Zomig

1 INDICATIONS AND USAGE ZOMIG is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use Only use ZOMIG if a clear diagnosis of migraine has been established. If a patient has no response to ZOMIG treatment for the first migraine attack, reconsider the diagnosis of migraine before ZOMIG is administered to treat any subsequent attacks.

ZOMIG is not indicated for the prevention of migraine attacks. Safety and effectiveness of ZOMIG have not been established for cluster headache. ZOMIG is a serotonin (5-HT) 1B/1D receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults Limitations of Use : Use only after a clear diagnosis of migraine has been established Not indicated for the prophylactic therapy of migraine Not indicated for the treatment of cluster headache

Recommended starting dose: 1.25 mg or 2.5 mg Maximum single dose: 5 mg May repeat dose after 2 hours if needed; not to exceed 10 mg in any 24-hour period Moderate or Severe Hepatic Impairment: 1.25 mg recommended (2.3, 8.6)

2.1Dosing Information The

recommended starting dose of ZOMIG 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 ZOMIG 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 ZOMIG, 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 ZOMIG in the treatment of an average of more than three migraines in a 30-day period has not been established.

2.3Dosing in Patients with Hepatic Impairment The

recommended dose of ZOMIG in patients with moderate to severe hepatic impairment is 1.25 mg (one-half of one 2.5 mg ZOMIG tablet) 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.

2.4Dosing in Patients

taking Cimetidine If ZOMIG is co-administered with cimetidine, limit the maximum single dose of ZOMIG to 2.5 mg, not to exceed 5 mg in any 24-hour period .

Myocardial Ischemia/Infarction, and Prinzmetal’s Angina : Perform cardiac evaluation in patients with multiple cardiovascular risk factors Arrhythmias : Discontinue ZOMIG if occurs Chest/Throat/Neck/Jaw Pain, Tightness, and Pressure : Generally not associated with myocardial ischemia; evaluate for CAD in patients at high risk Cerebral Hemorrhage, Subarachnoid Hemorrhage, and Stroke : Discontinue ZOMIG if occurs Gastrointestinal Ischemic Reactions and Peripheral Vasospastic Reactions : Discontinue ZOMIG if occurs Medication Overuse Headache : Detoxification may be necessary Serotonin Syndrome : Discontinue ZOMIG if occurs (5.7, 7.4)

5.1Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s

Angina ZOMIG is 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 ZOMIG. Some of these reactions occurred in patients without known CAD. 5-HT 1 agonists including ZOMIG 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 ZOMIG. Do not administer ZOMIG if there is evidence of CAD or coronary artery vasospasm . For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first ZOMIG dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following ZOMIG administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of ZOMIG.

5.2Arrhythmias 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-HT 1 agonists. Discontinue ZOMIG if these disturbances occur. ZOMIG is contraindicated in patients with Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders .

5.3Chest, Throat, Neck and Jaw Pain/Tightness/Pressure

As with other 5-HT 1 agonists, sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with ZOMIG and is usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. 5-HT 1 agonists including ZOMIG is contraindicated in patients with CAD or Prinzmetal’s variant angina .

5.4Cerebrovascular Events Cerebral

hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 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.

ZOMIG is contraindicated in patients with a history of stroke or transient ischemic attack .

5.5Other Vasospasm Reactions

5-HT 1 agonists, including ZOMIG, 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-HT 1 agonist, rule out a vasospastic reaction before receiving additional ZOMIG doses . Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established.

5.7Serotonin Syndrome Serotonin

syndrome may occur with triptans, including ZOMIG, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors . 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). The onset of symptoms usually rapidly occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue ZOMIG if serotonin syndrome is suspected .

5.8Increase in Blood Pressure Significant

elevations in systemic blood pressure have been reported in patients treated with 5-HT 1 agonists including patients without a history of hypertension; very rarely, these increases in blood pressure have been associated with serious adverse reactions. In healthy subjects treated with 5 mg of ZOMIG, an increase of 1 and 5 mm Hg in the systolic and diastolic blood pressure, respectively, was seen. In a study of patients with moderate to severe liver impairment, 7 of 27 patients experienced 20 to 80 mm Hg elevations in systolic and/or diastolic blood pressure after a dose of 10 mg of ZOMIG. As with all triptans, blood pressure should be monitored in ZOMIG-treated patients.

ZOMIG is contraindicated in patients with uncontrolled hypertension .

