"Nov. 13, 2012 -- Women who get migraines are more likely than those who don't to develop small areas of tissue changes in their brains, a new study shows. At the same time, these changes do not seem to affect the women's thinking or memory."...
Mechanism of Action
Frovatriptan is a 5-HT receptor agonist that binds with high affinity for 5-HT1B and 5-HT1D receptors. 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. 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).
Mean maximum blood concentrations (Cmax) in patients are achieved approximately 2-4 hours after administration of a single oral dose of frovatriptan 2.5 mg. The absolute bioavailability of an oral dose of frovatriptan 2.5 mg in healthy subjects is about 20% in males and 30% in females. Food has no significant effect on the bioavailability of frovatriptan, but delays tmax by one hour.
Binding of frovatriptan to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%, resulting in a blood:plasma ratio of about 2:1 in both males and females. The mean steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg is 4.2 L/kg in males and 3.0 L/kg in females.
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.
After an intravenous dose, mean clearance of frovatriptan was 220 and 130 mL/min in males and females, respectively. Renal clearance accounted for about 40% (82 mL/min) and 45% (60 mL/min) of total clearance in males and females, respectively. The mean terminal elimination half-life of frovatriptan in both males and females is approximately 26 hours.
The pharmacokinetics of frovatriptan are similar in migraine patients and healthy subjects.
Age: Mean AUC of frovatriptan was 1.5- to 2-fold higher in healthy elderly subjects (age 65 -77 years) compared to those in healthy younger subjects (age 21-37 years). There was no difference in tmax or t1/2 between the two populations.
Gender: There was no difference in the mean terminal elimination half-life of frovatriptan in males and females. Bioavailability was higher, and systemic exposure to frovatriptan was approximately 2-fold greater, in females than males, irrespective of age.
Renal Impairment: Since less than 10% of FROVA is excreted in urine after an oral dose, it is unlikely that the exposure to frovatriptan will be affected by renal impairment. The pharmacokinetics of frovatriptan following a single oral dose of 2.5 mg was not different in patients with renal impairment (5 males and 6 females, creatinine clearance 16-73 mL/min) and in subjects with normal renal function.
Hepatic Impairment: There is no clinical or pharmacokinetic experience with FROVA in patients with severe hepatic impairment. The AUC in subjects with mild (Child-Pugh 5 - 6) to moderate (Child-Pugh 7-9) hepatic impairment is about twice as high as the AUC in young, healthy subjects, but within the range found among normal elderly subjects.
Race: The effect of race on the pharmacokinetics of frovatriptan has not been examined.
(see also PRECAUTIONS: DRUG INTERACTIONS)
Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 (isozymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) in vitro at concentrations up to 250 to 500-fold higher than the highest blood concentrations observed in man at a dose of 2.5 mg. No induction of drug metabolizing enzymes was observed following multiple dosing of frovatriptan to rats or on addition to human hepatocytes in vitro. Although no clinical studies have been performed, it is unlikely that frovatriptan will affect the metabolism of co-administered drugs metabolized by these mechanisms.
Oral contraceptives: Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives compared to those not taking oral contraceptives.
Ergotamine: The AUC and Cmax of frovatriptan (2 x 2.5 mg dose) were reduced by approximately 25% when co-administered with ergotamine tartrate.
Propranolol: Propranolol increased the AUC of frovatriptan 2.5 mg in males by 60% and in females by 29%. The Cmax of frovatriptan was increased 23% in males and 16% in females in the presence of propranolol. The tmax as well as half-life of frovatriptan, though slightly longer in the females, were not affected by concomitant administration of propranolol.
Moclobemide: The pharmacokinetic profile of frovatriptan was unaffected when a single oral dose of frovatriptan 2.5 mg was administered to healthy female subjects receiving the MAO-A inhibitor, moclobemide, at an oral dose of 150 mg bid for 8 days.
The efficacy of FRO V A in the acute treatment of migraine headaches was demonstrated in five randomized, double-blind, placebo-controlled, outpatient trials. Two of these were dose-finding studies in which patients were randomized to receive doses of frovatriptan ranging from 0.5 - 40 mg. The three studies evaluating only one dose studied 2.5 mg. In these controlled short-term studies combined, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 - 69). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed for up to 24 hours after dosing. The associated symptoms nausea, vomiting, photophobia and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post dose. In two of the trials a second dose of FROVA was provided after the initial treatment, to treat recurrence of the headache within 24 hours. Other medication, excluding other 5-HT1 agonists and ergotamine containing compounds, was permitted from 2 hours after the first dose of FROVA. The frequency and time to use of additional medications were also recorded.
In all five placebo-controlled trials, the percentage of patients achieving a headache response 2 hours after treatment was significantly greater for those taking FROVA compared to those taking placebo (Table 1).
Lower doses of frovatriptan (1 mg or 0.5 mg) were not effective at 2 hours. Higher doses (5 mg to 40 mg) of frovatriptan showed no added benefit over 2.5 mg but did cause a greater incidence of adverse events.
Table 1: Percentage of Patients with Headache Response (Mild
or No Headache) 2 Hours Following Treatmenta
(frovatriptan 2.5 mg)
|1||42%* (n=90)||22% (n=91)|
|4||46%** (n=672)||27% (n=347)|
|5||37%** (n=438)||23% (n=225)|
|a ITT observed data, excludes patients who had missing data or were asleep; *p <0.05, **p <0.001 in comparison with placebo|
Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because trials are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.
The estimated probability of achieving an initial headache response by 2 hours following treatment is depicted in Figure 1.
Figure 1: Estimated Probability of Achieving Initial Headache
Response Within 2 Hours
Figure 1 shows a Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with frovatriptan 2.5 mg or placebo. The probabilities displayed are based on pooled data from four placebo-controlled trials described in Table 1 (Trials 1, 3, 4 and 5). Patients who did not achieve a response were censored at 24 hours.
In patients with migraine-associated nausea, photophobia and phonophobia at baseline there was a decreased incidence of these symptoms in FROVA treated patients compared to placebo. The estimated probability of patients taking a second dose or other medication for their migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
Figure 2: Estimated Probability of Patients Taking a Second
Dose or Other Medication for Migraine Over the 24 Hours Following the Initial
Dose of Study Treatment
Figure 2 is a Kaplan-Meier plot showing the probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study medication based on the data from four placebo-controlled trials described in Table 1 (Trials 1, 3, 4 and 5). The plot includes those patients who had a response to the initial dose and those who did not. The protocols did not permit remedication within 2 hours of the initial dose.
Efficacy was unaffected by a history of aura; gender; age, or concomitant medications commonly used by migraine patients.
Last reviewed on RxList: 4/17/2012
This monograph has been modified to include the generic and brand name in many instances.
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