Teva-Zolmitriptan Od (Teva Canada, 1.0 mg, 1 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

* For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING.

INDICATIONS AND CLINICAL USE

Adults

TEVA-ZOLMITRIPTAN (zolmitriptan) is indicated for the acute treatment of migraine attacks with or without aura.

TEVA-ZOLMITRIPTAN is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic, basilar, or ophthalmoplegic migraine (see CONTRAINDICATIONS). Safety and efficacy have not been established for cluster headache, which is present in an older, predominantly male population.

Pediatrics (< 12 years of age)

The safety and efficacy of zolmitriptan have not been studied in children under 12 years of age. Use of TEVA-ZOLMITRIPTAN in this age group is, therefore, not recommended (see WARNINGS and PRECAUTIONS, Special Populations).

Adolescents (12-17 years of age)

The safety and efficacy of zolmitriptan have not been established in patients 12-17 years of age. The use of TEVA-ZOLMITRIPTAN in adolescents is, therefore, not recommended (see WARNINGS AND PRECAUTIONS, Special Populations).

Geriatrics (> 65 years of age)

The safety and efficacy of zolmitriptan in patients over 65 years has not been established and use of TEVA-ZOLMITRIPTAN in this age group is not recommended (see WARNINGS AND PRECAUTIONS, Special Populations).

CONTRAINDICATIONS

TEVA-ZOLMITRIPTAN (zolmitriptan) is contraindicated under the following conditions:

• 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 Teva-Zolmitriptan. 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 zolmitriptan 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);
• in patients with hemiplegic, basilar or ophthalmoplegic migraine;
• 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 (for a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING).

WARNINGS AND PRECAUTIONS

General

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

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

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

Medication Overuse Headache: Overuse of acute migraine treatments has been associated with the exacerbation of headache (medication overuse headache, MOH) in susceptible patients. Withdrawal of the treatment may be necessary.

Cardiovascular

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events:

Zolmitriptan 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 zolmitriptan. In very rare cases angina pectoris has been reported.

TEVA-ZOLMITRIPTAN should not be given to patients who have documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). It is strongly recommended that TEVA-ZOLMITRIPTAN not be given to patients in whom unrecognized 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, TEVA-ZOLMITRIPTAN 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 TEVA-ZOLMITRIPTAN 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 TEVA-ZOLMITRIPTAN 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 TEVA-ZOLMITRIPTAN, 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 TEVA-ZOLMITRIPTAN, 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 TEVA-ZOLMITRIPTAN.

As with other 5HT_1B/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 zolmitriptan. Because 5-HT₁ agonists may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following TEVA-ZOLMITRIPTAN 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 TEVA-ZOLMITRIPTAN 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 TEVA-ZOLMITRIPTAN.

Premarketing Experience with Zolmitriptan

Among the more than 2,500 patients with migraine who participated in premarketing controlled clinical trials of zolmitriptan conventional tablets, no deaths or serious cardiac events were reported.

Postmarketing Experience with Zolmitriptan

Serious cardiovascular events have been reported in association with the use of zolmitriptan. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of reported cases that were actually caused by zolmitriptan 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 zolmitriptan 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 zolmitriptan. 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, zolmitriptan 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 zolmitriptan. 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 zolmitriptan 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. TEVA-ZOLMITRIPTAN is contraindicated in patients with uncontrolled or severe hypertension (see CONTRAINDICATIONS).

Dependence

The abuse potential of zolmitriptan has not been assessed in clinical trials.

Endocrine and Metabolism

Phenylketonuria: Patients with phenylketonuria should be informed that TEVA-ZOLMITRIPTAN OD contain phenylalanine (a component of aspartame). Each orally dispersible tablet contains 2.81 mg of phenylalanine.

Hepatic

TEVA-ZOLMITRIPTAN 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).

Immune

Rare hypersensitivity (anaphylaxis/anaphylactoid) reactions may occur in patients receiving 5-HT₁ agonists such as zolmitriptan. 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, TEVA-ZOLMITRIPTAN 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).

Neurologic

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 TEVA-ZOLMITRIPTAN.

Seizures: Caution should be observed if TEVA-ZOLMITRIPTAN 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 TEVA-ZOLMITRIPTAN 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).

Ophthalmologic

Binding to Melanin-Containing Tissues: 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.

Preclinical Toxicology

Carcinogenicity: 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.

Special Populations

Pregnant Women: 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 zolmitriptan for use during human pregnancy has not been established. TEVA-ZOLMITRIPTAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women: 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 TEVA-ZOLMITRIPTAN 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.

Pediatrics (<12 years of age): The safety and efficacy of zolmitriptan have not been studied in children under 12 years of age. Use of the drug in this age group is, therefore, not recommended.

Adolescents (12-17 years of age): Systemic exposure to the parent compound does not differ 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 zolmitriptan have not been established in patients 12-17 years of age. The use of TEVA-ZOLMITRIPTAN in adolescents is, therefore, not recommended.

