Ranolazine

Overview

Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Therapeutic benefits appear smaller in females than males. It is taken by mouth.[1][2] WP

Common side effects include constipation, headache, nausea, and dizziness. Serious side effects may include QT prolongation. Ranolazine is contraindicated (not recommended) in those with liver cirrhosis. How it works is not clear but may involve adenosine triphosphate.[1] WP

Ranolazine was approved for medical use in the United States in 2006. In 2022, it was the 232nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[1][3][4] WP

Uses, dosage and effects

Medical uses

Ranolazine is used to treat chronic angina. It may be used concomitantly with β blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. It is also effective at preventing atrial fibrillation, and has been studied as monotherapy as well as in combination with other medications used to treat irregular heartbeat.[5–8] WP

Its use is not recommended in Scotland as of 2019.[2] WP

Risks and side effects

Contraindications

Some contraindications for ranolazine are related to its metabolism and are described under Drug Interactions. Additionally, in clinical trials ranolazine slightly increased QT interval in some patients and the FDA label contains a warning for doctors to beware of this effect in their patients. The drug's effect on the QT interval is increased in the setting of liver dysfunction; thus it is contraindicated in persons with mild to severe liver disease.[6][9][10] WP

Side effects

The most common side effects are dizziness (11.5%) and constipation (10.9%). Other side effects include headache and nausea.[5][9] WP

Interactions

Drug interactions

Ranolazine is metabolized mainly by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6. For this reason, the doses of ranolazine and drugs that interact with those enzymes need to be adjusted when they are used by the same patient.[6] WP

Ranolazine should not be used with drugs such as ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A, nor with drugs that activate CYP3A, such as rifampin and phenobarbital.[6] WP

For drugs that are moderate CYP3A inhibitors, such as diltiazem, verapamil, and erythromycin, the dose of ranolazine should be reduced.[6] WP

Drugs that are metabolized by CYP2D6, such as tricyclic antidepressants, may need to be given at reduced doses when administered with ranolazine.[6] WP

Pharmacology

Mechanism of action

Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle in a variety of voltage-gated sodium channels. Inhibiting that current leads to reductions in intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential. Ranolazine also exhibits its effects on the delayed rectifier current (hERG/IKr potassium channels), it readily stimulates myogenesis, it reduces a pro-oxidant inflammation/oxidative condition, and activates the calcium signaling pathway.[6][9][11][12][13] WP

Ranolazine prolongs the action potential duration, with corresponding QT interval prolongation on electrocardiography, blocks the INa current, and prevents calcium overload caused by the hyperactive INa current, thus it stabilizes the membrane and reducing excitability.[14] WP

History

History

Syntex Inc. originally began developing ranolazine in 1985 and 61 studies were completed from then until 1994. Afterwards, Phase 2 studies were done; however, it was found that the formulation did not result in adequate plasma concentrations of drug. It is due to this that the sustained-release (SR) formulation of ranolazine was created.[15] WP

Roche acquired Syntex in 1994 In 1996, CV Therapeutics licensed the North American and European rights to ranolazine from Syntex, a subsidiary of Roche, which had discovered the drug and had developed it through Phase II trials in angina. In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche. In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini. In 2009, Gilead acquired CV Therapeutics. In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.[15–20] WP

Legal status

Legal status

Ranolazine was approved by the FDA in January 2006, for the treatment of patients with chronic angina as a second-line treatment in addition to other drugs. In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs. In April 2008 ranolazine was approved by the European EMEA for use in angina.[9][21] WP

Commercial aspects

Ranolazine is manufactured and sold as Ranexa by Gilead. According to a Gilead annual income statement, combined sales for Ranexa and another Gilead product, AmBisom, were $621 million for the fourth quarter of 2016.[22] WP

Ranolazine might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma. Research suggests that the transfer of a neurotransmitter from one type of skin cell, melanocytes to another, keratinocytes altered electrical activity and promoted melanoma initiation in preclinical models[23][24] WP

Chemistry

Formula

C24H33N3O4 PC

CAS number

95635-55-5 PC

Molar mass (g/mol)

427.5 PC

IUPAC name (computed by PubChem)

