Ranexa^® (Tablets) Instructions for Use

Marketing Authorization Holder

Menarini International Operations Luxembourg, S.A. (Luxembourg)

Manufactured By

Menarini-Von Heyden, GmbH (Germany)

Contact Information

BERLIN-CHEMIE/MENARINI PHARMA GmbH (Germany)

ATC Code

C01EB18 (Ranolazine)

Active Substance

Ranolazine (Rec.INN registered by WHO)

Dosage Forms

	Ranexa®	Extended-release film-coated tablets, 500 mg: 30, 60, or 100 pcs.
		Extended-release film-coated tablets, 1000 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets light orange in color, biconvex, oval-shaped, with the imprint “500” on one side.

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

Coating composition: Opadry II orange 85F93265 (polyethylene glycol 3350, partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide, yellow iron oxide (E172), red iron oxide (E172), carnauba wax (trace amounts)).

15 pcs. – blister packs (2) – cardboard cartons.
20 pcs. – blister packs (3) – cardboard cartons.
20 pcs. – blister packs (5) – cardboard cartons.

Extended-release film-coated tablets pale yellow in color, biconvex, oval-shaped, with the imprint “1000” on one side.

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

Coating composition: Opadry II yellow 33G92144 (triacetin, hypromellose 6cP, lactose monohydrate, polyethylene glycol 3350, titanium dioxide, yellow iron oxide (E172), carnauba wax).

15 pcs. – blister packs (2) – cardboard cartons.
15 pcs. – blister packs (4) – cardboard cartons.

Clinical-Pharmacological Group

Antianginal drug

Pharmacotherapeutic Group

Anti-anginal agent

Pharmacological Action

Antianginal drug. Ranolazine is an inhibitor of the late sodium current into myocardial cells.

The reduction of intracellular sodium accumulation leads to a decrease in the excess of intracellular calcium ions. This reduces the intracellular ionic imbalance during ischemia. The reduction of excess intracellular calcium promotes myocardial relaxation and, thus, reduces diastolic ventricular wall tension.

Clinical evidence of the inhibition of the late sodium current by ranolazine is a significant shortening of the QTc interval (QTc is the QT interval corrected for heart rate) and a positive effect on diastolic relaxation, identified in an open study involving patients with long QT syndrome (patients with LQT-3 syndrome, having SCN5A ΔKPQ gene mutations). These effects of the drug do not depend on changes in heart rate, blood pressure, or the degree of vasodilation.

The use of ranolazine significantly reduces the frequency of angina attacks per week and the consumption of short-acting nitroglycerin compared to placebo, regardless of patient gender. During treatment, the development of tolerance to ranolazine does not occur. After abrupt discontinuation of the drug, the frequency of angina attacks does not increase.

Ranolazine has a significant advantage over placebo in increasing the time to the onset of angina and the time to 1 mm ST-segment depression when taken at a dose of 500-1000 mg twice daily. The drug significantly improves exercise tolerance. A dose-effect relationship has been recorded for ranolazine: when taken at a higher dose, the antianginal effect was higher than when taken at a lower dose.

When adding ranolazine (1500 mg or 2000 mg per day, divided into two doses, compared to placebo for 12 weeks) to treatment with atenolol 50 mg/day, or amlodipine 5 mg/day, or diltiazem 180 mg/day, the efficacy of Ranexa^® exceeding placebo was proven regarding the duration of performed physical exercise for both studied doses of the drug (24 seconds longer compared to placebo). However, no differences in the duration of tolerable physical exercise were noted between the two doses of Ranexa^®.

Effects detected on ECG in patients treated with Ranexa^® included dose-dependent and plasma concentration-dependent prolongation of the QTc interval (about 6 ms when taking 1000 mg twice daily), a decrease in T-wave amplitude, and, in some cases, notched T waves.

ECG parameters in patients taking Ranolazine are the result of both the drug’s inhibition of the rapid delayed rectifier potassium current, which prolongs the ventricular action potential, and the inhibition of the late sodium current, which shortens the ventricular action potential. Population analysis showed that the use of ranolazine in both patients with stable angina and healthy volunteers leads to a mean QTc prolongation from baseline of 2.4 ms at a ranolazine plasma concentration of 1000 ng/ml. In patients with clinically significant hepatic impairment, the rate of QTc prolongation was higher.

