ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in more detail in other sections of the prescribing information:oMyocardial ischemia, myocardial infarction, and Prinzmetals angina [see Warnings and Precautions (5.1)] oArrhythmias [see Warnings and Precautions (5.2)]oChest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)]oCerebrovascular events [see Warnings and Precautions (5.4)]oOther vasospasm reactions [see Warnings and Precautions (5.5)]oMedication overuse headache [see Warnings and Precautions (5.6)]oSerotonin syndrome [see Warnings and Precautions (5.7)]oIncrease in blood pressure [see Warnings and Precautions (5.8)]oLocal irritation [see Warnings and Precautions (5.9)]oHypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.10)]oSeizures [see Warnings and Precautions (5.11)]. oMyocardial ischemia, myocardial infarction, and Prinzmetals angina [see Warnings and Precautions (5.1)] oArrhythmias [see Warnings and Precautions (5.2)]. oChest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings and Precautions (5.3)]. oCerebrovascular events [see Warnings and Precautions (5.4)]. oOther vasospasm reactions [see Warnings and Precautions (5.5)]. oMedication overuse headache [see Warnings and Precautions (5.6)]. oSerotonin syndrome [see Warnings and Precautions (5.7)]. oIncrease in blood pressure [see Warnings and Precautions (5.8)]. oLocal irritation [see Warnings and Precautions (5.9)]. oHypersensitivity reactions [see Contraindications (4), Warnings and Precautions (5.10)]. oSeizures [see Warnings and Precautions (5.11)]. Most 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 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 drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.Table 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 frequency of 1% or more in the group treated with IMITREX nasal spray 20 mg and that occurred at frequency greater than the placebo group are included in Table 1.Table 1. Adverse Reactions Reported by at Least 1% of Patients and at Greater Frequency than Placebo in Controlled Migraine Clinical TrialsAdverse ReactionPercent of Patients ReportingIMITREXNasal Spray5 mg(n 496)IMITREXNasal Spray10 mg(n 1,007)IMITREXNasal Spray20 mg(n 1,212)Placebo(n 704)Atypical sensations Burning sensation0.40.61.40.1Ear, nose, and throat Disorder/discomfort of nasal cavity/sinuses2.82.53.82.4 Throat discomfort0.81.82.40.9Gastrointestinal Nausea and/or vomiting12.211.013.511.3Neurological Bad/unusual taste13.519.324.51.7 Dizziness/vertigo1.01.71.40.9The 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 combination of these factors.CardiovascularHypotension, palpitations.NeurologicalDystonia, tremor.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Corneal OpacitiesDogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, mg/kg/day, and were present after month of treatment. Defects in the corneal epithelium were noted in 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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.MutagenesisSumatriptan 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 FertilityWhen 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 treatment-related decrease in fertility secondary to decrease in mating in animals treated with doses greater than mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both.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.Fertility studies of sumatriptan using the intranasal route have not been conducted.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.. 12.2 Pharmacodynamics. Blood PressureSignificant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without history of hypertension [see Warnings and Precautions (5.8)].Peripheral (Small) ArteriesIn healthy volunteers (N 18), trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect clinically significant increase in peripheral resistance.Heart RateTransient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptans development as treatment for migraine were not accompanied by any clinically significant changes in heart rate.. 12.3 Pharmacokinetics. AbsorptionIn trial of 20 female volunteers, the mean maximum concentration following 5- and 20-mg intranasal dose was and 16 ng/mL, respectively. The mean Cmax following 6-mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The mean Cmax is 18 ng/mL (range: 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 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, dose in each nostril, is equivalent to administration of single 10-mg dose in nostril.DistributionProtein 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.MetabolismIn vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the isoenzyme. Most of 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.EliminationThe elimination half-life of sumatriptan administered as nasal spray is approximately 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.Specific PopulationsAge: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, males and 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.Patients with Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined.Patients with 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.