Ranocardum^® (Tablets) Instructions for Use

Marketing Authorization Holder

Argumentum, LLC (Russia)

Manufactured By

Agio Pharmaceuticals, Ltd. (India)

ATC Code

C01EB18 (Ranolazine)

Active Substance

Ranolazine (Rec.INN WHO registered)

Dosage Forms

	Ranocardum®	Prolonged-release film-coated tablets 500 mg: 30, 60, or 100 pcs.
		Prolonged-release film-coated tablets 750 mg: 30, 60, or 100 pcs.
		Prolonged-release film-coated tablets 1000 mg: 30, 60, or 100 pcs.

Dosage Form, Packaging, and Composition

Prolonged-release film-coated tablets orange in color, biconvex, capsule-shaped.

Excipients: methacrylic acid copolymer – 65 mg, microcrystalline cellulose type 102 – 75 mg, hypromellose – 14 mg, sodium hydroxide – 2.5 mg, magnesium stearate – 8.5 mg.

Shell composition: Opadry 04B530005 orange – 18 mg (hypromellose – 9.9 mg, titanium dioxide – 3.942 mg, macrogol – 1.98 mg, talc – 1.8 mg, sunset yellow dye – 0.378 mg, macrogol – 2 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Prolonged-release film-coated tablets orange in color, biconvex, capsule-shaped, with a score on one side.

Excipients: methacrylic acid copolymer – 97.5 mg, microcrystalline cellulose type 102 – 113 mg, hypromellose – 21 mg, sodium hydroxide – 3.75 mg, magnesium stearate – 12.75 mg.

Shell composition: Opadry 04B530005 orange – 27 mg (hypromellose – 14.85 mg, titanium dioxide – 5.913 mg, macrogol – 2.97 mg, talc – 2.7 mg, sunset yellow dye – 0.567 mg, macrogol – 3 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Prolonged-release film-coated tablets orange in color, biconvex, capsule-shaped, with a score on one side.

Excipients: methacrylic acid copolymer – 130 mg, microcrystalline cellulose type 102 – 150 mg, hypromellose – 28 mg, sodium hydroxide – 5 mg, magnesium stearate – 17 mg.

Shell composition: Opadry 04B530005 orange – 36 mg (hypromellose – 19.8 mg, titanium dioxide – 7.884 mg, macrogol – 3.96 mg, talc – 3.6 mg, sunset yellow dye – 0.756 mg, macrogol – 4 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Antianginal drug

Pharmacotherapeutic Group

Anti-anginal agent

Pharmacological Action

Antianginal agent, inhibitor of the late sodium ion 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 tension of the ventricular wall.

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

Ranolazine has a significant advantage over placebo in increasing the time to the onset of an angina attack and to the appearance of 1 mm ST-segment depression when taken at a dose of 500-1000 mg twice daily. It 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.

In patients treated with ranolazine, dose- and plasma concentration-dependent prolongation of the QTc interval (about 6 ms with 1000 mg twice daily), reduction of T-wave amplitude, and, in some cases, biphasic T waves were observed. ECG parameters in patients taking Ranolazine are the result of both inhibition of the potassium current rate, which prolongs the ventricular action potential, and 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 incidence of arrhythmias was noted compared to placebo, including torsades de pointes ventricular tachycardia ≥8 beats per episode.

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

After oral administration of ranolazine, C_max of ranolazine in plasma is usually reached within 2-6 hours. The mean absolute bioavailability of ranolazine after oral administration is 35-50%, with a high degree of individual 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, AUC_0-12 at steady state averages 13,700 ng×h/ml after taking 500 mg twice daily. Food intake does not affect the rate and extent of ranolazine absorption.

Plasma protein binding is about 62%, mainly with alpha-1 acid glycoproteins, and to a lesser extent with albumin. The mean V_ss is about 180 L.

Ranolazine undergoes rapid and almost complete metabolism in the liver. The most important metabolic pathways for ranolazine are O-demethylation and N-dealkylation. Ranolazine is metabolized mainly by the CYP3A4 isoenzyme, as well as by the CYP2D6 isoenzyme. When taking 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%.

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.

Indications

Stable angina pectoris.

ICD codes

Dosage Regimen

Take orally regardless of meals.

The recommended initial dose 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.

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

Adverse Reactions

Cardiovascular system infrequently – flushing, marked decrease in blood pressure; rarely – cold extremities, orthostatic hypotension.

