Rannova

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RANNOVA (RANNOVA)

Composition:

Active substance: ranolazine;

One prolonged-release tablet contains ranolazine 500 mg or 750 mg;

Excipients: microcrystalline cellulose 101, copolymer of methacrylic acid and ethyl acrylate (1:1), sodium hydroxide, hypromellose E50, magnesium stearate;

Composition of the film coating AquaPolish P White 014.58C: hypromellose E5, hypromellose E15, hydroxypropylcellulose, polyethylene glycol 8000, titanium dioxide (E 171).

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical properties:

• 500 mg tablets: elongated, white or almost white, biconvex tablets, film-coated, with the imprint "500" on one side;
• 750 mg tablets: elongated, white or almost white, biconvex tablets, film-coated, with the imprint "750" on one side.

Pharmacotherapeutic group. Other cardiac preparations. Ranolazine.

ATC code C01EB18.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

The mechanism of action of ranolazine is largely unknown. Ranolazine may exert some antianginal effects by inhibiting the late sodium current into myocardial cells. This reduces intracellular accumulation of sodium and, consequently, decreases excess intracellular calcium ions. By reducing the late sodium current, ranolazine reduces intracellular ion imbalance during ischemia. This reduction in excess intracellular calcium promotes myocardial relaxation and thus reduces diastolic tension of the left ventricle. Clinical evidence of late sodium current inhibition by ranolazine was demonstrated by significant shortening of the QTc interval and improved diastolic relaxation observed in an open-label study involving 5 patients with long QT syndrome (patients with LQT3 syndrome carrying the SCN5A ΔKPQ mutation). These effects of the drug are independent of changes in heart rate, blood pressure, or vasodilation.

Pharmacodynamic effects.

Effects on hemodynamics.

Clinical studies have shown that in patients receiving ranolazine alone or in combination with other antianginal drugs, there was minimal reduction in mean heart rate (< 2 beats/min) and mean systolic blood pressure (< 3 mm Hg).

Electrocardiographic (ECG) effects.

In patients receiving ranolazine, dose- and plasma concentration-dependent prolongation of the QTc interval has been observed (approximately 6 ms with 1000 mg twice daily), reduction in T-wave amplitude, and, in some cases, notched T waves. This effect of ranolazine on ECG parameters is believed to result from inhibition of the rapid rectifier potassium current, which prolongs the ventricular action potential, as well as inhibition of the late sodium current, which shortens the ventricular action potential. Population analysis of pooled data from 1308 patients and healthy volunteers showed a mean QTc prolongation of 2.4 ms relative to baseline per 1000 ng/mL of ranolazine in plasma. This value corresponds to findings from pivotal clinical trials, where mean changes in QTcF (corrected using Fridericia’s formula) from baseline after doses of 500 mg and 750 mg twice daily were 1.9 ms and 4.9 ms, respectively. The slope was steeper in patients with clinically significant hepatic impairment.

In a large study (MERLIN-TIMI 36) involving 6560 patients with acute coronary syndrome (ACS) (unstable angina/non-ST-segment elevation myocardial infarction), no differences were observed between ranolazine and placebo regarding all-cause mortality (relative risk with ranolazine vs. placebo was 0.99), sudden cardiac death (relative risk with ranolazine vs. placebo was 0.87), or incidence of documented symptomatic arrhythmias (3.0% vs. 3.1%).

In the MERLIN-TIMI 36 study, among 3162 patients receiving ranolazine undergoing seven-day Holter monitoring, no proarrhythmic effects were recorded. Patients receiving ranolazine had significantly lower incidence of arrhythmias compared to those receiving placebo (80% vs. 87%), including ventricular tachycardia ≥ 8 beats (5% vs. 8%).

Clinical efficacy and safety.

Clinical studies have demonstrated the efficacy and safety of ranolazine when used as monotherapy for chronic angina, as well as when used in cases of inadequate clinical response to other antianginal medications.