In a single randomized placebo-controlled study of 696 adolescent migraineurs (aged 12-17 years), the efficacy of zolmitriptan tablets (2.5, 5 and 10 mg) was not established (see ADVERSE REACTIONS, Special Populations).

Geriatrics (> 65 years of age): The safety and efficacy of zolmitriptan 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.

Special Disease Conditions:

TEVA-ZOLMITRIPTAN 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).

Monitoring and Laboratory Tests

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.

Frequencies of adverse events are reported as follows:

Very common (≥10%)

Common (≥1% - <10%)

Uncommon (≥0.1% - <1%)

Rare (≥0.01% - <0.1%)

Very Rare (<0.01%)

Experience in Controlled Clinical Trials with Zolmitriptan

Typical 5-HT₁ Agonist Adverse Reactions: As with other 5-HT₁ agonists, zolmitriptan 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 ZOLMITRIPTAN CONVENTIONAL TABLET

Acute Safety: In placebo-controlled migraine trials, 1,673 patients received at least one dose of zolmitriptan. 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 zolmitriptan 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.

Table 1 Treatment Emergent Adverse Events in Five Single-Attack Placebo-Controlled Migraine Trials,

Reported by ≥1% Patients Treated With Zolmitriptan

Placebo zolmitriptan zolmitriptan zolmitriptan 1 mg 2.5 mg 5 mg Number of patients 401 163 498 1012 % incidence

Symptoms of potential cardiac origin:

Neck/Throat/Jaw Sensations*

Chest/Thorax Sensations*

Upper Limb Sensations*

Palpitations

3.0

1.2

0.5

0.7

6.1

1.8

2.4

7.0

3.4

4.2

0.2

10.9

3.8

4.1

2.2

Other Body Systems:

Neurological:

Dizziness

Nervousness

Somnolence

Thinking Abnormal

Tremor

Vertigo

Hyperesthesia

Digestive:

Diarrhea

Dry mouth

Dyspepsia

Dysphagia

Nausea

Vomit

Miscellaneous:

Asthenia

Limb Sensations (upper and lower)*

Limb Sensations (lower)*

Sensations - location unspecified*

Abdominal Pain

Reaction Aggravated

Head/face Sensations*

4.0

0.2

3.0

0.5

0.7

0.5

1.7

0.5

3.7

2.5

3.2

0.7

0.7

5.2

1.7

1.0

1.7

5.5

4.9

0.6

0.6

4.9

3.1

3.7

0.6

4.9

0.6

1.2

4.9

1.2

1.2

6.7

8.4

1.4

6.0

1.2

1.0

0.6

1.0

3.2

1.6

9.0

1.4

3.2

0.4

0.4

5.8

0.6

1.0

8.6

9.5

0.7

7.7

0.3

0.7

1.5

1.1

0.6

3.2

1.0

1.8

6.2

1.5

8.8

1.6

1.8

9.2

1.3

0.7

10.9 Myalgia

Myasthenia

Dyspnea

Rhinitis

Sweating

Taste Perversion

0.2

0.2

0.2

0.2

1.2

0.5

0.6

1.2

2.5

0.2

0.6

0.2

1.2

1.6

0.6

1.3

1.9

1.2

0.9

2.5

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

Zolmitriptan 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 zolmitriptan, 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 zolmitriptan 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 zolmitriptan 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 zolmitriptan (n=4,027) and reported an event divided by the total number of patients exposed to zolmitriptan. 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.

Atypical sensation: Uncommon was hyperesthesia.

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

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

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

Metabolic: Uncommon was edema. Rare were hyperglycemia and alkaline phosphatase increased.

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

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

Skin: Uncommon were pruritus, and rash. Rare reports were urticaria and angioedema.

Special Senses: Uncommon were dry eye, eye pain, hyperacusis, ear pain, parosmia, and tinnitus. Rare were diplopia and lacrimation.

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

EXPERIENCE IN CONTROLLED CLINICAL TRIALS WITH ZOLMITRIPTAN Orally Disintegrating Tablets

Acute Safety: In an international, placebo-controlled, double-blind trial to evaluate the efficacy and tolerability of zolmitriptan orally disintegrating tablet 2.5 mg in the acute treatment of adult patients with migraine, 231 patients received at least one dose of zolmitriptan orally disintegrating tablet. 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-HT_1B/1D) and were similar to those reported with the zolmitriptan conventional tablet. The most frequently reported adverse events (>2%) for zolmitriptan orally disintegrating tablet 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%).

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 Zolmitriptan. Events are classified within body system categories and enumerated in order of decreasing frequency.

Cardiac Disorders: Uncommon was tachycardia.

Gastrointestinal Disorders: Common was dysphagia.

Nervous System Disorders: Common was headache.

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 2: Adverse events in a single placebo-controlled adolescent study, reported by ≥1% of patients treated with zolmitriptan

Percentage of Patients

Zolmitriptan Body System and Adverse

Event (COSTART term) Placebo (N=176) 2.5 mg

(N=171)

5 mg

(N=174)

10 mg (N=178)

Cardiovascular Vasodilatation 0.6 0 2.9 3.9 Palpitation 0 0 1.1 0 Whole Body

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 zolmitriptan, the following adverse experiences have been reported in patients receiving marketed zolmitriptan 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 zolmitriptan 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).

