Zolmitriptano Labesfal

Zolmitriptano Labesfal Rapimelt is indicated for the acute treatment of migraine with or without aura.

Zolmitriptano Labesfal is indicated for the acute treatment of migraine with or without aura.

Acute treatment of migraine headache with or without aura.

Zolmitriptano Labesfal is not indicated for prophylaxis of migraine.

Posology

The recommended dose of Zolmitriptano Labesfal 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 Labesfal Rapimelt.

Zolmitriptan is equally effective whenever the tablets are taken during a migraine attack; although it is advisable that Zolmitriptano Labesfal 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 Labesfal Rapimelt in a 24 hour period should not exceed 10 mg.

Zolmitriptano Labesfal Rapimelt is not indicated for prophylaxis of migraine.

Paediatric population (Children below the age of 12 years)

The safety and efficacy of Zolmitriptano Labesfal Rapimelt in children aged 0-12 years has not yet been established. No data are available. Use of Zolmitriptano Labesfal Rapimelt in children is therefore not recommended.

Adolescents (12 - 17 years of age)

The efficacy of Zolmitriptano Labesfal Rapimelt was not demonstrated in a placebo controlled clinical trial for patients aged 12 to 17 years. Use of Zolmitriptano Labesfal Rapimelt in adolescents is therefore not recommended.

Elderly

The safety and efficacy of Zolmitriptano Labesfal 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 Labesfal 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 Labesfal Rapimelt. Zolmitriptano Labesfal 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.

Posology

The recommended dose of Zolmitriptano Labesfal 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 Labesfal.

Zolmitriptan is equally effective whenever the tablets are taken during a migraine attack; although it is advisable that Zolmitriptano Labesfal 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 Labesfal in a 24 hour period should not exceed 10 mg.

Zolmitriptano Labesfal is not indicated for prophylaxis of migraine.

Paediatric population (Children below the age of 12 years)

The safety and efficacy of Zolmitriptano Labesfal in children aged 0-12 years has not yet been established. No data are available. Use of Zolmitriptano Labesfal in children is therefore not recommended.

Adolescents (12 - 17 years of age)

The efficacy of Zolmitriptano Labesfal was not demonstrated in a placebo controlled clinical trial for patients aged 12 to 17 years. Use of Zolmitriptano Labesfal in adolescents is therefore not recommended.

Elderly

The safety and efficacy of Zolmitriptano Labesfal 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 Labesfal 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 Labesfal. Zolmitriptano Labesfal 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.

Posology

The recommended dose of Zolmitriptano Labesfal to treat a migraine attack is 2.5 mg. It is advisable that Zolmitriptano Labesfal 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 Zolmitriptano Labesfal could be considered. Caution is advised due to an increased incidence of side effects. A controlled clinical study failed to demonstrate superiority of the 5 mg dose over the 2.5 mg dose. Nevertheless a 5 mg dose may be of benefit in some patients.

The total daily intake should not exceed 10 mg. Not more than 2 doses of Zolmitriptano Labesfal should be taken in any 24-hour period.

Special populations

Use in patients aged over 65 years

The safety and efficacy of Zolmitriptano Labesfal in individuals aged over 65 years have not been evaluated. Use of Zolmitriptano Labesfal in the elderly is therefore not recommended.

Patients with hepatic impairment

The metabolism of Zolmitriptano Labesfal is reduced in patients with hepatic impairment. For patients with moderate or severe hepatic impairment, a maximum dose of 5 mg in 24 hours is recommended. However, no dose adjustment is required for patients with mild hepatic impairment.

Patients with renal impairment

No dosage adjustment required in patients with a creatinine clearance of more than 15 ml/min.

Interactions requiring dose adjustment

For patients taking MAO-A inhibitors, a maximum dose of 5 mg in 24 hours is recommended.

A maximum dose of 5 mg Zolmitriptano Labesfal in 24 hours is recommended in patients taking cimetidine.

A maximum dose of 5 mg Zolmitriptano Labesfal in 24 hours is recommended in patients taking specific inhibitors of CYP 1A2 such as fluvoxamine and the quinolones (eg ciprofloxacin).

Paediatric population

Use in Children (under 12 years of age)

Safety and efficacy of Zolmitriptano Labesfal in paediatric patients have not been evaluated. Use of Zolmitriptano Labesfal in children is therefore not recommended.

Adolescents (12 - 17 years of age)

The efficacy of Zolmitriptano Labesfal was not demonstrated in a placebo controlled clinical trial for patients aged 12 to 17 years. Use of Zolmitriptano Labesfal in adolescents is therefore not recommended.

Method of administration

For oral use.

The tablet need not be taken with liquid; the tablet dissolves on the tongue and is swallowed with saliva. This formulation can be used in situations in which liquids are not available, or to avoid the nausea and vomiting that may accompany the ingestion of tablets with liquids. However, a delay in the absorption of Zolmitriptano Labesfal from Zolmitriptano Labesfal can occur which may delay onset of action.

The blister pack should be peeled open as shown on the foil (tablets should not be pushed through the foil). The Zolmitriptano Labesfal tablet should be placed on the tongue, where it will dissolve and be swallowed with the saliva.

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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 Labesfal with ergotamine or ergotamine derivatives or other 5-HT₁ receptor agonists.

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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 Zomig with ergotamine or ergotamine derivatives or other 5-HT₁ receptor agonists.

Moderate or severe hypertension, and mild uncontrolled hypertension.

This class of compounds (5HT_1B/1D receptor agonists), has been associated with coronary vasospasm, as a result, patients with ischaemic heart disease were excluded from clinical trials. Therefore Zolmitriptano Labesfal should not be given to patients who have had myocardial infarction or have ischaemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease or patients who have symptoms or signs consistent with ischaemic heart disease.

Concurrent administration of ergotamine, derivatives of ergotamine (including methysergide), sumatriptan, naratriptan and other 5HT_1B/1D receptor agonists with Zolmitriptano Labesfal is contraindicated.

Zolmitriptano Labesfal should not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

Zolmitriptano Labesfal is contraindicated in patients with a creatinine clearance of less than 15 ml/min.

Zolmitriptano Labesfal 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 Labesfal 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 5HT_1B/1D agonists.

Zolmitriptano Labesfal 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 5HT_1B/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 Labesfal 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 5HT_1B/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 5HT_1B/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 5HT_1B/1D agonists, there have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving Zolmitriptano Labesfal.

Patients with phenylketonuria should be informed that Zolmitriptano Labesfal 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 Labesfal Rapimelt and an SSRI or SNRI is clinically warranted, particularly during treatment initiation and dosage increases.

Zolmitriptano Labesfal 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 Labesfal 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 5HT_1B/1D agonists.

Zolmitriptano Labesfal 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 5HT_1B/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 Labesfal, 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 5HT_1B/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 5HT_1B/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 5HT_1B/1D agonists, there have been rare reports of anaphylaxis/anaphylactoid reactions in patients receiving Zomig.

Patients with phenylketonuria should be informed that Zolmitriptano Labesfal 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 Labesfal and an SSRI or SNRI is clinically warranted, particularly during treatment initiation and dosage increases.

Zolmitriptano Labesfal should only be used where a clear diagnosis of migraine has been established. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. Zolmitriptano Labesfal is not indicated for use in hemiplegic, basilar or ophthalmoplegic migraine. Stroke and other cerebrovascular events have been reported in patients treated with 5HT_1B/1D agonists. It should be noted that migraneurs may be at risk of certain cerebrovascular events.

Zolmitriptano Labesfal should not be given to patients with symptomatic Wolff-Parkinson-White syndrome or arrythmias associated with other cardiac accessory conduction pathways.

In very rare cases, as with other 5HT_1B/1D agonists, coronary vasospasm, angina pectoris and myocardial infarction have been reported. Zolmitriptano Labesfal should not be given to patients with risk factors for ischaemic heart disease (e.g. smoking, hypertension, hyperlipidaemia, diabetes mellitus, heredity) without prior cardiovascular evaluation. Special consideration should be given to postmenopausal women and males over 40 with these risk factors. 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 5HT_1B/1D receptor agonists, heaviness, pressure or tightness over the precordium have been reported after the administration of Zolmitriptano Labesfal. If chest pain or symptoms consistent with ischaemic heart disease occur, no further doses of Zolmitriptano Labesfal should be taken until after appropriate medical evaluation has been carried out.

As with other 5HT_1B/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. The dose recommendation for Zolmitriptano Labesfal should not be exceeded.

Undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St John's wort (Hypericum perforatum).

Serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) has been reported following concomitant treatment with triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). These reactions can be severe. If concomitant treatment with Zolmitriptano Labesfal and an SSRI or SNRI is clinically warranted, appropriate observation of the patient is advised, particularly during treatment initiation, with dose increases, or with addition of another serotonergic medication.

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Zolmitriptano Labesfal, when administered as conventional oral tablets, if taken during the aura, has not been demonstrated to prevent the migraine headache and therefore Zolmitriptano Labesfal should be taken during the headache phase of migraine.

This medicinal product contains aspartame, a source of phenylalanine. May be harmful for people with phenylketonuria.

There was no significant impairment of performance of psychomotor tests with doses up to 20 mg zolmitriptan. Zolmitriptano Labesfal has no or negligible influence on the ability to drive and use machines. However it should be taken into account that somnolence may occur.

There was no significant impairment of performance of psychomotor tests with doses up to 20 mg zolmitriptan. Zomig has no or negligible influence on the ability to drive and use machines. However it should be taken into account that somnolence may occur.

