in healthy volunteers, 73% of the radioactivity is recovered in the urine and 25% in the feces. The clearance of ranolazine is dose-dependent and decreases with increasing dose. The elimination half-life is approximately 2–3 hours after intravenous administration. The terminal elimination half-life at steady state after oral administration of ranolazine is approximately 7 hours due to the limited rate of absorption.
Biotransformation.
Ranolazine undergoes rapid and extensive metabolism. In young healthy adults, approximately 13% of the radioactivity is recovered in plasma after a single oral dose of 500 mg [14C]-ranolazine.
A large number of metabolites have been identified in human plasma (47 metabolites), urine (> 100 metabolites) and feces (25 metabolites). 14 major metabolic pathways have been identified, of which O-demethylation and N-dealkylation are the most important. In vitro studies using human liver microsomes have shown that ranolazine is metabolized primarily by CYP3A4, as well as CYP2D6. When 500 mg ranolazine was administered twice daily to individuals with poor CYP2D6 activity (poor metabolizers), the AUC was 62% higher than that in individuals with normal CYP2D6 activity (extensive metabolizers). The corresponding difference for a dose of 1000 mg twice daily was 25%.
Special patient groups.
The influence of various factors on the pharmacokinetics of ranolazine was evaluated in a population pharmacokinetic study involving 928 patients with angina and healthy subjects.
The influence of gender.
Gender has no clinical effect on pharmacokinetic parameters.
Elderly patients.
Age alone has no clinical effect on pharmacokinetic parameters, however, in elderly patients, the effect of ranolazine may be enhanced due to age-related decline in renal function.
Body weight.
In individuals weighing 40 kg, the exposure to ranolazine is approximately 1.4 times greater than in individuals weighing 70 kg.
Congestive heart failure (CHF)
CHF NYHA classes III–IV leads to an increase in ranolazine plasma concentrations by approximately 1.3 times.
Kidney failure.
In a population pharmacokinetic analysis, a 1.2-fold increase in ranolazine exposure was observed in patients with moderate renal impairment (creatinine clearance 40 mL/min). In people with severe renal impairment (creatinine clearance 10–30 mL/min), a 1.3–1.8-fold increase in ranolazine exposure was observed.
The effect of dialysis on the pharmacokinetics of ranolazine has not been evaluated.
Liver failure.
The pharmacokinetics of ranolazine have been evaluated in patients with mild to moderate hepatic impairment. There are no data on the use of ranolazine in patients with severe hepatic impairment. In patients with mild hepatic impairment, the AUC of ranolazine was unchanged, while in patients with moderate hepatic impairment, the AUC increased 1.8-fold. In such patients, the increase in the QT interval was more pronounced.
Children.
The pharmacokinetic parameters of ranolazine in children (< 18 years) have not been studied.
Preclinical safety data.
Adverse reactions to ranolazine that were not observed in clinical studies but were seen in animals with effects similar to clinical effects: convulsions and increased mortality in rats and dogs at plasma ranolazine concentrations approximately 3 times higher than the maximum recommended clinical dose.
Chronic toxicity studies in rats have shown a treatment-related change in adrenal function at exposures slightly above those seen in clinical patients. This effect is associated with increases in plasma cholesterol. No similar changes have been observed in humans. No effects on the adrenocortical axis have been observed in humans.
In long-term carcinogenicity studies, no significant increase in the incidence of any type of tumor was observed at ranolazine doses up to 50 mg/kg/day (150 mg/m2/day) in mice and 150 mg/kg/day (900 mg/m2/day) in rats. These doses represent 0.1 and 0.8 times, respectively, the maximum recommended human dose of 2 g per mg/m2, and are the maximum tolerated doses in these species.
In male and female rats, oral administration of ranolazine, which resulted in an increase in AUC of 3.6 and 6.6 times, respectively, compared to that expected in humans, had no effect on fertility.
Embryofetotoxicity studies have been conducted in rats and rabbits. At maternal plasma exposures (AUC) of ranolazine similar to those expected in humans, no effects on offspring were observed in rabbits. In rats, at maternal exposures (AUC) 2 times the expected human exposure, no effects on offspring were observed, but at maternal exposures 7.5 times the expected human exposure, decreased fetal weight and impaired ossification were observed. At lactating females exposed to 1.3 times the expected human exposure, no postnatal mortality of offspring was observed, while at 3 times the expected human exposure, postnatal mortality was observed and ranolazine was excreted in rat milk. No adverse reactions were observed in newborn rat offspring at exposure levels similar to those in humans.
