Frovamigran^® (Tablets) Instructions for Use

Marketing Authorization Holder

Berlin-Chemie/Menarini Pharma, GmbH (Germany)

Manufactured By

Almac Pharma Services, Limited (United Kingdom)

ATC Code

N02CC07 (Frovatriptan)

Active Substance

Frovatriptan (Rec.INN registered by WHO)

Dosage Form

Frovamigran®

Film-coated tablets, 2.5 mg: 1, 2, 3, 2 or 6 pcs.

Dosage Form, Packaging, and Composition

Excipients: anhydrous lactose 99.93 mg, microcrystalline cellulose 28.10 mg, sodium carboxymethyl starch (type A) 7.03 mg, magnesium stearate 1.41 mg, colloidal silicon dioxide 0.14 mg.

Shell composition Opadry white (OY-L-28906) 4.5 mg (titanium dioxide -1.125 mg, lactose monohydrate – 0.945 mg, hypromellose – 1.800 mg, macrogol 3000 – 0.360 mg, triacetin – 0.270 mg).

1 pc. – non-blister contour packaging (1) – cardboard packs.
2 pcs. – non-blister contour packaging (1) – cardboard packs.
3 pcs. – non-blister contour packaging (1) – cardboard packs.
4 pcs. – non-blister contour packaging (1) – cardboard packs.
6 pcs. – non-blister contour packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Serotonin 5-HT₁ receptor agonist. Agent with antimigraine activity

Pharmacotherapeutic Group

Antimigraine agent

Pharmacological Action

Frovatriptan is a selective agonist of 5-HT_1B and 5-HT_1D serotonin receptors and does not exhibit significant pharmacological activity towards 5-HT_2-6 receptors, α-adrenoreceptors, histamine and benzodiazepine receptors. Frovatriptan selectively acts on the vessels of the dura mater, preventing their excessive dilation during a migraine attack. Frovatriptan causes selective constriction of cerebral arteries, while having virtually no effect on coronary arteries. Improvement in the condition during a migraine attack (reduction in pain intensity) is noted 2 hours after taking the drug. The maximum therapeutic effect of frovatriptan occurs 4 hours after taking the drug.

Pharmacokinetics

After oral administration of a single dose of 2.5 mg, the C_max of frovatriptan in the blood is achieved, on average, after 2-4 hours and is 4.2 ng/ml in men and 7.0 ng/ml in women. The mean value of the area under the concentration-time curve (AUC) in men is 50% lower than in women. Bioavailability is 22% in men and 30% in women. Food intake does not have a significant effect on the bioavailability of frovatriptan, but a slight increase in T_max time by approximately 1 hour is observed. Volume of distribution – 4.2 L/kg in men and 3.0 L/kg in women. The half-life of frovatriptan is approximately 26 hours.

Plasma protein binding is about 15%. It is metabolized in the liver by the cytochrome P450 isoenzyme, with subsequent excretion by the kidneys. Mean clearance in men is 216 ml/min, in women – 132 ml/min.

Indications

• Relief of migraine attacks with or without aura.

ICD codes

Dosage Regimen

For oral administration.

Frovamigran^® should be taken as early as possible from the onset of a migraine attack (onset of headache), but it is also effective when taken later.

Frovamigran^® should not be used for prophylactic purposes. The tablets should be taken without chewing, with a sufficient amount of water. If migraine symptoms are not relieved after taking the first dose, a repeated dose to relieve this attack is not recommended.

Use in adults (from 18 to 65 years)

The recommended dose of frovatriptan is 2.5 mg.

If after initial reduction of symptoms they reappear, a repeated dose should not be taken within 2 hours after taking the first dose.

The maximum daily dose is 5 mg.

Treatment of patients with reduced renal function does not require dose adjustment of the drug.

In mild to moderate hepatic impairment, no dose adjustment of the drug is required. In severe hepatic insufficiency, the use of Frovamigran^® is contraindicated.

Adverse Reactions

In clinical studies, the most common side effects (<10 %) are: dizziness, fatigue, paresthesia, headache, and flushing. These side effects are transient, well tolerated, and resolve spontaneously. Some of these effects may be components of the clinical picture of migraine itself.

Possible side effects are listed below in descending order of frequency: common (> 1/100 < 1/10), uncommon (> 1/1000 < 1/100), rare (> 1/10000 < 1/1000), and some of them may be associative symptoms of migraine.

From the central and peripheral nervous system

Common: dizziness, paresthesias, headache, drowsiness, dysesthesia, hypesthesia.

Uncommon: tremor, hyperesthesia, involuntary muscle contractions.

Rare: increased or decreased muscle tone, hyporeflexia, tongue paralysis, syncope.

From the psychiatric sphere

Uncommon: feeling of fear, insomnia, nervousness, anxiety, decreased attention, euphoria, depression, thinking impairment, depersonalization.

Rare: amnesia, worsening of depression.

From the digestive system

Common: nausea, dry mouth, dyspepsia, abdominal pain.

Uncommon: diarrhea, dysphagia, flatulence, constipation.

Rare: cheilitis, belching, gastroesophageal reflux, irritable bowel syndrome, hiccups, esophageal spasm, gastric ulcer, pain in the salivary gland area, stomatitis, toothache.

From the respiratory system

Common: feeling of tightness in the throat.

Uncommon: rhinitis, pharyngitis, sinusitis, laryngitis.

Rare: nosebleeds, hyperventilation.

From the musculoskeletal system

Common: bone pain.

Uncommon: back pain, arthralgia, arthrosis, muscle weakness.

From the organ of vision

Common: visual impairment.

Uncommon: eye pain, eye irritation, photophobia.

Rare: hemeralopia (night blindness).