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)].Racial Groups: The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n 34) and Caucasian (n 38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race differences.Drug Interaction StudiesMonoamine Oxidase-A Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels [see Contraindications (4), 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 coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration 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 trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to 40% increase in elimination half-life.A small trial evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.Xylometazoline: An in vivo drug interaction trial indicated that drops of xylometazoline (0.1% w/v), decongestant, administered 15 minutes prior to 20-mg nasal dose of sumatriptan did not alter the pharmacokinetics of sumatriptan.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of IMITREX nasal spray in the acute treatment of migraine headaches was demonstrated in randomized, double-blind, placebo-controlled trials, of which used the recommended dosing regimen and used the marketed formulation. Patients enrolled in these trials were predominately female (86%) and Caucasian (95%), with mean age of 41 years (range: 18 to 65 years). Patients were instructed to treat moderate to severe headache. Headache response, defined as reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. second dose of IMITREX nasal spray or other medication was allowed to 24 hours after the initial treatment for recurrent headache. The frequency and time to use of these additional treatments were also determined. In all trials, doses of 10 and 20 mg were compared with placebo in the treatment of to migraine attacks. Patients received doses as single spray into nostril. In trials, 5-mg dose was also evaluated.In all trials utilizing the market formulation and recommended dosage regimen, the percentage of patients achieving headache response hours after treatment was significantly greater among patients receiving IMITREX nasal spray at all doses (with one exception) compared with those who received placebo. In of the trials, there was statistically significant greater percentage of patients with headache response at hours in the 20-mg group when compared with the lower-dose groups (5 and 10 mg). There were no statistically significant differences between the 5- and 10-mg dose groups in any trial. The results from the controlled clinical trials are summarized in Table 2. Note that, in general, comparisons of results obtained in trials conducted under different conditions by different investigators with different samples of patients are ordinarily unreliable for purposes of quantitative comparison.Table 2. Percentage of Patients with Headache Response (No or Mild Pain) Hours following TreatmentIMITREXNasal Spray5 mgIMITREX Nasal Spray10 mgIMITREXNasal Spray20 mgPlaceboTrial 149%a 46%a 64%a,b,c 25%(n 121)(n 112)(n 118)(n 63)Trial 2Not applicable44%a 55%a,b 25%(n 273)(n 277)(n 138)Trial 3Not applicable54%a 63%a 35%(n 106)(n 202)(n 100)Trial 4Not applicable43%62%a,b 29%(n 106)(n 215)(n 112)Trial 5d 45%a 53%a 60%a,c 36%(n 296)(n 291)(n 286)(n 198)a P<0.05 in comparison with placebo.b P<0.05 in comparison with 10 mg.c P<0.05 in comparison with mg.d Data are for attack only of multi-attack trial for comparison.The estimated probability of achieving an initial headache response over the hours following treatment is depicted in Figure 1.Figure 1. Estimated Probability of Achieving Initial Headache Response within 120 Minutesa The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with intranasal sumatriptan. The averages displayed are based on pooled data from the clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients not achieving response within 120 minutes censored to 120 minutes.For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was lower incidence of these symptoms at hours following administration of IMITREX nasal spray compared with placebo.Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of second dose of study treatment or other medication. The estimated probability of patients taking second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.Figure 2. The Estimated Probability of Patients Taking Second Dose or Other Medication for Migraine over the 24 Hours following the Initial Dose of Study Treatmenta Kaplan-Meier plot based on data obtained in the clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within hours postdose.There is evidence that doses above 20 mg do not provide greater effect than 20 mg. There was no evidence to suggest that treatment with sumatriptan was associated with an increase in the severity of recurrent headaches. The efficacy of IMITREX nasal spray was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on efficacy.. Figure 1. estimated probability of initial headache response within 120 minutes. figure 2. probability of patients needing second dose or additional medication.