Indication
Treatment of stable angina.
Contraindication
Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section.
Severe renal impairment (creatinine clearance < 30 ml/min) (see sections “Method of administration and dosage” and “Pharmacokinetics”).
Moderate or severe hepatic impairment (see sections “Method of administration and dosage” and “Pharmacokinetics”).
Concomitant use of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) (see sections “Dosage and administration” and “Interaction with other medicinal products and other types of interactions”).
Concomitant use of class Ia (e.g. quinidine) or class III (e.g. dofetilide, sotalol) antiarrhythmics other than amiodarone.
Interaction with other medicinal products and other types of interactions
Effects of other drugs on ranolazine.
CYP3A4 or P-gp inhibitors.
Ranolazine is a substrate of cytochrome CYP3A4. CYP3A4 inhibitors increase the plasma concentration of ranolazine. With an increase in its plasma concentration, the manifestation of potential dose-dependent adverse reactions (e.g. nausea, dizziness) may increase. During treatment with ranolazine, the simultaneous use of ketoconazole at a dose of 200 mg twice a day increases the AUC of ranolazine by 3-3.9 times. The simultaneous use of ranolazine and potent CYP3A4 inhibitors (such as itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated (see section "Contraindications"). Grapefruit juice is also a potent CYP3A4 inhibitor.
Ranolazine is a P-gp substrate. P-gp inhibitors (e.g., cyclosporine, verapamil) increase ranolazine plasma levels. Verapamil (120 mg three times daily) increases steady-state plasma concentrations of ranolazine by 2.2-fold. Careful titration of Ranexa® is recommended in patients receiving P-gp inhibitors. A dose reduction may be necessary (see Dosage and Administration and Precautions).
CYP3A4 inducers.
Rifampicin (600 mg once daily) reduces steady-state ranolazine concentrations by approximately 95%. Ranexa® should not be initiated during CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) (see section 4.4).
CYP2D6 inhibitors.
Ranolazine is partially metabolized by CYP2D6, so inhibitors of this enzyme may increase the concentration of ranolazine in plasma. The potent CYP2D6 inhibitor paroxetine at a dose of 20 mg 1 time / day increases the average equilibrium plasma concentrations of ranolazine by an average of 1.2 times (when using ranolazine 1000 mg 2 times / day). No dose adjustment is required. At a dose of ranolazine 500 mg 2 times / day, the simultaneous use of a potent CYP2D6 inhibitor may lead to an increase in the AUC of ranolazine by approximately 62%.
Effect of ranolazine on other drugs.
Ranolazine is a moderate to high potency P-gp inhibitor and a weak CYP3A4 inhibitor, and therefore may increase plasma concentrations of P-gp or CYP3A4 substrates. The distribution of drugs transported by P-gp may also be increased.
When prescribing Ranexa®, dose adjustment of some, especially dependent CYP3A4 substrates (e.g. simvastatin, lovastatin), as well as CYP3A4 substrates with a narrow therapeutic range (e.g. cyclosporine, tacrolimus, sirolimus, everolimus) may be required, since Ranexa® may increase the plasma concentrations of these drugs.
Available data indicate that ranolazine is a weak inhibitor of CYP2D6. The use of Ranexa® 750 mg 2 times a day increases the plasma concentration of metoprolol by 1.8 times, therefore, when used simultaneously, the effect of metoprolol or other CYP2D6 substrates (e.g. propafenone, flecainide; to a lesser extent, this applies to tricyclic antidepressants and neuroleptics), as a result of which a dose reduction of these drugs may be required.
The potential for CYP2B6 inhibition has not been evaluated. Caution is advised when Ranexa® is co-administered with CYP2B6 substrates (e.g., bupropion, efavirenz, cyclophosphamide).
Digoxin.
There is evidence of an increase in plasma digoxin concentrations by an average of 1.5 times when used simultaneously with Ranexa®, therefore, it is necessary to monitor digoxin levels at the beginning and end of Ranexa® use.
