Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3484
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IMITREX (Spray)
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In controlled clinical trials, single doses of
5, 10, or 20 mg of IMITREX Nasal Spray administered into 1 nostril
were effective for the acute treatment of migraine in adults. A greater
proportion of patients had headache response following a 20-mg dose
than following a 5- or 10-mg dose (see CLINICAL TRIALS). Individuals
may vary in response to doses of IMITREX Nasal Spray. The choice of
dose should therefore be made on an individual basis, weighing the
possible benefit of the 20-mg dose with the potential for a greater
risk of adverse events. A 10-mg dose may be achieved by the administration
of a single 5-mg dose in each nostril. There is evidence that doses
above 20 mg do not provide a greater effect than 20 mg. If the headache returns, the dose may be repeated
once after 2 hours, not to exceed a total daily dose of 40 mg.
The safety of treating an average of more than 4 headaches in a 30-day
period has not been established.
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IMITREX (sumatriptan) Nasal Spray contains sumatriptan,
a selective 5-hydroxytryptaminereceptor subtype agonist.
Sumatriptan is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide,
and it has the following structure: The
empirical formula is CHNOS, representing a molecular weight of 295.4. Sumatriptan is
a white to off-white powder that is readily soluble in water and in
saline. Each IMITREX Nasal Spray contains 5 or 20 mg of sumatriptan
in a 100-��L unit dose aqueous buffered solution containing monobasic
potassium phosphate NF, anhydrous dibasic sodium phosphate USP, sulfuric
acid NF, sodium hydroxide NF, and purified water USP. The pH of the
solution is approximately 5.5. The osmolality of the solution is 372
or 742 mOsmol for the 5- and 20-mg IMITREX Nasal Spray, respectively.
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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-HT, or 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 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: In a study of 20 female volunteers, the mean maximum
concentration following a 5- and 20-mg intranasal dose was 5 and 16 ng/mL,
respectively. The mean Cfollowing a 6-mg subcutaneous
injection is 71 ng/mL (range, 49 to 110 ng/mL). The mean
Cis 18 ng/mL (range, 7 to 47 ng/mL) following
oral dosing with 25 mg and 51 ng/mL (range, 28 to 100 ng/mL)
following oral dosing with 100 mg of sumatriptan. In a study
of 24 male volunteers, the bioavailability relative to subcutaneous
injection was low, approximately 17%, primarily due to presystemic
metabolism and partly due to incomplete absorption. Protein binding, determined by equilibrium dialysis over the
concentration range of 10 to 1,000 ng/mL, is low, approximately
14% to 21%. The effect of sumatriptan on the protein binding of other
drugs has not been evaluated, but would be expected to be minor, given
the low rate of protein binding. The mean volume of distribution after
subcutaneous dosing is 2.7 L/kg and the total plasma clearance
is approximately 1,200 mL/min. The
elimination half-life of sumatriptan administered as a nasal spray
is approximately 2 hours, similar to the half-life seen after
subcutaneous injection. Only 3% of the dose is excreted in the urine
as unchanged sumatriptan; 42% of the dose is excreted as the major
metabolite, the indole acetic acid analogue of sumatriptan. Clinical and pharmacokinetic data indicate that administration
of two 5-mg doses, 1 dose in each nostril, is equivalent to administration
of a single 10-mg dose in 1 nostril.<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 effect of hepatic disease on the pharmacokinetics
of subcutaneously and orally administered sumatriptan has been evaluated,
but the intranasal dosage form has not been studied in hepatic impairment.
