Instructions Ranozin prolonged-release tablets 750 mg blister No. 60
Composition
active ingredient: ranolazine;
1 tablet contains ranolazine 375 mg or 500 mg or 750 mg;
excipients: microcrystalline cellulose, methacrylic acid-ethyl acrylate copolymer (1:1), hypromellose, sodium hydroxide, magnesium stearate;
coating for 375 mg tablets: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, FD&C Blue No. 2 (indigo carmine aluminum lake (E 132), red iron oxide (E 172), carnauba wax;
coating for 500 mg tablets: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), red iron oxide (E 172), carnauba wax;
coating for 750 mg tablets: polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, FD&C Blue No. 1 (brilliant blue (E 133)), FD&C Yellow No. 5 (tartrazine (E 102)), carnauba wax.
Dosage form
Extended-release tablets.
Main physicochemical properties:
375 mg tablets: oval-shaped tablets with a biconvex surface, film-coated, light blue in color with engraving "375" on one side and plain on the other side;
500 mg tablets: oval-shaped tablets with a biconvex surface, film-coated, light pink in color with engraving "500" on one side and smooth on the other side; inclusions are allowed;
750 mg tablets: oblong tablets with a biconvex surface, film-coated in light green color, engraved with "750" on one side and plain on the other side.
Pharmacotherapeutic group
Other cardiological agents. Ranolazine. ATC 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, will reduce left ventricular diastolic stress. Clinical evidence of inhibition of the late influx of sodium by ranolazine was manifested 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 (3 mmHg).
Effects detected by electrocardiography (ECG)
In patients treated with ranolazine, a dose- and plasma concentration-dependent prolongation of the QTc interval (approximately 6 ms at 1000 mg twice daily), a decrease 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 trials, where the mean changes from baseline in QTcF (Friedrichian-corrected) after 500 mg and 750 mg twice daily were 1.9 ms and 4.9 ms, respectively. The slope of the line was higher in patients with clinically significant hepatic impairment.
A large study (MERLIN-TIMI 36) in 6,560 patients with ACS (unstable angina/non-ST-segment elevation myocardial infarction) found no difference between ranolazine 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 ranolazine during 7-day Holter monitoring. Patients treated with ranolazine 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 trial, ranolazine 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 ranolazine 750 mg twice daily, 1000 mg twice daily, or placebo for 12 weeks. Ranolazine was superior to placebo in prolonging exercise tolerance over 12 weeks at both doses studied as add-on therapy. However, there was no difference in exercise tolerance between the two doses (24 seconds vs. placebo; p £ 0.03).
Ranolazine 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 adverse events and similar efficacy at 750 mg and 1000 mg twice daily, the recommended maximum dose is 750 mg twice daily.
In the second ERICA study, ranolazine was added to amlodipine 10 mg once daily (the maximum recommended dose). 565 patients were randomized to receive ranolazine at an initial dose of 500 mg twice daily or placebo for 1 week and then 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. Ranolazine 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 ranolazine 500 mg twice daily, 1000 mg twice daily, 1500 mg twice daily, or placebo, each for 1 week in a crossover design. Ranolazine demonstrated significant superiority over placebo in prolonging exercise tolerance, time to angina attack, and time to 1 mm ST-segment depression at all doses tested; 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, but a disproportionate increase in adverse events was observed. Therefore, the 1500 mg twice daily dose was excluded from further study.
A large, hard-endpoint study (MERLIN-TIMI 36) in 6,560 patients with ACS (unstable angina/non-ST-segment elevation myocardial infarction) found no difference between ranolazine and placebo in the risk of all-cause mortality (ratio of risk for ranolazine to placebo 0.99), sudden cardiac death (ratio of risk for ranolazine to placebo 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. The 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
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). There was also a significant increase in all-cause mortality in patients ≥ 75 years of age (9.2% vs. 5.1%, p = 0.074).
Pharmacokinetics.
After oral administration of ranolazine, the maximum concentration (Cmax) of ranolazine in the blood plasma is usually observed after 2-6 hours. With twice daily administration, steady state is usually achieved within 3 days.
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 ranolazine is dose-dependent. When the dose is increased from 500 mg to 1000 mg twice daily, a 2.5–3-fold increase in the area under the pharmacokinetic curve (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 ranolazine absorption.
Distribution
Ranolazine is approximately 62% bound to plasma proteins, primarily alpha-1 acid glycoprotein and to a lesser extent 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 to 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, after a single oral dose of 500 mg [14C]-ranolazine, approximately 13% of the radioactivity is recovered in plasma.
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 subjects with insufficient CYP2D6 activity (poor metabolizers), the AUC was 62% higher than that in subjects 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 volunteers.
The influence of gender
Gender has no clinical effect on pharmacokinetic parameters.
Elderly patients
Age 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
Pharmacokinetic parameters of ranolazine in children (
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 was associated with an increase in plasma cholesterol levels. 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 AUCs of ranolazine in maternal plasma similar to those expected in humans, no effects on offspring were observed in rabbits. In rats, at AUCs in the mother that were 2 times the expected human exposure, no effects on offspring were observed, but at exposures in the mother that were 7.5 times the expected human exposure, decreased fetal weight and impaired ossification were observed. At exposures in lactating dams that were 1.3 times the expected human exposure, no postnatal mortality of offspring was observed, whereas at exposures 3 times the expected human exposure, postnatal mortality was observed and ranolazine was excreted in rat milk. No adverse reactions in newborn rat offspring were observed at exposure levels similar to those in humans.
Indication
The drug Ranozin® is used alone or in combination therapy for the symptomatic treatment of stable angina, primarily in patients who have not had the proper effect or have developed intolerance to first-line antianginal drugs (beta-blockers and/or calcium antagonists).
Contraindication
- Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
- Severe renal failure (creatinine clearance
- Moderate or severe hepatic impairment.
- Concomitant use of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone).
- 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 and P-gp inhibitors
Ranolazine is a substrate of cytochrome CYP3A4. CYP3A4 inhibitors increase the concentration of ranolazine in the blood plasma. With an increase in its concentration in the blood plasma, 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 2 times a day increases the AUC of ranolazine by 3-3.9 times. The simultaneous use of ranolazine and potent CYP3A4 inhibitors (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 3 times a day) increases the steady-state plasma concentration of ranolazine by 2.2-fold. Careful titration of the dose of Ranozin® is recommended for patients taking P-gp inhibitors. A dose reduction of the drug may be necessary (see sections “Special warnings and precautions for use” and “Dosage and administration”).
CYP3A4 inducers
Rifampicin (600 mg once daily) reduces the steady-state concentrations of ranolazine by approximately 95%. Ranozin® should not be initiated during the use of CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) (see section "Special warnings and precautions for use").
CYP2D6 inhibitors
Ranolazine is partially metabolized by CYP2D6, so inhibitors of this enzyme may increase the concentration of ranolazine in the blood plasma. The potent CYP2D6 inhibitor paroxetine at a dose of 20 mg 1 time per day increases the average equilibrium concentration of ranolazine in the blood plasma by an average of 1.2 times (when using ranolazine 1000 mg 2 times per day). Dose adjustment is not required. At a dose of ranolazine 500 mg 2 times per 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 medicinal products
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. Distribution of drugs transported by P-gp may also be increased.
When prescribing Ranozin®, 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 Ranozin® may increase the concentration of these drugs in the blood plasma.
Available data indicate that ranolazine is a weak inhibitor of CYP2D6. The use of ranolazine 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 (for example, propafenone and flecainide, to a lesser extent tricyclic antidepressants and neuroleptics) may be enhanced, 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 recommended when Ranozin® is used concomitantly with CYP2B6 substrates (e.g., bupropion, efavirenz, cyclophosphamide).
Digoxin
There is evidence of an increase in the concentration of digoxin in blood plasma by an average of 1.5 times when used simultaneously with ranolazine, therefore, it is necessary to monitor digoxin levels at the beginning and end of the use of the drug Ranozin®.
Simvastatin
The metabolism and clearance of simvastatin are largely dependent on CYP3A4. The use of ranolazine 1000 mg 2 times a day increases the plasma concentration of simvastatin lactone and simvastatin acid by approximately 2 times. Also, in the framework of post-marketing surveillance, cases of rhabdomyolysis have been reported in patients taking ranolazine and simvastatin. For patients taking the drug Ranozin® at any dose, the dose of simvastatin should not exceed 20 mg per day.
Atorvastatin
Ranolazine 1000 mg twice daily increases the Cmax and AUC of atorvastatin 80 mg once daily by 1.4 and 1.3 times, respectively, and changes the Cmax and AUC of atorvastatin metabolites by less than 35%. When taking Ranozin®, a dose limitation of atorvastatin and appropriate clinical monitoring may be required.
When taking Ranozin®, it may be necessary to limit the dose of other statins metabolized by CYP3A4 (lovastatin).
Tacrolimus, cyclosporine, sirolimus, everolimus
The use of ranolazine in patients receiving tacrolimus (a CYP3A4 substrate) resulted in an increase in the latter's plasma concentration. When prescribing Ranozin® to patients receiving tacrolimus, it is recommended to monitor the concentration of tacrolimus in the blood plasma and, if necessary, adjust the tacrolimus dose. Such monitoring is also recommended when using other CYP3A4 substrates with a narrow therapeutic range (e.g., cyclosporine, sirolimus, everolimus).
