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Identification
Name Frovatriptan
Accession Number DB00998 (APRD00270)
Type small molecule
Groups approved
Description

Frovatriptan (Frova®) is a triptan drug developed by Vernalis for the treatment of migraine headaches, in particular those associated with menstruation. The product is licensed to Endo Pharmaceuticals in North America and Menarini in Europe.1 Frovatriptan causes vasoconstriction of arteries and veins that supply blood to the head. It is available as 2.5 mg tablets.

Frovatriptan has mean terminal elimination half-life of approximately 26 hours, which is substantially longer than other triptans.

Frovatriptan is available only by prescription in the United States, where a secondary New Drug Approval (sNDA) was filed in July 20062 and which is currently pending.3 The FDA anticipates completing its review of this application on or before the current PDUFA (Prescription Drug User Fee Act) review date of August 19, 2007. If the sNDA is approved, Frova® will be the only medication indicated in the U.S. for the short-term prevention of menstrual migraine (MM).
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Frovatriptan succinate
Synonyms
Frovatriptan succinate
Salts Not Available
Brand names
Name Company
Frova
Frovelan
Miguard
Brand mixtures Not Available
Categories
  • Vasoconstrictor Agents
  • Anti-inflammatory Agents
  • Anti-migraine Agents
  • Serotonin Agonists
CAS number 158747-02-5
Weight Average: 243.3043
Monoisotopic: 243.137162181
Chemical Formula C14H17N3O
InChI Key InChIKey=XPSQPHWEGNHMSK-SECBINFHSA-N
InChI
InChI=1S/C14H17N3O/c1-16-9-3-5-13-11(7-9)10-6-8(14(15)18)2-4-12(10)17-13/h2,4,6,9,16-17H,3,5,7H2,1H3,(H2,15,18)/t9-/m1/s1
Plain Text
IUPAC Name
(3R)-3-(methylamino)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide
SMILES
CN[C@@H]1CCC2=C(C1)C1=C(N2)C=CC(=C1)C(N)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Carbazoles
  • Tryptamines and Derivatives
Substructures
  • Indoles and Indole Derivatives
  • Aliphatic and Aryl Amines
  • Amino Ketones
  • Carbazoles
  • Pyrroles
  • Benzene and Derivatives
  • Carbamates and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Tryptamines and Derivatives
  • Imines
  • Benzoyl Derivatives
  • Carboxylic Acids and Derivatives
  • Cyclohexenes and Derivatives
  • Benzamides
Pharmacology
Indication For the acute treatment of migraine attacks with or without aura in adults.
Pharmacodynamics Frovatriptan is a second generation triptan 5-HT receptor agonist that binds with high affinity for 5-HT1B and 5-HT1D receptors. It is structurally distinct from, but pharmacologically related to other selective 5-HT1B/1D receptor agonists. Frovatriptan has no significant effects on GABAA mediated channel activity and has no significant affinity for benzodiazepine binding sites. Frovatriptan is believed to act on extracerebral, intracranial arteries and to inhibit excessive dilation of these vessels in migraine. Research has shown that migraine can be caused by the swelling of blood vessels around the brain. Frovatriptan eases the pain associated with migraine by narrowing these blood vessels. Frovatriptan has one of the highest affinities for the 5-HT1B of the second-generation triptan agonists.
Mechanism of action Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT1B receptor agonism.
Absorption Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.
Volume of distribution
  • 4.2 L/kg [males]
  • 3 L/kg [females]
Protein binding Binding to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%.
Metabolism In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.
Route of elimination Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose.
Half life 26 hours
Clearance
  • 220 mL/min [male receiving IV dose of 0.8 mg]
  • 130 mL/min [Female receiving IV dose of 0.8 mg]