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. IMITREX nasal spray is contraindicated in patients with:oIschemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetals angina [see Warnings and Precautions (5.1)] oWolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2)]oHistory of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at higher risk of stroke [see Warnings and Precautions (5.4)]oPeripheral vascular disease [see Warnings and Precautions (5.5)]oIschemic bowel disease [see Warnings and Precautions (5.5)]oUncontrolled hypertension [see Warnings and Precautions (5.8)]oRecent 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)]oConcurrent administration of monoamine oxidase (MAO)-A inhibitor or recent (within weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]oHypersensitivity to IMITREX (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.10)]oSevere hepatic impairment [see Clinical Pharmacology (12.3)]. oIschemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetals angina [see Warnings and Precautions (5.1)] oWolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see Warnings and Precautions (5.2)]. oHistory of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at higher risk of stroke [see Warnings and Precautions (5.4)]. oPeripheral vascular disease [see Warnings and Precautions (5.5)]. oIschemic bowel disease [see Warnings and Precautions (5.5)]. oUncontrolled hypertension [see Warnings and Precautions (5.8)]. oRecent 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)]. oConcurrent administration of monoamine oxidase (MAO)-A inhibitor or recent (within weeks) use of an MAO-A inhibitor [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]. oHypersensitivity to IMITREX (angioedema and anaphylaxis seen) [see Warnings and Precautions (5.10)]. oSevere hepatic impairment [see Clinical Pharmacology (12.3)]. oHistory of coronary artery disease or coronary artery vasospasm (4)oWolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders (4)oHistory of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4)oPeripheral vascular disease (4)oIschemic bowel disease (4)oUncontrolled hypertension (4)oRecent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan) or of an ergotamine-containing medication. (4)oConcurrent or recent (past weeks) use of monoamine oxidase-A inhibitor. (4)oHypersensitivity to IMITREX (angioedema and anaphylaxis seen). (4)oSevere hepatic impairment (4). oHistory of coronary artery disease or coronary artery vasospasm (4). oWolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders (4). oHistory of stroke, transient ischemic attack, or hemiplegic or basilar migraine (4). oPeripheral vascular disease (4). oIschemic bowel disease (4). oUncontrolled hypertension (4). oRecent (within 24 hours) use of another 5-HT1 agonist (e.g., another triptan) or of an ergotamine-containing medication. (4). oConcurrent or recent (past weeks) use of monoamine oxidase-A inhibitor. (4). oHypersensitivity to IMITREX (angioedema and anaphylaxis seen). (4). oSevere hepatic impairment (4).

DESCRIPTION SECTION.

11 DESCRIPTION. IMITREX nasal spray contains sumatriptan, selective 5-HT1B/1D receptor agonist. Sumatriptan is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide, and it has the following structure:The empirical formula is C14H21N3O2S, representing molecular weight of 295.4. Sumatriptan is white to off-white powder that is readily soluble in water and in saline.Each IMITREX nasal spray contains or 20 mg of sumatriptan in 100-microL 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.. sumatriptan chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended adult dose of IMITREX nasal spray for the acute treatment of migraine is mg, 10 mg, or 20 mg. The 20-mg dose may provide greater effect than the 5-mg and 10-mg doses, but may have greater risk of adverse reactions [see Clinical Studies (14)].The 5-mg and 20-mg doses are given as single spray in nostril. The 10-mg dose may be achieved by the administration of single 5-mg dose in each nostril.If the migraine has not resolved by hours after taking IMITREX nasal spray, or returns after transient improvement, additional dose may be administered at least hours after the first dose. The maximum daily dose is 40 mg in 24-hour period.The safety of treating an average of more than headaches in 30-day period has not been established.. oSingle dose of mg, 10 mg, or 20 mg of nasal spray. (2)oA second dose should only be considered if some response to the first dose was observed. Separate doses by at least hours. (2)oMaximum dose in 24-hour period: 40 mg. (2). oSingle dose of mg, 10 mg, or 20 mg of nasal spray. (2). oA second dose should only be considered if some response to the first dose was observed. Separate doses by at least hours. (2). oMaximum dose in 24-hour period: 40 mg. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Unit dose nasal spray devices containing mg or 20 mg sumatriptan.. Nasal spray: mg and 20 mg (3, 16).

DRUG INTERACTIONS SECTION.

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-HT1 Agonists. Because their vasospastic effects may be additive, coadministration 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 coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)].

GERIATRIC USE SECTION.

