Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1361
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IMITREX (Tablet)
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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 possiblebenefit
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).
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IMITREX Tablets
contain sumatriptan (as the succinate), a selective 5-hydroxytryptaminereceptor 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 CHNOS���CHO, 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.
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Mechanism of Action: Sumatriptan is
an agonist for a vascular 5-hydroxytryptaminereceptor
subtype (probably a member of the 5-HTfamily) having
only a weak affinity for 5-HT, 5-HT, and
5-HTreceptors and no significant affinity (as measured
using standard radioligand binding assays) or pharmacological activity
at 5-HT, 5-HTor 5-HTreceptor
subtypes or at alpha-, alpha-, or beta-adrenergic;
dopamine; dopamine; muscarinic; or benzodiazepine
receptors. The vascular 5-HTreceptor 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-HTreceptors
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.<br/>Pharmacokinetics: The mean maximum
concentration following oral dosing with 25 mg is 18 ng/mL
(range, 7 to 47 ng/mL) and 51 ng/mL (range, 28 to 100 ng/mL)
following oral dosing with 100 mg of sumatriptan. This compares
with a Cof 5 and 16 ng/mL following dosing with
a 5- and 20-mg intranasal dose, respectively. The mean Cfollowing a 6-mg subcutaneous injection is 71 ng/mL (range,
49 to 110 ng/mL). The bioavailability is approximately 15%, primarily
due to presystemic metabolism and partly due to incomplete absorption.
The Cis similar during a migraine attack and during
a migraine-free period, but the Tis slightly later
during the attack, approximately 2.5 hours compared to 2.0 hours.
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 200 mg, but the Cafter 100 mg
is approximately 25% less than expected (based on the 25-mg dose). A food effect study involving administration of IMITREX
Tablets 100 mg to healthy volunteers under fasting conditions
and with a high-fat meal indicated that the Cand 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 evaluated, but would be expected to be
minor, given the low rate of protein binding. The apparent volume
of distribution is 2.4 L/kg. The elimination
half-life of sumatriptan is approximately 2.5 hours. RadiolabeledC-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).<br/>Special Populations:<br/>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.<br/>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 Cand a T40 minutes
earlier compared to the healthy subjects (see DOSAGE AND ADMINISTRATION).<br/>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) (see PRECAUTIONS:
Geriatric Use).<br/>Gender: In a
study comparing females to males, no pharmacokinetic differences were
observed between genders for AUC, C, T, and half-life.<br/>Race: The systemic
clearance and Cof sumatriptan were similar in black
(N = 34) and Caucasian (N = 38) healthy male subjects.<br/>Drug Interactions:<br/>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 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.<br/>Alcohol: Alcohol
consumed 30 minutes prior to sumatriptan ingestion had no effect
on the pharmacokinetics of sumatriptan.
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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 and 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 2 weeks 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
24 hours of each other, nor should IMITREX and another 5-HTagonist. 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.
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IMITREX Tablets,
25, 50, and 100 mg of sumatriptan (base) as the succinate. IMITREX Tablets, 25 mg are white, triangular-shaped,
film-coated tablets debossed with���I���on one side and���25���on the other in blister packs of 9 tablets (NDC
0173-0735-00). IMITREX Tablets, 50 mg
are white, triangular-shaped, film-coated tablets debossed with���IMITREX
50���on one side and a chevron shape (^) on the other in blister
packs of 9 tablets (NDC 0173-0736-01). 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 0173-0737-01). Store between 36��and 86��F (2��and
30��C).