In patients treated with Ranolazine, a significantly lower frequency of arrhythmias was noted compared to placebo, including torsades de pointes ventricular tachycardia ≥8 beats per episode.

Effect on hemodynamics in patients treated with ranolazine as monotherapy or in combination with other antianginal agents, a slight decrease in heart rate (< 2 beats/min) and a decrease in systolic blood pressure (< 3 mm Hg) were noted.

Pharmacokinetics

Absorption

After oral administration of ranolazine, C_max of ranolazine in plasma is typically reached within 2-6 hours. The mean absolute bioavailability of ranolazine after oral administration is 35-50%, with high interindividual variability.

When the dose is increased from 500 to 1000 mg twice daily, a 2.5-3 fold increase in AUC at steady state is observed. When ranolazine is taken twice daily, C_ss is usually achieved within 3 days. In healthy volunteers, C_ss^max is approximately 1770 ng/ml, and AUC_0-12 at steady state averages 13,700 ng×h/ml after taking the drug at 500 mg twice daily. Food intake does not affect the rate and extent of ranolazine absorption.

Distribution

Approximately 62% of ranolazine is bound to plasma proteins, mainly to alpha-1 acid glycoprotein, and to a lesser extent to albumin. The mean V_ss is about 180 L.

Metabolism

Ranolazine undergoes rapid and almost complete metabolism in the liver. The most important pathways of ranolazine metabolism are O-demethylation and N-dealkylation. Ranolazine is metabolized mainly by the CYP3A4 isoenzyme, and also by the CYP2D6 isoenzyme. When taken at 500 mg twice daily, the AUC in people with deficient CYP2D6 isoenzyme activity exceeds that in people with normal metabolic rate by 62%.

A similar difference for the 1000 mg twice daily dose was 25%.

Excretion

Less than 5% of the administered dose of ranolazine is excreted unchanged in urine and feces. The clearance of ranolazine is dose-dependent, decreasing with increasing dose. The T_1/2 of ranolazine at steady state after oral administration is about 7 hours.

Pharmacokinetics in special clinical cases

In chronic heart failure (NYHA functional class III-IV ), the plasma concentration of ranolazine increases approximately 1.3-fold.

In patients with mild, moderate, and severe renal impairment, compared to volunteers with normal renal function, the AUC of ranolazine was on average 1.7-2 times higher. Significant interindividual variability in AUC was noted in volunteers with renal impairment. The AUC of pharmacologically active metabolites increased 5-fold in patients with severe renal impairment. The plasma residence time of ranolazine increases 1.2-fold in patients with moderate renal impairment (CrCl 30-60 ml/min). In patients with severe renal impairment (CrCl<30 ml/min), an increase in the plasma residence time of ranolazine by 1.3-1.8 times was found. The effect of dialysis on the pharmacokinetics of ranolazine has not been evaluated.

The AUC of ranolazine does not change in patients with mild hepatic impairment but increases 1.8-fold in cases of moderate hepatic impairment (7-9 points on the Child-Pugh scale); in such patients, QTc interval prolongation was more pronounced. There is no experience with the use of ranolazine in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale).

Indications

• Stable angina pectoris.

ICD codes

Dosage Regimen

The recommended initial dose of Ranexa^® for adults is 500 mg twice daily. After 2-4 weeks, the dose can be increased to 1000 mg twice daily if necessary. The maximum daily dose is 2000 mg.

If side effects caused by taking Ranexa^® occur (e.g., dizziness, nausea, or vomiting), the single dose should be reduced to 500 mg.

If the symptoms do not disappear after this, the use of the drug should be discontinued.

For patients with chronic heart failure (NYHA functional class III-IV), with mild and moderate renal impairment (CrCl 30-80 ml/min), mild hepatic impairment (5-6 points on the Child-Pugh scale), as well as for patients weighing less than 60 kg and patients over 75 years of age, dose titration is recommended.