Toxicity There is no direct experience of any patient taking an overdose of Frovatriptan. The maximum single dose of frovatriptan given to male and female patients with migraine was 40 mg (16 times the clinical dose) and the maximum single dose given to healthy male subjects was 100 mg (40 times the clinical dose) without significant adverse events.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Endo pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Frova 9 2.5 mg tablet Box 262.31 USD box
Frova 2.5 mg tablet 33.73 USD tablet
Patents
Country Patent Number Approved Expires (estimated)
United States 5464864 1995-11-07 2015-11-07
United States 5962501 1993-12-16 2013-12-16
Canada 2113726 2008-02-19 2012-06-17
Canada 2152630 2005-07-26 2013-12-16
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility Soluble PhysProp
logP 0.9 PhysProp
Predicted Properties
Property Value Source
water solubility 1.23e-01 g/l ALOGPS
logP 1.2 ALOGPS
logP 1.08 ChemAxon Molconvert
logS -3.3 ALOGPS
pKa 17.27 ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 70.91 ChemAxon Molconvert
rotatable bond count 2 ChemAxon Molconvert
refractivity 71.84 ChemAxon Molconvert
polarizability 27.55 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Markus F, Mikko K: Frovatriptan review. Expert Opin Pharmacother. 2007 Dec;8(17):3029-33. Pubmed
  2. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. Pubmed
  3. Balbisi EA: Frovatriptan: a review of pharmacology, pharmacokinetics and clinical potential in the treatment of menstrual migraine. Ther Clin Risk Manag. 2006 Sep;2(3):303-8. Pubmed
  4. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. Pubmed
  5. Elkind AH, Wade A, Ishkanian G: Pharmacokinetics of frovatriptan in adolescent migraineurs. J Clin Pharmacol. 2004 Oct;44(10):1158-65. Pubmed
  6. Jhee SS, Shiovitz T, Crawford AW, Cutler NR: Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review. Clin Pharmacokinet. 2001;40(3):189-205. Pubmed
External Links
Resource Link
PubChem Compound 77992 Link_out
PubChem Substance 46506288 Link_out
ChemSpider 70378 Link_out
BindingDB 50073689 Link_out
Therapeutic Targets Database DAP000063 Link_out
PharmGKB PA10269 Link_out
RxList http://www.rxlist.com/cgi/generic3/frova.htm Link_out
Drugs.com http://www.drugs.com/cdi/frovatriptan.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/fro1622.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Frovatriptan Link_out
ATC Codes
  • N02CC07
AHFS Codes Not Available
PDB Entries Not Available
FDA label show (871 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Citalopram Increased risk of CNS adverse effects
Desvenlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Dihydroergotamine Possible severe and prolonged vasoconstriction
Dihydroergotoxine Possible severe and prolonged vasoconstriction
Ergonovine Possible severe and prolonged vasoconstriction
Ergotamine Possible severe and prolonged vasoconstriction
Escitalopram Increased risk of CNS adverse effects
Fluoxetine Increased risk of CNS adverse effects
Fluvoxamine Increased risk of CNS adverse effects
Methylergonovine Possible severe and prolonged vasoconstriction
Methysergide Possible severe and prolonged vasoconstriction
Nefazodone Increased risk of CNS adverse effects
Paroxetine Increased risk of CNS adverse effects
Sertraline Increased risk of CNS adverse effects
Sibutramine Increased risk of CNS adverse effects
Tramadol Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Tranylcypromine Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.
Trazodone Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Trimipramine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Venlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Zolmitriptan Concomitant use of two serotonin 5-HT1D receptor agonists, such as zolmitriptan and frovatriptan, may result in additive vasoconstrictive effects. Concomitant use within 24 hours is contraindicated.
Food Interactions
  • Food does not affect amount of absorption but delays maximal levels by about 1 hour.
  • Take without regard to meals.
Targets