In the pivotal CARISA study, ranolazine was added to therapy with atenolol 50 mg once daily, amlodipine 5 mg once daily, or diltiazem 180 mg once daily. A total of 823 patients (23% women) were randomized to receive ranolazine 750 mg twice daily, 1000 mg twice daily, or placebo for 12 weeks. Ranolazine demonstrated efficacy superior to placebo in prolonging exercise duration over 12 weeks at both studied doses used as add-on therapy. However, no difference in exercise duration was observed between the two dose levels (24 seconds longer than placebo; p ≤ 0.03).

Ranolazine significantly reduced the number of angina attacks per week and the need for short-acting nitroglycerin compared to placebo. Tolerance to ranolazine did not develop during treatment, and no increase in angina attacks was observed after abrupt discontinuation of the drug. Improvement in exercise duration in women was approximately 33% of that observed in men at the dose of 1000 mg twice daily. However, both men and women showed similar reductions in frequency of angina attacks and nitroglycerin use. Given the dose-dependent adverse effects and similar efficacy at doses of 750 mg and 1000 mg twice daily, the recommended maximum dose is 750 mg twice daily.

In the second study, ERICA, ranolazine was added to treatment with amlodipine 10 mg once daily (maximum recommended dose). A total of 565 patients were randomized to receive ranolazine 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. Additionally, 45% of the study population also received long-acting nitrates. With ranolazine, there was a significant reduction in the number of angina attacks per week (p = 0.028) and use of short-acting nitroglycerin (p = 0.014) compared to placebo. Both the mean number of angina attacks and the number of nitroglycerin tablets used decreased by approximately one per week.

In the MARISA study—the main dose-ranging study—ranolazine was administered as monotherapy. A total of 191 patients were randomized into groups receiving ranolazine 500 mg twice daily, 1000 mg twice daily, 1500 mg twice daily, or placebo, each administered for one week in a crossover design. Ranolazine demonstrated significant superiority over placebo in prolonging exercise duration, time to angina onset, and time to 1 mm ST-segment depression at all studied doses, with a clear dose-response relationship. Compared to placebo, exercise duration increased significantly with ranolazine at all three doses, ranging 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 group; however, this was associated with a disproportionate increase in adverse reactions. Therefore, the 1500 mg twice daily dose was excluded from further investigation.

Results from a large outcomes trial (MERLIN-TIMI 36) involving 6560 patients with ACS (unstable angina/non-ST-segment elevation myocardial infarction) showed no differences between ranolazine and placebo regarding all-cause mortality (hazard ratio for ranolazine vs. placebo was 0.99), cardiovascular mortality (hazard ratio 0.87), or incidence of documented symptomatic arrhythmias (3.0% vs. 3.1%) when added to standard medical therapy (including beta-blockers, calcium channel blockers, nitrates, antiplatelets, lipid-lowering agents, and ACE inhibitors). Approximately half of the patients in the MERLIN-TIMI 36 study had a history of angina. Results showed that exercise duration increased by 31 seconds in patients receiving ranolazine compared to those receiving placebo (p = 0.002). The Seattle Angina Questionnaire demonstrated significant effects of ranolazine on several parameters, including frequency of angina attacks (p < 0.001), compared to placebo.

Only a small number of non-Caucasian patients were included in controlled clinical trials; therefore, conclusions regarding efficacy and safety in this patient group cannot be drawn.

In a Phase III, double-blind, placebo-controlled clinical trial (RIVER-PCI) involving 2604 patients aged ≥ 18 years with a history of chronic angina and incomplete revascularization after percutaneous coronary intervention (PCI), the dose was increased to 1000 mg twice daily. In the primary composite endpoint (time to first ischemia-driven revascularization or ischemia-related hospitalization without revascularization), no statistically significant difference was observed 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. All-cause mortality, cardiovascular mortality, incidence of major adverse cardiovascular events (MACE), and hospitalization for heart failure were similar across groups; however, MACE occurred more frequently in patients aged ≥ 75 years receiving ranolazine compared to placebo (17.0% vs. 11.3%, respectively); additionally, a notable increase in all-cause mortality was observed in patients aged ≥ 75 years (9.2% vs. 5.1%, p = 0.074).

Pharmacokinetics.