Digestive system frequently – constipation, nausea, vomiting; infrequently – abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort; rarely – pancreatitis, erosive duodenitis, oral hypoesthesia.

Nervous system frequently – dizziness, headache; infrequently – lethargy, syncope, hypoesthesia, drowsiness, tremor, postural dizziness; rarely – amnesia, confusion, loss of consciousness, parosmia.

Psychiatric disorders infrequently – anxiety, insomnia, clouding of consciousness, hallucinations; rarely – disorientation.

Visual system infrequently – blurred vision, visual disturbances.

Hearing and labyrinth disorders infrequently – vertigo, tinnitus; rarely – hearing loss.

Respiratory system infrequently – dyspnea, cough, epistaxis; rarely – sensation of throat tightness.

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

Skin and subcutaneous tissue disorders infrequently – pruritus, hyperhidrosis; rarely – cold sweat, skin rash.

Allergic reactions rarely – allergic dermatitis, urticaria, angioedema.

Musculoskeletal and connective tissue disorders infrequently – limb pain, muscle spasms, joint swelling.

Urinary system disorders infrequently – dysuria, hematuria, chromaturia; rarely – acute renal failure.

Reproductive system and breast disorders rarely – erectile dysfunction.

Investigations infrequently – increased plasma creatinine concentration, increased plasma urea concentration, prolonged corrected QTc interval, thrombocytosis and leukocytosis, weight loss; rarely – increased liver enzyme activity.

General disorders frequently – asthenia; infrequently – fatigue, peripheral edema.

Contraindications

Severe renal failure (CrCl<30 ml/min); moderate (Child-Pugh score 7-9) or severe (more than 9 points on the Child-Pugh scale) hepatic impairment; simultaneous use with potent inhibitors of the CYP3A4 isoenzyme (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone); simultaneous use with class IA antiarrhythmics (e.g., quinidine) or class III antiarrhythmics (e.g., dofetilide), except for amiodarone, with sotalol; children and adolescents under 18 years of age (efficacy and safety of the drug have not been established); pregnancy; lactation (breastfeeding); hypersensitivity to ranolazine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Use with caution in mild hepatic impairment (Child-Pugh score 5-6); mild or moderate renal impairment (CrCl 30-80 ml/min); in patients over 75 years of age; in patients with body weight less than 60 kg; in chronic heart failure (NYHA functional class III-IV); history of congenital long QT syndrome, family history; diagnosed acquired long QT interval; deficiency of the CYP2D6 isoenzyme; simultaneously with moderate inhibitors of the CYP3A4 isoenzyme (diltiazem, fluconazole, erythromycin); simultaneously with inducers of CYP3A4 isoenzyme activity (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort (Hypericum perforatum)); simultaneously with P-glycoprotein inhibitors (verapamil, cyclosporine).

In elderly patients, the effect of ranolazine may be enhanced due to age-related decline in renal function. An increased incidence of adverse effects is noted.

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

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 adverse effects is necessary; if necessary, the drug dose should be reduced or treatment discontinued.

Effect on ability to drive vehicles and operate machinery

Given the possibility of developing adverse effects such as dizziness, blurred vision, confusion, and hallucinations, patients should exercise caution 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.

Drug Interactions

Ranolazine is a substrate of cytochrome CYP3A4. Concurrent use with inhibitors of the CYP3A4 isoenzyme 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 intensify. Concurrent treatment with ketoconazole 200 mg twice daily increases the AUC of ranolazine by 3-3.9 times. Concurrent use of ranolazine and potent inhibitors of the CYP3A4 isoenzyme (including itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated.

Grapefruit juice is also a potent inhibitor 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 reduction in the ranolazine dose may be required.

Concurrent use of ranolazine with inducers of CYP3A4 isoenzyme activity (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) may lead to a decrease in the effectiveness of ranolazine. For example, rifampicin (600 mg once daily) reduces the C_ss of ranolazine in plasma by approximately 95%. Therefore, initiation of ranolazine should be avoided in patients receiving treatment with CYP3A4 isoenzyme inducers.

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 reduction in the ranolazine dose 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 substrates of Pgp or the CYP3A4 isoenzyme. Tissue distribution of drugs that are transported by Pgp may be increased.

There is evidence that Ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. Taking 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, to a lesser extent, tricyclic antidepressants and antipsychotics) may be enhanced, and a dose reduction of these drugs may be required.

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

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

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).

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

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.