Summary of Product Characteristics Updated 31-Jul-2019 | Accord-UK Ltd
For doses not realisable/practicable with this strength other strengths of this medicinal product are available.The recommended dose of zolmitriptan to treat a migraine attack is 2.5 mg. It is advisable that zolmitriptan is taken as early as possible after the onset of migraine headache but it is also effective if taken at a later stage.If symptoms of migraine should recur within 24 hours following an initial response, a second dose may be taken. If a second dose is required, it should not be taken within 2 hours of the initial dose. If a patient does not respond to the first dose, it is unlikely that a second dose will be of benefit in the same attack.If a patient does not achieve satisfactory relief with 2.5 mg doses, for subsequent attacks 5 mg doses of zolmitriptan could be considered.The total daily intake should not exceed 10 mg. Not more than 2 doses of zolmitriptan should be taken in any 24-hour period.Zolmitriptan is not indicated for prophylaxis of migraine.
Children (below 12 years of age)Safety and efficacy of zolmitriptan tablets in paediatric patients have not been evaluated. Use of zolmitriptan in children is therefore not recommended.
Adolescents (12 - 17 years of age)The efficacy of zolmitriptan tablets was not demonstrated in a placebo controlled clinical trial for patients aged 12 to 17 years. Use of zolmitriptan in adolescents is therefore not recommended.
Use in patients aged over 65 yearsThe safety and efficacy of zolmitriptan in individuals aged over 65 years have not been evaluated. Use of zolmitriptan in older people is therefore not recommended.
Patients with hepatic impairmentPatients with mild or moderate hepatic impairment require no dose adjustment, however for patients with severe hepatic impairment, a maximum dose of 5 mg in 24 hours is recommended.
Patients with renal impairmentNo dosage adjustment required in patients with a creatinine clearance of more than 15 ml/min. (See section 4.3 and section 5.2)
Interactions requiring dose adjustment (see section 4.5)For patients taking MAO-A inhibitors, a maximum dose of 5 mg in 24 hours is recommended. A maximum dose of 5 mg zolmitriptan in 24 hours is recommended in patients taking cimetidine.A maximum dose of 5 mg zolmitriptan in 24 hours is recommended in patients taking specificinhibitors of CYP 1A2 such as fluvoxamine and the quinolones (e.g. ciprofloxacin).
Method of administrationThe tablets should be swallowed whole and with water.
PregnancyThe safety of this medical product for use in human pregnancy has not been established. Evaluation of experimental animals studies does not indicate direct teratogenic effects. However, some findings in embryotoxicity studies suggested impaired embryo viability. Administration of zolmitriptan should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
BreastfeedingStudies have shown that zolmitriptan passes into the milk of lactating animals. No data exist for passage of zolmitriptan into human breast milk. Therefore, caution should be exercised when administering zolmitriptan to women who are breast-feeding. Infant exposure should be minimised by avoiding breast feeding for 24 hours after treatment.
Immune system disorders:Rare: hypersensitivity reactions including urticaria, angioedema and anaphylactic reactions.
Nervous system disorders:Common: abnormalities or disturbances of sensation; dizziness; headache; hyperaesthesia; paraesthesia; somnolence; warm sensation.
Cardiac disorders:Common: palpitations.Uncommon: tachycardia.Very rare: myocardial infarction; angina pectoris, coronary vasospasm.
Vascular disordersUncommon: Slight increase in blood pressure; transient increase in systemic blood 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 bloody diarrhoea or abdominal pain.
Musculoskeletal and connective tissue disorders:Common: muscle weakness; myalgia.
Renal and urinary disorders:Uncommon: polyuria; increased urinary frequency.Very rare: urinary urgency.
General disorders and administration site conditions:Common: asthenia; heaviness, tightness, pain or pressure in throat, neck, limbs or chest.Certain symptoms may be part of the migraine attack itself.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.