1. 5-hydroxytryptamine 1D receptor

Pharmacological action: yes
Actions: agonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P28221 Link_out
Gene: HTR1D Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. Pubmed
  3. Comer MB: Pharmacology of the selective 5-HT agonist frovatriptan. Headache. 2002 Apr;42 Suppl 2:S47-53. Pubmed
  4. Tfelt-Hansen P, De Vries P, Saxena PR: Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs. 2000 Dec;60(6):1259-87. Pubmed
  5. Deleu D, Hanssens Y: Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol. 2000 Jul;40(7):687-700. Pubmed
  6. Jahnichen S, Radtke OA, Pertz HH: Involvement of 5-HT1B receptors in triptan-induced contractile responses in guinea-pig isolated iliac artery. Naunyn Schmiedebergs Arch Pharmacol. 2004 Jul;370(1):54-63. Epub 2004 Jun 8. Pubmed
  7. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. Pubmed
  8. Parsons AA, Raval P, Smith S, Tilford N, King FD, Kaumann AJ, Hunter J: Effects of the novel high-affinity 5-HT-receptor ligand frovatriptan in human isolated basilar and coronary arteries. J Cardiovasc Pharmacol. 1998 Aug;32(2):220-4. Pubmed
  9. Balbisi EA: Frovatriptan: a review of pharmacology, pharmacokinetics and clinical potential in the treatment of menstrual migraine. Ther Clin Risk Manag. 2006 Sep;2(3):303-8. Pubmed
  10. Elkind AH, Wade A, Ishkanian G: Pharmacokinetics of frovatriptan in adolescent migraineurs. J Clin Pharmacol. 2004 Oct;44(10):1158-65. Pubmed
  11. Buchan P, Wade A, Ward C, Oliver SD, Stewart AJ, Freestone S: Frovatriptan: a review of drug-drug interactions. Headache. 2002 Apr;42 Suppl 2:S63-73. Pubmed

2. 5-hydroxytryptamine 1B receptor

Pharmacological action: yes
Actions: agonist

This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity

Organism class: human
UniProt ID: P28222 Link_out
Gene: HTR1B Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. Pubmed
  3. Comer MB: Pharmacology of the selective 5-HT agonist frovatriptan. Headache. 2002 Apr;42 Suppl 2:S47-53. Pubmed
  4. Parsons AA, Raval P, Smith S, Tilford N, King FD, Kaumann AJ, Hunter J: Effects of the novel high-affinity 5-HT-receptor ligand frovatriptan in human isolated basilar and coronary arteries. J Cardiovasc Pharmacol. 1998 Aug;32(2):220-4. Pubmed
  5. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. Pubmed
  6. Dodick DW, Sandrini G, Williams P: Use of the sustained pain-free plus no adverse events endpoint in clinical trials of triptans in acute migraine. CNS Drugs. 2007;21(1):73-82. Pubmed
  7. Tfelt-Hansen P, De Vries P, Saxena PR: Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs. 2000 Dec;60(6):1259-87. Pubmed
  8. Deleu D, Hanssens Y: Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol. 2000 Jul;40(7):687-700. Pubmed
  9. Markus F, Mikko K: Frovatriptan review. Expert Opin Pharmacother. 2007 Dec;8(17):3029-33. Pubmed
  10. Balbisi EA: Frovatriptan: a review of pharmacology, pharmacokinetics and clinical potential in the treatment of menstrual migraine. Ther Clin Risk Manag. 2006 Sep;2(3):303-8. Pubmed
  11. Elkind AH, Wade A, Ishkanian G: Pharmacokinetics of frovatriptan in adolescent migraineurs. J Clin Pharmacol. 2004 Oct;44(10):1158-65. Pubmed
  12. Buchan P, Wade A, Ward C, Oliver SD, Stewart AJ, Freestone S: Frovatriptan: a review of drug-drug interactions. Headache. 2002 Apr;42 Suppl 2:S63-73. Pubmed
Enzymes

1. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. Pubmed
  2. Buchan P, Keywood C, Wade A, Ward C: Clinical pharmacokinetics of frovatriptan. Headache. 2002 Apr;42 Suppl 2:S54-62. Pubmed
  3. Buchan P, Wade A, Ward C, Oliver SD, Stewart AJ, Freestone S: Frovatriptan: a review of drug-drug interactions. Headache. 2002 Apr;42 Suppl 2:S63-73. Pubmed
  4. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:45