ZOMIG(r) and ZOMIG RAPIMELT(r) are trade-marks of the AstraZeneca group of companies.

PRODUCT MONOGRAPH 1 TABLE OF CONTENTS 2 PART I: HEALTH PROFESSIONAL INFORMATION 3 SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 11 DRUG INTERACTIONS. 19 DOSAGE AND ADMINISTRATION 20 OVERDOSAGE 22 ACTION AND CLINICAL PHARMACOLOGY 23 STORAGE AND STABILITY 26 DOSAGE FORMS, COMPOSITION AND PACKAGING 26 PART II: SCIENTIFIC INFORMATION 28 PHARMACEUTICAL INFORMATION 28 CLINICAL TRIALS 29 DETAILED PHARMACOLOGY 34 TOXICOLOGY 36 REFERENCES 39 PART III: CONSUMER INFORMATION 42 PART III: CONSUMER INFORMATION 46

Pr ZOMIG(r) NASAL SPRAY (zolmitriptan) nasal spray

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

in patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular or peripheral vascular syndromes, valvular heart disease or cardiac arrhythmias (especially tachycardias). In addition, patients with other significant underlying cardiovascular diseases (e.g., atherosclerotic disease, congenital heart disease) should not receive ZOMIG. Ischemic cardiac syndromes include, but are not restricted to, angina pectoris of any type (e.g., stable angina of effort and vasospastic forms of angina such as the Prinzmetal's variant), all forms of myocardial infarction, and silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as transient ischemic attacks (TIAs). Peripheral vascular disease includes, but is not limited to, ischemic bowel disease, or Raynaud's syndrome (see WARNINGS AND PRECAUTIONS, Cardiovascular);

in patients with uncontrolled or severe hypertension as ZOMIG can give rise to increases in blood pressure (see WARNINGS AND PRECAUTIONS, Hematologic);

within 24 hours of treatment with another 5-HT1 agonist, or an ergotamine- containing or ergot-type medication like dihydroergotamine or methysergide (see DRUG INTERACTIONS);

concurrent administration of MAO inhibitors or use of zolmitriptan within 2 weeks of discontinuation of MAO inhibitor therapy (see DRUG INTERACTIONS);

in patients with hypersensitivity to zolmitriptan or any component of the formulation DOSAGE FORMS, COMPOSITION AND PACKAGING

WARNINGS AND PRECAUTIONS

ZOMIG (zolmitriptan) should only be used where a clear diagnosis of migraine has been established.

Lactose is a non-medicinal ingredient in ZOMIG tablets. Therefore, patients with rare hereditary problems of galactose intolerance (the Lapp lactase deficiency or glucose- galactose malabsorption) should not take ZOMIG tablets.

Although ZOMIG did not interfere with psychomotor performance in healthy volunteers, some patients in clinical trials experienced sedation with ZOMIG. Patients should thus be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that ZOMIG does not affect them adversely.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: ZOMIG has been associated with transient chest and/or neck pain and tightness which

may resemble angina pectoris. Following the use of other 5-HT1 agonists, in rare cases

these symptoms have been identified as being the likely result of coronary vasospasm or

myocardial ischemia. Rare cases of serious coronary events or arrhythmia have occurred following use of ZOMIG. In very rare cases angina pectoris has been reported.

ZOMIG should not be given to patients who have documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). It is strongly recommended that ZOMIG not be given to patients in whom unrecognised coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoking, obesity, diabetes, strong family history of CAD, female who is surgically or physiologically postmenopausal, or male who is over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is unknown. If, during the cardiovascular evaluation, the patient's medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, ZOMIG should not be administered (see CONTRAINDICATIONS).

These evaluations, however, may not identify every patient who has cardiac disease, and in very rare cases, serious cardiac events, such as myocardial infarction or coronary ischemia have occurred in patients without evidence of underlying cardiovascular disease.

For patients with risk factors predictive of CAD who are considered to have a satisfactory cardiovascular evaluation, the first dose of ZOMIG should be administered

in the setting of a physician's office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining electrocardiograms in patients with risk factors during the interval immediately following ZOMIG administration on the first occasion of use. However, an absence of drug-induced cardiovascular effects on the occasion of the initial dose does not preclude the possibility of such effects occurring with subsequent administrations.

Intermittent long-term users of ZOMIG, who have or acquire risk factors predictive of CAD, as described above, should receive periodic interval cardiovascular evaluations over the course of treatment.

If symptoms consistent with angina occur after the use of ZOMIG, ECG evaluation should be carried out to look for ischemic changes.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to ZOMIG.

As with other 5HT1B/1D agonists, atypical sensations over the precordium have been reported after the administration of zolmitriptan. Where such symptoms are thought to indicate ischemic heart disease, no further doses of zolmitriptan should be given and appropriate evaluation carried out. Discomfort in the chest, neck, throat and jaw (including pain, pressure, heaviness and tightness) has been reported after administration of ZOMIG. Because 5-HT1 agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following ZOMIG should be evaluated for the presence of CAD or a predisposition to variant angina before receiving additional doses, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud's syndrome following ZOMIG administration should be evaluated for atherosclerosis or predisposition to vasospasm (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Cardiac Events and Fatalities Associated with 5-HT1 Agonists As with other triptans, zolmitriptan may cause coronary artery vasospasm. Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of other 5-HT1 agonists. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low. Patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders should not receive ZOMIG.

Among the more than 2,500 patients with migraine who participated in premarketing controlled clinical trials of ZOMIG conventional tablets, no deaths or serious cardiac events were reported. In premarketing controlled clinical trials of ZOMIG Nasal Spray, more than 1300 patients participated and there were no deaths or serious cardiac events to report.

Serious cardiovascular events have been reported in association with the use of ZOMIG. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of reported cases that were actually caused by ZOMIG or to reliably assess causation in individual cases.

Cerebrovascular Events and Fatalities With 5-HT1 Agonists Migraineurs may be at risk of certain cerebrovascular events. Cerebral haemorrhage, subarachnoid haemorrhage, stroke, and other cerebrovascular events have been reported 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 agonist having been administered in the incorrect belief that the symptoms were a consequence of migraine, when they were not. Before treating migraine headaches with ZOMIG 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. If a patient does not respond to the first dose, the opportunity should be taken to review the diagnosis before a second dose is given. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, haemorrhage, TIA).

