Symptoms
Volunteers receiving single oral doses of 50 mg commonly experienced sedation.
Management
The elimination half-life of zolmitriptan is 2.5 to 3 hours, and therefore monitoring of patients after overdose with Zolmitriptano Ciclum Rapimelt should continue for at least 15 hours or while symptoms or signs persist.
There is no specific antidote to zolmitriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.
It is unknown what effect haemodialysis or peritoneal dialysis has on the serum concentrations of zolmitriptan.
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- Uncontrolled hypertension.
- Ischaemic heart disease.
- Coronary vasospasm/Prinzmetal's angina.
- A history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA)
- Concomitant administration of Zolmitriptano Ciclum with ergotamine or ergotamine derivatives or other 5-HT1 receptor agonists.
Not applicable.
Summary of the safety profile
Zolmitriptano Ciclum is well tolerated. Adverse reactions are typically mild/moderate, transient, not serious and resolve spontaneously without additional treatment.
Possible adverse reactions tend to occur within 4 hours of dosing and are no more frequent following repeated dosing.
Tabulated list of adverse reactions
Adverse reactions are classified according to frequency and system organ class. Frequency categories are defined according to the following convention: 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 the available data). The following undesirable effects have been reported following administration with zolmitriptan:
| System Organ Class | Frequency | Undesirable Effect |
| Immune system disorders | Rare | Anaphylaxis/Anaphylactoid Reactions; Hypersensitivity reactions |
| Nervous system disorder | Common | Abnormalities or disturbances of sensation; Dizziness; Headache; Hyperaesthesia; Paraesthesia; Somnolence; Warm sensation. |
| Cardiac disorders | Common | Palpitations. |
| Uncommon | Tachycardia. | |
| Very rare | Angina pectoris; Coronary vasospasm; Myocardial infarction. | |
| Vascular disorders | Uncommon | Transient increases in systemic blood pressure. |
| Gastrointestinal disorders | Common | Abdominal pain; Dry mouth; Nausea; Vomiting; Dysphagia. |
| Very rare | Bloody diarrhoea; Gastrointestinal infarction or necrosis; Gastrointestinal ischaemic events; Ischaemic colitis; Splenic infarction. | |
| Skin and subcutaneous tissue disorders | Rare | Angioedema; Urticaria. |
| 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. |
Reporting of suspected adverse reactions
Reporting 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.
An oral teratology study of zolmitriptan has been conducted. At the maximum tolerated doses, 1200 mg/kg/day (AUC 605 μg/ml.h : approx. 3700 x AUC of the human maximum recommended daily intake of 15 mg) and 30 mg/kg/day (AUC 4.9 μg/ml.h: approx. 30 x AUC of the human maximum recommended daily intake of 15 mg) in rats and rabbits, respectively, no signs of teratogenicity were apparent.
Five genotoxicity tests have been performed. It was concluded that Zolmitriptano Ciclum Rapimelt is not likely to pose any genetic risk in humans.
Carcinogenicity studies in rats and mice were conducted at the highest feasible doses and gave no suggestion of tumorogenicity.
Reproductive studies in male and female rats, at dose levels limited by toxicity, revealed no effect on fertility.
Zolmitriptano Ciclum Rapimelt is indicated for the acute treatment of migraine with or without aura.
Pharmacotherapeutic group: Selective serotonin (5HT1) agonists. ATC code: N02CC03
Mechanism of action
In pre-clinical studies, zolmitriptan has been demonstrated to be a selective agonist for the vascular human recombinant 5HT1B and 5HT1D receptor subtypes. Zolmitriptan is a high affinity 5HT1B/1D receptor agonist with modest affinity for 5HT1A receptors. Zolmitriptan has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5HT2-, 5HT3-, 5HT4-, alpha1-, alpha2-, or beta1-, adrenergic; H1-, H2-, histaminic; muscarinic; dopaminergic1, or dopaminergic2 receptors. The 5HT1D receptor is predominately located presynaptically at both the peripheral and central synapses of the trigeminal nerve and preclinical studies have shown that zolmitriptan is able to act at both these sites.
Clinical efficacy and safety
One 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.
Following oral administration of Zolmitriptano Ciclum conventional tablets zolmitriptan is rapidly and well absorbed (at least 64%) in man. The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite (183C91, the N-desmethyl metabolite) which is also a 5HT IB/1D 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 183C91, display dose-proportional AUC and Cmax over the dose range 2.5 to 50 mg. Absorption is rapid with 75% of Cmax achieved within 1 hour and plasma concentrations are sustained subsequently for 4 to 6 hours. Zolmitriptan absorption is unaffected by the presence of food. There is no evidence of accumulation on multiple dosing of zolmitriptan.
Zolmitriptan 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 (183C91) is active whilst the others are not. Plasma concentrations of 183C91 are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action of Zolmitriptano Ciclum Rapimelt. 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.
A study to evaluate the effect of liver disease on the pharmacokinetics of zolmitriptan showed that the AUC and Cmax were increased by 94% and 50% respectively in patients with moderate liver disease and by 226% and 47% in patients with severe liver disease compared with healthy volunteers. Exposure to the metabolites, including the active metabolite, was decreased. For the 183C91 metabolite, AUC and Cmax were reduced by 33% and 44% in patients with moderate liver disease and by 82% and 90% in patients with severe liver disease.
The plasma half-life (t½) of zolmitriptan was 4.7 hours in healthy volunteers, 7.3 hours in patients with moderate liver disease and 12 hours in those with severe liver disease. The corresponding t½ values for the 183C91 metabolite were 5.7 hours, 7.5 hours and 7.8 hours respectively.
Following intravenous administration, the mean total plasma clearance is approximately 10 ml/min/kg, of which one third 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 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.
