Continuing Education Activity

Ranolazine was FDA-approved in 2006 for the treatment of chronic angina. Angina is characterized by chest discomfort that occurs due to ischemia. Stable angina is treated to reduce ischemia symptoms and occurrence and prevent myocardial infarction and mortality. Standard therapy includes aspirin, P2Y12 inhibitors, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers, statins, beta-blockers, calcium-channel blockers, and nitrates. Ranolazine may be used in combination with these agents to treat angina. Off-label uses include the treatment of some arrhythmias, such as ventricular tachycardia. However, there is little data to support this use. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, and monitoring, of ranolazine, so providers can direct patient therapy in treating conditions for which it is indicated as part of the interprofessional team.

Objectives:

• Identify the mechanism of action of ranolazine.
• Summarize the approved and off-label indications for ranolazine.
• Review the adverse event profile for ranolazine.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with ranolazine.

Indications

Ranolazine was FDA-approved in 2006 for the treatment of chronic stable angina.[1][2][3]

Chronic stable angina affects an estimated >7 million people in America and is one of the major causes of significant morbidity in these patients. Stable angina is treated to reduce the symptoms and occurrence of ischemia and to prevent myocardial infarction and mortality.[4] Standard therapy includes aspirin, beta-blockers, P2Y12 inhibitors, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers, statins, calcium-channel blockers, and nitrates. Ranolazine may be used in combination with these agents to treat angina.

Off-label uses include the treatment of some arrhythmias, such as ventricular tachycardia. However, there is little data to support this use.[3]

Mechanism of Action

The mechanism of ranolazine's anti-anginal and anti-ischemic effects is not well understood. At the therapeutic level, it inhibits the late phase of inward sodium channels in ischemic cardiac myocytes, reducing the intracellular sodium concentration and thus reducing intracellular calcium influx via the Na-Ca channel. Decreased intracellular calcium reduces ventricular wall tension and thus reduces oxygen consumption. It does not affect blood pressure or heart rate. The Monotherapy Assessment of Ranolazine in Stable Angina (MARISA) trial randomized 191 patients with activity-limiting angina to 500 mg, 1000 mg, or 1500 mg twice daily or placebo for one week. Ranolazine significantly increased exercise duration compared to placebo and had negligible effects on heart rate and blood pressure.[5]

At higher concentrations, ranolazine inhibits rapid delayed rectifier potassium current, thus delaying action potential and prolonging QT interval. Ranolazine also inhibits fatty acid oxidation, which enhances glucose oxidation, reduces lactic acid production, and improves heart function.

Administration

Ranolazine is available as 500 mg and 1000 mg extended-release tablets. Dosing should begin at 500 mg twice daily and be titrated to 1000 mg twice daily as tolerated. The maximum recommended dose is 1000 mg twice a day. The tablets are film-coated and not scored; they should not be crushed, broken, or chewed. Food does not alter the rate of absorption or the area under the plasma concentration-time curve (AUC). Ranolazine can, therefore, be administered with or without meals. Peak plasma concentrations are reached between 2 to 5 hours, the half-life is 7 hours, and the steady-state is achieved within three days.

Dose adjustment is required when ranolazine is taken with moderate CYP3A inhibitors like verapamil, diltiazem, and erythromycin. The dose should not exceed 500 mg twice a day. Dosing should be titrated to clinical response in patients on concomitant P-glycoprotein inhibitors, for example, cyclosporine, because they may also increase ranolazine plasma concentrations.

Clinical Evidence

The Combination Assessment of Ranolazine in Stable Angina (CARISA) trial was a multinational, randomized, double-blind, placebo-controlled trial of patients with symptomatic chronic angina despite taking standard doses of diltiazem, atenolol, or amlodipine.[6] Patients were randomly assigned to receive a placebo or 750 mg or 1000 mg of ranolazine twice a day. Outcome measures included a change in exercise time, time to onset of symptoms, time to onset of ischemia, need for nitroglycerin, and the number of angina attacks. Exercise duration, time to angina symptoms, and time to ischemia increased more from baseline in both ranolazine groups compared to the placebo group. Exercise tolerance increased with ranolazine dose and plasma concentration. These changes were independent of heart rate, blood pressure, or background antianginal therapy. Angina attacks and nitroglycerin use were reduced by about seven days in the ranolazine group compared to placebo.

