Zolmitriptan

Zolmitriptan tablets are indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use: Only use zolmitriptan tablets if a clear diagnosis of migraine has been established. If a patient has no response to zolmitriptan tablets treatment for the first migraine attack, reconsider the diagnosis of migraine before zolmitriptan tablets are administered to treat any subsequent attacks. Zolmitriptan tablets are not indicated for the prevention of migraine attacks. Safety and effectiveness of zolmitriptan tablets have not been established for cluster headache.

2.1 Dosing Information The recommended starting dose of zolmitriptan tablets is 1.25 mg or 2.5 mg. The 1.25 mg dose can be achieved by manually breaking the functionally-scored 2.5 mg tablet in half. The maximum recommended single dose of zolmitriptan tablets is 5 mg. In controlled clinical trials, a greater proportion of patients had headache response following a 2.5 mg or 5 mg dose than following a 1 mg dose. There was little added benefit from the 5 mg dose compared to the 2.5 mg dose, but adverse reactions were more frequent with the 5 mg dose. If the migraine has not resolved by 2 hours after taking zolmitriptan tablets, or returns after a transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose is 10 mg in any 24-hour period. The safety of zolmitriptan tablets in the treatment of an average of more than three migraines in a 30-day period has not been established. 2.3 Dosing in Patients with Hepatic Impairment The recommended dose of zolmitriptan tablets in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg zolmitriptan tablets) because of increased zolmitriptan blood levels in these patients and elevation of blood pressure in some of these patients. Limit the total daily dose in patients with severe hepatic impairment to no more than 5 mg per day. 2.4 Dosing in Patients taking Cimetidine If zolmitriptan tablets is co-administered with cimetidine, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [see Drug Interactions (7.5), Clinical Pharmacology (12.3)].

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina Zolmitriptan tablets are contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD). There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of zolmitriptan tablets. Some of these reactions occurred in patients without known CAD. 5-HT1 agonists including zolmitriptan tablets may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving zolmitriptan tablets. Do not administer zolmitriptan tablets if there is evidence of CAD or coronary artery vasospasm [see CONTRAINDICATIONS (4)]. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first zolmitriptan tablets dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following zolmitriptan tablets administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of zolmitriptan tablets. 5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue zolmitriptan tablets if these disturbances occur. Zolmitriptan tablets are contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see CONTRAINDICATIONS (4)]. 5.3 Chest, Throat, Neck and Jaw Pain/Tightness/Pressure As with other 5-HT1 agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with zolmitriptan tablets and is usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT1 agonists including zolmitriptan tablets are contraindicated in patients with CAD or Prinzmetal’s variant angina [see CONTRAINDICATIONS (4)]. 5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions. Zolmitriptan tablets are contraindicated in patients with a history of stroke or transient ischemic attack [see CONTRAINDICATIONS (4)]. 5.5 Other Vasospasm Reactions 5-HT1 agonists, including zolmitriptan tablets, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional zolmitriptan tablets doses [see CONTRAINDICATIONS (4)]. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists has not been clearly established. 5.6 Medica…

Zolmitriptan tablets are contraindicated in patients with: Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), other significant underlying cardiovascular disease, or coronary artery vasospasm including Prinzmetal’s angina [see WARNINGS AND PRECAUTIONS (5.1)] . Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see WARNINGS AND PRECAUTIONS (5.2)] . History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [see WARNINGS AND PRECAUTIONS (5.4)] . Peripheral vascular disease (PVD) [see WARNINGS AND PRECAUTIONS (5.5)] . Ischemic bowel disease [see WARNINGS AND PRECAUTIONS (5.5)] . Uncontrolled hypertension [see WARNINGS AND PRECAUTIONS (5.8)] . Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) [see DRUG INTERACTIONS (7.1, 7.3)] . Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent use of a MAO-A inhibitor (that is within 2 weeks) [see DRUG INTERACTIONS (7.2),CLINICAL PHARMACOLOGY (12.3)] . Known hypersensitivity to zolmitriptan (angioedema and anaphylaxis seen) [see ADVERSE REACTIONS (6.2)].