N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]acetamide PC

SMILES

CC1=C(C(=CC=C1)C)NC(=O)CN2CCN(CC2)CC(COC3=CC=CC=C3OC)O PC

InChIKey

XKLMZUWKNUAPSZ-UHFFFAOYSA-N PC

PubChem CID

56959

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other Ranolazine Monograph for Professionals
2. Other British national formulary: BNF 76. 2018
3. Other The Top 300 of 2022
4. Other Ranolazine Drug Usage Statistics, United States, 2013 - 2022
5. Journal / agency Banon D, Filion KB, Budlovsky T, Franck C, Eisenberg MJ. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. The American Journal of Cardiology. March 2014. doi:10.1016/j.amjcard.2013.11.070 · PMID 24462341
6. Other Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information
7. Journal / agency Rosa GM, Dorighi U, Ferrero S, Brunacci M, Bertero G, Brunelli C. Ranolazine for the treatment of atrial fibrillation. Expert Opinion on Investigational Drugs. June 2015. doi:10.1517/13543784.2015.1036984 · PMID 25872749
8. Journal / agency De Vecchis R, Ariano C, Giasi A, Cioppa C. Antiarrhythmic effects of ranolazine used both alone for prevention of atrial fibrillation and as an add-on to intravenous amiodarone for its pharmacological cardioversion: a meta-analysis. Minerva Cardioangiologica. June 2018. doi:10.23736/S0026-4725.17.04349-3 · PMID 28497941
9. Journal / agency Kloner RA, Hines ME, Geunes-Boyer S. Efficacy and safety of ranolazine in patients with chronic stable angina. Postgraduate Medicine. November 2013. doi:10.3810/pgm.2013.11.2711 · PMID 24200760
10. Journal / agency FDA Approves New Treatment for Chest Pain. 31 January 2006
11. Journal / agency Noble D, Noble PJ. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart. July 2006. doi:10.1136/hrt.2005.078782 · PMID 16775091 · PMC1861316
12. Journal / agency Sokolov S, Peters CH, Rajamani S, Ruben PC. Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine. Frontiers in Pharmacology. 2013. doi:10.3389/fphar.2013.00078 · PMID 23801963 · PMC3689222
13. Journal / agency Thomsen MB, Matz J, Volders PG, Vos MA. Assessing the proarrhythmic potential of drugs: current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacology & Therapeutics. October 2006. doi:10.1016/j.pharmthera.2005.04.009 · PMID 16714061
14. Journal / agency Banerjee K, Ghosh RK, Kamatam S, Banerjee A, Gupta A. Role of Ranolazine in cardiovascular disease and diabetes: Exploring beyond angina. International Journal of Cardiology. January 2017. doi:10.1016/j.ijcard.2016.10.102 · PMID 27838121
15. Journal / agency Cardiovascular and Renal Drugs Advisory Committee Briefing Document
16. Other CV Therapeutics press release. 1 April 1996 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd. link 2
17. Other CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
18. Other Thepharmaletter.com 22 September 2008 Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa
19. Other Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
20. Other Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries. link 2
21. Journal / agency EMEA Ranolazine page at the EMEA. link 2
22. Other Gilead Sciences Announces Fourth Quarter and Full Year 2016 Financial Results
23. Journal / agency Redondo-Muñoz M, Rodriguez-Baena FJ, Aldaz P, Caballé-Mestres A, Moncho-Amor V, Otaegi-Ugartemendia M, Carrasco-Garcia E, Olias-Arjona A, Lasheras-Otero I, Santamaria E, Bocanegra A, Chocarro L, Grier A, Dzieciatkowska MM, Bigas C, Martin J, Urdiroz-Urricelqui U, Marzo F, Santamaria E, Kochan G, Escors D, Larrayoz IM, Heyn H, D'Alessandro A, Attolini CS, Matheu A, Wellbrock C, Benitah SA, Sanchez-Laorden B, Arozarena I. Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy. Nature Metabolism. September 2023. doi:10.1038/s42255-023-00861-4 · PMID 37563469 · PMC10513932
24. Other Eureka Alert: Electrical signals between skin cells may influence melanoma initiation

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