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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. IMITREX nasal spray mg (NDC 0173-0524-00) and 20 mg (NDC 0173-0523-00) are each supplied in boxes of nasal spray devices. Each unit dose spray supplies mg and 20 mg, respectively, of sumatriptan.Store between 2C and 30C (36F and 86F). Protect from light.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. IMITREX nasal spray is indicated for the acute treatment of migraine with or without aura in adults.Limitations of Use:oUse only if clear diagnosis of migraine headache has been established. If 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.oIMITREX is not indicated for the prevention of migraine attacks.oSafety and effectiveness of IMITREX nasal spray have not been established for cluster headache.. oUse only if clear diagnosis of migraine headache has been established. If 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.. oIMITREX is not indicated for the prevention of migraine attacks.. oSafety and effectiveness of IMITREX nasal spray have not been established for cluster headache.. IMITREX is serotonin (5-HT1B/1D) receptor agonist (triptan) indicated for acute treatment of migraine with or without aura in adults. (1)Limitations of Use:oUse only if clear diagnosis of migraine headache has been established. (1)oNot indicated for the prophylactic therapy of migraine attacks. (1)oNot indicated for the treatment of cluster headache. (1). oUse only if clear diagnosis of migraine headache has been established. (1). oNot indicated for the prophylactic therapy of migraine attacks. (1). oNot indicated for the treatment of cluster headache. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Risk of Myocardial Ischemia and/or Infarction, Prinzmetals Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular EventsInform patients that IMITREX nasal spray may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)].Anaphylactic/Anaphylactoid ReactionsInform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving IMITREX nasal spray. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with history of sensitivity to multiple allergens [see Contraindications (4), Warnings and Precautions (5.10)].Concomitant Use with Other Triptans or Ergot MedicationsInform patients that use of IMITREX nasal spray within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.3)].Serotonin SyndromeCaution patients about the risk of serotonin syndrome with the use of IMITREX nasal spray or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7), Drug Interactions (7.4)]. Medication Overuse HeadacheInform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping headache diary) [see Warnings and Precautions (5.6)].PregnancyAdvise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations (8.1)].LactationAdvise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)].Ability to Perform Complex TasksTreatment with IMITREX nasal spray may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of IMITREX nasal spray.Local IrritationInform patients that they may experience local irritation of their nose and throat. The symptoms will generally resolve in less than hours.How to Use IMITREX Nasal SprayProvide patients instruction on the proper use of IMITREX nasal spray. Caution patients to avoid spraying the contents of the device in their eyes.Trademarks are owned by or licensed to the GSK group of companies.GlaxoSmithKlineResearch Triangle Park, NC 27709 (C)2017 GSK group of companies or its licensor. IMN:5PI.

LACTATION SECTION.

8.2 Lactation. Risk SummarySumatriptan is excreted in human milk following subcutaneous administration (see Data). There is no information regarding sumatriptan concentrations in milk from lactating women following administration of IMITREX nasal spray. There are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for IMITREX nasal spray and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition.Clinical ConsiderationsInfant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX nasal spray.DataFollowing subcutaneous administration of 6-mg dose of IMITREX injection in lactating volunteers, sumatriptan was present in milk.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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.MutagenesisSumatriptan 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 FertilityWhen 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 treatment-related decrease in fertility secondary to decrease in mating in animals treated with doses greater than mg/kg/day. It is not clear whether this finding was due to an effect on males or females or both.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.Fertility studies of sumatriptan using the intranasal route have not been conducted.. 13.2 Animal Toxicology and/or Pharmacology. Corneal OpacitiesDogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, mg/kg/day, and were present after month of treatment. Defects in the corneal epithelium were noted in 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established.

OVERDOSAGE SECTION.

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 total daily dose of 60 mg (20 mg 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 0173-0524-00IMITREX(SUMATRIPTAN)NASAL SPRAY0.1 mL per unitFor Intranasal Use OnlyEach unit dose nasal spray contains mg of sumatriptan.1 Spray per unit.Do not test before use.Rx only6 Nasal Spray Units5 mgMade in India(C)2019 GSK group of companies or licensor. 62000000046138Rev. 1/20 62000000046138Rev. 1/20. Imitrex Nasal mg count carton.

PEDIATRIC USE SECTION.

