Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4282
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IMITREX (Injection)
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The maximum single recommended
adult dose of IMITREX Injection is 6 mg injected subcutaneously. If side
effects are dose limiting, then lower doses may be used (see Table 1). The
maximum recommended dose that may be given in 24 hours is two 6-mg injections
separated by at least 1 hour. Controlled clinical trials have failed
to show that clear benefit is associated with the administration of a second
6-mg dose in patients who have failed to respond to a first injection. In
patients receiving MAO inhibitors, decreased doses of sumatriptan should be
considered (see WARNINGS: Concomitant Drug Use and CLINICAL PHARMACOLOGY:
Drug Interactions: Monoamine Oxidase Inhibitors). An autoinjection device is available
for use with the 4- and 6-mg prefilled syringe cartridges to facilitate self-administration
in patients using the 4- or 6-mg dose. With this device, the needle penetrates
approximately 1/4 inch (5 to 6 mm). Since the injection is intended to
be given subcutaneously, intramuscular or intravascular delivery should be
avoided. Patients should be directed to use injection sites with an adequate
skinand subcutaneous thickness to accommodate the length of the needle. In
patients receiving doses other than 4 or 6 mg, only the 6-mg single-dose
vial dosage form should be used. Parenteral drug products should be inspected
visually for particulate matter and discoloration before administration whenever
solution and container permit.
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IMITREX (sumatriptan
succinate) Injection is 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. IMITREX Injection is a clear, colorless
to pale yellow, sterile, nonpyrogenic solution for subcutaneous injection.
Each 0.5 mL of IMITREX Injection 8 mg/mL solution contains 4 mg
of sumatriptan (base) as the succinate salt and 3.8 mg of sodium chloride,
USP in Water for Injection, USP. Each 0.5 mL of IMITREX Injection 12 mg/mL
solution contains 6 mg of sumatriptan (base) as the succinate salt and
3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range
of both solutions is approximately 4.2 to 5.3. The osmolality of both injections
is 291 mOsmol.
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Mechanism of Action: Sumatriptan has been
demonstrated to be a selective agonist for a vascular 5-hydroxytryptaminereceptor
subtype (probably a member of the 5-HTfamily) with no significantaffinity (as measured using standard radioligand binding assays) or pharmacological
activity at 5-HT, 5-HTreceptor subtypes or at alpha-,
alpha-, or beta-adrenergic; dopamine; dopamine;
muscarinic; or benzodiazepine receptors. The vascular
5-HTreceptor subtype to which sumatriptan binds selectively,
and through which it presumably exerts its antimigrainous effect, has been
shown to be present on cranial arteries in both dog and primate, on the human
basilar artery, and in the vasculature of the isolated dura mater of humans.
In these tissues, sumatriptan activates this receptor to cause vasoconstriction,
an action in humans correlating with the relief of migraine and cluster headache.
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/>Corneal Opacities: Dogs receiving oral sumatriptan developed corneal opacities
and defects in the corneal epithelium. Corneal opacities were seen at the
lowest dosage tested, 2 mg/kg/day, and were present after 1 month
of treatment. Defects in the corneal epithelium were noted in a 60-week study.
Earlier examinations for these toxicities were not conducted and no-effect
doses were not established; however, the relative exposure at the lowest dose
tested was approximately 5 times the human exposure after a 100-mg oral dose
or 3 times the human exposure after a 6-mg subcutaneous dose.<br/>Melanin Binding: In rats with a single subcutaneous dose (0.5 mg/kg)
of radiolabeled sumatriptan, the elimination half-life of radioactivity from
the eye was 15 days, suggesting that sumatriptan and its metabolites
bind to the melanin of the eye. The clinical significance of this binding
is unknown.<br/>Pharmacokinetics: Pharmacokinetic parameters
following a 6-mg subcutaneous injection into the deltoid area of the arm in
9 males (mean age, 33 years; mean weight, 77 kg) were systemic
clearance: 1,194��149 mL/min (mean��S.D.),
distribution half-life: 15��2 minutes, terminal half-life:
115��19 minutes, and volume of distribution central compartment:
50��8 liters. Of this dose, 22%��4% was
excreted in the urine as unchanged sumatriptan and 38%��7%
as the indole acetic acid metabolite. After a single
6-mg subcutaneous manual injection into the deltoid area of the arm in 18
healthy males (age, 24��6 years; weight, 70 kg), the
maximum serum concentration (C) was (mean��standard
deviation) 74��15 ng/mL and the time to peak concentration
(T) was 12 minutes after injection (range, 5 to 20 minutes). In this study, the same dose injected subcutaneously
in the thigh gave a Cof 61��15 ng/mL by
manual injection versus 52��15 ng/mL by autoinjector
techniques. The Toramount absorbed was not significantly altered
by either the site or technique of injection. The bioavailability
of sumatriptan via subcutaneous site injection to 18 healthy male subjects
was 97%��16% of that obtained following intravenous injection.
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.<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. There
were no statistically significant differences in the pharmacokinetics of subcutaneously
administered sumatriptan in hepatically impaired patients compared to healthycontrols. However, 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.<br/>Age: The pharmacokinetics of 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/>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: In vitro studies with
human microsomes suggest that sumatriptan is metabolized by monoamine oxidase
(MAO), predominantly the A isoenzyme. In a study of 14 healthy females,
pretreatment with MAO-A inhibitor decreased the clearance of 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. No significant effect
was seen with an MAO-B inhibitor.<br/>Pharmacodynamics:<br/>Typical Physiologic Responses:
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IMITREX Injection should not be
given intravenously because of its potential to cause coronary vasospasm. IMITREX Injection
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 Injection. 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: Other Vasospasm-Related Events and WARNINGS: Risk of
Myocardial Ischemia and/or Infarction and Other AdverseCardiac Events). Because IMITREX
Injection may increase blood pressure, it should not be given to patients
with uncontrolled hypertension. IMITREX
Injection 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 Injection and another 5-HTagonist. IMITREX Injection should not be administered to patients
with hemiplegic or basilar migraine. IMITREX Injection is contraindicated in patients with hypersensitivity
to sumatriptan or any of its components. IMITREX Injection is contraindicated in patients with severe
hepatic impairment.
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IMITREX Injection contains sumatriptan (base) as the succinate
salt and is supplied as a clear, colorless to pale yellow, sterile, nonpyrogenic
solution as follows: (NDC 0173-0739-00) IMITREX STATdose
System, 4 mg, containing 2 prefilled single-dose syringe
cartridges, 1 IMITREX STATdose Pen, and instructions for
use. (NDC 0173-0739-02) Two 4-mg single-dose prefilled
syringe cartridges for use with IMITREX STATdose System. (NDC
0173-0479-00) IMITREX STATdose System, 6 mg, containing 2 prefilled single-dose
syringe cartridges, 1 IMITREX STATdose Pen, and instructions for use. (NDC
0173-0478-00) Two 6-mg single-dose prefilled syringe cartridges for use with
IMITREX STATdose System. (NDC 0173-0449-02) IMITREX
Injection single-dose vial (6 mg/0.5 mL) in cartons containing 5
vials. Store between 2��and 30��C (36��and 86��F). Protect from light.
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General: Chest, jaw, or neck tightness
is relatively common after administration of IMITREX Injection. Chest discomfort
and jaw or neck tightness have been reported following use of IMITREX Tablets
and have also been reported infrequently following the administration of IMITREX (sumatriptan)
Nasal Spray. 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: Risk of Myocardial Ischemia and/or Infarction
and Other Adverse Cardiac Events and WARNINGS: Other Vasospasm-Related Events). 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 or cluster 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: Drug-Associated Cerebrovascular Events and Fatalities). For
a given attack, if a patient does not respond to the first dose of sumatriptan,
the diagnosis of migraine or cluster headache should be reconsidered before
administration of a second dose.<br/>Binding to Melanin-Containing Tissues: Because sumatriptan binds to melanin, it could accumulate
in melanin-rich tissues (such as the eye) 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 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 (see CLINICAL
PHARMACOLOGY: Melanin Binding).<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 CLINICAL PHARMACOLOGY: Corneal Opacities). Patients who are advised to self-administer IMITREX Injection
in medically unsupervised situations should receive instruction on the proper
use of the product from the physician or other suitably qualified health care
professional prior to doing so for the first time.<br/>Information for Patients: With the autoinjector, the needle penetrates approximately
1/4 of an inch (5 to 6 mm). Since the injection is intended to be given
subcutaneously, intramuscular or intravascular delivery should be avoided.
