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| IUPAC_name = (''RS'')-''N''-(2,6-Dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide
| IUPAC_name = (''RS'')-''N''-(2,6-Dimethylphenyl)-2-[4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]acetamide
| image = Ranolazine.svg
| image = Ranolazine.svg
| width = 250
| width = 275
| chirality = [[Racemic mixture]]
| chirality = [[Racemic mixture]]


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| legal_UK = <!-- GSL / P / POM / CD -->
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = Rx-only
| legal_US = Rx-only
| routes_of_administration = Oral
| routes_of_administration = [[Oral administration|By mouth]] ([[Tablet (pharmacy)|tablets]])


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability = 35 to 50%
| bioavailability = 35 to 50%
| protein_bound = 62%
| protein_bound = ~62%
| metabolism = Extensive in [[liver]] ([[CYP3A]], [[CYP2D6]]) and [[Human_gastrointestinal_tract#Lower_gastrointestinal_tract|intestine]]
| metabolism = [[Liver|Hepatic]], [[cytochrome P450 oxidase|CYP]] extensively involved
| elimination_half-life = 7 hours
| elimination_half-life = 7 hours
| excretion = [[Kidney|Renal]] (75%) and fecal (25%)
| excretion = [[Kidney|Renal]] (75%) and fecal (25%)
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| StdInChIKey = XKLMZUWKNUAPSZ-UHFFFAOYSA-N
| StdInChIKey = XKLMZUWKNUAPSZ-UHFFFAOYSA-N
}}
}}

'''Ranolazine''', sold under the [[trade name]] '''Ranexa''' by [[Gilead Sciences]], is a drug to treat [[angina]] that was first approved in 2006.
'''Ranolazine''', sold under the [[trade name]] '''Ranexa''' by [[Gilead Sciences]], is a drug to treat [[angina]] that was first approved in 2006.


==Medical uses==
==Medical uses==
Ranolazine is used to treat chronic [[angina]].<ref name=Banon>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</ref>
Ranolazine is used to treat chronic [[angina]].<ref name=Banon>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</ref> It may be used concomitantly with [[Beta blocker|β blocker]]s, [[Nitrovasodilator|nitrate]]s, [[calcium channel blocker]]s, [[Antiplatelet drug|antiplatelet therapy]], [[Lipid-lowering agent|lipid-lowering therapy]], [[ACE inhibitor]]s, and [[Angiotensin II receptor antagonist|angiotensin receptor blocker]]s.<ref name="Ranexa PI">{{cite web|title=Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information|url=http://www.gilead.com/~/media/Files/pdfs/medicines/cardiovascular/ranexa/ranexa_pi.ashx|publisher=Gilead Sciences, Inc. Foster City, CA 94404|accessdate=8 September 2016}}</ref>


==Contraindications==
==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<ref name=Kloner/> and the FDA label contains a warning for doctors to beware of this effect in their patients.<ref name=Label/> 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.<ref name="FDANews-2006">{{cite news |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108587.htm |title=FDA Approves New Treatment for Chest Pain |publisher=FDA News |date=2006-01-31 |accessdate=2011-03-02}}</ref>
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<ref name=Kloner/> and the FDA label contains a warning for doctors to beware of this effect in their patients.<ref name="Ranexa PI" /> 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.<ref name="FDANews-2006">{{cite news |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108587.htm |title=FDA Approves New Treatment for Chest Pain |publisher=FDA News |date=2006-01-31 |accessdate=2011-03-02}}</ref>


==Side effects==
==Side effects==
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==Drug interactions==
==Drug interactions==
Ranolazine is metabolized by the [[CYP3A]] enzyme. It also inhibits another metabolizing enzyme, [[CYP2D6|cytochrome CYP2D6]].<ref name=Label/> 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 is metabolized mainly by the [[CYP3A]] enzyme. It also inhibits another metabolizing enzyme, [[CYP2D6|cytochrome CYP2D6]].<ref name="Ranexa PI" /> 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 like [[ketoconazole]], [[clarithromycin]], and [[nelfinavir]] that strongly inhibit CYP3A nor with drugs that activate CYP3A like [[rifampin]] and [[phenobarbital]]. <ref name="Label">{{cite web|title=Prescribing Information (2013)|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021526s026lbl.pdf|website=U.S. Food and Drug Administration}}</ref>
Ranolazine should not be used with drugs like [[ketoconazole]], [[clarithromycin]], and [[nelfinavir]] that strongly inhibit CYP3A nor with drugs that activate CYP3A like [[rifampin]] and [[phenobarbital]].<ref name="Ranexa PI" />


For drugs that are moderate CYP3A inhibitors like [[diltiazem]], [[verapamil]], [[erythromycin]], the dose of ranolazine should be reduced.<ref name=Label/>
For drugs that are moderate CYP3A inhibitors like [[diltiazem]], [[verapamil]], [[erythromycin]], the dose of ranolazine should be reduced.<ref name="Ranexa PI" />


