Oral bioavailability of Frovatriptan is 22%-30% and is not affected by food. Although the maximum concentration in the plasma is achieved in 2-3 hours, 60%-70% of this is achieved in 1 hour. A steady state is achieved in 4-5 days. Plasma protein binding is low at 15%. The most unique feature is the relative terminal long half-life of about 26 hours. Frovatriptan is chiefly metabolized by CYP1A2 and is cleared by the kidney and liver making moderate failure of either organ not a limiting factor in treatment[1]. Frovatriptan (0.1, 0.2, and 0.3 mg/kg; a single bolus intraduodenal administration) treatment produces an increase in carotid vascular resistance, which is sustained for at least 5 hours in dogs[2].

Absorption, Distribution and Excretion
Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.
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.
4.2 L/kg [males]
3 L/kg [females]
220 mL/min [male receiving IV dose of 0.8 mg]
130 mL/min [Female receiving IV dose of 0.8 mg]
Protein binding: Low (approximately 15%) to serum proteins.
Volume of distribution (VolD): Steady state : 4.2 L/kg in males and 3.0 L/kg in females.
The absolute bioavailability of an oral dose of frovatriptan is about 20% in males and 30% in females. The rate and extent of absorption are not affected by administration with food.
Elimination: Renal: Following a single oral 2.5 mg dose of radiolabeled frovatriptan, 32% of the dose was recovered in urine. Radiolabeled compounds excreted in the urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan, desmethyl frovatriptan and several other minor metabolites. Fecal: Following a single oral 2.5 mg dose of radiolabeled frovatriptan, 62% of the dose was recovered in feces.
For more Absorption, Distribution and Excretion (Complete) data for FROVATRIPTAN (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
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-HT_1B/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.
In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. 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. 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.
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-HT_1B/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

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Biological Half-Life
26 hours
Elimination: Intravenous administration: Approximately 26 hours.

Toxicity Summary
Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT_1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT_1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT_1B receptor agonism.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
There is no published experience with frovatriptan during breastfeeding. If frovatriptan is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Painful, burning nipples and breast pain have been reported after doses of sumatriptan and other triptans. This has occasionally been accompanied by a decrease in milk production.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A review of four European adverse reaction databases found 26 reported cases of, painful, burning nipples, painful breasts, breast engorgement and/or painful milk ejection in women who took a triptan while nursing. Pain was sometimes intense and occasionally led to decreased milk production. Pain generally subsided with time as the drug was eliminated. The authors proposed that triptans may cause vasoconstriction of the arteries in the breast, nipples, and the arteries surrounding the alveoli and milk ducts, causing a painful sensation and a painful milk ejection reflex.

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Protein Binding
Binding to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%.

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Interactions
Concurrent use /of frovatriptan/ with oral contraceptives has resulted in a 30% increase in the area under the plasma concentration-time curve (AUC) and peak plasma concentration of frovatriptan.
Concurrent use /of frovatriptan/ with ergotamine tartrate has resulted in a 25% decrease in the area under the plasma concentration-time curve (AUC) and peak plasma concentration of frovatriptan.
Concurrent use /of frovatriptan with selective serotonin reuptake inhibitors, such as: fluoxetine, fluvoxamine, paroxetine or sertraline/ may result in weakness, hyperreflexia, and incoordination; careful observation of the patients is recommended.
Concurrent use /of frovatriptan/ with propranolol increased the area under the plasma concentration-time curve (AUC) in males by 60% and in females by 29%. the peak plasma concentration was increased by 23% in males and 16% in females; however the half-life of frovatriptan in both populations, though slightly longer in females was not affected by concomitant administration of propranolol.
A delay of 24 hours between administration of dihydroergotamine, ergotamine, or methylsergide or other 5-hydroxytryptamine agonists and frovatriptan is recommended because of the possibility of additive and/or prolonged vasoconstriction.

