RAZINE Ranolazine 500mg Extended-release Tablet 1's
RXDRUG-DR-XY37422-1pc
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
Ranolazine is indicated for the treatment of chronic angina. It can also be used as add-on therapy with beta-blocker, nitrates, calcium channel blockers, antiplatelet therapy, lipid lowering therapy, ACE inhibitors and Angiotensin II receptor blockers.
Dosage/Direction for Use
Ranolazine tablets should be swallowed whole and not crushed, broken, or chewed. They may be taken with or without food.
Adults: Ranolazine Extended release tablets dosing should be initiated at 500 mg twice daily and increased to 1000 mg twice daily as needed based on clinical symptoms. The maximum recommended daily dose of ranolazine is 1000 mg twice daily. If a dose of ranolazine is missed, the prescribed dose should be taken at the next scheduled time. The next dose should not be doubled. Ranolazine may be taken with or without meals. Ranolazine tablets should be swallowed whole and not crushed, broken, or chewed. Or as prescribed by the physician.
Elderly: 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.
Patients with Renal and Hepatic Impairment: Careful dose titration is recommended in patients with mild to moderate renal and hepatic impairment (creatinine clearance 30-80 mL/min). Ranolazine is contraindicated in patients with severe renal & hepatic impairment (creatinine clearance <30 mL/min).
Low weight: 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.
Congestive heart failure (CHF): Dose titration in patients with moderate to severe CHF (NYHA Class III-IV) should be exercised with caution.
Pediatric patients: Ranolazine is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
Adults: Ranolazine Extended release tablets dosing should be initiated at 500 mg twice daily and increased to 1000 mg twice daily as needed based on clinical symptoms. The maximum recommended daily dose of ranolazine is 1000 mg twice daily. If a dose of ranolazine is missed, the prescribed dose should be taken at the next scheduled time. The next dose should not be doubled. Ranolazine may be taken with or without meals. Ranolazine tablets should be swallowed whole and not crushed, broken, or chewed. Or as prescribed by the physician.
Elderly: 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.
Patients with Renal and Hepatic Impairment: Careful dose titration is recommended in patients with mild to moderate renal and hepatic impairment (creatinine clearance 30-80 mL/min). Ranolazine is contraindicated in patients with severe renal & hepatic impairment (creatinine clearance <30 mL/min).
Low weight: 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.
Congestive heart failure (CHF): Dose titration in patients with moderate to severe CHF (NYHA Class III-IV) should be exercised with caution.
Pediatric patients: Ranolazine is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
Administration
May be taken with or without food: Swallow whole, do not break/chew/crush.
Contraindications
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, vonconazol, posaconazol, 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.
Special Precautions
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 previously mentioned 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 previously-mentioned risk factors.
QT prolongation: 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 1000 mg 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.
QT prolongation: 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 1000 mg 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.
Use In Pregnancy & Lactation
There are no adequate data from the use of Ranolazine in pregnant women. Animal studies are insufficient with respect to effects on pregnancy and embryofoetal development. The potential risk for humans is unknown. Ranolazine should not be used during pregnancy unless clearly necessary. 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.
Adverse Reactions
Undesirable effects in patients receiving Ranolazine are generally mild to moderate in severity and often develop within the first 2 weeks of treatment. These were reported during the Phase 3 clinical development program, which included a total of 1,030 chronic angina patients treated with Ranolazine.
The adverse events, considered to be at least possibly related to treatment, are listed as follows 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.
Psychiatric disorders: Uncommon: anxiety, insomnia. Rare: disorientation.
Nervous system disorders: Common: dizziness, headache. Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness. Rare: amnesia, depressed level of consciousness, loss of consciousness, parosmia.
Eye disorders: Uncommon: blurred vision, visual disturbance.
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, and epistaxis. Rare: throat tightness.
Gastrointestinal disorders: Common: constipation, vomiting, nausea. Uncommon: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort. Rare: pancreatitis, erosive duodenitis, oral hypoaesthesia.
