indication

For the treatment of chronic angina. It should be used in combination with amlodipine, beta-blockers or nitrates.

pharmacology

Ranolazine has antianginal and anti-ischemic effects that do not depend upon reductions in heart rate or blood pressure. It is the first new anti-anginal developed in over 20 years.

mechanism of action

The mechanism of action of ranolazine is unknown. It does not increase the rate-pressure product, a measure of myocardial work, at maximal exercise. In vitro studies suggest that ranolazine is a P-gp inhibitor. Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia. Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia.

toxicity

In the event of overdose, the expected symptoms would be dizziness, nausea/vomiting, diplopia, paresthesia, and confusion. Syncope with prolonged loss of consciousness may develop.

biotransformation

Hepatic, metabolized mainly by CYP3A and to a lesser extent by CYP2D6. The pharmacologic activity of the metabolites has not been well characterized.

absorption

Absorption is highly variable. After oral administration of ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of oral ranolazine relative to that from a solution is 76%.

half life

7 hours

route of elimination

Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces.

drug interactions

Amiodarone: Possible additive effect on QT prolongation

Amprenavir: Amprenavir, a strong CYP3A4 inhibitor, may increase the serum concentratin of ranolazine by inhibiting its metabolism. Concomitant therapy is contraindicated.

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atazanavir: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum level of ranolazine. Concomitant therapy is contraindicated.

Bicalutamide: CYP3A4 inhibitors like ranolazine may increase the serum concentration of ranolazine. Consider therapy modification.

Bretylium: Possible additive effect on QT prolongation

Clarithromycin: Clarithromycin, a strong CYP3A4 inhibitor, may increase the serum level of ranolazine. Concomitant therapy is contraindicated.

Clotrimazole: CYP3A4 Inhibitors (Moderate) such as clotrimazole may increase the serum concentration of ranolazine. Limit the ranolazine dose to a maximum of 500mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Monitor for increased effects/toxicity of ranolazine during concomitant use.

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. The manufacturer contraindicates the use of ranolazine and strong CYP3A4 inhibitors (such as the azole antifungals).1 Monitor for increased effects/toxicity of ranolazine during concomitant use.

Digoxin: Ranolazine may increase the serum level of digoxin. Monitor for changes in the serum level and therapeutic and adverse effects of digoxin if ranolazine is initiated, discontinued or dose changed.

Diltiazem: Diltiazem may increase the serum concentration of ranolazine. Consider alternate therapy or limit ranolazine dose to 500 mg twice daily and monitor for changes in the therapeutic and adverse effects if diltiazem is initiated, discontinued or dose changed.

Dirithromycin: Increased levels of ranolazine - risk of toxicity

Disopyramide: Possible additive effect on QT prolongation

Dofetilide: Possible additive effect on QT prolongation

Erythromycin: Increased levels of ranolazine - risk of toxicity

Fluconazole: Increased levels of ranolazine - risk of toxicity

Fosamprenavir: Increased levels of ranolazine - risk of toxicity

Ibutilide: Possible additive effect on QT prolongation

Indinavir: Indinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of ranolazine by decreasing its metabolism. Concomitant therapy is contraindicated.

Itraconazole: Increased levels of ranolazine - risk of toxicity

Ketoconazole: Increased levels of ranolazine - risk of toxicity

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Moricizine: Possible additive effect on QT prolongation

Nelfinavir: Increased levels of ranolazine - risk of toxicity

Procainamide: Possible additive effect on QT prolongation

Quinidine: Possible additive effect on QT prolongation

Ritonavir: Increased levels of ranolazine - risk of toxicity

Saquinavir: Increased levels of ranolazine - risk of toxicity

Simvastatin: Ranolazine may increase the serum concentration of simvastatin. Monitor for changes in the therapeutic and adverse effects of simvastatin if ranolazine is initiated, discontinued or dose changed.

Sotalol: Possible additive effect on QT prolongation

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Tamoxifen: Ranolazine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Ranolazine, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Ranolazine is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Ranolazine. Concomitant therapy should be avoided.

Thioridazine: Possible additive effect on QT prolongation

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tipranavir: Increased levels of ranolazine - risk of toxicity

Tolterodine: Ranolazine may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Topotecan: The p-glycoprotein inhibitor, Ranolazine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Ranolazine may decrease the effect of Tramadol by decreasing active metabolite production.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Verapamil: Verapamil, a CYP3A4 inhibitor, may increase the serum concentration of Ranolazine. Concomitant therapy is contraindicated.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of ranolazine by decreasing its metabolism. Additive QTc prolongation may also occur. Concomitant therapy is contraindicated.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).