After oral administration, peak plasma concentration (Cmax) of ranolazine is generally observed within 2–6 hours. At twice-daily dosing, steady state is typically achieved within 3 days.

Absorption.

The mean absolute bioavailability of ranolazine after oral administration of immediate-release tablets is 35–50%, with high inter-individual variability. The effect of ranolazine is dose-dependent. Increasing the dose from 500 mg to 1000 mg twice daily results in a 2.5- to 3-fold increase in steady-state AUC. In a pharmacokinetic study in healthy volunteers, steady-state Cmax averaged approximately 1770 (SD 1040) ng/mL, and steady-state AUC0–12 averaged 13700 (SD 8290) ng × h/mL after administration of 500 mg twice daily. Food intake does not affect the rate or extent of ranolazine absorption.

Distribution.

Approximately 62% of ranolazine is bound to plasma proteins, primarily to alpha-1 acid glycoprotein and weakly to albumin. The mean steady-state volume of distribution (Vss) is approximately 180 L.

Elimination.

Ranolazine is primarily eliminated via metabolism. Less than 5% of the dose is excreted unchanged in urine and feces. After a single oral dose of 500 mg radiolabeled [14C] ranolazine in healthy volunteers, 73% of radioactivity was recovered in urine and 25% in feces. Ranolazine clearance is dose-dependent and decreases with increasing dose. The elimination half-life is approximately 2–3 hours after intravenous administration. The terminal half-life at steady state after oral administration is approximately 7 hours due to rate-limited 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 radioactivity was detected in plasma.

A large number of metabolites have been identified in human plasma (47 metabolites), urine (>100 metabolites), and feces (25 metabolites). Fourteen major metabolic pathways have been identified, with O-demethylation and N-dealkylation being the most important. In vitro studies using human liver microsomes indicate that ranolazine is metabolized primarily by CYP3A4 and also by CYP2D6. After administration of 500 mg ranolazine twice daily, AUC in individuals with reduced CYP2D6 activity (poor metabolizers) exceeds that in individuals with normal CYP2D6 activity (extensive metabolizers) by 62%. The corresponding difference for the 1000 mg twice daily dose was 25%.

Special patient populations.

The impact of various factors on ranolazine pharmacokinetics was evaluated in a population pharmacokinetic study involving 928 patients with angina and healthy individuals.

Effect of sex.

Sex has no clinically relevant effect on pharmacokinetic parameters.

Elderly patients.

Age alone has no clinically relevant effect on pharmacokinetic parameters; however, the effect of ranolazine may be enhanced in elderly patients due to age-related decline in renal function.

Body weight.

The exposure to ranolazine in individuals weighing 40 kg is approximately 1.4 times higher than in those weighing 70 kg.

Heart failure (HF).

NYHA class III–IV heart failure increases plasma ranolazine concentration by approximately 1.3-fold.

Renal impairment.

Studies evaluating the effect of renal function on ranolazine pharmacokinetics have shown that in patients with mild, moderate, or severe renal impairment, ranolazine AUC is on average 1.7–2 times higher than in individuals with normal renal function. There was also considerable inter-individual variability in AUC among subjects with renal impairment. AUC of metabolites increases with declining renal function. The AUC of one of the pharmacologically active metabolites of ranolazine was increased 5-fold in patients with severe renal impairment.

Population pharmacokinetic analysis revealed a 1.2-fold increase in ranolazine exposure in patients with moderate renal impairment (creatinine clearance 40 mL/min). In patients with severe renal impairment (creatinine clearance 10–30 mL/min), ranolazine exposure was increased 1.3–1.8-fold.

The effect of dialysis on ranolazine pharmacokinetics has not been evaluated.

Hepatic impairment.

Ranolazine pharmacokinetics have been evaluated in patients with mild to moderate hepatic impairment. Data on the use of ranolazine in patients with severe hepatic impairment are lacking. In patients with mild hepatic impairment, ranolazine AUC is unchanged, whereas in patients with moderate hepatic impairment, AUC is increased 1.8-fold. In these patients, QT interval prolongation was more pronounced.

Pediatric population.