Special Cardiovascular Pharmacology Studies With Another 5-HT1 Agonist In subjects (n=10) with suspected coronary artery disease undergoing angiography, a 5-HT1 agonist at a subcutaneous dose of 1.5 mg produced an 8% increase in aortic blood pressure, an 18% increase in pulmonary artery blood pressure, and an 8% increase in systemic vascular resistance. In addition, mild chest pain or tightness was reported by four subjects. Clinically significant increases in blood pressure were experienced by three of the subjects (two of whom also had chest pain/discomfort). Diagnostic angiogram results revealed that 9 subjects had normal coronary arteries and 1 had insignificant coronary artery disease. In an additional study with this same drug, migraine patients (n=35) free of cardiovascular disease were subjected to assessments of myocardial perfusion by positron emission tomography while receiving a subcutaneous 1.5 mg dose in the absence of a migraine attack. Reduced coronary vasodilatory reserve (~10%), increased coronary resistance (~20%), and decreased hyperaemic myocardial blood flow (~10%) were noted. The relevance of these findings to the use of the recommended oral dose of this 5-HT1 agonist is not known. Similar studies have not been done with ZOMIG. However, owing to the common pharmacodynamic actions of 5-HT1 agonists, the possibility of cardiovascular effects of the nature described above should be considered for any agent of this pharmacological class. Other Vasospasm-Related Events: 5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm. Peripheral vascular ischemia has been reported with 5-HT1 agonists (see ADVERSE REACTIONS). Very rare reports of splenic infarction and gastrointestinal ischemic events including ischemic colitis, gastrointestinal infarction or necrosis, which may present as bloody diarrhea or abdominal pain, have been received. Increased Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients receiving other 5-HT1 agonists with and without a history of hypertension. Very rarely these increases in blood pressure have been associated with significant clinical events. Isolated reports of chest pain, pulmonary edema, coronary vasospasm, transient cerebral ischemia, angina and subarachnoid hemorrhage have been received (see CONTRAINDICATIONS). In patients with controlled hypertension, ZOMIG should be administered with caution, as transient increases in blood pressure and peripheral vascular resistance have been observed in a small portion of patients. In pharmacodynamic studies, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen in volunteers with 5 mg ZOMIG. In the headache trials, vital signs were measured only in a small, single-centre inpatient study, and no effect on blood pressure was seen. In a study of patients with moderate to severe liver disease, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic or diastolic blood pressure after a 10 mg ZOMIG dose. Significant elevations in systemic blood pressure, including hypertensive crisis, have been reported on rare occasions in patients with and without a history of hypertension who received 5-HT1 agonists. ZOMIG is contraindicated in patients with uncontrolled or severe hypertension (see CONTRAINDICATIONS).

Patients with phenylketonuria should be informed that ZOMIG RAPIMELT orally dispersible tablets contain phenylalanine (a component of aspartame). Each orally dispersible tablet contains 2.81 mg of phenylalanine.

ZOMIG should be administered with caution to patients with moderate or severe hepatic impairment, using a dose lower than 2.5 mg (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Rare hypersensitivity (anaphylaxis/anaphylactoid) reactions may occur in patients receiving 5- HT1 agonists such as ZOMIG. Such reactions can be life threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. Owing to the possibility of cross-reactive hypersensitivity reactions, ZOMIG should not be used in patients having a history of hypersensitivity to chemically-related 5-HT1 receptor agonists (see Adverse Events in PRECAUTIONS ADVERSE REACTIONS).

Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine or who experience a headache that is atypical for them. There have been rare reports where patients received 5-HT1 agonists for severe headache that were subsequently shown to have been secondary to an evolving neurological lesion. For newly diagnosed patients or patients presenting with atypical symptoms, the diagnosis of migraine should be reconsidered if no response is seen after the first dose of ZOMIG.

Caution should be observed if ZOMIG is to be used in patients with a history of epilepsy or structural brain lesions, which lower the convulsion threshold.

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with ZOMIG and SSRIs (e.g., fluoxetine, paroxetine, sertraline) or SNRIs (e.g., venlafaxine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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) (see DRUG INTERACTIONS).

When pigmented rats were given a single oral dose of 10 mg/kg of radiolabelled zolmitriptan, the radioactivity in the eye after 7 days, the latest time point examined, was still 75% of the values measured after 4 hours. This suggests that zolmitriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin rich tissues over time, it raises the possibility that zolmitriptan could cause toxicity in these tissues after extended use. However, no effects on the retina related to treatment with zolmitriptan were noted in any of the toxicity studies. No systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, however, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Carcinogenicity studies by oral gavage were carried out in rats and mice at doses up to 400 mg/kg/day. In mice the total exposure at the highest dose level was approximately 800 times that seen after a single 10 mg dose in humans and there was no effect on tumour type or incidence. In male rats at this dose level, where total exposure was

approximately 3000 times that seen after a single 10 mg dose in humans, there was an increase in the incidence of thyroid follicular hyperplasia and benign adenomata. This has been shown to be due to an increase in thyroxine clearance caused by zolmitriptan at this dose level with a resultant chronic stimulation of the thyroid. There was no effect on tumour profile at the dose level of 100 mg/kg/day that gave an exposure multiple of approximately 800. Mutagenicity: Zolmitriptan was mutagenic in an Ames test, in 2 of 5 strains of Salmonella typhimurium tested, in the presence of, but not in the absence of, metabolic activation. It was not mutagenic in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay. The nasal spray formulation was not mutagenic in two further Ames tests. Zolmitriptan was clastogenic in an in vitro human lymphocyte assay both in the absence of and the presence of metabolic activation. Zolmitriptan was not clastogenic in an in vivo mouse micronucleus assay. In three rat bone marrow micronucleus assays with the nasal spray formulation, the results overall were negative. In a mouse bone marrow micronucleus assay with the nasal spray formulation, there were sporadic increases in micronucleus erythrocytes, but the results were equivocal. Zolmitriptan was not genotoxic in an unscheduled DNA synthesis study.

