IMITREX

1 INDICATIONS AND USAGE IMITREX injection is indicated in adults for (1) the acute treatment of migraine, with or without aura, and (2) the acute treatment of cluster headache. Limitations of Use • Use only if a clear diagnosis of migraine or cluster headache has been established. If a patient has no response to the first migraine or cluster headache attack treated with IMITREX injection, reconsider the diagnosis before IMITREX injection is administered to treat any subsequent attacks. • IMITREX injection is not indicated for the prevention of migraine or cluster headache attacks. IMITREX injection is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for: • Acute treatment of migraine with or without aura in adults. ( 1 ) • Acute treatment of cluster headache in adults. ( 1 ) Limitations of Use • Use only if a clear diagnosis of migraine or cluster headache has been established. ( 1 ) • Not indicated for the prophylactic therapy of migraine or cluster headache attacks. ( 1 )

2 DOSAGE AND ADMINISTRATION • For subcutaneous use only. ( 2.1 ) • Acute treatment of migraine: single dose of 4 mg or 6 mg. ( 2.1 ) • Acute treatment of cluster headache: single dose of 6 mg. ( 2.1 ) • Maximum dose in a 24-hour period: 12 mg, separate doses by at least 1 hour. ( 2.1 ) • The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) which may cause allergic reactions in latex-sensitive patients. ( 2.2 ) 2.1 Dosing Information The maximum single recommended adult dose of IMITREX injection for the acute treatment of migraine or cluster headache is 6 mg injected subcutaneously. For the treatment of migraine, if side effects are dose limiting, the lower dose of 4 mg may be used [see Clinical Studies ( 14.1 )] . For the treatment of cluster headache, the efficacy of lower doses has not been established. The maximum cumulative dose that may be given in 24 hours is 12 mg, two 6-mg injections separated by at least 1 hour. A second 6-mg dose should only be considered if some response to a first injection was observed. 2.2 Administration Using the IMITREX STATdose Pen An autoinjector device (IMITREX STATdose Pen) is available for use with 4-mg and 6-mg prefilled syringe cartridges. With this device, the needle penetrates approximately 1/4 inch (5 to 6 mm). The injection is intended to be given subcutaneously, and intramuscular or intravascular delivery must be avoided. Instruct patients on the proper use of IMITREX STATdose Pen and direct them to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) [see Warnings and Precautions (5.9)] .

4 CONTRAINDICATIONS IMITREX injection is contraindicated in patients with: • Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) 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 or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke [s ee Warnings and Precautions ( 5.4 )] . • Peripheral vascular disease [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 ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-hydroxytryptamine 1 (5-HT 1 ) agonist [see Drug Interactions ( 7.1 , 7.3 )] . • Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor [see Drug Interactions ( 7.2 ), Clinical Pharmacology ( 12.3 )]. • Hypersensitivity to IMITREX (angioedema and anaphylaxis seen) [see Warnings and Precautions ( 5.9 )] . • Severe hepatic impairment [see Clinical Pharmacology ( 12.3 )] . • History of coronary artery disease or coronary artery vasospasm. ( 4 ) • Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders. ( 4 ) • History of stroke, transient ischemic attack, or hemiplegic or basilar migraine. ( 4 ) • Peripheral vascular disease. ( 4 ) • Ischemic bowel disease. ( 4 ) • Uncontrolled hypertension. ( 4 ) • Recent (within 24 hours) use of another 5-HT 1 agonist (e.g., another triptan) or of an ergotamine-containing medication. ( 4 ) • Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor. ( 4 ) • Hypersensitivity to IMITREX (angioedema and anaphylaxis seen). ( 4 ) • Severe hepatic impairment. ( 4 )

