Ranolazine

Article Author:
Mirembe Reed
Article Editor:
Diala Nicolas
Updated:
1/17/2019 8:30:55 AM
PubMed Link:
Ranolazine

Indications

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

Angina is characterized by chest discomfort that occurs due to ischemia. Stable angina is treated to reduce the symptoms and occurrence of ischemia and to 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.

Mechanism of Action

The mechanism of ranolazine's anti-anginal and anti-ischemic effects is not well understood. It inhibits late sodium currents in cardiac cells which decreases intracellular calcium overload and improves coronary blood flow. It does not significantly reduce 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 in comparison to placebo and had negligible effects on heart rate and blood pressure. [4][5][6][4]

Ranolazine also inhibits fatty acid oxidation. This enhances glucose oxidation, reduces the production of lactic acid and improves heart function.

Administration

Ranolazine is available as 500-mg and 1000-mg extended-release tablets. The tablets are film-coated and not scored; they should not be crushed, broken or chewed. Dosing should begin at 500 mg twice daily and titrated to 1000 mg twice daily as tolerated. The maximum recommended dose is 1000 mg twice a day. Food does not alter the rate of absorption or the area under 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 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. Patients were randomly assigned to receive 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 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][8][9][10]

Adverse Effects

In clinical trials, approximately 6% of patients discontinued treatment because of an adverse event versus 3% in the placebo groups. The most common adverse events that led to discontinuation 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.

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

Contraindications

Ranolazine is metabolized in the liver mainly by CYP3A4  and CYP2D6 enzymes. It is also a substrate of P-glycoprotein. Strong 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, 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.

Ranolazine inhibits the tubular secretion of creatinine. This does not affect 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 who are 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 interval.

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 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 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 the drug is chiefly prescribed by cardiologists, it can be prescribed by primary care providers and nurse practitioners. It is important for healthcare workers who prescribe this agent to know that at high doses of ranolazine 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 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. Prior to starting the drug, a baseline ECG is recommended as the drug is known to prolong the QT syndrome.


References

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[2] Teoh IH,Banerjee M, Effect of ranolazine on glycaemia in adults with and without diabetes: a meta-analysis of randomised controlled trials. Open heart. 2018;     [PubMed PMID: 30613407]
[3] Pavasini R,Camici PG,Crea F,Danchin N,Fox K,Manolis AJ,Marzilli M,Rosano GMC,Lopez-Sendon JL,Pinto F,Balla C,Ferrari R, Anti-anginal drugs: Systematic review and clinical implications. International journal of cardiology. 2018 Dec 4;     [PubMed PMID: 30538056]
[4] Cirakoglu OF,Kul S,Sayın MR, Successful Use of Ranolazine in a Patient With Vasospastic Angina. The Canadian journal of cardiology. 2019 Jan;     [PubMed PMID: 30528380]
[5] Sanfuentes B,Bulnes JF, Ranolazine as an additional antianginal therapy in patients with stable symptomatic coronary artery disease. Medwave. 2018 Nov 12;     [PubMed PMID: 30451816]
[6] Rambarat CA,Elgendy IY,Handberg EM,Bairey Merz CN,Wei J,Minissian MB,Nelson MD,Thomson LEJ,Berman DS,Shaw LJ,Cook-Wiens G,Pepine CJ, Late sodium channel blockade improves angina and myocardial perfusion in patients with severe coronary microvascular dysfunction: Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction ancillary study. International journal of cardiology. 2019 Feb 1;     [PubMed PMID: 30293664]
[7] Patel N,Kluger J, Ranolazine for Prevention of Atrial Fibrillation after Cardiac Surgery: A Systematic Review. Cureus. 2018 May 6;     [PubMed PMID: 30009098]
[8] Bazoukis G,Tse G,Letsas KP,Thomopoulos C,Naka KK,Korantzopoulos P,Bazoukis X,Michelongona P,Papadatos SS,Vlachos K,Liu T,Efremidis M,Baranchuk A,Stavrakis S,Tsioufis C, Impact of ranolazine on ventricular arrhythmias - A systematic review. Journal of arrhythmia. 2018 Apr;     [PubMed PMID: 29657587]
[9] Turgeon RD,Pearson GJ,Graham MM, Pharmacologic Treatment of Patients With Myocardial Ischemia With No Obstructive Coronary Artery Disease. The American journal of cardiology. 2018 Apr 1;     [PubMed PMID: 29394999]
[10] Zeng X,Zhang Y,Lin J,Zheng H,Peng J,Huang W, Efficacy and Safety of Ranolazine in Diabetic Patients: A Systematic Review and Meta-analysis. The Annals of pharmacotherapy. 2017 Dec 1;     [PubMed PMID: 29231052]