Post-market reports show that dysphagia has been reported commonly when using zolmitriptan.

As with other 5-HT_1B/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

Drug-Drug Interactions

Ergot-Containing Drugs: 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 zolmitriptan 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 zolmitriptan 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).

Cimetidine and other 1A2 Inhibitors: 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 zolmitriptan 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 zolmitriptan 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 zolmitriptan 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 zolmitriptan and 1 g acetaminophen, there was no significant effect on the pharmacokinetics of zolmitriptan. Zolmitriptan reduced the AUC and Cmax of acetaminophen by 11% and 31% respectively and delayed the Tmax of acetaminophen by 1 hour.

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

DOSAGE AND ADMINISTRATION

Dosing Considerations

The following general statements apply to all dosage formulations of zolmitriptan:

TEVA-ZOLMITRIPTAN is recommended only for the acute treatment of migraine attacks. TEVA-ZOLMITRIPTAN should not be used prophylactically.

The recommended adult starting dose for TEVA-ZOLMITRIPTAN 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 zolmitriptan in a one month period remains to be established.

Hepatic Impairment: 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, Hepatic).

Hypertension: TEVA-ZOLMITRIPTAN 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.

Cimetidine and other 1A2 Inhibitors: Patients taking cimetidine and other 1A2 inhibitors should not exceed a dose of 5 mg TEVA-ZOLMITRIPTAN in any 24 hour period (see DRUG INTERACTIONS).

Recommended Dose and Dosage Adjustment

TEVA-ZOLMITRIPTAN CONVENTIONAL TABLETS

Adults: The minimal effective single adult dose of TEVA-ZOLMITRIPTAN is 1 mg. The recommended single dose is 2.5 mg.

In controlled clinical trials, single doses of 1 mg, 2.5 mg or 5 mg zolmitriptan 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 zolmitrtiptan tablets (see ADVERSE EVENTS, Table 1, and Part II: CLINICAL TRIALS, Table 4).

TEVA-ZOLMITRIPTAN OD TABLETS

Adults: The minimal effective single adult dose of zolmitriptan is 1 mg. The recommended single dose is 2.5 mg. TEVA-ZOLMITRIPTAN OD 2.5 mg orally dispersible tablet cannot be broken in half to approximate a 1 mg dose.

The TEVA-ZOLMITRIPTAN OD tablet rapidly dissolves when placed on the tongue and is swallowed with the patient’s saliva. TEVA-ZOLMITRIPTAN OD 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.

Administration

ZOLMITRIPTAN CONVENTIONAL TABLETS

The tablet should be swallowed with water.

TEVA-ZOLMITRIPTAN OD TABLETS

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

OVERDOSAGE

There is no experience with clinical overdose. Volunteers receiving single 50 mg oral doses of 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 zolmitriptan 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action and Pharmacodynamics

Zolmitriptan is a selective 5-hydroxytryptamine1 (5-HT_1B/1D) receptor agonist. It exhibits a high affinity at human recombinant 5-HT_1B and 5-HT_1D receptors and modest affinity for 5-HT_1A 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-HT_1B/1D and modest affinity for 5-HT_1A 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-HT_1B/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.

Pharmacokinetics

ZOLMITRIPTAN CONVENTIONAL TABLETS

Absorption and Bioavailability: 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 AUC_0-4 and C_max for zolmitriptan were decreased by 40% and 25%, respectively and mean T_max was delayed by one-half hour compared to the same patients during a migraine free period.

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

Distribution: 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.

Metabolism and Excretion: 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-HT_1B/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 T_max is approximately 2 to 3 hours.

Special Populations and Conditions

Adolescents (12 - 17 years of age): 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.

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

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

Race: 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 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 N-desmethyl metabolite, was decreased. For the N-desmethyl 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 (t_½) 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 t_½ 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).

Renal Insufficiency: Following oral dosing in patients with severe renal impairment (ClCr ≥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).

Hypertension: 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

TEVA-ZOLMITRIPTAN tablets and OD tablets should be stored at room temperature between 15 and 30ºC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms and Packaging

TEVA-ZOLMITRIPTAN 1 mg tablets are green, round, biconvex, film-coated tablet, engraved with C1 on one side and plain on the other side. Available in blister packs of 3 and 6 tablets and bottles of 50 tablets.

TEVA-ZOLMITRIPTAN 2.5 mg tablets are yellow, round biconvex film-coated tablets engraved with Z2.5 on one side and plain on the other side. Available in blister packs of 3 and 6 tablets and bottles of 50 tablets.

TEVA-ZOLMITRIPTAN OD 1 mg tablets are white to off-white, round flat-face bevel edged compressed tablet, engraved with N on one side and 1 on the other side. Available in blister packs of 2 and 6 tablets.

TEVA-ZOLMITRIPTAN OD 2.5 mg tablets are white to off-white, round flat-face bevel edged compressed tablets, engraved with 93 on one side and 8147 on the other side. Available in blister packs of 2 and 6 tablets.