Mechanism of actionZolmitriptan has been demonstrated to be a selective agonist for 5HT1B/1D receptors mediating vascular contraction. Zolmitriptan has high affinity for human recombinant 5HTIB and 5HTID receptors, and modest affinity for 5HTIA receptors. Zolmitriptan has no significant affinity or pharmacological activity at other 5HT receptor subtypes (5HT2, 5HT3, 5HT4) or adrenergic, histaminic, muscarinic or dopaminergic receptors. Pharmacodynamic effectsIn animal models, the administration of zolmitriptan causes vasoconstriction in the carotid arterial circulation. In addition, experimental studies in animals suggest that zolmitriptan inhibits central and peripheral trigeminal nerve activity with inhibition of neuropeptide release (calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and Substance P).
Clinical efficacy and safetyIn clinical studies with zolmitriptan conventional tablets the onset of efficacy is apparent from one hour, with increasing efficacy being noted between 2 and 4 hours on headache and other symptoms of migraine such as nausea, photophobia and phonophobia.Zolmitriptan, when administered as conventional oral tablets, is consistently effective in migraine with or without aura and in menstrually associated migraine. Zolmitriptan, when administered as conventional oral tablets, if taken during the aura, has not been demonstrated to prevent the migraine headache and therefore zolmitriptan should be taken during the headache phase of migraine.Paediatric populationOne controlled clinical trial in 696 adolescents with migraine failed to demonstrate superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg and 10 mg over placebo. Efficacy was not demonstrated.
AbsorptionFollowing oral administration of zolmitriptan conventional tablets, zolmitriptan is rapidly and well absorbed (at least 64%) after oral administration to man. The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite (the N-desmethyl metabolite) which is also a 5HT1B/1D receptor agonist and is 2 to 6 times as potent, in animal models, as zolmitriptan.In healthy subjects, when given as a single dose, zolmitriptan and its active metabolite, the N-desmethyl metabolite , display dose-proportional AUC and Cmax over the dose range 2.5 to 50 mg. Absorption of zolmitriptan is rapid. In healthy volunteers, 75% of Cmax is achived within 1 hour, and after this the concentration of zolmitriptan in plasma is maintained at approximately this level until 4-5 hours after dosing.Zolmitriptan absorption is unaffected by the presence of food. There was no evidence of accumulation on multiple dosing of zolmitriptan. Plasma concentration of zolmitriptan and its metabolites are lower in the first 4 hours after drug administration during a migraine compared with a migraine-free period, suggesting delayed absorption consistent with the reduced rate of gastric emptying observed during a migraine attack.
Biotransformation and eliminationZolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. There are three major metabolites: the indole acetic acid, (the major metabolite in plasma and urine), the N-oxide and N-desmethyl analogues. The N-desmethylated metabolite is active whilst the others are not. Plasma concentrations of the N-desmethylated metabolite are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action of zolmitriptan. Over 60% of a single oral dose is excreted in the urine (mainly as the indole acetic acid metabolite) and about 30% in faeces mainly as unchanged parent compound. Following intravenous administration, the mean total plasma clearance is approximately 10 ml/min/kg, of which one quarter is renal clearance. Renal clearance is greater than glomerular filtration rate suggesting renal tubular secretion. The volume of distribution following intravenous administration is 2.4 L/kg. Plasma protein binding of zolmitriptan and the N-desmethyl metabolite is low (approximately 25%). The mean elimination half-life of zolmitriptan is 2.5 to 3 hours. The half-lives of its metabolites are similar, suggesting their elimination is formation-rate limited.
Special populationsRenal clearance of zolmitriptan and all its metabolites is reduced (7-8 fold) in patients with moderate to severe renal impairment compared to healthy subjects, although the AUC of the parent compound and the active metabolite were only slightly higher (16 and 35% respectively) with a 1 hour increase in half-life to 3 to 3.5 hours. These parameters are within the ranges seen in healthy volunteers.The metabolism of zolmitriptan is reduced in hepatic impairment in proportion to the extent of the impairment. Zolmitriptan AUC and Cmax were increased by 226% and 50%, respectively and the half life was prolonged to 12 h in subjects with severe liver disease compared to healthy subjects. Exposure to the metabolites, including the active metabolite was reduced.The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers.
Pack sizes:3, 6, 12 or 18 tablets.Not all pack sizes may be marketed
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