ZOMIG™ (zolmitriptan) Tablets contain zolmitriptan, which is a selective 5-hydroxytryptamine _1B/1D (5-HT_1B/1D) receptor agonist. Zolmitriptan is chemically designated as (S)-4-[[3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone.

The empirical formula is C₁₆H₂₁N₃O₂, representing a molecular weight of 287.36. Zolmitriptan is a white to almost white powder that is readily soluble in water. ZOMIG is supplied as 2.5 mg (yellow) and 5 mg (pink) tablets for oral administration. The film-coated tablets contain anhydrous lactose NF, microcrystalline cellulose NF, sodium starch glycolate NF, magnesium stearate NF, hydroxypropyl methylcellulose USP, titanium dioxide USP, polyethylene glycol 400 NF, yellow iron oxide NF (2.5 mg tablet), red iron oxide NF (5 mg tablet), and polyethylene glycol 8000 NF.

ZOMIG is indicated for the acute treatment of migraine with or without aura in adults.

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

In controlled clinical trials, single doses of 1, 2.5 and 5 mg of zolmitriptan were effective for the acute treatment of migraines in adults. A greater proportion of patients had headache response following a 2.5 or 5 mg dose than following a 1 mg dose (see Table 1). In the only direct comparison of 2.5 and 5 mg, there was little added benefit from the larger dose but side effects are generally increased at 5 mg (see Table 2). Patients should, therefore, be started on 2.5 mg or lower. A dose lower than 2.5 mg can be achieved by manually breaking a 2.5 mg tablet in half.

If the headache returns, the dose may be repeated after 2 hours, not to exceed 10 mg within a 24 hour period. Controlled trials have not adequately established the effectiveness of a second dose if the initial dose is ineffective.

The safety of treating an average of more than three headaches in a 30 day period has not been 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 with blood pressure monitoring is recommended (see CLINICAL PHARMACOLOGY and WARNINGS).

2.5 mg Tablets - Yellow, biconvex, film-coated, scored tablets containing 2.5 mg of zolmitriptan identified with "ZOMIG" and "2.5" debossed on one side are supplied in cartons containing a blister pack of 6 tablets. (NDC 0310-0210-20).

5 mg Tablets - Pink, biconvex, film-coated tablets containing 5 mg of zolmitriptan identified with "ZOMIG" and "5" debossed on one side are supplied in cartons containing a blister pack of 3 tablets. (NDC 0310-0211-25).

Although not reported with zolmitriptan in clinical trials, serious cardiac events, including some that have been fatal, have rarely occurred following use of 5-HT₁ agonists. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Incidence in Controlled Clinical Trials

Among 2,633 patients treated with ZOMIG in the active and placebo controlled trials, no patients withdrew for reasons related to adverse events, but as patients treated a single headache in these trials, the opportunity for discontinuation was limited. In a long term, open label study where patients were allowed to treat multiple migraine attacks for up to 1 year, 8% (167 out of 2,058) withdrew from the trial because of adverse experience. The most common events were paresthesia, asthenia, nausea, dizziness, pain, chest or neck tightness or heaviness, somnolence and warm sensation.

Table 2 lists the adverse events that occurred in ³2% of the 2,074 patients in any one of the ZOMIG 1 mg, ZOMIG 2.5 mg or ZOMIG 5 mg dose groups of the controlled clinical trials. Only events that were more frequent in a ZOMIG group compared to the placebo groups are included. The events cited reflect experience gained under closely monitored conditions of 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 behavior, 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.

ZOMIG is generally well tolerated. Across all doses, most adverse reactions were mild and transient and did not lead to long-lasting effects. The incidence of adverse events in controlled clinical trials was not affected by gender, weight, or age of the 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.

Other Events

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. 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, tachycardia and thrombophlebitis.

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 leukopenia.

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 and irritability.

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

Skin: Infrequent were pruritus, rash and urticaria.

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, urinary urgency. Rare were miscarriage and dysmenorrhea.

DRUG ABUSE AND DEPENDENCE

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

All drug interaction studies 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.

Fluoxetine: The pharmacokinetics of zolmitriptan as well as its effect on blood pressure were unaffected by 4 weeks of pretreatment with oral fluoxetine (20 mg/day).

