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
Fluvatriptan is rapidly absorbed from the duodenum, but its oral bioavailability is low. Radiolabeled compounds excreted in urine include unmetabolized fluvatriptan, hydroxylated fluvatriptan, N-acetyldesmethylfluvatriptan, hydroxylated N-acetyldesmethylfluvatriptan, and desmethylfluvatriptan, as well as several other minor metabolites. Less than 10% of the drug is excreted in urine after oral administration of fluvatriptan. Dosage: Men: 4.2 L/kg; Women: 3 L/kg; Men: 220 mL/min (0.8 mg intravenously); Women: 130 mL/min; Protein binding: Low (approximately 15%). Volume of distribution (VolD): Steady-state: Men 4.2 L/kg, Women 3.0 L/kg. The absolute bioavailability of oral fluvatriptan is approximately 20% in men and approximately 30% in women. Food does not affect the rate and extent of absorption.
Excretion: Renal: Following a single oral dose of 2.5 mg of radiolabeled fluvatriptan, 32% of the dose is excreted in the urine. Radiolabeled compounds excreted in the urine include unmetabolized fluvatriptan, hydroxylated fluvatriptan, N-acetyldesmethylfluvatriptan, hydroxylated N-acetyldesmethylfluvatriptan, desmethylfluvatriptan, and several other minor metabolites. Fecal: Following a single oral dose of 2.5 mg of radiolabeled fluvatriptan, 62% of the dose is recovered in the feces.
For more complete data on absorption, distribution, and excretion of fluvatriptan (7 items), please visit the HSDB record page.
Metabolism/Metabolites
In vitro studies indicate that cytochrome P450 1A2 appears to be the major enzyme involved in the metabolism of fluvatriptan, with metabolites including hydroxylated fluvatriptan, N-acetyldesmethylfluvatriptan, hydroxylated N-acetyldesmethylfluvatriptan, and desmethylfluvatriptan, as well as several other minor metabolites. Desmethylfluvatriptan exhibits a lower affinity for the 5-HT_1B/1D receptor compared to the parent compound. The N-acetyldesmethyl metabolite shows no significant affinity for the 5-HT receptor. The activities of other metabolites are unclear.
In vitro experiments suggest that cytochrome P450 1A2 appears to be the major enzyme involved in the metabolism of fluvatriptan. Following a single oral administration of 2.5 mg of radiolabeled fluvatriptan to healthy male and female subjects, 32% of the dose was excreted in the urine and 62% in the feces. Radiolabeled compounds excreted in urine include unchanged fluvatriptan, hydroxylated fluvatriptan, N-acetyldesmethylfluvatriptan, hydroxylated N-acetyldesmethylfluvatriptan, and desmethylfluvatriptan, as well as several other minor metabolites. Desmethylfluvatriptan exhibits a lower affinity for the 5-HT1B/1D receptor compared to the parent compound. The N-acetyldesmethyl metabolite shows no significant affinity for the 5-HT receptor. The activities of other metabolites are unclear. In vitro studies suggest that cytochrome P450 1A2 appears to be the major enzyme in fluvatriptan metabolism, producing metabolites including hydroxylated fluvatriptan, N-acetyldesmethylfluvatriptan, hydroxylated N-acetyldesmethylfluvatriptan, and desmethylfluvatriptan, as well as several other minor metabolites. Desmethylfluvatriptan exhibits a lower affinity for the 5-HT1B/1D receptor compared to the parent compound. The N-acetyldesmethyl metabolite has no significant affinity for the 5-HT_1B/1D receptor. The activity of other metabolites is unknown.
Elimination pathway: The radiolabeled compound is excreted in the urine, including unmetabolized fluvatriptan, hydroxylated fluvatriptan, N-acetyldesmethylfluvatriptan, hydroxylated N-acetyldesmethylfluvatriptan, and desmethylfluvatriptan, as well as several other minor metabolites. Less than 10% of fluvatriptan is excreted in the urine after oral administration.
Half-life: 26 hours
Elimination: Intravenous administration: approximately 26 hours.