Reproductive studies in male and female rats, at dose levels limited by toxicity, revealed no effect on fertility or reproduction.

Reproduction studies in rats and rabbits dosed during the period of organogenesis have been performed at levels limited by maternal toxicity. In rats dosed orally by gavage at 1200 mg/kg/day, giving a total exposure 3000 - 5000 times that seen following a single 10 mg dose in humans, there was a slight increase in early resorptions but no effect on fetal malformations. At a dose of 400 mg/kg/day in rats, an exposure multiple of approximately 1100, there were no effects of any kind on the fetus. The maximum achieved dose in rabbits was 30 mg/kg/day that gave a total exposure 30 - 40 times that seen following a single 10 mg dose in humans and there were no fetal effects. The safety of ZOMIG for use during human pregnancy has not been established. ZOMIG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether zolmitriptan and/or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when considering the administration of ZOMIG to nursing women. Lactating rats dosed with zolmitriptan had milk levels equivalent to maternal plasma levels at 1 hour and 4 times higher than plasma levels at 4 hours.

The safety and efficacy of ZOMIG have not been studied in children under 12 years of age. Use of the drug in this age group is, therefore, not recommended.

significantly between adolescents and adults, however exposure to the active metabolite is greater in adolescents (see ACTION AND CLINICAL PHARMACOLOGY). The safety and efficacy of ZOMIG have not been established in patients 12-17 years of age. The use of ZOMIG in adolescents is, therefore, not recommended. In a single randomized placebo-controlled study of 696 adolescent migraineurs (aged 12-17 years), the efficacy of ZOMIG tablets (2.5, 5 and 10 mg) was not established (see ADVERSE REACTIONS, Special Populations).

The safety and efficacy of ZOMIG have not been studied in individuals over 65 years of age. The risk of adverse reactions to this drug may be greater in elderly patients as they are more likely to have decreased hepatic function, be at higher risk for CAD, and experience blood pressure increases that may be more pronounced. Clinical studies did not include patients over 65 year of age. Its use in this age group is, therefore, not recommended.

ZOMIG should be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic function (see WARNINGS AND PRECAUTIONS, Hepatic).

Zolmitriptan is not known to interfere with commonly employed clinical laboratory tests.

ADVERSE REACTIONS

Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HT1 agonists. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, angina pectoris, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, General).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Experience in Controlled Clinical Trials with ZOMIG (zolmitriptan)

Typical 5-HT1 Agonist Adverse Reactions: 1

As with other 5-HT

agonists, ZOMIG has been associated with sensations of heaviness, pressure, tightness or pain which may be intense. These may occur in any part of the body including the chest, throat, neck, jaw and upper limb.

In very rare cases, as with other 5-HT1 agonists, angina pectoris and myocardial infarction have been reported. 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. Isolated reports of chest pain, pulmonary edema, coronary vasospasm, transient cerebral ischemia, angina and subarachnoid hemorrhage have been received (see WARNINGS AND PRECAUTIONS, Cardiovascular, Increased Blood Pressure). There have been rare reports of hypersensitivity reactions including urticaria and angioedema (see WARNINGS AND PRECAUTIONS, Immune).

EXPERIENCE WITH ZOMIG CONVENTIONAL TABLET (zolmitriptan)

Acute Safety:

In placebo-controlled migraine trials, 1,673 patients received at least one dose of ZOMIG. The following table (Table 1) lists adverse events that occurred in five placebo- controlled clinical trials in migraine patients. Events that occurred at an incidence of 1% or more in any one of the ZOMIG 1 mg, 2.5 mg or 5 mg dose groups and that occurred at a higher incidence than in the placebo group are included. The events cited reflect experience gained under closely monitored conditions in clinical trials, in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behaviour, and the kinds of patients treated may differ.

Several of the adverse events appear dose related, notably paresthesia, sensation of heaviness or tightness in chest, neck, jaw and throat, dizziness, somnolence, and possibly asthenia and nausea.

Number of patients	Zomig Zomig Zomi Placebo 1 mg 2.5 mg 5 mg 401 163 498 1012
% incidence
Symptoms of potential cardiac origin:
neck/throat/jaw sensations *	3.0	6.1	7.0	10.9
chest/thorax sensations *	1.2	1.8	3.4	3.8
upper limb sensations *	0.5	2.4	4.2	4.1
palpitations Other Body Systems:	0.7	0	0.2	2.2
Neurological:
dizziness	4.0	5.5	8.4	9.5
nervousness	0.2	0	1.4	0.7
somnolence	3.0	4.9	6.0	7.7

Table 1 Treatment Emergent Adverse Events in Five Single-Attack Placebo-Controlled Migraine Trials, Reported by >=1% Patients Treated With ZOMIG

Zomig 1 mg

Zomig

2.5 mg

Zomig 5 mg

Number of patients 401 163 498 1012

thinking abnormal	0.5	0	1.2	0.3
tremor	0.7	0.6	1.0	0.7
vertigo	0	0	0	1.5
hyperesthesia	0	0	0.6	1.1
Digestive:
diarrhea	0.5	0.6	1.0	0.6
dry mouth	1.7	4.9	3.2	3.2
dyspepsia	0.5	3.1	1.6	1.0
dysphagia	0	0	0	1.8
nausea	3.7	3.7	9.0	6.2
vomit Miscellaneous:	2.5	0.6	1.4	1.5
asthenia	3.2	4.9	3.2	8.8
limb sensations (upper and lower) *	0.7	0.6	0.4	1.6
limb sensations (lower) *	0.7	1.2	0.4	1.8
sensations - location unspecified *	5.2	4.9	5.8	9.2
abdominal pain	1.7	1.2	0.6	1.3
reaction aggravated	1.0	1.2	1.0	0.7
head/face sensations *	1.7	6.7	8.6	10.9
myalgia	0.2	0	0.2	1.3
myasthenia	0.2	0	0.6	1.9
dyspnea	0.2	0.6	0.2	1.2
rhinitis	0.2	1.2	1.2	0.9
sweating	1.2	0	1.6	2.5
taste perversion	0.5	2.5	0.6	0.7

The term sensation encompasses adverse events described as pain, discomfort, pressure, heaviness, tightness, heat/burning sensations, tingling and paresthesia

ZOMIG is generally well tolerated. Across all doses, most adverse events were mild to moderate in severity as well as transient and self-limiting. The incidence of adverse events in controlled clinical trials was not affected by gender, weight, or age of patients; use of prophylactic medications; or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse events.

