Razine

Ranolazine.

Each film coated extended release tablet contains: Ranolazine 500 mg.

Pharmacology: Pharmacodynamics: Mechanism of Action: 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: Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg 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 1000 mg twice daily, Cmax and AUC0-_T 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: 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.
Metabolism and Excretion: 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.

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, anti-platelet therapy, lipid lowering therapy, ACE inhibitors and Angiotensin II receptor blockers.

Posology: Initiate Ranolazine dosing at 500 mg twice daily and increase 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, take the prescribed dose at the next scheduled time; do not double the next dose.
Dose modification: 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.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Geriatric Use: 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.
Use in Patients with Hepatic Impairment: 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.
Use in Patients with Renal Impairment: 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.
Use in Patients with Heart Failure: 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.
Use in Patients with Diabetes Mellitus: 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.
Method of Administration: Take Ranolazine with or without meals. Swallow Ranolazine tablets whole; do not crush, break, or chew.

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.

Ranolazine is contraindicated in patients: Hypersensitivity to the active substance or to any of the excipients.
Taking strong inhibitors of CYP3A.
Taking inducers of CYP3A.
With clinically significant hepatic impairment.

QT Interval Prolongation: Ranolazine blocks IKr and prolongs that QTc interval in a dose-related manner.
Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death. However, there is little experience with doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval.

Pregnancy: 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 is 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: 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.

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 1000 mg 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 reaction 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 a 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 1000 mg 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 Drugs on Ranolazine: Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp).
CYP3A Inhibitors: 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 concentration 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: Down-titrate Ranolazine based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine.
CYP3A and P-gp Inducers: 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 (1000 mg twice daily) by approximately 95% by induction of CYP3A and, probably, P-gp.
CYP2D6 Inhibitors: 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.
Digoxin: Digoxin (0.125 mg) does not significantly alter ranolazine levels.
Effects of Ranolazine on Other Drugs: 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 of 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: 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 (1000 mg 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 1000 mg twice daily.
Drugs Transported by P-gp: Ranolazine (1000 mg twice daily) causes a 1.5-fold elevation of digoxin plasma concentration. The dose of digoxin may have to be adjusted.
Drugs Metabolized by CYP2D6: Ranolazine or its metabolites partially inhibit CYPD6. 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.

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