Food intake does not affect the bioavailability of the drug, so it can be taken regardless of meals. The tablets should be swallowed whole with a sufficient amount of liquid, without crushing, breaking, or chewing.

Adverse Reactions

Side effects observed in patients taking Ranexa^® are mostly mild to moderate in severity and usually develop within the first 2 weeks of treatment. The following are side effects for which a possible relationship with the use of Ranexa^® has been recognized.

Definition of frequency of adverse reactions: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), and very rare (<1/10,000).

Metabolism and nutrition disorders uncommon – decreased appetite, anorexia, dehydration.

Psychiatric disorders uncommon – anxiety, insomnia, confusion, hallucinations; rare – disorientation.

Nervous system disorders common – dizziness, headache; uncommon – lethargy, syncope, hypoesthesia, somnolence, tremor, postural dizziness; rare – amnesia, confusion, loss of consciousness, parosmia.

Eye disorders uncommon – blurred vision, visual disturbances.

Ear and labyrinth disorders uncommon – vertigo, tinnitus; rare – hearing loss.

Cardiac and vascular disorders uncommon – flushing, pronounced decrease in blood pressure; rare – cold extremities, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, cough, epistaxis; rare – sensation of throat tightness.

Gastrointestinal disorders common – constipation, nausea, vomiting; uncommon – abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort; rare – pancreatitis, erosive duodenitis, oral hypoesthesia.

Skin and subcutaneous tissue disorders uncommon – pruritus, hyperhidrosis; rare – allergic dermatitis, urticaria, cold sweat, skin rash, angioedema.

Musculoskeletal and connective tissue disorders uncommon – pain in extremity, muscle spasms, joint swelling.

Renal and urinary disorders uncommon – dysuria, hematuria, chromaturia; rare – acute renal failure.

Reproductive system and breast disorders rare – erectile dysfunction.

Investigations uncommon – increased blood creatinine, increased blood urea, prolonged corrected QT interval, thrombocytosis and leukocytosis, decreased body weight; rare – increased hepatic enzymes.

General disorders and administration site conditions common – asthenia; uncommon – fatigue, peripheral edema.

Contraindications

• Severe renal impairment (CrCl<30 ml/min);
• Moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment;
• Concomitant use with potent inhibitors of the CYP3A4 isoenzyme (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone);
• Concomitant use with class I A antiarrhythmics (e.g., quinidine) or class III antiarrhythmics (e.g., dofetilide), except for amiodarone; sotalol;
• Children and adolescents under 18 years of age (efficacy and safety of the drug have not been established);
• Pregnancy;
• Breastfeeding period;
• Lactase deficiency, hereditary lactose intolerance, glucose-galactose malabsorption syndrome (for 1000 mg only);
• Hypersensitivity to the components of the drug.

With caution

• Mild hepatic impairment (5-6 points on the Child-Pugh scale);
• Mild or moderate renal impairment (CrCl 30-80 ml/min);
• Age over 75 years;
• Body weight less than 60 kg;
• Chronic heart failure (NYHA functional class III-IV);
• History of congenital long QT syndrome, family history; diagnosed acquired QT prolongation;
• Deficiency of the CYP2D6 isoenzyme;
• Concomitant use with moderate inhibitors of the CYP3A4 isoenzyme (diltiazem, fluconazole, erythromycin);
• Concomitant use with inducers of CYP3A4 isoenzyme activity (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort (Hypericum perforatum);
• Concomitant use with P-glycoprotein inhibitors (verapamil, cyclosporine).

Use in Pregnancy and Lactation

Due to the lack of data, the use of Ranexa^® during pregnancy and breastfeeding is contraindicated.

There are no data on the use of ranolazine in pregnant women.

The penetration of ranolazine into breast milk has not been studied.

Use in Hepatic Impairment

Contraindication: moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment.

For patients with mild hepatic impairment (5-6 points on the Child-Pugh scale), dose titration of the drug is recommended.

Use in Renal Impairment

Contraindication: severe renal impairment (CrCl<30 ml/min).

For patients with mild and moderate renal impairment (CrCl 30-80 ml/min), dose titration of the drug is recommended.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in patients over 75 years of age (dose titration is recommended).