Long Term Safety:

In a long-term open label study in which patients were allowed to treat multiple migraine attacks for up to one year, 8% (167 of 2,058) of patients withdrew from the study due to an adverse experience. In this study, migraine headaches could be treated with either a single 5 mg dose of ZOMIG, or an initial 5 mg dose followed by a second 5 mg dose if necessary (5+5 mg). The most common adverse events (defined as occurring at an incidence of at least 5%) recorded for the 5 mg and 5+5 mg doses, respectively, comprised, in descending order of frequency: neck/throat sensations * (16%, 15%), head/face sensations *

(15%, 14%), asthenia (14%, 14%), sensations * location unspecified (12%, 11%), limb sensations * (11%, 11%), nausea (12%, 8%), dizziness (11%, 9%), somnolence (10%, 10%), chest/thorax sensations * (7%, 7%), dry mouth (4%, 5%), and hyperesthesia (5%, 4%). Due to the lack of a placebo arm in this study, the role of ZOMIG in causation cannot be reliably determined. ( *See footnote for Table 1). The long term safety of a 2.5 mg dose was not assessed in this study.

Other Events:

The frequencies of less commonly reported adverse clinical events are presented below. Because the reports include events observed in open and uncontrolled studies, the role of ZOMIG in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used ZOMIG (n=4,027) and reported an event divided by the total number of patients exposed to ZOMIG. All reported events 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. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse events are those occurring in 1/100 to 1/1,000 patients and rare adverse events are those occurring in fewer than 1/1,000 patients.

Atypical sensation

: Infrequent was hyperesthesia.

General

: Infrequent were allergy reaction, chills, facial edema, fever, malaise and photosensitivity.

Cardiovascular

: Infrequent were arrhythmias, hypertension and syncope. Rare were bradycardia, extrasystoles, postural hypotension, QT prolongation, and thrombophlebitis. Rare reports of tachycardia, palpitations and transient increases in systemic blood pressure in patients with or without a history of hypertension (see WARNINGS AND PRECAUTIONS, Cardiovascular, Increased Blood Pressure).

Digestive

: Infrequent were increased appetite, tongue edema, esophagitis, gastroenteritis, liver function abnormality and thirst. Rare were anorexia, constipation, gastritis, hematemesis, pancreatitis, melena and ulcer.

Hemic

: Infrequent was ecchymosis. Rare were cyanosis, thrombocytopenia, eosinophilia and leucopenia.

Metabolic

: Infrequent was edema. Rare were hyperglycemia and alkaline phosphatase increased.

Musculoskeletal

: Infrequent were back pain, leg cramps and tenosynovitis. Rare were arthritis, tetany and twitching.

Neurological

: Infrequent were agitation, anxiety, depression, emotional lability and insomnia. Rare were akathesia, amnesia, apathy, ataxia, dystonia, euphoria, hallucinations, cerebral ischemia, hyperkinesia, hypotonia, hypertonia, irritability and headache.

Respiratory

: Infrequent were bronchitis, bronchospasm, epistaxis, hiccup, laryngitis and yawn. Rare were apnea and voice alteration.

Skin: Infrequent were pruritus, and rash. Rare reports were urticaria and angioedema. Special Senses: Infrequent were dry eye, eye pain, hyperacusis, ear pain, parosmia, and tinnitus. Rare were diplopia and lacrimation.

Urogenital

: Infrequent were hematuria, cystitis, polyuria, urinary frequency and urinary urgency. Rare were miscarriage and dysmenorrhea.

EXPERIENCE IN CONTROLLED CLINICAL TRIALS WITH ZOMIG RAPIMELT

(zolmitriptan)

Acute Safety: In an international, placebo-controlled, double-blind trial to evaluate the efficacy and tolerability of ZOMIG RAPIMELT 2.5 mg in the acute treatment of adult patients with migraine, 231 patients received at least one dose of ZOMIG RAPIMELT. Most of the adverse events were of mild or moderate intensity, and no patients withdrew from the trial because of adverse events. The types of adverse events reported were consistent with known effects of this class of compound (5-HT1B/1D) and were similar to those reported with the ZOMIG conventional tablet. The most frequently reported adverse events (>2%) for ZOMIG RAPIMELT 2.5 mg versus placebo, respectively, were asthenia (3% vs. 1%), tightness (3% vs. <1%), somnolence (3% vs. 2%), dizziness (3% vs. 1%), paresthesia (3% vs. 2%), hyperesthesia (2% vs. 0%), pharyngitis (2% vs. 0%), and nausea (2% vs. 1%).

EXPERIENCE IN CONTROLLED CLINICAL TRIALS WITH ZOMIG NASAL

SPRAY (zolmitriptan)

Acute Safety:

Among 1,383 patients treating 3,398 attacks with zolmitriptan nasal spray in a blinded placebo-controlled trial, there was a low withdrawal rate related to adverse events: 5 mg (1.3%), 2.5 mg (0%), 1 mg (0.8%) 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 ZOMIG Nasal Spray. The most common adverse events in clinical trials for ZOMIG Nasal Spray were: unusual taste, paresthesia, hyperesthesia, and dizziness. Table 2 lists the adverse events that occurred in >= 1% of the 1,383 patients in the 2.5 mg tablet, placebo, 1 mg, 2.5 mg and 5 mg nasal spray dose groups of the controlled clinical trial.

