Imitrex Oral Warnings & Precautions

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Imitrex Oral - Warnings & Precautions [Sumatriptan]

MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of IMITREX Tablets in patients receiving MAO-A inhibitors is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).

Selective serotonin reuptake inhibitors (SSRIs) (e. g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.

Drug/ Laboratory Test Interactions:

IMITREX Tablets are not known to interfere with commonly employed clinical laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenesis:

In carcinogenicity studies, rats and mice were given sumatriptan by oral gavage (rats, 104 weeks) or drinking water (mice, 78 weeks). Average exposures achieved in mice receiving the highest dose (target dose of 160 mg/ kg/ day) were approximately 40 times the exposure attained in humans after the maximum recommended single oral dose of 100 mg. The highest dose administered to rats (160 mg/ kg/ day, reduced from 360 mg/ kg/ day during week 21) was approximately 15 times the maximum recommended single human oral dose of 100 mg on a mg/ m 2 basis. There was no evidence of an increase in tumors in either species related to sumatriptan administration.

Mutagenesis:

Sumatriptan was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian Chinese hamster V79/ HGPRT assay). In 2 cytogenetics assays (the in vitro human lymphocyte assay and the in vivo rat micronucleus assay) sumatriptan was not associated with clastogenic activity.

Impairment of Fertility:

In a study in which male and female rats were dosed daily with oral sumatriptan prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with 50 and 500 mg/ kg/ day. The highest no-effect dose for this finding was 5 mg/ kg/ day, or approximately one half of the maximum recommended single human oral dose of 100 mg on a mg/ m 2 basis. It is not clear whether the problem is associated with treatment of the males or females or both combined. In a similar study by the subcutaneous route there was no evidence of impaired fertility at 60 mg/ kg/ day, the maximum dose tested, which is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/ m 2 basis.

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.

Pregnancy Registry:

To monitor fetal outcomes of pregnant women exposed to IMITREX, GlaxoSmithKline maintains a Sumatriptan Pregnancy Registry. Physicians are encouraged to register patients by calling (800) 336-2176.

Nursing Mothers:

Sumatriptan is excreted in human breast milk. Therefore, caution should be exercised when considering the administration of IMITREX Tablets to a nursing woman.

Pediatric Use:

Safety and effectiveness of IMITREX Tablets in pediatric patients have not been established. Completed placebo-controlled clinical trials 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 includes a limited number of reports that describe pediatric patients who have experienced adverse events, some clinically serious, after use of subcutaneous sumatriptan and/ or oral sumatriptan. These reports include events similar in nature to those reported rarely in adults.

A myocardial infarct 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.

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).