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General: Chest discomfort
and jaw or neck tightness have been reported following use of IMITREX
Tablets and have also been reported infrequently following administration
of IMITREX (sumatriptan) Nasal Spray. Chest, jaw,
or neck tightness is relatively common after administration of IMITREX
Injection. Only rarely have these symptoms been associated with ischemic
ECG changes. However, because sumatriptan may cause coronary artery
vasospasm, patients who experience signs or symptoms suggestive of
angina following sumatriptan should be evaluated for the presence
of CAD or a predisposition to Prinzmetal variant angina before receiving
additional doses of sumatriptan, and should be monitored electrocardiographically
if dosing is resumed and similar symptoms recur. Similarly, patients
who experience other symptoms or signs suggestive of decreased arterial
flow, such as ischemic bowel syndrome or Raynaud syndrome following
sumatriptan should be evaluated for atherosclerosis or predisposition
to vasospasm (see WARNINGS). IMITREX should
also be administered with caution to patients with diseases that may
alter the absorption, metabolism, or excretion of drugs, such as impaired
hepatic or renal function. There have been
rare reports of seizure following administration of sumatriptan. Sumatriptan
should be used with caution in patients with a history of epilepsy
or conditions associated with a lowered seizure threshold. Care should be taken to exclude other potentially
serious neurologic conditions before treating headache in patients
not previously diagnosed with migraine headache or who experience
a headache that is atypical for them. There have been rare reports
where patients received sumatriptan for severe headaches that were
subsequently shown to have been secondary to an evolving neurologic
lesion (see WARNINGS). For a given attack,
if a patient does not respond to the first dose of sumatriptan, the
diagnosis of migraine should be reconsidered before administration
of a second dose. Overuse of acute migraine
treatments has been associated with the exacerbation of headache (medication
overuse headache) in susceptible patients. Withdrawal of the treatment
may be necessary.<br/>Binding to Melanin-Containing Tissues: In rats treated with a single subcutaneous dose
(0.5 mg/kg) or oral dose (2 mg/kg) of radiolabeled sumatriptan,
the elimination half-life of radioactivity from the eye was 15 and
23 days, respectively, suggesting that sumatriptan and/or its
metabolites bind to the melanin of the eye. Because there could be
an accumulation in melanin-rich tissues over time, this raises the
possibility that sumatriptan could cause toxicity in thesetissues
after extended use. However, no effects on the retina related to treatment
with sumatriptan were noted in any of the oral or subcutaneous toxicity
studies. Although no systematic monitoring of ophthalmologic function
was undertaken in clinical trials, and no specific recommendations
for ophthalmologic monitoring are offered, prescribers should be aware
of the possibility of long-term ophthalmologic effects.<br/>Corneal Opacities: Sumatriptan causes corneal opacities and defects
in the corneal epithelium in dogs; this raises the possibility that
these changes may occur in humans. While patients were not systematically
evaluated for these changes in clinical trials, and no specific recommendations
for monitoring are being offered, prescribers should be aware of the
possibility of these changes (see ANIMALTOXICOLOGY).<br/>Information for Patients: See PATIENT INFORMATION
at the end of this labeling for the text of the separate leaflet provided
for patients.<br/>Laboratory Tests: No specific laboratory
tests are recommended for monitoring patients prior to and/or after
treatment with sumatriptan.<br/>Drug Interactions:<br/>Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine
Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have
been reported during combined use of SSRIs or SNRIs and triptans (see
WARNINGS).<br/>Ergot-Containing Drugs: Ergot-containing drugs have been reported to cause
prolonged vasospastic reactions. Because there is a theoretical basis
that these effects may be additive, use of ergotamine-containing or
ergot-type medications (like dihydroergotamine or methysergide) and
sumatriptan within 24 hours of each other should be avoided (see
CONTRAINDICATIONS).<br/>Monoamine Oxidase-A Inhibitors: 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).<br/>Drug/Laboratory Test Interactions: IMITREX Tablets
are not known to interfere with commonly employed clinical laboratory
tests.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>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/mbasis. There was no evidence of an increase
in tumors in either species related to sumatriptan administration.<br/>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.<br/>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/mbasis. 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/mbasis.<br/>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.<br/>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/mbasis. 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/mbasis. 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/mbasis. 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/mbasis.<br/>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/mbasis. 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/mbasis. 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/mbasis. 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/mbasis.<br/>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/mbasis. 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/mbasis. 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/mbasis.<br/>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.<br/>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.<br/>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.<br/>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).
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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.