MAO Inhibitors: Following one week of administration of 150 mg bid moclobemide, a specific MAO-A inhibitor, there was an increase of about 25% in both C_max and AUC for zolmitriptan and a 3-fold increase in the C_max and AUC of the active N-desmethyl metabolite of zolmitriptan (see CONTRAINDICATIONS and PRECAUTIONS).

Selegiline, a selective MAO-B inhibitor, at a dose of 10 mg/day for 1 week, had no effect on the pharmacokinetics of zolmitriptan and its metabolite.

Propranolol: C_max and AUC of zolmitriptan increased 1.5-fold after one week of dosing with propranolol (160 mg/day). C_max 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.

Acetaminophen: A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its N-desmethyl metabolite. However, zolmitriptan delayed the T_max of acetaminophen by one hour.

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

Oral Contraceptives: Retrospective analysis of pharmacokinetic data across studies indicated that mean plasma concentrations of zolmitriptan were generally higher in females taking oral contraceptives compared to those not taking oral contraceptives. Mean C_max and AUC of zolmitriptan were found to be higher by 30% and 50%, respectively, and T_max was delayed by one-half hour in females taking oral contraceptives. The effect of zolmitriptan on the pharmacokinetics of oral contraceptives has not been studied.

Cimetidine: Following the administration of cimetidine, the half life and AUC of a 5 mg dose of zolmitriptan and its active metabolite were approximately doubled (see PRECAUTIONS).

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

MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of zolmitriptan in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Concomitant use of other 5-HT_1B/1D agonists within 24 hours of ZOMIG treatment is not recommended. (see CONTRAINDICATIONS).

Following administration of cimetidine, the half life and AUC of zolmitriptan and its active metabolites were approximately doubled (see CLINICAL PHARMACOLOGY).

Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with 5HT₁ agonists. If concomitant treatment with zolmitriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.

Drug/Laboratory Test Interactions

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

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

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

Because of the potential of this class of compounds (5-HT_1B/1D agonists) to cause coronary vasospasm, ZOMIG should not be given to patients with documented ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). It is strongly recommended that 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, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male 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 modest, at best. If, during the cardiovascular evaluation, the patient's medical history, electrocardiographic or other investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, zolmitriptan should not be administered (see CONTRAINDICATIONS). Among the more than 2,500 patients with migraine who participated in premarketing controlled clinical trials of ZOMIG Tablets, no documented episodes of myocardial ischemia or infarction were reported. For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of zolmitriptan take place in the setting of a physician's office or similar medically staffed and equipped facility unless the patient has previously received zolmitriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following ZOMIG, in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of ZOMIG and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use ZOMIG.

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

Cardiac Events and Fatalities associated with 5HT₁ agonists

Among the more than 2,500 patients with migraine who participated in premarketing controlled clinical trials of ZOMIG Tablets, no deaths or serious cardiac events were reported. However, the potential for adverse cardiac events exists. 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 5HT₁ agonists. Considering the extent of use of 5HT₁ 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.

Cerebrovascular Events and Fatalities with 5HT₁ agonists

Cerebral hemorrhage, subarachnoid hemorrhage, 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 experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. Stroke, hemorrhage, transient ischemic attack).

Other Vasospasm-Related Events

5HT₁ agonists may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with 5HT₁ agonists.

Increase in Blood Pressure

Significant elevations in systemic blood pressure have been reported on rare occasions in patients with and without a history of hypertension treated with 5-HT₁ agonists. Zolmitriptan is contraindicated in patients with uncontrolled hypertension. In volunteers, an increase of 1 and 5 mmHg in the systolic and diastolic blood pressure, respectively, was seen at 5 mg. In the headache trials, vital signs were measured only in the small inpatient study and no effect on blood pressure was seen. In a study of patients with moderate to severe liver disease, 7 of 27 experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of zolmitriptan. (see CONTRAINDICATIONS).

An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5HT₁ agonist in a study evaluating subjects undergoing cardiac catheterization.

General

As with other 5-HT_1B/1D agonists, sensations of tightness, pain, pressure, and heaviness have been reported after treatment with ZOMIG tablets in the precordium, throat, neck and jaw. These events have not been associated with arrhythmias or ischemic ECG changes in clinical trials. Because drugs in this class may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal's variant angina before receiving additional doses of medication, 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 the use of any 5-HT agonist are candidates for further evaluation. (see

WARNINGS

Zolmitriptan should also be administered with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs, such as impaired hepatic function (see CLINICAL PHARMACOLOGY).

