Ranolazine

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Ranolazine
Ranolazine.svg
Systematic (IUPAC) name
(RS)-N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a606015
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (US)
Legal status -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 35 to 50%
Protein binding 62%
Metabolism Hepatic, CYP extensively involved
Half-life 7 hours
Excretion Renal (75%) and fecal (25%)
Identifiers
CAS number 142387-99-3 YesY
ATC code C01EB18
PubChem CID 56959
DrugBank DB00243
ChemSpider 51354 YesY
UNII A6IEZ5M406 YesY
ChEMBL CHEMBL1404 YesY
Chemical data
Formula C24H33N3O4 
Mol. mass 427.537 g/mol
 YesY (what is this?)  (verify)

Ranolazine, sold under the trade name Ranexa by Gilead Sciences (who acquired the developer, CV Therapeutics in 2009), is an antianginal medication. On January 31, 2006, ranolazine was approved for use in the United States by the Food and Drug Administration (FDA) for the treatment of chronic angina pectoris.[1]

Mechanism of action[edit]

Ranolazine is believed to have its effects via altering the transcellular late sodium current. It affects the sodium-dependent calcium channels during myocardial ischemia in rabbits by altering the intracellular sodium level.[2] Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia in rats.[3] The effects of ranolazine on the NaV 1.7 and NaV 1.8 sodium channels also make it potentially useful in the treatment of neuropathic pain.[4][5]

Ranolazine, a partial fatty acid oxidation inhibitor, shifts ATP production from fatty acid to more oxygen-efficient carbohydrate oxidation,[6][7] though this effect does not occur at the serum levels achieved with standard dosing.

Inhibition of fatty acid oxidation (e.g., with etomoxir or ranolazine) was also found to sensitize human leukemia cells to apoptosis induction.[8]

Indications for use[edit]

Ranolazine is indicated for the treatment of chronic angina; it may be used in combination with beta blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. It has been shown to decrease angina episodes in individuals with coronary artery disease on maximal doses of amlodipine.[9] In addition, it has been shown to both decrease angina episodes and increase exercise tolerance in individuals taking concomitant atenolol, amlodipine, or diltiazem.[10]

Unlike other antianginal medications, such as nitrates and beta blockers, ranolazine does not significantly alter either the heart rate or blood pressure, so it is of particular use in individuals with angina who are not responsive to maximal tolerated doses of other antianginal medications.

It would seem – from the mechanism of action – that ranolazine may be of benefit in individuals with non-ST-elevation acute coronary syndromes (ACS) and acute myocardial infarction (heart attack). However the recently completed Merlin/TIMI-36 trial showed no benefit in this population.[11]

Contraindications[edit]

Ranolazine is known to increase the QT interval on the electrocardiogram.[12] While the mean increase in the corrected QT interval (QTc) is approximately 6 ms, about 5% of individuals may have QTc prolongations of 15 ms or longer.[13]

Extended QT intervals increase the risk of sudden cardiac death. The increase was 60% in adults, independently of other known risk factors, in an analysis of the Rotterdam Study.[14] In a recent case report, ranolazine was thought to be the major contributor to a new onset torsade de pointes of a patient whose only new medication was ranolazine. [15] For this reason, caution is advised when ranolazine is used in combination with other medications that increase the QT interval.

Ranolazine'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.[1]

Metabolism[edit]

Ranolazine is metabolized in the liver, particularly by one of the cytochrome CYP3A enzymes, a member of the cytochrome P450 system.[16]

Drug interactions[edit]

Ranolazine is not significantly metabolized by cytochrome CYP2D6. However it does inhibit this enzyme.[16] For this reason the doses of other medications metabolized by cytochrome CYP2D6 may need to be reduced to prevent toxicity.

Drugs that may interact with ranolazine include:[17]

Caution should be used when administering ranolazine in combination with any of the above medications, but some combinations may be considered relatively safe. For instance, in the CARISA trial, ranolazine was used in individuals taking diltiazem without any adverse events attributable to the combination.[10]

Trials[edit]

MERLIN TIMI 36 trial[edit]

This is the recent development in the field of ranolazine. This study was done in 6560 post-ACS NSTEMI patients followed up for one year. Although ranolazine did not show significant benefit in the study's primary endpoints of cardiovascular death, myocardial infarction, or recurrent ischemia; it exhibited a potential benefit in arrhythmia.

Among patients with ACS, ranolazine, an inhibitor of late INa, has antiarrhythmic effects as assessed by Holter monitoring. In particular, patients treated with ranolazine had fewer episodes of VT > 8 beats, SVT, and ventricular pauses > 3 seconds. Ranolazine was associated with a 37% reduction in risk of VT lasting >= 8 beats. Reduction in VT >= 8 beats was significant and consistent in high-risk subgroups based on ejection fraction, corrected QT interval, TIMI risk score, history of heart failure, and the presence or absence of ischemia on ECG.

Earlier, ranolazine increasing QT interval (about 2 to 6 ms) was of concern, which has a theoretical risk of causing arrhythmia. Findings of MERLIN TIMI 36 should mitigate this concern. However, studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.

Based on encouraging safety data shown in MERLIN TIMI 36 trial, CV Therapeutics has applied to the US FDA for first-line angina indication. It has also applied to the U.S. Food and Drug Administration (FDA) for two more indications, such as HbA1c reduction in coronary artery disease patients with diabetes and antiarrhythmic benefits. Based on initial evaluation of data presented, the FDA has accepted the application and has set the action date as 27 July 2008.

