RANEXA Ranolazine 375mg Prolonged Release Tablet 1's

Ranolazine (Ranexa) 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 1st-line antianginal therapies (eg, β-blockers and/or calcium antagonists).

 

Patients should be given the Ranexa package leaflet and the Patient Alert Card and instructed to present their Patient Alert Card and medication list to their health care professional at each visit.
Adults: The recommended initial dose of Ranexa 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 (Ranexa) to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after dose reduction, treatment should be discontinued.
Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors: Careful dose titration is recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole, erythromycin) or P gp inhibitors (e.g. verapamil, ciclosporin).
Concomitant administration of potent CYP3A4 inhibitors is contraindicated: Renal impairment: Careful dose titration is recommended in patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min). Ranexa is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min).
Hepatic impairment: Careful dose titration is recommended in patients with mild hepatic impairment. Ranolazine (Ranexa) is contraindicated in patients with moderate or severe hepatic impairment.
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.
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 Ill-IV) should be exercised with caution.
Paediatric population: The safety and efficacy of Ranolazine (Ranexa) in children below the age of 18 years have not been established.
No data are available.
Method of administration: Ranolazine (Ranexa) tablets should be swallowed whole and not crushed, broken, or chewed. They may be taken with or without food.

 

Overdosage

May be taken with or without food: Swallow whole, do not break/chew/crush.

Hypersensitivity to the active substance or to any of the excipients listed.
Severe renal impairment (creatinine clearance < 30 ml/min).
Moderate or severe hepatic impairment.
Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone).
Concomitant administration of Class la (e.g. quinidine) or Class Ill (e.g. dofetilide, sotalol) antiarrhythmics other than amiodarone.

Caution should be exercised when prescribing or uptitrating ranolazine to patients in whom an increased exposure is expected: Concomitant administration of moderate CYP3A4 inhibitors and P-gp inhibitors; mild hepatic impairment; mild to moderate renal impairment (CrCl 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 Ranexa 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 (eg, by genotyping) or is previously known to be EM, Ranexa 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 1,000 ng/mL, which is approximately equal to a 2- to 7-msec increase over the plasma concentration range for ranolazine 500-1,000 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.
Drug-Drug Interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of efficacy. Ranexa should not be used in patients treated with CYP3A4 inducers (eg, rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort).
Renal Impairment: Renal function decreases with age and it is therefore important to check renal function at regular intervals during treatment with ranolazine.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects of Ranexa on the ability to drive and use machines have been performed. Ranexa may cause dizziness, blurred vision, diplopia, confusional state, abnormal coordination, hallucination, which may affect the ability to drive and use machines.
Impairment of Fertility: In animals, reproduction studies indicated no adverse effects on fertility. The effect of ranolazine on human fertility is unknown.
Use in pregnancy: 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 development. The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly necessary.
Use in lactation: It is unknown whether ranolazine is excreted in human breast milk. The excretion of ranolazine in milk has not been studied in animals. Ranexa should not be used during breastfeeding.
Use in children: The safety and efficacy of Ranexa in children <18 years have not been established. No data are available.

 

Use In Pregnancy & Lactation

Undesirable effects in patients receiving Ranexa 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 Ranexa.
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, 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, coordination abnormal, gait disturbance, parosmia.
Eye Disorders: Uncommon: Blurred vision, visual disturbance, 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. Rare: 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.
Investigations: Uncommon: Increased blood creatinine, blood urea and platelet or white blood cell count; prolonged QT-corrected interval, decreased weight.
Rare: Elevated levels of hepatic enzyme.
The adverse event profile was generally similar in the MERLIN-TIMI 36 study. In this long-term study, acute renal failure was also reported with an incidence <1% in placebo and ranolazine patients. Evaluations in patients who may be considered at higher risk of adverse events when treated with other antianginal medicinal products eg, 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 Ranexa (placebo-corrected frequencies) in elderly (≥75 years) than younger patients (<75 years): Constipation (8% vs 5%), nausea (6% vs 3%), hypotension (5% vs 1%) and vomiting (4% vs 1%).
In patients with mild or moderate renal impairment (CrCl ≥30-80 mL/min) compared to those with normal renal function (CrCl >80 mL/min), the most commonly reported events and their placebo-corrected frequencies included: Constipation (8% vs 4%), dizziness (7% vs 5%) and nausea (4% vs 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% vs 2%), vomiting (6% vs 1%) and hypotension (4% vs 2%).
Laboratory Findings: Small, clinically insignificant, reversible elevations in serum creatinine levels have been observed in healthy subjects and patients treated with Ranexa. 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.

 

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 (eg, nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment with ketoconazole 200 mg twice daily increased the AUC of ranolazine by 3- to 3.9-fold during ranolazine treatment. Combining ranolazine with potent CYP3A4 inhibitors (eg, itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated. Grapefruit juice is also a potent CYP3A4 inhibitor.
Diltiazem (180-360 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 Ranexa is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (eg, erythromycin, fluconazole). Down-titration of Ranexa may be required.
Ranolazine is a substrate for P-gp. Inhibitors of P-gp (eg, cyclosporin, verapamil) increase plasma levels of ranolazine. Verapamil (120 mg 3 times daily) increases ranolazine steady state concentrations 2.2-fold. Careful dose titration of Ranexa is recommended in patients treated with P-gp inhibitors. Down-titration of Ranexa may be required.
CYP3A4 Inducers: Rifampicin (600 mg once daily) decreases ranolazine steady-state concentrations by approximately 95%. Initiation of treatment with Ranexa should be avoided during administration of inducers of CYP3A4 (eg, 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 1,000 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.
Dose adjustment of sensitive CYP3A4 substrates (eg, simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporin, tacrolimus, sirolimus, everolimus) may be required as Ranexa may increase plasma concentrations of these drugs.
Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranexa 750 mg twice daily increased plasma concentrations of metoprolol by 1.8-fold. Therefore, the exposure to metoprolol or other CYP2D6 substrates (eg, propafenone and flecainide or to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased during co-administration with Ranexa, 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 (eg, bupropion, efavirenz, cyclophosphamide).
Digoxin: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported when Ranexa and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of Ranexa therapy.
Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa 1,000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid by about 2-fold. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranexa and simvastatin, in post-marketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranexa.
Atorvastatin: Ranexa 1,000 mg twice daily increased C_max and AUC of atorvastatin 80 mg once daily by 1.4- and 1.3-fold, respectively and changed the C_max and AUC of atorvastatin metabolites <35%. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered when taking Ranexa.
Dose limitation of other statins, metabolized by CYP3A4 (eg, lovastatin), may be considered when taking Ranexa.
Tacrolimus, Cyclosporin, Sirolimus, Everolimus: 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 Ranexa and tacrolimus and that tacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporin, sirolimus, everolimus).
Drugs Transported by the Organic Cation Transporter-2 (OCT2): Plasma exposure of metformin (1,000 mg twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when co-administered with Ranexa 500 mg and 1,000 mg 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 (eg, terfenadine, astemizole, mizolastine), certain antiarrhythmics (eg, quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants (eg, imipramine, doxepin, amitriptyline).

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Anti-Anginal Drugs