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sumatriptan succinate
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IMITREX (Tablet)
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Serious cardiac events,
including some that have been fatal, have occurred following the use
of IMITREX Injection or Tablets. These events are extremely rare and
most have been reported in patients with risk factors predictive of
CAD. Events reported have included coronary artery vasospasm, transient
myocardial ischemia, myocardial infarction, ventricular tachycardia,
and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS,
and PRECAUTIONS). Significant hypertensive episodes, including hypertensive crises,
have been reported on rare occasions in patients with or without a
history of hypertension (see WARNINGS).<br/>Incidence in Controlled Clinical Trials: Table 2 lists
adverse events that occurred in placebo-controlled clinical trials
in patients who took at least 1 dose of study drug. Only events that
occurred at a frequency of 2% or more in any group treated with IMITREX
Tablets and were more frequent in that group than in the placebo group
are included in Table 2. The events cited reflect experience gained
under closely monitored conditions of clinical trials in a highly
selected patient population. In actual clinical practice or in other
clinical trials, these frequency estimates may not apply, as the conditions
of use, reporting behavior, and the kinds of patients treated may
differ. Events that
occurred at a frequency of 2% or more in the group treated with IMITREX
Tablets and that occurred more frequently in that group than the placebo
group. Other events that occurred in more
than 1% of patients receiving IMITREX Tablets and at least as often
on placebo included nausea and/or vomiting, migraine, headache, hyposalivation,
dizziness, and drowsiness/sleepiness. IMITREX
Tablets are generally well tolerated. Across all doses, most adverse
reactions were mild and transient and did not lead to long-lasting
effects. The incidence of adverse events in controlled clinical trials
was not affected by gender or age of the patients. There were insufficient
data to assess the impact of race on the incidence of adverse events.<br/>Other Events Observed in Association With the Administration
of IMITREX Tablets: In the paragraphs
that follow, the frequencies of less commonly reported adverse clinical
events are presented. Because the reports include events observed
in open and uncontrolled studies, the role of IMITREX Tablets in their
causation cannot be reliably determined. Furthermore, variability
associated with adverse event reporting, the terminology used to describe
adverse events, etc., limit the value of quantitative frequency estimates
provided. Event frequencies are calculated as the number of patients
who used IMITREX Tablets (25, 50, or 100 mg) and reported an
event divided by the total number of patients (N = 6,348)
exposed to IMITREX Tablets. All reported events are included except
those already listed in the previous table, those too general to be
informative, and those not reasonably associated with the use of the
drug. Events are further classified within body system categoriesand enumerated in order of decreasing frequency using the following
definitions: frequent adverse events are defined as those occurring
in at least 1/100 patients, infrequent adverse events are those occurring
in 1/100 to 1/1,000 patients, and rare adverse events are those occurring
in fewer than 1/1,000 patients.<br/>Atypical Sensations: Frequent
were burning sensation and numbness. Infrequent was tight feeling
in head. Rare were dysesthesia.<br/>Cardiovascular: Frequent
were palpitations, syncope, decreased blood pressure, and increased
blood pressure. Infrequent were arrhythmia, changes in ECG, hypertension,
hypotension, pallor, pulsating sensations, and tachycardia. Rare were