Composition

TEVA-ZOLMITRIPTAN CONVENTIONAL TABLETS

Nonmedicinal ingredients: lactose spray dried, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and the Film Coating ingredients containing the following:

1mg:

FD&C Blue/Brilliant Blue FCF Aluminum 3-5% Lake, Iron Oxide Yellow, Macrogol/Polyethylene Glycol 3350, Polyvinyl Alcohol, Talc, Titanium Dioxide.

2.5 mg:

Iron Oxide Yellow, Macrogol/Polyethylene Glycol 3350, Polyvinyl Alcohol, Talc, Titanium Dioxide.

TEVA-ZOLMITRIPTAN OD TABLETS

Nonmedicinal ingredients: aspartame, citric acid, colloidal silicon dioxide, corn starch, croscarmellose sodium, lactose monohydrate, mannitol, magnesium stearate, orange flavour, sodium bicarbonate

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Zolmitriptan

Chemical Name: (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone

Molecular Formula and Molecular Mass: C₁₆H₂₁N₃O₂ and 287.36

Structural Formula:

Physiochemical Properties: White to almost white powder

Solubility: slightly soluble in water (1.3 mg/mL at 25ºC), 0.1M hydrochloric acid (33 mg/mL at 25ºC) pKa: 9.64 ± 0.01

Partition co-efficient: octanol-1-ol/water partition log KD=-1.0

Melting point: 136ºC

CLINICAL TRIALS

The efficacy of zolmitriptan was not affected by the presence of aura and was independent of headache duration pre-treatment, relationship to menses, gender, age or weight of the patient, pre-treatment nausea and concomitant use of common migraine prophylactic drugs.

ZOLMITRIPTAN CONVENTIONAL TABLET

The efficacy of zolmitriptan conventional tablets in the acute treatment of migraine attacks was evaluated in five randomized, double blind, placebo controlled studies, of which 2 utilized the 1 mg dose, 2 utilized the 2.5 mg dose and 4 utilized the 5 mg dose. In all studies, the effect of zolmitriptan was compared to placebo in the treatment of a single migraine attack. All studies used the marketed formulation. Study 1 was a single-centre study in which patients treated their headaches in a clinic setting. In the other studies, patients treated their headaches as outpatients. In Study 4, patients who had previously used sumatriptan were excluded, whereas in the other studies no such exclusion was applied. Patients enrolled in these five studies were predominantly female (82%) and Caucasian (97%) with a mean age of 40 years (range 12-65). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed at 1, 2, and, in most studies, 4 hours after dosing. Associated symptoms such as nausea, photophobia and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post dose. A second dose of zolmitriptan tablets or other medication was allowed 2 to 24 hours after the initial dose, to treat persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded.

Table 3 shows efficacy results for zolmitriptan conventional tablets in 5 placebo-controlled trials, 4 of which were multi-centre. The percentage of patients with pain relief (grade1/0) at 2 hours after treatment (the primary endpoint measure) was significantly greater among patients receiving zolmitriptan at all doses compared to those on placebo. In Study 3, which directly compared the 1 mg, 2.5 mg and 5 mg doses, there was a statistically significant greater proportion of patients with headache response at 2 hours in the higher dose groups (2.5 mg or 5 mg) than in the 1 mg group. There was no statistically significant difference between the 2.5 mg and 5 mg dose groups for the primary endpoint measure of pain relief (1/0) at 2 hours, or at any other time point measured.

Table 3: Percentage of Patients with Pain Relief (1/0)

♦

at 2 Hours - Intent to Treat Population

* p≤ 0.05 in comparison with placebo

** p≤ 0.01 in comparison with 1 mg

†

p ≤ 0.01 in comparison with placebo

• = Not studied

♦

Pain Relief is defined as a reduction in headache severity from grade 3 or 2 (severe or moderate) to grade 1 or 0 (mild or no pain)

The proportion of patients being pain free at 2 hours was statistically significantly greater for patients receiving zolmitriptan conventional tablets at doses of 1, 2.5 and 5 mg compared with placebo in Study 3.

For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of zolmitriptan as compared to placebo.

Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The probability of taking a second zolmitriptan dose or other medication for migraine over 24 hours following the initial dose of study treatment was lower for zolmitriptan treated groups as compared to placebo. For the 1 mg dose, the probability of taking a second dose was similar to placebo and greater than with either the 2.5 or 5 mg dose.

In an open label study conducted to evaluate long-term safety, patients treated multiple migraine headaches with 5 mg doses of zolmitriptan for up to 1 year. A total of 31,579 migraine attacks were treated during the course of the study (mean number of headaches treated per patient was 15). An analysis of patients who treated at least 30 migraine attacks of moderate or severe intensity (n = 233) suggests that the 2 hour headache response rate is maintained with repeated use of zolmitriptan.