Pharmacokinetic parameters of ranolazine have not been studied in children (< 18 years).

Preclinical safety data.

Adverse reactions observed in animals at plasma concentrations similar to those in clinical studies, but not observed in clinical trials, include seizures and increased mortality in rats and dogs at ranolazine plasma concentrations approximately 3 times higher than those achieved with the recommended maximum clinical dose.

Chronic toxicity studies in rats showed a treatment-related effect on adrenal glands at exposures slightly exceeding those in clinical patients. This effect is associated with increased plasma cholesterol levels. Similar changes have not been observed in humans. No effect on the adrenal axis has been observed in humans.

In long-term carcinogenicity studies, no significant increase in tumor incidence of any type was observed in mice receiving ranolazine up to 50 mg/kg/day (150 mg/m²/day) or in rats receiving up to 150 mg/kg/day (900 mg/m²/day). These doses represent 0.1 and 0.8 times, respectively, the maximum recommended human dose of 2 g/m²/day and are the maximum tolerated doses for these species.

Oral administration of ranolazine to male and female rats, resulting in AUC increases of 3.6 and 6.6 times, respectively, compared to those expected in humans, had no effect on fertility.

Embryo-fetal toxicity studies were conducted in rats and rabbits. No effects on offspring were observed in rabbits at maternal exposure (AUC) levels similar to those expected in humans. In rats, no adverse effects on offspring were observed at maternal exposure (AUC) levels twice those expected in humans; however, at maternal exposure levels 7.5 times higher than those in humans, reduced fetal weight and delayed ossification were observed. When exposure in lactating females was 1.3 times higher than expected in humans, no postnatal mortality in offspring was observed; however, at threefold higher exposure, postnatal mortality was observed, and ranolazine was shown to be excreted into rat milk. No adverse effects were observed in newborn rat offspring at exposure levels similar to those in humans.

Clinical characteristics.

Indications.

Treatment of stable angina.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section «Composition».
• Severe renal impairment (creatinine clearance < 30 mL/min) (see sections «Dosage and administration» and «Pharmacokinetics»).
• Moderate to severe hepatic impairment (see sections «Dosage and administration» and «Pharmacokinetics»).
• Concomitant use of strong 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 forms of interaction»).
• Concomitant use of class Ia (e.g., quinidine) or class III (e.g., dofetilide, sotalol) antiarrhythmic agents, except amiodarone.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on ranolazine.

CYP3A4 or P-gp inhibitors.

Ranolazine is a substrate of cytochrome CYP3A4. CYP3A4 inhibitors increase plasma concentrations of ranolazine. Increased plasma concentrations may enhance the occurrence of dose-dependent adverse reactions (e.g., nausea, dizziness). During treatment with ranolazine, concomitant administration of ketoconazole 200 mg twice daily increases the AUC of ranolazine by 3–3.9 times. Concomitant use of ranolazine with strong CYP3A4 inhibitors (such as itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated (see section «Contraindications»). Grapefruit juice is also a strong CYP3A4 inhibitor.

Diltiazem (180–360 mg once daily), a moderate CYP3A4 inhibitor, increases dose-dependent steady-state plasma concentrations of ranolazine by 1.5–2.4 times. For patients receiving diltiazem and other moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole), careful and cautious dose titration of RANNOVA is recommended. Dose reduction of RANNOVA may be necessary (see sections «Dosage and administration» and «Special precautions for use»).

Ranolazine is a substrate of P-gp. P-gp inhibitors (e.g., cyclosporine, verapamil) increase plasma levels of ranolazine. Verapamil (120 mg three times daily) increases steady-state plasma concentrations of ranolazine by 2.2 times. For patients receiving P-gp inhibitors, careful dose titration of RANNOVA is recommended. Dose reduction of the medicinal product may be necessary (see sections «Dosage and administration» and «Special precautions for use»).

CYP3A4 inducers.

Rifampicin (600 mg once daily) reduces steady-state concentrations of ranolazine by approximately 95%. Initiation of treatment with RANNOVA should not be started during concomitant use of CYP3A4 inducers (e.g., rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) (see section «Special precautions for use»).

