Identification

Name
Frovatriptan
Accession Number
DB00998  (APRD00270)
Type
Small Molecule
Groups
Approved, Investigational
Description

Frovatriptan is a triptan drug developed by Vernalis for the treatment of migraine headaches, in particular those associated with menstruation. Frovatriptan causes vasoconstriction of arteries and veins that supply blood to the head.

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Frovatriptan succinate36K05YF32G158930-09-7WHTHWNUUXINXHN-SBSPUUFOSA-N
Frovatriptan succinate monohydrateD28J6W18HY158930-17-7CUETXFMONOSVJA-KLQYNRQASA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FrovaTablet, film coated2.5 mg/1OralLake Erie Medical Dba Quality Care Produts Llc2010-08-182017-06-01Us
FrovaTablet2.5 mgOralEndo Pharmaceuticals2008-01-04Not applicableCanada
FrovaTablet, film coated2.5 mg/1OralEndo Pharmaceuticals, Inc.2001-11-08Not applicableUs
FrovaTablet, film coated2.5 mg/1OralUnit Dose Services2001-11-08Not applicableUs50436 002620180907 15195 1gy6emr
FrovaTablet, film coated2.5 mg/1OralStat Rx USA2001-11-08Not applicableUs
Frovatriptan SuccinateTablet, film coated2.5 mg/1OralPar Pharmaceutical2015-10-05Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-frovatriptanTablet2.5 mgOralApotex Corporation2014-08-11Not applicableCanada
FrovatriptanTablet, film coated2.5 mg/1OralMylan Pharmaceuticals2016-04-29Not applicableUs
Frovatriptan SuccinateTablet, film coated2.5 mg/1OralGlenmark Pharmaceuticals Inc.,Usa2016-03-11Not applicableUs
Teva-frovatriptanTablet2.5 mgOralEndo Pharmaceuticals2015-01-16Not applicableCanada
International/Other Brands
Allergo filmtabletten / Frovelan / Miguard
Categories
UNII
H82Q2D5WA7
CAS number
158747-02-5
Weight
Average: 243.3043
Monoisotopic: 243.137162181
Chemical Formula
C14H17N3O
InChI Key
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
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

Pharmacology

Indication

For the acute treatment of migraine attacks with or without aura in adults.

Associated Conditions
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.

TargetActionsOrganism
A5-hydroxytryptamine receptor 1D
agonist
Human
A5-hydroxytryptamine receptor 1B
agonist
Human
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
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3---(T;T) / (C;T)T AlleleEffect Directly StudiedPatients with this genotype have an increased likelihood of responding to frovatriptan when treating (condition: cluster headache).Details

Interactions

Drug Interactions
DrugInteraction
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe metabolism of Frovatriptan can be decreased when combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbirateroneThe serum concentration of Frovatriptan can be increased when it is combined with Abiraterone.
AcepromazineThe risk or severity of adverse effects can be increased when Frovatriptan is combined with Acepromazine.
AceprometazineThe risk or severity of adverse effects can be increased when Frovatriptan is combined with Aceprometazine.
AcetophenazineThe risk or severity of adverse effects can be increased when Frovatriptan is combined with Acetophenazine.
AlimemazineThe risk or severity of adverse effects can be increased when Frovatriptan is combined with Alimemazine.
AlmotriptanThe risk or severity of adverse effects can be increased when Almotriptan is combined with Frovatriptan.
AlosetronAlosetron may increase the serotonergic activities of Frovatriptan.
AlprazolamThe risk or severity of adverse effects can be increased when Alprazolam is combined with Frovatriptan.
AmikacinThe risk or severity of adverse effects can be increased when Amikacin is combined with Frovatriptan.
Food Interactions
  • Food does not affect amount of absorption but delays maximal levels by about 1 hour.
  • Take without regard to meals.

References

Synthesis Reference

Samir Naik, Anthony Crasto, Narendra Joshi, Sachin Srivastava, "Amorphous frovatriptan succinate and process for the preparation thereof." U.S. Patent US20070299123, issued December 27, 2007.

US20070299123
General References
  1. Markus F, Mikko K: Frovatriptan review. Expert Opin Pharmacother. 2007 Dec;8(17):3029-33. [PubMed:18001261]
  2. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. [PubMed:11735616]
  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:18360605]
  4. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. [PubMed:15311727]
  5. Elkind AH, Wade A, Ishkanian G: Pharmacokinetics of frovatriptan in adolescent migraineurs. J Clin Pharmacol. 2004 Oct;44(10):1158-65. [PubMed:15342617]
  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:11327198]
External Links
Human Metabolome Database
HMDB0015133
KEGG Drug
D07997
PubChem Compound
77992
PubChem Substance
46506288
ChemSpider
70378
BindingDB
50073689
ChEBI
134991
ChEMBL
CHEMBL1279
Therapeutic Targets Database
DAP000063
PharmGKB
PA164754891
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Frovatriptan
ATC Codes
N02CC07 — Frovatriptan
AHFS Codes
  • 28:32.28 — Selective Serotonin Agonists
FDA label
Download (871 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2RecruitingTreatmentAnalgesic Overuse Headache / Medication Overuse Headache1
3CompletedPreventionMenstrually Associated Migraine1
3CompletedTreatmentMigraines2
4CompletedPreventionMigraines1
4CompletedTreatmentMenstrual Migraine (MM) Headaches1
Not AvailableCompletedTreatmentHaemorrhage / Migraines / Spotting1
Not AvailableCompletedTreatmentMigraines1