For a given attack, if a patient does not respond to the first dose of zolmitriptan, the diagnosis of migraine headache should be reconsidered before administration of a second dose.

Binding to Melanin-Containing Tissues

When pigmented rats were given a single oral dose of 10 mg/kg of radiolabeled zolmitriptan the radioactivity in the eye after 7 days, the latest time point examined, was still 75% of the value 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, this 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. Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Information for Patients

See PATIENT INFORMATION.

Laboratory Tests

No monitoring of specific laboratory tests is recommended.

Drug Interactions

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

MAO-A inhibitors increase the systemic exposure of zolmitriptan. Therefore, the use of zolmitriptan in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Concomitant use of other 5-HT_1B/1D agonists within 24 hours of ZOMIG treatment is not recommended. (see CONTRAINDICATIONS).

Following administration of cimetidine, the half life and AUC of zolmitriptan and its active metabolites were approximately doubled (see CLINICAL PHARMACOLOGY).

Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with 5HT₁ agonists. If concomitant treatment with zolmitriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.

Drug/Laboratory Test Interactions

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Carcinogenicity studies by oral gavage were carried out in mice and rats at doses up to 400 mg/kg/day. Mice were dosed for 85 weeks (males) and 92 weeks (females). The exposure (plasma AUC of parent drug) at the highest dose level was approximately 800 times that seen in humans after a single 10 mg dose (the maximum recommended total daily dose). There was no effect of zolmitriptan on tumor incidence. Control, low dose and middle dose rats were dosed for 104-105 weeks; the high dose group was sacrificed after 101 weeks (males) and 86 weeks (females) due to excess mortality. Aside from an increase in the incidence of thyroid follicular cell hyperplasia and thyroid follicular cell adenomas seen in male rats receiving 400 mg/kg/day, an exposure approximately 3000 times that seen in humans after dosing with 10 mg, no tumors were noted.

Mutagenesis: Zolmitriptan was mutagenic in an Ames test, in 2 of 5 strains of S. 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. Zolmitriptan was clastogenic in an in vitro human lymphocyte assay both in the absence of and the presence of metabolic activation; it was not clastogenic in an in vivo mouse micronucleus assay. It was also not genotoxic in an unscheduled DNA synthesis study.

Impairment of Fertility: Studies of male and female rats administered zolmitriptan prior to and during mating and up to implantation have shown no impairment of fertility at doses up to 400 mg/kg/day. Exposure at this dose was approximately 3000 times exposure at the maximum recommended human dose of 10 mg/day.

Pregnancy

Pregnancy Category C: There are no adequate and well controlled studies in pregnant women; therefore, zolmitriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals was associated with embryolethality and fetal abnormalities. When pregnant rats were administered oral zolmitriptan during the period of organogenesis at doses of 100, 400 and 1200 mg/kg/day, there was a dose related increase in embryolethality which became statistically significant at the high dose. The maternal plasma exposures at these doses were approximately 280, 1100 and 5000 times the exposure in humans receiving the maximum recommended total daily dose of 10 mg. The high dose was maternally toxic, as evidenced by a decreased maternal body weight gain during gestation. In a similar study in rabbits, embryolethality was increased at the maternally toxic doses of 10 and 30 mg/kg/day (maternal plasma exposures equivalent to 11 and 42 times exposure in humans receiving the maximum recommended total daily dose of 10 mg), and increased incidences of fetal malformations (fused sternebrae, rib anomalies) and variations (major blood vessel variations, irregular ossification pattern of ribs) were observed at 30 mg/kg/day. Three mg/kg/day was a no effect dose (equivalent to human exposure at a dose of 10 mg). When female rats were given zolmitriptan during gestation, parturition, and lactation, an increased incidence of hydronephrosis was found in the offspring at the maternally toxic dose of 400 mg/kg/day (1100 times human exposure).

Nursing Mothers

It is not known whether zolmitriptan is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when zolmitriptan is administered to a nursing woman. 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.

Pediatric Use

Safety and effectiveness of ZOMIG in pediatric patients have not been established.