In a small group of healthy individuals there was no significant impairment of performance of psychomotor tests with doses up to 20 mg Zolmitriptano Labesfal. Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as drowsiness and other symptoms may occur during a migraine attack.

Summary of the safety profile

Zolmitriptano Labesfal 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:

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.

Summary of the safety profile

Zomig 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:

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.

Possible undesirable effects are typically transient, tend to occur within four hours of dosing, are no more frequent following repeated dosing and resolve spontaneously without additional treatment.

The following definitions apply to the incidence of the undesirable effects:

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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following undesirable effects have been reported following administration of Zolmitriptano Labesfal:

Certain symptoms, may be part of the migraine attack itself.

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 at: www.mhra.gov.uk/yellowcard

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 Labesfal 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.

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 Labesfal 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.

Volunteers receiving single oral doses of 50 mg commonly experienced sedation.

The elimination half-life of Zolmitriptano Labesfal is 2.5 to 3 hours, and therefore monitoring of patients after overdose with Zolmitriptano Labesfal should continue for at least 15 hours or while symptoms or signs persist.

There is no specific antidote to Zolmitriptano Labesfal. 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 Zolmitriptano Labesfal.

Following oral administration of Zolmitriptano Labesfal 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 C_max over the dose range 2.5 to 50 mg. Absorption is rapid with 75% of C_max 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 Labesfal 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 C_max 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 C_max 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 Labesfal Rapimelt was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and C_max for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the t_max 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 t_max 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.

Following oral administration of Zomig 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 C_max over the dose range 2.5 to 50 mg. Absorption is rapid with 75% of C_max 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 Labesfal. 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 C_max 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 C_max 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 Labesfal was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and C_max for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the t_max 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 t_max 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.

Absorption

Following oral administration of Zolmitriptano Labesfal conventional tablets, Zolmitriptano Labesfal 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 5HT_1B/1D receptor agonist and is 2 to 6 times as potent, in animal models, as Zolmitriptano Labesfal.

In healthy subjects, when given as a single dose, Zolmitriptano Labesfal and its active metabolite, the N-desmethyl metabolite, display dose-proportional AUC and C_max over the dose range 2.5 to 50 mg. Absorption of Zolmitriptano Labesfal is rapid. In healthy volunteers, 75% of C_max is achieved within 1 hour, and after this the concentration of Zolmitriptano Labesfal in plasma is maintained at approximately this level until 4-5 hours after dosing.

Zolmitriptano Labesfal absorption is unaffected by the presence of food. There was no evidence of accumulation on multiple dosing of Zolmitriptano Labesfal.

Plasma concentration of Zolmitriptano Labesfal 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.

Zolmitriptano Labesfal orodispersible tablet was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and C_max for Zolmitriptano Labesfal and its active metabolite 183C91. Clinical pharmacology data show that the t_max for Zolmitriptano Labesfal 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 t_max for the active metabolite was similar for both formulations (median 3h).

Distribution

The volume of distribution following intravenous administration is 2.4 l/kg. Plasma protein binding of Zolmitriptano Labesfal and the N-desmethyl metabolite is low (approximately 25%).

Biotransformation and elimination

Zolmitriptano Labesfal 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 Zolmitriptano Labesfal. The mean elimination half-life of Zolmitriptano Labesfal is 2.5 to 3 hours. The half-lives of its metabolites are similar, suggesting their elimination is formation-rate limited. 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.

Hepatic impairment

The metabolism of Zolmitriptano Labesfal is reduced in hepatic impairment in proportion to the extent of the impairment.

A study to evaluate the effect of liver disease on the pharmacokinetics of Zolmitriptano Labesfal showed that the AUC and C_max 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 C_max were reduced by 33% and 44% in patients with moderate liver disease and by 82% and 90% in patients with severe liver disease.

Renal impairment

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.

Renal clearance of Zolmitriptano Labesfal 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.

Elderly people

The pharmacokinetics of Zolmitriptano Labesfal in healthy elderly subjects were similar to those in healthy young volunteers.

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 Labesfal 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.

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 Labesfal 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.

Preclinical effects in single and repeat dose toxicity studies were observed only at exposures well in excess of the maximum human exposure.

The findings from in vitro and in vivo genetic toxicity studies show that genotoxic effects of Zolmitriptano Labesfal are not to be expected under the conditions of clinical use.

No tumours relevant to the clinical use were found in mouse and rat carcinogenicity studies.

As with other 5HT_1B/1D receptor agonists, Zolmitriptano Labesfal binds to melanin.

The blister pack should be peeled open as shown on the foil (tablets should not be pushed through the foil). The Zolmitriptano Labesfal 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.

The blister pack should be peeled open as shown on the foil (tablets should not be pushed through the foil). The Zolmitriptano Labesfal 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.

No special requirements