J Pharm Sci.2019 Feb;108(2):851-859;Drug Des Devel Ther.2016 Oct 3;10:3225-3236.

Frovatriptan is a member of carbazoles.
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.
Frovatriptan is a Serotonin-1b and Serotonin-1d Receptor Agonist. The mechanism of action of frovatriptan is as a Serotonin 1b Receptor Agonist, and Serotonin 1d Receptor Agonist.
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 2006[2] 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).
See also: Frovatriptan Succinate (has salt form).

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Drug Indication
For the acute treatment of migraine attacks with or without aura in adults.
FDA Label

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Mechanism of Action
Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT_1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT_1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT_1B receptor agonism.
Frovatriptan is believed to act on extracerebral, intracranial arteries and to inhibit excessive dilation of these vessels in migraine. In anesthetized dogs and cats, intravenous administration of frovatriptan produced selective constriction of the carotid vascular bed and had no effect on blood pressure (both species) or coronary resistance (in dogs).
Frovatriptan succinate is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors. Frovatriptan is structurally distinct from, but pharmacologically related to, other selective 5-HT1B/1D receptor agonists (e.g., almotriptan, naratriptan, rizatriptan, sumatriptan). Because the mechanisms involved in the pathogenesis of migraine are not clearly understood, the precise mechanism of action of 5-HT1 receptor agonists in the management of migraine has yet to be established. However, current data suggest that 5-HT1 receptor agonists, including frovatriptan, may ameliorate migraine through selective constriction of certain intracranial blood vessels, inhibition of neuropeptide release, and/or reduced transmission in the trigeminal pain pathway.
Frovatriptan has no significant effects on GABAA mediated channel activity and has not 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.

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Therapeutic Uses
Tryptamines; Carbazoles
Frovatriptan is indicated for the acute treatment of migraine attacks with or without aura in adults. /Included in US product labeling/

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Drug Warnings
As with other 5-HT1 agonists, sensations of pain, tightness, pressure and heaviness have been reported in the chest, throat, neck and jaw after treatment with frova. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials with FROVA. Because 5-HT1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists. Patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome following the use of any 5-HT1 agonist are candidates for further evaluation. If a patient has no response for the first migraine attack treated with frova, the diagnosis of migraine should be reconsidered before frovatriptan is administered to treat any subsequent attacks.
Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. stroke, hemorrhage, transient ischemic attack).
Frovatriptan is not indicated in the management of hemiplegic or basilar migraine. Frovatriptan is not indicated for use in cluster headache, which is present in an older, predominately male population. Safety and efficacy of frovatriptan in this condition have not been established. Frovatriptan is not intended for the prophylactic therapy of migraine.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
For more Drug Warnings (Complete) data for FROVATRIPTAN (11 total), please visit the HSDB record page.

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Pharmacodynamics
Frovatriptan is a second generation triptan 5-HT receptor agonist that binds with high affinity for 5-HT_1B and 5-HT_1D receptors. It is structurally distinct from, but pharmacologically related to other selective 5-HT_1B/1D receptor agonists. Frovatriptan has no significant effects on GABA_A 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-HT_1B of the second-generation triptan agonists.

C14H17N3O

243.31

243.137

158747-02-5

Frovatriptan succinate hydrate;158930-17-7;Frovatriptan succinate;158930-09-7;Frovatriptan-d3 hydrochloride

77992

Typically exists as solid at room temperature

1.27g/cm3

515.2ºC at 760mmHg

265.4ºC

1.01E-10mmHg at 25°C

1.667

2.618

3

2

2

18

333

1

CN[C@@H]1CCC2=C(C3=C(N2)C=CC(C(N)=O)=C3)C1

XPSQPHWEGNHMSK-SECBINFHSA-N

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

(6R)-6-(methylamino)-6,7,8,9-tetrahydro-5H-carbazole-3-carboxamide

SB 209509 Miguard Frovatriptan

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)