Use in the Elderly

Although the pharmacokinetic disposition of the drug in the elderly is similar to that seen in younger adults, there is no information about the safety and effectiveness of zolmitriptan in this population because patients over age 65 were excluded from the controlled clinical trials. (see CLINICAL PHARMACOLOGY: Special Populations)

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

The elimination half-life of ZOMIG is 3 hours (see 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 plasma concentrations of zolmitriptan.

ZOMIG should not be given to patients with ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal's variant angina, or other significant underlying cardiovascular disease (see WARNINGS).

Because ZOMIG may increase blood pressure, it should not be given to patients with uncontrolled hypertension (see WARNINGS).

ZOMIG should not be used within 24 hours of treatment with another 5HT₁ agonist, or an ergotamine-containing or ergot-type medication like dihydroergotamine or methysergide.

ZOMIG should not be administered to patients with hemiplegic or basilar migraine.

Concurrent administration of MAO A inhibitors or use of zolmitriptan within 2 weeks of discontinuation of MAO A inhibitor therapy is contraindicated (see DRUG INTERACTIONS and PRECAUTIONS: Drug Interactions).

ZOMIG is contraindicated in patients who are hypersensitive to zolmitriptan or any of its inactive ingredients.

Mechanism of Action

Zolmitriptan binds with high affinity to human recombinant 5-HT_1D and 5-HT_1B receptors. Zolmitriptan exhibits modest affinity for 5-HT_1A receptors, but 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 also has high affinity for 5-HT_1B/1D and modest affinity for 5-HT_1A receptors.

Current theories proposed to explain the etiology of migraine headache suggest that symptoms are due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of zolmitriptan for the treatment of migraine headache can most likely be attributed to the agonist effects at the 5HT_1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

Pharmacokinetics

Zolmitriptan is well absorbed after oral administration with peak plasma concentrations occurring in 2 hours. Mean absolute bioavailability is approximately 40%. Zolmitriptan displays linear kinetics over the dose range of 2.5 to 50 mg. The mean elimination half-life of zolmitriptan and of the active N-desmethyl metabolite is 3 hours. Zolmitriptan is converted to an active N-desmethyl metabolite such that the metabolite concentrations are about two t.i.d. that of zolmitriptan. Because the 5HT_1B/1D potency of the 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 T_max for this metabolite is approximately 2 to 3 hours. No accumulation occurred on multiple dosing. Food has no significant effect on the bioavailability of zolmitriptan.

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

Total radioactivity recovered in urine and feces was 65% and 30% of the administered dose, respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. 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.

Mean total plasma clearance 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.

During a moderate to severe migraine attack, 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.

Special Populations

Age: Zolmitriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65-76 years were similar to those in younger non-migraineur volunteers (age 18-39 yrs).

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

Renal Impairment: Clearance of zolmitriptan was reduced by 25% in patients with severe renal impairment (Clcr>5<25 mL/min) compared to the normal group (Clcr > = 70 mL/min); no significant change in clearance was observed in the moderately renally impaired group (Clcr>26<50 mL/min).

Hepatic Impairment: In severely hepatically impaired patients, the mean C_max, T_max, and AUC_0-¥ of zolmitriptan were increased 1.5, 2 (2 vs 4 hrs), and 3 fold, respectively, compared to normals. Seven out of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a 10 mg dose. Zolmitriptan should be administered with caution in subjects with liver disease, generally using doses less than 2.5 mg (See WARNINGS and PRECAUTIONS).

Hypertensive Patients: No differences in the pharmacokinetics of zolmitriptan or its effects on blood pressure were seen in mild to moderate hypertensive volunteers compared to normotensive controls.

Race: Retrospective analysis of pharmacokinetic data between Japanese and Caucasians revealed no significant differences.

Drug Interactions

See DRUG INTERACTIONS.

Clinical Studies

The efficacy of ZOMIG Tablets in the acute treatment of migraine headaches was demonstrated in five randomized, double b.i.d. 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; all studies used the marketed formulation. In study 1, 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 5 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 ZOMIG Tablets or other medication was allowed 2 to 24 hours after the initial treatment for persistent and recurrent headache. The frequency and time to use of these additional treatments were also recorded. In all studies, the effect of zolmitriptan was compared to placebo in the treatment of a single migraine attack.

