化合物详情

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).

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 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).

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).

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).

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.

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).

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)

Frovatriptan's production and use as a drug for the treatment of migraine headaches may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 3.7X10-9 mm Hg at 25 °C indicates frovatriptan will exist solely in the particulate phase in the atmosphere. Particulate-phase frovatriptan will be removed from the atmosphere by wet or dry deposition. Frovatriptan contains the indole chromophore which absorbs at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight. If released to soil, frovatriptan is expected to have no mobility based upon an estimated Koc of 6200. An estimated pKa value of 10.6 (secondary amine) indicates that frovatriptan will exist primarily as a cation in the environment. Vo...

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.

As with other 5-HT1 receptor agonists, there is no specific antidote for frovatriptan. The elimination half-life of frovatriptan is 26 hours, therefore if overdose occurs, the patient should be monitored closely for at least 48 hours and be given any necessary symptomatic treatment. (L1712)

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.

Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.

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.

/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 d...

No indication of carcinogenicity to humans (not listed by IARC).

References: DOI:10.1016/j.drudis.2019.09.022

/OTHER TOXICITY INFORMATION/ When pigmented rats were given a single oral dose of 5 mg/kg of radiolabeled frovatriptan, the radioactivity in the eye after 28 days was 87% of the value measured after 8 hours. This suggests that frovatriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin rich tissues over time, this raises the possibility that frovatriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with frovatriptan were noted in the toxicity studies. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials and no specific recommendations for ophthalmologic monitoring are made, prescribers should be aware of the possibility...

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.

/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/

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.