FORMULATION

Each extended release tablet contains:

Ranolazine…500mg

INDICATIONS

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.

CONTRAINDICATIONS

Hypersensitivity to the active ingredients or any other ingredients in the product. Patients with pre-existing QT prolongation; with hepatic impairment (Child-Pugh Classes A [mild], B [moderate] or C [severe]); patients on QT-prolonging drugs; and on potent and moderately potent CYP3A inhibitors, including diltiazem.

DOSAGE AND ADMINISTRATION

Ranolazine Extended release tablets dosing should be initiated at 500mg twice daily and increased to 1000mg twice daily as needed based on clinical symptoms. The maximum recommended daily dose of Ranolazine is 1000mg 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 not crushed, broken, or chewed.

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

Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000mg b.i.d., the mean steady-state Cmax was 2569ng/mL; 95% of Cmax values were between 420 and 6080ng/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 b.i.d. dosing with Ranolazine. At steady state mover the dose range 500 to 1000mg b.i.d., Cmax and AUC (0-t) increase slightly more than proportionally to dose, 2.2 and 2.4 fold, respectively. With twice daily dosing, the peak/trough ratio of the Ranolazine plasma concentration is 1.6 to 3.0.

Absorption and Distribution

After oral administration of Ranolazine, peak plasma concentrations of Ranolazine are reached between 2 and 5 hours. Because Ranolazine is a substrate of P-glycoprotein (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

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 500mg to 1500mg b.i.d., 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 metabolized mainly by CYP3A and to a lesser extent by CYP2D6.

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).

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 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. 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.

USE IN PREGNANCY AND 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.

CAUTION

Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without a prescription.

STORE AT TEMPERATURES NOT EXCEEDING 30ÎC

AVAILABILITY

Ranolazine (Razine) 500mg Extended Release Tablets X 30 tablets/box in Alu-alu blister