Rapimig

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

Composition:

Active substance: zolmitriptan;

1 tablet contains 2.5 or 5 mg of zolmitriptan;

Excipients: mannite 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 physico-chemical properties: white, round, flat tablets with bevelled edges.

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 human recombinant 5-HT1B/1D serotonin receptors in blood vessels. It has moderate affinity for serotonin 5-HT1A receptors and lacks significant affinity or pharmacological activity for 5-HT2, 5-HT3, and 5-HT4 serotonin receptors, as well as for α1-, α2-, β1-adrenergic receptors, H1 and H2 histamine receptors, M-cholinergic receptors, and D1 and D2 dopaminergic receptors.

The drug causes vasoconstriction, primarily of cranial vessels, and blocks the release of neuropeptides, including vasoactive intestinal peptide, a key effector neurotransmitter in the reflex activation causing vasodilation, which underlies the pathogenesis of migraine. It stops the development of a migraine attack without exerting direct analgesic action. In addition to suppressing the migraine attack, it alleviates nausea, vomiting (especially during left-sided attacks), photophobia, and phonophobia. It affects brainstem centers associated with migraine, which explains the sustained, repeated 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 drug's effect 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 from the gastrointestinal tract. Drug absorption is not affected by food intake. The mean absolute bioavailability is approximately 40%. Plasma protein binding is 25%. The time to reach maximum plasma concentration is 1 hour, and therapeutic plasma concentrations are maintained for the next 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 the maximum blood concentration is achieved within one hour.

Elimination of zolmitriptan is primarily due to hepatic biotransformation, followed by renal excretion of metabolites. There are three main metabolites: indoleacetic acid (the primary metabolite in plasma and urine), 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 a single oral dose, more than 60% is excreted in urine (mainly as the metabolite indoleacetic acid), and nearly 30% is excreted in feces as the parent compound. After 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 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 in patients with moderate to severe renal impairment was reduced (by 7–8 times) compared to healthy volunteers, although the AUC of the parent compound and active metabolite increased only slightly (by 16% and 35%, respectively), and the elimination half-life increased by 1 hour, reaching 3–3.5 hours. These parameters remain within the ranges observed in healthy volunteers.

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

Clinical characteristics.

Indications.

Acute 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.

Cerebrovascular disorders and history of 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 studies in healthy volunteers, there is no pharmacokinetic interaction or clinically relevant interaction between zolmitriptan and ergotamine. However, since a theoretical risk of coronary spasm may increase, Rapimig should be administered no sooner than 24 hours after treatment with ergotamine-containing medications. Conversely, ergotamine-containing medications should be administered no sooner than 6 hours after administration of Rapimig.

Following administration of moclobemide, a specific MAO-A inhibitor, a slight increase (26%) in the AUC (area under the curve) of zolmitriptan and a threefold increase in the 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 non-specific inhibitor of P450 enzymes, 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). In patients receiving cimetidine, zolmitriptan should be administered at a dose not exceeding 5 mg per day. Due to the overall interaction profile, a potential interaction with specific inhibitors of CYP1A2 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 (an 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 changes in mental status, 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 definitively established. Prior to initiating treatment for headache in patients who have not previously been diagnosed with migraine, or in patients prone to migraine who are experiencing atypical symptoms, other neurological conditions should be ruled out. Rapimig must not be administered in cases of hemiplegic, basilar, or ophthalmoplegic migraine. In patients receiving 5HT1B/1D agonists, stroke and other cerebrovascular adverse events may occur. Individuals predisposed to migraine may experience certain symptoms associated with cerebrovascular insufficiency.

Rapimig is contraindicated in patients with symptomatic Wolff–Parkinson–White syndrome or arrhythmias associated with other accessory cardiac conduction pathways.

In isolated cases, as with other 5HT1B/1D agonists, coronary spasm, angina pectoris, and myocardial infarction have been reported. In patients with risk factors for ischemic heart disease (such as smoking, elevated blood pressure, hyperlipidemia, diabetes, or family history), Rapimig should be prescribed only after a cardiovascular evaluation. Particular caution is required 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 observed with other 5HT1B/1D agonists. If chest pain or symptoms suggestive of ischemic heart disease occur, Rapimig should be discontinued until appropriate medical evaluation has been performed.

Transient increases in blood pressure may occur in patients both with and without a history of hypertension, as 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 dosage.

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

Serotonin syndrome (including mental status changes, autonomic instability, and neuromuscular abnormalities) has been reported following concomitant administration 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 warranted, appropriate patient monitoring is recommended, particularly at the start 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 pain. 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 medication or are actually caused 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 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 affect reaction speed when 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.

Nevertheless, drivers and individuals whose work requires high concentration should be warned that during a migraine attack, drowsiness and other symptoms 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 tablet administration.

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 where liquid is not readily available or to avoid nausea and vomiting that may occur when taking a tablet with liquid.

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

Hepatic impairment

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

Renal impairment

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

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

Patients taking MAO-A inhibitors should take zolmitriptan at a dose not exceeding 5 mg per day. The maximum recommended daily dose of zolmitriptan in patients taking cimetidine is 5 mg per day.

A 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 medication is not used for the 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 in case of 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 the serum concentration 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 any 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, angioedema, and anaphylactic reactions.

Nervous system disorders: common – sensory disturbances, dizziness, headache, hyperesthesia, paresthesia, somnolence, feeling 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 elevation of 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, muscle pain.

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

General disorders: common – asthenia, sensations 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 the reach of children.

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

Prescription status. Prescription only.

Manufacturer.

Actavis Ltd.

Actavis Ltd.

Manufacturer's address and place of business.

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

Date of last review.