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 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, multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled 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. myocardial infarction has been reported in 14-year-old male following the use of oral IMITREX; clinical signs occurred within 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Blood PressureSignificant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without history of hypertension [see Warnings and Precautions (5.8)].Peripheral (Small) ArteriesIn healthy volunteers (N 18), trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect clinically significant increase in peripheral resistance.Heart RateTransient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptans development as treatment for migraine were not accompanied by any clinically significant changes in heart rate.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionIn trial of 20 female volunteers, the mean maximum concentration following 5- and 20-mg intranasal dose was and 16 ng/mL, respectively. The mean Cmax following 6-mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The mean Cmax is 18 ng/mL (range: 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 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, dose in each nostril, is equivalent to administration of single 10-mg dose in nostril.DistributionProtein 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.MetabolismIn vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the isoenzyme. Most of 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.EliminationThe elimination half-life of sumatriptan administered as nasal spray is approximately 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.Specific PopulationsAge: The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, males and 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.Patients with Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined.Patients with 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.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)].Racial Groups: The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n 34) and Caucasian (n 38) healthy male subjects. Intranasal sumatriptan has not been evaluated for race differences.Drug Interaction StudiesMonoamine Oxidase-A Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels [see Contraindications (4), 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 coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration 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 trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to 40% increase in elimination half-life.A small trial evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.Xylometazoline: An in vivo drug interaction trial indicated that drops of xylometazoline (0.1% w/v), decongestant, administered 15 minutes prior to 20-mg nasal dose of sumatriptan did not alter the pharmacokinetics of sumatriptan.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryData from prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.DataHuman Data: The Sumatriptan/Naratriptan/Treximet (sumatriptan and naproxen sodium) Pregnancy Registry, 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 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 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, infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and infants had pyloric stenosis. No other birth defect was reported for more than infants in this group.In 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]). 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 migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with 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 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 decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationIMITREX (IM-i-trex)(sumatriptan)nasal sprayWhat is the most important information should know about IMITREXIMITREX can cause serious side effects, including:Heart attack and other heart problems. Heart problems may lead to death.Stop taking IMITREX and get emergency medical help right away if you have any of the following symptoms of heart attack:odiscomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes backosevere tightness, pain, pressure, or heaviness in your chest, throat, neck, or jawopain or discomfort in your arms, back, neck, jaw, or stomachoshortness of breath with or without chest discomfort obreaking out in cold sweatonausea or vomitingofeeling lightheadedIMITREX is not for people with risk factors for heart disease unless heart exam is done and shows no problem. You have higher risk for heart disease if you:ohave high blood pressureohave high cholesterol levelsosmokeoare overweightohave diabetesohave family history of heart diseaseWhat is IMITREXIMITREX is prescription medicine used to treat acute migraine headaches with or without aura in adults.IMITREX is not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines.IMITREX is not used to prevent or decrease the number of migraine headaches you have.It is not known if IMITREX is safe and effective to treat cluster headaches.It is not known if IMITREX is safe and effective in children under 18 years of age.Do not use IMITREX if you have:oheart problems or history of heart problemsonarrowing of blood vessels to your legs, arms, stomach, or kidneys (peripheral vascular disease)ouncontrolled high blood pressureosevere liver problemsohemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.ohad stroke, transient ischemic attacks (TIAs), or problems with your blood circulationotaken any of the following medicines in the last 24 hours:oalmotriptan (AXERT)ofrovatriptan (FROVA)orizatriptan (MAXALT, MAXALT-MLT)oergotamines (CAFERGOT, ERGOMAR, MIGERGOT)oeletriptan (RELPAX)onaratriptan (AMERGE)osumatriptan and naproxen (TREXIMET)odihydroergotamine (D.H.E. 45, MIGRANAL) Ask your healthcare provider if you are not sure if your medicine is listed above.1.an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of this leaflet for complete list of ingredients in IMITREX.Before you use IMITREX, tell your healthcare provider about all of your medical conditions, including if you:ohave high blood pressure.ohave high cholesterol.ohave diabetes.osmoke.oare overweight.ohave heart problems or family history of heart problems or stroke.ohave kidney problems.ohave liver problems.ohave had epilepsy or seizures.oare not using effective birth control.oare pregnant or plan to become pregnant. It is not known if IMITREX can harm your unborn baby.oare breastfeeding or plan to breastfeed. IMITREX passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you use IMITREX.