Comparative Bioavailability Study

A single-dose, crossover comparative bioavailability study was performed with 21 healthy, non-smoking, male and non post-menopausal female subjects under fasting conditions following administration of two formulations of zolmitriptan tablets: Teva-Zolmitriptan 2.5 mg Tablets (manufactured by Teva Canada Limited, Canada) and Zomig^® 2.5 mg Tablets (AstraZeneca Canada Inc., Canada). The pharmacokinetic plasma data for Zolmitriptan and Zomig^® are tabulated below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Teva-Zolmitriptan FC 2.5 mg Tablets (Teva Canada Limited, Canada)

^† Zomig^® 2.5 mg Tablets (AstraZeneca Canada Inc., Canada), purchased in Canada.

^§ Expressed as the arithmetic mean (CV%) only

ZOLMITRIPTAN ORALLY DISINTEGRATING TABLET

The efficacy and tolerability of zolmitriptan 2.5 mg orally disintegrating tablets in the acute treatment of adult patients with migraine was evaluated in an international, randomized, placebo-controlled, double-blind trial. A total of 471 patients [87% female; 97% Caucasian; mean age 41 years (18 - 62)] were exposed to trial medication, 231 were randomized to zolmitriptan and 240 to placebo. Each patient was instructed to treat a single migraine of moderate or severe intensity with double-blind medication. If sufficient relief was not obtained 2 hours after the first dose, a second dose or escape medication could be taken. Headache response, defined as a reduction of headache pain from moderate or severe at the time of treatment to mild or none at assessment, was evaluated at 0.5, 1, 2, and 4 hours after the first dose. The primary endpoint was headache response at 2 hours.

When compared to the placebo treatment group, a statistically significant greater proportion of the zolmitriptan orally disintegrating tablets group experienced a headache response within 2 hours of initial dosing (primary endpoint, see Table 4). Patients treating with zolmitriptan orally disintegrating tablets also had statistically significant headache response relative to placebo at 0.5, 1 and 4 hours post-dose.

Table 4 Percentage of Patients with Headache Response* at 2 Hours Post-Dose by

Treatment Group (ITT Population)

^a Percentages are based upon the total number of patients in the ITT population for which data were available at 2 hours following a single attack.

ITT Intent to treat population – the subset of randomized patients who received trial medication and who received at least one efficacy evaluation.

* Headache response is the diminution of headache pain from moderate or severe at the time of treatment to mild or none at the assessment.

Assessment of the number of patients who were pain-free after treating a migraine attack revealed that 27% of patients treating with zolmitriptan orally disintegrating tablets were pain free at 2 hours compared to 7% treating with placebo (p<0.001). The number of patients pain-free through 24 hours after treatment with a single dose of trial medication was also greater in the zolmitriptan orally disintegrating tablets (23%) than in the placebo (7%) group.

The median time to second treatment (second dose or escape medication) was more than twice as long in the zolmitriptan orally disintegrating tablets treatment group relative to placebo, 5 hours and 45 minutes versus 2 hours and 10 minutes.

The efficacy and tolerability of zolmitriptan orally disintegrating 2.5 mg tablets in the acute treatment of adult patients with migraine was also evaluated in a second randomized, multi-centre, parallel-group, placebo-controlled, double-blind trial. A total of 565 patients [85% female; 85% Caucasian; mean age 41 years (18 - 65)] were randomized to zolmitriptan (n=281) or placebo (n=284) and consumed at least 1 dose of study medication. Each patient was instructed to treat two separate migraine headaches of mild, moderate, or severe intensity with double-blind medication. For each migraine, if sufficient relief was not obtained 2 hours after the first dose, a second dose or escape medication could be taken. The primary endpoint was the overall pain-free response rate over two migraine attacks at 2 hours after dosing. Pain-free response was defined as an improvement in headache pain from mild, moderate or severe to no pain at assessment (2 hours after dosing). When compared to the placebo treatment group, a statistically significant proportion of the zolmitriptan orally disintegrating tablets group experienced a pain-free response within 2 hours of dosing (see Table 5).

Table 5 Pain Free Response* at 2 Hours Post-Dose by Treatment Group (ITT

Population)

^a Percentages are based upon the total number of attacks (N) in the ITT population for which data were available at 2 hours.

^b Primary efficacy endpoint was the overall pain-free response rate over 2 migraine attacks. ^c The analysis of the first and second attacks individually was performed as a secondary variable and not statistically analysed.

ITT Intent to treat population – the subset of randomized patients who received trial medication and who received at least one efficacy evaluation.

* Pain-free response is the improvement in migraine headache pain intensity from mild, moderate or severe to no pain at the assessment.

Remedication rates were higher in the placebo group for both attacks, compared to the zolmitriptan orally disintegrating tablets treatment group and time to remedication was statistically significantly shorter in the placebo group (p<0.001).

Patients treating migraines with zolmitriptan orally disintegrating tablets were more likely to experience relief of nausea, photophobia, and phonophobia relative to placebo at the primary endpoint of 2 hours.

