Professional Information — 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 CONTRAINDICATIONS). The safety and effectiveness of FROVA have not been established for cluster headache, which is present in an older, predominately male, population.

Dosage and Administration

The recommended dose is a single tablet of FROVA (frovatriptan 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 frovatriptan should not exceed 3 tablets (3 x 2.5 mg per day).

There is no evidence that a second dose of frovatriptan 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.

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 WARNINGS).

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 WARNINGS)

FROVA should not be given to patients with uncontrolled hypertension (see WARNINGS).

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-HT₁ agonist, an ergotamine containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide.

FROVA is contraindicated in patients who are hypersensitive to frovatriptan or any of the inactive ingredients in the tablets.

Adverse Reactions

Serious cardiac events, including some that have been fatal, have occurred following use of 5-HT₁ 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 CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).

Incidence in Controlled Clinical Trials:

Among 1554 patients treated with FROVA in four placebo-controlled trials (Trials 1, 3, 4 and 5 in Table 1), 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 frovatriptan 2.5 mg (i.e., 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 frovatriptan 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 Table 1). These studies involved 2392 patients (1554 frovatriptan 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 frovatriptan 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.

Other Events Observed in Association with FROVA:

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 frovatriptan 2.5 mg and 838 placebo) are included, except those already listed in Table 2, 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: Frequent: dysesthesia and hypoesthesia. Infrequent: tremor, hyperesthesia, migraine aggravated, involuntary muscle contractions, vertigo, ataxia, abnormal gait and speech disorder. Rare: hypertonia, hypotonia, abnormal reflexes and tongue paralysis.

Gastrointestinal: Frequent: vomiting, abdominal pain and diarrhea. Infrequent: dysphagia, flatulence, constipation, anorexia, esophagospasm and saliva increased. Rare: change in bowel habits, cheilitis, eructation, gastroesophageal reflux, hiccup, peptic ulcer, salivary gland pain, stomatitis and toothache.

Body as a whole: Frequent: pain. Infrequent: asthenia, rigors, fever, hot flushes and malaise. Rare: feeling of relaxation, leg pain and edema mouth.

Psychiatric: Frequent: insomnia and anxiety. Infrequent: confusion, nervousness, agitation, euphoria, impaired concentration, depression, emotional lability, amnesia, thinking abnormal and depersonalization. Rare: depression aggravated, abnormal dreaming and personality disorder.

Musculoskeletal: Infrequent: myalgia, back pain, arthralgia, arthrosis, leg cramps and muscle weakness.

Respiratory: Frequent: sinusitis and rhinitis. Infrequent: pharyngitis, dyspnea, hyperventilation and laryngitis.

Vision disorders: Frequent: vision abnormal. Infrequent: eye pain, conjunctivitis and abnormal lacrimation.

Skin and appendages: Frequent: sweating increased. Infrequent: pruritis, and bullous eruption.

Hearing and vestibular disorders: Frequent: tinnitus. Infrequent: ear ache, and hyperacusis.

Heart rate and rhythm: Frequent: palpitation. Infrequent: tachycardia. Rare: bradycardia.

Metabolic and nutritional disorders: Infrequent: thirst and dehydration. Rare: hypocalcemia and hypoglycemia.

Special senses, other disorders: Infrequent: taste perversion.

Urinary system disorders: Infrequent: micturition frequency and polyuria. Rare: nocturia, renal pain and abnormal urine.

Cardiovascular disorders, general: Infrequent: abnormal ECG.

Platelet, bleeding and clotting disorders: Infrequent: epistaxis. Rare: purpura.

Autonomic nervous system: Rare: syncope.

Postmarketing Experience

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: Seizure.

Drug Interactions

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 CONTRAINDICATIONS).

Concomitant use of other 5HT_1B/1D agonists within 24 hours of FROVA treatment is not recommended (see CONTRAINDICATIONS).

Selective Serotonin Reuptake Inhibitors / Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. (See WARNINGS).

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-HT₁ agonists, as a class, have not been associated with drug abuse.

Overdosage

There is no direct experience of any patient taking an overdose of FROVA. 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.

The effects of hemo- or peritoneal dialysis on blood concentrations of frovatriptan are unknown.

Description

FROVA (frovatriptan succinate) tablets contain frovatriptan succinate, a selective 5-hydroxy-tryptamine₁ (5-HT_1B/1D) receptor subtype agonist, as the active ingredient. Frovatriptan 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 C₁₄H₁₇N₃O.C₄H₆O₄.H₂O, representing a molecular weight of 379.4. Frovatriptan succinate is a white to off-white powder that is soluble in water. Each FROVA tablet for oral administration contains 3.91 mg frovatriptan succinate, equivalent to 2.5 mg of frovatriptan 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.

Clinical Pharmacology

Mechanism of Action

Frovatriptan is a 5-HT receptor agonist that binds with high affinity for 5-HT_1B and 5-HT_1D receptors. 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. 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).

Pharmacokinetics

Mean maximum blood concentrations (C_max) 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 t_max 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-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.

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.

Special Populations

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 t_max or t_1/2 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.

Drug Interactions (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 C_max and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives compared to those not taking oral contraceptives.

Ergotamine:

The AUC and C_max 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 C_max 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.

Clinical Trials

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 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.

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 FROVA.

Clinical Studies

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 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.

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 FROVA.

How Supplied / Storage and Handling

FROVA tablets, containing 2.5 mg of frovatriptan (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.

Rx Only

Manufactured for:
Endo Pharmaceuticals Inc.
Chadds Ford, PA 19317

Manufactured by:
Almac Pharma Services Limited
Craigavon, BT63 5UA, UK

FROVA is a registered trademark of Vernalis Development Limited.

© 2007 Endo Pharmaceuticals Inc.                                                            PX544-3 / April, 2007

Patient Counseling Information

Physicians should instruct their patients to read the patient package insert before taking FROVA. See PATIENT INFORMATION 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).