Razine

375 mg tablet: Yellow colored, oval shaped, biconvex, film coated, extended-release tablets plain on both sides.
500 mg tablet: Orange colored, oval shaped, biconvex, film coated, extended release tablets debossed with "RZ1" on one side and plain on other side.
Each film coated extended release tablet contains: Ranolazine 375 mg or 500 mg.

Anti-Angina.
Pharmacology: Pharmacodynamics: 375 mg tablet: The mechanism of action of Ranolazine is largely unknown. Ranolazine may have some antianginal effects by inhibition of the late sodium current in cardiac cells. This reduces intracellular sodium accumulation and consequently decreases intracellular calcium overload. Ranolazine, via its action to decrease the late sodium current, is considered to reduce these intracellular ionic imbalances during ischemia. This reduction in cellular calcium overload is expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness. Clinical evidence of inhibition of the late sodium current by Ranolazine is provided by a significant shortening of the QTc interval and an improvement in diastolic relaxation in an open-label study of 5 patients with a long QT syndrome (LQT3 having the SCN5A ΔKPQ gene mutation). These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.
500 mg tablet: The mechanism of action of Ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain. The QT prolongation effect of Ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.
Pharmacokinetics: 375 mg tablet: After oral administration of Ranolazine, peak plasma concentrations (Cmax) are typically observed between 2 and 6 hours. Steady state is generally achieved within 3 days of twice-daily dosing.
500 mg tablet: Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1 g twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of Ranolazine are similar in healthy volunteers. The apparent terminal half-life of Ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with Ranolazine. At steady state over the dose range of 500 to 1 g twice daily, Cmax and AUC0-τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough peak ratio of the Ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of Ranolazine is unaffected by age, gender, or food.
Absorption and Distribution: 375 mg tablet: The mean absolute bioavailability of Ranolazine after oral administration of immediate-release Ranolazine tablets ranged from 35-50%, with large inter-individual variability. Ranolazine exposure increases more than in proportion to dose. There was a 2.5- to 3-fold increase in steady-state AUC as the dose was increased from 500 mg to 1 g twice daily. In a pharmacokinetic study in healthy volunteers, steady-state Cmax was, on average, approximately 1770 (SD 1040) ng/mL, and steady-state AUC0-12 was, on average, 13,700 (SD 8290) ng·hr/mL following a dose of 500 mg twice daily. Food does not affect the rate and extent of absorption of Ranolazine. Approximately 62% of Ranolazine is bound to plasma proteins, mainly alpha-1 acid glycoprotein and weakly to albumin. The mean steady-state volume of distribution (Vss) is about 180 L.
500 mg tablet: After oral administration of Ranolazine, peak plasma concentrations of Ranolazine are reached between 2 and 5 hours. After oral administration of 14C-Ranolazine as a solution, 73% of the dose is systemically available as Ranolazine or metabolites. The bioavailability of Ranolazine from Ranolazine tablets relative to that from a solution of Ranolazine is 76%. Because Ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of Ranolazine. Food (high-fat breakfast) has no important effect on the Cmax and AUC of Ranolazine. Therefore, Ranolazine may be taken without regard to meals. Over the concentration range of 0.25 to 10 μg/mL, Ranolazine is approximately 62% bound to human plasma proteins.
