Frovamigran

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FROVAMIGRAN (FROVAMIGRAN)

Composition:

Active substance: frovatriptan

One tablet contains 3.91 mg of frovatriptan succinate monohydrate, equivalent to 2.5 mg of frovatriptan;

Excipients: anhydrous lactose, microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, titanium dioxide (E 171), hypromellose, polyethylene glycol 3000, triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets, embossed with “m” on one side and “2.5” on the other.

Pharmacotherapeutic group.

Analgesics. Drugs used for the treatment of migraine. Selective serotonin 5HT₁-receptor agonist. Frovatriptan.

ATC code N02CC07.

Pharmacological Properties

Pharmacodynamics. Frovatriptan is a selective 5-HT receptor agonist with high affinity for 5-HT_1B and 5-HT_1D binding sites, as demonstrated by radioligand binding assays, and shows potent agonist activity at 5-HT_1B and 5-HT_1D receptors in functional bioassays.

This compound exerts selective action on 5-HT_1B/1D receptors and has no significant affinity for 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆, α-adrenergic, or histamine receptors. Frovatriptan has no significant affinity for benzodiazepine binding sites. It is believed that frovatriptan selectively acts on extracerebral intracranial arteries, preventing excessive dilation of these vessels during migraine attacks. At clinically relevant concentrations, frovatriptan causes constriction of isolated human cerebral arteries, while having little or no effect on human coronary arteries.

The clinical efficacy of frovatriptan in the treatment of migraine and associated headache symptoms was evaluated in three multicenter, placebo-controlled studies. In these trials, frovatriptan 2.5 mg consistently outperformed placebo both in terms of headache response at 2 and 4 hours after dosing and time to first response. The headache relief rate (reduction from moderate or severe headache to no headache or mild headache) at 2 hours was 37–46% with frovatriptan and 21–27% with placebo.

The rate of complete pain relief at 2 hours was 9–14% with frovatriptan and 2–3% with placebo.

Maximum therapeutic effect of frovatriptan is achieved 4 hours after administration.

In a clinical study comparing frovatriptan 2.5 mg with sumatriptan 100 mg, the efficacy of frovatriptan was slightly lower than that of sumatriptan at both 2 and 4 hours after administration. The incidence of adverse events was slightly lower with 2.5 mg frovatriptan compared to 100 mg sumatriptan. No study comparing 2.5 mg frovatriptan with 50 mg sumatriptan has been conducted.

Transient changes in systolic blood pressure (within normal limits) were observed in healthy elderly patients after a single oral dose of 2.5 mg.

Pharmacokinetics.

Absorption. After a single oral dose of 2.5 mg frovatriptan administered to healthy volunteers, mean peak plasma concentrations (C_max) observed between 2 and 4 hours post-dose were 4.2 ng/mL in males and 7.0 ng/mL in females. Mean values of the area under the plasma concentration-time curve (AUC) were 42.9 and 94.0 ng·hr/mL in males and females, respectively. Oral bioavailability was 22% in males and 30% in females. Pharmacokinetic parameters of frovatriptan in healthy volunteers were similar to those in migraine patients. The pharmacokinetics of frovatriptan during migraine attacks did not differ from those during attack-free periods. Within the dose range studied (1 to 40 mg), frovatriptan generally exhibited linear pharmacokinetics in clinical trials. Food intake did not significantly affect the bioavailability of frovatriptan, although it slightly delayed the rate of absorption by approximately 1 hour.

Distribution. The volume of distribution of frovatriptan after intravenous administration of 0.8 mg was 4.2 L/kg in males and 3.0 L/kg in females. Plasma protein binding of frovatriptan is low (approximately 15%). The extent of reversible binding of frovatriptan to blood cells under equilibrium conditions was about 60%, with no gender difference. At equilibrium, the ratio of drug concentration in blood to that in plasma was 2:1.

