IMITREX

GlaxoSmithKline LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use IMITREX safely and effectively. See full prescribing information for IMITREX.IMITREX (sumatriptan) Nasal SprayInitial U.S. Approval: 1992INDICATIONS AND USAGEIMITREX is a serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for acute treatment of migraine with or without aura in adults. (1) Limitations of Use: •Use only if a clear diagnosis of migraine headache has been established. (1) •Not indicated for the prophylactic therapy of migraine attacks. (1) •Not indicated for the treatment of cluster headache. (1) DOSAGE AND ADMINISTRATION •Single dose of 5 mg, 10 mg, or 20 mg of nasal spray. (2) •A second dose should only be considered if some response to the first dose was observed. Separate doses by at least 2 hours. (2) •Maximum dose in a 24-hour period: 40 mg. (2) DOSAGE FORMS AND STRENGTHSNasal spray: 5 mg and 20 mg (3, 16)CONTRAINDICATIONS •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-HT1 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) 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. (5.11) Side EffectsMost common adverse reactions (≥1% and >placebo) were burning sensation, disorder/discomfort of nasal cavity/sinuses, throat discomfort, nausea and/or vomiting, bad/unusual taste, and dizziness/vertigo. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKlineat 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONSPregnancy: Based on animal data, may cause fetal harm. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 IMITREX INDICATIONS AND USAGE
• 2 IMITREX DOSAGE AND ADMINISTRATION
• 3 DOSAGE FORMS AND STRENGTHS
• 4 IMITREX CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina
  • 5.2 Arrhythmias
  • 5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
  • 5.4 Cerebrovascular Events
  • 5.5 Other Vasospasm Reactions
  • 5.6 Medication Overuse Headache
  • 5.7 Serotonin Syndrome
  • 5.8 Increase in Blood Pressure
  • 5.9 Local Irritation
  • 5.10 Anaphylactic/Anaphylactoid Reactions
  • 5.11 Seizures
• 6 IMITREX ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Ergot-Containing Drugs
  • 7.2 Monoamine Oxidase-A Inhibitors
  • 7.3 Other 5-HT Agonists
  • 7.4 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 IMITREX DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• PRINCIPAL DISPLAY PANELIMITREX (SUMATRIPTAN)NASAL SPRAY5 mg0.1 mL per unitFor Intranasal Use OnlyEach unit dose nasal spray contains 5 mg of sumatriptan.1 Spray per unit.Do not test before use.Rx only6 Nasal Spray Units©2012, GlaxoSmithK

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

IMITREX^® Nasal Spray is indicated for the acute treatment of migraine with or without aura in adults.

Limitations of Use:

• •Use only if a clear diagnosis of migraine headache has been established. If a patient has no response to the first migraine attack treated with IMITREX, reconsider the diagnosis of migraine before IMITREX is administered to treat any subsequent attacks.
• •IMITREX is not indicated for the prevention of migraine attacks.
• •Safety and effectiveness of IMITREX Nasal Spray have not been established for cluster headache.

2 DOSAGE AND ADMINISTRATION

The recommended adult dose of IMITREX Nasal Spray for the acute treatment of migraine is 5 mg, 10 mg, or 20 mg. The 20-mg dose may provide a greater effect than the 5-mg and 10-mg doses, but may have a greater risk of adverse reactions [see Clinical Studies (14)].

The 5-mg and 20-mg doses are given as a single spray in 1 nostril. The 10-mg dose may be achieved by the administration of a single 5-mg dose in each nostril.

If the migraine has not resolved by 2 hours after taking IMITREX Nasal Spray, or returns after a transient improvement, 1 additional dose may be administered at least 2 hours after the first dose. The maximum daily dose is 40 mg in a 24-hour period.

The safety of treating an average of more than 4 headaches in a 30‑day period has not been established.

3 DOSAGE FORMS AND STRENGTHS

Unit dose nasal spray devices containing 5 mg or 20 mg sumatriptan.

4 CONTRAINDICATIONS

IMITREX Nasal Spray 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, 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 [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-hydroxytryptamine₁ (5-HT₁) 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) and Clinical Pharmacology (12.3)]
• •Hypersensitivity to IMITREX (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.10)]
• •Severe hepatic impairment [see Clinical Pharmacology (12.3)]

5 WARNINGS AND PRECAUTIONS

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina

The use of IMITREX Nasal Spray 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 Nasal Spray. Some of these reactions occurred in patients without known CAD. IMITREX Nasal Spray 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 Nasal Spray. If there is evidence of CAD or coronary artery vasospasm, IMITREX Nasal Spray is contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of IMITREX Nasal Spray in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of IMITREX Nasal Spray. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of IMITREX Nasal Spray.