Elimination: 375 mg tablet: Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excreted unchanged in the urine and feces. Following oral administration of a single 500 mg dose of [14C]-Ranolazine to healthy subjects, 73% of the radioactivity was recovered in urine and 25% in feces. Clearance of Ranolazine is dose-dependent, decreasing with increased dose. The elimination half-life is about 2-3 hours after intravenous administration. The terminal half-life at steady state after oral administration of Ranolazine is about 7 hours, due to the absorption rate-limited elimination.
Biotransformation: 375 mg tablet: Ranolazine undergoes rapid and extensive metabolism. In healthy young adults, Ranolazine accounts for approximately 13% of the radioactivity in plasma following a single oral 500 mg dose of [14C]-Ranolazine. A large number of metabolites has been identified in human plasma (47 metabolites), urine (>100 metabolites), and feces (25 metabolites). Fourteen primary pathways have been identified of which O-demethylation and N-dealkylation are the most important. In vitro studies using human liver microsomes indicate that Ranolazine is metabolized primarily by CYP3A4, but also by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolizers, PM) had 62% higher AUC than subjects with CYP2D6 metabolizing capacity (extensive metabolizers, EM). The corresponding difference at the 1 g twice-daily dose was 25%.
Metabolism and Excretion: 500 mg tablet: Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of Ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of Ranolazine, and display apparent half-lives ranging from 6 to 22 hours.
Toxicology: Preclinical Safety Data: 375 mg tablet: Adverse reactions not observed in clinical studies, but seen in animals at levels similar to clinical exposure, were as follows: Ranolazine was associated with convulsions and increased mortality in rats and dogs at plasma concentrations approximately 3-fold higher than at the proposed maximum clinical dose. Chronic toxicity studies in rats indicated that treatment was associated with adrenal changes at exposures slightly greater than those seen in clinical patients. This effect is associated with increased plasma cholesterol concentrations. No similar changes have been identified in humans. No effect on the adreno-cortical axis was noted in humans. In long-term carcinogenicity studies at doses of Ranolazine up to 50 mg/kg/day (150 mg/m²/day) in mice and 150 mg/kg/day (900 mg/m²/day) in rats, no relevant increases in the incidence of any tumor types were seen. These doses are equivalent to 0.1 and 0.8 times, respectively, the maximum recommended human dose of 2 grams on a mg/m² basis, and represent the maximum tolerated doses in these species. Signs of embryonal and maternal toxicity, but not teratogenicity, were seen at doses of Ranolazine up to 400 mg/kg/day (2400 mg/m²/day) in rats and 150 mg/kg/day (1800 mg/m²/day) in rabbits. These doses represent 2.7 and 2 times, respectively, the maximum recommended human dose. Animal studies do not indicate direct or indirect harmful effects of Ranolazine with respect to male or female fertility.
500 mg tablet: Carcinogenesis, Mutagenesis, Impairment of Fertility - Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays. There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m²/day) and 50 mg/kg/day for 24 months in mice (150 mg/m²/day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the maximum recommended human dose (MRHD) of 2 grams on a surface area basis. A published study reported that Ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily. The clinical significance of this finding is unclear; Reproductive Toxicology Studies - Animal reproduction studies with Ranolazine were conducted in rats and rabbits. There was an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones in fetuses of pregnant rats dosed at 400 mg/kg/day (2 times the MRHD on a surface area basis). Reduced ossification of sternebrae was observed in fetuses of pregnant rabbits dosed at 150 mg/kg/day (1.5 times the MRHD on a surface area basis). These doses in rats and rabbits were associated with an increased maternal mortality rate.