Simvastatin.
The metabolism and clearance of simvastatin are largely dependent on CYP3A4. Administration of Ranexa® 1000 mg twice daily increases plasma concentrations of simvastatin lactone and simvastatin acid approximately 2-fold. Rhabdomyolysis has also been reported in postmarketing surveillance in patients receiving Ranexa® and simvastatin. For patients receiving Ranexa® at any dose, the dose of simvastatin should not exceed 20 mg daily.
Atorvastatin.
Ranexa® 1000 mg twice daily increases the Cmax and AUC of atorvastatin 80 mg once daily by 1.4-fold and 1.3-fold, respectively, and changes the Cmax and AUC of atorvastatin metabolites by less than 35%. Atorvastatin dose limitation and appropriate clinical monitoring may be required when Ranexa® is administered.
When taking Ranexa®, the dose of other statins metabolized by CYP3A4 (lovastatin) may need to be limited.
Tacrolimus, cyclosporine, sirolimus, everolimus.
Administration of ranolazine to patients receiving tacrolimus (a CYP3A4 substrate) has been shown to increase plasma concentrations of tacrolimus. When Ranexa® is administered to patients receiving tacrolimus, it is recommended that tacrolimus plasma concentrations be monitored and the tacrolimus dose adjusted as necessary. Such monitoring is also recommended when other CYP3A4 substrates with a narrow therapeutic window are used (e.g., cyclosporine, sirolimus, everolimus).
Drugs transported by organic cation transporter-2 (OCT2). When Ranexa® was administered at doses of 500 mg and 1000 mg twice daily to patients with type 2 diabetes, the plasma concentrations of co-administered metformin (1000 mg twice daily) increased 1.4- and 1.8-fold, respectively. The concentrations of other OCT2 substrates, including pindolol and varenicline, may be altered to a similar extent.
There is a theoretical risk that concomitant treatment with ranolazine and other drugs that prolong the QTc interval may result in a pharmacodynamic interaction and an increased risk of ventricular arrhythmias. For example, such drugs include some antihistamines (such as terfenadine, astemizole, mizolastine), some antiarrhythmics (such as quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants (such as imipramine, doxepin, amitriptyline).
Application features
Caution should be exercised when prescribing or increasing the dose of ranolazine to patients in whom its effects may be enhanced, such as those with the following conditions:
simultaneous use of moderate CYP3A4 inhibitors (see sections “Method of administration and dosage” and “Interaction with other medicinal products and other types of interactions”);
concomitant use of P-gp inhibitors (see sections “Method of administration and dosage” and “Interaction with other medicinal products and other types of interactions”);
mild hepatic insufficiency (see sections “Method of administration and dosage” and “Pharmacokinetics”);
mild or moderate renal insufficiency (creatinine clearance 30–80 ml/min) (see sections “Method of administration and dosage”, “Adverse reactions” and “Pharmacokinetics”);
elderly patients (see sections “Method of administration and dosage”, “Adverse reactions” and “Pharmacokinetics”);
patients with low body weight (≤ 60 kg) (see sections “Method of administration and dosage”, “Adverse reactions” and “Pharmacokinetics”);
Moderate or severe CHF (NYHA classes III-IV) (see sections “Method of administration and dosage” and “Pharmacokinetics”).
In patients with several of the above factors, additional enhancement of the effect can be expected. Dose-dependent adverse reactions may occur. When using Ranexa® 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 treatment should be discontinued.
The risk of increased pharmacological effects of ranolazine, leading to an increased incidence of adverse reactions in the above groups, is increased in patients with insufficient CYP2D6 activity (patients with slow metabolizers) compared with patients with strong CYP2D6 activity (patients with fast metabolizers) (see section "Pharmacokinetics"). The above precautions are designed to take into account the possible risk in patients with slow CYP2D6 metabolizers and should be taken into account in cases where the CYP2D6 metabolism status is unknown. For patients with fast CYP2D6 metabolizers, these precautions are of less importance. In patients for whom the CYP2D6 extensive metabolism status is determined (e.g. by genotyping) or known, Ranexa® can be used with caution if the patient has a combination of several of the above risk factors.
QT prolongation.