5 WARNINGS AND PRECAUTIONS • Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. ( 5.1 ) • Arrhythmias: Discontinue IMITREX if occurs. ( 5.2 ) • Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for coronary artery disease in patients at high risk. ( 5.3 ) • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs. ( 5.4 ) • Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue IMITREX if occurs. ( 5.5 ) • Medication overuse headache: Detoxification may be necessary. ( 5.6 ) • Serotonin syndrome: Discontinue IMITREX if occurs. ( 5.7 ) • Seizures: Use with caution in patients with epilepsy or a lowered seizure threshold. ( 5.10 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina The use of IMITREX injection is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of IMITREX injection. Some of these reactions occurred in patients without known CAD. IMITREX injection may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX injection. If there is evidence of CAD or coronary artery vasospasm, IMITREX injection is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of IMITREX injection in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of IMITREX injection. For such patients, consider periodic cardiovascular evaluation in intermittent long‑term users of IMITREX injection. 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-HT 1 agonists. Discontinue IMITREX injection if these disturbances occur. IMITREX injection is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with IMITREX injection and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of IMITREX injection is contraindicated in patients with CAD and those with Prinzmetal’s variant angina. 5.4 Cerebrovascular 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. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX injection if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. IMITREX injection is contraindicated in patients with a history of stroke or TIA. 5.5 Other Vasospasm Reactions IMITREX injection 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 non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional injections of IMITREX. 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 has not been clearly established. 5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. 5.7 Serotonin Syndrome Serotonin syndrome may occur with IMITREX injection, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug Interactions ( 7.4 )] . 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 occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue IMITREX injection if serotonin syndrome is suspected. 5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with IMITREX. IMITREX injection is contraindicated in patients with uncontrolled hypertension. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have occurred in patients receiving IMITREX. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. IMITREX injection is contraindicated in patients with a history of hypersensitivity reaction to IMITREX. The needle shield of the prefilled syringe contains dry natural rubber (a latex derivative) that has the potential to cause allergic reactions in latex-sensitive individuals. 5.10 Seizures Seizures have been reported following administration of IMITREX. Some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent. IMITREX injection should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

7 DRUG INTERACTIONS 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 IMITREX injection within 24 hours of each other is contraindicated. 7.2 Monoamine Oxidase-A Inhibitors MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of IMITREX injection in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology ( 12.3 )] . 7.3 Other 5-HT 1 Agonists Because their vasospastic effects may be additive, coadministration of IMITREX injection and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions ( 5.7 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Myocardial ischemia, myocardial infarction, and Prinzmetal’s angina [see Warnings and Precautions ( 5.1 )] • Arrhythmias [see Warnings and Precautions ( 5.2 )] • Chest, throat, neck, and/or 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 )] • Hypersensitivity reactions [see Contraindications ( 4 ), Warnings and Precautions ( 5.9 )] • Seizures [see Warnings and Precautions ( 5.10 )] Most common adverse reactions (≥5% and >placebo) were injection site reactions, tingling, dizziness/vertigo, warm/hot sensation, burning sensation, feeling of heaviness, pressure sensation, flushing, feeling of tightness, and numbness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Migraine Headache Table 1 lists adverse reactions that occurred in 2 U.S. placebo‑controlled clinical trials in patients with migraines (Studies 2 and 3) following either a single 6‑mg dose of IMITREX injection or placebo. Only reactions that occurred at a frequency of 2% or more in groups treated with IMITREX injection 6 mg and that occurred at a frequency greater than the placebo group are included in Table 1 . Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Patients with Migraine (Studies 2 and 3) Adverse Reaction IMITREX Injection 6 mg Subcutaneous (n = 547) % Placebo (n = 370) % Atypical sensations 42 9 Tingling 14 3 Warm/hot sensation 11 4 Burning sensation 7 <1 Feeling of heaviness 7 1 Pressure sensation 7 2 Feeling of tightness 5 <1 Numbness 5 2 Feeling strange 2 <1 Tight feeling in head 2 <1 Cardiovascular Flushing 7 2 Chest discomfort 5 1 Tightness in chest 3 <1 Pressure in chest 2 <1 Ear, nose, and throat Throat discomfort 3 <1 Discomfort: nasal cavity/sinuses 2 <1 Injection site reaction a 59 24 Miscellaneous Jaw discomfort 2 0 Musculoskeletal Weakness 5 <1 Neck pain/stiffness 5 <1 Myalgia 2 <1 Neurological Dizziness/vertigo 12 4 Drowsiness/sedation 3 2 Headache 2 <1 Skin Sweating 2 1 a Includes injection site pain, stinging/burning, swelling, erythema, bruising, bleeding. The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Cluster Headache In the controlled clinical trials assessing the efficacy of IMITREX injection as a treatment for cluster headache (Studies 4 and 5), no new significant adverse reactions were detected that had not already been identified in trials of IMITREX in patients with migraine. Overall, the frequency of adverse reactions reported in the trials of cluster headache was generally lower than in the migraine trials. Exceptions include reports of paresthesia (5% IMITREX injection, 0% placebo), nausea and vomiting (4% IMITREX injection, 0% placebo), and bronchospasm (1% IMITREX injection, 0% placebo). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of IMITREX tablets, IMITREX nasal spray, and IMITREX injection. 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. Cardiovascular Hypotension, palpitations. Neurological Dystonia, tremor. Reproductive System and Breast Disorders Breast pain [see Use in Specific Populations ( 8.2 )] .