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.IMITREX and certain other medicines can affect each other, causing serious side effects.Especially tell your healthcare provider if you take antidepressant medicines called:oselective serotonin reuptake inhibitors (SSRIs)oserotonin norepinephrine reuptake inhibitors (SNRIs)otricyclic antidepressants (TCAs)omonoamine oxidase inhibitors (MAOIs)Ask your healthcare provider or pharmacist for list of these medicines if you are not sure.Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine.How should use IMITREXoCertain people should use their first dose of IMITREX in their healthcare providers office or in another medical setting. Ask your healthcare provider if you should use your first dose in medical setting. oUse IMITREX exactly as your healthcare provider tells you to use it.oYour healthcare provider may change your dose. Do not change your dose without first talking with your healthcare provider.oIf you do not get any relief after your first nasal spray, do not use second nasal spray without first talking with your healthcare provider.oIf your headache comes back after the first nasal spray or you only get some relief from your headache, you can use second nasal spray hours after the first nasal spray.oDo not use more than 40 mg of IMITREX nasal spray in 24-hour period.oIt is not known how using IMITREX nasal spray for long time affects the nose and throat.oIf you use too much IMITREX, call your healthcare provider or go to the nearest hospital emergency room right away.oYou should write down when you have headaches and when you use IMITREX so you can talk with your healthcare provider about how IMITREX is working for you.What should avoid while using IMITREXIMITREX can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive car, use machinery, or do anything where you need to be alert.What are the possible side effects of IMITREXIMITREX may cause serious side effects. See What is the most important information should know about IMITREXThese serious side effects include:ochanges in color or sensation in your fingers and toes (Raynauds syndrome)ostomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include:osudden or severe stomach painostomach pain after mealsoweight lossofeveronausea or vomitingoconstipation or diarrheaobloody diarrheaoproblems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include:ocramping and pain in your legs or hipsofeeling of heaviness or tightness in your leg musclesoburning or aching pain in your feet or toes while restingonumbness, tingling, or weakness in your legsocold feeling or color changes in or both legs or feetomedication overuse headaches. Some people who use too many IMITREX nasal sprays may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX.oserotonin syndrome. Serotonin syndrome is rare but serious problem that can happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome:omental changes such as seeing things that are not there (hallucinations), agitation, or comaofast heartbeatochanges in blood pressureohigh body temperatureotight musclesotrouble walkingolocal irritation. Some people who use IMITREX nasal spray may have irritation of their throat and nose. Symptoms of local irritation of the throat and nose include: burning, numbness, tingling sensation, nasal discharge, pain or soreness.ohives (itchy bumps); swelling of your tongue, mouth, or throat.oseizures. Seizures have happened in people taking IMITREX who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take IMITREX.The most common side effects of IMITREX nasal spray include:ounusual or bad taste in your mouth onauseaovomitingodizzinessowarm, hot, burning feelingTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of IMITREX.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store IMITREX Nasal SprayoStore IMITREX between 36F to 86F (2C to 30C).oStore your medicine away from light.Keep IMITREX and all medicines out of the reach of children.General information about the safe and effective use of IMITREX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use IMITREX for condition for which it was not prescribed. Do not give IMITREX to other people, even if they have the same symptoms you have. It may harm them.This Patient Information leaflet summarizes the most important information about IMITREX. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about IMITREX that is written for healthcare professionals.For more information, go to www.gsk.com or call 1-888-825-5249.What are the ingredients in IMITREX Nasal SprayActive ingredient: sumatriptanInactive ingredients: monobasic potassium phosphate NF, anhydrous dibasic sodium phosphate USP, sulfuric acid NF, sodium hydroxide NF, and purified water USP.IMITREX and AMERGE are trademarks owned by or licensed to the GSK group of companies. The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2017 GSK group of companies or its licensor.IMN:5PPIThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised December 2017Instructions for UseIMITREX (IM-i-trex)(sumatriptan)nasal sprayFor use in the nose only. Do not spray in your eyes.Step 1. Remove the IMITREX nasal spray unit from the plastic pack (see Figure A).Do not remove the unit until you are ready to use. The unit contains only spray. Do not test before use. Figure AStep 2. While sitting down, gently blow your nose to clear your nasal passages (see Figure B).Figure BStep 3. Keeping your head in an upright position, gently close nostril with your index finger and breathe out gently through your mouth (see Figure C).Figure CFigure DStep 4. With your other hand, hold the container with your thumb supporting the container at the bottom, and your index and middle fingers on either side of the nozzle (see Figure D). Insert the nozzle into your open nostril about 