IKr blockade and QTc prolongation are dose-dependent with ranolazine. A population analysis of pooled data from patients and healthy volunteers showed that the plasma concentration-dependent QTc prolongation can be estimated to be 2.4 ms per 1000 ng/ml, which is approximately equivalent to an increase of 2 to 7 ms over the range of ranolazine plasma concentrations from 500 to 1000 mg twice daily. Therefore, caution should be exercised in treating patients with a history of congenital long QT syndrome or a family history of hereditary long QTc or known acquired long QTc, and in patients receiving treatment with drugs that affect the QTc interval (see Interactions with other medicinal products and other forms of interaction).
Interaction with medicines.
Concomitant use with CYP3A4 inducers may result in reduced efficacy of the drug. Ranexa® should not be used in patients receiving treatment with inducers of CYP3A4 activity (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) (see section "Interaction with other medicinal products and other forms of interaction").
Kidney failure.
Renal function declines with age, and therefore it is important to regularly monitor renal function during treatment with ranolazine (see sections 4.2, 4.8, 4.9, 5.1, and 5.2).
Lactose.
Ranexa® 1000 contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium.
This medicine contains less than 1 mmol sodium (23 mg) per prolonged-release tablet, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Pregnancy.
There are limited data on the use of ranolazine in pregnant women. Animal studies have shown embryotoxicity (see section 5.3). The potential risk to humans is unknown. Ranexa® should not be used during pregnancy unless clearly necessary.
Breast-feeding.
It is not known whether ranolazine is excreted in human milk. Available pharmacodynamic/toxicological data from studies in rats indicate that ranolazine is excreted in breast milk (for details, see section 5.3). A risk to the breast-fed child cannot be excluded. Ranexa® should not be used by women during breast-feeding.
Fertility.
Animal studies have not shown any harmful effects of the medicinal product on fertility (see section 5.3). The effect of ranolazine on fertility in humans is unknown.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effects of Ranexa® on the ability to drive and use machines have not been conducted. Ranexa® may cause dizziness, blurred vision, double vision, confusion, incoordination and hallucinations (see section 4.8), which may adversely affect the ability to drive and use machines.
Method of administration and doses
Adults.
The recommended initial dose of Ranexa® is 500 mg twice daily. After 2–4 weeks, the dose may be increased to 1000 mg twice daily if necessary (see section “Pharmacodynamics”). The recommended maximum dose is 1000 mg twice daily. If the patient experiences adverse reactions caused by the use of the drug (e.g. dizziness, nausea, vomiting), the dose of Ranexa® may be reduced (titration). Treatment is discontinued if adverse reactions do not resolve after dose reduction.
Concomitant treatment with CYP3A4 inhibitors and P-gp inhibitors.
Careful dose selection is recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole, erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin) (see sections 4.4 and 4.5).
Concomitant use with potent CYP3A4 inhibitors is contraindicated (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).
Kidney failure.
In patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), careful dose selection is recommended (see sections 4.4, 4.8 and 5.2). Ranexa® is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.3 and 5.2).
Liver failure.
Caution is advised in patients with mild hepatic impairment (see sections 4.4 and 5.2). Ranexa® is contraindicated in patients with moderate to severe hepatic impairment (see sections 4.3 and 5.2).
Elderly patients.
Dose selection for elderly patients should be carried out with caution (see section "Special instructions"). In the elderly, the effect of ranolazine may be increased due to possible age-related decline in renal function (see section "Pharmacokinetics"). Elderly patients have an increased incidence of adverse reactions (see section "Adverse reactions").
Low body weight.
The incidence of adverse reactions is increased in patients with low body weight (≤ 60 kg). Dose selection for patients with low body weight should be carried out with caution (see sections "Special instructions", "Adverse reactions" and "Pharmacokinetics").
Congestive heart failure (CHF).
Dose selection should be carried out with caution in patients with moderate or severe CHF (NYHA classes III-IV) (see sections "Special instructions for use" and "Pharmacokinetics").
Method of application.
Ranexa® extended-release tablets should be swallowed whole, without crushing, breaking, or chewing. The medication can be taken with or without food.
Children
Ranexa® is not recommended for use in children (under 18 years of age) due to insufficient data on safety and efficacy.
Overdose
When studying the tolerability of the increase to
