Rapimig

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAPIMIG (RAPIMIG)

Composition:

Active substance: zolmitriptan;

1 tablet contains zolmitriptan 2.5 or 5 mg;

Excipients: mannitol E 421, calcium silicate, microcrystalline cellulose, aspartame, sodium starch glycolate (type A), crospovidone (type B), orange flavour, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Orodispersible tablets.

Main physicochemical characteristics: white, round, flat tablets with a bevelled edge.

Pharmacotherapeutic group. Medicinal products used in migraine. Selective serotonin 5HT₁-receptor agonists. Zolmitriptan. ATC code N02C C03.

Pharmacological Properties

Pharmacodynamics

Zolmitriptan is a selective agonist of recombinant human 5-HT1B/1D serotonin vascular receptors. It has moderate affinity for serotonin 5-HT1A receptors, but lacks significant affinity or pharmacological activity at 5-HT2-, 5-HT3-, 5-HT4-serotonin receptors, as well as at α1-, α2-, β1-adrenergic receptors, H1- and H2-histamine receptors, M-cholinergic receptors, and D1- and D2-dopaminergic receptors.

The drug induces vasoconstriction, primarily of cranial vessels, and blocks the release of neuropeptides, including calcitonin gene-related peptide (CGRP), which is the main effector transmitter of reflex activation causing vasodilation underlying the pathogenesis of migraine. It stops the development of a migraine attack without direct analgesic action. In addition to aborting the migraine attack, it reduces nausea, vomiting (especially during left-sided attacks), photophobia, and phonophobia. It affects brainstem centers associated with migraine, which explains the sustained recurrent effect when treating a series of several migraine attacks in a single patient. It is highly effective in the comprehensive treatment of migraine status (a series of several severe, consecutive migraine attacks lasting 2–5 days). It relieves menstrually-associated migraine.

The effect of the drug begins within 15–20 minutes and reaches its maximum within one hour after administration. The maximum effect is observed when the drug is taken during the onset of an attack.

Pharmacokinetics

After oral administration, the drug is well absorbed in the gastrointestinal tract. Drug absorption is not affected by food intake. The mean absolute bioavailability is approximately 40%. Plasma protein binding is 25%. Time to reach peak plasma concentration is 1 hour; therapeutic plasma concentrations are maintained for the subsequent 4–6 hours. No drug accumulation occurs with repeated dosing.

Zolmitriptan undergoes extensive hepatic biotransformation, forming an N-desmethyl metabolite that has 2–6 times greater pharmacological activity than the parent compound. 85% of peak blood concentration is achieved within one hour.

Elimination of zolmitriptan is primarily determined by hepatic biotransformation, followed by renal excretion of metabolites. There are three main metabolites: indole acetic acid (the primary metabolite in plasma and urine), and N-oxide and N-desmethyl analogs. Only the N-desmethyl metabolite is pharmacologically active. Plasma concentrations of the N-desmethyl metabolite are approximately two times lower than those of the parent drug, but it may enhance the therapeutic effect of zolmitriptan. After single oral administration, over 60% of the dose is excreted in urine (mainly as the metabolite indole acetic acid), and nearly 30% is excreted in feces as unchanged compound. Following intravenous administration, total plasma clearance averages approximately 10 mL/min/kg, of which one-third is renal clearance. Renal clearance exceeds the glomerular filtration rate, indicating active tubular secretion. The volume of distribution after intravenous administration is 2.4 L/kg. Plasma protein binding of zolmitriptan and its N-desmethyl metabolite is low (approximately 25%). The mean elimination half-life of zolmitriptan is 2.5–3 hours. The half-life of its metabolites is similar, indicating that their elimination is limited by the rate of formation.

Renal clearance of zolmitriptan and all its metabolites is reduced (by 7–8 times) in patients with moderate to severe renal impairment compared to healthy volunteers, although the AUC of the parent compound and active metabolite increased only slightly (by 16% and 35%, respectively), and elimination half-life increased by 1 hour, reaching 3–3.5 hours. These parameters remain within the range observed in healthy volunteers.

The pharmacokinetics of zolmitriptan in healthy elderly volunteers is similar to that in healthy young volunteers.

Clinical characteristics.

Indications.

Treatment of migraine attacks, with or without aura.

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product.

Severe or moderate arterial hypertension, as well as mild uncontrolled blood pressure elevation. Ischemic heart disease, including history of myocardial infarction. Angiospastic angina (Prinzmetal's angina). Peripheral vascular disease. Symptoms or signs consistent with ischemic heart disease.

Concomitant use of ergotamine, ergotamine derivatives (including methysergide), sumatriptan, naratriptan, or other 5HT1B/1D receptor agonists.

History of cerebrovascular disorders or transient ischemic attack (TIA).

Creatinine clearance below 15 mL/min.

Interaction with other medicinal products and other forms of interaction.