Drugs that are metabolized by CYP2D6 like [[tricyclic antidepressants]] may need to be given at reduced doses when administered with ranolazine.<ref name=Label/>
Drugs that are metabolized by CYP2D6 like [[tricyclic antidepressants]] may need to be given at reduced doses when administered with ranolazine.<ref name="Ranexa PI" />


==Mechanism of action==
==Mechanism of action==
Ranolazine inhibits the late inward sodium current in heart muscle.<ref>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 PMCID 1861316</ref> Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle.<ref name=Kloner/>
Ranolazine inhibits persistent or late inward sodium current (''I''<sub>Na</sub>) in heart muscle<ref>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 PMCID 1861316</ref> in a variety of [[Sodium_channel#Voltage-gated|voltage-gated sodium channel]]s.<ref>{{cite journal|last1=Sokolov|first1=S|last2=Peters|first2=CH|last3=Rajamani|first3=S|last4=Ruben|first4=PC|title=Proton-dependent inhibition of the cardiac sodium channel Na<sub>v</sub>1.5 by ranolazine|journal=Frontiers in Pharmacology|date=2013|volume=4|pages=78|doi=10.3389/fphar.2013.00078|pmid=23801963|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689222/pdf/fphar-04-00078.pdf|accessdate=8 September 2016|pmc=3689222}}</ref> Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle.<ref name=Kloner/> The [[Drug-induced QT prolongation|QT prolongation effect]] of ranolazine on the surface electrocardiogram is the result of inhibition of [[hERG |''I''<sub>Kr</sub>]], which prolongs the ventricular [[action potential]].<ref name="Ranexa PI" />


==Legal status==
==Legal status==
⚫
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.<ref name=Kloner/> In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.<ref name=Kloner/> In April 2008 ranolazine was approved by the European EMEA for use in angina.<ref>EMEA [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000805/human_med_001009.jsp&mid=WC0b01ac058001d124 Ranolazine page at the EMEA]</ref>

⚫
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.<ref name=Kloner/> In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.<ref name=Kloner/> In April 2008 ranolazine was approved by the European EMEA for use in angina.<ref>EMEA [http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000805/human_med_001009.jsp&mid=WC0b01ac058001d124 Ranolazine page at the EMEA]</ref>


==History==
==History==

In 1996, CV Therapeutics licensed the North American and European rights to ranolazine from [[Syntex]], a subsidiary of [[Hoffmann-La Roche|Roche]], which had discovered the drug and had developed it through Phase II trials in angina.<ref>CV Therapeutics press release. April 1, 1996 [http://www.thefreelibrary.com/CV+THERAPEUTICS+LICENSES+LATE-STAGE+ANTI-ANGINAL+DRUG+FROM+SYNTEX...-a018143758 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd.]</ref> In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche.<ref>CV Therapeutics, 22 June 2006 [http://www.prnewswire.com/news-releases/cv-therapeutics-acquires-rights-to-ranolazine-in-asia-56223507.html CV Therapeutics Acquires Rights to Ranolazine in Asia]</ref> In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to [[Menarini]].<ref>Thepharmaletter.com 22 September 2008 [http://www.thepharmaletter.com/article/italy-s-menarini-to-pay-up-to-385-million-for-rights-to-cv-thera-s-ranexa Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa]</ref>
In 1996, CV Therapeutics licensed the North American and European rights to ranolazine from [[Syntex]], a subsidiary of [[Hoffmann-La Roche|Roche]], which had discovered the drug and had developed it through Phase II trials in angina.<ref>CV Therapeutics press release. April 1, 1996 [http://www.thefreelibrary.com/CV+THERAPEUTICS+LICENSES+LATE-STAGE+ANTI-ANGINAL+DRUG+FROM+SYNTEX...-a018143758 CV Therapeutics Licenses Late-Stage Anti-Anginal Drug from Syntex (U.S.A.), an Affiliate of Roche Holding Ltd.]</ref> In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche.<ref>CV Therapeutics, 22 June 2006 [http://www.prnewswire.com/news-releases/cv-therapeutics-acquires-rights-to-ranolazine-in-asia-56223507.html CV Therapeutics Acquires Rights to Ranolazine in Asia]</ref> In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to [[Menarini]].<ref>Thepharmaletter.com 22 September 2008 [http://www.thepharmaletter.com/article/italy-s-menarini-to-pay-up-to-385-million-for-rights-to-cv-thera-s-ranexa Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa]</ref>
In 2009, Gilead acquired CV Therapeutics.<ref>Reuters, via the New York Times. 12 March 2009. [http://www.nytimes.com/2009/03/13/business/13biotech.html?_r=0 Gilead, a White Knight, to Buy CV Therapeutics]</ref> In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.<ref>Menarini press release. 18 June 2013 [http://www.menariniapac.com/2013/06/menarini-group-announces-agreement-with-gilead-sciences-to-commercialize-ranexa-ranolazine-in-50-new-countries/ Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries]</ref>
In 2009, Gilead acquired CV Therapeutics.<ref>Reuters, via the New York Times. 12 March 2009. [http://www.nytimes.com/2009/03/13/business/13biotech.html?_r=0 Gilead, a White Knight, to Buy CV Therapeutics]</ref> In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.<ref>Menarini press release. 18 June 2013 [http://www.menariniapac.com/2013/06/menarini-group-announces-agreement-with-gilead-sciences-to-commercialize-ranexa-ranolazine-in-50-new-countries/ Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries]</ref>
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{{reflist|2}}


