IMITREX- sumatriptan spray
`GlaxoSmithKline LLC
`----------
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use IMITREX safely and effectively. See full
`prescribing information for IMITREX.
`IMITREX (sumatriptan) Nasal Spray
`Initial U.S. Approval: 1992
`
`INDICATIONS AND USAGE
`) receptor agonist (triptan) indicated for acute treatment of migraine with or without
`
`IMITREX is a serotonin (5-HT
`aura in adults. (1)
`Limitations of Use:
`
`1B/1D
`
`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)
`
`•••
`
`•• •
`
`Nasal spray: 5 mg and 20 mg (3, 16)
`
`DOSAGE FORMS AND STRENGTHS
`
`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)
`
`••••••• •••
`
`• •• •••••
`
`ADVERSE REACTIONS
`Most common adverse reactions (≥1% and >placebo) were burning sensation, disorder/discomfort of nasal cavity/sinuses,
`Exhibit 1046
`throat discomfort, nausea and/or vomiting, bad/unusual taste, and dizziness/vertigo. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-
`IPR2017-00807
`ARGENTUM
`
`000001
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`FDA-1088 or www.fda.gov/medwatch.
`
`USE IN SPECIFIC POPULATIONS
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
`
`Revised: 11/2013
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 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 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
`1
`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 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
`*
`Sections or subsections omitted from the full prescribing information are not listed.
`
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`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 30day 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-hydroxytryptamine (5-HT ) agonist
`1
`1
`
`• • • ••••
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`

`[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)]
`
`1
`
`1
`
`• • •
`
`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-
`HT agonists. Discontinue IMITREX Nasal Spray if these disturbances occur. IMITREX Nasal Spray
`1
`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-
`HT agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the
`1
`cerebrovascular events were primary, the 5-HT agonist having been administered in the incorrect
`1
`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
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`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-HT agonist, rule out a
`1
`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 5HT agonists. Since visual disorders may be part of a migraine attack, a causal relationship
`1
`between these events and the use of 5-HT agonists have not been clearly established.
`1
`
`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-HT agonists, including patients
`1
`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
`
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`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.
`
`Table 1. Adverse Reactions Reported by at Least 1% of Patients and at a Greater Frequency
`Than Placebo in Controlled Migraine Clinical Trials
`Percent of Patients Reporting
`IMITREX
`IMITREX
`IMITREX
`Nasal Spray
`Nasal Spray
`Nasal Spray
`5 mg
`10 mg
`20 mg
`(n = 496)
`(n = 1,007)
`(n = 1,212)
`
`Placebo
`(n = 704)
`
`Adverse Reaction
`Atypical sensations
`
`
`
`Burning sensation
`
`Ear, nose, and throat
`
`
`
`
`
`Disorder/discomfort of nasal cavity/sinuses
`
`Throat discomfort
`
`Gastrointestinal
`
`0.4
`
`2.8
`
`0.8
`
`0.6
`
`2.5
`
`1.8
`
`1.4
`
`3.8
`
`2.4
`
`0.1
`
`2.4
`
`0.9
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`
`Nausea and/or vomiting
`
`Neurological
`
`
`
`
`
`Bad/unusual taste
`
`Dizziness/vertigo
`
`12.2
`
`11.0
`
`13.5
`
`11.3
`
`13.5
`
`1.0
`
`19.3
`
`1.7
`
`24.5
`
`1.4
`
`1.7
`
`0.9
`
`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
`1
`Because their vasospastic effects may be additive, co-administration of IMITREX Nasal Spray and
`other 5-HT agonists (e.g., triptans) within 24 hours of each other is contraindicated.
`1
`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
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`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 14yearold 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.
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`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 halflife 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
` receptor agonist. Sumatriptan is
`IMITREX Nasal Spray contains sumatriptan, a selective 5-HT
`1B/1D
`chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide, and it has
`the following structure:
`
`The empirical formula is C H N O S, representing a molecular weight of 295.4. Sumatriptan is a
`14 21 3 2
`white to off-white powder that is readily soluble in water and in saline.
`Each IMITREX Nasal Spray contains 5 or 20 mg of sumatriptan in a 100-μL unit dose aqueous buffered
`solution containing monobasic potassium phosphate NF, anhydrous dibasic sodium phosphate USP,
`sulfuric acid NF, sodium hydroxide NF, and purified water USP. The pH of the solution is
`approximately 5.5. The osmolality of the solution is 372 or 742 mOsmol for the 5- and 20-mg IMITREX
`Nasal Spray, respectively.
`
`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
` receptors. Sumatriptan presumably
`Sumatriptan binds with high affinity to human cloned 5-HT
`1B/1D
`exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the
`5HT
` receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which
`1B/1D
`result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release..
`
`12.2 Pharmacodynamics
`Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been
`reported in patients with and without a history of hypertension [see Warnings and Precautions (5.8)].