1/2 inch. Do not press the blue plunger yet. Figure EStep 5. Keep your head upright and close your mouth. While gently taking breath in through your nose, press the blue plunger firmly to release the dose of IMITREX nasal spray (see Figure E).Figure FStep 6. Keep your head level and remove the nozzle from your nostril. While holding your head level, gently breathe in through your nose and out through your mouth for 10 to 20 seconds (see Figure F).Do not breathe in deeply.IMITREX and AMERGE are trademarks owned by or licensed to the GSK group of companies. The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2017 GSK group of companies or its licensor.December 2017IMN:5PIL. odiscomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes back. osevere tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw. opain or discomfort in your arms, back, neck, jaw, or stomach. oshortness of breath with or without chest discomfort obreaking out in cold sweat. onausea or vomiting. ofeeling lightheaded. ohave high blood pressure. ohave high cholesterol levels. osmoke. oare overweight. ohave diabetes. ohave family history of heart disease. oheart problems or history of heart problems. onarrowing of blood vessels to your legs, arms, stomach, or kidneys (peripheral vascular disease). ouncontrolled high blood pressure. osevere liver problems. ohemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.. ohad stroke, transient ischemic attacks (TIAs), or problems with your blood circulation. otaken any of the following medicines in the last 24 hours:. oalmotriptan (AXERT). ofrovatriptan (FROVA). orizatriptan (MAXALT, MAXALT-MLT). oergotamines (CAFERGOT, ERGOMAR, MIGERGOT). oeletriptan (RELPAX). onaratriptan (AMERGE). osumatriptan and naproxen (TREXIMET). odihydroergotamine (D.H.E. 45, MIGRANAL). Ask your healthcare provider if you are not sure if your medicine is listed above.. 1.an allergy to sumatriptan or any of the ingredients in IMITREX. See the end of this leaflet for complete list of ingredients in IMITREX.. ohave high blood pressure.. ohave high cholesterol.. ohave diabetes.. osmoke.. oare overweight.. ohave heart problems or family history of heart problems or stroke.. ohave kidney problems.. ohave liver problems.. ohave had epilepsy or seizures.. oare not using effective birth control.. oare pregnant or plan to become pregnant. It is not known if IMITREX can harm your unborn baby.. oare breastfeeding or plan to breastfeed. IMITREX passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you use IMITREX.. oselective serotonin reuptake inhibitors (SSRIs). oserotonin norepinephrine reuptake inhibitors (SNRIs). otricyclic antidepressants (TCAs). omonoamine oxidase inhibitors (MAOIs). oCertain people should use their first dose of IMITREX in their healthcare providers office or in another medical setting. Ask your healthcare provider if you should use your first dose in medical setting. oUse IMITREX exactly as your healthcare provider tells you to use it.. oYour healthcare provider may change your dose. Do not change your dose without first talking with your healthcare provider.. oIf you do not get any relief after your first nasal spray, do not use second nasal spray without first talking with your healthcare provider.. oIf your headache comes back after the first nasal spray or you only get some relief from your headache, you can use second nasal spray hours after the first nasal spray.. oDo not use more than 40 mg of IMITREX nasal spray in 24-hour period.. oIt is not known how using IMITREX nasal spray for long time affects the nose and throat.. oIf you use too much IMITREX, call your healthcare provider or go to the nearest hospital emergency room right away.. oYou should write down when you have headaches and when you use IMITREX so you can talk with your healthcare provider about how IMITREX is working for you.. ochanges in color or sensation in your fingers and toes (Raynauds syndrome). ostomach and intestinal problems (gastrointestinal and colonic ischemic events). Symptoms of gastrointestinal and colonic ischemic events include:. osudden or severe stomach pain. ostomach pain after meals. oweight loss. ofever. onausea or vomiting. oconstipation or diarrhea. obloody diarrhea. oproblems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include:ocramping and pain in your legs or hipsofeeling of heaviness or tightness in your leg musclesoburning or aching pain in your feet or toes while restingonumbness, tingling, or weakness in your legsocold feeling or color changes in or both legs or feet. ocramping and pain in your legs or hips. ofeeling of heaviness or tightness in your leg muscles. oburning or aching pain in your feet or toes while resting. onumbness, tingling, or weakness in your legs. ocold feeling or color changes in or both legs or feet. omedication overuse headaches. Some people who use too many IMITREX nasal sprays may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with IMITREX.. oserotonin syndrome. Serotonin syndrome is rare but serious problem that can happen in people using IMITREX, especially if IMITREX is used with anti-depressant medicines called SSRIs or SNRIs.. Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome:omental changes such as seeing things that are not there (hallucinations), agitation, or comaofast heartbeatochanges in blood pressureohigh body temperatureotight musclesotrouble walking. omental changes such as seeing things that are not there (hallucinations), agitation, or coma. ofast heartbeat. ochanges in blood pressure. ohigh body temperature. otight muscles. otrouble walking. olocal irritation. Some people who use IMITREX nasal spray may have irritation of their throat and nose. Symptoms of local irritation of the throat and nose include: burning, numbness, tingling sensation, nasal discharge, pain or soreness.. ohives (itchy bumps); swelling of your tongue, mouth, or throat.. oseizures. Seizures have happened in people taking IMITREX who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take IMITREX.. ounusual or bad taste in your mouth onausea. ovomiting. odizziness. owarm, hot, burning feeling. oStore IMITREX between 36F to 86F (2C to 30C).. oStore your medicine away from light.. figure A. figure B. figure C. figure D. Figure E. Figure F.