Metabolism. After oral administration of 2.5 mg radiolabeled frovatriptan, 32% of the administered dose was excreted in urine and 62% in feces. Radiolabeled frovatriptan was excreted in urine as unchanged frovatriptan, hydroxy frovatriptan, N-acetyl desmethyl frovatriptan, hydroxy N-acetyl desmethyl frovatriptan, desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan had approximately threefold lower affinity for 5-HT₁ receptors than the parent compound. N-acetyl desmethyl frovatriptan had negligible affinity for 5-HT₁ receptors. The activity of other metabolites has not been studied.

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

Frovatriptan is not an inhibitor of monoamine oxidase (MAO) or cytochrome P450 isoenzymes, and therefore has minimal potential for drug interactions (see section "Interaction with other medicinal products and other forms of interaction"). Frovatriptan is not a substrate of MAO.

Elimination.

Elimination of frovatriptan is biphasic, with a dominant distribution phase between 2 and 6 hours. Mean systemic clearance was 216 mL/min in males and 132 mL/min in females. 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, independent of patient gender, although the terminal elimination phase becomes dominant around 12 hours post-dose.

Gender.

In males, AUC and C_max values for frovatriptan are lower (by approximately 50%) than in females. This difference is at least partially related to concomitant use of oral contraceptives. Based on clinical efficacy and safety data obtained with 2.5 mg frovatriptan, dose adjustment according to patient gender is not required (see section "Dosage and administration").

Elderly patients.

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

Renal impairment.

Systemic exposure to frovatriptan and its t_1/2 were not significantly different in males and females with impaired renal function (creatinine clearance 16–73 mL/min) compared to healthy volunteers.

Hepatic impairment.

After oral administration in male and female subjects aged 44 to 57 years with mild to moderate hepatic impairment (Child-Pugh classes A and B), mean plasma concentrations of frovatriptan were within the range observed in healthy young and elderly individuals. There is no pharmacokinetic or clinical experience with frovatriptan in patients with severe hepatic impairment (see section "Contraindications").

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients. Myocardial infarction, ischemic heart disease, coronary artery spasm (e.g., Prinzmetal's angina), peripheral vascular disease, or symptoms or signs suggestive of ischemic heart disease in medical history. Moderate or severe arterial hypertension, as well as uncontrolled mild arterial hypertension. Stroke, history of cerebrovascular disorders or transient ischemic attacks. Severe hepatic impairment (Child-Pugh class C). Concomitant administration of frovatriptan and ergotamine or ergot derivatives, including methysergide, or other 5-hydroxytryptamine (5-HT₁) receptor agonists.

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated.

Ergotamine and ergot derivatives (including methysergide), as well as other 5-HT₁ receptor agonists. Risk of developing arterial hypertension and coronary artery constriction due to additive vasospastic effects when administered simultaneously to terminate the same migraine attack (see section «Contraindications»). The effects of these drugs may be additive. A 24-hour interval should be observed after the last dose of frovatriptan before administering ergotamine-containing medications. Similarly, after taking ergotamine-containing medications, a minimum 24-hour interval should be observed before taking frovatriptan (see section «Special precautions»).

Concomitant use is not recommended.

Monoamine oxidase inhibitors. Frovatriptan is not a substrate of monoamine oxidase-A; however, despite this, the risk of serotonin syndrome or arterial hypertension cannot be completely excluded (see section «Pharmacokinetics»).

Concomitant use requires caution.

Selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline). Potential risk of arterial hypertension, coronary vessel spasm, or serotonin syndrome. Strict adherence to the recommended dose is crucial for preventing the aforementioned conditions. Methylergonovine. Risk of developing arterial hypertension and coronary vessel constriction. Fluvoxamine. This is a potent inhibitor of cytochrome CYP1A2. It has been shown to increase blood levels of frovatriptan by 27–49%.

Oral contraceptives. In women taking oral contraceptives, plasma concentrations of frovatriptan are approximately 30% higher compared to women not taking these agents. However, no increase in the frequency of adverse events associated with the use of oral contraceptives has been reported.

St. John's wort (Hypericum perforatum). As with other triptans, concomitant use of frovatriptan and herbal preparations containing St. John's wort may increase the risk of serotonin syndrome.

Special precautions for use.

Frovatriptan should be used only for a clearly established diagnosis of migraine. The drug is not indicated for the treatment of hemiplegic, basilar, or ophthalmoplegic migraine. As with other treatments for migraine attacks, other potentially serious neurological conditions should be excluded before initiating treatment for headache in patients without a prior diagnosis of migraine or in patients with atypical migraine manifestations. It should be noted that patients with migraine have an increased risk of certain cerebrovascular events (stroke or transient ischemic attacks). The safety and efficacy of frovatriptan administration during the aura phase of migraine, prior to the onset of the headache phase, have not been established. Like other 5-HT₁ receptor agonists, frovatriptan must not be used in patients at risk of ischemic heart disease, including individuals who smoke heavily on a daily basis or those receiving nicotine replacement therapy, without prior cardiovascular evaluation (see section «Contraindications»). Particular attention should be paid to postmenopausal women and men over 40 years of age who have the aforementioned risk factors. However, cardiovascular examination cannot identify all patients with cardiovascular disorders. In isolated cases, severe cardiovascular events have occurred in patients without prior cardiovascular disease following the use of 5-HT₁ receptor agonists. Transient symptoms such as chest pain or tightness radiating up to the throat may be associated with frovatriptan use (see section «Adverse reactions»). Frovatriptan therapy should be discontinued immediately if ischemic heart disease is suspected based on the aforementioned symptoms, and further diagnostic evaluation should be performed.

Patients should be informed about early signs or symptoms of hypersensitivity reactions, including skin reactions, angioedema, or anaphylaxis (see section «Adverse reactions»). In case of a serious allergic reaction/hypersensitivity reaction, frovatriptan treatment should be stopped immediately and the drug must not be restarted.

A 24-hour interval is recommended after frovatriptan administration before using ergotamine-containing medications. Similarly, at least a 24-hour interval should be observed after taking ergotamine-containing medications before administering frovatriptan (see sections «Contraindications» and «Interaction with other medicinal products and other forms of interaction»). With very frequent use of the drug (repeated administration over several consecutive days, indicative of drug overuse), the active substance may accumulate, potentially leading to increased adverse effects. Prolonged use of analgesics to relieve headache may paradoxically lead to worsening of headache. If such an adverse event occurs or medication-overuse headache is suspected, the patient should discontinue frovatriptan and consult a physician. In patients with frequent or daily headaches who regularly use analgesics for headache relief, medication-overuse headache should be considered, which may occur despite (or as a result of) the use of these medications. The recommended dose of frovatriptan should not be exceeded.

Adverse events may occur more frequently when triptans (5-HT agonists) are used concomitantly with herbal medicinal products containing St. John’s wort (Hypericum perforatum).

The product contains lactose; therefore, it is contraindicated in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

The safety of frovatriptan use during pregnancy has not been established. Preclinical studies have revealed reproductive toxicity. The potential risk of reproductive toxicity in humans is unknown. Frovatriptan is not recommended for use in pregnant women or in women of childbearing potential who are not using contraception, except in cases of clear medical necessity.

Breastfeeding .

Although passage of frovatriptan and/or its metabolites into human breast milk has not been confirmed, its use during breastfeeding is not recommended, except in cases of clear medical necessity. In preclinical studies, frovatriptan and/or its metabolites were excreted into breast milk, reaching concentrations in milk up to four times higher than the maximum blood levels. Risk to the fetus/newborn who is breastfed cannot be excluded. If use is necessary, strict adherence to 24-hour intervals between doses is required.

Ability to affect reaction speed when driving or operating machinery.