There were no statistically significant differences in the pharmacokinetics
of subcutaneously administered sumatriptan in hepatically impaired
patients compared to healthy controls. However, the liver plays an
important role in the presystemic clearance of orally administered
sumatriptan. In 1 small study involving oral sumatriptan in hepatically
impaired patients (N = 8) matched for sex, age, and weight
with healthy subjects, the hepatically impaired patients had an approximately
70% increase in AUC and Cand a T40 minutes
earlier compared to the healthy subjects. The bioavailability of nasally
absorbed sumatriptan following intranasal administration, which would
not undergo first-pass metabolism, should not be altered in hepatically
impaired patients. The bioavailability of the swallowed portion of
the intranasal sumatriptan dose has not been determined, but would
be increased in these patients. The swallowed intranasal dose is small,
however, compared to the usual oral dose, so that its impact should
be minimal.<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).
Intranasal sumatriptan has not been evaluated for age differences
(see PRECAUTIONS: Geriatric Use).<br/>Race: The systemic clearance and Cof sumatriptan
were similar in black (n = 34) and Caucasian (n = 38)
healthy male subjects. Intranasal sumatriptan has not been evaluated
for race differences.<br/>Drug Interactions:<br/>Monoamine Oxidase Inhibitors: Treatment with monoamine oxidase inhibitors (MAOIs)
generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS
and PRECAUTIONS). MAOI interaction studies
have not been performed with intranasal sumatriptan. Due to gut and
hepatic metabolic first-pass effects, the increase of systemic exposure
after coadministration of an MAO-A inhibitor with oral sumatriptan
is greater than after coadministration of the MAOI with subcutaneous
sumatriptan. The effects of an MAOI on systemic exposure after intranasal
sumatriptan would be expected to be greater than the effect after
subcutaneous sumatriptan but smaller than the effect after oral sumatriptan
because only swallowed drug would be subject to first-pass effects. In a study of 14 healthy females, pretreatment with
an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan.
Under the conditions of this experiment, the result was a 2-fold increase
in the area under the sumatriptan plasma concentration x time curve
(AUC), corresponding to a 40% increase in elimination half-life. This
interaction was not evident with an MAO-B inhibitor. A small study 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/>Xylometazoline: An in vivo drug interaction study indicated that
3 drops of xylometazoline (0.1% w/v), a decongestant, administered
15 minutes prior to a 20-mg nasal dose of sumatriptan did not
alter the pharmacokinetics of sumatriptan.
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IMITREX Nasal Spray
should not be given to patients with history, symptoms, or signs of
ischemic cardiac, cerebrovascular, or peripheral vascular syndromes.
In addition, patients with other significant underlying cardiovascular
diseases should not receive IMITREX Nasal Spray. Ischemic cardiac
syndromes include, but are not limited to, angina pectoris of any
type (e.g., stable angina of effort 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 Nasal Spray may increase
blood pressure, it should not be given to patients with uncontrolled
hypertension. Concurrent administration of MAO-A inhibitors or use within 2 weeks
of discontinuation of MAO-A inhibitor therapy is contraindicated (see
CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions). IMITREX
Nasal Spray and any ergotamine-containing or ergot-type medication
(like dihydroergotamine or methysergide) should not be used within
24 hours of each other, nor should IMITREX Nasal Spray and another
5-HTagonist. IMITREX Nasal Spray should not be administered
to patients with hemiplegic or basilar migraine. IMITREX Nasal Spray is contraindicated
in patients with hypersensitivity to sumatriptan or any of its components. IMITREX Nasal
Spray is contraindicated in patients with severe hepatic impairment.
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IMITREX Nasal
Spray 5 mg (NDC 0173-0524-00) and 20 mg (NDC 0173-0523-00)
are each supplied in boxes of 6 nasal spray devices. Each unit dose
spray supplies 5 and 20 mg, respectively, of sumatriptan. Store between 36��and
86��F (2��and 30��C). Protect from light.
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General: Chest discomfort
and jaw or neck tightness have been reported infrequently following
the administration of IMITREX Nasal Spray and have also been reported
following use of IMITREX Tablets. 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 Nasal Spray 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 headache 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. Comparable studies were
not performed by the intranasal route. Because there could be an accumulation
in melanin-rich tissues over time, this raises the possibility that
sumatriptan could cause toxicity in these tissues 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 ANIMAL TOXICOLOGY).<br/>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.<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 Nasal
Spray in patients receiving MAO-A inhibitors is contraindicated (see
CLINICAL PHARMACOLOGY and CONTRAINDICATIONS).<br/>Drug/Laboratory Test Interactions: IMITREX Nasal Spray is 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 184 times the exposure attained in humans
after the maximum recommended single intranasal dose of 20 mg.