Table 2 Adverse events in a single placebo-controlled study, with an incidence of >= 1% of patients in any ZOMIG Nasal Spray treatment group by body system

Body System and

Percentage of Patients

Adverse event (COSTART defined) a	2.5mg (N=233)	Placebo b (N=228)	1.0 mg (N=238)	2.5 mg (N=224)	5.0 mg (N=236)
SYMPTOMS OF POTENTIAL CARDIAC ORIGIN
Pain Throat	1.3%	0.4%	0.0%	2.7%	2.1%
Pressure Throat	0.9%	0.0%	0.4%	0.0%	1.3%
Tightness Throat	1.3%	0.9%	1.3%	0.4%	1.7%
Tightness Neck	1.3%	0.0%	0.0%	0.0%	0.8%
Tightness Chest	1.3%	0.0%	0.8%	0.4%	0.8%
Palpitation	1.3%	0.4%	1.7%	1.3%	0.0%
BODY / ABDOMEN
Pain Abdominal	0.4%	0.9%	1.7%	1.3%	0.8%
BODY / GENERAL
Asthenia	2.1%	0.4%	0.4%	0.9%	2.1%
Heaviness Other	1.7%	0.0%	0.0%	0.9%	0.0%
Pain Local Specific	0.0%	0.4%	1.7%	0.9%	2.5%
Reaction Aggravation c	0.0%	2.2%	0.4%	0.9%	2.1%
DIGESTIVE
Dry Mouth	1.3%	0.0%	1.7%	2.2%	1.3%
Nausea	1.3%	0.9%	1.3%	0.9%	1.7%
NERVOUS SYSTEM / CNS
Dizziness	1.7%	3.5%	2.9%	0.4%	0.0%
Insomnia	0.0%	0.0%	1.3%	1.3%	0.9%
Somnolence	0.4%	1.3%	0.8%	0.4%	1.7%
NERVOUS SYSTEM / GENERAL
Hyperesthesia	0.9%	0.0%	0.8%	0.4%	2.1%
Hypesthesia	1.3%	0.4%	0.4%	0.9%	0.8%
NERVOUS SYSTEM / PNS
Paresthesia	4.3%	3.9%	4.2%	3.1 %	5.9%
Sensation Warm	2.1%	2.2%	0.4%	0.9 %	0.0%
RESPIRATORY
Disorder or Discomfort of Nasal Cavity	0.9%	1.3%	2.1%	0.9 %	1.3%
SPECIAL SENSES
Unusual Taste	1.3%	3.1%	7.6%	13.4 %	16.9%
a The Patient may have had more than 1 adverse event.

Tablet * ZOMIG Nasal Spray

The placebo treatment group included patients treated with placebo nasal spray and oral placebo.
Events reported under this term includes increased nausea and increased headache.

* The incidences reported in this table are from one single placebo-controlled study. The treatment-emergent adverse events in five single-attack placebo-controlled migraine trials, reported by >=1% patients treated with ZOMIG 1 mg, 2.5 mg and 5 mg tablets are

listed in Table 1.

Local Adverse Reactions:

Among 922 patients using an active zolmitriptan nasal spray to treat 2311 attacks in the controlled clinical study, approximately 3% noted local irritation or soreness at the site of administration. Adverse events of any kind, perceived in the

nasopharynx (which may include systemic effects of triptans) were severe in about 1% of patients and approximately 60% resolved in 1 hour. The adverse experience profile seen with ZOMIG Nasal Spray is similar to that seen with ZOMIG conventional tablets and ZOMIG RAPIMELT tablets, except for localized adverse events related to nasal dosing.

Overall Results of Clinical Trials

In a pool of 51 placebo-controlled and open labelled studies the above adverse events were reported at the described frequencies, with the exception of the following adverse events which were reported at a greater frequency. In total 17,301 patients with migraine were treated with ZOMIG, ZOMIG RAPIMELT or ZOMIG Nasal Spray. Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Common (frequent) adverse events were those occurring in 1/10 to 1/100 patients and uncommon (infrequent) adverse events are those occurring in 1/100 to 1/1,000 patients.

Cardiac Disorders: Uncommon was tachycardia. Nervous System Disorders: Common was headache.

Respiratory

: Common was epistaxis for ZOMIG Nasal Spray only.

Vascular Disorders

: Uncommon was transient increases in systemic blood pressure. Sensations of heaviness, tightness, pain or pressure in the throat, neck, limbs or chest were

common and consistent with those observed in Tables 1 and 2.

Adverse Drug Reactions in Special Population

Adolescents (12-17 years of age)

Table 3 lists the adverse events observed in a single randomized placebo-controlled study of 696 adolescent migraineurs aged 12-17 years (see WARNINGS AND PRECAUTIONS, Special Populations).

Table 3 Adverse events in a single placebo-controlled adolescent study, reported by >= 1% of patients treated with ZOMIG

Percentage of Patients

Body System

and Adverse Event

Placebo

2.5 mg

ZOMIG

5 mg

10 mg

(COSTART term)

Cardiovascular

(N=176)

(N=171)

(N=174)

(N=178)

Vasodilatation 0.6 0 2.9 3.9

Palpitation 0 0 1.1 0

Percentage of Patients

Body System

and Adverse Event

Placebo

2.5 mg

ZOMIG

5 mg

10 mg

(COSTART term)

Whole Body

(N=176)

(N=171)

(N=174)

(N=178)

