Ranolazine
Clinical data | |
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Trade names | Ranexa, Aspruzyo Sprinkle, Corzyna |
AHFS/Drugs.com | Monograph |
MedlinePlus | a606015 |
License data |
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Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
intestine | |
Elimination half-life | 1.4 to 1.9 hours[4] |
Excretion | Kidney (75%) and fecal (25%) |
Identifiers | |
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JSmol) | |
Chirality | Racemic mixture |
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Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain.[5] Typically it is used together with other medications when those are insufficient.[5][6] Therapeutic benefits appear smaller in females than males.[5] It is taken by mouth.[5]
Common side effects include constipation, headache, nausea, and dizziness.
Ranolazine was approved for medical use in the United States in 2006.[5] In 2021, it was the 202th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[7][8]
Medical uses
Ranolazine is used to treat chronic
Its use is not recommended in Scotland as of 2019.[6]
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[13] and the FDA label contains a warning for doctors to beware of this effect in their patients.[10] 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.[14]
Side effects
The most common side effects are dizziness (11.5%) and constipation (10.9%).[9] Other side effects include headache and nausea.[13]
Drug interactions
Ranolazine is metabolized mainly by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6.[10] 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 such as
For drugs that are moderate CYP3A inhibitors, such as diltiazem, verapamil, and erythromycin, the dose of ranolazine should be reduced.[10]
Drugs that are metabolized by CYP2D6, such as
Mechanism of action
Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle[15] in a variety of voltage-gated sodium channels.[16] 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.[13] The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.[10] 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.[17]
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.[18]
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.[19]
Roche acquired Syntex in 1994
Society and culture
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.[13] In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.[13] In April 2008 ranolazine was approved by the European EMEA for use in angina.[25]
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.[26]
Ranolazine might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma.[27] 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[28]
References
- ^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
- ^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
- ^ "Summary Basis of Decision (SBD) for Corzyna". Health Canada. 23 October 2014. Retrieved 29 May 2022.
- ^ Jerling, M. (2006). Clinical pharmacokinetics of ranolazine. Clinical pharmacokinetics, 45, 469-491.
- ^ a b c d e f g h i "Ranolazine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 22 March 2019.
- ^ ISBN 9780857113382.
- ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
- ^ "Atomoxetine - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
- ^ PMID 24462341.
- ^ a b c d e f g "Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information". Gilead Sciences, Inc. Foster City, CA 94404. Retrieved 8 September 2016.
- S2CID 31659714.
- PMID 28497941.
- ^ S2CID 2084618.
- ^ "FDA Approves New Treatment for Chest Pain". FDA News. 31 January 2006. Retrieved 2 March 2011.
- PMID 16775091.
- PMID 23801963.
- PMID 16714061.
- PMID 27838121.
- ^ a b "Cardiovascular and Renal Drugs Advisory Committee Briefing Document" (PDF). Food and Drug Administration.
- ^ 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. Archived 7 November 2017 at the Wayback Machine
- ^ CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
- ^ Thepharmaletter.com 22 September 2008 Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa
- ^ Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
- ^ Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries Archived 7 November 2017 at the Wayback Machine
- ^ EMEA Ranolazine page at the EMEA
- ^ "Gilead Sciences Announces Fourth Quarter and Full Year 2016 Financial Results". Gilead.
- ^ Nature Matabolism: Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy
- ^ Eureka Alert: Electrical signals between skin cells may influence melanoma initiation