Comparative Bioequivalence study:

A comparative bioavailability has been conducted between TEVA-ZOLMITRIPTAN OD 2.5 mg (Teva Canada Limited) and Zomig Rapimelt^TM Tablets 2.5 mg (AstraZeneca, Canada) after a single dose in 31 healthy, non-smoking male and female subjects under fasting conditions.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Zolmitriptan (1 x 2.5 mg) From measured data Geometric Mean Arithmetic Mean (CV %)

^*TEVA-ZOLMITRIPTAN OD 2.5 mg (Teva Canada Limited)

^† Zomig Rapimelt^TM Tablets 2.5 mg (AstraZeneca, Canada) were purchased in Canada. ^§ Expressed as the arithmetic mean (CV %) only.

DETAILED PHARMACOLOGY

Pharmacodynamics

in vitro: Receptor specificity studies using radioligand binding assays and isolated intact tissue assays have shown that zolmitriptan is a selective 5-HT₁ partial receptor agonist which exhibits a high affinity at human recombinant 5-HT_1D (pKi = 9.2) and 5-HT_1B (pKi = 8.2) receptors and modest affinity for 5-HT_1A receptors (pKi = 7.0). Zolmitriptan had no significant affinity or pharmacological activity at 5-HT₂, 5-HT₃, 5-HT₄, alpha₁, alpha₂, or beta₁, -adrenergic; H₁, H₂, histaminic; muscarinic; dopamine₁, or dopamine₂, receptors.

in vivo: In anesthetized animals, zolmitriptan (0.3 - 100 µg/kg i.v.) caused dose-related and sustained reductions in carotid arterial blood flow and conductance (ED₅₀ for dogs: 2.9 µg/kg; for cats: 1.1 µg/kg). This reflected a constriction of cranial arteriovenous anastomoses (AVA), with a very minor contribution from the extracranial circulation. No equivalent reductions occurred in cerebral blood flow and conductance in these animals. At doses of 30 µg/kg and 100 µg/kg, i.v., zolmitriptan inhibited trigeminal ganglion electrically stimulated release of calcitonin gene related peptide in anesthetized cats. The effect of trigeminal ganglion stimulation on vasoactive intestinal peptide was also attenuated, in this animal model, by 100 µg/kg zolmitriptan administered i.v. Over a dose range of 3 - 30 µg/kg (i.v.), zolmitriptan caused a dose-related inhibition of neurogenic plasma protein extravasation into the ipsilateral dura mater following electrical stimulation of the trigeminal ganglion.

At higher doses (>100 µg/kg), zolmitriptan produced some systemic cardiovascular effects (notably inconsistent and poorly dose-related increases in blood pressure and heart rate in conscious animals). These systemic effects were species-specific and modified by anesthesia. Apart from its selective vasoconstrictor action in vascular beds supplied by the carotid artery, zolmitriptan had little or no effect at doses up to 1 mg/kg in other major systemic vascular beds, including the coronary and pulmonary circulations. Only in dog renal vasculature was zolmitriptan found also to cause dose-related vasoconstrictor responses.

Zolmitriptan elicited some central nervous system and behavioural effects at high doses (1 or 2 mg/kg), but the severity of these effects were species-specific.

Zolmitriptan exhibited no general autonomic effects, but at low doses (3 -100 µg/kg i.v.) had a selective effect on the sympathetic innervation to the carotid vasculature consistent with agonist activity at pre-junctional inhibitory 5-HT_1D -like receptors.

Zolmitriptan did not cause any important respiratory effects except at high doses (>1 mg/kg). However, at these doses other central nervous system and behavioural effects may contribute.

Zolmitriptan had no effects on gastrointestinal function except at very high doses (30 mg/kg, p.o.). Likewise, the drug was without important effect on renal function and barbiturate sleeping times.

The metabolism of zolmitriptan in man results in the formation of a pharmacologically active N-demethylated derivative (see ACTION AND CLINICAL PHARMACOLOGY). This metabolite exhibited the same pharmacological specificity as the parent molecule, but was 2 to 6 times more potent at 5-HT_1D receptors. The cardiovascular profile of the metabolite was qualitatively the same as that of zolmitriptan.

Pharmacokinetics

Absorption of radiolabelled drug-related material was rapid following oral administration of zolmitriptan to mice, rats, rabbits and dogs with C_max occurring within 1 hour of dosing. In the rat, C_max was reached at 0.5 hour with a secondary peak at 3 hours after dosing. This occurred in both males and females. A second peak was not detected following intravenous administration therefore it is likely a result of continuing absorption lower in the gastrointestinal tract. Oral bioavailabilities of 50% in mice (10 mg/kg), 41% in rats (10 mg/kg), 25% in rabbits (10 mg/kg) and 79% in dogs (2 mg/kg) suggest significant first pass metabolism, particularly in the rabbit. In man, absorption is at least 64% after oral administration, with a mean absolute bioavailability of the parent compound of approximately 40%.

