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IMITREX(sumatriptan succinate)tablet, film coated
DESCRIPTION
IMITREX Tablets contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine1 receptor subtype agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure:
The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline. Each IMITREX Tablet for oral administration contains 35, 70, or 140mg of sumatriptan succinate equivalent to 25, 50, or 100mg of sumatriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate. Each 100-mg tablet also contains hypromellose, iron oxide, titanium dioxide, and triacetin.
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 also 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
The mean maximum concentration following oral dosing with 25mg is 18ng/mL (range: 7 to 47ng/mL) and 51ng/mL (range: 28 to 100ng/mL) following oral dosing with 100mg of sumatriptan. This compares with a Cmax of 5 and 16ng/mL following dosing with a 5- and 20-mg intranasal dose, respectively. The mean Cmax following a 6-mg subcutaneous injection is 71ng/mL (range: 49 to 110ng/mL). The bioavailability is approximately 15%, primarily due to presystemic metabolism and partly due to incomplete absorption. The Cmax is similar during a migraine attack and during a migraine-free period, but the Tmax is slightly later during the attack, approximately 2.5hours compared to 2.0hours. When given as a single dose, sumatriptan displays dose proportionality in its extent of absorption (area under the curve [AUC]) over the dose range of 25 to 200mg, but the Cmax after 100mg is approximately 25% less than expected (based on the 25-mg dose).
A food effect study involving administration of IMITREX Tablets 100mg to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax and AUC were increased by 15% and 12%, respectively, when administered in the fed state.
Plasma protein binding is low (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 apparent volume of distribution is 2.4L/kg.
The elimination half-life of sumatriptan is approximately 2.5hours. Radiolabeled 14C-sumatriptan administered orally is largely renally excreted (about 60%) with about 40% found in the feces. Most of the radiolabeled compound excreted in the urine is the major metabolite, indole acetic acid (IAA), which is inactive, or the IAA glucuronide. Only 3% of the dose can be recovered as unchanged sumatriptan.
In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme, and inhibitors of that enzyme may alter sumatriptan pharmacokinetics to increase systemic exposure. No significant effect was seen with an MAO-B inhibitor (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions).
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 liver plays an important role in the presystemic clearance of orally administered sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration may be markedly increased in patients with liver disease. In 1 small study of 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 (see DOSAGE AND ADMINISTRATION).
Age
The pharmacokinetics of oral sumatriptan in the elderly (mean age: 72years, 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: 30years) (see PRECAUTIONS: Geriatric Use).
Gender
In a study comparing females to males, no pharmacokinetic differences were observed between genders for AUC, Cmax, Tmax, and half-life.
Race
The systemic clearance and Cmax of sumatriptan were similar in black (N=34) and Caucasian (N=38) healthy male subjects.
Drug Interactions
Monoamine Oxidase Inhibitors
Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS).
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 monoamine oxidase inhibitors (MAOI) with subcutaneous sumatriptan. 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.
Alcohol
Alcohol consumed 30minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.
CLINICAL STUDIES
The efficacy of IMITREX Tablets in the acute treatment of migraine headaches was demonstrated in 3, randomized, double-blind, placebo-controlled studies. Patients enrolled in these 3 studies were predominately female (87%) and Caucasian (97%), with a mean age of 40years (range, 18 to 65 years). 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 4hours 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 Tablets or other medication was allowed 4 to 24hours after the initial treatment for recurrent headache. Acetaminophen was offered to patients in Studies 2 and 3 beginning at 2hours after initial treatment if the migraine pain had not improved or worsened. Additional medications were allowed 4 to 24hours after the initial treatment for recurrent headache or as rescue in all 3 studies. The frequency and time to use of these additional treatments were also determined. In all studies, doses of 25, 50, and 100mg were compared to placebo in the treatment of migraine attacks. In 1 study, doses of 25, 50, and 100mg were also compared to each other.
In all 3 trials, the percentage of patients achieving headache response 2 and 4hours after treatment was significantly greater among patients receiving IMITREX Tablets at all doses compared to those who received placebo. In 1 of the 3 studies, there was a statistically significant greater percentage of patients with headache response at 2 and 4hours in the 50- or 100-mg group when compared to the 25-mg dose groups. There were no statistically significant differences between the 50- and 100-mg dose groups in any study. The results from the 3 controlled clinical trials are summarized in Table1.
Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.
Table 1. Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours Following Treatment
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Placebo
2 hr 4 hr
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IMITREX Tablets
25 mg
2 hr 4 hr
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IMITREX Tablets
50 mg
2 hr 4 hr
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IMITREX Tablets
100 mg
2 hr 4 hr
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Study 1
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27% 38%
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52%a 67%a
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61%ab 78%ab
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62%ab 79%ab
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(N = 94)
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(N = 298)
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(N = 296)
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(N = 296)
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Study 2
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26% 38%
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52%a 70%a
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50%a 68%a
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56%a 71%a
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(N = 65)
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(N = 66)
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(N = 62)
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(N = 66)
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Study 3
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17% 19%
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52%a 65%a
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54%a 72%a
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57%a 78%a
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(N = 47)
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(N = 48)
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(N = 46)
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(N = 46)
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ap<0.05 in comparison with placebo.
bp<0.05 in comparison with 25mg.
The estimated probability of achieving an initial headache response over the 4hours following treatment is depicted in Figure 1.
aThe figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with sumatriptan. The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients not achieving response and/or taking rescue within 240minutes censored to 240minutes.
For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2hours (Study 1) and at 4hours (Studies 1, 2, and 3) following administration of IMITREX Tablets compared to placebo.
As early as 2hours in Studies 2 and 3 or 4hours in Study 1, through 24hours 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 24hours following the initial dose of study treatment is summarized in Figure2.
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 50mg do not provide a greater effect than 50mg. 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 Tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; relationship to menses; 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 Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults.
IMITREX Tablets are 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 Tablets have not been established for cluster headache, which is present in an older, predominantly male population.
CONTRAINDICATIONS
IMITREX Tablets 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 Tablets. 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 Tablets may increase blood pressure, they 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 Tablets should not be administered to patients with hemiplegic or basilar migraine.
IMITREX Tablets and any ergotamine-containing or ergot-type medication (like dihydroergotamine or methysergide) should not be used within 24hours of each other, nor should IMITREX and another 5-HT1 agonist.
IMITREX Tablets are contraindicated in patients with hypersensitivity to sumatriptan or any of their components.
IMITREX Tablets are contraindicated in patients with severe hepatic impairment.
WARNINGS
IMITREX Tablets 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 40 years 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 tablets 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 Tablets 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 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
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.
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.
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 1hour 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 conseq |
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