A.Menarini Pharmaceuticals Ltd

FROVEX 2.5 mg film-coated tablets

Each film-coated tablet contains 2.5 mg of frovatriptan (as succinate monohydrate).

Excipients: approximately 100 mg of lactose per tablet.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Round biconvex white film-coated tablet, debossed with “m” on one side and “2.5” on the other.

Acute treatment of the headache phase of migraine attacks with or without aura.

General

Frovatriptan should be taken as early as possible after the onset of a migraine attack but it is also effective when taken at a later stage. Frovatriptan should not be used prophylactically. The tablets should be swallowed whole with water.

If a patient does not respond to the first dose of frovatriptan, a second dose should not be taken for the same attack, since no benefit has been shown.

Frovatriptan may be used for subsequent migraine attacks.

Adults (18 to 65 years of age)

The recommended dose of frovatriptan is 2.5 mg.

If the migraine recurs after initial relief, a second dose may be taken, providing there is an interval of at least 2 hours between the two doses.

The total daily dose should not exceed 5 mg per day.

Children and adolescents (under 18 years)

There are no data of the use of frovatriptan in children and adolescents. Therefore, its use in this age group is not recommended.

Elderly (over 65 years)

Frovatriptan data in patients over 65 years remain limited. Therefore, its use in this category of patients is not recommended.

Renal impairment

No dosage adjustment is required in patients with renal impairment (see 5.2 Pharmacokinetic properties).

Hepatic impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment (see 5.2 Pharmacokinetic properties). Frovatriptan is contraindicated in patients with severe hepatic impairment (see 4.3 Contra-indications).

- patients with a history of myocardial infarction, ischaemic heart disease, coronary vasospasm (e.g. Prinzmetal's angina), peripheral vascular disease, patients presenting with symptoms or signs compatible with ischaemic heart disease.

- Moderately severe or severe hypertension, uncontrolled mild hypertension.

- previous cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

- severe hepatic impairment (Child-Pugh C).

- Concomitant administration of frovatriptan with ergotamine or ergotamine derivatives (including méthysergide) or other 5-hydroxytryptamine (5-HT₁) receptor agonists.

Frovatriptan should only be used where a clear diagnosis of migraine has been established.

Frovatriptan is not indicated for the management of hemiplegic, basilar or ophthalmoplegic migraine.

As with other treatments of migraine attack, it is necessary to exclude other, potentially serious, neurological conditions before treating the headache of patients without a previous diagnosis of migraine, or migraine patients presenting with atypical symptoms. It should be noted that migraineurs present an increased risk of certain cerebral vascular events (eg CVA or TIA).

The safety and efficacy of frovatriptan administered during the aura phase, before the headache phase of migraine, has not been established.

As for other 5-HT₁ receptor agonists, frovatriptan must not be administered to patients at risk of coronary artery disease (CAD, including heavy smokers or users of nicotine substitution therapy without a prior cardiovascular evaluation (see 4.3 Contraindications). Specific attention should be given to post- menopausal women and men over 40 years of age presenting with these risk factors.

However, cardiac evaluations may not identify every patient who has cardiac disease. In very rare cases serious cardiac events have occurred in patients with no underlying cardio-vascular disease when taking 5-HT₁ receptor agonists.

Frovatriptan administration can be associated with transient symptoms including chest pain or tightness which may be intense and involve the throat. (see 4.8 Undesirable effects).

Where such symptoms are thought to indicate ischaemic heart disease no further doses of frovatriptan should be taken and additional investigations should be carried out.

It is advised to wait 24 hours following the use of frovatriptan before administering an ergotamine- type medication. At least 24 hours should be elapse after administration of an ergotamine-containing preparation before frovatriptan is given (see 4.3 Contraindications and 4.5 Interactions with other medicinal products and other forms of interactions).

In case of too frequent use (repeated administration several days in a row corresponding to a misuse of the product), the active substance can accumulate leading to an increase of the side-effects.