Tightness 1.1 2.9 5.7 11.2

Asthenia 1.1 1.8 1.1 5.1

Pain 0 1.8 1.7 5.1

Neck Pain 0 0.6 1.7 3.4

Abdominal Pain 0.6 1.2 0 1.7

Headache 0 1.2 2.9 1.1

Malaise 0 0 2.3 0.6

Pressure 0 1.8 0.6 0.6

Stiffness 0 0 0.6 2.8

Heaviness 1.1 0.6 0 1.1

Digestive

Nausea 1.1 5.8 2.9 7.9

Vomiting 1.1 0.6 1.7 4.5

Dry Mouth 0.6 1.8 1.1 1.1

Nervous System

Dizziness 2.3 4.7 4.6 9.0

Paresthesia 0 1.8 4.6 6.2

Somnolence 1.7 1.2 1.7 2.8

Hypertonia 0 0.6 1.7 1.1

Internasal Paresthesia 0 2.3 0.6 0

Tremor 0 0 0 1.7

Hyperesthesia 0 0 0 1.1

Respiratory System

Pharyngitis 0.6 2.9 2.3 1.7

Dyspnea 0.6 0 1.1 0.6

Musculoskeletal

Myalgia 0 0 1.1 0.6

Skin and Appendages

Sweating 0 0 0 1.7

Special Senses

Eye Pain 0 0.6 1.1 0.6

Amblyopia 0 0 0 1.1

Post-Market Adverse Drug Reactions

In addition to the adverse experiences reported during clinical testing of ZOMIG, the following adverse experiences have been reported in patients receiving marketed ZOMIG from worldwide use since approval. There are insufficient data to support an estimate of their incidence or to establish causality. Serious adverse events have occurred during post-marketing surveillance following the use of ZOMIG oral tablets. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, angina pectoris and myocardial infarction (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS). As with other 5-HT1B/1D agonists, there have been very rare reports of anaphylaxis or anaphylactoid reactions and gastrointestinal ischemic events including ischemic colitis, gastrointestinal infarction, splenic infarction, or necrosis, which may present as bloody diarrhea or abdominal pain. Post-marketing experience with other triptans include a limited number of reports that describe pediatric (under 12 years of age) and adolescent (12 - 17 years of age) patients who have experienced clinically serious adverse events that are similar in nature to those reported as rare occurrences in adults.

DRUG INTERACTIONS

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis for these effects being additive, the use of ergot-containing or ergot-type medications (like dihydroergotamine or methysergide and zolmitriptan) within 24 hours of each other is contraindicated (see CONTRAINDICATIONS).

Other 5-HT1 Agonists: The administration of ZOMIG with other 5-HT1 agonists has not been evaluated in migraine patients. As an increased risk of coronary vasospasm is a theoretical possibility with co-administration of 5-HT1 agonists, use of these drugs within 24 hours of each other is contraindicated (see CONTRAINDICATIONS). All drug interaction studies with drugs listed below were performed in healthy volunteers using a single 10 mg dose of ZOMIG and a single dose of the other drug, except where otherwise noted. MAO Inhibitors: In a limited number of subjects, following one week administration of 150 mg b.i.d. moclobemide, a specific MAO-A inhibitor, there was an increase of approximately 26% in both AUC and Cmax for zolmitriptan and a 3-fold increase in the AUC and Cmax of the active N-desmethyl metabolite. Administration of selegiline, a selective MAO-B inhibitor, at a dose of 10 mg/day for one week, had no effect on the pharmacokinetic parameters of zolmitriptan and the active N-desmethyl metabolite. The specificity of selegiline diminishes with higher doses and varies between patients. Therefore, co-administration of zolmitriptan in patients taking MAO inhibitors is contraindicated (see CONTRAINDICATIONS).

Following administration of cimetidine, a general P450 inhibitor, the half life and AUC of zolmitriptan and its active metabolite were approximately doubled. Patients taking cimetidine should not exceed a dose of 5 mg ZOMIG in any 24 hour period. Based on the overall interaction profile, an interaction with specific inhibitors of CYP 1A2 cannot be excluded. Therefore, the same dose reduction is

recommended with compounds of this type, such as fluvoxamine and the quinolones (e.g., ciprofloxacin). Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed. Oral Contraceptives: Retrospective analysis of pharmacokinetic data across studies indicated that mean plasma concentrations of zolmitriptan were generally greater in females taking oral contraceptives compared to those not taking oral contraceptives. Mean Cmax and AUC of zolmitriptan were found to be higher by 30% and 50%, respectively, and Tmax was delayed by 30 minutes in females taking oral contraceptives. The effect of ZOMIG on the pharmacokinetics of oral contraceptives has not been studied. Propranolol: Propranolol, at a dose of 160 mg/day for 1 week increased the Cmax and AUC of zolmitriptan by 1.5-fold. Cmax and AUC of the N-desmethyl metabolite were reduced by 30% and 15%, respectively. There were no interactive effects on blood pressure or pulse rate following administration of propranolol with zolmitriptan.

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors:

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (see WARNINGS AND PRECAUTIONS).

The pharmacokinetics and effects of ZOMIG on blood pressure were unaffected by 4-week pre-treatment with oral fluoxetine (20 mg/day). The effects of zolmitriptan on fluoxetine metabolism were not assessed. Acetaminophen: After concurrent administration of single 10 mg doses of ZOMIG and 1 g acetaminophen, there was no significant effect on the pharmacokinetics of ZOMIG. ZOMIG reduced the AUC and Cmax of acetaminophen by 11% and 31% respectively and delayed the Tmax of acetaminophen by 1 hour.

Metoclopramide (single 10 mg dose) had no effect on the pharmacokinetics of ZOMIG or its metabolites.

Xylometazoline: An in vivo drug interaction study with ZOMIG Nasal Spray indicated that 1 spray (100 uL dose) of xylometazoline (0.1% w/v), a decongestant, administered 30 minutes prior to a 5 mg nasal dose of zolmitriptan did not alter the pharmacokinetics of zolmitriptan.

DOSAGE AND ADMINISTRATION

ZOMIG (zolmitriptan) is recommended only for the acute treatment of migraine attacks. ZOMIG should not be used prophylactically.

The recommended adult starting dose for ZOMIG is 2.5 mg (see individual dosage forms under DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustment). If the headache returns, the dose may be repeated after 2 hours. A dose should not be repeated, regardless of dosage form, within 2 hours. A total cumulative dose of 10 mg should not be exceeded in any 24 hour period. Controlled trials have not established the effectiveness of a second dose if the initial dose is ineffective. The safety of treating more than 3 migraine headaches with ZOMIG in a one month period remains to be established.

Patients with moderate to severe hepatic impairment have decreased clearance of zolmitriptan and significant elevation in blood pressure was observed in some patients. Use of a low dose (<2.5 mg) with blood pressure monitoring is recommended (see ACTION AND CLINICAL PHARMACOLOGY and WARNINGS AND PRECAUTIONS,

ZOMIG should not be used in patients with uncontrolled or severe hypertension. Patients with mild to moderate hypertension should be treated cautiously at the lowest effective dose.

Patients taking cimetidine and other 1A2 inhibitors should not exceed a dose of 5 mg ZOMIG in any 24 hour period (see DRUG INTERACTIONS).

