Ranolazine

drugbox
IUPAC_name="N"-(2,6-dimethylphenyl)-2- [4- [2-hydroxy-3-(2-methoxyphenoxy)
propyl] piperazin-1-yl] acetamide

---

width=280
CAS_number=142387-99-3
ATC_prefix=C01
ATC_suffix=EB18
ATC_supplemental=
PubChem=56959
DrugBank=APRD01300
C=24|H=33|N=3|O=4
molecular_weight=427.537 g/mol
bioavailability=35 to 50%
protein_bound=62%
metabolism=Hepatic, CYP extensively involved
elimination_half-life=7 hours
excretion=Renal (75%) and fecal (25%)
pregnancy_AU=
pregnancy_US=C
pregnancy_category=
legal_AU=
legal_UK=
legal_US=Rx-only
legal_status=
routes_of_administration=Oral
licence_EU = Latixa
licence_US = Ranolazine

Ranolazine, sold under the trade name Ranexa by CV Therapeutics, is an antianginal medication. On January 31 2006, ranolazine was approved for use in the United States by the FDA for the treatment of chronic angina pectoris.cite news |url=http://www.fda.gov/bbs/topics/news/2006/NEW01306.html |title=FDA Approves New Treatment for Chest Pain |publisher=FDA News |date=2006-01-31 |accessdate=2007-02-04]

Mechanism of action

Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia.cite journal | author=Hale SL, Kloner RA. | title=Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit | journal=J Cardiovasc Pharmacol Ther | year=2006 | volume=11 | issue=4 | pages=249–55 | pmid=17220471 | doi=10.1177/1074248406294607] Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia.cite journal | author=Fraser H, Belardinelli L, Wang L, Light PE, McVeigh JJ, Clanachan AS. | title=Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts | journal=J Mol Cell Cardiol | year=2006 | volume=41 | issue=6 | pages=1031–8 | pmid=17027025 | doi=10.1016/j.yjmcc.2006.08.012]

Indications for use

Ranolazine is indicated for use in the treatment of chronic stable angina in individuals with angina which is refractory to more standard anti-anginal medications. It has been shown to decrease angina episodes in individuals with coronary artery disease on maximal doses of amlodipine.cite journal | author=Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L; ERICA Investigators. | title=Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial | journal=J Am Coll Cardiol | year=2006 | volume=48 | issue=3 | pages=566–75 | pmid=16875985 | doi=10.1016/j.jacc.2006.05.044] In addition, it has been shown to both decrease angina episodes and increase exercise tolerance in individuals taking concomitant atenolol, amlodipine, or diltiazem.cite journal | author=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. | title=Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial | journal=JAMA | year=2004 | volume=291 | issue=3 | pages=309–16 | pmid=14734593 | doi=10.1001/jama.291.3.309]

Unlike other antianginal medications such as nitrates and beta blockers, ranolazine does not significantly alter either the heart rate or blood pressure. For this reason, it is of particular use in individuals with angina that is refractory to maximal tolerated doses of other anti-anginal medications.

While it would seem from the mechanism of action that ranolazine may be of benefit in individuals with non-ST-elevation acute coronary syndromes and acute myocardial infarction (heart attack), the recently completed Merlin/TIMI-36 trial showed no benefit in this population.cite journal |author=Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, "et al" |title=Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial |journal=JAMA |volume=297 |issue=16 |pages=1775–83 |year=2007 |pmid=17456819 |doi=10.1001/jama.297.16.1775]

Contraindications

Ranolazine is known to increase the QT interval on the electrocardiogram. While the mean increase in the QTc is approximately 6 msec, about 5 percent of individuals may have QTc prolongations of 15 msec or longer.

Metabolism

Ranolazine is metabolized in the liver, particularly by one of the cytochrome CYP3A enzymes, a member of the cytochrome P450 system.cite journal | author=Jerling M. | title=Clinical pharmacokinetics of ranolazine | journal=Clin Pharmacokinet | year=2006 | volume=45 | issue=5 | pages=469–91 | pmid=16640453 | doi=10.2165/00003088-200645050-00003]

Drug interactions

While ranolazine is not significantly metabolized by cytochrome CYP2D6, it does inhibit this enzyme. Because of this, the doses of medications metabolized by cytochrome CYP2D6 may need to be reduced to prevent toxicity.

Drugs that may interact with ranolazine include:Macrolide antibiotics
** Ritonavir (Norvir)
** Grapefruit products or grapefruit juice
* QTc prolonging drugs, including:
** Class Ia antiarrhythmic agents (eg, quinidine)
** Class III antiarrhythmic agents (eg, dofetilide, sotalol)
** Certain antipsychotics (eg, thioridazine, ziprasidone)

While caution should be used when administrating ranolazine in combination with any of the above medications, 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.

MERLIN TIMI 36 Trial

This is the recent development in the field of Ranolazine. This study was done in 6560 post ACS NSTEMI patients followed up for 1 year. Although, Ranolazine did not show significant benefit in study's primary endpoint of CV death, MI, or recurrent ischemia; it exhibited a potential benefit in arrhythmia.

Among patients with ACS, ranolazine, an inhibitor of late INa, has anti-arrhythmic 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 there was a concern that Ranolazine increases QT interval (approximately 2 to 6 ms) 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 anti-arrhythmic agent are warranted.

Based on encouraging safety data shown in MERLIN TIMI 36 trial, CV therapeutics has applied to US FDA for first line angina indication. It has also applied to US FDA for 2 more indication such as HbA1c reduction in coronary artery disease patients with diabetes and antiarrhythmic benefits. Based on initial evaluation of data presented, US FDA has accepted the application and have set the action date as 27th July 2008.

European Approval

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).”

References