Ranolazine

Last updated

Ranolazine
Ranolazine.svg
Clinical data
Trade names Ranexa, Aspruzyo Sprinkle, Corzyna
AHFS/Drugs.com Monograph
MedlinePlus a606015
License data
Routes of
administration 		By mouth
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 1.4 to 1.9 hours [4]
Excretion Kidney (75%) and fecal (25%)
Identifiers
  • (RS)-N-(2,6-Dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.149.259 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H33N3O4
Molar mass 427.545 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • O=C(Nc1c(cccc1C)C)CN3CCN(CC(O)COc2ccccc2OC)CC3
  • InChI=1S/C24H33N3O4/c1-18-7-6-8-19(2)24(18)25-23(29)16-27-13-11-26(12-14-27)15-20(28)17-31-22-10-5-4-9-21(22)30-3/h4-10,20,28H,11-17H2,1-3H3,(H,25,29) Yes check.svgY
  • Key:XKLMZUWKNUAPSZ-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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]

Contents

Common side effects include constipation, headache, nausea, and dizziness. [5] Serious side effects may include QT prolongation. [5] Ranolazine is contraindicated (not recommended) in those with liver cirrhosis. [5] How it works is not clear but may involve adenosine triphosphate. [5]

Ranolazine was approved for medical use in the United States in 2006. [5] In 2021, it was the 202nd most commonly prescribed medication in the United States, with more than 1 million prescriptions. [7] [8]

Medical uses

Ranolazine is used to treat chronic angina. [9] It may be used concomitantly with β blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. [10] 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. [11] [12]

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 ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A, nor with drugs that activate CYP3A, such as rifampin and phenobarbital. [10]

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 tricyclic antidepressants, may need to be given at reduced doses when administered with ranolazine. [10]

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 [19] 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. [20] In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche. [21] In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini. [22] In 2009, Gilead acquired CV Therapeutics. [23] In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia. [24]

Society and culture

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]

Related Research Articles

<span class="mw-page-title-main">Verapamil</span> Calcium channel blocker medication

Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina, and supraventricular tachycardia. It may also be used for the prevention of migraines and cluster headaches. It is given by mouth or by injection into a vein.

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Flecainide</span> Antiarrhythmic medication

Flecainide is a medication used to prevent and treat abnormally fast heart rates. This includes ventricular and supraventricular tachycardias. Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments. Its use does not decrease a person's risk of death. It is taken by mouth or injection into a vein.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Nadolol</span> Non-selective beta blocker used in the treatment of high blood pressure and chest pain

Nadolol, sold under the brand name Corgard among others, is a medication used to treat high blood pressure, heart pain, atrial fibrillation, and some inherited arrhythmic syndromes. It has also been used to prevent migraine headaches and complications of cirrhosis. It is taken orally.

<span class="mw-page-title-main">Procainamide</span> Medication to treat cardiac arrhythmias

Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. In addition to blocking the INa current, it inhibits the IKr rectifier K+ current. Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.

<span class="mw-page-title-main">Azimilide</span> Chemical compound

Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.

<span class="mw-page-title-main">Bepridil</span> Calcium channel blocker medication

Bepridil is an diamine calcium channel blocker once used to treat angina pectoris. It is no longer sold in the United States.

<span class="mw-page-title-main">Dronedarone</span> Medication

Dronedarone, sold under the brand name Multaq, is a class III antiarrhythmic medication developed by Sanofi-Aventis. It was approved by the US Food and Drug Administration (FDA) in July 2009. Besides being indicated in arrhythmias, it was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. The FDA label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in people with moderate to severe congestive heart failure.

<span class="mw-page-title-main">Elvitegravir</span> Chemical compound

Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012, for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014, the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. On November 5, 2015, the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.

<span class="mw-page-title-main">Cobicistat</span> Chemical compound

Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.

<span class="mw-page-title-main">F15845</span> Cardiac drug

F15845 is a cardiac drug proposed to have beneficial effects for the treatment of angina pectoris, arrhythmias and ischemia by inhibiting the persistent sodium current. The drug, currently in phase II of clinical trials, targets the persistent sodium current with selectivity and produces minimal adverse effects in current experimental studies.

<span class="mw-page-title-main">Cabozantinib</span> Chemical compound

Cabozantinib, sold under the brand names Cometriq and Cabometyx among others, is an anti-cancer medication used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and also inhibits AXL and RET. It was discovered and developed by Exelixis Inc.