In all five studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving ZOMIG Tablets at all doses (except for the 1 mg dose in the smallest study) compared to those who received placebo. In the two studies that evaluated the 1 mg dose, there was a statistically significant greater percentage of patients with headache response at 2 hours in the higher dose groups (2.5 and/or 5 mg) compared to the 1 mg dose group. There were no statistically significant differences between the 2.5 and 5 mg dose groups (or of doses up to 20 mg) for the primary endpoint of headache response at 2 hours in any study. The results of these controlled clinical studies are summarized in Table 1.

Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.

For patients with migraine associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of ZOMIG 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 efficacy of ZOMIG was unaffected by presence of aura; duration of headache prior to treatment; relationship to menses; gender, age or weight of the patient; pretreatment nausea or concomitant use of common migraine prophylactic drugs.

Information for the Consumer on ZOMIG (zolmitriptan) Tablets

Please read this leaflet carefully before you administer ZOMIG Tablets. This provides a summary of the information available on your medicine. Please do not throw away this leaflet until you have finished your medicine. You may need to read this leaflet again. This leaflet does not contain all the information on ZOMIG Tablets. For further information or advice, ask your doctor or pharmacist.

Information About Your Medicine

The name of your medicine is ZOMIG Tablets. It can be obtained only by prescription from your doctor. The decision to use ZOMIG Tablets is one that you and your doctor should make jointly, taking into account your individual preferences and medical circumstances. If you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or a male over the age of 40), you should tell your doctor, who should evaluate you for heart disease in order to determine if ZOMIG Tablets are appropriate for you.

1. The Purpose of Your Medicine: ZOMIG Tablets are intended to relieve your migraine, but not to prevent or reduce the number of attacks you experience. Use ZOMIG Tablets only to treat an actual migraine attack.

2. Important Questions to Consider Before Using ZOMIG Tablets: If the answer to any of the following questions is YES or if you do not know the answer, then you must discuss it with your doctor before you use ZOMIG Tablets.

Remember, if you answered YES to any of the above questions, then you must discuss it with your doctor.

3. The Use of ZOMIG Tablets During Pregnancy: Do not use ZOMIG Tablets if you are pregnant, think you might be pregnant, are trying to become pregnant, or are not using adequate contraception, unless you have discussed this with your doctor.

4. How to Use ZOMIG Tablets: Adults should be started on a 2.5 mg dose or lower administered by mouth. A dose lower than 2.5 mg can be achieved by manually breaking a 2.5 mg tablet in half. If your headache comes back after your initial dose, a second dose may be administered anytime after 2 hours of administering the dose. For any attack where you have no response to the first dose, do not take a second dose without first consulting with your doctor. Do not administer more than a total of 10 mg of ZOMIG Tablets in any 24-hour period. Discard any unused tablets or its portion that have been removed from the blister packaging.

5. Side Effects to Watch for:

6. What to Do if an Overdose Is Taken: If you have taken more medication than you have been told, contact either your doctor, hospital emergency department, or nearest poison control center immediately. This medicine was prescribed for your particular condition and should not be used by others or for any other condition.

7. Storing Your Medicine: Keep your medicine in a safe place where children cannot reach it. It may be harmful to children. Store your medication away from heat, light, moisture and at a controlled room temperature. If your medication has expired (the expiration date is printed on the treatment pack), throw it away as instructed. If your doctor decides to stop your treatment, do not keep any leftover medicine unless your doctor tells you to. Throw away your medicine as instructed. Be sure that discarded tablets are out of the reach of children.

Also see WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ZOLMITRIPTAN - ORAL

(zol-meh-TRIP-tan)

COMMON BRAND NAME(S): Zomig

USES: Zolmitriptan is used to treat migraines. It helps to relieve headaches, pain, and other symptoms of migraines, including nausea, vomiting, and sensitivity to light/sound. Prompt treatment allows you to get back to your normal routine and may decrease your need for other pain medications. Zolmitriptan does not prevent future migraines or reduce how often you may get a migraine.

Zolmitriptan belongs to a group of drugs called "triptans." Migraines are thought to occur when certain blood vessels in the brain become swollen (dilated). This drug works by helping blood vessels in the brain to return to normal size. It may also block pain signals in the brain.

HOW TO USE: Read the Patient Information Leaflet available from your pharmacist before you start using zolmitriptan and each time you get a refill. Ask your doctor or pharmacist if you have any questions.

