Zolmitriptano Actavis

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

Zolmitriptano Actavis Spray is indicated for the acute treatment of migraine with or without aura in adults.

Limitations of Use

• Only use ZOMIG if a clear diagnosis of migraine has been established.If a patient has no response to ZOMIG treatment for the first migraine attack, reconsider the diagnosis of migraine before ZOMIG is administered to treat any subsequent attacks.
• ZOMIG is not indicated for the prevention of migraine attacks.
• Safety and effectiveness of ZOMIG have not been established for cluster headache.
• Not recommended in patients with moderate or severe hepatic impairment.

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

Posology

The recommended dose of Zolmitriptano Actavis 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 Actavis Rapimelt.

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

Zolmitriptano Actavis Rapimelt is not indicated for prophylaxis of migraine.

Paediatric population (Children below the age of 12 years)

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

Adolescents (12 - 17 years of age)

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

Elderly

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

Dosing Information

The recommended starting dose for Zolmitriptano Actavis spray is 2.5 mg. As the individual response to Zolmitriptano Actavis spray may vary, the dose should be adjusted on an individual basis. The maximum recommended single dose of ZOMIG is 5 mg.

In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose.

If the migraine has not resolved by 2 hours after taking ZOMIG, or returns after a transient improvement, another dose may be administered at least 2 hours after the previous dose.

The maximum daily dose should not exceed 10 mg in any 24-hour period.

The safety of ZOMIG in the treatment of an average of more than four headaches in a 30-day period has not been established.

Dosing in Patients with Hepatic Impairment

Zolmitriptano Actavis spray is not recommended in patients with moderate to severe hepatic impairment because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. The recommended dosage of Zolmitriptano Actavis spray in patients with mild hepatic impairment is the same as for patients with normal hepatic function.

Dosing in Patients taking Cimetidine

If ZOMIG is co-administered with cimetidine, limit the maximum single dose of ZOMIG to 2.5 mg, not to exceed 5 mg in any 24-hour period.

Posology

The recommended dose of Zolmitriptano Actavis 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 Actavis.

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

Zolmitriptano Actavis is not indicated for prophylaxis of migraine.

Paediatric population (Children below the age of 12 years)

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

Adolescents (12 - 17 years of age)

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

Elderly

The safety and efficacy of Zolmitriptano Actavis 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 Actavis 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 Actavis. Zolmitriptano Actavis 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.

-

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

ZOMIG is contraindicated in patients with:

• Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), other significant underlying cardiovascular disease, or coronary artery vasospasm including Prinzmetal's angina
• Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders
• History of stroke, transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at higher risk of stroke
• Peripheral vascular disease (PVD)
• Ischemic bowel disease
• Uncontrolled hypertension
• Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide)
• Concurrent administration of an MAO-A inhibitor or recent discontinuation of a MAO-A inhibitor (that is within 2 weeks)
• Known hypersensitivity to ZOMIG (angioedema and anaphylaxis seen)

-

- 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.

Zolmitriptano Actavis 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 Actavis 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 Actavis 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 Actavis 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 Actavis.

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina

ZOMIG is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD). There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of ZOMIG. Some of these reactions occurred in patients without known CAD. 5-HT1 agonists including ZOMIG may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving ZOMIG. Do not administer ZOMIG if there is evidence of CAD or coronary artery vasospasm.

Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure

As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with ZOMIG and is usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists.

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Discontinue ZOMIG if a cerebrovascular event occurs.

As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, other potentially serious neurological conditions should be excluded. ZOMIG should not be administered to patients with a history of stroke or transient ischemic attack.

Other Vasospasm Reactions

5-HT1 agonists, including ZOMIG, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional ZOMIG doses.

Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g. ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Serotonin Syndrome

Serotonin syndrome may occur with triptans, including ZOMIG, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. ZOMIG treatment should be discontinued if serotonin syndrome is suspected.

Increase in Blood Pressure

Significant elevations in systemic blood pressure have been reported in patients treated with 5-HT1 agonists including patients without a history of hypertension. Very rarely these increases in blood pressure have been associated with significant clinical events. In healthy subjects treated with 5 mg of ZOMIG oral tablet, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen. In a study of patients with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of ZOMIG oral tablet. As with all triptans, blood pressure should be monitored in ZOMIG-treated patients. ZOMIG is contraindicated in patients with uncontrolled hypertension.

Patient Counseling Information

See FDA-Approved Patient Labeling (PATIENT INFORMATION)

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's angina, Other Vasospasm-related Events, and Cerebrovascular Events

Inform patients that ZOMIG may cause serious cardiovascular side effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms.

Medication Overuse Headache

Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).

Serotonin Syndrome

Inform patients about the risk of serotonin syndrome with the use of ZOMIG or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).

Pregnancy

Inform patients that ZOMIG should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.

