DESCRIPTION

IMITREX (sumatriptan) Nasal Spray contains sumatriptan, a selective 5-hydroxytryptamine1 receptor subtype agonist. Sumatriptan is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide, and it has the following structure:

The empirical formula is C14H21N3O2S, representing a molecular weight of 295.4. Sumatriptan is a white to off-white powder that is readily soluble in water and in saline. Each IMITREX Nasal Spray contains 5 or 20mg 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 742mOsmol for the 5- and 20-mg IMITREX Nasal Spray, respectively.

CLINICAL PHARMACOLOGY

Mechanism of Action

Sumatriptan is an agonist for a vascular 5-hydroxytryptamine1 receptor subtype (probably a member of the 5-HT1D family) having only a weak affinity for 5-HT1A, 5-HT5A, and 5-HT7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT2, 5-HT3, or 5-HT4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors.

The vascular 5-HT1 receptor subtype that sumatriptan activates is present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels. Such an action may contribute to the antimigrainous effect of sumatriptan in humans.

In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

Pharmacokinetics

In a study 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 Cmax following a 6-mg subcutaneous injection is 71 ng/mL (range: 49 to 110 ng/mL). The mean Cmax is 18 ng/mL (range: 7 to 47 ng/mL) following oral dosing with 25mg and 51 ng/mL (range: 28 to 100 ng/mL) following oral dosing with 100 mg of sumatriptan. In a study 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.

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 eva luated, but would be expected to be minor, given the low rate of protein binding. The mean volume of distribution after subcutaneous dosing is 2.7L/kg and the total plasma clearance is approximately 1,200 mL/min.

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.

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.

Special Populations

Renal Impairment:The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be expected as sumatriptan is largely metabolized to an inactive substance.

Hepatic Impairment: The effect of hepatic disease on the pharmacokinetics of subcutaneously and orally administered sumatriptan has been eva luated, but the intranasal dosage form has not been studied in hepatic impairment. There were no statistically significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in hepatically impaired patients compared to healthy controls. However, the liver plays an important role in the presystemic clearance of orally administered sumatriptan. In 1 small study involving oral sumatriptan in hepatically impaired patients (N=8) matched for sex, age, and weight with healthy subjects, the hepatically impaired patients had an approximately 70% increase in AUC and Cmax and a Tmax 40minutes earlier compared to the healthy subjects. The bioavailability of nasally absorbed sumatriptan following intranasal administration, which would not undergo first-pass metabolism, should not be altered in hepatically impaired patients. The bioavailability of the swallowed portion of the intranasal sumatriptan dose has not been determined, but would be increased in these patients. The swallowed intranasal dose is small, however, compared to the usual oral dose, so that its impact should be minimal.

Age: The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in patients 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 eva luated for age differences (see PRECAUTIONS: Geriatric Use).

Race: The systemic clearance and Cmax of sumatriptan were similar in black (n=34) and Caucasian (n = 38) healthy male subjects. Intranasal sumatriptan has not been eva luated for race differences.

Drug Interactions

Monoamine Oxidase Inhibitors: Treatment with monoamine oxidase inhibitors (MAOIs) generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS).

MAOI 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 MAOI with subcutaneous sumatriptan. The effects of an MAOI 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 study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan. Under the conditions of this experiment, the result was a 2-fold increase in the area under the sumatriptan plasma concentration x time curve (AUC), corresponding to a 40% increase in elimination half-life. This interaction was not evident with an MAO-B inhibitor.

A small study eva luating 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 study 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.

CLINICAL TRIALS

The efficacy of IMITREX Nasal Spray in the acute treatment of migraine headaches was demonstrated in 8, randomized, double-blind, placebo-controlled studies, of which 5 used the recommended dosing regimen and used the marketed formulation. Patients enrolled in these 5 studies were predominately female (86%) and Caucasian (95%), with a mean age of 41 (range of 18 to 65). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24hours postdose. A second dose of IMITREX Nasal Spray or other medication was allowed 2 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 studies, doses of 10 and 20mg were compared to placebo in the treatment of 1 to 3 migraine attacks. Patients received doses as a single spray into 1 nostril. In 2 studies, a 5-mg dose was also eva luated.

In all 5 trials utilizing the market formulation and recommended dosage regimen, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving IMITREX Nasal Spray at all doses (with one exception) compared to those who received placebo. In 4 of the 5 studies, there was a statistically significant greater percentage of patients with headache response at 2hours in the 20-mg group when compared to the lower dose groups (5 and 10mg). There were no statistically significant differences between the 5- and 10-mg dose groups in any study. The results from the 5 controlled clinical trials are summarized in Table1. Note that, in general, comparisons of results obtained in studies conducted under different conditions by different investigators with different samples of patients are ordinarily unreliable for purposes of quantitative comparison.

ap<0.05 in comparison with placebo.

bp<0.05 in comparison with 10mg.

cp<0.05 in comparison with 5mg.

dData are for attack 1 only of multiattack study for comparison.