The minimal effective single adult dose of ZOMIG is 1 mg. The recommended single dose is 2.5 mg. The 1 mg dose can be approximated by manually breaking a 2.5 mg conventional tablet in half.

In controlled clinical trials, single doses of 1 mg, 2.5 mg or 5 mg ZOMIG conventional tablets were shown to be effective in the acute treatment of migraine headaches. In the only direct comparison of the 2.5 and 5 mg doses, there was little added benefit from the higher dose, while side effects increased with 5 mg ZOMIG tablets (see ADVERSE EVENTS, Table 1, and Part II: CLINICAL TRIALS, Table 4).

Adults: The minimal effective single adult dose of ZOMIG is 1 mg. The recommended single dose is 2.5 mg. The ZOMIG RAPIMELT 2.5 mg orally dispersible tablet cannot be broken in half to approximate a 1 mg dose. The ZOMIG RAPIMELT orally dispersible tablet rapidly dissolves when placed on the tongue and is swallowed with the patient's saliva. ZOMIG 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 tablets.

: As stated for ZOMIG conventional tablets and ZOMIG RAPIMELT, the recommended initial starting dose of ZOMIG is 2.5 mg. For patients for whom a 2.5 mg dose of zolmitriptan is not optimally effective, a 5 mg dose of ZOMIG Nasal Spray is recommended.

In a controlled clinical trial, single doses of 0.5, 1.0, 2.5 and 5.0 mg ZOMIG Nasal Spray were shown to be effective in the acute treatment of migraine headaches (see Part II: CLINICAL TRIALS, Table 7). The 5 mg nasal spray dose provided significantly improved pain relief over 2.5 mg oral tablet (seen at 15, 30, 45, 60, and 120 minutes). The 2.5 mg dose of ZOMIG Nasal Spray did not provide any benefit over the 2.5 mg oral tablet. ZOMIG Nasal Spray is administered as a single dose into one nostril. The nasal spray provides an alternative non-oral formulation of zolmitriptan to that of ZOMIG conventional tablets and ZOMIG RAPIMELT.

The tablet should be placed on the tongue, where it will dissolve with the saliva. Water is not needed for the dispersible tablet.

The nasal spray should be administered into one nostril only. The device is a single dose unit and must not be primed before use. Patients should be advised to read the consumer information leaflet regarding the use of the nasal spray device prior to administration.

OVERDOSAGE

There is no experience with clinical overdose. Volunteers receiving single 50 mg oral doses of ZOMIG (zolmitriptan) commonly experienced sedation. The elimination half-life of zolmitriptan is 2.5 - 3 hours (see ACTION AND CLINICAL PHARMACOLOGY), 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 serum concentrations of zolmitriptan.

ACTION AND CLINICAL PHARMACOLOGY

ZOMIG (zolmitriptan) is a selective 5-hydroxytryptamine1 (5-HT1B/1D) receptor agonist. It exhibits a high affinity at human recombinant 5-HT1B and 5-HT1D receptors and modest affinity for 5-HT1A receptors. Zolmitriptan has no significant affinity (as measured by radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, 5-HT4, alpha1, alpha2, or beta1, -adrenergic; H1, H2, histaminic; muscarinic; dopamine1, or dopamine2, receptors. The N-desmethyl metabolite of zolmitriptan also has high affinity for 5-HT1B/1D and modest affinity for 5-HT1A receptors. It has been proposed that symptoms associated with migraine headaches arise from the activation of the trigemino-vascular system, which results in local cranial vasodilation and neurogenic inflammation involving the antidromic release of sensory neuropeptides [Vasoactive Intestinal Peptide (VIP), Substance P and calcitonin gene related peptide (CGRP)]. The therapeutic activity of zolmitriptan for the treatment of migraine headache is thought to be attributable to its agonist effects at 5-HT1B/1D receptors on the intracranial blood vessels, including the arterio-venous anastamoses, and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

In man, zolmitriptan is rapidly and well absorbed (at least 64%) after oral administration with peak plasma concentrations occurring in 2 hours. The mean absolute bioavailability of the parent compound is approximately 40%. Food has no significant effect on the bioavailability of zolmitriptan.

During a moderate to severe migraine attack in male and female patients, mean AUC0-4 and Cmax for zolmitriptan were decreased by 40% and 25%, respectively and mean Tmax was delayed by one-half hour compared to the same patients during a migraine free period.

When given as a single dose to healthy volunteers, zolmitriptan displayed linear kinetics over the dose range of 2.5 to 50 mg.

The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of zolmitriptan over the concentration range of 10 - 1000 ng/L is 25%.

There is no evidence of accumulation on multiple dosing with zolmitriptan up to doses of 10 mg.

Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. The enzymes responsible for the metabolism of zolmitriptan remain to be fully characterized. The mean elimination half-life of zolmitriptan is approximately 2.5 to 3 hours. Mean total plasma clearance of zolmitriptan is 31.5 mL/min/kg, of which one-sixth is renal clearance. The renal clearance is greater than the glomerular filtration rate suggesting renal tubular secretion.

In a study in which radiolabelled zolmitriptan was orally administered to healthy volunteers, 64% and 30% of the administered 14C-zolmitriptan dose was excreted in the urine and feces, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. The indole acetic acid and N-oxide metabolites, which are inactive, accounted for 31% and 7% of the dose, respectively, while the active N-desmethyl metabolite accounted for 4% of the dose. Conversion of zolmitriptan to the active N-desmethyl metabolite occurs such that metabolite concentrations are approximately two thirds that of zolmitriptan. Because the 5-HT1B/1D potency of the N-desmethyl metabolite is 2 to 6 times that of the parent, the metabolite may contribute a substantial portion of the overall effect after zolmitriptan administration. The half-life of the active N-desmethyl metabolite is 3 hours and the Tmax is approximately 2 to 3 hours.

