Ranexa® 500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RANEXA® 500 / RANEXA® 1000 (RANEXA® 500 / RANEXA® 1000)

Composition:

Active ingredient: ranolazine;

One 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, polyvinyl alcohol partially hydrolyzed, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), carnauba wax;

One 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), yellow iron oxide (E 172), carnauba wax.

Pharmaceutical form. Extended-release tablets.

Main physicochemical properties:

• 500 mg tablets: light orange, film-coated, oval-shaped, biconvex tablets with "500" embossed on one side, the other side smooth;
• 1000 mg tablets: pale yellow, film-coated, oval-shaped, biconvex tablets with "1000" embossed on one side, the other side smooth.

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 cardiac cells. This reduces intracellular accumulation of sodium and, consequently, decreases excess intracellular calcium ions. By reducing the late sodium current, ranolazine reduces intracellular ionic imbalance during ischemia. This reduction in excess intracellular calcium promotes myocardial relaxation and thus reduces left ventricular diastolic tension. Clinical evidence of ranolazine's inhibition of the late sodium current was demonstrated by a 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 treated with ranolazine alone or in combination with other antianginal drugs, there was a reduction in mean heart rate (< 2 beats/min) and mean systolic blood pressure (< 3 mm Hg).

Electrocardiographic (ECG) effects.

In patients treated with Ranexa®, prolongation of the QTc interval dependent on dose and plasma concentration (approximately 6 ms with 1000 mg twice daily) was observed, along with reduced T-wave amplitude and, in some cases, bifid 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 relative to baseline of 2.4 ms per 1000 ng/mL of ranolazine in plasma. This value corresponds to data obtained from pivotal clinical trials, where mean changes in QTcF (corrected by Fridericia’s formula) compared to baseline after doses of 500 mg and 750 mg twice daily were 1.9 and 4.9 ms, respectively. The slope of the relationship was steeper in patients with clinically significant hepatic impairment.

In the large MERLIN-TIMI 36 study involving 6560 patients with acute coronary syndrome (unstable angina/myocardial infarction without ST-segment elevation), no differences were observed between Ranexa® and placebo regarding all-cause mortality risk (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 Ranexa® treatment during 7-day Holter monitoring, no proarrhythmic effects were recorded. Patients receiving Ranexa® 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 Ranexa® when used as monotherapy for chronic angina, as well as when used in patients with inadequate clinical response to other antianginal medications.

In the pivotal CARISA study, Ranexa® 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 Ranexa® 750 mg twice daily, 1000 mg twice daily, or placebo for 12 weeks. Ranexa® demonstrated superior efficacy compared to placebo in prolonging exercise duration over 12 weeks at both studied doses when used as add-on therapy. However, no difference in exercise duration was observed between the two doses (24 seconds compared to placebo; p ≤ 0.03).

Treatment with Ranexa® 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 frequency 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 angina attack frequency and nitroglycerin use. Due to 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, Ranexa® was added to amlodipine 10 mg once daily (maximum recommended dose). A total of 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. Additionally, 45% of the study population also received long-acting nitrates. Treatment with Ranexa® resulted in a significant reduction in weekly angina attacks (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-finding study—ranolazine was administered as monotherapy. A total of 191 patients were randomized to receive Ranexa® at doses of 500 mg twice daily, 1000 mg twice daily, 1500 mg twice daily, or placebo, each administered for one week in a crossover design. Ranexa® 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, showing a 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. 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 study.

In a large outcome-driven study (MERLIN-TIMI 36) involving 6560 patients with acute coronary syndrome (unstable angina/myocardial infarction without ST-segment elevation), no differences were observed between Ranexa® and placebo regarding all-cause mortality risk (hazard ratio for ranolazine vs. placebo was 0.99), sudden cardiac death due to cardiovascular causes (hazard ratio for ranolazine vs. placebo was 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 showed significant effects of ranolazine on certain 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 the efficacy and safety of the drug in this patient group cannot be made.