`Peripheral (Small) Arteries: In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan
`on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in
`peripheral resistance.
`Heart Rate: Transient increases in blood pressure observed in some patients in clinical trials carried out
`during sumatriptan’s development as a treatment for migraine were not accompanied by any clinically
`significant changes in heart rate.
`
`12.3 Pharmacokinetics
`Absorption and Bioavailability: In a trial of 20 female volunteers, the mean maximum concentration
`following a 5- and 20-mg intranasal dose was 5 and 16 ng/mL, respectively. The mean C
` following a
`max
`6mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The mean C
` is 18 ng/mL (range:
`max
`7 to 47 ng/mL) following oral dosing with 25 mg and 51 ng/mL (range: 28 to 100 ng/mL) following oral
`dosing with 100 mg of sumatriptan. In a trial of 24 male volunteers, the bioavailability relative to
`subcutaneous injection was low, approximately 17%, primarily due to presystemic metabolism and partly
`due to incomplete absorption.
`Clinical and pharmacokinetic data indicate that administration of two 5-mg doses, 1 dose in each nostril,
`is equivalent to administration of a single 10-mg dose in 1 nostril.
`Distribution: Protein binding, determined by equilibrium dialysis over the concentration range of 10 to
`1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of
`other drugs has not been evaluated. The apparent volume of distribution is 2.7 L/kg.
`Metabolism:In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO,
`predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted in the urine is the
`major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive.
`Elimination: The elimination half-life of sumatriptan administered as a nasal spray is approximately
`2 hours, similar to the half-life seen after subcutaneous injection. Only 3% of the dose is excreted in the
`urine as unchanged sumatriptan; 42% of the dose is excreted as the major metabolite, the indole acetic
`acid analogue of sumatriptan. The total plasma clearance is approximately 1,200 mL/min.
`Special Populations: Age: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2
`males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were
`similar to that in healthy male subjects (mean age: 30 years). Intranasal sumatriptan has not been evaluated
`for age differences.
`Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been
`examined.
`Hepatic Impairment: The effect of mild to moderate hepatic disease on the pharmacokinetics of the
`intranasal formulation of sumatriptan has not been evaluated. Sumatriptan bioavailability following
`intranasal administration is 17%, similar to that after oral administration (15%). Following oral
`administration, an approximately 70% increase in Cmax and AUC was observed in one small trial of
`patients with moderate liver impairment (n = 8) matched for sex, age and weight with healthy subjects (n
`= 8). Similar changes can be expected following intranasal administration.
`
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`The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied.
`The use of IMITREX Nasal Spray in patients with severe hepatic impairment is contraindicated [see
`Contraindications (4)].
` of subcutaneous sumatriptan were similar in black (n = 34) and
`Race: The systemic clearance and C
`max
`Caucasian (n = 38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race
`differences.
`Drug Interaction Studies: Monoamine Oxidase-A Inhibitors:Treatment with MAO-A inhibitors generally
`leads to an increase of sumatriptan plasma levels [see Contraindications (4) and Drug Interactions (7.2)].
`MAO inhibitors interaction studies have not been performed with intranasal sumatriptan.
`Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after co-
`administration of an MAO-A inhibitor with oral sumatriptan is greater than after co-administration of the
`MAO inhibitors with subcutaneous sumatriptan. The effects of an MAO inhibitor on systemic exposure
`after intranasal sumatriptan would be expected to be greater than the effect after subcutaneous
`sumatriptan but smaller than the effect after oral sumatriptan because only swallowed drug would be
`subject to first-pass effects.
`In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of
`subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma
`concentration-time curve (AUC), corresponding to a 40% increase in elimination halflife.
`A small trial evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a
`25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.
`Xylometazoline: An in vivo drug interaction trial indicated that 3 drops of xylometazoline (0.1% w/v), a
`decongestant, administered 15 minutes prior to a 20-mg nasal dose of sumatriptan did not alter the
`pharmacokinetics of sumatriptan.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis: In carcinogenicity studies in mouse and rat in which sumatriptan was administered
`orally for 78 and 104 weeks, respectively, there was no evidence in either species of an increase in
`tumors related to sumatriptan administration.
`Carcinogenicity studies of sumatriptan using the nasal route have not been conducted.
`Mutagenesis: Sumatriptan was negative in in vitro(bacterial reverse mutation [Ames], gene cell mutation
`in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat
`micronucleus) assays.
`Impairment of Fertility: When sumatriptan was administered by subcutaneous injection to male and
`female rats prior to and throughout the mating period, there was no evidence of impaired fertility at
`doses up to 60 mg/kg/day. When sumatriptan (5, 50, or 500 mg/kg/day) was administered orally to male
`and female rats prior to and throughout the mating period, there was a treatment-related decrease in
`fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day. It is
`not