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 IMITREX Nasal Spray if these disturbances occur. IMITREX Nasal Spray 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 may occur after treatment with IMITREX Nasal Spray and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of IMITREX Nasal Spray 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-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. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue IMITREX Nasal Spray if a cerebrovascular event occurs.

Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, exclude other potentially serious neurological conditions. IMITREX Nasal Spray is contraindicated in patients with a history of stroke or TIA.

5.5 Other Vasospasm Reactions

IMITREX Nasal Spray 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-HT₁ agonist, rule out a vasospastic reaction before using additional IMITREX Nasal Spray.

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 have 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 Nasal Spray, particularly during co-administration 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 Nasal Spray 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-HT₁ agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with IMITREX. IMITREX Nasal Spray is contraindicated in patients with uncontrolled hypertension.

5.9 Local Irritation

Local irritative symptoms such as burning, numbness, paresthesia, discharge, and pain or soreness were reported in approximately 5% of patients in controlled clinical trials and were noted to be severe in about 1%. The symptoms were transient and generally resolved in less than 2 hours. Limited examinations of the nose and throat did not reveal any clinically noticeable injury in these patients. The consequences of extended and repeated use of Imitrex Nasal Spray on the nasal and/or respiratory mucosa have not been systematically evaluated in patients.

5.10 Anaphylactic/Anaphylactoid Reactions

Anaphylactic/anaphylactoid reactions 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 Nasal Spray is contraindicated in patients with a history of hypersensitivity reaction to IMITREX.

5.11 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 Nasal Spray should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail 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, 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)]
• •Local irritation [see Warnings and Precautions (5.9)]
• •Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.10)]
• •Seizures [see Warnings and Precautions (5.11)]

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.

Table 1 lists adverse reactions that occurred in worldwide placebo-controlled clinical trials in 3,419 patients with migraine. Only treatment-emergent adverse reactions that occurred at a frequency of 1% or more in the group treated with IMITREX Nasal Spray 20 mg and that occurred at a frequency greater than the placebo group are included in Table 1.

The incidence of adverse reactions 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 reactions.

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. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to IMITREX or a combination of these factors.

Cardiovascular: Hypotension, palpitations.

Neurological: Dystonia, tremor.

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 Nasal Spray within 24 hours of each other is contraindicated.

7.2 Monoamine Oxidase-A Inhibitors

MAO-A inhibitors increase systemic exposure by up to 7-fold. Therefore, the use of IMITREX Nasal Spray in patients receiving MAO-A inhibitors is contraindicated [see Clinical Pharmacology (12.3)].

7.3 Other 5-HT Agonists

Because their vasospastic effects may be additive, co-administration of IMITREX Nasal Spray and other 5-HT₁ 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 co-administration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled trials in pregnant women. 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. Developmental toxicity studies of sumatriptan by the intranasal route have not been conducted. IMITREX Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

8.3 Nursing Mothers

Sumatriptan is excreted in human milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Nasal Spray.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. IMITREX Nasal Spray is not recommended for use in patients younger than 18 years of age.

Two controlled clinical trials evaluated IMITREX Nasal Spray (5 to 20 mg) in 1,248 adolescent migraineurs aged 12 to 17 years who treated a single attack. The trials did not establish the efficacy of IMITREX Nasal Spray compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single-attack trials, 3 multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These trials did not establish the efficacy of oral IMITREX compared with placebo in the treatment of migraine in adolescents. Adverse reactions observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse reactions in these patients appeared to be both dose- and age-dependent, with younger patients reporting reactions more commonly than older adolescents.

Postmarketing experience documents that serious adverse reactions have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal IMITREX. These reports include reactions similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14‑year‑old male following the use of oral IMITREX; clinical signs occurred within 1 day of drug administration. Clinical data to determine the frequency of serious adverse reactions in pediatric patients who might receive subcutaneous, oral, or intranasal IMITREX are not presently available.

8.5 Geriatric Use

Clinical trials of IMITREX Nasal Spray did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving IMITREX Nasal Spray [see Warnings and Precautions (5.1)].

10 OVERDOSAGE

In clinical trials, the highest single doses of IMITREX Nasal Spray administered without significant reactions were 40 mg to 12 volunteers and 40 mg to 85 subjects with migraine, which is twice the highest single recommended dose. In addition, 12 volunteers were administered a total daily dose of 60 mg (20 mg 3 times daily) for 3.5 days without significant adverse reactions.

Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation.

The elimination half‑life of sumatriptan is approximately 2 hours [see Clinical Pharmacology (12.3)], and therefore monitoring of patients after overdose with IMITREX Nasal Spray should continue for at least 10 hours or while symptoms or signs persist.

It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

11 DESCRIPTION

IMITREX Nasal Spray contains sumatriptan, a selective 5-HT_1B/1D receptor agonist. Sumatriptan is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide, and it has the following structure: