Ranolazine

Ranolazine
Clinical data
AHFS/Drugs.com Monograph
MedlinePlus a606015
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		 By mouth (tablets)
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability 35 to 50%
    Protein binding ~62%
    Metabolism Extensive in liver (CYP3A, CYP2D6) and intestine
    Elimination half-life 7 hours
    Excretion Renal (75%) and fecal (25%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    ChEBI
    ChEMBL
    Chemical and physical data
    Formula C24H33N3O4
    Molar mass 427.537 g/mol
    3D model (JSmol)
    Chirality Racemic mixture
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    Ranolazine, sold under the trade name Ranexa by Gilead Sciences, is a drug to treat angina that was first approved in 2006.

    Medical uses

    Ranolazine is used to treat chronic angina.[1] It may be used concomitantly with β blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.[2]

    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[3] and the FDA label contains a warning for doctors to beware of this effect in their patients.[2] 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.[4]

    Side effects

    The most common side effects are dizziness (11.5%) and constipation (10.9%).[1] Other side effects include headache and nausea.[3]

    Drug interactions

    Ranolazine is metabolized mainly by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6.[2] 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.

    Ranolazine should not be used with drugs like ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A nor with drugs that activate CYP3A like rifampin and phenobarbital.[2]

    For drugs that are moderate CYP3A inhibitors like diltiazem, verapamil, erythromycin, the dose of ranolazine should be reduced.[2]

    Drugs that are metabolized by CYP2D6 like tricyclic antidepressants may need to be given at reduced doses when administered with ranolazine.[2]

    Mechanism of action

    Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle[5] in a variety of voltage-gated sodium channels.[6] 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.[3] The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.[2] 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.[7]

    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.[8]

    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.[3] In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.[3] In April 2008 ranolazine was approved by the European EMEA for use in angina.[9]

    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.[10]

    Roche acquired Syntex in 1994[10] 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.[11] In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche.[12] In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini.[13] In 2009, Gilead acquired CV Therapeutics.[14] In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.[15]

    Commercial aspects

    Ranolazine is manufactured and sold as Ranexa by Gilead. According to an Gilead annual income statement, combined sales for Ranexa and other Gilead product AmBisome were $621 million for the fourth quarter of 2016.[16]

    References

    1. 1 2 Banon D et al. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. Am J Cardiol. 2014 Mar 15;113(6):1075-82. PMID 24462341
    2. 1 2 3 4 5 6 7 "Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information". Gilead Sciences, Inc. Foster City, CA 94404. Retrieved 8 September 2016.
    3. 1 2 3 4 5 Kloner RA, et al. Efficacy and safety of ranolazine in patients with chronic stable angina. Postgrad Med. 2013 Nov;125(6):43-52. PMID 24200760
    4. ↑ "FDA Approves New Treatment for Chest Pain". FDA News. 2006-01-31. Retrieved 2011-03-02.
    5. ↑ D Noble and P J Noble. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–calcium overload Heart. Jul 2006; 92(Suppl 4): iv1–iv5. PMID 16775091 PMC 1861316
    6. ↑ Sokolov, S; Peters, CH; Rajamani, S; Ruben, PC (2013). "Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine" (PDF). Frontiers in Pharmacology. 4: 78. doi:10.3389/fphar.2013.00078. PMC 3689222. PMID 23801963. Retrieved 8 September 2016.
    7. ↑ Thomsen, Morten B. (2006). "Assessing the proarrhythmic potential of drugs: Current status of models and surrogate parameters of torsades de pointes arrhythmias". Pharmacology & Therapeutics: 151–163. doi:10.1016/j.pharmthera.2005.04.009.
    8. ↑ Banerjee, Kinjal (2017). "Role of Ranolazine in cardiovascular disease and diabetes: Exploring beyond angina". International Journal of Cardiology: 557. doi:10.1016/j.ijcard.2016.10.102.
    9. ↑ EMEA Ranolazine page at the EMEA
    10. 1 2 "Cardiovascular and Renal Drugs Advisory Committee Briefing Document" (PDF).
    11. ↑ CV Therapeutics press release. April 1, 1996 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd.
    12. ↑ CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
    13. ↑ Thepharmaletter.com 22 September 2008 Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa
    14. ↑ Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
    15. ↑ Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries
    16. ↑ "Gilead Sciences Announces Fourth Quarter and Full Year 2016 Financial Results". Gilead.
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