Frovatriptan

243.30400

243.30

H82Q2D5WA7

DTXSID0023080

N02CC07|N - Nervous system

71.90000

2.61860

1.27g/cm3

515.2ºC at 760mmHg

265.4ºC

1.667

Soluble|In water, 1.9X10+4 mg/L at 25 °C (est)|1.23e-01 g/L

1.01E-10mmHg at 25°C

Henry's Law constant = 6.2X10-13 atm-cu m/mol at 25 °C (est)

pKa = 10.6 (secondary amine) (est)

MW = 379.4 ... white to off-white powder ... soluble in water /Succinate/|Hydroxyl radical reaction rate constant = 3.0X10-10 cu cm/molecule-sec at 25 °C (est)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl frovatriptan succinate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Frovatriptan Succinate/

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.

In large prospective controlled trials, the different triptans have not been associated with serum enzyme elevations or hepatotoxicity; however, the frequency of monitoring in most studies was limited and rates of ALT elevations not reported. There have been rare individual reports of cholestatic hepatitis after the use of triptans, largely associated with zolmitriptan. Typically, the onset of injury was within 1 to 2 weeks of taking several doses of the zolmitriptan for a protracted and severe migraine attack. Recurrent jaundice with intermittent therapy has also been reported (Case 1). The pattern of serum enzyme elevations was mixed or cholestatic, and recovery was complete within 1 to 2 months. Allergic manifestations (rash, fever, eosinophilia) were not present and autoantibodies did not develop.

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.

Safety and effectiveness of Frova in pediatric patients have not been established; therefore, Frova is not recommended for use in patients under 18 years of age. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults.

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

Frovatriptan's production and use as a drug for the treatment of migraine headaches(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6200(SRC), determined from a structure estimation method(2), indicates that frovatriptan is expected to be immobile in soil(SRC). An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will exist primarily as a cation in the environment. Volatilization of frovatriptan from moist soil surfaces is not expected to be an important fate process(SRC) because cations do not volatilize. Frovatriptan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.7X10-9 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6200(SRC), determined from a structure estimation method(2), indicates that frovatriptan is not expected to adsorb to suspended solids and sediment(SRC). An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will primarily exist in cation form in the environment. Volatilization from water surfaces is not expected(SRC) because cations do not volatilize. According to a classification scheme(4), an estimated BCF of 2(SRC), from an estimated log Kow of 1.3(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), frovatriptan, which has an estimated vapor pressure of 3.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase frovatriptan may be removed from the air by wet or dry deposition(SRC). Frovatriptan contains the indole chromophore which absorbs at wavelengths > 290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

Frovatriptan is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Frovatriptan contains the indole chromophore which absorbs at wavelengths > 290 nm(2) and therefore may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 2 was calculated for frovatriptan(SRC), using an estimated log Kow of 1.3(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of frovatriptan can be estimated to be 6200(SRC). According to a classification scheme(2), this estimated Koc value suggests that frovatriptan is expected to be immobile in soil. An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will exist primarily as a cation in the environment and cations generally adsorb to soil and sediment more strongly than their neutral counterparts(4).

An estimated pKa value of 10.6 (secondary amine)(1) indicates that frovatriptan will exist primarily as a cation in the environment. Frovatriptan is expected to be essentially nonvolatile from moist soil and water surfaces since cations do not volatilize. Frovatriptan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.7X10-9 mm Hg(SRC), determined from a fragment constant method(2).

While data specific to frovatriptan were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

It is not known whether frovatriptan is distributed into human breast milk. However, frovatriptan is distributed into the milk of lactating rats with the maximum concentration being four times higher than that seen in blood.

Occupational exposure to frovatriptan may occur through inhalation and dermal contact with this compound at workplaces where frovatriptan is produced or used. Exposure to frovatriptan among the general population may be limited to those administered this substance as a drug. (SRC)

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

The triptans are a group of serotonin receptor agonists that are useful in the therapy of vascular headaches and migraine. The triptans are generally used in low doses for a limited period of time and have not been associated with serum enzyme elevations, but some have been implicated in rare instances of clinically apparent, acute cholestatic hepatitis.

Migraine Headache Agents

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

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.

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.

Endogenous compounds and drugs that bind to and activate SEROTONIN RECEPTORS. Many serotonin receptor agonists are used as ANTIDEPRESSANTS; ANXIOLYTICS; and in the treatment of MIGRAINE DISORDERS. (See all compounds classified as Serotonin Receptor Agonists.)

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]|220 mL/min [male 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.

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.

26 hours|Elimination: Intravenous administration: Approximately 26 hours.

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.

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

/SIGNS AND SYMPTOMS/ 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).|/SIGNS AND SYMPTOMS/ Risk of coronary vasospasm, myocardial ischemia and/or infarction, life-threatening cardiac rhythm disturbances, and death associated with use of 5-HT1 receptor agonists. Use of frovatriptan not recommended in patients with known or suspected ischemic or vasospastic heart disease (see Cautions: Contraindications) or in patients in whom unrecognized coronary artery disease is likely (e.g., postmenopausal women, men older than 40 years of age, patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, family history of coronary artery disease) unless a prior cardiovascular evaluation provides satisfactory evidence that the patient does not have coronary artery disease, ischemic heart disease, or other underlying cardiovascular disease.

(+)-(R)-5,6,7,8-tetrahydro-6-(methylamino)carbazole-3-carboxamide succinate (1:1), monohydrate

Oral: Tablets, film-coated: 2.5 mg (of frovatriptan), Frova, (Endo). /Frovatriptan succinate/

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients