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 evaluation 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 evaluation, 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 evaluation, 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 evaluation 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 1 hour 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 1 hour 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 Serotonin syndrome may occur with triptans, including IMITREX, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
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 can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication.
Treatment with IMITREX should be discontinued if serotonin syndrome is suspected.
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.
Concomitant Drug Use In patients taking MAO-A inhibitors, sumatriptan plasma levels attained after treatment with recommended doses are 7-fold higher following oral administration than those obtained under other conditions.
Accordingly, the coadministration of IMITREX Tablets and an MAO-A inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).
Hypersensitivity Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving sumatriptan.
Such reactions can be life threatening or fatal.
In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS).
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 × 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 evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure.
Alcohol: Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.
Patients (N = 670) have received single oral doses of 140 to 300 mg without significant adverse effects.
Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events.
Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation.
The elimination half-life of sumatriptan is approximately 2.5 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with IMITREX Tablets should continue for at least 12 hours or while symptoms or signs persist.
It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.
IMITREX Tablets contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine 1 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 C 14 H 21 N 3 O 2 S•C 4 H 6 O 4 , 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 140 mg of sumatriptan succinate equivalent to 25, 50, or 100 mg 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.
Imitrex Tablets Chemical Structure
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 40 years (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 4 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.
A second dose of IMITREX Tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache.
Acetaminophen was offered to patients in Studies 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or worsened.
Additional medications were allowed 4 to 24 hours 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 100 mg were compared to placebo in the treatment of migraine attacks.
In 1 study, doses of 25, 50, and 100 mg were also compared to each other.
In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours 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 4 hours 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 Table 1.
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.
Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours Following Treatment Placebo 2 hr 4 hr IMITREX Tablets 25 mg 2 hr 4 hr IMITREX Tablets 50 mg 2 hr 4 hr IMITREX Tablets 100 mg 2 hr 4 hr Study 1 27% 38% 52% a 67% a 61% ab 78% ab 62% ab 79% ab (N = 94) (N = 298) (N = 296) (N = 296) Study 2 26% 38% 52% a 70% a 50% a 68% a 56% a 71% a (N = 65) (N = 66) (N = 62) (N = 66) Study 3 17% 19% 52% a 65% a 54% a 72% a 57% a 78% a (N = 47) (N = 48) (N = 46) (N = 46) a P <0.05 in comparison with placebo.
b P <0.05 in comparison with 25 mg.
The estimated probability of achieving an initial headache response over the 4 hours following treatment is depicted in Figure 1.
Estimated Probability of Achieving Initial Headache Response Within 240 Minutes a a The 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 240 minutes censored to 240 minutes.
For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Study 1) and at 4 hours (Studies 1, 2, and 3) following administration of IMITREX Tablets compared to placebo.
As early as 2 hours in Studies 2 and 3 or 4 hours in Study 1, through 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.
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 a a Kaplan-Meier plot based on data obtained in the 3 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 2 hours postdose.
There is evidence that doses above 50 mg do not provide a greater effect than 50 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 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.
Estimated Probability of Achieving Initial Headache Response Within 240 Minutes* 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 Treatment*
IMITREX Tablets, 100 mg of sumatriptan (base) as the succinate.
IMITREX Tablets, 100 mg, are pink, triangular-shaped, film-coated tablets debossed with “IMITREX 100” on one side and a chevron shape (^) on the other in blister packs of 9 tablets (NDC 54868-5118-0).
Store between 36° and 86°F (2° and 30°C).
Geriatric Use The use of sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly (see WARNINGS).
MECHANISM OF ACTION
Mechanism of Action Sumatriptan is an agonist for a vascular 5‑hydroxytryptamine 1 receptor subtype (probably a member of the 5‑HT 1D family) having only a weak affinity for 5‑HT 1A , 5‑HT 5A , and 5‑HT 7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5‑HT 2 , 5‑HT 3, or 5‑HT 4 receptor subtypes or at alpha 1 ‑, alpha 2 ‑, or beta‑adrenergic; dopamine 1 ; dopamine 2 ; muscarinic; or benzodiazepine receptors.
The vascular 5‑HT 1 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‑HT 1 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.
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.
Pediatric Use Safety and effectiveness of IMITREX Tablets in pediatric patients under 18 years of age have not been established; therefore, IMITREX Tablets are not recommended for use in patients under 18 years of age.
Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single attack.
The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo in the treatment of migraine in adolescents.
Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.
Five controlled clinical trials (2 single attack studies, 3 multiple attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs.
These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents.
Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.
The frequency of all adverse events in these patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents.
Postmarketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan.
These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death.
A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration.
Since clinical data to determine the frequency of serious adverse events in pediatric patients who might receive injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in patients aged younger than 18 years is not recommended.