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The possibility of MOH should be taken into consideration in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Do not exceed the recommended dose of frovatriptan.

This medicinal product contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Undesirable effects may be more common during concomitant use of triptans (5HT agonists) and herbal preparations containing St John's Wort (Hypericum perforatum).

CONCOMITANT USE CONTRAINDICATED

Ergotamine and ergotamine derivatives (including méthysergide) and other 5 HT1 agonists

Risks of hypertension and coronary artery constriction due to additive vasospastic effects when used concomitantly for the same migraine attack (see 4.3 Contraindications).

Effects can be additive. It is recommended to wait at least 24 hours after administration of ergotamine-type medication before administering frovatriptan. Conversely it is recommended to wait 24 hours after frovatriptan administration before administering an ergotamine-type medication (see 4.4 Special warnings and precautions for use).

CONCOMITANT USE NOT RECOMMENDED

Monoamine Oxidase Inhibitors

Frovatriptan is not a substrate for MAO-A, however a potential risk of serotonin syndrome or hypertension cannot be excluded (see 5.2 Pharmacokinetic Properties).

CONCOMITANT USE REQUIRING CAUTION

Selective serotonin-reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Potential risk of hypertension, coronary vasoconstriction or serotonin syndrome.

Strict adherence to the recommended dose is an essential factor to prevent this syndrome.

Methylergometrine

Risks of hypertension, coronary artery constriction.

Fluvoxamine

Fluvoxamine is a potent inhibitor of cytochrome CYP1A2 and has been shown to increase the blood levels of frovatriptan by 27-49%.

Oral contraceptives

In female subjects taking oral contraceptives, concentrations of frovatriptan were 30% higher than in females not taking oral contraceptives. No increased incidence in the adverse event profile was reported.

Hypericum perforatum (St. John wort) (oral route)

As with other triptans the risk of the occurence of serotonin syndrome may be increased.

Pregnancy

The safety of frovatriptan in pregnant women has not been established.

Studies in animals have shown reproductive toxicity (see 5.3 Preclinical safety data). The potential risk for humans is unknown. Frovatriptan should not be used during pregnancy unless clearly necessary.

Lactation

Frovatriptan and/or its metabolites are excreted in the milk of lactating rats with the maximum concentration in milk being four-fold higher than maximum blood levels. Although it is not known whether frovatriptan or its metabolites are excreted in human breast milk, the administration of frovatriptan to women who are breastfeeding is not recommended, unless is clearly needed. In this case, a 24 hours interval must be observed.

No studies on the effects on the ability to drive and use machines have been performed.

Migraine or treatment with frovatriptan may cause somnolence. Patients should be advised to evaluate their ability to perform complex tasks such as driving during migraine attacks and following administration of frovatriptan.

Frovatriptan has been administered to over 2700 patients at the recommended dose of 2.5 mg and the most common side effects (<10%) include dizziness, fatigue, paraesthesia, headache and vascularflushing. The undesirable effects reported in clinical trials with frovatriptan were transient, generally mild to moderate and resolved spontaneously. Some of the symptoms reported as undesirable effects may be associated symptoms of migraine.

The table below shows all the adverse reactions that are considered to be related to treatment with 2.5 mg frovatriptan and showed a greater incidence than with placebo in the 4 placebo controlled trials. They are listed in decreasing incidence by body-system.

In two open long-term clinical studies the observed effects were not different from those listed above.

There have been post-marketing reports of hypersensitivity reactions of unknown frequency, including cutaneous disorders and anaphylaxis.

There is limited data on overdose with frovatriptan tablets. The maximum single oral dose of frovatriptan given to male and female patients with migraine was 40 mg (16 times the recommended clinical dose of 2.5 mg) and the maximum single dose given to healthy male subjects was 100 mg (40 times the recommended clinical dose). Both were not associated with side effects other than those mentioned in section 4.8. However, one post-marketing serious case of coronary vasospasm has been reported, following intake of 4 times the recommended dose of frovatriptan on three consecutive days, in a patient taking migraine prophylactic treatment with a tricyclic antidepressant. The patient recovered.