Approval[edit]

Europe[edit]

On 24 April 2008, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorisation for the medicinal product Latixa, 375-mg, 500-mg and 750-mg, prolonged-release tablets intended for treatment of patients with stable angina pectoris. The applicant for this medicinal product is CV Therapeutics Europe Limited. The approved indication is: “Latixa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta blockers and/or calcium antagonists).”

United States[edit]

The Food and Drug Administration has approved a new, first-line indication for ranolazine for the treatment of chronic angina. The new labeling also provides information showing ranolazine reduced arrhythmias, including ventricular arrhythmias, new onset atrial fibrillation and a potentially dangerous slow heartbeat known as bradycardia in patients with coronary artery disease. In addition, the new labeling states Ranexa reduces hemoglobin A1c (HbA1c) in patients with diabetes.

According to the revised labeling, ranolazine is indicated for the treatment of chronic angina and may be used alone or in combination with traditional therapies for chronic angina, such as beta blockers, calcium channel blockers and nitrates, and common cardioprotective treatments for cardiovascular disease, such as antiplatelet therapy, lipid-lowering therapy, ACE inhibitors and angiotensin receptor blockers.

Ranolazine may now be used as part of a medical therapy regimen for chronic angina patients, regardless of whether or not they receive a stent or other medical intervention. Ranolazine does not reduce heart rate or blood pressure and, unlike long-acting nitrates, ranolazine can be prescribed for patients taking oral erectile dysfunction treatments.

These new labeling changes were supported by a supplemental new drug application submitted in September 2007 that included data from the 6,560-patient MERLIN TIMI 36 trial, which showed no adverse trend in death or arrhythmia in a high-risk acute coronary syndromes patient population.

The revised labeling includes new language noting a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia and new atrial fibrillation) in patients treated with Ranexa versus placebo. This difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization or a reduction in arrhythmia symptoms.

The revised labeling also includes new language noting ranolazine produces small reductions in HbA1c. Though ranolazine should not be considered a treatment for diabetes, it may be a particularly useful medication for the reduction of chronic angina in this patient population, which is difficult to treat because some antianginal medications, such as beta blockers, increase HbA1c.

References[edit]

  1. ^ a b "FDA Approves New Treatment for Chest Pain". FDA News. 2006-01-31. Retrieved 2011-03-02. 
  2. ^ Hale SL, Kloner RA. (2006). "Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit". J Cardiovasc Pharmacol Ther 11 (4): 249–55. doi:10.1177/1074248406294607. PMID 17220471. 
  3. ^ Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS. (2006). "Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts". J Mol Cell Cardiol 41 (6): 1031–8. doi:10.1016/j.yjmcc.2006.08.012. PMID 17027025. 
  4. ^ Gould HJ, Garrett C, Donahue RR, Paul D, Diamond I, Taylor BK (December 2009). "Ranolazine Attenuates Behavioral Signs of Neuropathic Pain". Behavioural Pharmacology 20 (8): 755–8. doi:10.1097/FBP.0b013e3283323c90. PMC 2975014. PMID 19773645. 
  5. ^ Casey GP, Roberts JS, Paul D, Diamond I, Gould HJ (January 2010). "Ranolazine attenuation of CFA-induced mechanical hyperalgesia". Pain Medicine (Malden, Mass.) 11 (1): 119–26. doi:10.1111/j.1526-4637.2009.00763.x. PMID 20447295. 
  6. ^ Ranolazine: A novel partial inhibitor of fatty acid oxidation for angina; KN Mahesh Kumar, S Sandhiya; Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry - 605 006, India; http://www.ijp-online.com/article.asp?issn=0253-7613;year=2006;volume=38;issue=4;spage=302;epage=304;aulast=Mahesh
  7. ^ European Journal of Heart Failure; Partial fatty acid oxidation inhibitors: a potentially new class of drugs for heart failure; http://eurjhf.oxfordjournals.org/content/4/1/3.full.pdf+html
  8. ^ Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction; Ismael Samudio,1 Romain Harmancey, et al.; http://www.jci.org/articles/view/38942/pdf
  9. ^ Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators. (2006). "Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial". J Am Coll Cardiol 48 (3): 566–75. doi:10.1016/j.jacc.2006.05.044. PMID 16875985. 
  10. ^ a b Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA; Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators. (2004). "Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial". JAMA 291 (3): 309–16. doi:10.1001/jama.291.3.309. PMID 14734593. 
  11. ^ Morrow DA, Scirica BM, Karwatowska-Prokopczuk E et al. (2007). "Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial". JAMA 297 (16): 1775–83. doi:10.1001/jama.297.16.1775. PMID 17456819. 
  12. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021526s004lbl.pdf
  13. ^ "What is Ranexa". CV Therapeutics. Retrieved 2007-02-04. 
  14. ^ http://content.onlinejacc.org/cgi/content/full/47/2/362, February 3, 2006.
  15. ^ The potential contribution of ranolazine to Torsade de Pointe http://www.sciencedirect.com/science/article/pii/S0975358313000867
  16. ^ a b Jerling M. (2006). "Clinical pharmacokinetics of ranolazine". Clin Pharmacokinet 45 (5): 469–91. doi:10.2165/00003088-200645050-00003. PMID 16640453. 
  17. ^ "Patient information sheet: Ranolazine". FDA. 2006-06-14. Archived from the original on 2006-12-18. Retrieved 2007-02-04.