Handling of Zolmitriptano Actavis spray device

The Zolmitriptano Actavis Spray device is packaged in a carton and is a blue colored plastic device with a gray protection cap, labeled to indicate the nominal dose. Caution patients to not remove the gray protection cap until prior to dosing. The Zolmitriptano Actavis Spray device is placed in a nostril and actuated to deliver a single dose. Caution patients to avoid spraying the contents of the device in their eyes.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Zolmitriptan was administered to mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females); rats were dosed for 101 weeks (males) and 86 weeks (females). There was no evidence of drug-induced tumors in mice at plasma exposures (AUC) up to approximately 700 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/day. In rats, there was an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas in male rats receiving 400 mg/kg/day. No increase in tumors was observed in rats at 100 mg/kg/day, a dose associated with a plasma AUC ≈700 times that in humans at the MRHD.

Mutagenesis

Zolmitriptan was positive in an in vitro bacterial reverse mutation (Ames) assay and in an in vitro chromosomal aberration assay in human lymphocytes. Zolmitriptan was negative in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay and in oral in vivo micronucleus assays in mouse and rat.

Impairment of Fertility

Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation showed no impairment of fertility at oral doses up to 400 mg/kg/day. The plasma exposure (AUC) at this dose was approximately 3000 times that in humans at the MRHD.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women; therefore, zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures.

When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established. When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryo-fetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of hydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.

Nursing Mothers

It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZOMIG, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In rats, oral dosing with zolmitriptan resulted in levels in milk up to 4 times higher than in plasma.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

A single, multicenter, double-blind, randomized placebo-controlled, study was conducted to evaluate the efficacy of ZOMIG 5 mg nasal spray in the acute treatment of migraine headache in 171 evaluable adolescent subjects 12 to 17 years of age. Efficacy was not established in that study.

Adverse reactions observed in this study were similar in nature and frequency to those reported in clinical trials of Zolmitriptano Actavis Spray in adults. The most commonly reported adverse reactions ( ≥ 2% and > placebo) were dysgeusia (7%), nasal discomfort (3%), dizziness (2%), nasal congestion (2%), nausea (2%), and throat irritation (2%).

Zolmitriptano Actavis Spray has not been studied in pediatric patients age 11 years and under. In the postmarketing experience with triptans, including ZOMIG, there is a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events; those that were reported are similar in nature to those reported rarely in adults.

Geriatric Use

Clinical studies of ZOMIG did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving ZOMIG. The pharmacokinetics of zolmitriptan were similar in geriatric patients (aged > 65 years) compared to younger patients.

Patients With Hepatic Impairment

The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. After oral administration, zolmitriptan blood levels were increased in patients with moderate to severe hepatic impairment, and significant elevation in blood pressure was observed in some of these patients. Zolmitriptano Actavis spray is not recommended in patients with moderate to severe hepatic impairment.

Zolmitriptano Actavis 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 Actavis 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 Actavis 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 Actavis, 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 Actavis 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 Actavis 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 Actavis 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.

Summary of the safety profile

Zolmitriptano Actavis 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.

The following adverse reactions are discussed in more detail in other sections of labeling:

• Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina
• Arrhythmias
• Chest and or Throat, Neck and Jaw Pain/Tightness/Pressure
• Cerebrovascular Events
• Other Vasospasm Reactions
• Medication Overuse Headache
• Serotonin Syndrome
• Increase in Blood Pressure

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Among 460 patients treating 1180 single attacks with zolmitriptan nasal spray in a blinded placebo controlled trial (Study 1), there was a low withdrawal rate related to adverse reactions: 5 mg (1.3%), 2.5 mg (0%), and placebo (0.4%). None of the withdrawals were due to a serious event. One patient was withdrawn due to abnormal ECG changes from baseline that were incidentally found 23 days after the last dose of Zolmitriptano Actavis Spray.

The most common adverse reactions ( ≥ 5% and > placebo) in any dosage strength in clinical trials for Zolmitriptano Actavis Spray were: unusual taste, paresthesia, hyperesthesia, and dizziness. The incidence of adverse reactions was generally dose-related.

Table 1 lists the adverse reactions from the controlled clinical trial (Study 1) that occurred in ≥ 2% of patients in either the 2.5 or 5 mg zolmitriptan nasal spray dose groups and with an incidence greater than placebo.

Table 1: Adverse reactions with an incidence of ≥ 2% and greater than placebo of patients in each of the ZOMIG 2.5 and 5 mg nasal spray treatment groups by body system.

In Study 1, adverse clinical reactions occurring in ≥ 1% and < 2% of patients in all attacks in either zolmitriptan nasal spray dose group and with incidence greater than that of placebo were pain abdominal, chills, pressure throat, edema face, pressure chest, palpitation, dysphagia, arthralgia, myalgia, and depersonalization.

The incidence of adverse reactions in controlled clinical trials was not affected by gender, weight, or age of the patients (18-39 vs. 40-65 years of age), or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions.

