|By mouth (tablets)|
|Bioavailability||35 to 50%|
|Metabolism||Extensive in liver (CYP3A, CYP2D6) and intestine|
|Biological half-life||7 hours|
|Excretion||Renal (75%) and fecal (25%)|
|Chemical and physical data|
|Molar mass||427.537 g/mol|
|3D model (JSmol)|
|(what is this?)|
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.
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.
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.
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.
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.
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.
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.
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.
Ranolazine, trade name Ranexa, is manufactured and sold by Gilead. According to the Gilead annual income statement, combined sales for Ranexa and other Gilead product AmBisome were $621 million for the fourth quarter of 2016, compared to the total product sales of $7.2 billion of the same quarter. This is down from $8.4 billion in the same quarter from 2015.
Product sales for the entire year of 2016 were $30 billion, down from $32.2 billion in 2015. These are further broken down by country, with $19.3 billion in the US, $6.1 billion in Europe, $2.5 billion from Japan with $2.1 billion from other countries combined. Overall, sales decreased in each country with the exception of Japan and the other combined countries with $21.2 billion in the US, $7.2 billion in Europe, $1.9 billion in Japan and $1.9 billion from combined other countries.
According to The Wall Street Journal, the most current financial information for 2016 for Gilead Sciences Inc. is as follows: The net income growth is -25.44%, revenue is $30.23 billion, revenue growth is -5.37% and EBITDA is +$19.55 billion.
The 2016 balance sheet information shows that Gilead has a total debt of $26.35 billion, total liabilities of $37.61 billion, total shareholder’s equity of $18.89 billion and cash & short-term investment of $11.90 billion.
- 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
- "Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information". Gilead Sciences, Inc. Foster City, CA 94404. Retrieved 8 September 2016.
- 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
- "FDA Approves New Treatment for Chest Pain". FDA News. 2006-01-31. Retrieved 2011-03-02.
- 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
- 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 . PMID 23801963. Retrieved 8 September 2016.
- 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.
- Banerjee, Kinjal (2017). "Role of Ranolazine in cardiovascular disease and diabetes: Exploring beyond angina". International Journal of Cardiology: 557.
- EMEA Ranolazine page at the EMEA
- "Cardiovascular and Renal Drugs Advisory Committee Briefing Document" (PDF).
- 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.
- 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
- "Gilead Sciences Announces Fourth Quarter and Full Year 2016 Financial Results". Gilead.
- "Gilead Sciences Inc". The Wall Street Journal.
- "Gilead Sciences Inc". The Wall Street Journal.