The highest dose administered to rats (160 mg/kg/day, reduced
from 360 mg/kg/day during week 21) was approximately 78 times
the maximum recommended single intranasal dose of 20 mg on a
mg/mbasis. There was no evidence of an increase in tumors
in either species related to sumatriptan administration. Local effects
on nasal and respiratory tissue after chronic intranasal dosing in
animals have not been evaluated (see WARNINGS).<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 twice the maximum recommended single human intranasal
dose of 20 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 29 times the
maximum recommended single human intranasal dose of 20 mg ona mg/mbasis. Fertility studies, in which sumatriptan
was administered by the intranasal route, were not conducted.<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. Reproductive toxicity
studies for sumatriptan by the intranasal route have not been conducted. There are no adequate and well-controlled studies
in pregnant women. Therefore, IMITREX Nasal Spray 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 48 times
the maximum single recommended human intranasal dose of 20 mg
on a mg/mbasis. By the intravenous route, the highest
no-effect dose was 0.75 mg/kg/day, or approximately 0.7 times
the maximum single recommended human intranasal dose of 20 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 approximately 6 times the maximum single recommended
human intranasal dose of 20 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 29 times the maximum recommended
single human intranasal dose of 20 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 29 times
the maximum single recommended human intranasal dose of 20 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 14 times the maximum single recommended human
intranasal dose of 20 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
24 times the maximum single recommended human intranasal dose
of 20 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
29 times the maximum recommended single human intranasal dose
of 20 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 29 times the maximum single recommended human intranasal dose
of 20 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 49 times the maximum single
recommended human intranasal dose of 20 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 40 times the maximum single recommended
human intranasal dose of 20 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 Nasal Spray.<br/>Pediatric Use: Safety and effectiveness
of IMITREX Nasal Spray in pediatric patients under 18 years of age
have not been established; therefore, IMITREX Nasal Spray is 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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In clinical trials, the highest single doses
of IMITREX Nasal Spray administered without significant adverse effects
were 40 mg to 12 volunteers and 40 mg to 85 migraine patients,
which is twice the highest single recommended dose. In addition, 12
volunteers were administered a total daily dose of 60 mg (20 mg
3 times daily) for 3.5 days without significant 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 about 2 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring
of patients after overdose with IMITREX Nasal Spray should continue
for at least 10 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
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IMITREX (Spray)
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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: Among 3,653 patients
treated with IMITREX Nasal Spray in active- and placebo-controlled
clinical trials, less than 0.4% of patients withdrew for reasons related
to adverse events. Table 2 lists adverse events that occurred
in worldwide placebo-controlled clinical trials in 3,419 migraineurs.
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
estimatesmay not apply, as the conditions of use, reporting behavior,
and the kinds of patients treated may differ. Only events that occurred at a frequency of 1% or more in the
IMITREX Nasal Spray 20-mg treatment group and were more frequent in
that group than in the placebo group are included in Table 2. Phonophobia also occurred in more than 1% of
patients but was more frequent on placebo. IMITREX
Nasal Spray is 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, weight, or age of the patients; use of
prophylactic medications; or presence of aura. 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 Nasal Spray: 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 Nasal Spray in their causation cannot be reliably
determined. Furthermore, variability associatedwith adverse event
reporting, the terminology used to describe adverse events, etc.,
limit the value of the quantitative frequency estimates provided.
