persistent and recurrent headache. The frequency and time to use of these additional WARNINGS treatments were also recorded. ZOMIG* (zolmitriptan) should only be used where a clear diagnosis of migraine Table 1 shows efficacy results for ZOMIG" in 5 placebo-controlled trials, 4 of which were has been established. multicenter. The percentage of patients with pain relief (grade 1/0) at 2 hours after treatment Risk of Myocardial Ischemia ami/or Infarction and Other Adverse Cardiac Events: (the primary endpoint measure) was significantly greater among patients receiving ZOMIG* 2DWB* has beMassccMedwMtmis^ chest siMfrJMkpste and 8ghtoe& UZomis: at all doses compared to those on placebo. In Study 3, which directly compared the 1 mg, which may resemble angina pectoris. Following the use of other 5-HTj 2.5 mg and 5 mg doses, there was a statistically significant greater proportion of patients with agonists, In rare cases these symptoms have been Identified as being the likely zolmitriptan tablets 2.5 mg headache response at 2 and 4 hours in the higher dose groups (2.5 mg or 5 mg) than in the result of coronary vasospasm or myocardial Ischemia. Rare cases of serious 1 mg group. There was no statistically significant difference between the 2.5 mg and 5 mg PHARMACOLOGICAL CLASSIFICATION coronary events or arrhythmia have occurred following use ot S-HTt agonists, dose groups for the primary endpoint measure of pain relief (1/0) at 2 hours, or at any other including ZOMIG*. ZOMIG* should not be given to patients who have documented 5-HTi Receptor Agonist time point measured. Ischemic or vasospastic coronary artery disease (see CONTRAINDICATIONS). THERAPEUTIC CLASSIFICATION Table 1: Percentage of Patients with Pain Relief (1/0)* at 1,2 and 4 hours - It Is strongly recommended thai ZOMIG* not be given to patients In whom Migraine Therapy Intent to Treat Population unrecognized coronary artery disease (CAD) is predicted by the presence ACTIONS AND CLINICAL PHARMACOLOGY of risk factors (e.g., hypertension, hypercholesterolemia, smoking, obesity, ZOMIG* (zolmitriptan) is a selective 5-hydroxytryptaminet (5-HTIB/IDJ receptor agonist. Study Hour Placebo Zomig* Dose (mg) diabetes, strong family history of CAD, female who Is surgically or Post-dose 1 2.S 5 It exhibits a high affinity at human recombinant 5-HTIB and 5-HTID receptors and modest physiologically postmenopausal, or male who is over 40 years of age) unless affinity fa 5-HTIA receptors. Zolmitriptan has no significant affinity (as measured by radioligand a cardiovascular evaluation provides satisfactory clinical evidence that the % % % % patient is reasonably free of coronary artery and Ischemic myocardial disease binding assays) or pharmacological activity at 5-HT2,5-HT3,5-HTi alpha;, alpfia2, or 1 15 1 2i 1 2 15 27 62* or other significant underlying cardiovascular disease. The sensitivity of cardiac betai, -adrenergic; Hi, H2, histaminic; muscarinic; dopamines or dopamine?, receptors. diagnostic procedures to detect cardiovascular disease or predisposition to The N-rJesmethyl metabolite of zolmitriptan also has high affinity for 5-HTIB/ID and modest 4 70 68 71 (N=20) (N=22) coronary artery vasospasm is unknown, if, during the cardiovascular evaluation, affinity for 5-HTu receptors. |_ (N=2I) the pattern's medical history or electrocardiographic Investigations reveal findings It has been proposed that symptoms associated with migraine headaches arise from the indicative of or consistent with coronary artery vasospasm or myocardial 1 18 activation of the trigemino-vascular system, which results in local cranial vasodilation and Ischemia, ZOMIG* should not be administered (see CONTRAINDICATIONS). 2 2 21 < neurogenic inflammation involving the antidromic release of sensory neuropeptides 61* For patients with risk factors predictive ot CAD who are considered to have (N=99) (Vaso-actNe Intestinal Peptide (VIP), Substance P and calcitonin gene related peptide (CGRP)]. (N=2I3) a satisfactory cardiovascular evaluation, the first dose of ZOMIG* should be The therapeutic activity of zolmitriptan for the treatment of migraine headache is thought to administered in the setting of a physician's office or similar medically staffed 1 24 V 44* be attributable to its agonist effects at 5-HTIMD receptors on the intracranial blood vessels, ", and equipped facility. Because cardiac Ischemia can occur In the absence of 3 2 32 50* \ 65'" including the arteriovenous anastamoses, and sensory nerves of the trigeminal system which clinical symptoms, consideration should be given to obtaining electrocardio­ 4 31 58' «'74*» 75* result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. grams In patients with risk factors during the Interval immediately following (N=I40) (N=I4I) (N=2»8) Pharmacokinetics (N=280) ZOMIG* administration on the first occasion of use. However, an absence of drug-induced cardiovascular effects on the occasion af me inttiat dose Absorption and Bioavailability: In man, zolmitriptan is rapidly and well absorbed (at least / 21 r „t does not preclude the possibility of such effects occurring with subsequent 64%) after oral administration with peak plasma concentrations occurring in 2 hours. Trie 4 2 44 59* administrations. mean absolute bioavailability of the parent compound is approximately 40%. Food has no 4 60 80* significant effect on the bioavailability of zolmitriptan. (l*=56) (N=498) Intermittent long-term users of ZOMIG* who have or acquire risk factors During a moderate to severe migraine attack in male and female patients, mean AUC0_4 and Cmax for zolmitriptan were decreased by 40% and 25%, respectively and mean tmax 1 26 35, predictive of CAD, as described above, should receive periodic Interval was delayed by one-half hour compared to the same patients during a migraine free period. S 2 36 62 cardiovascular evaluations over the course of treatment. 4 35 71* Plasma Kinetics and Disposition: When given as a single dose to healthy volunteers, If symptoms consistent with angina occur after the use of ZOMIG*, ECG (N=IOl) (N=200) zolmitriptan displayed linear kinetics over the dose range of 2.5 to 50 mg. evaluation should be carried out to look for Ischemic changes. The mean apparent volume of distribution is 7.0 L/kg. Plasma protein binding of zolmitriptan *p<0.05 in comparison with placebo. "p<0.01 in comparison with 1 mg The systematic approach described above Is Intended to reduce the over the concentration range of 10 -1000 ng/L is 25%. tp<0.0l in comparison with placebo - = Not studied likelihood that patients with unrecognized cardiovascular disease will There is no evidence of accumulation on multiple dosing with zolmitriptan up to doses of 10 mg. be Inadvertently exposed to ZOMIG*. * Pain Relief is defined as a reduction in headache severity from grade 3 or 2 (severe or Biotransformation and Elimination: Zolmitriptan is eliminated largely by hepatic moderate) to grade 1 or 0 (mild or no pain). Cardiac Events and Fatalities Associated With 5-HT, Agonists: In special cardiovascular biotransformation followed by urinary excretion of the metabolites. The enzymes responsible for studies (see below), another 5-HT, agonist has been shown to cause coronary vasospasm. the metabolism of zolmitriptan remain to be My characterized. The mean elimination half-life The proportion of patients pain free at 2 hours was statistically significantly greater for ZOMIG* has not been tested under similar conditions, however, owing to the common pharmaco­ of zolmitriptan is approximately 2.5 to 3 hours. Mean total plasma clearance of zolmitriptan is patients receiving ZOMIG* tablets at doses of 1,2.5 and 5 mg compared with placebo in dynamic actions of 5-HT, agonists, the possibility of cardiovascular effects of the nature 31.5 mL/mirVkg, of which one-sixth is renal clearance. The renal clearance is greater than Study 3. described below should be considered for all agents of this class. Serious adverse cardiac the glomerular filtration rate suggesting renal tubular secretion. For patients with migraine associated photophobia, phonophobia, and nausea at baseline, events, including acute myocardial infarction, life threatening disturbance of cardiac rhythm, In a study in which radiolabeled zolmitriptan was administered orally to healthy volunteers, there was a decreased incidence of these symptoms following administration of ZOMIG® as and death have been reported within a few hours following the administration of 5-HT, agonists. 64% and 30% of trie administered "C-zolmitriptan dose was excreted in the urine and feces, compared to placebo (see Table 2). Considering the extent of use of 5-HT, agonists in patients with migraine, the incidence of these respectively. About 8% of the dose was recovered in the urine as unchanged zolmitriptan. events is extremely low. Table 2. Improvement in Non-Headache Symptoms* The indole acetic acid and N-oxide metabolites, which are inactive, accounted for 31% and 7% Patients with symptomatic Wolff-Parkinson-White syndrome or arrhythmias associated of the dose, respectively, while the active N-desmethyl metabolite accounted for 4% of the with other cardiac accessory conduction pathway disorders should not receive ZOMIG*. dose. Symptom Patients free of non-headache symptoms at 2 hours, % (Percentage improvement over baseline) Premarketing Experience with ZOMIG Tablets: Among the more than 2,500 patients with migraine who participated in premarketing controlled clinical trials of ZOMIG tablets, Conversion of zolmitriptan to the active