Preclinical studies in the rat, rabbit, and Cynomolgus monkey have shown that the disposition of zolmitriptan is similar following nasal and oral administration. Total recoveries of radioactivity in urine and feces following oral administration of zolmitriptan were 65% and 30% of the administered dose, respectively. About 8% of the oral dose was recovered in the urine as unchanged zolmitriptan. The indole acetic acid metabolite accounted for 31% of the dose, followed by N-oxide (7%) and N-desmethyl (4%) metabolites. The indole acetic acid and N-oxide metabolites are inactive. In addition, preclinical studies in the rat and rabbit have shown that the disposition of zolmitriptan is similar following single and multiple nasal and oral administration.

In all animal species elimination from plasma was rapid with t_½ of 1 to 2 hours. There were no apparent differences due to gender or route of administration. The t_½ in man was 2.5 to 3 hours.

In the toxicity studies, exposure was generally linear with increasing dose. The pharmacokinetics following multiple dosing were similar to those observed after single dose administration. However, in the rat, exposures to zolmitriptan and the indole acetic acid metabolite increased time-dependently for the first 52 weeks of chronic dosing and subsequently decreased at 78 and 104 weeks. In the teratology studies, the exposure to zolmitriptan and the metabolites were not significantly different between pregnant and non-pregnant rats. However, in female rabbits, there appeared to be an increase in exposure over the dosing period. After chronic dosing to the dog, there was a slight variation in exposure to the N-oxide metabolite that increased relative to zolmitriptan.

The tissue distribution of zolmitriptan was investigated in the male rat using both albino and pigmented strains. The highest levels of distribution were found in the liver, kidney and glandular tissues. Minimal crossing of the blood-brain barrier was observed. The radioactive drug-related material was rapidly eliminated. Levels of radioactivity in the tissue of albino and pigmented rats were comparable at all time points, apart from the eye which had higher levels in the pigmented rat, indicating an association with melanin. In a study with pigmented rats, in which animals were given a single oral dose of 10 mg/kg radiolabelled zolmitriptan, radioactivity was notable in the eye up to 7 days (last time point examined) after drug administration and was still 75% of the value measured at the 4 hour time point post-dose.

Studies in pregnant rats and rabbits demonstrated exposure to the placenta and fetus while nursing rats had milk levels of radioactivity equivalent to plasma at 1 hour post dose and four times higher than plasma at 4 hours post dose.

Metabolite patterns of zolmitriptan are qualitatively similar in all animal species and man. Zolmitriptan was the major component of all urinary and faecal samples from mice, rats and rabbits while the indole acetic acid metabolite formed the major component in dogs and man.

Drug-related material was rapidly excreted in all species. Urine was the primary route of excretion, >50% of the dose, except after oral dosing to rodents that accounted for 30-35% of the dose. Biliary excretion in the rat was minimal (<4%) despite the excretion of 22% of an intravenous dose, indicating direct secretion into the gut.

TOXICOLOGY

Acute Toxicity

In oral acute studies in mice the approximate lethal dose of zolmitriptan was 1000 mg/kg and in rats the approximate lethal dose was between 1000 and 1500 mg/kg. Although exposure was not measured, the approximate oral lethal dose of zolmitriptan in rodents is about 20,000 times the usual human dose of 2.5 mg. The approximate lethal dose was 50 - 100 mg/kg following intravenous administration. Animals were found dead without premonitory signs.

Long-Term Toxicity

Repeated dose studies in rats (up to 1000 mg/kg/day) and dogs (up to 100 mg/kg/day) have revealed little toxicity other than clinical signs, which are associated with an excess of the pharmacological action of this class of compound. Dose limiting factors were: in rats, sporadic deaths at the highest dose level, in dogs, clinical and behavioural changes, believed to be due to perturbations of 5-HT_1D regulated central nervous system pathways. Details of each study are provided in Table 6.

In toxicity studies in which zolmitriptan nasal spray formulation was administered to rats (6 times daily for up to 6 months) and monkeys (8 times daily for 1 month) by the nasal route, the formulation was generally well tolerated. In monkeys, there was no indication of systemic toxicity or local irritation in the nasal cavity. In rats, a reversible minimal or mild rhinitis and nasopharyngitis was observed after 1 month at 72 mg/kg/day, with a no effect level of 18 mg/kg/day. This corresponds to approximately four-fold the maximum daily human exposure when expressed in terms of exposure per unit area of the nasal epithelium. There was no similar finding after 6 months of intranasal dosing at 72 mg/kg/day. Zolmitriptan nasal spray formulation is practically a non-irritant to the rabbit eye.

Table 6: Long-Term Toxicity

REFERENCES

1. 1. Becker WJ, Lee D. Zolmitriptan nasal spray is effective, fast-acting and well tolerated during both short- and long-term treatment. Cephalalgia 2001; 21(4):271.
2. 2.

   Charlesworth BR, Dowson AJ, Purdy A, Becker WJ, Boes-Hansen S, Farkkila M. Speed of

   Onset and Efficacy of Zolmitriptan Nasal Spray in the Acute Treatment of Migraine. CNS Drugs 2003; 17 (9): 653-667.

3. 3.

   Dowson AJ. 311C90: patient profiles and typical case histories of migraine management.

   Neurology 1997; 48 (Suppl 3): S29-S33.