Skin and subcutaneous tissue disorders: Uncommon: pruritus, hyperhydrosis. Rare: allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders: Uncommon: pain in extremity, muscle cramp, joint swelling.
Renal and urinary disorders: Uncommon: dysuria, haematuria, chromaturia.
Reproductive system and breast disorders: Rare: erectile dysfunction.
General disorders and administration site conditions: Common: asthenia. Uncommon: fatigue, peripheral edema.
Investigations: Uncommon: increased blood creatinine, increased blood urea, prolonged QT corrected interval, increased platelet or white blood cell count, decreased weight. Rare: elevated levels of hepatic enzyme.
The adverse event profile was generally similar in the MERLIN-TIMI 36 study. Evaluations in patients who may be considered at higher risk of adverse events when treated with other anti-anginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or obstructive airway disease, confirmed that these conditions were not associated with clinically meaningful increases in the incidence of adverse events.
Elderly, renal impairment and low weight: In general, adverse events occurred more frequently among elderly patients and patients with renal impairment; however, the types of events in these subgroups were similar to those observed in the general population. Of the most commonly reported, the following events occurred more often with Ranolazine (placebo-corrected frequencies) in elderly (≥75 years of age) than younger patients (<75 years of age): constipation (8% versus 5%), nausea (6% versus 3%), hypotension (5% versus 1%), and vomiting (4% versus 1%).
In patients with mild or moderate renal impairment (creatinine clearance ≥30-80 ml/min) compared to those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reported events and their placebo-corrected frequencies included: constipation (8% versus 4%), dizziness (7% versus 5%), and nausea (4% versus 2%).
In general, the type and frequency of adverse events reported in patients with low body weight (≤60 kg) were similar to those of patients with higher weight (>60 kg); however, the placebo-corrected frequencies of the following common adverse events were higher in low body weight than heavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus 2%).
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.
The adverse events, considered to be at least possibly related to treatment, are listed as follows 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.
Psychiatric disorders: Uncommon: anxiety, insomnia. Rare: disorientation.
Nervous system disorders: Common: dizziness, headache. Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness. Rare: amnesia, depressed level of consciousness, loss of consciousness, parosmia.
Eye disorders: Uncommon: blurred vision, visual disturbance.
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, and epistaxis. Rare: throat tightness.
Gastrointestinal disorders: Common: constipation, vomiting, nausea. Uncommon: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort. Rare: pancreatitis, erosive duodenitis, oral hypoaesthesia.
Skin and subcutaneous tissue disorders: Uncommon: pruritus, hyperhydrosis. Rare: allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders: Uncommon: pain in extremity, muscle cramp, joint swelling.
Renal and urinary disorders: Uncommon: dysuria, haematuria, chromaturia.
Reproductive system and breast disorders: Rare: erectile dysfunction.
General disorders and administration site conditions: Common: asthenia. Uncommon: fatigue, peripheral edema.
Investigations: Uncommon: increased blood creatinine, increased blood urea, prolonged QT corrected interval, increased platelet or white blood cell count, decreased weight. Rare: elevated levels of hepatic enzyme.
The adverse event profile was generally similar in the MERLIN-TIMI 36 study. Evaluations in patients who may be considered at higher risk of adverse events when treated with other anti-anginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or obstructive airway disease, confirmed that these conditions were not associated with clinically meaningful increases in the incidence of adverse events.
Elderly, renal impairment and low weight: In general, adverse events occurred more frequently among elderly patients and patients with renal impairment; however, the types of events in these subgroups were similar to those observed in the general population. Of the most commonly reported, the following events occurred more often with Ranolazine (placebo-corrected frequencies) in elderly (≥75 years of age) than younger patients (<75 years of age): constipation (8% versus 5%), nausea (6% versus 3%), hypotension (5% versus 1%), and vomiting (4% versus 1%).
In patients with mild or moderate renal impairment (creatinine clearance ≥30-80 ml/min) compared to those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reported events and their placebo-corrected frequencies included: constipation (8% versus 4%), dizziness (7% versus 5%), and nausea (4% versus 2%).