8.1 Pregnancy Risk Summary Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population (see Data) . In developmental toxicity studies in rats and rabbits, oral administration of sumatriptan to pregnant animals was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to pregnant rabbits, sumatriptan was embryolethal (see Data) . In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy. Data Human Data: The Sumatriptan/Naratriptan/TREXIMET (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study, collected data for sumatriptan from January 1996 to September 2012. The Registry documented outcomes of 626 infants and fetuses exposed to sumatriptan during pregnancy (528 with earliest exposure during the first trimester, 78 during the second trimester, 16 during the third trimester, and 4 unknown). The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to sumatriptan was 4.2% (20/478 [95% CI: 2.6% to 6.5%]) and during any trimester of exposure was 4.2% (24/576 [95% CI: 2.7% to 6.2%]). The sample size in this study had 80% power to detect at least a 1.73- to 1.91-fold increase in the rate of major malformations. The number of exposed pregnancy outcomes accumulated during the registry was insufficient to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Of the 20 infants with reported birth defects after exposure to sumatriptan in the first trimester, 4 infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and 3 infants had pyloric stenosis. No other birth defect was reported for more than 2 infants in this group. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not. Of the 2,257 births with first-trimester exposure to sumatriptan, 107 infants were born with malformations (relative risk 0.99 [95% CI: 0.91 to 1.21]). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with a population control group. Of the 415 women who redeemed prescriptions for sumatriptan during the first trimester, 15 had infants with major congenital malformations (OR 1.16 [95% CI: 0.69 to 1.94]) while for the 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy, 20 had infants with major congenital malformations (OR 1.83 [95% CI: 1.17 to 2.88]), each compared with the population comparison group. Additional smaller observational studies evaluating use of sumatriptan during pregnancy have not suggested an increased risk of teratogenicity. Animal Data: Oral administration of sumatriptan to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal blood vessel (cervicothoracic and umbilical) abnormalities. The highest no-effect dose for embryofetal developmental toxicity in rats was 60 mg/kg/day. Oral administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in increased incidences of embryolethality and fetal cervicothoracic vascular and skeletal abnormalities. Intravenous administration of sumatriptan to pregnant rabbits during the period of organogenesis resulted in an increased incidence of embryolethality. The highest oral and intravenous no-effect doses for developmental toxicity in rabbits were 15 and 0.75 mg/kg/day, respectively. Oral administration of sumatriptan to rats prior to and throughout gestation resulted in embryofetal toxicity (decreased body weight, decreased ossification, increased incidence of skeletal abnormalities). The highest no-effect dose was 50 mg/kg/day. In offspring of pregnant rats treated orally with sumatriptan during organogenesis, there was a decrease in pup survival. The highest no-effect dose for this effect was 60 mg/kg/day. Oral treatment of pregnant rats with sumatriptan during the latter part of gestation and throughout lactation resulted in a decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day.