Ranolazine
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Ranolazine
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| Systematic (IUPAC) name | |
| N-(2,6-dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy) propyl]piperazin-1-yl]acetamide |
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| Identifiers | |
| CAS number | |
| ATC code | C01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C24H33N3O4 |
| Mol. mass | 427.537 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 35 to 50% |
| Protein binding | 62% |
| Metabolism | Hepatic, CYP extensively involved |
| Half life | 7 hours |
| Excretion | Renal (75%) and fecal (25%) |
| Therapeutic considerations | |
| Pregnancy cat. |
C(US) |
| Legal status | |
| Routes | Oral |
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.[1]
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[edit] 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.[2] Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia.[3]
[edit] 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.[4] In addition, it has been shown to both decrease angina episodes and increase exercise tolerance in individuals taking concomitant atenolol, amlodipine, or diltiazem.[5]
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.[6]
[edit] 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.[7]
Because of this, caution should be used when ranolazine is used in combination with other medications that increase the QT interval. In addition, because the effect of ranolazine on the QT interval is increased in the setting of liver dysfunction, it is contraindicated in the setting of mild, moderate, or severe liver disease.[1]
[edit] Metabolism
Ranolazine is metabolized in the liver, particularly by one of the cytochrome CYP3A enzymes, a member of the cytochrome P450 system.[8]
[edit] Drug interactions
While ranolazine is not significantly metabolized by cytochrome CYP2D6, it does inhibit this enzyme.[8] 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:[9]
- Digoxin
- Simvastatin (Zocor)
- Cyclosporine (Gengraf, Neoral, Restasis, Sandimmune)
- various antidepressant medicines
- Inhibitors of cytochrome CYP3A, including:
- Diltiazem
- Verapamil
- Ketoconazole and other azole antifungals
- 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.[5]
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).”