Studies investigating interactions between the medicinal product and caffeine, ergotamine, dihydroergotamine, paracetamol, metoclopramide, pizotifen, fluoxetine, rifampicin, and propranolol have been conducted, and no clinically significant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed.

Based on data obtained from healthy volunteers, there is no pharmacokinetic interaction or clinically relevant interaction between zolmitriptan and ergotamine. However, since a theoretical risk of coronary spasm exists, Rapimig should not be administered earlier than 24 hours after taking ergotamine-containing preparations. Conversely, ergotamine-containing preparations should not be administered earlier than 6 hours after taking Rapimig.

Following administration of moclobemide, a specific MAO-A inhibitor, a slight increase (26%) in zolmitriptan AUC (area under the curve) and a threefold increase in AUC of the active metabolite were observed. Therefore, patients taking an MAO-A inhibitor should receive zolmitriptan at a dose not exceeding 5 mg per day. The drugs should not be used concomitantly when moclobemide is administered at doses exceeding 150 mg twice daily.

Following administration of cimetidine, a general P450 inhibitor, the elimination half-life of zolmitriptan increased by 44% and AUC by 48%. Furthermore, cimetidine doubled the elimination half-life and AUC of the active N-desmethyl metabolite (183C91). Patients taking cimetidine should receive zolmitriptan at a dose not exceeding 5 mg per day. Due to the overall interaction profile, potential interactions with specific CYP1A2 inhibitors cannot be excluded. Therefore, dose reduction is also recommended when using such compounds as fluvoxamine and quinolones (e.g., ciprofloxacin).

From a pharmacokinetic standpoint, selegiline (MAO-B inhibitor) and fluoxetine (SSRI) do not interact with zolmitriptan. However, following concomitant administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), cases of serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) have been reported.

Like other 5HT1B/1D receptor agonists, zolmitriptan may delay the absorption of other medicinal products.

Concomitant use of other 5HT1B/1D agonists during zolmitriptan treatment should be avoided within 24 hours. Similarly, concomitant use of zolmitriptan during treatment with other 5HT1B/1D agonists should be avoided within 24 hours.

Special precautions for use

Rapimig should only be used when a diagnosis of migraine has been clearly established. Prior to initiating treatment for headache in patients who have not previously been diagnosed with migraine, or in patients with a history of migraine who are experiencing atypical symptoms, other neurological conditions should be ruled out. Rapimig should not be administered in patients with hemiplegic, basilar, or ophthalmoplegic migraine. In patients receiving 5HT1B/1D agonists, there have been reports of stroke and other cerebrovascular adverse events. Individuals predisposed to migraine may experience symptoms suggestive of cerebrovascular insufficiency.

Rapimig should not be prescribed to patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other accessory cardiac conduction pathways.

Rare cases of coronary spasm, angina pectoris, and myocardial infarction have been reported, similar to those observed with other 5HT1B/1D agonists. In patients with risk factors for ischemic heart disease (such as smoking, hypertension, hyperlipidemia, diabetes mellitus, or family history), Rapimig should be prescribed only after a cardiovascular evaluation. Particular caution is advised in postmenopausal women and men over 40 years of age who have such risk factors. However, cardiovascular screening cannot identify all patients with underlying heart disease, and serious cardiac events have occurred in patients with no prior history of cardiovascular disorders.

Some patients have reported sensations of heaviness, pressure, or tightness in the chest area after taking Rapimig, similar to effects reported with other 5HT1B/1D agonists. If chest pain or symptoms suggestive of ischemic heart disease occur, Rapimig should be discontinued until appropriate medical evaluation is performed.

Transient increases in blood pressure may occur in patients both with and without a history of hypertension, similar to effects seen with other 5HT1B/1D agonists. Such blood pressure elevations are very rarely associated with serious clinical consequences. Rapimig should be used at doses not exceeding the recommended dose.

Concomitant use of triptans and herbal preparations containing St. John’s wort (Hypericum perforatum) may increase the frequency of adverse reactions.

Cases of serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) have been reported following concomitant use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). These reactions may be severe. If concomitant use of zolmitriptan and SSRIs or SNRIs is clinically indicated, appropriate patient monitoring is recommended, particularly at the initiation of treatment, with dose escalation, or when adding another serotonergic agent (see section "Interaction with other medicinal products and other forms of interaction").

Prolonged use of any analgesic for headache may exacerbate headache. In such cases, treatment should be discontinued and medical advice sought. Medication-overuse headache should be suspected in patients with frequent or daily headaches that fail to respond to regular analgesic use or that are precipitated by such treatment.

Rapimig contains aspartame (a source of phenylalanine), which may be harmful to patients with phenylketonuria. One 2.5 mg tablet contains 4 mg of aspartame; one 5 mg tablet contains 8 mg of aspartame.

Use during pregnancy or breastfeeding

The safety of zolmitriptan use during pregnancy has not been established. Rapimig should be used during pregnancy only if the potential therapeutic benefit to the mother outweighs the potential risk to the fetus/child.