Your dosage is based on your medical condition and response to treatment.

Take this medication by mouth, with or without food, at the first sign of a migraine as directed by your doctor. If there is no improvement in your symptoms, do not take any more doses of this medication before talking to your doctor. If your symptoms are only partly relieved, or if your headache comes back, you may take a second dose after 2 hours or as directed by your doctor. Do not take more than 10 milligrams in a 24-hour period.

If you have certain conditions that increase your risk of heart disease and you have never taken this medication before, you may need to be monitored for rare but serious side effects (e.g., chest pain) when you take the first dose. Your doctor may ask you to take the first dose in the office. See Precautions section for more information.

Tell your doctor if your condition does not improve or if it worsens.

SIDE EFFECTS: Tingling/numbness, nausea, dry mouth, weakness, drowsiness, or dizziness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: blue fingers/toes/nails, cold feeling in the hands/feet.

Pain/pressure/tightness in the chest/neck/jaw can occur shortly after using zolmitriptan. These side effects are usually not serious. However, you may not be able to tell them apart from a rare but very serious reaction related to a lack of blood flow to the heart, brain, or other parts of the body. Therefore, seek immediate medical attention if you notice any of these unlikely side effects: chest/jaw/left arm pain, fainting, irregular/pounding heartbeat, vision changes, severe nausea, weakness on one side of the body, confusion, seizures, slurred speech, sudden or severe stomach/abdominal pain, trouble swallowing, bloody diarrhea.

This medication may rarely cause a very serious condition called serotonin syndrome. The risk increases when this medication is used with certain other drugs such as other "triptans" used to treat migraine headaches (e.g., sumatriptan, eletriptan), certain antidepressants including SSRIs (e.g., citalopram, fluoxetine, paroxetine) and NSRIs (e.g., duloxetine, venlafaxine), or a certain drug to treat obesity (sibutramine). Before taking this drug, tell your doctor if you take any of these medications. Serotonin syndrome may be more likely when you start or increase the dose of any of these medications. Seek immediate medical attention if you develop some of the following symptoms: hallucinations, unusual restlessness, loss of coordination, fast heartbeat, severe dizziness, high fever, severe nausea/vomiting/diarrhea, twitchy muscles.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: See also How to Use section.

Before taking zolmitriptan, tell your doctor or pharmacist if you are allergic to it; or to other "triptan" migraine drugs; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: heart disease (e.g., chest pain, heart attack, irregular heartbeat, coronary artery disease, vasospasm), blood flow problems in the brain (e.g., stroke, transient ischemic attack), blood vessel disease (e.g., peripheral vascular disease, ischemic bowel disease), uncontrolled high blood pressure (hypertension), certain types of headaches (hemiplegic or basilar migraine), severe liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood circulation disorder (e.g., Raynaud's disease), kidney disease.

Before using this medication, tell your doctor or pharmacist if you have any condition that increases your risk of heart disease, including: high cholesterol level, high blood pressure, diabetes, smoking history, family history of heart disease or stroke, overweight, female after menopause, male older than 40 years.

If you are at high risk for heart disease, your doctor may want to check your heart before prescribing zolmitriptan.

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any other activity that requires alertness. Limit alcoholic beverages.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Because of the possible harm to the nursing infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: See also Side Effects section.

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: sibutramine.

Do not take MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, tranylcypromine) for at least 2 weeks before or after taking this drug.

This drug should not be used within 24 hours of the following medication because very serious interactions may occur: ergot-type drugs (e.g., ergotamine, dihydroergotamine, methysergide), other "triptan" migraine drugs (e.g., sumatriptan).

If you are currently using any of the above medications, tell your doctor or pharmacist before starting zolmitriptan.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription products you may use, especially of: hormonal birth control (pill, patch, ring), cimetidine, certain types of antidepressants (e.g., SSRIs such as fluoxetine/paroxetine/sertraline, NSRIs such as venlafaxine), St John's wort.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, amitriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

Cimetidine is a nonprescription drug that is commonly used to treat extra stomach acid. Because it may interact with zolmitriptan, ask your pharmacist about other products to treat stomach acid.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., EKG) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: Not applicable.

STORAGE: Store the US product at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture.

Store the Canadian product at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture.

Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.