Ranolazine


Article Author:
Mirembe Reed


Article Editor:
Diala Nicolas


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
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Saad Nazir
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Hussain Sajjad
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Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
1/17/2019 8:30:55 AM

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.


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Ranolazine - Questions

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A 63-year-old female with congestive heart failure and left ventricular ejection fraction of 48%, and chronic stable angina presents for her annual physical exam. Her home medication list includes metoprolol succinate 25 mg a day, amlodipine 2.5 mg a day, aspirin 81 mg a day, isosorbide mononitrate 60 mg a day, and atorvastatin 40 mg a day. She complains that she experiences occasional chest pain that is relieved with rest. Resting EKG is normal except for bradycardia, blood pressure 108/70 mmHg, respiratory rate 18/minute, and heart rate 58 beats per minute. She has not tolerated higher doses of beta blockers or calcium channel blockers in the past and has therefore been maintained on her current dosage regimen. What drug therapy should be considered to manage her angina symptoms further?



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What is the mechanism of action of ranolazine?



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A 73-year-old man with a medical history of hypertension, hyperlipidemia, chronic stable angina and type 2 diabetes. He takes simvastatin 20 mg daily, lisinopril 10 mg daily, clopidogrel 75 mg daily, ranolazine 1000 mg twice a day and glipizide 2.5 mg a day. His provider would like to initiate metformin therapy because the Hemoglobin A1c is 9. What drug interactions should prompt concern?



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A 67-year-old male is admitted to the hospital with an exacerbation of chronic obstructive pulmonary disease. His past medical history includes hypertension, asthma, stable angina, and heart failure with preserved ejection fraction. Home medications include simvastatin 20 mg a day, lisinopril 5 mg, aspirin 162 mg a day, albuterol inhaler as needed, ranolazine 500 mg bid, and furosemide 80 mg twice a day. He is treated with furosemide 80 mg IV twice a day. On day 3 of admission, his fluid status assessment shows that she is negative 2 liters but her serum creatinine has increased from 1.2 mg/dl on admission to 2.3 mg/dl. Blood urea nitrogen has gone up from 18 to 31. The team decides that her acute kidney injury is likely prerenal and holds furosemide therapy. What other medications should be held?



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An 88-year-old man has a past medical history of hypertension, chronic stable angina, diabetes mellitus type 2, atrial fibrillation, and end-stage renal disease on dialysis. He takes loratadine 10 mg a day, amiodarone 200 mg a day, atenolol 100 mg a day, amlodipine 10 mg a day, ranolazine 1000 mg twice a day, metformin 500 mg twice a day, apixaban 2.5 mg twice a day, and atorvastatin 10 mg a day. His son brings him to the emergency department and reports that he fills his dad's pillbox once a week on Sunday. He reports that when he stopped by to visit yesterday on Wednesday evening, he noticed that the metformin doses for the past 3 days were still in the pillbox but the ranolazine doses for a week only had four pills left. He suspects that his father took 2000 mg of ranolazine twice a day for the past 3 days. The patient's vital signs are within normal limits, and his blood glucose is 284 mg/dL. What is the next course of action?



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Ranolazine - References

References

Batran RA,Gopal K,Aburasayn H,Eshreif A,Almutairi M,Greenwell AA,Campbell SA,Saleme B,Court EA,Eaton F,Light PE,Sutendra G,Ussher JR, The antianginal ranolazine mitigates obesity-induced nonalcoholic fatty liver disease and increases hepatic pyruvate dehydrogenase activity. JCI insight. 2019 Jan 10;     [PubMed]
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]
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]
Cirakoglu OF,Kul S,Sayın MR, Successful Use of Ranolazine in a Patient With Vasospastic Angina. The Canadian journal of cardiology. 2019 Jan;     [PubMed]
Sanfuentes B,Bulnes JF, Ranolazine as an additional antianginal therapy in patients with stable symptomatic coronary artery disease. Medwave. 2018 Nov 12;     [PubMed]
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]
Patel N,Kluger J, Ranolazine for Prevention of Atrial Fibrillation after Cardiac Surgery: A Systematic Review. Cureus. 2018 May 6;     [PubMed]
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]
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]
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]

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