In a small group of healthy individuals there was no pharmacokinetic interaction with ergotamine. Concomitant administration of zolmitriptan with ergotamine/caffeine was well tolerated and did not result in any increase in adverse events or blood pressure changes as compared with zolmitriptan alone.
Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed.
Selegiline, an MAO-B inhibitor, and fluoxetine (a selective serotonin reuptake inhibitor; SSRI) had no effect on the pharmacokinetic parameters of zolmitriptan.
Zolmitriptano Ciclum Rapimelt was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the tmax for zolmitriptan can be later for the orally dispersible tablet (range 0.6 to 5h, median 3h) compared to the conventional tablet (range 0.5 to 3h, median 1.5h). The tmax for the active metabolite was similar for both formulations (median 3h).
Renal impairment
Renal clearance of zolmitriptan and all its metabolites is reduced (7 to 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.
Elderly
The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers.
Zolmitriptano Ciclum Rapimelt should only be used where a clear diagnosis of migraine has been established. Care should be taken to exclude other potentially serious neurological conditions. There are no data on the use of Zolmitriptano Ciclum Rapimelt in hemiplegic or basilar migraine. Migraneurs may be at risk of certain cerebrovascular events. Cerebral haemorrhage, subarachnoid haemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5HT1B/1D agonists.
Zolmitriptano Ciclum Rapimelt should not be given to patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathways.
In very rare cases, as with other 5HT1B/1D agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. In patients with risk factors for ischaemic heart disease, cardiovascular evaluation prior to commencement of treatment with this class of compounds, including Zolmitriptano Ciclum Rapimelt, is recommended. These evaluations, however, may not identify every patient who has cardiac disease, and in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease.
As with other 5HT1B/1D agonists, atypical sensations over the precordium have been reported after the administration of zolmitriptan. If chest pain or symptoms consistent with ischaemic heart disease occur, no further doses of zolmitriptan should be taken until after appropriate medical evaluation has been carried out.
As with other 5HT1B/1D agonists transient increases in systemic blood pressure have been reported in patients with and without a history of hypertension; very rarely these increases in blood pressure have been associated with significant clinical events.
As with other 5HT1B/1D agonists, there have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving Zolmitriptano Ciclum.
Patients with phenylketonuria should be informed that Zolmitriptano Ciclum Rapimelt contains phenylalanine (a component of aspartame). Each 2.5 mg orally dispersible tablet contains 2.81 mg of phenylalanine.
Excessive use of an acute anti-migraine medicinal product may lead to an increased frequency of headache, potentially requiring withdrawal of treatment.
Serotonin Syndrome has been reported with combined use of triptans, and Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs). Serotonin Syndrome is a potentially life-threatening condition, and it may include signs and symptoms such as: mental status changes (e.g. agitation, hallucinations, coma), autonomic instability, (e.g. tachycardia, labile blood-pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, in-coordination), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Careful observation of the patient is advised, if concomitant treatment with Zolmitriptano Ciclum Rapimelt and an SSRI or SNRI is clinically warranted, particularly during treatment initiation and dosage increases.
There was no significant impairment of performance of psychomotor tests with doses up to 20 mg zolmitriptan. Zolmitriptano Ciclum has no or negligible influence on the ability to drive and use machines. However it should be taken into account that somnolence may occur.
Posology
The recommended dose of Zolmitriptano Ciclum Rapimelt to treat a migraine attack is 2.5 mg.
If symptoms persist or return within 24 hours, a second dose of zolmitriptan has been shown to be effective. If a second dose is required, it should not be taken within 2 hours of the initial dose.
If a patient does not achieve satisfactory relief with 2.5 mg doses, subsequent attacks can be treated with 5 mg doses of Zolmitriptano Ciclum Rapimelt.
Zolmitriptan is equally effective whenever the tablets are taken during a migraine attack; although it is advisable that Zolmitriptano Ciclum Rapimelt is taken as early as possible after the onset of migraine headache.
In the event of recurrent attacks, it is recommended that the total intake of Zolmitriptano Ciclum Rapimelt in a 24 hour period should not exceed 10 mg.
Zolmitriptano Ciclum Rapimelt is not indicated for prophylaxis of migraine.
Paediatric population (Children below the age of 12 years)
The safety and efficacy of Zolmitriptano Ciclum Rapimelt in children aged 0-12 years has not yet been established. No data are available. Use of Zolmitriptano Ciclum Rapimelt in children is therefore not recommended.
Adolescents (12 - 17 years of age)
The efficacy of Zolmitriptano Ciclum Rapimelt was not demonstrated in a placebo controlled clinical trial for patients aged 12 to 17 years. Use of Zolmitriptano Ciclum Rapimelt in adolescents is therefore not recommended.
Elderly
The safety and efficacy of Zolmitriptano Ciclum Rapimelt in individuals aged over 65 years have not been established.
Hepatic impairment
Metabolism is reduced in patients with hepatic impairment. Therefore for patients with moderate or severe hepatic impairment a maximum dose of 5 mg in 24 hours is recommended.
Renal impairment
No dosage adjustment required.
Method of administration
To be taken by oral administration.
Zolmitriptano Ciclum Rapimelt rapidly dissolves when placed on the tongue and is swallowed with the patient's saliva. A drink of water is not required when taking Zolmitriptano Ciclum Rapimelt. Zolmitriptano Ciclum Rapimelt can be taken when water is not available thus allowing early administration of treatment for a migraine attack. This formulation may also be beneficial for patients who suffer from nausea and are unable to drink during a migraine attack, or for patients who do not like swallowing conventional tablet.
The blister pack should be peeled open as shown on the foil (tablets should not be pushed through the foil). The Zolmitriptano Ciclum Rapimelt tablet should be placed on the tongue, where it will dissolve and be swallowed with the saliva.
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