375 mg tablet: Ranolazine is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists).
500 mg tablet: Ranolazine is indicated for the treatment of chronic angina. Ranolazine may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

Ranolazine tablets should be swallowed whole and not crushed, broken, or chewed. They may be taken with or without meals.
Posology: 375 mg tablet: The recommended initial dose of Ranolazine is 375 mg twice daily. After 2-4 weeks, the dose should be titrated to 500 mg twice daily and, according to the patient's response, further titrated to a recommended maximum dose of 750 mg twice daily. If a patient experiences treatment-related adverse events (e.g. dizziness, nausea, or vomiting), down-titration of Ranolazine to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after dose reduction, treatment should be discontinued.
500 mg tablet: Initiate Ranolazine dosing at 500 mg twice daily and increase to 1 g twice daily, as needed, based on clinical symptoms. The maximum recommended daily dose of Ranolazine is 1 g twice daily. If a dose of Ranolazine is missed, take the prescribed dose at the next scheduled time; do not double the next dose. Or as prescribed by the physician.
Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors: 375 mg tablet: Careful dose titration is recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole, and erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin). Concomitant administration of potent CYP3A4 inhibitors is contraindicated.
Dose Modification: 500 mg tablet: Dose adjustments may be needed when Ranolazine is taken in combination with certain other drugs. Limit the maximum dose of Ranolazine to 500 mg twice daily in patients on diltiazem, verapamil, and other moderate CYP3A inhibitors. Down-titrate Ranolazine based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine.
Geriatric Use: 375 mg tablet: Dose titration in elderly patients should be exercised with caution. Elderly may have increased Ranolazine exposure due to age-related decrease in renal function. The incidence of adverse events was higher in the elderly.
500 mg tablet: In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy.
Pediatric Use: 375 mg tablet: The safety and efficacy of Ranolazine in children below the age of 18 years have not been established. Ranolazine is not recommended in patients below the age of 18 years.
500 mg tablet: Safety and effectiveness have not been established in pediatric patients.
Low weight: 375 mg tablet: The incidence of adverse events was higher in patients with low weight (≤60 kg). Dose titration in patients with low weight should be exercised with caution.
Patients with Renal Impairment: 375 mg tablet: Careful dose titration is recommended in patients with mild to moderate renal impairment (creatinine clearance 30-80 mL/min). Ranolazine is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min).
500 mg tablet: In patients with varying degrees of renal impairment, Ranolazine plasma levels increased up to 50%. The pharmacokinetics of Ranolazine has not been assessed in patients on dialysis.
Patients with Hepatic Impairment: 375 mg tablet: Careful dose titration is recommended in patients with mild hepatic impairment. Ranolazine is contraindicated in patients with moderate or severe hepatic impairment.
500 mg tablet: Ranolazine is contraindicated in patients with clinically significant hepatic impairment. Plasma concentrations of Ranolazine were increased by 30% in patients with mild (Child-Pugh Class A) and by 60% in patients with moderate (Child-Pugh Class B) hepatic impairment. This was not enough to account for the 3-fold increase in QT prolongation seen in patients with mild to severe hepatic impairment.
Patients with Heart Failure: 375 mg tablet: Dose titration in patients with moderate to severe CHF (NYHA Class III-IV) should be exercised with caution.
500 mg tablet: Heart failure (NYHA Class I to IV) had no significant effect on Ranolazine pharmacokinetics. Ranolazine had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of Ranolazine is required in patients with heart failure.
Patients with Diabetes Mellitus: 500 mg tablet: A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on Ranolazine pharmacokinetics. No dose adjustment is required in patients with diabetes. Ranolazine produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. Ranolazine should not be considered a treatment for diabetes.

375 mg tablet: In an oral high-dose tolerability study in angina patients, the incidence of dizziness, nausea, and vomiting increased in a dose-dependent manner. In addition to these adverse events, diplopia, lethargy, and syncope were observed in an intravenous overdose study in healthy volunteers. In the event of overdose, the patient should be closely monitored and the treatment should be symptomatic and supportive. Approximately 62% of Ranolazine is bound to plasma proteins, and therefore, complete clearance by hemodialysis is unlikely.
500 mg tablet: High oral doses of Ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope. In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Since Ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing Ranolazine.

375 mg tablet: Hypersensitivity to Ranolazine. Severe renal impairment (creatinine clearance <30 mL/min). Moderate or severe hepatic impairment. Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone). Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol) antiarrhythmics other than amiodarone.
500 mg tablet: Ranolazine is contraindicated in patients with Hypersensitivity to the active substance or to any of the excipients, patients taking strong inhibitors of CYP3A, patients taking inducers of CYP3A and patients with clinically significant hepatic impairment.