CYP2D6 inhibitors.

Ranolazine is partially metabolized by CYP2D6; therefore, inhibitors of this enzyme may increase plasma concentrations of ranolazine. The strong CYP2D6 inhibitor paroxetine 20 mg once daily increases mean steady-state plasma concentrations of ranolazine by an average of 1.2 times (with ranolazine 1000 mg twice daily). Dose adjustment is not required. With a ranolazine dose of 500 mg twice daily, concomitant use of a strong CYP2D6 inhibitor may increase the AUC of ranolazine by approximately 62%.

Effects of ranolazine on other medicinal products.

Ranolazine is a P-gp inhibitor with moderate to high potency and a weak inhibitor of CYP3A4; therefore, it may increase plasma concentrations of P-gp or CYP3A4 substrates. It may also increase distribution of medicinal products transported by P-gp.

When prescribing RANNOVA, dose adjustment may be required for certain highly sensitive CYP3A4 substrates (e.g., simvastatin, lovastatin) and for CYP3A4 substrates with a narrow therapeutic index (e.g., cyclosporine, tacrolimus, sirolimus, everolimus), since RANNOVA may increase plasma concentrations of these medicinal products.

Available data indicate that ranolazine is a weak inhibitor of CYP2D6. Administration of ranolazine 750 mg twice daily increases plasma concentrations of metoprolol by 1.8 times; therefore, concomitant use may potentiate the effects of metoprolol or other CYP2D6 substrates (e.g., propafenone, flecainide; to a lesser extent tricyclic antidepressants and neuroleptics), which may necessitate dose reduction of these agents.

The potential for CYP2B6 inhibition has not been evaluated. Caution is recommended when using RANNOVA concomitantly with CYP2B6 substrates (e.g., bupropion, efavirenz, cyclophosphamide).

Digoxin.

Data indicate that plasma concentrations of digoxin increase on average by 1.5 times when coadministered with ranolazine; therefore, monitoring of digoxin levels is necessary at the beginning and upon discontinuation of RANNOVA treatment.

Simvastatin.

Metabolism and clearance of simvastatin are largely dependent on CYP3A4. Administration of ranolazine 1000 mg twice daily increases plasma concentrations of simvastatin lactone and simvastatin acid by approximately 2 times. Cases of rhabdomyolysis have also been reported in post-marketing surveillance in patients taking ranolazine and simvastatin. For patients taking RANNOVA at any dose, the dose of simvastatin should not exceed 20 mg daily.

Atorvastatin.

Administration of ranolazine 1000 mg twice daily increases Cmax and AUC of atorvastatin (80 mg once daily) by 1.4 and 1.3 times, respectively, and alters Cmax and AUC of atorvastatin metabolites by less than 35%. When taking RANNOVA, dose limitation of atorvastatin and appropriate clinical monitoring may be required.

Dose limitation of other statins metabolized by CYP3A4 (e.g., lovastatin) may also be necessary when taking RANNOVA.

Tacrolimus, cyclosporine, sirolimus, everolimus.

Administration of ranolazine to patients receiving tacrolimus (a CYP3A4 substrate) resulted in increased plasma concentrations of tacrolimus. When prescribing RANNOVA to patients receiving tacrolimus, monitoring of tacrolimus plasma concentrations is recommended, with dose adjustment as necessary. Such monitoring is also recommended when using other CYP3A4 substrates with a narrow therapeutic index (e.g., cyclosporine, sirolimus, everolimus).

Medicinal products transported by organic cation transporter 2 (OCT2). In patients with type 2 diabetes, administration of ranolazine at doses of 500 mg and 1000 mg twice daily increased plasma concentrations of concomitantly administered metformin (1000 mg twice daily) by 1.4 and 1.8 times, respectively. Plasma concentrations of other OCT2 substrates, including pindolol and varenicline, may be altered to a similar extent.

There is a theoretical risk that concomitant use of ranolazine with other drugs that prolong the QTc interval may result in pharmacodynamic interaction and increased risk of ventricular arrhythmias. Examples include certain antihistamines (e.g., terfenadine, astemizole, mizolastine), certain antiarrhythmic agents (particularly quinidine, disopyramide, procainamide), erythromycin, and tricyclic antidepressants (e.g., imipramine, doxepin, amitriptyline).

Special precautions for use.

Caution should be exercised when initiating or increasing the dose of ranolazine in patients in whom its effects may be enhanced due to the following conditions:

• concomitant use of moderate CYP3A4 inhibitors (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction");
• concomitant use of P-gp inhibitors (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction");
• mild hepatic impairment (see sections "Dosage and administration" and "Pharmacokinetics");
• mild to moderate renal impairment (creatinine clearance 30–80 mL/min) (see sections "Dosage and administration", "Adverse reactions", and "Pharmacokinetics");
• elderly patients (see sections "Dosage and administration", "Adverse reactions", and "Pharmacokinetics");
• patients with low body weight (≤ 60 kg) (see sections "Dosage and administration", "Adverse reactions", and "Pharmacokin游戏副本");
• moderate to severe chronic heart failure (NYHA class III–IV) (see sections "Dosage and administration" and "Pharmacokinetics").

In patients who have several of the above-mentioned factors, further enhancement of the drug effect may be expected. Dose-dependent adverse reactions may occur. When using RANNOVA in patients with a combination of several of the above-mentioned factors, frequent monitoring for adverse reactions is recommended, and the dose of ranolazine should be reduced or treatment discontinued if necessary.

The risk of enhanced pharmacological effect of ranolazine, leading to an increased frequency of adverse reactions in the above-mentioned patient groups, is higher in patients with reduced CYP2D6 activity (poor metabolizers) compared to patients with high CYP2D6 activity (ultrarapid metabolizers) (see section "Pharmacokinetics"). The aforementioned precautions are designed considering the potential risk for patients who are poor CYP2D6 metabolizers and should be applied when the CYP2D6 metabolic status is unknown. These precautions are less relevant for patients who are ultrarapid metabolizers. RANNOVA may be administered cautiously to patients with known or determined (e.g., by genotyping) ultrarapid CYP2D6 metabolism, particularly if the patient has a combination of several of the aforementioned risk factors.

QT interval prolongation.

Dose-dependent blockade of IKr and QTc interval prolongation have been associated with ranolazine. A population analysis of pooled data from studies involving patients and healthy volunteers showed that the concentration-dependent QTc prolongation can be estimated at 2.4 ms per 1000 ng/mL, corresponding approximately to an increase of 2 to 7 ms across the plasma concentration range observed with doses of 500 to 1000 mg twice daily. Therefore, caution is advised when treating patients with a history of congenital long QT syndrome, familial history of prolonged QT interval, known acquired QT prolongation, or those receiving concomitant treatment with medicinal products known to prolong the QTc interval (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with medicinal products.

Concomitant use with CYP3A4 inducers may result in reduced efficacy of the medicinal product. RANNOVA should not be administered to patients receiving treatment with CYP3A4 inducers (e.g., rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment.

Renal function declines with age; therefore, regular monitoring of renal function during ranolazine treatment is important (see sections "Dosage and administration", "Contraindications", "Adverse reactions", and "Pharmacokinetics").

Sodium.

This medicinal product 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 during pregnancy are limited. Animal studies have shown embryotoxicity (see section "Preclinical safety data"). The potential risk in humans is unknown. RANNOVA should not be used during pregnancy except in cases of extreme necessity.

Breastfeeding.

It is unknown whether ranolazine passes into human breast milk. Available pharmacodynamic/toxicological data from rat studies indicate that ranolazine is excreted into milk (see section "Preclinical safety data"). A risk to the breastfed infant cannot be excluded. RANNOVA should not be administered to women who are breastfeeding.

Fertility.

Animal studies have not shown any adverse effect of the medicinal product on fertility (see section "Preclinical safety data"). The effect of ranolazine on human fertility is unknown.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of ranolazine on the ability to drive or operate machinery have not been conducted. RANNOVA may cause dizziness, blurred vision, diplopia, confusion, coordination disturbances, and hallucinations (see section "Adverse reactions"), which may impair the ability to drive or operate machinery.

Dosage and Administration.

Adults.

The recommended initial dose of RANNOVA is 500 mg twice daily. After 2–4 weeks, the dose may be increased, if necessary, to 750 mg twice daily (see section "Pharmacodynamics"). The recommended maximum dose is 1000 mg twice daily. If adverse reactions associated with the use of the medicinal product occur (e.g., dizziness, nausea, vomiting), the dose of RANNOVA may be reduced (titration). Treatment should be discontinued if adverse reactions persist after dose reduction.

Concomitant use with CYP3A4 and P-gp inhibitors.

Careful dose titration is recommended for patients receiving moderate CYP3A4 inhibitors (e.g., diltiazem, fluconazole, erythromycin) or P-gp inhibitors (e.g., verapamil, cyclosporine) (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Concomitant use with strong CYP3A4 inhibitors is contraindicated (see sections "Contraindications" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Renal Impairment.

Careful dose titration is recommended for patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) (see sections "Special Warnings and Precautions for Use", "Adverse Reactions", and "Pharmacokinetics"). RANNOVA is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications" and "Pharmacokinetics").

Hepatic Impairment.

Careful dose titration is recommended for patients with mild hepatic impairment (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). RANNOVA is contraindicated in patients with moderate to severe hepatic impairment (see sections "Contraindications" and "Pharmacokinetics").

Elderly Patients.

Dose titration in elderly patients should be performed with caution (see section "Special Warnings and Precautions for Use"). The effect of ranolazine may be enhanced in the elderly due to possible age-related decline in renal function (see section "Pharmacokinetics"). Elderly patients have an increased frequency of adverse reactions (see section "Adverse Reactions").

Low Body Weight.

The frequency of adverse reactions is increased in patients with low body weight (≤ 60 kg). Dose titration in patients with low body weight should be performed with caution (see sections "Special Warnings and Precautions for Use", "Adverse Reactions", and "Pharmacokinetics").

Chronic Heart Failure (CHF).

Dose titration should be performed with caution in patients with moderate or severe CHF (NYHA classes III–IV) (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Administration.

RANNOVA prolonged-release tablets should be swallowed whole, without crushing, breaking, or chewing. The medicinal product may be taken independently of food intake.

Children.

RANNOVA is not recommended for use in children (under 18 years of age) due to insufficient data on safety and efficacy.

Overdose.

In studies evaluating the tolerability of increased oral doses of ranolazine in patients with angina, the incidence of dizziness, nausea, and vomiting increased in a dose-dependent manner. In studies assessing the effects of intravenous overdose in healthy volunteers, in addition to these adverse events, diplopia, somnolence, and syncope were observed. In case of overdose, close monitoring of the patient is required; symptomatic and supportive therapy is recommended. Since approximately 62% of ranolazine is protein-bound in plasma, complete elimination by hemodialysis is unlikely.

During post-marketing surveillance, cases of intentional ranolazine overdose, administered alone or in combination with other drugs, resulting in fatal outcomes, have been reported.

Adverse Reactions

Adverse reactions in patients taking ranolazine are generally mild to moderate in severity and often occur during the first two weeks of treatment. Data on adverse reactions were obtained from Phase III clinical trials involving 1030 patients with chronic angina who received ranolazine therapy.

The adverse reactions associated with the use of the medicinal product, listed by system organ classes and absolute frequency, are presented below. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Metabolism and nutrition disorders.

Uncommon: anorexia, decreased appetite, dehydration.

Rare: hyponatremia.

Psychiatric disorders.

Uncommon: anxiety, insomnia, confusion, hallucinations.

Rare: disorientation.

Nervous system disorders.

Common: dizziness, headache.

Uncommon: lethargy, syncope, hypesthesia, somnolence, tremor, postural dizziness, paresthesia.

Rare: amnesia, disturbance of consciousness, loss of consciousness, coordination disorder, gait disturbance, parosmia.

Frequency not known: myoclonus.

Eye disorders.