4. 4. Dowson AJ. Can oral 311C90, a novel 5-HT_1D agonist, prevent migraine headache when taken during an aura? European Neurology 1996; 36 (Suppl 2): 28-31.
5. 5.

   Earl NL. Clinical safety of 311C90: Aggregated data from patients and volunteers to date.

   European Neurology 1996; 36 (Suppl 2): 8-12.

6. 6.

   Edmeads JG. Extending Therapeutic options? Prospects for the future. European Neurology

   1996; 36 (Suppl 2): 32-33.

7. 7.

   Ferrari MD. The clinical effectiveness of 311C90 in the acute treatment of migraine.

   European Neurology 1996; 36 (Suppl 2): 4-7.

8. 8.

   Ferrari MD. 311C90: Increasing the options for therapy with effective acute antimigraine 5-

   HT_1B/1D receptor agonists. Neurology 1997; 48 (Suppl 3): S21-S24.

9. 9. Geraud GE. Evaluation of the long-term safety and efficacy of 311C90 in the treatment of migraine. European Neurology 1996; 36(Suppl 2): 24-27.
10. 10. Goadsby PJ, Edvinsson L. Peripheral and central trigeminovascular activation in cats is blocked by the serotonin (5-HT)-1D receptor agonist 311C90. Headache 1994; 34:394-399.
11. 11. Goadsby PJ, Hoskin KL. Inhibition of trigeminal neurons by intravenous administration of the serotonin (5-HT)1B D receptor agonist zolmitriptan (311C90): are brain stem sites therapeutic target in migraines? Pain 1996; 67(2/3): 355-359.
12. 12.

    Kemp J, Yates R. Zolmitriptan nasal spray exhibits rapid and dose-proportional absorption.

    Cephalalgia 2000;21(4):418.

13. 13. Lee D, Purdy A, Charlesworth B, Hughes J. Efficacy of zolmitriptan nasal spray in mild, moderate and severe migraine: Relationship to timing of dosing. Cephalalgia 2001;21(4):419.
14. 14. Loder E, Freitag FG, Adelman J, Pearlman S, Abu-Shakra S. Pain-free rates with zolmitriptan 2.5 mg ODT in the acute treatment of migraine: results of a large double-blind placebo-controlled trial. Current Medical Research and Opinion 2005; 21(3): 381-389.
15. 15. Nairn K, Yates R, Kemp J, Dane A. Rapid, dose-proportional absorption of zolmitriptan nasal spray: Comparison with the oral tablet formulation. Neurology 2001;56(8)(Suppl 3):A356-7.
16. 16. Purdy A, Reunanen M, Lee D. High efficacy and tolerability nasal spray extends to long-term treatment of migraine. Cephalalgia 2001;21(4):418-9.
17. 17.

    Rapoport AM, Ramadan NM, Adelman JU,Mathew NT, Elkind AH, Kudrow DB, Earl NL.

    Optimizing the dose of zolmitriptan (Zomig 311C90) for the acute treatment of migraine. A double-blind placebo controlled, dose range-finding study. Neurology 1997;49:1210-1218.

18. 18.

    Seaber E, On N, Phillips S, Churchus R, Posner J, Rolan P. The tolerability and

    pharmacokinetics of the novel antimigraine compound 311C90 in healthy male volunteers. Brit J of Clin Pharmacol 1996; 41(2): 141-147.

19. 19.

    Thomsen LL, Dixon R, Lassen LH, Giboens M, Langemark M, Bendtsen L, Daugaard D,

    Olesen J. 311C90 (Zolmitriptan), a novel centrally and peripheral acting oral 5-hydroxytryptamine-1D agonist: a comparison of its absorption during a migraine attack and in a migraine-free period. Cephalalgia 1996; 16(4): 270-275.

20. 20. Visser WH, Klein K, Cox R, Jones D, Ferrari M. 311C90, a new central and peripherally acting 5-HT₁D receptor agonist in the acute oral treatment of migraine. Neurology 1996; 46: 522-526.
21. 21. Yates R, Sorensen J, Bergstrom M, Antoni G, Kemp J. Distribution and pharmacokinetics of zolmitriptan following administration by nasal spray. Cephalalgia 2001;21(4):417-8.
22. 22. Zagami AS. 311C90: Long-term efficacy and tolerability profile for the acute treatment of migraine. Neurology 1997; 48 (Suppl 3): S25-S28
23. 23. Zomig^® (zolmitriptan) Tablets, Zomig Rapimelt^® (zolmitriptan) orally disintegrating tabletsProduct Monograph, AstraZeneca Canada Inc., Date of Revision: November 1, 2012.
24. 24.

    A Comparative Bioavailability Study of Two Formulations of Zolmitriptan 2.5 mg Tablets

    Under Fasting Conditions in Healthy Male and Female subjects. Data on file at Teva Canada Limited.

25. 25.

    A Comparative Bioavailability Study of Two Formulations of Zolmitriptan Orally

    Disintegrating 2.5 mg Tablets under fasting conditions in healthy subjects. Data on file at Teva Canada Limited.