375 mg tablet: Caution should be exercised when prescribing or up-titrating Ranolazine to patients in whom an increased exposure is expected; concomitant administration of moderate CYP3A4 inhibitors; concomitant administration of P-gp inhibitors; mild hepatic impairment; mild to moderate renal impairment (creatinine clearance 30-80 mL/min); elderly; patients with low weight (≤60 kg); patients with moderate to severe CHF (NYHA Class III-IV). In patients with a combination of these factors, additional exposure increases are expected. Dose-dependent side effects are likely to occur. If Ranolazine is used in patients with a combination of several of these factors, monitoring of adverse events should be frequent, the dose reduced, and treatment discontinued, if needed. The risk for increased exposure leading to adverse events in these different subgroups is higher in patients lacking CYP2D6 activity (poor metabolizers, PM) than subjects with CYP2D6 metabolizing capacity (extensive metabolizers, EM). The above precautions are based on the risk in a CYP2D6 PM patient, and are needed when the CYP2D6 status is unknown. There is a lower need for precautions in patients with CYP2D6 EM status. If the CYP2D6 status of the patient has been determined (e.g. by genotyping) or is previously known to be EM, Ranolazine can be used with caution in these patients when they have a combination of several of the above risk factors.
QT Interval Prolongation: 375 mg tablet: A population-based analysis of combined data from patients and healthy volunteers demonstrated that the slope of the plasma concentration-QTc relationship was estimated to be 2.4 msec per 1000 ng/mL, which is approximately equal to a 2- to 7-msec increase over the plasma concentration range for Ranolazine 500 to 1 g twice daily. Therefore, caution should be observed when treating patients with a history of congenital or a family history of long QT syndrome, in patients with known acquired QT interval prolongation, and in patients treated with drugs affecting the QTc interval.
500 mg tablet: Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of pro-arrhythmia or sudden death. However, there is little experience with high doses (>1 g twice daily) or exposure, other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval.
Drug-drug interactions: 375 mg tablet: Co-administration with CYP3A4 inducers is expected to lead to lack of efficacy. Ranolazine should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort).
Patients with Renal impairment: 375 mg tablet: Renal function decreases with age and it is therefore important to check renal function at regular intervals during treatment with Ranolazine.
Effects on Ability to Drive and Use Machine: No studies on the effects of Ranolazine on the ability to drive and use machines have been performed. Ranolazine may cause dizziness, blurred vision, diplopia, confusional state, and abnormal coordination, hallucination, which may affect the ability to drive and use machines.

Pregnancy: 375 mg tablet: There are no adequate data from the use of Ranolazine in pregnant women. Animal studies are insufficient with respect to effects on pregnancy and embryofetal. The potential risk for humans is unknown. Ranolazine should not be used during pregnancy unless clearly necessary.
500 mg tablet: Pregnancy Category C: In animal studies, Ranolazine at exposures 1.5 (rabbit) to 2 (rat) times the usual human exposure caused maternal toxicity and misshapen sternebrae and reduced ossification in offspring. These doses in rats and rabbits were associated with an increased maternal mortality rate. There are no adequate well-controlled studies in pregnant women. Ranolazine should be used during pregnancy only when the potential benefit to the patient justifies the potential risk to the fetus.
Nursing Mothers: 375 mg tablet: It is unknown whether Ranolazine is excreted in human breast milk. The excretion of Ranolazine in milk has not been studied in animals. Ranolazine should not be used during breast-feeding.
500 mg tablet: It is not known whether Ranolazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Ranolazine in nursing infants, decide whether to discontinue nursing or to discontinue Ranolazine, taking into account the importance of the drug to the mother.

