Frova Information
Frova () Description
Frova () (Frova () triptan succinate) tablets contain Frova () triptan succinate, a selective 5-hydroxy-tryptamine (5-HT) receptor subtype agonist, as the active ingredient. Frova () triptan succinate is chemically designated as R-(+) 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monosuccinate monohydrate and it has the following structure:
The empirical formula is CHNO.CHO.HO, representing a molecular weight of 379.4. Frova () triptan succinate is a white to off-white powder that is soluble in water. Each Frova () tablet for oral administration contains 3.91 mg Frova () triptan succinate, equivalent to 2.5 mg of Frova () triptan base. Each tablet also contains the inactive ingredients lactose NF, microcrystalline cellulose NF, colloidal silicon dioxide NF, sodium starch glycolate NF, magnesium stearate NF, hydroxypropylmethylcellulose USP, polyethylene glycol 3000 USP, triacetin USP, and titanium dioxide USP.
Frova () Clinical Pharmacology
Frova () triptan is a 5-HT receptor agonist that binds with high affinity for 5-HT and 5-HT receptors. Frova () triptan has no significant effects on GABA mediated channel activity and has no significant affinity for benzodiazepine binding sites.
Frova () triptan 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 Frova () triptan 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 (C) in patients are achieved approximately 2 - 4 hours after administration of a single oral dose of Frova () triptan 2.5 mg. The absolute bioavailability of an oral dose of Frova () triptan 2.5 mg in healthy subjects is about 20% in males and 30% in females. Food has no significant effect on the bioavailability of Frova () triptan, but delays t by one hour.
Binding of Frova () triptan 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 Frova () triptan following intravenous administration of 0.8 mg is 4.2 L/kg in males and 3.0 L/kg in females.
In vitro,
1B/1D
After an intravenous dose, mean clearance of Frova () triptan 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 Frova () triptan in both males and females is approximately 26 hours.
The pharmacokinetics of Frova () triptan are similar in migraine patients and healthy subjects.
The efficacy of Frova () 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 Frova () triptan 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-HT 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 Frova () triptan (1 mg or 0.5 mg) were not effective at 2 hours. Higher doses (5 mg to 40 mg) of Frova () triptan showed no added benefit over 2.5 mg but did cause a greater incidence of adverse events.
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 Frova () triptan 2.5 mg or placebo. The probabilities displayed are based on pooled data from four placebo-controlled trials described in (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 (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 Frova () .
Frova () Indications And Usage
Frova () is indicated for the acute treatment of migraine attacks with or without aura in adults.
Frova () is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see ). The safety and effectiveness of Frova () have not been established for cluster headache, which is present in an older, predominately male, population.
Frova () Contraindications
Frova () should not be given to patients with ischemic heart disease (e.g. angina pectoris, history of myocardial infarction, or documented silent ischemia), or to patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal’s variant angina or other significant underlying cardiovascular disease (see ).
Frova () should not be given to patients with cerebrovascular syndromes including (but not limited to) strokes of any type as well as transient ischemic attacks.
Frova () should not be given to patients with peripheral vascular disease including (but is not limited to) ischemic bowel disease (see )
Frova () should not be given to patients with uncontrolled hypertension (see ).
Frova () should not be administered to patients with hemiplegic or basilar migraine.
Frova () should not be used within 24 hours of treatment with another 5-HT agonist, an ergotamine containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide.
Frova () is contraindicated in patients who are hypersensitive to Frova () triptan or any of the inactive ingredients in the tablets.
Frova () Warnings
Frova () should only be used where a clear diagnosis of migraine has been established.
Because of the potential of this class of compound (5-HT agonists) to cause coronary vasospasm, Frova () triptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see ). It is strongly recommended that Frova () triptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic, or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, Frova () triptan should not be administered (see ).
For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of Frova () triptan take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received Frova () triptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following administration of Frova () in these patients with risk factors.
It is recommended that patients who are intermittent long-term users of 5-HT agonists, including Frova () and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use Frova () .
The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease would be inadvertently exposed to Frova () triptan.
In young healthy subjects, there were statistically significant increases in systolic and diastolic blood pressure after single doses of 80 mg Frova () triptan (32 times the clinical dose) and above. These increases were transient, resolved spontaneously and were not clinically significant. At the recommended dose of 2.5 mg, transient changes in systolic blood pressure were recorded in some elderly subjects (65 - 77 years). Any increases were generally small, resolved spontaneously, and blood pressure remained within the normal range. Frova () triptan is contraindicated in patients with uncontrolled hypertension (see ).
An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT agonist in a study evaluating subjects undergoing cardiac catheterization.
Frova () Precautions
Physicians should instruct their patients to read the patient package insert before taking Frova () . See at the end of this labeling for the text of the separate leaflet provided for patients.
Patients should be cautioned about the risk of serotonin syndrome with the use of Frova () or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Due to a theoretical risk of a pharmacodynamic interaction, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and Frova () within 24 hours of each other should be avoided (see ).
Concomitant use of other 5HT agonists within 24 hours of Frova () treatment is not recommended (see ).
Selective Serotonin Reuptake Inhibitors / Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
WARNINGS
Carcinogenesis:
Impairment of Fertility:
2
When pregnant rats were administered Frova () triptan during the period of organogenesis at oral doses of 100, 500 and 1000 mg/kg/day (equivalent to 130, 650 and 1300 times the maximum recommended human dose [MRHD] on a mg/m basis) there were dose related increases in incidences of both litters and total numbers of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis, and hydroureters. A no-effect dose for renal effects was not established. This signifies a syndrome of related effects on a specific organ in the developing embryo in all treated groups, which is consistent with a slight delay in fetal maturation. This delay was also indicated by a treatment related increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups. Slightly lower fetal weights and an increased incidence of early embryonic deaths in treated rats were observed; although not statistically significant compared to control, the latter effect occurred in both the embryo-fetal developmental study and in the prenatal-postnatal developmental study. There was no evidence of this latter effect at the lowest dose level studied, 100 mg/kg/day (equivalent to 130 times the MRHD on a mg/m basis). When pregnant rabbits were dosed throughout organogenesis at doses up to 80 mg/kg/day (equivalent to 210 times the MRHD on a mg/m basis) no effects on fetal development were observed.