The effects of frovatriptan on the ability to drive or operate machinery have not been studied. Migraine and frovatriptan therapy may cause somnolence. Patients should be advised to critically assess their ability to perform complex tasks, such as driving a vehicle, during migraine attacks and while taking frovatriptan.

Dosage and Administration

Frovatriptan should be used as early as possible during a migraine attack, although the drug has therapeutic effect when administered at later stages of an attack. Frovatriptan should not be used for prophylactic purposes. Tablets should be swallowed whole with water, without chewing. If the first dose of frovatriptan does not produce a therapeutic effect, an additional dose should not be administered during the same migraine attack, as there is no evidence supporting potential therapeutic benefit. In such cases, frovatriptan may be used during subsequent migraine attacks.

Adults aged up to 65 years. The recommended dose of frovatriptan is 2.5 mg. If migraine symptoms recur after initial relief, administration of an additional recommended dose is permitted, provided that the interval between the two doses of frovatriptan is at least 2 hours. The maximum daily dose of frovatriptan should not exceed 5 mg.

Elderly patients (over 65 years of age).

Data on the use of frovatriptan in patients over 65 years of age remain limited. Therefore, the use of frovatriptan in patients of this age group is not recommended.

Renal impairment.

Dose adjustment of the medicinal product in patients with renal impairment is not required (refer to section «Pharmacological Properties»).

Hepatic impairment.

Dose adjustment of the medicinal product in patients with mild to moderate hepatic impairment is not required (refer to section «Pharmacological Properties»). Frovatriptan therapy is contraindicated in patients with severe hepatic impairment (refer to section «Contraindications»).

Children.

There is currently no information regarding the safety and efficacy of frovatriptan in children under 18 years of age; therefore, its use in this age group is not recommended.

Overdose.

Information on cases of frovatriptan overdose is limited. The highest single oral dose of frovatriptan administered to male and female patients suffering from migraine was 40 mg (16 times higher than the recommended clinical dose of 2.5 mg), and the highest single oral dose administered to healthy male volunteers was 100 mg (40 times higher than the recommended clinical dose). In both cases, overdose did not result in adverse reactions not listed in the section «Adverse Reactions». There has been one post-marketing case of coronary artery spasm in a patient who was taking tricyclic antidepressants for migraine prophylaxis. Coronary artery spasm developed after administration of a frovatriptan dose four times higher than recommended, over three consecutive days. The patient recovered. There is no specific antidote for frovatriptan. The effects of hemodialysis or peritoneal dialysis on frovatriptan plasma concentrations are unknown. Treatment. In case of frovatriptan overdose, patients should be under close medical supervision for at least 48 hours. Supportive treatment should be administered as necessary.

Adverse Reactions

Frovatriptan has been administered to over 2,700 patients at the recommended dose of 2.5 mg.

The most common adverse reactions (< 10%) include dizziness, fatigue, paresthesia, headache, and hot flushes. Adverse effects reported during clinical trials with frovatriptan were generally transient, mild to moderate in intensity, and resolved spontaneously. Some of the symptoms reported as adverse effects may be concomitant symptoms of migraine.

The table below lists all adverse reactions considered to be related to the administration of 2.5 mg frovatriptan and occurring at a higher frequency compared to placebo in four placebo-controlled studies.

Adverse reactions are listed in decreasing order of frequency by organ system. Reactions known from post-marketing experience are marked with an asterisk*.

The adverse reaction profile mentioned above did not differ from those observed during two open-label, long-term clinical studies.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years. Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store at a temperature not exceeding 30 °C. Keep the blister in the original packaging. Store out of reach of children.

Packaging. Blister pack containing 2 or 6 film-coated tablets; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Marketing Authorization Holder. Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder. 1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.

Manufacturer. A. Menarini Manufacturing Logistics and Services S.r.l.

Manufacturer's address and place of business.

Via Campo di Pile, 67100 L’Aquila (AQ), Italy.