There is no specific antidote for frovatriptan. The elimination half-life of frovatriptan is approximately 26 hours (5.2.Pharmacokinetic properties).

The effects of haemodialysis or peritoneal dialysis on serum concentrations of frovatriptan are unknown.

Treatment

In case of overdose with frovatriptan, the patient should be monitored closely for at least 48 hours and be given any necessary supportive therapy.

Pharmacotherapeutic group: selective 5-HT₁ receptor agonists (N: central nervous system)

ATC code: N02C C07

Frovatriptan is a selective agonist for 5-HT receptors, which shows high affinity for 5-HT_1B and 5-HT_1D binding sites in radioligand assays and exhibits potent agonist effects at 5-HT_1B and 5-HT_1D receptors in functional bioassays. It exhibits marked selectivity for 5-HT_1B/1D receptors and has no significant affinity for 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆, α- adrenoreceptors, or histamine receptors. Frovatriptan has no significant affinity for benzodiazepine binding sites.

Frovatriptan is believed to act selectively on extracerebral, intracranial arteries to inhibit the excessive dilatation of these vessels in migraine. At clinically relevant concentrations, frovatriptan produced constriction of human isolated cerebral arteries with little or no effect on isolated human coronary arteries.

The clinical efficacy of frovatriptan for treatment of migraine headache and accompanying symptoms was investigated in three multicenter placebo controlled studies. In these studies frovatriptan 2.5 mg was consistently superior to placebo in terms of headache response at 2 and 4 hours post-dosing and time to first response. Pain relief (reduction from moderate-or severe headache to no or mild pain) after 2 hours was 37-46% for frovatriptan and 21-27% for placebo.

Complete pain relief after 2 hours was 9-14% for frovatriptan and 2-3% for placebo. Maximum efficacy with frovatriptan is reached in 4 hours.

In a clinical study comparing frovatriptan 2.5 mg with sumatriptan 100 mg, the efficacy of frovatriptan 2.5 mg was slightly lower than that of sumatriptan 100 mg at 2 hours and 4 hours. The frequency of undesirable events was slightly lower with frovatriptan 2.5 mg compared to sumatriptan 100 mg. No study comparing frovatriptan 2.5 mg and sumatriptan 50 mg has been carried out.

In elderly subjects in good health, transient changes in systolic arterial pressure (within normal limits) have been observed in some subjects, following a single oral dose of frovatriptan 2.5 mg.

Absorption

After administration of a single oral 2.5 mg dose to healthy subjects, the mean maximum blood concentration of frovatriptan (C_max), reached between 2 and 4 hours, was 4.2 ng/mL in males and 7.0 ng/mL in females. The mean area under the curve (AUC) was 42.9 and 94.0 ng.h/mL for males and females respectively.

The oral bioavailability was 22% in males and 30% in females. The pharmacokinetics of frovatriptan were similar between healthy subjects and migraine patients and there was no difference in pharmacokinetic parameters in the patients during a migraine attack or between attacks.

Frovatriptan displayed generally linear pharmacokinetics over the dose range used in clinical studies (1 mg to 40 mg).

Food had no significant effect on the bioavailability of frovatriptan, but delayed t_max slightly by approximately 1 hour.

Distribution

The steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg was 4.2 L/kg in males and 3.0 L/kg in females.

Binding of frovatriptan to serum proteins was low (approximately 15%). Reversible binding to blood cells at steady state was approximately 60% with no difference between males and females. The blood : plasma ratio was about 2:1 at equilibrium.