angina, atherosclerosis, bradycardia, cerebral ischemia, cerebrovascular
lesion, heart block, peripheral cyanosis, thrombosis, transient myocardial
ischemia, and vasodilation.<br/>Ear, Nose, and Throat: Frequent were sinusitis, tinnitus; allergic rhinitis;
upper respiratory inflammation; ear, nose, and throat hemorrhage;
external otitis; hearing loss; nasal inflammation; and sensitivity
to noise. Infrequent were hearing disturbances and otalgia. Rare was
feeling of fullness in the ear(s).<br/>Endocrine and Metabolic: Infrequent
was thirst. Rare were elevated thyrotropin stimulating hormone (TSH)
levels; galactorrhea; hyperglycemia; hypoglycemia; hypothyroidism;
polydipsia; weight gain; weight loss; endocrine cysts, lumps, and
masses; and fluid disturbances.<br/>Eye: Rare
were disorders of sclera, mydriasis, blindness and low vision, visual
disturbances, eye edema and swelling, eye irritation and itching,
accommodation disorders, external ocular muscle disorders, eye hemorrhage,
eye pain, and keratitis and conjunctivitis.<br/>Gastrointestinal: Frequent were diarrhea and gastric symptoms. Infrequent
were constipation, dysphagia, and gastroesophageal reflux. Rare were
gastrointestinal bleeding, hematemesis, melena, peptic ulcer, gastrointestinal
pain, dyspeptic symptoms, dental pain, feelings of gastrointestinal
pressure, gastritis, gastroenteritis, hypersalivation, abdominal distention,
oral itching and irritation, salivary gland swelling, and swallowing
disorders.<br/>Hematological Disorders: Rare
was anemia.<br/>Musculoskeletal: Frequent
was myalgia. Infrequent was muscle cramps. Rare were tetany; muscle
atrophy, weakness, and tiredness; arthralgia and articular rheumatitis;
acquired musculoskeletal deformity; muscle stiffness, tightness, and
rigidity; and musculoskeletal inflammation.<br/>Neurological: Frequent
were phonophobia and photophobia. Infrequent were confusion, depression,
difficulty concentrating, disturbance of smell, dysarthria, euphoria,
facial pain, heat sensitivity, incoordination, lacrimation, monoplegia,
sleep disturbance, shivering, syncope, and tremor. Rare were aggressiveness,
apathy, bradylogia, cluster headache, convulsions, decreased appetite,
drug abuse, dystonic reaction, facial paralysis, hallucinations, hunger,
hyperesthesia, hysteria, increased alertness, memory disturbance,
neuralgia, paralysis, personality change, phobia, radiculopathy, rigidity,
suicide, twitching, agitation, anxiety, depressive disorders, detachment,
motor dysfunction, neurotic disorders, psychomotor disorders, taste
disturbances, and raised intracranial pressure.<br/>Respiratory: Frequent
was dyspnea. Infrequent was asthma. Rare were hiccoughs, breathing
disorders, cough, and bronchitis.<br/>Skin: Frequent was sweating. Infrequent were erythema,
pruritus, rash, and skin tenderness. Rare were dry/scaly skin, tightness
of skin, wrinkling of skin, eczema, seborrheic dermatitis, and skin
nodules.<br/>Breasts: Infrequent
was tenderness. Rare were nipple discharge; breast swelling; cysts,
lumps, and masses of breasts; and primary malignant breast neoplasm.<br/>Urogenital: Infrequent
were dysmenorrhea, increased urination, and intermenstrual bleeding.
Rare were abortion and hematuria, urinary frequency, bladder inflammation,
micturition disorders, urethritis, urinary infections, menstruation
symptoms, abnormal menstrual cycle, inflammation of fallopian tubes,
and menstrual cycle symptoms.<br/>Miscellaneous: Frequent
was hypersensitivity. Infrequent were fever, fluid retention, and
overdose. Rare were edema, hematoma, lymphadenopathy, speech disturbance,
voice disturbances, contusions.<br/>Other Events Observed in the Clinical Development of IMITREX: The following adverse events occurred in clinical
trials with IMITREX Injection and IMITREX Nasal Spray. Because the
reports include events observed in open and uncontrolled studies,
the role of IMITREX in their causation cannot be reliably determined.