{{Channelergics}}
{{Piperazines}}
{{Piperazines}}


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[[Category:Alcohols]]
[[Category:Antianginals]]
[[Category:Antianginals]]
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[[Category:Carboxamides]]
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[[Category:Phenol ethers]]
[[Category:Piperazines]]
[[Category:Piperazines]]
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[[Category:Phenol ethers]]
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[[Category:Alcohols]]
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[[Category:Carboxamides]]

Revision as of 15:23, 8 September 2016

Ranolazine
Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa606015
License data
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability35 to 50%
Protein binding~62%
MetabolismExtensive in liver (CYP3A, CYP2D6) and intestine
Elimination half-life7 hours
ExcretionRenal (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 InfoCard100.149.259 Edit this at Wikidata
Chemical and physical data
FormulaC24H33N3O4
Molar mass427.537 g/mol g·mol−1
3D model (JSmol)
ChiralityRacemic 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) checkY
  • Key:XKLMZUWKNUAPSZ-UHFFFAOYSA-N checkY
  (verify)

Ranolazine, sold under the trade name Ranexa by Gilead Sciences, is a drug to treat angina that was first approved in 2006.

Medical uses

Ranolazine is used to treat chronic angina.[1] It may be used concomitantly with β blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.[2]

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[3] and the FDA label contains a warning for doctors to beware of this effect in their patients.[2] 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.[4]

Side effects

The most common side effects are dizziness (11.8%) and constipation (10.9%).[1] Other side effects include headache and nausea.[3]

Drug interactions

Ranolazine is metabolized mainly by the CYP3A enzyme. It also inhibits another metabolizing enzyme, cytochrome CYP2D6.[2] 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 like ketoconazole, clarithromycin, and nelfinavir that strongly inhibit CYP3A nor with drugs that activate CYP3A like rifampin and phenobarbital.[2]

For drugs that are moderate CYP3A inhibitors like diltiazem, verapamil, erythromycin, the dose of ranolazine should be reduced.[2]

Drugs that are metabolized by CYP2D6 like tricyclic antidepressants may need to be given at reduced doses when administered with ranolazine.[2]

Mechanism of action

Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle[5] in a variety of voltage-gated sodium channels.[6] Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle.[3] The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.[2]

Legal status

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.[3] In 2007 the label was updated to make ranolazine a first-line treatment, alone or with other drugs.[3] In April 2008 ranolazine was approved by the European EMEA for use in angina.[7]

History

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.[8] In 2006, CV Therapeutics acquired the remaining worldwide rights to ranolazine from Roche.[9] In 2008 CV Therapeutics exclusively licensed rights for ranolazine in Europe and some other countries to Menarini.[10] In 2009, Gilead acquired CV Therapeutics.[11] In 2013 Gilead expanded the partnership with Menarini to include additional countries, including those in Asia.[12]

References

  1. ^ a b 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
  2. ^ a b c d e f g "Ranexa (ranolazine) Extended-Release Tablets, for Oral Use. Full Prescribing Information". Gilead Sciences, Inc. Foster City, CA 94404. Retrieved 8 September 2016.
  3. ^ a b c d e 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
  4. ^ "FDA Approves New Treatment for Chest Pain". FDA News. 2006-01-31. Retrieved 2011-03-02.
  5. ^ 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 PMCID 1861316
  6. ^ 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 3689222. PMID 23801963. Retrieved 8 September 2016.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ EMEA Ranolazine page at the EMEA
  8. ^ 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.
  9. ^ CV Therapeutics, 22 June 2006 CV Therapeutics Acquires Rights to Ranolazine in Asia
  10. ^ Thepharmaletter.com 22 September 2008 Italy's Menarini to pay up to $385 million for rights to CV Thera's Ranexa
  11. ^ Reuters, via the New York Times. 12 March 2009. Gilead, a White Knight, to Buy CV Therapeutics
  12. ^ Menarini press release. 18 June 2013 Memarii Group announces agreement with Gilead Sciences to commercialize Ranexa® (ranolazine) in 50 new countries
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