The estimated probability of achieving an initial headache response over the 2hours following treatment is depicted in Figure1.

Figure 1. Estimated Probability of Achieving Initial Headache Response Within 120Minutesa

aThe 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 5 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 a lower incidence of these symptoms at 2hours following administration of IMITREX Nasal Spray compared to 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 a second dose of study treatment or other medication. The estimated probability of patients taking a 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 a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatmenta

aKaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within 2hours postdose.

There is evidence that doses above 20 mg do not provide a 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 patient; 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.

INDICATIONS AND USAGE

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

IMITREX Nasal Spray is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and effectiveness of IMITREX Nasal Spray have not been established for cluster headache, which is present in an older, predominantly male population.

CONTRAINDICATIONS

IMITREX Nasal Spray should not be given to patients with history, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition, patients with other significant underlying cardiovascular diseases should not receive IMITREX Nasal Spray. Ischemic cardiac syndromes include, but are not limited to, angina pectoris of any type (e.g., stable angina of effort, vasospastic forms of angina such as the Prinzmetal variant), all forms of myocardial infarction, and silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as transient ischemic attacks. Peripheral vascular disease includes, but is not limited to, ischemic bowel disease (see WARNINGS).

Because IMITREX Nasal Spray may increase blood pressure, it should not be given to patients with uncontrolled hypertension.

Concurrent administration of MAO-A inhibitors or use within 2weeks of discontinuation of MAO-A inhibitor therapy is contraindicated (see CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions).

IMITREX Nasal Spray and any ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide) should not be used within 24 hours of each other, nor should IMITREX Nasal Spray and another 5-HT1 agonist.

IMITREX Nasal Spray should not be administered to patients with hemiplegic or basilar migraine.

IMITREX Nasal Spray is contraindicated in patients with hypersensitivity to sumatriptan or any of its components.

IMITREX Nasal Spray is contraindicated in patients with severe hepatic impairment.

WARNINGS

IMITREX Nasal Spray should only be used where a clear diagnosis of migraine headache has been established.

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Sumatriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, male over 40years of age) unless a cardiovascular eva luation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular eva luation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see CONTRAINDICATIONS).

For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular eva luation, it is strongly recommended that administration of the first dose of sumatriptan nasal spray take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following IMITREX Nasal Spray in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular eva luation as they continue to use sumatriptan.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan.

Drug-Associated Cardiac Events and Fatalities

Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of IMITREX® (sumatriptan succinate) Injection or IMITREX® (sumatriptan succinate) Tablets. Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low.

The fact that sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan use support the conclusion that some of these cases were caused by the drug. In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.

Premarketing Experience With Sumatriptan: Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event.

Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving oral sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome.

Among the more than 1,900 patients with migraine who participated in premarketing controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan that may have reflected coronary artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia, but without accompanying clinical symptoms or signs. Of these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment.

Postmarketing Experience With Sumatriptan: Serious cardiovascular events, some resulting in death, have been reported in association with the use of IMITREX Injection or IMITREX Tablets. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the longer the latency between the administration of IMITREX and the onset of the clinical event, the less likely the association is to be causative. Accordingly, interest has focused on events beginning within 1hour of the administration of IMITREX.

Cardiac events that have been observed to have onset within 1 hour of sumatriptan administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.

Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm. However, among domestic reports of serious cardiac events within 1hour of sumatriptan administration, almost all of the patients had risk factors predictive of CAD and the presence of significant underlying CAD was established in most cases (see CONTRAINDICATIONS).

Drug-Associated Cerebrovascular Events and Fatalities

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack).

Other Vasospasm-Related Events

Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan. Visual disorders may also be part of a migraine attack.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including treatment with IMITREX, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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).

Increase in Blood Pressure

Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. Sumatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS). Sumatriptan should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients.

Local Irritation

Of the 3,378 patients using the nasal spray (5-, 10-, or 20-mg doses) on 1 or 2 occasions in controlled clinical studies, approximately 5% noted irritation in the nose and throat. Irritative symptoms such as burning, numbness, paresthesia, discharge, and pain or soreness were noted to be severe in about 1% of patients treated. The symptoms were transient and in approximately 60% of the cases, the symptoms resolved in less than 2hours. 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 eva luated in patients. No increase in the incidence of local irritation was observed in patients using IMITREX Nasal Spray repeatedly for up to 1year.

In inhalation studies in rats dosed daily for up to 1month at exposures as low as one half the maximum daily human exposure (based on dose per surface area of nasal cavity), epithelial hyperplasia (with and without keratinization) and squamous metaplasia were observed in the larynx at all doses tested. These changes were partially reversible after a 2-week drug-free period. When dogs were dosed daily with various formulations by intranasal instillation for up to 13weeks at exposures of 2 to 4 times the maximum daily human exposure (based on dose per surface area of nasal cavity), respiratory and nasal mucosa exhibited evidence of