<span class="mw-page-title-main">Budiodarone</span> Chemical compound

Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

<span class="mw-page-title-main">AZD1305</span> Chemical compound

AZD1305 is an experimental drug candidate that is under investigation for the management and reversal of cardiac arrhythmias, specifically atrial fibrillation and flutter. In vitro studies have shown that this combined-ion channel blocker inhibits rapidly the activating delayed-rectifier potassium current (IKr), L-type calcium current, and inward sodium current (INa).

QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.

<span class="mw-page-title-main">Cobimetinib</span> Chemical compound

Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used to treat melanoma and histiocytic neoplasms. Cobimetinib is a MEK inhibitor. Cobimetinib is marketed by Genentech.

Pralsetinib, sold under the brand name Gavreto, is a medication approved for RET mutation-positive medullary thyroid cancer (MTC) and RET fusion-positive differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) therapy. Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ↑ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. ↑ "Summary Basis of Decision (SBD) for Corzyna". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  4. ↑ Jerling, M. (2006). Clinical pharmacokinetics of ranolazine. Clinical pharmacokinetics, 45, 469-491.
  5. 1 2 3 4 5 6 7 8 9 "Ranolazine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 22 March 2019.
  6. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 210. ISBN   9780857113382.
  7. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  8. ↑ "Atomoxetine - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  9. 1 2 Banon D, Filion KB, Budlovsky T, Franck C, Eisenberg MJ (March 2014). "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. 113 (6): 1075–1082. doi:10.1016/j.amjcard.2013.11.070. PMID   24462341.
  10. 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.
  11. ↑ Rosa GM, Dorighi U, Ferrero S, Brunacci M, Bertero G, Brunelli C (June 2015). "Ranolazine for the treatment of atrial fibrillation". Expert Opinion on Investigational Drugs. 24 (6): 825–836. doi:10.1517/13543784.2015.1036984. PMID   25872749. S2CID   31659714.
  12. ↑ De Vecchis R, Ariano C, Giasi A, Cioppa C (June 2018). "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. 66 (3): 349–359. doi:10.23736/S0026-4725.17.04349-3. PMID   28497941.
  13. 1 2 3 4 5 Kloner RA, Hines ME, Geunes-Boyer S (November 2013). "Efficacy and safety of ranolazine in patients with chronic stable angina". Postgraduate Medicine. 125 (6): 43–52. doi:10.3810/pgm.2013.11.2711. PMID   24200760. S2CID   2084618.
  14. ↑ "FDA Approves New Treatment for Chest Pain". FDA News. 31 January 2006. Retrieved 2 March 2011.
  15. ↑ Noble D, Noble PJ (July 2006). "Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload". Heart. 92 (Suppl 4): iv1–iv5. doi:10.1136/hrt.2005.078782. PMC   1861316 . PMID   16775091.
  16. ↑ Sokolov S, Peters CH, Rajamani S, Ruben PC (2013). "Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine". Frontiers in Pharmacology. 4: 78. doi: 10.3389/fphar.2013.00078 . PMC   3689222 . PMID   23801963.
  17. ↑ Thomsen MB, Matz J, Volders PG, Vos MA (October 2006). "Assessing the proarrhythmic potential of drugs: current status of models and surrogate parameters of torsades de pointes arrhythmias". Pharmacology & Therapeutics. 112 (1): 150–70. doi:10.1016/j.pharmthera.2005.04.009. PMID   16714061.
  18. ↑ Banerjee K, Ghosh RK, Kamatam S, Banerjee A, Gupta A (January 2017). "Role of Ranolazine in cardiovascular disease and diabetes: Exploring beyond angina". International Journal of Cardiology. 227: 556–564. doi:10.1016/j.ijcard.2016.10.102. PMID   27838121.
  19. 1 2 "Cardiovascular and Renal Drugs Advisory Committee Briefing Document" (PDF). Food and Drug Administration .
  20. ↑ 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
  21. ↑ CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
  22. ↑ Thepharmaletter.com 22 September 2008 Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa
  23. ↑ Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
  24. ↑ 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
  25. ↑ EMEA Ranolazine page at the EMEA Archived 5 October 2016 at the Wayback Machine
  26. ↑ "Gilead Sciences Announces Fourth Quarter and Full Year 2016 Financial Results". Gilead.
  27. ↑ Redondo-Muñoz M, Rodriguez-Baena FJ, Aldaz P, Caballé-Mestres A, Moncho-Amor V, Otaegi-Ugartemendia M, et al. (September 2023). "Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy". Nature Metabolism. 5 (9): 1544–1562. doi:10.1038/s42255-023-00861-4. PMC   10513932 . PMID   37563469.
  28. ↑ Eureka Alert: Electrical signals between skin cells may influence melanoma initiation
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.