Absorption: Zolmitriptan nasal spray is rapidly absorbed via the nasopharynx as detected in a Photon Emission Tomography (PET) study using [11C]-zolmitriptan. Zolmitriptan was detected in plasma by 5 minutes and peak plasma concentration generally was achieved by 3 hours. (Approximately 40% of Cmax is achieved between 10-15 minutes after dosing). The time at which maximum plasma concentrations were observed was similar after single (1 day) or multiple (4 day) nasal dosing. Plasma concentrations of zolmitriptan are sustained for 4 to 6 hours after dosing. Zolmitriptan displays linear kinetics after multiple doses of 2.5 mg, 5 mg, or 10 mg. Increases in zolmitriptan and the N-desmethyl metabolite plasma concentrations were observed with multiple dosing but these were predictable from the single dose data and the dosing interval used in this study. The mean absolute bioavailability of ZOMIG Nasal Spray is approximately 41% and is similar to the tablet. The mean relative bioavailability of the nasal spray formulation is 102%, compared to the oral tablet. Zolmitriptan and its active metabolite display dose proportionality after single or multiple dosing. Dose proportional increases in zolmitriptan and N-desmethyl metabolite Cmax and AUC were observed for 2.5 and 5 mg nasal spray doses. The pharmacokinetics for elimination of zolmitriptan and its active N-desmethyl metabolite are similar 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.

Plasma protein binding of zolmitriptan is 25% over the concentration range of 10 - 1000 ng/mL. The mean (+-SD) apparent volume of distribution for zolmitriptan nasal spray formulation is 8.3 +-3.6 L/kg.

The mean elimination half-life for zolmitriptan and its active N- desmethyl metabolite following nasal spray administration are approximately 3 hours, which is similar to the half-life values seen after oral tablet administration. The half-life values were similar for zolmitriptan and the N-desmethyl metabolite after single (1 day) and multiple (4 day) nasal dosing.

Mean total plasma clearance 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. The plasma concentrations and pharmacokinetics of zolmitriptan and the three major metabolites for the nasal spray and conventional tablet formulations are similar.

In a single dose pharmacokinetic study of 5 mg zolmitriptan, systemic exposure to the parent compound was not found to differ significantly between adolescents and adults. However, plasma levels of the active metabolite were significantly greater (40 - 50%) in adolescents than adults.

Zolmitriptan pharmacokinetics in healthy elderly non- migraineur (non-migraine sufferers) volunteers (age 65 - 76) were similar to those in younger non-migraineur volunteers (age 18 - 39).

Mean plasma concentrations of zolmitriptan were up to 1.5-fold greater in females than in males.

The effect of race on the pharmacokinetics of zolmitriptan has not been systematically evaluated. Retrospective analysis of pharmacokinetic data between Japanese and Caucasian subjects revealed no significant differences.

Hepatic Insufficiency: A study to evaluate the effect of liver disease on the pharmacokinetics of zolmitriptan showed that the AUC and Cmax were increased by 94% and 50% respectively in patients with moderate liver disease and by 226% and 47% in patients with severe liver disease compared with healthy volunteers. Exposure to the metabolites, including the active N-desmethyl metabolite, was decreased. For the N-desmethyl metabolite, AUC and Cmax were reduced by 33% and 44% in patients with moderate liver disease and by 82% and 90% in patients with severe liver disease. The effect of hepatic disease on the pharmacokinetics of zolmitriptan nasal spray has not been evaluated. Because of the similarity in exposure zolmitriptan tablets and nasal spray should have similar dosage adjustments and should be administered with caution in subjects with liver disease generally using doses less than 2.5 mg (see WARNINGS AND PRECAUTIONS). The plasma half-life (t1/2) 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 t1/2 values for the N-desmethyl metabolite were 5.7 hours, 7.5 hours and 7.8 hours respectively. Seven out of 27 patients with hepatic impairment (4 with moderate and 3 with severe liver disease) experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg dose. Zomitriptan should be administered with caution in subjects with moderate or severe liver disease (see WARNINGS AND PRECAUTIONS, Hepatic and DOSAGE AND ADMINISTRATION).

>=5 - <=25 mL/min), clearance of zolmitriptan was reduced by 25% compared to normal (ClCr

>=70 mL/min). There was no significant change observed in the clearance of zolmitriptan in patients with moderate renal impairment (ClCr >=26 - <=50 mL/min). The effects of renal impairment on the pharmacokinetics of zolmitriptan nasal spray have not been evaluated.

No differences in the pharmacokinetics of zolmitriptan were noted in mild to moderate hypertensive volunteers compared to normotensive controls. In this study involving a limited number of patients, small dose-dependent increases in systolic and diastolic blood pressure (approximately 3 mm Hg) did not differ between mild/moderate hypertensives and normotensive controls.

STORAGE AND STABILITY

ZOMIG conventional tablets, ZOMIG RAPIMELT and ZOMIG Nasal Spray should be stored at room temperature between 15 and 30oC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ZOMIG 2.5 mg conventional tablets are yellow, round biconvex film-coated tablets intagliated 'Z' on one side. Available in blister packs of 3 and 6 tablets. ZOMIG RAPIMELT orally dispersible 2.5 mg tablets are white, round, uncoated tablets intagliated 'Z' on one side with a bevelled edge. Available in blister packs of 2 and 6 tablets. ZOMIG Nasal Spray is packaged as a single dose spray unit and supplies either 2.5 mg or 5 mg of zolmitriptan. The blue coloured plastic device with a grey protection cap is packaged in a carton and labelled to indicate the nominal dose. Patients should be cautioned to not remove the grey protection cap until prior to dosing. The ZOMIG Nasal Spray device is placed in a nostril and actuated to deliver a single dose, after which the device must be discarded. Patients should be cautioned to avoid spraying the contents of the device in their eyes. ZOMIG Nasal Spray is supplied in boxes of 6 single use nasal spray units.

Nonmedicinal ingredients: anhydrous lactose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400 and 8000, sodium starch glycolate, titanium dioxide, yellow iron oxide.

Nonmedicinal ingredients: aspartame, citric acid, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, orange flavour, sodium bicarbonate.

Nonmedicinal ingredients: citric acid, disodium phosphate (dodecahydrate or dihydrate), purified water.

Product	Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients *
ZOMIG (r)	oral	conventional tablet / 2.5 mg	anhydrous lactose
ZOMIG RAPIMELT (r)	oral	orally dispersible tablet / 2.5 mg	none
ZOMIG (r) NASAL SPRAY	intranasal	nasal spray / 2.5 mg, 5 mg	none