In a phase 3, 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. No statistically significant difference was observed between the ranolazine group (26.2%) and the placebo group (28.3%) in the primary composite endpoint (time to ischemia-driven revascularization or hospitalization due to ischemia without revascularization), hazard ratio 0.95, 95% CI 0.82–1.10, p = 0.48. Risk of all-cause mortality, cardiovascular death, major adverse cardiovascular events (MACE), and hospitalization for heart failure was similar across groups; however, serious adverse cardiovascular events were more frequent in patients aged ≥ 75 years receiving ranolazine compared to placebo (17.0% vs. 11.3%, respectively); in addition, 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 of Ranexa®, peak plasma concentration (Cmax) of ranolazine is generally observed within 2–6 hours. At twice-daily dosing, 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 high inter-individual variability. The effect of Ranexa® is dose-dependent. Increasing the dose from 500 mg to 1000 mg twice daily results in a 2.5–3-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 of ranolazine is approximately 7 hours due to absorption rate-limited elimination.

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 demonstrated that ranolazine is primarily metabolized by CYP3A4, and also by CYP2D6. At a dose of 500 mg 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, enhanced effects of ranolazine may occur in elderly patients due to age-related decline in renal function.

Body weight.

The effect of ranolazine in individuals weighing 40 kg is approximately 1.4 times greater than in those weighing 70 kg.

Chronic heart failure (CHF).

NYHA class III–IV CHF leads to an approximately 1.3-fold increase in plasma ranolazine concentration.

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 was 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. 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 was unchanged, whereas in patients with moderate hepatic impairment, AUC was increased 1.8-fold. In these patients, QT interval prolongation was more pronounced.

Children.

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

Preclinical safety data.

Adverse reactions to ranolazine not observed in clinical studies but identified in animals as effects similar to clinical effects include seizures and increased mortality in rats and dogs at plasma ranolazine concentrations approximately 3 times higher than the proposed 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 concentration. Similar changes have not been observed in humans. No effect on the adrenal cortical axis has been observed in humans.

In long-term carcinogenicity studies, no significant increase in tumor incidence of any type was observed in mice at doses up to 50 mg/kg/day (150 mg/m²/day) and in rats at doses 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 and are the maximum tolerated doses for these species.

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

Embryo-fetal toxicity studies were conducted in rats and rabbits. At maternal exposure (AUC) levels similar to those expected in humans, no effects on offspring were observed in rabbits. In rats, at maternal exposure (AUC) levels twice the expected human level, no adverse effects on offspring were observed; however, when maternal exposure was 7.5 times higher than in humans, reduced fetal weight and delayed ossification were observed. When maternal exposure during lactation was 1.3 times higher than expected in humans, no postnatal mortality in offspring was observed; however, at 3-fold higher exposure, postnatal mortality occurred, and ranolazine transfer into rat milk was confirmed. 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 or severe hepatic impairment (see sections "Dosage and administration" and "Pharmacokin游戏副本

Special precautions for use.

Caution should be exercised when prescribing or increasing the dose of ranolazine in patients in whom its effects may be enhanced, such as in the following conditions:

• concomitant use of moderate CYP3A4 inhibitors (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interactions");
• concomitant use of P-gp inhibitors (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interactions");
• 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 "Pharmacokinetics");
• moderate to severe chronic heart failure (NYHA classes III–IV) (see sections "Dosage and administration" and "Pharmacokinetics").

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

The risk of enhanced pharmacological effect of ranolazine, leading to an increased frequency of adverse reactions in the above-mentioned groups, is higher in patients with reduced CYP2D6 activity (poor metabolizers) compared to patients with extensive CYP2D6 activity (extensive metabolizers) (see section "Pharmacokinetics"). The above precautions are designed considering the potential risk for patients who are poor CYP2D6 metabolizers and should be taken into account when the CYP2D6 metabolic status is unknown. For patients who are extensive CYP2D6 metabolizers, these precautions are of less importance. Ranexa® may be used cautiously in patients with known or determined (e.g., by genotyping) extensive CYP2D6 metabolic status, particularly if the patient has a combination of several of the above risk factors.

QT interval prolongation.