375 mg tablet: Undesirable effects in patients receiving Ranolazine are generally mild to moderate in severity and often develop within the first 2 weeks of treatment. The adverse events, considered to be at least possibly related to treatment, are listed below by body system, organ class, and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000).
Metabolism and nutrition disorders: Uncommon: anorexia, decreased appetite, dehydration.
Rare: hyponatremia.
Psychiatric disorders: Uncommon: anxiety, insomnia, confusional state, hallucination.
Rare: disorientation.
Nervous system disorders: Common: dizziness, headache.
Uncommon: lethargy, syncope, hypoesthesia, somnolence, tremor, postural dizziness, paresthesia.
Rare: amnesia, depressed level of consciousness, loss of consciousness, abnormal coordination, gait disturbance, parosmia.
Eye disorders: Uncommon: blurred vision, visual disturbance, and diplopia.
Ear and labyrinth disorders: Uncommon: vertigo, tinnitus.
Rare: impaired hearing.
Vascular disorders: Uncommon: hot flush, 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 hypoesthesia.
Skin and subcutaneous tissue disorders: Uncommon: pruritus, hyperhidrosis.
Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders: Uncommon: pain in extremity, muscle cramp, joint swelling, muscular 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 and administration site conditions: Common: asthenia.
Uncommon: fatigue, peripheral edema.
Laboratory findings: Small, clinically insignificant, reversible elevations in serum creatinine levels have been observed in healthy subjects and patients treated with Ranolazine. There was no renal toxicity related to these findings. A renal function study in healthy volunteers demonstrated a reduction in creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal tubular secretion of creatinine.
500 mg tablet: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2,018 patients with chronic angina were treated with Ranolazine in controlled clinical trials. Of the patients treated with Ranolazine, 1,026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks duration. In addition, upon study completion, 1,251 patients received treatment with Ranolazine in open-label, long-term studies; 1,227 patients were exposed to Ranolazine for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years. At recommended doses, about 6% of patients discontinued treatment with Ranolazine because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on Ranolazine than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1 g twice daily are poorly tolerated. In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions (>4% and more common on Ranolazine than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction profile was observed. The following additional adverse reactions occurred at an incidence of 0.5 to 2.0% in patients treated with Ranolazine and were more frequent than the incidence observed in placebo-treated patients: Cardiac Disorders: bradycardia, palpitations.
Ear and Labyrinth Disorders: tinnitus, vertigo.
Gastrointestinal Disorders: abdominal pain, dry mouth, vomiting.
General Disorders and Administrative Site Adverse Events: peripheral edema.
Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.
Vascular Disorders: hypotension, orthostatic hypotension.
Other (<0.5%) but potentially medically important adverse reactions observed more frequently with Ranolazine than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, blurred vision, confusional state, hematuria, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia. A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for Ranolazine, but there was no apparent proarrhythmic effect in these high-risk patients.
Laboratory Abnormalities: Ranolazine produces small reductions in hemoglobin A1c. Ranolazine is not a treatment for diabetes. Ranolazine produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function. The elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of Ranolazine, and is not accompanied by changes in BUN. In healthy volunteers, Ranolazine 1 g twice daily had no effect upon the glomerular filtration rate. The elevated creatinine levels are likely due to a blockage of creatinine's tubular secretion by Ranolazine or one of its metabolites.