Uncommon: blurred vision, visual disturbances, diplopia.

Ear and labyrinth disorders.

Uncommon: dizziness, tinnitus.

Rare: hearing decreased.

Vascular disorders.

Uncommon: flushing, hypotension.

Rare: peripheral coldness, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnea, cough, epistaxis.

Rare: throat tightness.

Gastrointestinal disorders.

Common: constipation, vomiting, nausea.

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

Rare: pancreatitis, erosive duodenitis, oral hypesthesia.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, hyperhidrosis.

Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash.

Musculoskeletal and connective tissue disorders.

Uncommon: limb pain, muscle spasms, joint swelling, muscle weakness.

Renal and urinary disorders.

Uncommon: dysuria, hematuria, chromaturia.

Rare: acute renal failure, urinary retention.

Reproductive system and breast disorders.

Rare: erectile dysfunction.

General disorders.

Common: asthenia.

Uncommon: fatigue, peripheral edema.

Additional test findings.

Uncommon: increased blood creatinine, increased blood urea, QTc interval prolongation, increased platelet or leukocyte count, weight decreased.

Rare: increased liver enzymes.

The overall adverse event profile is similar to that observed in the MERLIN-TIMI 36 study. In this long-term study, acute renal failure was also reported at a frequency of less than 1% in both placebo and ranolazine groups. Assessments in patients who may be at increased risk for adverse events with other antianginal drugs—such as patients with diabetes, Class I or II heart failure, or obstructive respiratory diseases—confirmed that these conditions were not associated with clinically significant increases in the frequency of adverse events.

An increased frequency of adverse events was observed in patients receiving ranolazine in the RIVER-PCI study (see section "Pharmacodynamics"). In this study, patients with incomplete revascularization after percutaneous coronary intervention received up to 1000 mg of ranolazine twice daily or placebo for 70 weeks. During this study, congestive heart failure was reported more frequently in the ranolazine group (2.2%) compared to the placebo group (1.0%).

Transient ischemic attacks also occurred more frequently in patients receiving 1000 mg of ranolazine twice daily compared to placebo (1.0% vs. 0.2%, respectively); however, the incidence of stroke did not differ between these treatment groups (1.7% in the ranolazine group vs. 1.5% in the placebo group).

Age, renal impairment, and low body weight.

Overall, adverse reactions occurred more frequently in elderly patients and those with renal impairment; however, the types of events in these subgroups were similar to those observed in the general patient population. In elderly patients (≥ 75 years) compared to younger patients (< 75 years), placebo-corrected rates of adverse reactions with ranolazine use were higher for constipation (8% vs. 5%), nausea (6% vs. 3%), hypotension (5% vs. 1%), and vomiting (4% vs. 1%).

In patients with mild to moderate renal impairment (creatinine clearance ≥ 30–80 mL/min) compared to those with normal renal function (creatinine clearance > 80 mL/min), placebo-corrected rates during drug treatment were higher for constipation (8% vs. 4%), dizziness (7% vs. 5%), and nausea (4% vs. 2%).

Generally, the type and frequency of adverse reactions observed in patients with low body weight (≤ 60 kg) were similar to those in patients with higher body weight (> 60 kg). However, in patients with low body weight, the placebo-corrected frequency was higher for common events such as nausea (14% vs. 2%), vomiting (6% vs. 1%), and arterial hypotension (4% vs. 2%).

Laboratory findings.

In healthy volunteers and patients receiving ranolazine, a slight, reversible increase in serum creatinine levels has been observed, which is not clinically significant. This finding was not associated with renal failure. Studies of renal function in healthy volunteers showed reduced creatinine clearance without changes in glomerular filtration rate, consistent with inhibition of renal tubular secretion of creatinine.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

20 tablets in a blister; 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

STADA Arzneimittel AG / STADA Arzneimittel AG;
Adamed Pharma S.A. / Adamed Pharma S.A.

Manufacturer's address and location of business.

Stadastrasse 2-18, 61118 Bad Vilbel, Germany;
ul. Marszalka Jozefa Pilsudskiego 5, Pabianice, 95-200, Poland.