IKr blockade and QTc interval prolongation are dose-dependent with ranolazine. A population analysis of pooled data from studies in patients and healthy volunteers showed that the relationship between QTc prolongation and plasma concentration of the drug can be estimated as 2.4 ms per 1000 ng/mL, corresponding to an increase of approximately 2 to 7 ms across the plasma concentration range achieved with doses of 500 to 1000 mg twice daily. Therefore, caution is required when treating patients with a history of congenital long QT syndrome, familial history of long QT syndrome, or known acquired QT prolongation, as well as patients receiving medications that affect QTc interval duration (see section "Interaction with other medicinal products and other forms of interactions").

Drug interactions.

Concomitant use with CYP3A4 inducers may lead to reduced efficacy of the medicinal product. Ranexa® should not be administered to patients receiving treatment with CYP3A4 activity inducers (e.g., rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) (see section "Interaction with other medicinal products and other forms of interactions").

Renal impairment.

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

Lactose.

Ranexa® 1000 contains lactose. The medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption.

Sodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per prolonged-release tablet, i.e., it is practically 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 to humans is unknown. Ranexa® should not be used during pregnancy unless absolutely necessary.

Breastfeeding.

It is unknown whether ranolazine is excreted in human breast milk. Available pharmacodynamic/toxicological data from rat studies indicate that ranolazine is excreted in breast milk (see section "Preclinical safety data" for details). Risk to the breastfed infant cannot be excluded. Ranexa® should not be used in women who are breastfeeding.

Fertility.

Animal studies did not reveal 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 influence the ability to drive and use machines.

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

Method of Administration and Dosage.

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 a patient experiences adverse reactions related to the use of the drug (e.g., dizziness, nausea, vomiting), the dose of Ranexa® may be reduced (titration). Treatment should be discontinued if adverse reactions persist after dose reduction.

Concomitant treatment with CYP3A4 inhibitors and P-gp inhibitors.

Careful dose titration is recommended for patients receiving treatment with 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"). Ranexa® 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"). Ranexa® is contraindicated in patients with moderate to severe hepatic impairment (see sections "Contraindications" and "Pharmacokinetics").

Elderly Patients.

Dose titration should be performed cautiously in elderly patients (see section "Special Warnings and Precautions for Use"). In the elderly, the effect of ranolazine may be enhanced 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 cautiously (see sections "Special Warnings and Precautions for Use", "Adverse Reactions", and "Pharmacokinetics").

Chronic Heart Failure (CHF).

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

Method of Administration.

Ranexa®, prolonged-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.

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

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

Adverse Reactions

Adverse reactions in patients treated with Ranexa® are generally mild to moderate in severity and most commonly 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 Ranexa® therapy.

The adverse reactions associated with the use of the drug, categorized by system organ classes and absolute frequency, are listed below. Frequency was 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, hypoesthesia, somnolence, tremor, postural dizziness, paresthesia.

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

Frequency not known: myoclonus.

Eye disorders.

Uncommon: blurred vision, visual disturbances, diplopia.

Ear and labyrinth disorders.

Uncommon: vertigo, tinnitus.

Rare: hearing decreased.

Vascular disorders.

Uncommon: flushing, hypotension.

Rare: peripheral coldness, orthostatic hypotension.

Respiratory system 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 hypoesthesia.

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 study findings.

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

Rare: increased liver enzymes.

The adverse event profile is generally consistent with that observed in the MERLIN-TIMI 36 study. In this long-term study, acute renal failure was reported with a frequency of less than 1% in both placebo and ranolazine-treated patients. Analyses of patients potentially 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 treated with 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, a higher incidence of congestive heart failure was reported in the ranolazine group compared to placebo (2.2% vs. 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 in patients 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), the following adverse reactions occurred more frequently with Ranexa® (placebo-corrected frequency): 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 patients with normal renal function (creatinine clearance > 80 mL/min), the following adverse reactions occurred more frequently (placebo-corrected frequency): 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 treated with Ranexa®, a slight reversible increase in serum creatinine levels has been observed, which is not clinically significant. This finding was not associated with renal failure. Renal function studies 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 marketing authorization is very important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 5 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

No special storage conditions required. Keep out of the reach of children.

Packaging.

10 tablets in a blister; 6 blisters in a cardboard box; 15 or 20 tablets in a blister, 4 or 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Menarini von Heyden GmbH.

Manufacturer's address.

Leipziger Strasse 7-13, 01097 Dresden, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.