Special Precautions

Ranexa^® is intended for continuous therapy.

For patients with mild or moderate renal impairment (CrCl 30-80 ml/min), dose titration is recommended. Ranexa^® is contraindicated in patients with severe renal impairment (CrCl < 30 ml/min).

For patients with mild hepatic impairment (5-6 points on the Child-Pugh scale), dose titration is recommended. Ranexa^® is contraindicated in patients with moderate (7-9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment.

In elderly patients, the effect of Ranexa^® may be enhanced due to age-related decline in renal function. An increased frequency of side effects is observed.

Dose selection for patients weighing less than 60 kg should be done with caution, as cases of side effects in such patients were observed more frequently.

Chronic heart failure

Dose selection for patients with moderate or severe chronic heart failure (NYHA functional class III-IV) should be done with caution. Frequent monitoring for the development of side effects is necessary; if necessary, the dose of the drug should be reduced or treatment discontinued.

QT interval prolongation

Population analysis of pooled data from studies of patients and healthy volunteers showed that the relationship between QTc interval duration and plasma concentration can be estimated as 2.4 ms per 1000 ng/ml, which approximately corresponds to an increase from 2 to 7 ms for the plasma concentration range corresponding to a dose of 500 to 1000 mg of ranolazine taken twice daily. Therefore, caution should be exercised when treating patients with a history of congenital long QT syndrome, a family history of long QT syndrome, patients with known acquired QT prolongation, and patients receiving treatment with drugs that affect the QT interval.

Insufficient activity of the CYP2D6 isoenzyme

The risk of an increased incidence of adverse effects in the specified groups is higher in patients with insufficient activity of the CYP2D6 isoenzyme (patients with “slow” metabolism) compared to patients with normal metabolizing capacity of the CYP2D6 isoenzyme (patients with “fast” metabolism). Precautions are designed taking into account the risk for patients with “slow” metabolism of the CYP2D6 isoenzyme and are necessary if the metabolic status of the CYP2D6 isoenzyme is unknown. For patients with “fast” metabolism of the CYP2D6 isoenzyme, such precautions are not necessary. In patients with an identified (e.g., by genotyping) or previously known intensive metabolic status of the CYP2D6 isoenzyme, the drug Ranexa^® should be used with caution if the patient has a combination of several of the risk factors listed above.

Effect on the ability to drive vehicles and machinery

No studies have been conducted on the effect of ranolazine on the ability to drive vehicles and operate machinery. Given the possibility of developing adverse effects such as dizziness, blurred vision, confusion, and hallucinations, caution should be exercised when driving vehicles and operating machinery, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms: dizziness, nausea and vomiting, diplopia, lethargy, fainting. Symptoms may increase with increasing dose.

Treatment: symptomatic therapy. Within 30 minutes after taking the drug, measures can be taken to prevent its absorption from the gastrointestinal tract (gastric lavage, use of activated charcoal). Hemodialysis is not very effective.

Drug Interactions

Concomitant use is contraindicated

Potent inhibitors of the CYP3A4 isoenzyme

Ranolazine is a substrate of cytochrome CYP3A4. Concomitant use with inhibitors of the CYP3A4 isoenzyme activity increases the plasma concentration of ranolazine. With an increase in the plasma concentration of the drug, potential dose-dependent adverse effects (e.g., nausea, dizziness) may also be enhanced. Concomitant treatment with ketoconazole 200 mg twice daily increases the AUC of ranolazine by 3-3.9 times.

Concomitant use of ranolazine and potent inhibitors of the CYP3A4 isoenzyme (e.g., itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated.

Grapefruit juice is also a potent inhibitor of the CYP3A4 isoenzyme.

Concomitant use with caution

Moderate inhibitors of the CYP3A4 isoenzyme

Diltiazem (180-360 mg once daily), a moderate inhibitor of the CYP3A4 isoenzyme, causes a dose-dependent increase in the mean C_ss of ranolazine in plasma by 1.5-2.4 times. For patients receiving diltiazem and other moderate inhibitors of the CYP3A4 isoenzyme (e.g., erythromycin, fluconazole), dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary.