SPL UNCLASSIFIED SECTION.

5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetals 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 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 (Prinzmetals angina), even in patients without history of CAD.Perform 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 negative cardiovascular evaluation, consider administering the first dose of IMITREX nasal spray in 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy Risk SummaryData from prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal Risk: Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.DataHuman Data: The Sumatriptan/Naratriptan/Treximet (sumatriptan and naproxen sodium) Pregnancy Registry, 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 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 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, infants had ventricular septal defects, including one infant who was exposed to both sumatriptan and naratriptan, and infants had pyloric stenosis. No other birth defect was reported for more than infants in this group.In 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]). 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 migraine disease comparison group who redeemed prescriptions for sumatriptan before pregnancy only, compared with 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 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 decrease in pup survival. The highest no-effect dose for this finding was 100 mg/kg/day.. 8.2 Lactation. Risk SummarySumatriptan is excreted in human milk following subcutaneous administration (see Data). There is no information regarding sumatriptan concentrations in milk from lactating women following administration of IMITREX nasal spray. There are no data on the effects of sumatriptan on the breastfed infant or the effects of sumatriptan on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for IMITREX nasal spray and any potential adverse effects on the breastfed infant from sumatriptan or from the underlying maternal condition.Clinical ConsiderationsInfant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX nasal spray.DataFollowing subcutaneous administration of 6-mg dose of IMITREX injection in lactating volunteers, sumatriptan was present in milk.. 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 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, multiple-attack trials) evaluating oral IMITREX (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled 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. myocardial infarction has been reported in 14-year-old male following the use of oral IMITREX; clinical signs occurred within 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oMyocardial ischemia/infarction and Prinzmetals angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. (5.1)oArrhythmias: Discontinue IMITREX if occurs. (5.2)oChest/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)oCerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs. (5.4)oGastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue IMITREX if occurs. (5.5)oMedication overuse headache: Detoxification may be necessary. (5.6)oSerotonin syndrome: Discontinue IMITREX if occurs. (5.7)oSeizures: Use with caution in patients with epilepsy or lowered seizure threshold. (5.11). oMyocardial ischemia/infarction and Prinzmetals angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors. (5.1). oArrhythmias: Discontinue IMITREX if occurs. (5.2). oChest/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). oCerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue IMITREX if occurs. (5.4). oGastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue IMITREX if occurs. (5.5). oMedication overuse headache: Detoxification may be necessary. (5.6). oSerotonin syndrome: Discontinue IMITREX if occurs. (5.7). oSeizures: Use with caution in patients with epilepsy or lowered seizure threshold. (5.11). 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetals 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 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 (Prinzmetals angina), even in patients without history of CAD.Perform 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 negative cardiovascular evaluation, consider administering the first dose of IMITREX nasal spray in 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 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 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 Prinzmetals 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 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 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 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 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 Raynauds syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out 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 migraine attack, causal relationship between these events and the use of 5-HT1 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 marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes transient worsening of headache) may be necessary.. 5.7 Serotonin Syndrome. Serotonin syndrome may occur with IMITREX nasal spray, 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 new or greater dose of 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 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 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 history of sensitivity to multiple allergens. IMITREX nasal spray is contraindicated in patients with history of hypersensitivity reaction to IMITREX.. 5.11 Seizures Seizures have been reported following administration of IMITREX. Some have occurred in patients with either 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 history of epilepsy or conditions associated with lowered seizure threshold.