Event frequencies are calculated as the number of patients who used
IMITREX Nasal Spray (5, 10, or 20 mg in controlled and uncontrolled
trials) and reported an event divided by the total number of patients
(N = 3,711) exposed to IMITREX Nasal Spray. 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 categories and enumerated in order of decreasing frequency
using the following definitions: 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: Infrequent were tingling, warm/hot sensation, numbness,
pressure sensation, feeling strange, feeling of heaviness, feeling
of tightness, paresthesia, cold sensation, and tight feeling in head.
Rare were dysesthesia and prickling sensation.<br/>Cardiovascular: Infrequent were flushing and hypertension (see WARNINGS),
palpitations, tachycardia, changes in ECG, and arrhythmia (see WARNINGS
and PRECAUTIONS). Rare were abdominal aortic aneurysm, hypotension,
bradycardia, pallor, and phlebitis.<br/>Chest Symptoms: Infrequent
were chest tightness, chest discomfort, and chest pressure/heaviness
(see PRECAUTIONS: General).<br/>Ear, Nose, and Throat: Infrequent
were disturbance of hearing and ear infection. Rare were otalgia and
Meniere disease.<br/>Endocrine and Metabolic: Infrequent
was thirst. Rare were galactorrhea, hypothyroidism, and weight loss.<br/>Eye: Infrequent were irritation of eyes and visual disturbance.<br/>Gastrointestinal: Infrequent
were abdominal discomfort, diarrhea, dysphagia, and gastroesophageal
reflux. Rare were constipation, flatulence/eructation, hematemesis,
intestinal obstruction, melena, gastroenteritis, colitis, hemorrhage
of gastrointestinal tract, and pancreatitis.<br/>Mouth and Teeth: Infrequent
was disorder of mouth and tongue (e.g., burning of tongue, numbness
of tongue, dry mouth).<br/>Musculoskeletal: Infrequent were neck pain/stiffness, backache, weakness,
joint symptoms, arthritis, and myalgia. Rare were muscle cramps, tetany,
intervertebral disc disorder, and muscle stiffness.<br/>Neurological: Infrequent were drowsiness/sedation, anxiety, sleep
disturbances, tremors, syncope, shivers, chills, depression, agitation,
sensation of lightness, and mental confusion. Rare were difficulty
concentrating, hunger, lacrimation, memory disturbances, monoplegia/diplegia,
apathy, disturbance of smell, disturbance of emotions, dysarthria,
facial pain, intoxication, stress, decreased appetite, difficulty
coordinating, euphoria, and neoplasm of pituitary.<br/>Respiratory: Infrequent were dyspnea and lower respiratory tract
infection. Rare was asthma.<br/>Skin: Infrequent
were rash/skin eruption, pruritus, and erythema. Rare were herpes,
swelling of face, sweating, and peeling of skin.<br/>Urogenital: Infrequent
were dysuria, disorder of breasts, and dysmenorrhea. Rare were endometriosis
and increased urination.<br/>Miscellaneous: Infrequent
were cough, edema, and fever. Rare were hypersensitivity, swelling
of extremities, voice disturbances, difficulty in walking, and lymphadenopathy.<br/>Other Events Observed in the Clinical Development of IMITREX: The following adverse events occurred in clinical
trials with IMITREX Injection and IMITREX Tablets. 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/>Breasts: Breast swelling; cysts, lumps, and masses of breasts;
nipple discharge; primary malignant breast neoplasm; and tenderness.<br/>Cardiovascular: Abnormal
pulse, angina, atherosclerosis, cerebral ischemia, cerebrovascular
lesion, heart block, peripheral cyanosis, pulsating sensations, Raynaud
syndrome, thrombosis, transient myocardial ischemia, 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), and vasodilation.<br/>Ear, Nose, and Throat: Allergic rhinitis; ear, nose, and throat hemorrhage;
external otitis; feeling of fullness in the ear(s); hearing disturbances;
hearing loss; nasal inflammation; sensitivity to noise; sinusitis;
tinnitus; and upper respiratory inflammation.<br/>Endocrine and Metabolic: Dehydration;
endocrine cysts, lumps, and masses; elevated thyrotropin stimulating
hormone (TSH) levels; fluid disturbances; hyperglycemia; hypoglycemia;
polydipsia; and weight gain.<br/>Eye: Accommodation disorders, blindness and low vision,
conjunctivitis, disorders of sclera, external ocular muscle disorders,
eye edema and swelling, eye itching, eye hemorrhage, eye pain, keratitis,
mydriasis, and vision alterations.<br/>Gastrointestinal: Abdominal distention, dental pain, disturbances of