From the skin

Common: hyperhidrosis.

Uncommon: itching.

Rare: urticaria, erythema, piloerection (goosebumps).

From the cardiovascular system

Common: palpitations, flushing with skin redness.

Uncommon: tachycardia, increased blood pressure.

Rare: bradycardia.

From the organ of hearing

Uncommon: noise or pain in the ears.

Rare: hyperacusis, itching in the ears.

From the organ of taste

Uncommon: taste perception disorder.

From metabolism

Uncommon: thirst, dehydration.

Rare: hypocalcemia, hypoglycemia.

From the urinary system

Uncommon: frequent urination, polyuria.

Rare: nocturnal polyuria, kidney area pain, darkening of urine.

From the blood system

Rare: nosebleed, purpura.

Other disorders

Common: fatigue, impaired temperature perception.

Uncommon: asthenia, fever.

Rare: lymphadenopathy.

Laboratory parameters

Rare: increased bilirubin concentration, decreased blood calcium concentration.

Contraindications

• Hypersensitivity to frovatriptan or other components of the drug;
• Hemiplegic, basilar or ophthalmoplegic forms of migraine;
• Congenital metabolic disorders (galactosemia, lactase deficiency or glucose-galactose malabsorption syndrome);
• Lactose intolerance;
• Coronary heart disease (CHD) (including myocardial infarction, post-infarction cardiosclerosis, Prinzmetal’s angina), as well as symptoms suggesting its presence;
• Occlusive peripheral arterial diseases;
• Stroke or transient cerebrovascular accident (including in history);
• Controlled moderate and severe arterial hypertension, uncontrolled arterial hypertension;
• Severe hepatic failure (Child-Pugh class C);
• Concomitant use of medicinal products containing ergotamine or its derivatives (including methysergide) or other drugs for migraine therapy from the group of 5HT₁ receptor agonists and within 24 hours after their administration;
• Concomitant use of MAO inhibitors (MAO);
• Age of patients under 18 and over 65 years.

Use in Pregnancy and Lactation

Due to the lack of clinical data confirming the safety of the drug use during pregnancy, the use of Frovamigran^® during pregnancy is not recommended.

There are no data on the excretion of Frovamigran^® with breast milk, therefore, if it is necessary to use it during lactation, breastfeeding is not recommended for 24 hours after taking the drug.

Use in Hepatic Impairment

In mild to moderate hepatic impairment, no dose adjustment of the drug is required. In severe hepatic insufficiency, the use of Frovamigran^® is contraindicated.

Use in Renal Impairment

Treatment of patients with reduced renal function does not require dose adjustment of the drug.

Pediatric Use

Contraindicated in patients under 18 years of age.

Geriatric Use

Contraindicated in patients over 65 years of age.

Special Precautions

Frovamigran^® should be used only if the diagnosis of migraine is not in doubt.

As with the use of other agents intended for the relief of migraine attacks, in patients who are diagnosed with migraine for the first time or in patients with migraine with atypical symptoms, before starting treatment for headache, it is necessary to exclude the possibility of other neurological diseases with potentially severe consequences. It must be remembered that patients with migraine have an increased risk of developing certain cerebrovascular complications (e.g., stroke or transient ischemic attack). The effectiveness of Frovamigran^® when used before the development of headache (in the aura phase) has not been confirmed. Similar to other 5-HT₁ receptor agonists, Frovamigran^® should not be used in patients who are at risk of developing cardiovascular pathology (including smokers or patients on nicotine replacement therapy) without prior exclusion of cardiovascular diseases. In this case, special attention should be paid to women in the postmenopausal period and men over 40 years of age.

The absence of cardiovascular diseases does not exclude the possibility of side effects from this system. After taking Frovamigran^®, such transient side effects as pain and a feeling of tightness in the chest may occur. The pain can be intense and radiate to the neck area. If there is reason to believe that these symptoms are a manifestation of CHD, further use of Frovamigran^® should not be prescribed; an appropriate diagnostic examination should be performed. The interval between taking Frovamigran^® and any agent containing ergotamine should be 24 hours.

The recommended dose of Frovamigran^® should not be exceeded. In case of too frequent use of the drug (repeated doses over several consecutive days), the active substance may accumulate in the body, which leads to an increase in the number of side effects.

Influence on the ability to drive vehicles and mechanisms

Studies on the effect of Frovamigran^® on the ability to drive a vehicle have not been conducted. Drowsiness can be both a symptom of migraine and a result of prescribing Frovamigran^®. Therefore, during the period of using Frovamigran^®, patients should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

In case of overdose, an increase in dose-dependent side effects is possible.

Treatment there is no specific antidote. Gastric lavage and/or intake of activated charcoal, symptomatic therapy are recommended. The effect of hemodialysis and peritoneal dialysis on plasma concentration is unknown.

Drug Interactions

With simultaneous administration during the same migraine attack of frovatriptan with ergotamine, its derivatives or other 5-HT₁ receptor agonists, there is a risk of increased blood pressure (the interval between doses should be at least 24 hours).

Concomitant use with MAO inhibitors is not recommended, as the risk of serotonin syndrome and increased blood pressure cannot be completely excluded.

With the combined use of Frovamigran^® and oral preparations of St. John’s wort and selective serotonin reuptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline), the risk of developing serotonin syndrome increases. Concomitant use with fluvoxamine (a cytochrome CYP1A2 inhibitor) may lead to an increase in the concentration of frovatriptan in the blood by 27-49%. When taking oral contraceptives, the plasma concentration of frovatriptan increases by 30%, while no increase in the number of side effects is observed.

Storage Conditions

Store at a temperature not exceeding 30°C (86°F). Keep the medicine out of the reach of children!

Shelf Life

Shelf life – 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.