Inducers of CYP3A4 isoenzyme activity

Concomitant use of ranolazine with inducers of CYP3A4 isoenzyme activity (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort (Hypericum perforatum)) may lead to a decrease in the drug’s effectiveness. For example, rifampicin (600 mg once daily) reduces the C_ss of ranolazine in plasma by approximately 95%. Therefore, ranolazine should not be initiated in patients receiving treatment with CYP3A4 isoenzyme inducers.

P-glycoprotein inhibitors

Ranolazine is a substrate of P-glycoprotein (Pgp). Pgp inhibitors (e.g., cyclosporine, verapamil) increase the plasma concentration of ranolazine. Verapamil (120 mg three times daily) increases the C_ss of ranolazine by 2.2 times. For patients receiving treatment with Pgp inhibitors, dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary. On the other hand, Ranolazine is a moderate inhibitor of Pgp and a weak inhibitor of the CYP3A4 isoenzyme and may increase the plasma concentration of Pgp or CYP3A4 isoenzyme substrates. Tissue distribution of drugs that are transported by Pgp may be increased.

Substrates of the CYP2D6 isoenzyme

There is evidence that Ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. Administration of ranolazine 750 mg twice daily increases the plasma concentration of metoprolol by 1.8 times. Therefore, when used concomitantly with ranolazine, the effect of metoprolol or other substrates of the CYP2D6 isoenzyme (e.g., propafenone and flecainide, and to a lesser extent, tricyclic antidepressants and antipsychotics) may be enhanced, and therefore a dose reduction of these drugs may be required.

Substrates of the CYP2B6 isoenzyme

The potential for inhibition of the CYP2B6 isoenzyme has not been established. Caution is recommended when co-administered with substrates of the CYP2B6 isoenzyme (e.g., bupropion, efavirenz, cyclophosphamide).

Digoxin

There is evidence of an average 1.5-fold increase in the plasma concentration of digoxin with concomitant use of digoxin and ranolazine. Therefore, monitoring of digoxin levels is necessary at the beginning and after the end of ranolazine therapy.

Substrates of the CYP3A4 isoenzyme

Ranolazine is a weak inhibitor of the CYP3A4 isoenzyme, which may lead to an increase in the plasma concentration of CYP3A4 isoenzyme substrates and require dose adjustment of sensitive CYP3A4 isoenzyme substrates (e.g., simvastatin, lovastatin) and CYP3A4 isoenzyme substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus, everolimus).

Simvastatin

The metabolism and clearance of simvastatin are highly dependent on the CYP3A4 isoenzyme. Administration of ranolazine 1000 mg twice daily increases the concentration of simvastatin lactone, simvastatin acid, which increases HMG-CoA reductase inhibition by 1.4-1.6 times. High-dose simvastatin is associated with the development of rhabdomyolysis, and cases of rhabdomyolysis have also been described with the concomitant use of ranolazine and simvastatin. The maximum dose of simvastatin for patients concomitantly taking Ranolazine should not exceed 20 mg/day. For other statins metabolized by the CYP3A4 isoenzyme (lovastatin), dose limitation may be possible.

Tacrolimus, cyclosporine, sirolimus, everolimus

An increase in the plasma concentration of tacrolimus, a substrate of the CYP3A4 isoenzyme, was noted in patients taking ranolazine. When tacrolimus and ranolazine are used concomitantly, monitoring of tacrolimus plasma concentration is recommended and, if necessary, dose adjustment should be performed. This approach is also recommended for other CYP3A4 isoenzyme substrates with a narrow therapeutic range (e.g., cyclosporine, sirolimus, everolimus).

Drugs that prolong the QT interval

There is a theoretical possibility that when ranolazine is used concomitantly with other drugs that prolong the QT interval, a pharmacodynamic interaction may occur and the risk of ventricular arrhythmias may increase. Such drugs include certain antihistamines (e.g., terfenadine, astemizole, mizolastine), certain antiarrhythmic drugs (e.g., quinidine, disopyramide, procainamide), as well as erythromycin and tricyclic antidepressants (e.g., imipramine, doxepin, amitriptyline).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 4 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.