liver function tests, dyspeptic symptoms, feelings of gastrointestinal
pressure, gallstones, gastric symptoms, gastritis, gastrointestinal
pain, hypersalivation, hyposalivation, oral itching and irritation,
peptic ulcer, retching, salivary gland swelling, and swallowing disorders.<br/>Hematological Disorders: Anemia.<br/>Injection Site Reaction:<br/>Miscellaneous: Contusions,
fluid retention, hematoma, hypersensitivity to various agents, jaw
discomfort, miscellaneous laboratory abnormalities, overdose,���serotonin
agonist effect,���and speech disturbance.<br/>Musculoskeletal: Acquired
musculoskeletal deformity, arthralgia and articular rheumatitis, muscle
atrophy, muscle tiredness, musculoskeletal inflammation, need to flex
calf muscles, rigidity, tightness, and various joint disturbances
(pain, stiffness, swelling, ache).<br/>Neurological: Aggressiveness, bradylogia, cluster headache, convulsions,
detachment, disturbances of taste, drug abuse, dystonia, facial paralysis,
globus hystericus, hallucinations, headache, heat sensitivity, hyperesthesia,
hysteria, increased alertness, malaise/fatigue, migraine, motor dysfunction,
myoclonia, neuralgia, neurotic disorders, paralysis, personality change,
phobia, photophobia, psychomotor disorders, radiculopathy, raised
intracranial pressure, relaxation, stinging sensations, transient
hemiplegia, simultaneous hot and cold sensations, suicide, tickling
sensations, twitching, and yawning.<br/>Pain and Other Pressure Sensations: Chest pain, neck tightness/pressure, throat/jaw
pain/tightness/pressure, and pain (location specified).<br/>Respiratory: Breathing
disorders, bronchitis, diseases of the lower respiratory tract, hiccoughs,
and influenza.<br/>Skin: Dry/scaly
skin, eczema, seborrheic dermatitis, skin nodules, skin tenderness,
tightness of skin, and wrinkling of skin.<br/>Urogenital: Abortion,
abnormal menstrual cycle, bladder inflammation, hematuria, inflammation
of fallopian tubes, intermenstrual bleeding, menstruation symptoms,
micturition disorders, renal calculus, urethritis, urinary frequency,
and urinary infections.<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 likely to 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 Nasal Spray
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 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 nasal spray take place in the setting of
a physician's office or similar medically staffed and equipped
facility unless the patient has previously received sumatriptan. Because
cardiac ischemia can occur in the absence of clinical symptoms, consideration
should be given to obtaining on the first occasion of use an electrocardiogram
(ECG) during the interval immediately following IMITREX Nasal Spray,
in these patients with risk factors. It is recommended that patients who
are intermittent long-term users of sumatriptan and who have or acquire
risk factors predictive of CAD, as described above, undergo periodic
interval cardiovascular 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 (sumatriptan
succinate) Tablets. Considering the extent of use of sumatriptan in
patients with migraine, the incidence of these events is extremely
low. The fact that sumatriptan can cause
coronary vasospasm, that some of these events have occurred in patients
with no prior cardiac disease history and with documented absence
of CAD, and the close proximity of the events to sumatriptan use support
the conclusion that some of these cases were caused by the drug. In
many cases, however, where there has been known underlying coronary
artery disease, the relationship is uncertain.<br/>Premarketing Experience With Sumatriptan: Among approximately 4,000 patients with migraine
who participated in premarketing controlled and uncontrolled clinical
trials of sumatriptan nasal spray, 1 patient experienced an asymptomatic
subendocardial infarction possibly subsequent to a coronary vasospastic
event. Of 6,348 patients with migraine
who participated in premarketing controlled and uncontrolled clinical
trials of oral sumatriptan, 2 experienced clinical adverse events
shortly after receiving oral sumatriptan that may have reflected coronary
vasospasm. Neither of these adverse events was associated with a serious
clinical outcome. Among the more than 1,900
patients with migraine who participated in premarketing controlled