In the Efficacy of Ranolazine in Chronic Angina (ERICA) trial, ranolazine reduced the frequency of anginal symptoms and nitroglycerin use compared to placebo in patients with coronary artery disease who still had symptoms despite therapy with amlodipine 10 mg a day.[7]

Adverse Effects

The most common adverse events were dizziness, headaches, nausea, debility, and constipation. Other side effects included the following: syncope, confusion,  tinnitus, vertigo, blurred vision, dyspnea, hematuria, bradycardia, palpitations, hypotension, orthostatic hypotension, thrombocytopenia, leukopenia, abdominal pain, dry mouth, vomiting, anorexia, dyspepsia, peripheral edema, angioedema, renal failure, eosinophilia, paresthesia, tremor, pulmonary fibrosis, and excessive sweating.[8] There have been a few cases of ranolazine-induced myopathy, but this is very rare, and the prognosis for such cases is good following cessation of the drug.[9][10][9]

Postmarketing adverse effects include hallucinations, tremors, paresthesia, abnormal coordination, dysuria, and rash. Reported neurologic effects are usually dose-dependent and resolve upon discontinuation.[11]

Contraindications

Ranolazine is metabolized in the liver mainly by CYP3A4  and CYP2D6 enzymes. It is also a substrate of P-glycoprotein. Potent CYP3A4 inhibitors like ketoconazole, clarithromycin, and ritonavir increase ranolazine levels, and concomitant use is contraindicated. Moderate CYP3A4 inhibitors such as diltiazem, fluconazole, erythromycin, and verapamil increase ranolazine levels. When used together, the ranolazine dose should not exceed 500 mg twice a day, and close monitoring is needed. CY3A4 inducers such as rifampin, carbamazepine, phenytoin, and St. John’s Wort decrease ranolazine plasma levels, and concomitant use is not recommended. There are no recommended dose adjustments for patients with hepatic impairment, but usage is contraindicated in patients with cirrhosis of the liver.[12]

Ranolazine inhibits the tubular secretion of creatinine, although this does not affect the glomerular filtration rate. However, acute renal failure in patients with marked severe impairment (creatinine clearance [CrCl] less than 30 ml per minute) has been reported. Discontinue therapy if renal failure occurs and do not initiate therapy in patients with a CrCl less than 30 ml per minute. Use in dialysis patients is contraindicated.

Ranolazine may prolong QT via inhibition of potassium current (IKr). Torsades de pointes was not reported as a side effect in clinical trials, but the risk may increase in patients also taking other QT-prolonging medications. Hepatic impairment may also lead to increased plasma concentrations, and hence, prolonged QTc interval. Caution is advised in patients with a family history of long QT syndrome and patients with known prolonged QT intervals.[13]

Co-administration of ranolazine and metformin, each at a dose of 1000 mg twice a day, resulted in increased plasma concentrations of metformin. Patients on ranolazine 1000 mg twice a day should not exceed a total daily dose of 1700 mg metformin, and their blood glucose should be followed closely.

There is a lack of data on the use of ranolazine in pregnant women, during lactation, and in the pediatric population. Close monitoring is required in patients 75 years of age or older as they are more likely to experience adverse effects with ranolazine.

Monitoring

• Monitor QT in patients on ranolazine and other QT-prolonging drugs.
• Concomitant use of ranolazine and metformin increases metformin levels. Monitor blood glucose and for side effects of metformin in these patients.
• Monitor serum creatinine, BUN, and urine output in patients with CrCl less than 60 ml per minute.
• Monitor for neurologic side effects.

Toxicity

High doses of ranolazine can cause dose-dependent increases in dizziness, tremor, dysphagia, hallucinations, unsteady gait, nausea, and vomiting. Supportive therapy should be given in cases of overdose. ECG monitoring may be necessary if a ranolazine overdose occurs. Ranolazine is about 62% bound to plasma proteins, so hemodialysis will not effectively clear it in case of an overdose.

Enhancing Healthcare Team Outcomes

Ranolazine is a relatively new drug for angina. While cardiologists chiefly prescribe the medication, it can be prescribed by primary care providers, including physician assistants and nurse practitioners. It is crucial for all interprofessional healthcare team members who prescribe this agent or manage patients who have had it prescribed to know that high doses of ranolazine cause dose-dependent increases in dizziness, tremor, dysphagia, hallucinations, unsteady gait, nausea, and vomiting. This interprofessional team includes clinicians (MDs, DOs, NPs, and PAs), specialists, mid-level practitioners, nurses, and pharmacists. Supportive therapy should be given in cases of overdose. ECG monitoring may be necessary if a ranolazine overdose occurs. Ranolazine is about 62% bound to plasma proteins, so hemodialysis will not effectively clear it in case of an overdose. In addition, the patient's renal function needs to be monitored. Before starting the drug, a baseline ECG is recommended as the drug is known to prolong the QT syndrome. With an interprofessional approach to ranolazine therapy, better patient outcomes are achievable while limiting potential adverse events. [Level 5]

Researchers are examining the potential role of ranolazine in atrial fibrillation, but it has not yet received FDA approval for that purpose.[11]