Pharmacoeconomics

Manufacturers
  • Endo pharmaceuticals inc
Packagers
  • DispenseXpress Inc.
  • Elan Pharmaceuticals Inc.
  • Endo Pharmaceuticals Inc.
  • Pharmaceutical Development and Manufacturing Services Ltd.
  • Stat Rx Usa
  • Warner Chilcott Co. Inc.
Dosage forms
FormRouteStrength
TabletOral2.5 mg
Tablet, film coatedOral2.5 mg/1
Prices
Unit descriptionCostUnit
Frova 9 2.5 mg tablet Box262.31USD box
Frova 2.5 mg tablet33.73USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5962501No1993-12-162013-12-16Us
CA2113726No2008-02-192012-06-17Canada
CA2152630No2005-07-262013-12-16Canada
US5464864No1995-11-072015-11-07Us
US5827871No1995-10-272015-10-27Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySolubleNot Available
logP0.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.123 mg/mLALOGPS
logP1.2ALOGPS
logP1.08ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)14.54ChemAxon
pKa (Strongest Basic)10.42ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area70.91 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity71.84 m3·mol-1ChemAxon
Polarizability27.55 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9934
Blood Brain Barrier+0.986
Caco-2 permeable-0.5794
P-glycoprotein substrateSubstrate0.602
P-glycoprotein inhibitor INon-inhibitor0.8862
P-glycoprotein inhibitor IINon-inhibitor0.7244
Renal organic cation transporterNon-inhibitor0.6147
CYP450 2C9 substrateNon-substrate0.7785
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5
CYP450 1A2 substrateInhibitor0.6997
CYP450 2C9 inhibitorNon-inhibitor0.8842
CYP450 2D6 inhibitorNon-inhibitor0.8614
CYP450 2C19 inhibitorNon-inhibitor0.6656
CYP450 3A4 inhibitorNon-inhibitor0.5316
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5744
Ames testNon AMES toxic0.7623
CarcinogenicityNon-carcinogens0.9456
BiodegradationNot ready biodegradable0.9406
Rat acute toxicity1.9582 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9878
hERG inhibition (predictor II)Inhibitor0.6428
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as carbazoles. These are compounds containing a three ring system containing a pyrrole ring fused on either side to a benzene ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Carbazoles
Direct Parent
Carbazoles
Alternative Parents
Indolecarboxamides and derivatives / 3-alkylindoles / Aralkylamines / Benzenoids / Pyrroles / Heteroaromatic compounds / Primary carboxylic acid amides / Amino acids and derivatives / Dialkylamines / Azacyclic compounds
show 4 more
Substituents
Carbazole / Indolecarboxamide derivative / Indolecarboxylic acid derivative / 3-alkylindole / Indole / Aralkylamine / Benzenoid / Heteroaromatic compound / Pyrrole / Amino acid or derivatives
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
Gene Name
HTR1D
Uniprot ID
P28221
Uniprot Name
5-hydroxytryptamine receptor 1D
Molecular Weight
41906.38 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. [PubMed:11735616]
  3. Comer MB: Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan. Headache. 2002 Apr;42 Suppl 2:S47-53. [PubMed:12028320]
  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:11152011]
  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:10883409]
  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:15185063]
  7. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. [PubMed:15311727]
  8. Parsons AA, Raval P, Smith S, Tilford N, King FD, Kaumann AJ, Hunter J: Effects of the novel high-affinity 5-HT(1B/1D)-receptor ligand frovatriptan in human isolated basilar and coronary arteries. J Cardiovasc Pharmacol. 1998 Aug;32(2):220-4. [PubMed:9700983]
  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:18360605]
  10. Elkind AH, Wade A, Ishkanian G: Pharmacokinetics of frovatriptan in adolescent migraineurs. J Clin Pharmacol. 2004 Oct;44(10):1158-65. [PubMed:15342617]
  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:12028322]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
Gene Name
HTR1B
Uniprot ID
P28222
Uniprot Name
5-hydroxytryptamine receptor 1B
Molecular Weight
43567.535 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Balbisi EA: Frovatriptan succinate, a 5-HT1B/1D receptor agonist for migraine. Int J Clin Pract. 2004 Jul;58(7):695-705. [PubMed:15311727]
  3. Comer MB: Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan. Headache. 2002 Apr;42 Suppl 2:S47-53. [PubMed:12028320]
  4. Parsons AA, Raval P, Smith S, Tilford N, King FD, Kaumann AJ, Hunter J: Effects of the novel high-affinity 5-HT(1B/1D)-receptor ligand frovatriptan in human isolated basilar and coronary arteries. J Cardiovasc Pharmacol. 1998 Aug;32(2):220-4. [PubMed:9700983]
  5. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. [PubMed:11735616]
  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:17190530]
  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:11152011]
  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:10883409]
  9. Markus F, Mikko K: Frovatriptan review. Expert Opin Pharmacother. 2007 Dec;8(17):3029-33. [PubMed:18001261]
  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:18360605]
  11. Elkind AH, Wade A, Ishkanian G: Pharmacokinetics of frovatriptan in adolescent migraineurs. J Clin Pharmacol. 2004 Oct;44(10):1158-65. [PubMed:15342617]
  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:12028322]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Easthope SE, Goa KL: Frovatriptan. CNS Drugs. 2001;15(12):969-76; discussion 977-8. [PubMed:11735616]
  2. Buchan P, Keywood C, Wade A, Ward C: Clinical pharmacokinetics of frovatriptan. Headache. 2002 Apr;42 Suppl 2:S54-62. [PubMed:12028321]
  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:12028322]
  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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  5. Fovatriptan FDA label [File]

Drug created on June 13, 2005 07:24 / Updated on September 22, 2018 22:42