4 CONTRAINDICATIONS ZOMIG is 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 . Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders . History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke . Peripheral vascular disease (PVD) . Ischemic bowel disease . Uncontrolled hypertension . Recent use (i.e., within 24 hours) of another 5-HT 1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide) . Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent use of a MAO-A inhibitor (that is within 2 weeks) . Known hypersensitivity to ZOMIG (angioedema and anaphylaxis seen) . History of coronary artery disease (CAD) or coronary vasospasm Symptomatic Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders History of stroke, transient ischemic attack, or hemiplegic or basilar migraine Peripheral vascular disease Ischemic bowel disease Uncontrolled hypertension Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan), or an ergotamine-containing medication Monoamine oxidase (MAO)-A inhibitor used in past 2 weeks Known hypersensitivity to ZOMIG or zolmitriptan orally disintegrating tablets

8.1Pregnancy Risk Summary There

are no adequate data on the developmental risk associated with the use of ZOMIG in pregnant women. In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to pregnant animals resulted in embryolethality and fetal abnormalities (malformations and variations) at clinically relevant exposures . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rates of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Animal Data When zolmitriptan was administered to pregnant rats during the period of organogenesis at oral doses of 100, 400, and 1200 mg/kg/day (plasma exposures (AUCs) ≈280, 1100, and 5000 times the human AUC at the maximum recommended human dose (MRHD) of 10 mg/day), there was a dose-related increase in embryolethality. A no-effect dose for embryolethality was not established.

When zolmitriptan was administered to pregnant rabbits during the period of organogenesis at oral doses of 3, 10, and 30 mg/kg/day (plasma AUCs ≈1, 11, and 42 times the human AUC at the MRHD), there were increases in embryolethality and in fetal malformations and variations. The no-effect dose for adverse effects on embryofetal development was associated with a plasma AUC similar to that in humans at the MRHD. When female rats were given zolmitriptan during gestation, parturition, and lactation at oral doses of 25, 100, and 400 mg/kg/day (plasma AUCs ≈70, 280, and 1100 times that in human at the MRHD), an increased incidence of hydronephrosis was found in the offspring. The no-effect dose was associated with a plasma AUC ≈280 times that in humans at the MRHD.

The following adverse reactions are described elsewhere in other sections of the prescribing information: Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina . Arrhythmias . Chest and or Throat, Neck and Jaw Pain/Tightness/Pressure . Cerebrovascular Events . Other Vasospasm Reactions . Medication Overuse Headache . Serotonin Syndrome . Increase in Blood Pressure . Most common adverse reactions (≥5% and > placebo) were neck/throat/jaw pain/tightness/pressure, dizziness, paresthesia, asthenia, somnolence, warm/cold sensation, nausea, heaviness sensation, and dry mouth To report SUSPECTED ADVERSE REACTIONS, contact Avema Pharma Solutions at 1-877-753-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 ZOMIG 1 mg, 2.5 mg, or 5 mg dose groups in the controlled clinical trials of ZOMIG in patients with migraines (Studies 1, 2, 3, 4, and 5) . Only adverse reactions that were at least 2% more frequent in a ZOMIG 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 * Placebo (n=401) ZOMIG 1 mg (n=163) ZOMIG 2.5 mg (n=498) ZOMIG 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% * Only adverse reactions that were at least 2% more frequent in a ZOMIG group compared to the placebo group are included.

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 ZOMIG 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 ZOMIG 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 ZOMIG tablets and reported a reaction divided by the total number of patients exposed to ZOMIG tablets (n=4,027).

Reactions were further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: infrequent adverse reactions (those occurring in 1/100 to 1/1,000 patients) and rare adverse reactions (those occurring in less than 1/1,000 patients). General: Infrequent were allergic reactions. Cardiovascular: Infrequent were arrhythmias, hypertension, and syncope.

Rare was tachycardia. Neurological: Infrequent were agitation, anxiety, depression, emotional lability and insomnia; Rare were amnesia, hallucinations, and cerebral ischemia. Skin: Infrequent were pruritus, rash and urticaria. Urogenital : Infrequent were polyuria, urinary frequency and urinary urgency.

6.2Postmarketing Experience The

following adverse reactions were identified during post approval use of ZOMIG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions enumerated include all except those already listed in the Clinical Trials Experience section above or the Warnings and Precautions section. Hypersensitivity Reactions: As with other 5‑HT 1B/1D agonists, there have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving ZOMIG. ZOMIG is contraindicated in patients with a history of hypersensitivity reaction to ZOMIG.