There are no data on the excretion of zolmitriptan into human breast milk. Therefore, Rapimig should be used with caution in breastfeeding women. To minimize exposure to the infant, breastfeeding should be avoided for at least 24 hours after maternal administration of the drug.

Ability to influence reaction rate while driving or operating machinery

In a small group of healthy volunteers receiving doses up to 20 mg, no significant effect on psychomotor performance was observed.

However, patients who drive or operate machinery should be warned that during a migraine attack, symptoms such as drowsiness and other neurological disturbances may occur.

Method of Administration and Dosage

The medication is not intended for the prevention of migraine attacks. Rapimig should be taken as early as possible after the onset of a migraine attack, although the effectiveness of the drug does not depend on the time elapsed between the start of the attack and administration of the tablet.

The tablet may be taken without liquid. It is placed on the tongue, where it dissolves and is swallowed with saliva. This dosage form can be used in situations when liquid is not available or to avoid nausea and vomiting that may occur when swallowing a tablet with liquid.

This dosage form dissolves rapidly in the oral cavity; however, occasionally a delay in absorption of zolmitriptan and a delayed onset of action may still occur.

The blister pack should be opened by peeling off the foil, not by pushing the tablet through the foil.

The recommended dose of Rapimig for relief of a migraine attack is 1 tablet (2.5 mg). If symptoms do not resolve or recur within 24 hours, administration of a second dose may be effective. If a second dose is required, it should be taken no sooner than 2 hours after the first dose. If the 2.5 mg dose is insufficient, the single dose may be increased to 5 mg (higher single dose).

The maximum daily dose should not exceed 10 mg. No more than 2 doses of zolmitriptan should be administered within any 24-hour period.

Patients aged 65 years and older

The safety and efficacy of zolmitriptan tablets in patients aged 65 years and older have not been studied. Therefore, zolmitriptan is not recommended for treatment of this patient group.

Hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic dysfunction. In patients with severe hepatic impairment, the daily dose of the drug should not exceed 5 mg.

Renal impairment

Dosage adjustment is not required in patients with creatinine clearance above 15 mL/min.

Interactions requiring dosage adjustment (see section "Interaction with other medicinal products and other types of interactions")

Patients taking MAO-A inhibitors should be administered zolmitriptan at a dose not exceeding 5 mg per day. The maximum recommended daily dose of zolmitriptan in patients taking cimetidine is no more than 5 mg per day.

The maximum daily dose of zolmitriptan of 5 mg is recommended for patients taking specific CYP1A2 inhibitors, such as fluvoxamine and quinolones (e.g., ciprofloxacin).

Children

The drug is not used for treatment of children (under 18 years of age).

Overdose

Symptoms: Sedative effects were observed in volunteers who received a single 50 mg dose of zolmitriptan. Monitoring of patients after overdose should continue for at least 15 hours or until symptoms or signs have resolved.

Treatment: Gastric lavage and administration of activated charcoal. In cases of severe intoxication, intensive care procedures are recommended, including maintenance of airway patency, adequate oxygenation and ventilation, and monitoring and support of cardiovascular function. There is no specific antidote.

It is unknown how hemodialysis or peritoneal dialysis affects serum concentrations of zolmitriptan.

Adverse reactions.

Adverse effects are usually transient, occur within 4 hours after taking the medication, do not increase in frequency upon repeated administration, and resolve spontaneously without additional treatment.

Adverse effects are classified according to their frequency of occurrence as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.

Immune system disorders: rare – hypersensitivity reactions, including urticaria, Quincke's edema (angioedema), and anaphylactic reactions.

Nervous system disorders: common – sensory disturbances, dizziness, headache, hyperesthesia, paresthesia, somnolence, sensation of warmth.

Cardiac disorders: common – palpitations; uncommon – tachycardia; very rare – myocardial infarction, angina pectoris, coronary spasm.

Vascular disorders: uncommon – slight increase in blood pressure, transient increase in systemic arterial pressure.

Gastrointestinal disorders: common – abdominal pain, nausea, vomiting, dry mouth, dysphagia; very rare – ischemia or infarction (e.g. intestinal ischemia, intestinal infarction, splenic infarction), which may present as diarrhea with blood or abdominal pain.

Musculoskeletal and connective tissue disorders: common – muscle weakness, myalgia.

Renal and urinary disorders: uncommon – polyuria, frequent urination; very rare – imperative urges to urinate.

General disorders: common – asthenia, sensation of heaviness, tightness, pain or pressure in the throat, neck, chest, and extremities.

Some of these symptoms may be related to migraine itself.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of reach of children.

Packaging. 2 or 6 tablets in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Actavis Ltd.

Actavis Ltd.

Manufacturer's address and place of business.

VBL015, VBL016 Bulebel Industrial Estate, Zittun ZTN 3000, Malta /
VBL015, BLB016, Bulebel Industrial Estate, Zejtun ZTN3000, Malta.