Metabolism

Following oral administration of radiolabelled frovatriptan 2.5 mg to healthy male subjects, 32% of the dose was recovered in urine and 62% in faeces. Radiolabelled compounds excreted in urine were unchanged frovatriptan, hydroxy frovatriptan, N-acetyl desmethyl frovatriptan, hydroxy N-acetyl desmethyl frovatriptan, and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan had about 3-fold lower affinity at 5-HT1 receptors than the parent compound. N-acetyl desmethyl frovatriptan had negligible affinity at 5-HT1 receptors. The activity of other metabolites has not been studied.

The results of in vitro studies have provided strong evidence that CYP1A2 is the cytochrome P450 isoenzyme primarily involved in the metabolism of frovatriptan. Frovatriptan does not inhibit or induce CYP1A2 in vitro.

Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 isozymes and therefore has little potential for drug-drug interactions (see 4.5 Interactions with other medicinal products and other forms of interactions). Frovatriptan is not a substrate for MAO.

EliminationThe elimination of frovatriptan is biphasic with a distribution phase prevailing between 2 and 6 hours. Mean systemic clearance was 216 and 132 mL/min in males and females, respectively. Renal clearance accounted for 38% (82 mL/min) and 49% (65 mL/min) of total clearance in males and females, respectively. The terminal elimination half-life is approximately 26 hours, irrespective of the sex of the subjects, however the terminal elimination phase only becomes dominant after about 12 hours.

Gender

AUC and C_max values for frovatriptan are lower (by approximately 50%) in males than in females. This is due, at least in part, to the concomitant use of oral contraceptives. Based on the efficacy or safety of the 2.5 mg dose in clinical use, dosage adjustment with respect to gender is not necessary (See 4.2 Posology and method of administration).

Elderly

In healthy elderly subjects (65 to 77 years) AUC is increased by 73% in males and by 22% in females, compared to younger subjects (18 to 37 years). There was no difference in t_max or t_1/2 between the two populations (see 4.2 Posology and method of administration).

Renal impairment

Systemic exposure to frovatriptan and its t_1/2 were not significantly different in male and female subjects with renal impairment (creatinine clearance 16 - 73 mL/min), compared to that in healthy subjects.

Hepatic impairment

Following oral administration in male and female subjects aged 44 to 57, with mild or moderate hepatic impairment (Child-Pugh grades A and B), mean blood concentrations of frovatriptan were within the range observed in healthy young and elderly subjects. There is no pharmacokinetic or clinical experience with frovatriptan in subjects with severe hepatic impairment (See 4.3 Contra-indications).

During toxicity studies after single or repeated administration, preclinical effects were only observed at exposure levels in excess of the maximum exposure level in man.

Standard genotoxicity studies did not reveal a clinically relevant genotoxic potential of frovatriptan.

Frovatriptan was foetotoxic in rats, but in rabbits foetotoxicity was observed only at maternally toxic dose levels.

Frovatriptan was not potentially carcinogenic in standard rodent carcinogenicity studies and in

p53 (+/-) mouse studies at exposures considerably higher than anticipated in humans.

Tablet core

Lactose, anhydrous

Microcrystalline cellulose

Silica, colloidal anhydrous

Sodium starch glycollate (Type A)

Magnesium stearate

Film Coat

Opadry white:

Hypromellose (E 464)

Titanium dioxide (E 171)

Lactose, anhydrous

Macrogol 3000

Triacetin

Not applicable

Blister: 3 years

Bottle: 2 years

Do not store above 30°C.

Blister: store in the original package.

Bottle: keep the container tightly closed.

Child-proof HDPE bottles containing 30 tablets.

PVC/PE/ACLAR/Aluminium blister packs with 1, 2, 3, 4, 6 and 12 tablets.

Not all pack sizes may be marketed.

No special requirements.

Menarini International Operations Luxembourg S.A.

1, Avenue de la Gare

L-1611, Luxembourg

PA 865/9/1

Date of first authorisation: 17^th May 2002

Date of last renewal: 31^st October 2006

August 2008