Toxicity Summary
Triptans' anti-migraine effects involve three distinct pharmacological mechanisms: (1) stimulation of presynaptic 5-HT1D receptors, thereby inhibiting dural vasodilation and inflammation; (2) direct inhibition of trigeminal nucleus cell excitability through 5-HT1B/1D receptor agonism in the brainstem; and (3) vasoconstriction of the meninges, dura mater, cerebral vessels, or pia mater due to vascular 5-HT1B receptor agonism.

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Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation There is currently no published experience regarding the use of fluvatriptan during lactation. If a mother of an older infant requires fluvatriptan, this is not a reason to discontinue breastfeeding, but until more data is available, it is best to choose alternative medications, especially when breastfeeding newborns or premature infants. Nipple pain, burning sensation, and breast pain have been reported after taking sumatriptan and other triptans. This is sometimes accompanied by reduced milk production.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
A review of four European adverse reaction databases found 26 reports of nipple pain, burning sensation, breast pain, breast engorgement, and/or painful milk ejection in breastfeeding women taking triptans. The pain was sometimes severe and occasionally led to reduced milk production. The pain usually subsided gradually as the drug was metabolized. The authors suggest that triptans may cause vasoconstriction in the breast, nipple, and arteries surrounding the alveoli and ducts, resulting in pain and painful milk ejection reflex.
Protein binding
The binding rate with serum proteins is low (approximately 15%). The reversible binding rate with blood cells at equilibrium is approximately 60%.
Interactions
Concomitant use of fluvatriptan with oral contraceptives increases the area under the plasma concentration-time curve (AUC) and peak plasma concentration of fluvatriptan by 30%.
Concomitant use of fluvatriptan with ergotamine tartrate decreases the AUC and peak plasma concentration of fluvatriptan by 25%.
Concomitant use of fluvatriptan with selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, or sertraline) may cause muscle weakness, hyperreflexia, and incoordination; close monitoring of patients is recommended.
Concomitant use of fluvatriptan and propranolol increases the AUC by 60% in male patients and 29% in female patients. Peak plasma concentration increases by 23% in male patients and 16% in female patients; however, the half-life of fluvatriptan is not affected by concomitant use of propranolol in either sex, although the half-life is slightly longer in female patients.
Because there may be additive and/or prolonged vasoconstrictive effects, it is recommended to take dihydroergotamine, ergotamine, methylergotamine or other serotonin agonists 24 hours before taking fluvatriptan.

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

Frovatriptan is a carbazole drug. Frovatriptan is a triptan developed by Vernalis for the treatment of migraines, particularly menstrual-related migraines. Frovatriptan causes vasoconstriction in the arteries and veins supplying blood to the head. Frovatriptan is a serotonin 1b and serotonin 1d receptor agonist. Its mechanism of action is as a serotonin 1b and serotonin 1d receptor agonist. Frovatriptan (Frova®) is a triptan developed by Vernalis for the treatment of migraines, particularly menstrual-related migraines. The product has been licensed to Endo Pharmaceuticals in North America and Menarini in Europe. [1] Frovatriptan causes vasoconstriction in the arteries and veins supplying blood to the head. It is available in 2.5 mg tablets. The average terminal elimination half-life of Frovatriptan is about 26 hours, which is much longer than other triptans. In the United States, Frovatriptan is available only by prescription. The U.S. Food and Drug Administration (FDA) filed a second New Drug Application (sNDA) in July 2006[2], which is currently under review.[3] The FDA expects to complete its review of the application on or before August 19, 2007, the review date set by the Prescription Drug User Fee Act (PDUFA). If the sNDA is approved, Frova® will be the only drug approved in the United States for the short-term prevention of menstrual migraine (MM). See also: Fluvatriptan succinate (in saline form).