In general, the type and frequency of adverse events reported in patients with low body weight (≤60 kg) were similar to those of patients with higher weight (>60 kg); however, the placebo-corrected frequencies of the following common adverse events were higher in low body weight than heavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus 2%).
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.
Drug Interactions
Effects of Other Medicinal Products on Ranolazine: CYP3A4 or P-gp inhibitors: 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, posaconazole, 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, quinidine, 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.
CYP3A4 inducers: 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).
CYP2D6 inhibitors: 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 1000 mg 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%.
Effects of Ranolazine on Other Medicinal Products: 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. Available data suggest that ranolazine is a mild inhibitor of CYP2D6. The exposure of CYP2D6 substrates (e.g. tricyclic antidepressants and antipsychotics) may be increased during co-administration of 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: 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.
Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranolazine 1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid, and the HMG-CoA reductase inhibitor activity by 1.4- to 1.6-fold.
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).
CYP3A4 inducers: 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).
CYP2D6 inhibitors: 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 1000 mg 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%.
Effects of Ranolazine on Other Medicinal Products: 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. Available data suggest that ranolazine is a mild inhibitor of CYP2D6. The exposure of CYP2D6 substrates (e.g. tricyclic antidepressants and antipsychotics) may be increased during co-administration of 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: 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.
Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranolazine 1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid, and the HMG-CoA reductase inhibitor activity by 1.4- to 1.6-fold.
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).
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacology: Pharmacodynamics: The mechanism of action of Ranolazine is largely unknown. Ranolazine may have some anti-anginal 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. These effects do not depend upon changes in heart rate, blood pressure, or vasodilation. Minimal decreases in mean heart rate (<2 beats per minute) and mean systolic blood pressure (<3 mm Hg) were observed in patients treated with Ranolazine either alone or in combination with other anti-anginal medicinal products in controlled studies. Dose and plasma concentration-related increases in the QTc interval (about 6 msec at 1000 mg twice daily), reductions in T wave amplitude, and in some cases notched T waves, have been observed in patients treated with Ranolazine. These effects of Ranolazine on the surface electrocardiogram are believed to result from inhibition of the fast-rectifying potassium current, which prolongs the ventricular action potential, and from inhibition of the late sodium current, which shortens the ventricular action potential. A population analysis of combined data from 1,308 patients and healthy volunteers demonstrated a mean increase in QTc from baseline of 2.4 msec per 1000 ng/ml ranolazine plasma concentration. This value is consistent with data from pivotal clinical studies, where mean changes from baseline in QTcF (Fridericia's correction) after doses of 500 and 750 mg twice daily were 1.9 and 4.9 msec, respectively. The slope is higher in patients with clinically significant hepatic impairment. In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was no difference between Ranolazine and placebo in the risk of all-cause mortality (relative risk Ranolazine: placebo 0.99), sudden cardiac death (relative risk Ranolazine: placebo 0.87), or the frequency of symptomatic documented arrhythmias (3.0% versus 3.1%). No proarrhythmic effects were observed in 3,162 patients treated with Ranolazine based on 7-day Holter monitoring in the MERLIN-TIMI 36 study. There was a significantly lower incidence of arrhythmias in patients treated with Ranolazine (74%) versus placebo (83%), including ventricular tachycardia ≥8 beats (5% versus 8%).
Pharmacokinetics: 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.
Absorption: The mean absolute bioavailability of Ranolazine after oral administration of immediate-release ranolazine tablets ranged from 35-50%, with large interindividual 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 1000 mg 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 x h/ml following a dose of 500 mg twice daily. Food does not affect the rate and extent of absorption of Ranolazine.
Distribution: 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.
Metabolism: 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 is 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 1000 mg twice-daily dose was 25%.
Elimination: 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.
Elderly: Age alone had no clinically relevant effect on pharmacokinetic parameters. However, the elderly may have increased Ranolazine exposure due to age-related decrease in renal function.