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 increase the potential risk of ventricular arrhythmias. For example, such drugs include some antihistamines (terfenadine, astemizole, mizolastine), some antiarrhythmics (including quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants (e.g. 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 “Interaction with other medicinal products and other types of interactions” and “Method of administration and dosage”);
- simultaneous use of P-gp inhibitors (see sections "Interaction with other medicinal products and other types of interactions" and "Method of administration and dosage");
- mild hepatic insufficiency (see sections "Pharmacokinetics" and "Method of administration and dosage");
- mild or moderate renal insufficiency (creatinine clearance 30–80 ml/min) (see sections “Pharmacokinetics”, “Dosage and administration” and “Adverse reactions”);
- elderly patients (see sections "Pharmacokinetics", "Method of administration and dosage" and "Adverse reactions");
- patients with low body weight (≤ 60 kg) (see sections “Pharmacokinetics”, “Method of administration and dosage” and “Adverse reactions”);
- moderate or severe CHF (NYHA classes III–IV) (see sections “Pharmacokinetics” and “Method of administration and dosage”).
In patients with several of the above factors, an additional increase in effect can be expected. Dose-dependent adverse reactions may occur. When using ranolazine 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 action of ranolazine, leading to an increase in the frequency of adverse reactions in the above groups, is increased in patients with insufficient CYP2D6 activity (patients with slow metabolizers) compared to patients with strong CYP2D6 activity (patients with accelerated metabolizers) (see section "Pharmacokinetics"). The above precautions are designed to take into account the possible risk for patients with slow CYP2D6 metabolism and should be taken into account in cases where the CYP2D6 metabolism status is unknown. For patients with accelerated CYP2D6 metabolism, such precautions are of less importance. In patients for whom the intensive CYP2D6 metabolism status is determined (e.g. by genotyping) or known, the drug Ranozin® should 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 ms to 7 ms over the range of ranolazine plasma concentrations from 500 mg 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).
Drug interactions
Concomitant use with CYP3A4 inducers may lead to a decrease in the effectiveness of the drug. Ranozin® 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 types of interactions").
Kidney failure
Renal function declines with age, therefore it is important to regularly monitor renal function during treatment with ranolazine (see sections "Pharmacokinetics", "Contraindications", "Dosage and Administration" and "Adverse Reactions").
Azo dye E102 (750 mg tablet): the medicinal product contains the azo dye tartrazine E 102, which may cause allergic reactions.
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
Data on the use of ranolazine in pregnant women are limited. Animal studies have shown embryotoxicity (see section "Preclinical safety data"). The potential risk for humans is unknown. The drug Ranozin® should not be used during pregnancy unless clearly necessary.
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 “Preclinical safety data”). A risk to the breast-fed child cannot be excluded. Ranozin® should not be used by women during breastfeeding.
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
No studies on the effects of ranolazine on the ability to drive or use machines have been conducted. Ranolazine may cause dizziness, blurred vision, double vision, confusion, incoordination and hallucinations (see section 4.8), which may adversely affect the ability to drive or use machines.
Method of administration and doses
Adults
The recommended initial dose of Ranozin® is 375 mg twice daily. After 2–4 weeks, the dose may be increased to 500 mg twice daily if necessary, and depending on the patient's response, further increased to the recommended maximum dose of 750 mg twice daily (see section "Pharmacodynamics").
If the patient experiences adverse reactions caused by the use of the drug (e.g. dizziness, nausea, vomiting), the dose of Ranozin® may be reduced to 500 mg or 375 mg 2 times a day. 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 for patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole, erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin) (see sections 4.5 and 4.4).
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 insufficiency (creatinine clearance 30–80 ml/min), careful dose selection is recommended (see sections “Pharmacokinetics”, “Special instructions for use” and “Adverse reactions”). The drug Ranozin® is contraindicated in patients with severe renal insufficiency (creatinine clearance
Liver failure
Careful and cautious dose selection is recommended for patients with mild hepatic impairment (see sections "Pharmacokinetics" and "Special Instructions for Use"). Ranozin® is contraindicated in patients with moderate and severe hepatic impairment (see sections "Pharmacokinetics" and "Contraindications").
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"). An increased frequency of adverse reactions has been recorded in elderly patients (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 "Pharmacokinetics", "Special instructions for use" and "Adverse reactions").
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 "Pharmacokinetics" and "Special warnings and precautions for use").
Method of application
Ranozin® prolonged-release tablets should be swallowed whole, without crushing, breaking or chewing. The medicine can be taken regardless of food intake.
Children.
The safety and effectiveness of ranolazine in children under 18 years of age have not been studied.
Overdose
When studying the