All reported events are included except those already listed, those
too general to be informative, and those not reasonably associated
with the use of the drug.<br/>Atypical Sensations: Feeling
strange, prickling sensation, tingling, and hot sensation.<br/>Cardiovascular: Abdominal
aortic aneurysm, abnormal pulse, flushing, phlebitis, Raynaud syndrome,
and various transient ECG changes (nonspecific ST or T wave changes,
prolongation of PR or QTc intervals, sinus arrhythmia, nonsustained
ventricular premature beats, isolated junctional ectopic beats, atrial
ectopic beats, delayed activation of the right ventricle).<br/>Chest Symptoms: Chest
discomfort.<br/>Endocrine and Metabolic: Dehydration.<br/>Ear, Nose, and Throat: Disorder/discomfort
nasal cavity and sinuses, ear infection, Meniere disease, and throat
discomfort.<br/>Eye: Vision alterations.<br/>Gastrointestinal: Abdominal
discomfort, colitis, disturbance of liver function tests, flatulence/eructation,
gallstones, intestinal obstruction, pancreatitis, and retching.<br/>Injection Site Reaction:<br/>Miscellaneous: Difficulty in walking, hypersensitivity to various
agents, jaw discomfort, miscellaneous laboratory abnormalities,���serotonin
agonist effect,���swelling of the extremities, and swelling
of the face.<br/>Mouth and Teeth: Disorder
of mouth and tongue (e.g., burning of tongue, numbness of tongue,
dry mouth).<br/>Musculoskeletal: Arthritis, backache, intervertebral disc disorder,
neck pain/stiffness, need to flex calf muscles, and various joint
disturbances (pain, stiffness, swelling, ache).<br/>Neurological: Bad/unusual
taste, chills, diplegia, disturbance of emotions, sedation, globus
hystericus, intoxication, myoclonia, neoplasm of pituitary, relaxation,
sensation of lightness, simultaneous hot and cold sensations, stinging
sensations, stress, tickling sensations, transient hemiplegia, and
yawning.<br/>Respiratory: Influenza
and diseases of the lower respiratory tract and lower respiratory
tract infection.<br/>Skin: Skin
eruption, herpes, and peeling of the skin.<br/>Urogenital: Disorder
of breasts, endometriosis, and renal calculus.<br/>Postmarketing Experience (Reports for Subcutaneous or Oral
Sumatriptan): The following
section enumerates potentially important adverse events that have
occurred in clinical practice and that have been reported spontaneously
to various surveillance systems. The events enumerated represent reports
arising from both domestic and nondomestic use of oral or subcutaneous
dosage forms of sumatriptan. The events enumerated include all except
those already listed in the ADVERSE REACTIONS section above or those
too general to be informative. Because the reports cite events reported
spontaneously from worldwide postmarketing experience, frequency of
events and the role of sumatriptan in their causation cannot be reliably
determined. It is assumed, however, that systemic reactions following
sumatriptan use are likelyto be similar regardless of route of administration.<br/>Blood: Hemolytic
anemia, pancytopenia, thrombocytopenia.<br/>Cardiovascular: Atrial
fibrillation, cardiomyopathy, colonic ischemia (see WARNINGS), Prinzmetal
variant angina, pulmonary embolism, shock, thrombophlebitis.<br/>Ear, Nose, and Throat: Deafness.<br/>Eye: Ischemic
optic neuropathy, retinal artery occlusion, retinal vein thrombosis,
loss of vision.<br/>Gastrointestinal: Ischemic
colitis with rectal bleeding (see WARNINGS), xerostomia.<br/>Hepatic: Elevated
liver function tests.<br/>Neurological: Central nervous system vasculitis, cerebrovascular
accident, dysphasia, serotonin syndrome, subarachnoid hemorrhage.<br/>Non-Site Specific: Angioneurotic
edema, cyanosis, death (see WARNINGS), temporal arteritis.<br/>Psychiatry: Panic
disorder.<br/>Respiratory: Bronchospasm in patients with and without a history
of asthma.<br/>Skin: Exacerbation
of sunburn, hypersensitivity reactions (allergic vasculitis, erythema,
pruritus, rash, shortness of breath, urticaria; in addition, severe
anaphylaxis/anaphylactoid reactions have been reported [see WARNINGS]),
photosensitivity.<br/>Urogenital: Acute
renal failure.
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IMITREX Tablets should
only be used where a clear diagnosis of migraine headache has been
established.<br/>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, or 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 orelectrocardiographic 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.<br/>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.<br/>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 clinicaltrials of sumatriptan nasal spray, 1 patient experienced an asymptomatic
subendocardial infarction possibly subsequent to a coronary vasospastic
event.<br/>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 tobe 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).<br/>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 symptomsexperienced 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).<br/>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.<br/>Selective Serotonin: 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).<br/>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.<br/>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).<br/>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).
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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.
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IMITREX
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