Patients with renal impairment: In a study evaluating the influence of renal function on Ranolazine pharmacokinetics, Ranolazine AUC was on average 1.7- to 2-fold higher in subjects with mild, moderate, and severe renal impairment compared with subjects with normal renal function. There was a large inter-individual variability in AUC in subjects with renal impairment. The AUC of metabolites increased with decreased renal function. The AUC of one pharmacologically active ranolazine metabolite was 5-fold increased in patients with severe renal impairment. In the population pharmacokinetic analysis, a 1.2-fold increase in Ranolazine exposure was estimated in subjects with moderate impairment (creatinine clearance 40 ml/min). In subjects with severe renal impairment (creatinine clearance 10-30 ml/min), a 1.3- to 1.8-fold increase in ranolazine exposure was estimated. The influence of dialysis on the pharmacokinetics of Ranolazine has not been evaluated.
Patients with hepatic impairment: The pharmacokinetics of Ranolazine has been evaluated in patients with mild or moderate hepatic impairment. There are no data in patients with severe hepatic impairment. Ranolazine AUC was unaffected in patients with mild hepatic impairment but increased 1.8-fold in patients with moderate impairment. QT prolongation was more pronounced in these patients.
Patients with Lower Body weight: Compared to subjects weighing 70 kg, exposure was estimated to be about 1.4-fold higher in subjects weighing 40 kg.
Patients with CHF: CHF NYHA Class Ill and IV were estimated to have about 1.3-fold higher plasma concentrations.
Pharmacokinetics: 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.
Absorption: The mean absolute bioavailability of Ranolazine after oral administration of immediate-release ranolazine tablets ranged from 35-50%, with large interindividual 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 1000 mg 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 x h/ml following a dose of 500 mg twice daily. Food does not affect the rate and extent of absorption of Ranolazine.
Distribution: 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.
Metabolism: 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 is 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 1000 mg twice-daily dose was 25%.
Elimination: 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.
Elderly: Age alone had no clinically relevant effect on pharmacokinetic parameters. However, the elderly may have increased Ranolazine exposure due to age-related decrease in renal function.
Patients with renal impairment: In a study evaluating the influence of renal function on Ranolazine pharmacokinetics, Ranolazine AUC was on average 1.7- to 2-fold higher in subjects with mild, moderate, and severe renal impairment compared with subjects with normal renal function. There was a large inter-individual variability in AUC in subjects with renal impairment. The AUC of metabolites increased with decreased renal function. The AUC of one pharmacologically active ranolazine metabolite was 5-fold increased in patients with severe renal impairment. In the population pharmacokinetic analysis, a 1.2-fold increase in Ranolazine exposure was estimated in subjects with moderate impairment (creatinine clearance 40 ml/min). In subjects with severe renal impairment (creatinine clearance 10-30 ml/min), a 1.3- to 1.8-fold increase in ranolazine exposure was estimated. The influence of dialysis on the pharmacokinetics of Ranolazine has not been evaluated.
Patients with hepatic impairment: The pharmacokinetics of Ranolazine has been evaluated in patients with mild or moderate hepatic impairment. There are no data in patients with severe hepatic impairment. Ranolazine AUC was unaffected in patients with mild hepatic impairment but increased 1.8-fold in patients with moderate impairment. QT prolongation was more pronounced in these patients.
Patients with Lower Body weight: Compared to subjects weighing 70 kg, exposure was estimated to be about 1.4-fold higher in subjects weighing 40 kg.
Patients with CHF: CHF NYHA Class Ill and IV were estimated to have about 1.3-fold higher plasma concentrations.
MedsGo Class
Anti-Anginal Drugs
Features
Brand
RAZINE
Full Details
Dosage Strength
500 mg
Drug Ingredients
- Ranolazine
Drug Packaging
Extended-Release Tablet 1's
Generic Name
Ranolazine
Dosage Form
Extended-Release Tablet
Registration Number
DR-XY37422
Drug Classification
Prescription Drug (RX)
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