Ranolazine
Indications
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. It has been shown to decrease angina episodes in patients with coronary artery disease on maximal doses of amlodipine. Because Ranolazine prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs.The effect on angina rate or exercise tolerance appeared to be smaller in women than men.
Pharmacology
Ranolazine has anti-ischemlc and antlanginal effects that do not depend upon reductions in heart rate or blood pressure.The exact mechanism of action of ranolazine is unknown. 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.
Absorption: Cmax: 2-5 h
Half-life: 6-22 h
Distribution: 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. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. Following a single oral dose of Ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces.
Absorption: Cmax: 2-5 h
Half-life: 6-22 h
Distribution: 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. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. Following a single oral dose of Ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces.
Dosage & Administration
Initiate Ranolazine dosing at 500 mg twice daily and increase to 1000 mg twice daily, if needed, based on clinical symptoms. Take Ranolazine with or without meals. Swallow Ranolazine tablets whole; do not crush, break or chew. 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.
Pediatric use: Safety and effectiveness in pediatric patients have not been established.
Pediatric use: Safety and effectiveness in pediatric patients have not been established.
Interaction
CYP 3A Inhibitors: Do not use Ranolazine with strong CYP 3A inhibitors. With moderate CYP 3A inhibitors (e.g., diltiazem, verapamil, erythromycin) limit maximum dose of ranolazine to 500 mg twice daily.
CYP 3A Inducers: Do not use Ranolazine with inducers.
P-gp Inhibitors (e.g., Cyclosporin): May need to lower the Ranolazine dose based on clinical dose.
Drugs transported by P-gp or metabolized by CYP2D6 (eg., digoxin, TCA): May need reduced doses of these drugs when used with ranolazine.
CYP 3A Inducers: Do not use Ranolazine with inducers.
P-gp Inhibitors (e.g., Cyclosporin): May need to lower the Ranolazine dose based on clinical dose.
Drugs transported by P-gp or metabolized by CYP2D6 (eg., digoxin, TCA): May need reduced doses of these drugs when used with ranolazine.
Contraindications
Ranolazine is contraindicated in patients:
- With pre-existing QT prolongation
- With hepatic impairment
- Taking QT prolonging drugs
- Taking potent and moderately potent CYP3A inhibitors such as ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir, including diltiazem.
Side Effects
- 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
Pregnancy & Lactation
Pregnancy Category C. There are no adequate studies assessing the effect of ranolazine on the developing fetus. 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.lt is not known whether ranolazine is excreted in human milk. Because of the potentiality for serious adverse reactions from ranolazine in nursing infants, a decision should be made whether to discontinue nursing or to discontinue Ranolazine, taking into account the importance of the drug to the mother.
Precautions & Warnings
Ranolazine blocks QTc 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.
Co-administration of ranolazine with digoxin increases the plasma concentrations of digoxin by approximately 1.5-fold and the dose of digoxin may have to be reduced accordingly. The dose of other P-gp substrates may have to be reduced as well when ranolazine Is co-admlnistered. Caution should be exercised when co-adminlstering ranolazine with P-gp inhibitors such as ritonavir or cydosporine.
Co-administration of ranolazine with digoxin increases the plasma concentrations of digoxin by approximately 1.5-fold and the dose of digoxin may have to be reduced accordingly. The dose of other P-gp substrates may have to be reduced as well when ranolazine Is co-admlnistered. Caution should be exercised when co-adminlstering ranolazine with P-gp inhibitors such as ritonavir or cydosporine.
Overdose Effects
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.
Therapeutic Class
Other Anti-anginal & Anti-ischaemic drugs
Storage Conditions
Store Ranolazine tablets at 25°C with excursion permitted to 15° to 30°C. Protect from light and moisture.