7.1 Ergot-containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine containing or ergot-type medications (like dihydroergotamine or methysergide) and zolmitriptan tablets within 24 hours of each other is contraindicated [see CONTRAINDICATIONS (4)]. 7.2 MAO-A Inhibitors MAO-A inhibitors increase the systemic exposure of zolmitriptan and its active N-desmethyl metabolite. Therefore, the use of zolmitriptan tablets in patients receiving MAO-A inhibitors is contraindicated [see CONTRAINDICATIONS (4), CLINICAL PHARMACOLOGY (12.3)]. 7.3 5-HT1B/1D agonists Concomitant use of other 5-HT1B/1D agonists (including triptans) within 24 hours of zolmitriptan tablets treatment is contraindicated because the risk of vasospastic reactions may be additive [see CONTRAINDICATIONS (4)]. 7.4 Selective Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors Cases of life-threatening serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) [see WARNINGS AND PRECAUTIONS (5.7)]. 7.5 Cimetidine Following administration of cimetidine, the half-life and blood levels of zolmitriptan and its active N-desmethyl metabolite were approximately doubled [see CLINICAL PHARMACOLOGY (12.3)]. If cimetidine and zolmitriptan tablets are used concomitantly, limit the maximum single dose of zolmitriptan tablets to 2.5 mg, not to exceed 5 mg in any 24-hour period [see DOSAGE AND ADMINISTRATION (2.4), CLINICAL PHARMACOLOGY (12.3)].

The following adverse reactions are described elsewhere in other sections of the prescribing information: Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina [see WARNINGS AND PRECAUTIONS (5.1)]. Arrhythmias [see WARNINGS AND PRECAUTIONS (5.2)]. Chest and or Throat, Neck and Jaw Pain/Tightness/Pressure [see WARNINGS AND PRECAUTIONS (5.3)]. Cerebrovascular Events [see WARNINGS AND PRECAUTIONS (5.4)]. Other Vasospasm Reactions [see WARNINGS AND PRECAUTIONS (5.5)]. Medication Overuse Headache [see WARNINGS AND PRECAUTIONS (5.6)]. Serotonin Syndrome [see WARNINGS AND PRECAUTIONS (5.7)]. Increase in Blood Pressure [see WARNINGS AND PRECAUTIONS (5.8)]. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. 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 reaction. The most common adverse reactions (≥5% and > placebo) in these trials were neck/throat/jaw pain, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth. Table 1 lists the adverse reactions that occurred in ≥2% of the 2,074 patients in any one of the zolmitriptan tablets 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of zolmitriptan tablets in patients with migraines (Studies 1, 2, 3, 4, and 5) [see Clinical Studies (14)]. Only adverse reactions that were at least 2% more frequent in a zolmitriptan tablets group compared to the placebo group are included. Several of the adverse reactions 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: Adverse Reaction Incidence in Five Pooled Placebo-Controlled Migraine Clinical Trials* * Only adverse reactions that were at least 2% more frequent in a zolmitriptan tablets group compared to the placebo group are included. Placebo (n=401) Zolmitriptan tablets 1 mg (n=163) Zolmitriptan tablets 2.5 mg (n=498) Zolmitriptan tablets 5 mg (n=1012) ATYPICAL SENSATIONS 6% 12% 12% 18% Paresthesia (all types) 2% 5% 7% 9% Warm/cold sensation 4% 6% 5% 7% PAIN AND PRESSURE SENSATIONS 7% 13% 14% 22% Chest- pain/tightness/pressure and/or heaviness 1% 2% 3% 4% Neck/throat/jaw - pain/tightness/pressure 3% 4% 7% 10% Heaviness other than chest or neck 1% 1% 2% 5% Other- Pressure/tightness/heaviness 0% 2% 2% 2% DIGESTIVE 8% 11% 16% 14% Dry mouth 2% 5% 3% 3% Dyspepsia 1% 3% 2% 1% Dysphagia 0% 0% 0% 2% Nausea 4% 4% 9% 6% NEUROLOGICAL 10% 11% 17% 21% Dizziness 4% 6% 8% 10% Somnolence 3% 5% 6% 8% Vertigo 0% 0% 0% 2% OTHER Asthenia 3% 5% 3% 9% Sweating 1% 0% 2% 3% There were no differences in the incidence of adverse reactions in controlled clinical trials in the following subgroups: gender, weight, age, use of prophylactic medications, or presence of aura. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Less Common Adverse Reactions with zolmitriptan tablets: In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled studies, the role of zolmitriptan tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Adverse reaction frequencies were calculated as the number of patients who used zolmitriptan tablets and reported a reaction divided by the total number of patients exposed to zolmitriptan tablets (n=4,027). Reactions …