Local Adverse Reactions

Among 460 patients using ZOMIG 2.5mg or 5mg in the controlled clinical trial, approximately 3% noted local irritation or soreness at the site of administration. Adverse reactions of any kind, perceived in the nasopharynx (which may include systemic effects of triptans) were severe in about 1% of patients and approximately 57% resolved in 1 hour. Nasopharyngeal examinations, in a subset of patients participating in two long term trials of up to one year duration, failed to demonstrate any clinically significant changes with repeated use of Zolmitriptano Actavis Spray.

All nasopharyngeal adverse reactions with an incidence of ≥ 2% of patients in any zolmitriptan nasal spray dose groups are included in ADVERSE REACTIONS Table 1.

Other Adverse Reactions

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled studies, the role of ZOMIG in their causation cannot be reliably determined.

Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used Zolmitriptano Actavis Spray and reported a reaction divided by the total number of patients exposed to ZOMIG Nasal Spray (n=3059). All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients and rare adverse reactions are those occurring in fewer than 1/1,000 patients.

General: Infrequent: allergic reactions.

Cardiovascular: Infrequent: arrhythmias, hypertension, syncope and tachycardia. Rare: angina pectoris and myocardial infarct.

Digestive: Rare: stomatitis.

Neurological: Infrequent: agitation, amnesia, anxiety, depression, insomnia, and nervousness. Rare: convulsions.

Respiratory: Infrequent: bronchitis, increased cough, dyspnea, epistaxis, laryngeal edema, pharyngitis, rhinitis, and sinusitis.

Skin: Infrequent: pruritus, rash, and urticaria.

Urogenital: Infrequent: polyuria and urinary urgency. Rare: urinary frequency.

Special senses: Infrequent: tinnitus. Rare: conjunctivitis, dry eye, and visual field defect.

The adverse experience profile seen with Zolmitriptano Actavis Spray is similar to that seen with ZOMIG tablets and ZOMIG-ZMT tablets except for the occurrence of local adverse reactions from the nasal spray (see ZOMIG tablet/ZOMIG-ZMT oral disintegrating tablet Prescribing Information).

Postmarketing Experience

The following adverse reactions were identified during post approval use of ZOMIG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The reactions enumerated include all except those already listed in the Clinical Trials Experience section above or the Warnings and Precautions section.

Hypersensitivity Reactions

As with other 5-HT1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving ZOMIG. ZOMIG is contraindicated in patients with a history of hypersensitivity reaction to ZOMIG.

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.

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 Actavis 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.

There is no experience with acute overdose. Clinical study subjects receiving single 50 mg oral doses of zolmitriptan commonly experienced sedation.

The elimination half-life of ZOMIG is 3 hours and therefore monitoring of patients after overdose with ZOMIG 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 hemodialysis or peritoneal dialysis has on the plasma 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 Actavis 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.

Following oral administration of Zolmitriptano Actavis 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 Actavis 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 Actavis 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.

Absorption

Zolmitriptan nasal spray is rapidly absorbed via the nasopharynx as detected in a Photon Emission Tomography (PET) study using 11C zolmitriptan. The mean relative bioavailability of the nasal spray formulation is 102%, compared with the oral tablet. Zolmitriptan was detected in plasma by 5 minutes and peak plasma concentration generally was achieved by 3 hours. The time at which maximum plasma concentrations were observed was similar after single (1 day) or multiple (4 days) nasal dosing. Plasma concentrations of zolmitriptan are sustained for 4 to 6 hours after dosing. Zolmitriptan and its active N-desmethyl metabolite display linear kinetics after single or multiple doses of Zolmitriptano Actavis spray over the dose range of 0.1 to 10 mg.

The pharmacokinetics of the N-desmethyl metabolite are similar to that of zolmitriptan for all nasal spray dosages. The N-desmethyl metabolite is detected in plasma by 15 minutes and peak plasma concentration is generally achieved by 3 hours after administration.

Food has no significant effect on the bioavailability of zolmitriptan.

Distribution

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10-1000 ng/mL. The mean apparent volume of distribution for zolmitriptan nasal spray formulation is 8.4 L/kg.

Metabolism

Zolmitriptan is converted to an active N-desmethyl metabolite such that the metabolite concentrations are about two-thirds that of zolmitriptan. Because the 5HT_1B/1D potency of the metabolite is 2 to 6 times that of the parent compound, the metabolite may contribute a substantial portion of the overall effect after ZOMIG administration.

Excretion

The mean elimination half-life for zolmitriptan and N-desmethyl metabolite following single or multiple nasal spray administration are approximately 3 hours, similar to the half-life values seen after oral tablet administration.

In a study with orally administered zolmitriptan, total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. In urine, unchanged zolmitriptan and N-desmethyl metabolite accounted for 8% and 4% of the dose, respectively, whereas the inactive indole acetic acid and N-oxide metabolites accounted for 31% and 7% of the dose, respectively.

Mean total plasma clearance for zolmitriptan nasal spray is 25.9 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

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 Actavis. 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 Actavis 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.

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 Actavis 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 Actavis 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.

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