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

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Mechanism of Action
The anti-migraine effects of triptans involve three distinct pharmacological actions: (1) stimulation of presynaptic 5-HT_1D receptors, thereby inhibiting dural vasodilation and inflammation; (2) direct inhibition of trigeminal nucleus cell excitability via 5-HT_1B/1D receptor agonism in the brainstem; and (3) vasoconstriction of meninges, dura mater, cerebral vessels, or pia mater via vasoconstriction of vascular 5-HT_1B receptor agonism.
Fluvatriptan is thought to act on extracranial and intracranial arteries and inhibit excessive dilation of these vessels during migraines. In anesthetized dogs and cats, intravenous administration of fluvatriptan selectively constricted the carotid vascular bed without affecting blood pressure (both animals) or coronary resistance (dogs).
Fluvatriptan succinate is a selective agonist of 5-hydroxytryptamine (5-HT) 1B and 1D receptors. Fluvatriptan has a different structure than other selective 5-HT1B/1D receptor agonists (e.g., amotriptan, naratriptan, rizatriptan, sumatriptan), but their pharmacological effects are related. Because the pathogenesis of migraine is not fully understood, the exact mechanism of action of 5-HT1 receptor agonists in treating migraine remains to be determined. However, existing data suggest that 5-HT1 receptor agonists, including fluvatriptan, may relieve migraine by selectively constricting certain intracranial blood vessels, inhibiting neuropeptide release, and/or reducing neurotransmission in the trigeminal neuralgia pathway. Fluvatriptan has no significant effect on GABAA-mediated channel activity and has low affinity for benzodiazepine binding sites. Fluvatriptan is thought to act on extracranial and intracranial arteries and inhibit the excessive dilation of these vessels during migraines.
Therapeutic Uses
Tryptamines; Carbazoles
Fluvatriptan is indicated for the treatment of acute migraine attacks in adults with or without aura. /US Product Label Contains/

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Drug Warnings
As with other 5-HT1 receptor agonists, patients may experience chest, throat, neck, and jaw pain, tightness, pressure, and heaviness after taking fluvatriptan. In clinical trials of fluvatriptan, these symptoms were not associated with arrhythmias or ischemic ECG changes. Because 5-HT1 receptor agonists can cause coronary artery spasm, patients should be evaluated for coronary artery disease if they develop signs or symptoms suggestive of angina after taking the medication. Patients with a confirmed diagnosis of coronary artery disease (CAD) and variant angina (Prinzmetal angina) should not receive 5-HT1 receptor agonist treatment. Further evaluation should be performed if patients develop other signs or symptoms suggesting reduced arterial blood flow after using any 5-HT1 receptor agonist, such as ischemic bowel disease or Raynaud's syndrome. If a patient does not respond to initial treatment of migraine attacks with fluvatriptan, the diagnosis of migraine should be re-evaluated before re-administering fluvatriptan for subsequent migraine attacks.
Reports have indicated that patients receiving 5-HT1 receptor agonist treatment have experienced cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events; some of these cases have resulted in death. In some cases, the cerebrovascular event may be primary because the patient's symptoms were mistakenly attributed to migraine when they were not, hence the use of 5-HT1 receptor agonists. It is important to note that migraine sufferers may have an increased risk of certain cerebrovascular events (such as stroke, hemorrhage, and transient ischemic attack).
Fluvatriptan is not indicated for the treatment of hemiplegic or basilar artery type migraine. Fluvatriptan is not indicated for the treatment of cluster headaches, which are more common in the elderly and predominantly male. The safety and efficacy of fluvatriptan in treating cluster headaches have not been established. Fluvatriptan is not indicated for the prophylactic treatment of migraines.
FDA Pregnancy Risk Classification: Category C/Risk cannot be ruled out. Currently, adequate, well-controlled clinical studies are lacking, and animal studies have not shown any risk to the fetus or lack relevant data. Taking this medication during pregnancy may harm the fetus; however, the potential benefits may outweigh the potential risks. For more complete data on drug warnings for FROVATRIPTAN (11 in total), please visit the HSDB records page.

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Pharmacodynamics
Frovatriptan is a second-generation triptan 5-HT receptor agonist that binds with high affinity to both 5-HT_sub>1B and 5-HT_sub>1D receptors. Its structure differs from other selective 5-HT_sub>1B/1D receptor agonists, but is pharmacologically related. Frovatriptan has no significant effect on GABA_sub>A-mediated channel activity and no significant affinity for benzodiazepine binding sites. Frovatriptan is thought to act on extracranial and intracranial arteries and inhibit the excessive dilation of these vessels in migraines. Studies suggest that migraines may be caused by swelling of blood vessels around the brain. Fluvatriptan relieves migraine pain by constricting these blood vessels. Among second-generation triptan agonists, fluvatriptan has the highest affinity for the 5-HT1B receptor.

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.)