Effects of Other Medicinal Products on Ranolazine: 500 mg tablet: Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp).
CYP3A4 or P-gp inhibitors: 375 mg tablet: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4 increase plasma concentrations of Ranolazine. The potential for dose-related adverse events (e.g. nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment with ketoconazole 200 mg twice daily increased the AUC of Ranolazine by 3.0- to 3.9-fold during Ranolazine treatment. Combining Ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, parconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated. Grapefruit juice is also a potent CYP3A4 inhibitor. Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent increases in average Ranolazine steady-state concentrations of 1.5- to 2.4-fold. Careful dose titration of Ranolazine is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranolazine may be required. Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasma levels of Ranolazine. Verapamil (120 mg three times daily) increases Ranolazine steady-state concentrations 2.2-fold. Careful dose titration of Ranolazine is recommended in patients treated with P-gp inhibitors. Down-titration of Ranolazine may be required.
CYP3A: 500 mg tablet: Do not use Ranolazine with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of Ranolazine 3.2-fold. Limit the dose of Ranolazine to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products. Diltiazem (180-360 mg daily) and verapamil (120 mg three times daily) increase Ranolazine steady-state plasma concentrations about 2-fold. Weak CYP3A inhibitors such as simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to Ranolazine in healthy volunteers.
P-gp inhibitors: 500 mg tablet: Down-titrate Ranolazine based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine.
CYP3A4 inducers: 375 mg tablet: Rifampicin (600 mg once daily) decreases Ranolazine steady-state concentrations by approximately 95%. Initiation of treatment with Ranolazine should be avoided during administration of inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort).
CYP3A and P-gp Inducers: 500 mg tablet: Avoid co-administration of Ranolazine and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort. Rifampin (600 mg once daily) decreases the plasma concentration of Ranolazine (1 g twice daily) by approximately 95% by induction of CYP3A and, probably, P-gp.
CYP2D6 Inhibitors: 375 mg tablet: Ranolazine is partially metabolized by CYP2D6; therefore, inhibitors of this enzyme may increase plasma concentrations of Ranolazine. The potent CYP2D6 inhibitor paroxetine, at a dose of 20 mg once daily, increased steady-state plasma concentrations of Ranolazine 1 g twice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twice daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in Ranolazine AUC of about 62%.
500 mg tablet: The potent CYP2D6 inhibitor, paroxetine (20 mg once daily), increases Ranolazine concentrations 1.2-fold. No dose adjustment of Ranolazine is required in patients treated with CYP2D6 inhibitors.
Effects of Ranolazine on other medicinal products: 375 mg tablet: Ranolazine is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which are transported by P-gp may be increased. Dose adjustment of sensitive CYP3A4 substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, tacrolimus, sirolimus, everolimus) may be required as Ranolazine may increase plasma concentrations of these drugs. Available data suggest that Ranolazine is a mild inhibitor of CYP2D6. Ranolazine 750 mg twice daily increased plasma concentrations of metoprolol by 1.8-fold. Therefore, the exposure to metoprolol or other CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased during co-administration with Ranolazine, and lower doses of these medicinal products may be required. The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).
Digoxin: 375 mg tablet: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported when Ranolazine and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of Ranolazine therapy.
500 mg tablet: Digoxin (0.125 mg) does not significantly alter Ranolazine levels.
Simvastatin: 375 mg tablet: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranolazine 1 g twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid by about 2 folds. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranolazine and simvastatin, in post-marketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranolazine.
Atorvastatin: 375 mg tablet: Ranolazine 1 g twice daily increased Cmax and AUC of atorvastatin 80 mg once daily by 1.4- and 1.3-fold, respectively and changed the Cmax and AUC of atorvastatin metabolites less than 35%. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered when taking Ranolazine. Dose limitation of other statins, metabolized by CYP3A4 (e.g. lovastatin), may be considered when taking Ranolazine.
Tacrolimus, ciclosporin, sirolimus, everolimus: 375 mg tablet: Increased plasma concentrations of tacrolimus, a CYP3A4 substrate, have been observed in patients after Ranolazine administration. It is recommended that tacrolimus blood levels are monitored when co-administering Ranolazine and tacrolimus and that tacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, sirolimus, everolimus).
Drugs transported by the Organic Cation Transporter-2 (OCT2): 375 mg tablet: Plasma exposure of metformin (1 g twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when co-administered with Ranolazine 500 mg and 1 g twice daily, respectively. The exposure of other OCT2 substrates, including but not limited to pindolol and varenicline, may be affected to a similar degree. There is a theoretical risk that concomitant treatment of Ranolazine with other drugs known to prolong the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin, and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).
Effects of Ranolazine on Other Drugs: 500 mg tablet: In vitro studies indicate that Ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. Ranolazine and its most abundant metabolites are not known to inhibit the metabolism of substrates for CYP 1A2, 2C8, 2C9, 2C19, or 2E1 in human liver microsomes, suggesting that Ranolazine is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
Drugs Metabolized by CYP3A: 500 mg tablet: The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each increased about 2-fold in healthy subjects receiving simvastatin (80 mg once daily) and Ranolazine (1 g twice daily). Dose adjustments of simvastatin are not required when Ranolazine is co-administered with simvastatin. The pharmacokinetics of diltiazem is not affected by Ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and Ranolazine 1 g twice daily.
Drugs Transported by P-gp: 500 mg tablet: Ranolazine (1 g twice daily) causes a 1.5-fold elevation of digoxin plasma concentrations. The dose of digoxin may have to be adjusted.
Drugs Metabolized by CYP2D6: 500 mg tablet: Ranolazine or its metabolites partially inhibit CYP2D6. There are no studies of concomitant use of Ranolazine with other drugs metabolized by CYP2D6, such as tricyclic antidepressants and antipsychotics, but lower doses of CYP2D6 substrates may be required.

Store at temperatures not exceeding 30°C.

Anti-Anginal Drugs

C01EB18 - ranolazine ; Belongs to the class of other cardiac preparations.

Rx