There are no adequate and well-controlled studies in pregnant women; therefore, Frova () triptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Frova () Adverse Reactions
Serious cardiac events, including some that have been fatal, have occurred following use of 5-HT agonists. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation (see , and ).
Among 1554 patients treated with Frova () in four placebo-controlled trials (Trials 1, 3, 4 and 5 in ), only 1% (16) patients withdrew because of treatment-emergent adverse events. In a long term, open-label study where patients were allowed to treat multiple migraine attacks with Frova () for up to 1 year, 5% (26/496) patients discontinued due to treatment-emergent adverse events.
The treatment-emergent adverse events that occurred most frequently following administration of Frova () triptan 2.5 mg (in at least 2% of patients), and at an incidence ≥1% greater than with placebo, in the four placebo-controlled trials were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, hot or cold sensation and chest pain.
Table 2 lists treatment-emergent adverse events reported within 48 hours of drug administration that occurred with Frova () triptan 2.5 mg at an incidence of ≥ 2% and more often than on placebo, in the first attack in four placebo-controlled trials (Trials 1, 3, 4 and 5 in ). These studies involved 2392 patients (1554 Frova () triptan 2.5 mg and 838 placebo). The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these incidence estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ.
Other events that occurred at ≥2% on Frova () triptan that were equally or more common in the placebo group were somnolence and nausea.
Frova () is generally well tolerated. The incidence of adverse events in clinical trials did not increase when up to 3 doses were used within 24 hours. The majority of adverse events were mild or moderate and transient. The incidence of adverse events in four placebo-controlled clinical trials was not affected by gender, age or concomitant medications commonly used by migraine patients. There were insufficient data to assess the impact of race on the incidence of adverse events.
In the paragraphs that follow, the incidence of less commonly reported adverse events in four placebo-controlled trials are presented. Variability associated with adverse event reporting, the terminology used to describe adverse events etc, limit the value of the incidence estimates provided. The incidence of each adverse event is calculated as the number of patients reporting the event at least once divided by the number of patients who used Frova () . All adverse events reported within 48 hours of drug administration in the first attack in four placebo controlled trials involving 2392 patients (1554 Frova () triptan 2.5 mg and 838 placebo) are included, except those already listed in , those too general to be informative, those not reasonably associated with the use of the drug and those which occurred at the same or a greater incidence in the placebo group. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in at least 1/100 patients, infrequent adverse events are those occurring in between 1/100 and 1/1000 patients, and rare adverse events are those occurring in fewer than 1/1000 patients.
Central and peripheral nervous system:
Gastrointestinal:
Body as a whole:
Psychiatric:
Musculoskeletal:
Respiratory:
Vision disorders:
Skin and appendages:
Hearing and vestibular disorders:
Heart rate and rhythm:
Metabolic and nutritional disorders:
Special senses, other disorders:
Urinary system disorders:
Cardiovascular disorders, general:
Platelet, bleeding and clotting disorders:
Autonomic nervous system:
Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. Information is often incomplete so that a definite causal relationship to drug exposure can often not be established.
Central and peripheral nervous system:
Frova () Drug Abuse And Dependence
Although the abuse potential of Frova () has not been specifically assessed in clinical trials, no abuse of, tolerance to, withdrawal from, or drug-seeking behavior was observed in patients who received Frova () . The 5-HT agonists, as a class, have not been associated with drug abuse.
Frova () Overdosage
There is no direct experience of any patient taking an overdose of Frova () . The maximum single dose of Frova () triptan 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-HT receptor agonists, there is no specific antidote for Frova () triptan. The elimination half-life of Frova () triptan 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.
The effects of hemo- or peritoneal dialysis on blood concentrations of Frova () triptan are unknown.
Frova () Dosage And Administration
The recommended dose is a single tablet of Frova () (Frova () triptan 2.5 mg) taken orally with fluids.
If the headache recurs after initial relief, a second tablet may be taken, providing there is an interval of at least 2 hours between doses. The total daily dose of Frova () triptan should not exceed 3 tablets (3 x 2.5 mg per day).
There is no evidence that a second dose of Frova () triptan is effective in patients who do not respond to a first dose of the drug for the same headache.
The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established.
Frova () How Supplied
Frova () tablets, containing 2.5 mg of Frova () triptan (base) as the succinate, are available as round, white, film-coated tablets debossed with 2.5 on one side and “E” on the other side. The tablets are available in:
Blister card of 9 tablets, 1 blister card per carton (NDC 63481-025-09)
Store at controlled room temperature, 25°C (77°F) excursions permitted to 15 - 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. Protect from moisture.
U.S. Patent Nos 5,962,501, 5,827,871, 5,637,611 and 5,464,864 and 5,616,603.
Manufactured for: Chadds Ford, PA 19317
Manufactured by:Almac Pharma Services LimitedCraigavon, BT63 5UA, UK
Frova () is a registered trademark of Vernalis Development Limited.
© 2007 Endo Pharmaceuticals Inc. PX544-3 / April, 2007
Frova ()
Frova () Package Label - Principal Display Panel – Tablet Blister Pack
Frova () Package Label - Principal Display Panel – Tablet Blister Pack Professional Sample
