Ranolazine

Ranolazine is an antianginal belonging to Metabolic modulators.

Ranolazine is an anti-anginal drug used for the treatment of chronic angina, alone or may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

Absorption of Ranolazine is highly variable. The time to peak plasma concentration is approximately 2-5 hours. Approximately 62% of the administered dose of ranolazine is bound to plasma proteins The mean apparent volume of distribution of ranolazine is reported to be 53.2 L. The apparent terminal half-life of ranolazine is 7 hours. It is excreted via urine (approximately 75%) and the remainder in feces (<5% as an unchanged drug).

Ranolazine shows common side effects like Nausea, constipation, headache, dizziness, etc.

Ranolazine is available in the form of Oral tablets and Oral Granules.

Ranolazine is available in India, the US, Australia, the UK, China, Japan, and Italy.

Ranolazine belonging to the Metabolic modulators acts as an antianginal agent.

Ranolazine exert its antianginal and anti-ischemic effects through concentration-, voltage-, and frequency-dependent inhibition of the late Na current and other cardiac ion channels and transporters. It may decrease the magnitude of the late Na current resulting in a net reduction in intracellular Na concentrations, reversal of Ca overload, restoration of ventricular pump function, and prevention of ischemia-induced arrhythmias. Its antianginal effects are not dependent upon reductions in heart rate or BP and QT interval prolongation effect is caused by inhibition of rapid delayed rectifier K current (Ikr), which prolongs the ventricular action potential.

The Data of Onset of action and Duration of action of Ranolazine is not available.

The Tmax was found within 2-5 hours (oral tablet) and 4-10 hours (oral granules) following the administration.

Ranolazine is available in the form of Oral tablets and Oral Granules.

Ranolazine Tablets are taken orally usually twice a day.

Sprinkle Ranolazine Granules on 1 tablespoonful of soft food (eg, applesauce, yogurt) and swallow immediately; do not crush or chew.

Ranolazine is an anti-anginal drug used for the treatment of chronic angina, alone or may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. Ranolazine is used to relieve chest pain in conditions like chronic angina.

Ranolazine is an antianginal belonging to Metabolic modulators.

Ranolazine effects 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 (I_Na). However, the relationship between this inhibition to angina symptoms is uncertain. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of rapid delayed rectifier K current (Ikr), which prolongs the ventricular action potential.

Ranolazine is approved for use in the following clinical indications

• Chronic angina

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.

Although not approved, there have been certain off-label indications. These include

• Ventricular tachycardia

• Chronic angina

Oral Dose:

Initial: 500 mg twice daily; may increase to 1,000 mg twice daily as needed (based on symptoms).

Maximum recommended dose: 1,000 mg twice daily.

• Ventricular tachycardia (off-label use)

Oral Dose: 500 to 1,000 mg every 12 hours.

Ranolazine is available in various strengths as 500mg and 1000mg.

Ranolazine is available in the form of Oral Tablet and Oral Granules.

Avoid drinking grapefruit juice or eating grapefruit while taking Ranolazine.

Ranolazine is contraindicated in patients with

● Taking strong inhibitors of CYP3A

● Taking inducers of CYP3A

● With liver cirrhosis

• QT Interval Prolongation

Ranolazine blocks rapid delayed rectifier K current (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 proarrhythmia or sudden death. However, there is little experience with high doses (>1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.

• Renal Failure

Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] <30 mL/min) while taking RANOLAZINE. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue RANOLAZINE and treat appropriately. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL <60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.

There are no data on the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. However, ranolazine is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ranolazine and any potential adverse effects on the breastfed infant from Ranolazine or from the underlying maternal condition.

Adverse events have been observed in animal reproduction studies. Ranolazine should be used during pregnancy only if clearly needed; safety has not been established during pregnancy, but this drug has been used without apparent harmful effects.

Avoid drinking grapefruit juice or eating grapefruit while taking Ranolazine.

• Common Adverse effects

Bradycardia, hypotension, orthostatic hypotension, palpitation, peripheral edema, Dizziness, headache, confusion, syncope, vertigo, Hyperhidrosis, Constipation, abdominal pain, anorexia, dyspepsia, nausea, vomiting, xerostomia, Hematuria, Weakness, Blurred vision, Tinnitus, Dyspnea.