Pregnancy Pregnancy Category C.
In reproductive toxicity studies in rats and rabbits, oral treatment with sumatriptan was associated with embryolethality, fetal abnormalities, and pup mortality.
When administered by the intravenous route to rabbits, sumatriptan has been shown to be embryolethal.
There are no adequate and well-controlled studies in pregnant women.
Therefore, IMITREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In assessing this information, the following findings should be considered.
Embryolethality : When given orally or intravenously to pregnant rabbits daily throughout the period of organogenesis, sumatriptan caused embryolethality at doses at or close to those producing maternal toxicity.
In the oral studies this dose was 100 mg/kg/day, and in the intravenous studies this dose was 2.0 mg/kg/day.
The mechanism of the embryolethality is not known.
The highest no-effect dose for embryolethality by the oral route was 50 mg/kg/day, which is approximately 9 times the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
By the intravenous route, the highest no-effect dose was 0.75 mg/kg/day, or approximately one tenth of the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at 12.5 mg/kg/day, the maximum dose tested, did not cause embryolethality.
This dose is equivalent to the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
Additionally, in a study in rats given subcutaneous sumatriptan daily prior to and throughout pregnancy at 60 mg/kg/day, the maximum dose tested, there was no evidence of increased embryo/fetal lethality.
This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m 2 basis.
Teratogenicity : Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in an increased incidence of blood vessel abnormalities (cervicothoracic and umbilical) at doses of approximately 250 mg/kg/day or higher.
The highest no-effect dose was approximately 60 mg/kg/day, which is approximately 6 times the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
Oral treatment of pregnant rabbits with sumatriptan during the period of organogenesis resulted in an increased incidence of cervicothoracic vascular and skeletal abnormalities.
The highest no-effect dose for these effects was 15 mg/kg/day, or approximately 3 times the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
A study in which rats were dosed daily with oral sumatriptan prior to and throughout gestation demonstrated embryo/fetal toxicity (decreased body weight, decreased ossification, increased incidence of rib variations) and an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) at 500 mg/kg/day.
The highest no-effect dose was 50 mg/kg/day, or approximately 5 times the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, at a dose of 60 mg/kg/day, the maximum dose tested, there was no evidence of teratogenicity.
This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m 2 basis.
Pup Deaths: Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in a decrease in pup survival between birth and postnatal day 4 at doses of approximately 250 mg/kg/day or higher.
The highest no-effect dose for this effect was approximately 60 mg/kg/day, or 6 times the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
Oral treatment of pregnant rats with sumatriptan from gestational day 17 through postnatal day 21 demonstrated a decrease in pup survival measured at postnatal days 2, 4, and 20 at the dose of 1,000 mg/kg/day.
The highest no-effect dose for this finding was 100 mg/kg/day, approximately 10 times the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
In a similar study in rats by the subcutaneous route there was no increase in pup death at 81 mg/kg/day, the highest dose tested, which is equivalent to 8 times the maximum single recommended human oral dose of 100 mg on a mg/m 2 basis.
Nursing Mothers Sumatriptan is excreted in human breast milk following subcutaneous administration.
Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Tablets.
INFORMATION FOR PATIENTS
Information for Patients See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.
Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan or other triptans, especially during combined use with SSRIs or SNRIs.
DOSAGE AND ADMINISTRATION
In controlled clinical trials, single doses of 25, 50, or 100 mg of IMITREX Tablets were effective for the acute treatment of migraine in adults.
There is evidence that doses of 50 and 100 mg may provide a greater effect than 25 mg (see CLINICAL TRIALS).
There is also evidence that doses of 100 mg do not provide a greater effect than 50 mg.
Individuals may vary in response to doses of IMITREX Tablets.
The choice of dose should therefore be made on an individual basis, weighing the possible benefit of a higher dose with the potential for a greater risk of adverse events.
If the headache returns or the patient has a partial response to the initial dose, the dose may be repeated after 2 hours, not to exceed a total daily dose of 200 mg.
If a headache returns following an initial treatment with IMITREX Injection, additional single IMITREX Tablets (up to 100 mg/day) may be given with an interval of at least 2 hours between tablet doses.
The safety of treating an average of more than 4 headaches in a 30-day period has not been established.
Because of the potential of MAO-A inhibitors to cause unpredictable elevations in the bioavailability of oral sumatriptan, their combined use is contraindicated (see CONTRAINDICATIONS).
Hepatic disease/functional impairment may also cause unpredictable elevations in the bioavailability of orally administered sumatriptan.
Consequently, if treatment is deemed advisable in the presence of liver disease, the maximum single dose should in general not exceed 50 mg (see CLINICAL PHARMACOLOGY for the basis of this recommendation).