clinical trials of subcutaneous sumatriptan, there were 8 patients
who sustained clinical events during or shortly after receiving sumatriptan
that may have reflected coronary artery vasospasm. Six of these 8
patients had ECG changes consistent with transient ischemia, but without
accompanying clinical symptoms or signs. Of these 8 patients, 4 had
either findings suggestive of CAD or risk factors predictive of CAD
prior to study enrollment.<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 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).<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 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).<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/>Serotonin Syndrome: The development of a potentially life-threatening
serotonin syndrome may occur with triptans, including treatment with
IMITREX, particularly during combined use with selective serotonin
reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors
(SNRIs). If concomitant treatment with sumatriptan and an SSRI (e.g.,
fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram)
or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful
observation of the patient is advised, particularly during treatment
initiation and dose increases. Serotonin syndrome symptoms may include
mental status changes (e.g., agitation, hallucinations, coma), autonomic
instability (e.g., tachycardia, labile blood pressure, hyperthermia),
neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).<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/>Local Irritation: Of the 3,378
patients using the nasal spray (5-, 10-, or 20-mg doses) on 1 or 2
occasions in controlled clinical studies, approximately 5% noted irritation
in the nose and throat. Irritative symptoms such as burning, numbness,
paresthesia, discharge, and pain or soreness were noted to be severe
in about 1% of patients treated. The symptoms were transient and in
approximately 60% of the cases, the symptoms resolved in less than
2 hours. Limitedexaminations of the nose and throat did not
reveal any clinically noticeable injury in these patients. The consequences of extended and repeated use of IMITREX
Nasal Spray on the nasal and/or respiratory mucosa have not been systematically
evaluated in patients. No increase in the incidence of local irritation
was observed in patients using IMITREX Nasal Spray repeatedly for
up to 1 year. In inhalation studies
in rats dosed daily for up to 1 month at exposures as low as
one half the maximum daily human exposure (based on dose per surface
area of nasal cavity), epithelial hyperplasia (with and without keratinization)
and squamous metaplasia were observed in the larynx at all doses tested.
These changes were partially reversible after a 2-week drug-free period.
When dogs were dosed daily with various formulations by intranasal
instillation for up to 13 weeks at exposures of 2 to 4 times
the maximum daily human exposure (based on dose per surface area of
nasal cavity), respiratory and nasal mucosa exhibited evidence of
epithelial hyperplasia, focal squamous metaplasia, granulomata, bronchitis,
and fibrosing alveolitis. A no-effect dose was not established. The
changes observed in both species are not considered to be signs of
either preneoplastic or neoplastic transformation. Local effects on nasal and respiratory tissues after chronic
intranasal dosing in animals have not been studied.<br/>Concomitant Drug Use: In patients taking MAO-A inhibitors, sumatriptan
plasma levels attained after treatment with recommended doses are
2-fold (following subcutaneous administration) to 7-fold (following
oral administration) higher than those obtained under other conditions.
Accordingly, the coadministration of IMITREX Nasal Spray and anMAO-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 Nasal
Spray is indicated for the acute treatment of migraine attacks with
or without aura in adults. IMITREX Nasal
Spray is not intended for the prophylactic therapy of migraine or
for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS).
Safety and effectiveness of IMITREX Nasal Spray have not been established
for cluster headache, which is present in an older, predominantly
male population.
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dailymed-instance:name |
IMITREX
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