• Rare Adverse effects

Angioedema, ataxia, decreased glycosylated hemoglobin, decreased T-wave amplitude, dysuria, eosinophilia, hallucination, hypoesthesia, hypoglycemia (diabetic patients), increased blood urea nitrogen, increased serum creatinine, leukopenia, pancytopenia, paresthesia, pruritus, pulmonary fibrosis, renal failure, skin rash, thrombocytopenia, torsade de pointes, tremor, T-wave changes, urinary retention, urine discoloration.

• Strong CYP3A Inhibitors

Do not use Ranolazine with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir.

• Moderate CYP3A Inhibitors

Limit the dose of Ranolazine to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products.

• P-Gp Inhibitors

Concomitant use of Ranolazine and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate Ranolazine based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine.

• CYP3A Inducers

Do not use Ranolazine with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort.

• Drugs Metabolized by CYP3A

Limit the dose of simvastatin in patients on any dose of Ranolazine to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as Ranolazine may increase plasma concentrations of these drugs.

• Drugs Transported By P-Gp

Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted.

• Drugs Metabolized by CYP2D6

The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranolazine, and lower doses of these drugs may be required.

• Drugs Transported by OCT2

In subjects with type 2 diabetes mellitus, concomitant use of Ranolazine 1000 mg twice daily and metformin results in increased plasma levels of metformin. When Ranolazine 1000 mg twice daily is co-administered with metformin, the metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with Ranolazine 500 mg twice daily.

The common side effects of Ranolazine include the following

• Common
  

Nausea, constipation, headache, dizziness.

• Rare

Fast, pounding, or irregular heartbeat, difficulty breathing, fainting.

• Pregnancy

Pregnancy Category C

There are no available data on Ranolazine use in pregnant women to inform of any drugs associated risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures 4 times the maximum recommended human dose (MRHD). Embryofetal toxicity studies were conducted in rats and rabbits orally administered ranolazine during organogenesis. In rats, decreased fetal weight and reduced ossification were observed at doses (corresponding to 4-fold the AUC for the MRHD) that caused maternal weight loss. No adverse fetal effects were observed in either species exposed (AUC) to ranolazine at exposures (AUC) equal to the MRHD.

• Nursing Mothers

There are no data on the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. However, ranolazine is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ranolazine and any potential adverse effects on the breastfed infant from Ranolazine or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

• Geriatric Use

Of the chronic angina patients treated with Ranolazine in controlled studies, 496 (48%) were ≥65 years of age, and 114 (11%) were ≥75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients ≥65 years compared to younger patients, but patients ≥75 years of age on Ranolazine, compared to placebo, had a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. 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.

• 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 an overdose. Severe tremors, unsteady gait/incoordination, dysphasia, and hallucinations have been reported in cases of overdose with Ranolazine.
• Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine.

Pharmacodynamic

Ranolazine exerts both antianginal and ischemic effects independent of lowering heart rate or blood pressure. It blocks the rapid delayed rectifier K current (IKr), the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest nor during exercise.

Pharmacokinetics

• Absorption

Absorption of Ranolazine is highly variable. The time to peak plasma concentration is approximately 2-5 hours.

• Distribution

Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for alpha-1 acid glycoprotein. The mean apparent volume of distribution of ranolazine is reported to be 53.2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L.

• Metabolism and Excretion

The apparent terminal half-life of ranolazine is 7 hours. It is excreted via urine (approximately 75%) and the remainder in feces (<5% as an unchanged drug).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021526s028lbl.pdf
• https://www.uptodate.com/contents/ranolazine-drug-information?search=Ranolazine&source=panel_search_result&selectedTitle=1~57&usage_type=panel&kp_tab=drug_general&display_rank=1#F2528161

• https://medlineplus.gov/druginfo/meds/a606015.html
• https://reference.medscape.com/drug/ranexa-aspruzyo-sprinkle-ranolazine-342284
• https://www.mims.com/india/drug/info/ranolazine?type=full&mtype=generic
• https://go.drugbank.com/drugs/DB00243
• https://www.drugs.com/mtm/ranolazine.html