Patients should be directed to use injection sites with an adequate skin and
subcutaneous thickness to accommodate the length of the needle. 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/>Migraine Prophylactic Medications: There is no evidence that concomitant use of migraine prophylactic
medications has any effect on the efficacy of sumatriptan. In 2 Phase III
trials in the US, a retrospective analysis of 282 patients who had been using
prophylactic drugs (verapamil n = 63, amitriptyline n = 57, propranolol n
= 94, for 45 other drugs n = 123) were compared to those who had not used
prophylaxis (N = 452). There were no differences in relief rates at 60 minutes
postdose for IMITREX Injection, whether or not prophylactic medications were
used.<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 sumatriptan in patients
receiving MAO-A inhibitors is not ordinarily recommended. If the clinical
situation warrants the combined use of sumatriptan and an MAOI, the dose of
sumatriptan employed should be reduced (see CLINICAL PHARMACOLOGY: Drug Interactions: Monoamine Oxidase Inhibitors and WARNINGS: Concomitant
Drug Use).<br/>Drug/Laboratory Test Interactions: IMITREX is not known
to interfere with commonly employed clinical laboratory tests.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: 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 were approximately 110 times the exposure
attained in humans after the maximum recommended single dose of 6 mg.
The highest dose to rats was approximately 260 times the maximum single
dose of 6 mg on a mg/mbasis. There was no evidence of an
increase in tumors in either species related to sumatriptan administration. 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. A fertility study
(Segment I) by the subcutaneous route, during which male and female rats were
dosed daily with sumatriptan prior to and throughout the mating period, has
shown no evidence of impaired fertility at doses equivalent to approximately
100 times the maximum recommended single human dose of 6 mg on a mg/mbasis.
However, following oral administration, a treatment-related decrease in fertility,
secondary to a decrease in mating, was seen for rats treated with 50 and 500 mg/kg/day.
The no-effect dose for this finding was approximately 8 times the maximum
recommended single human dose of 6 mg on a mg/mbasis. It
is not clear whether the problem is associated with the treatment of males
or females or both.<br/>Pregnancy: Pregnancy Category C. Sumatriptan has been shown to be embryolethal
in rabbits when given daily at a dose approximately equivalent to the maximum
recommended single human subcutaneous dose of 6 mg on a mg/mbasis.
There is no evidence that establishes that sumatriptan is a human teratogen;
however, there are no adequate and well-controlled studies in pregnant women.
IMITREX Injection should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. In assessing
this information, the following additional findings should be considered.<br/>Embryolethality: When given intravenously to pregnant rabbits daily throughout
the period of organogenesis, sumatriptan caused embryolethality at doses at
or close to those producing maternal toxicity. The mechanism of the embryolethality
is not known. These doses were approximately equivalent to the maximum single
human dose of 6 mg on a mg/mbasis. The
intravenous administration of sumatriptan to pregnant rats throughout organogenesis
at doses that are approximately 20 times a human dose of 6 mg on a mg/mbasis,
did not cause embryolethality. Additionally, in a study of pregnant rats given
subcutaneous sumatriptan daily prior to and throughout pregnancy, there was
no evidence of increased embryo/fetal lethality.<br/>Teratogenicity: Term fetuses from
Dutch Stride rabbits treated during organogenesis with oral sumatriptan exhibited
an increased incidence of cervicothoracic vascular and skeletal abnormalities.
The functional significance of these abnormalities is not known. The highest
no-effect dose for these effects was 15 mg/kg/day, approximately 50 times
the maximum single dose of 6 mg on a mg/mbasis. In
a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout
pregnancy, there was no evidence of teratogenicity.<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 Injection.<br/>Pediatric Use: Safety and effectiveness
of IMITREX Injection in pediatric patients under 18 years of age have not
been established; therefore, IMITREX Injection 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: Risk of Myocardial Ischemia and/or
Infarction and Other Adverse Cardiac Events).
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Patients (N = 269) have received single injections
of 8 to 12 mg without significant adverse effects. Volunteers (N = 47)
have received single subcutaneous doses of up to 16 mg without serious
adverse events. No gross overdoses in clinical practice
have been reported. Coronary vasospasm was observed after intravenous administration
of IMITREX Injection (see CONTRAINDICATIONS). Overdoses would be expected
from animal data (dogs at 0.1 g/kg, rats at 2 g/kg) to possibly
cause convulsions, tremor, inactivity, erythema of the extremities, reduced
respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation,
hair loss, and scab formation), and paralysis. The half-life of elimination
of sumatriptan is about 2 hours (see CLINICAL PHARMACOLOGY: Pharmacokinetics),
and therefore monitoring of patients after overdose with IMITREX Injection
should continue while symptoms or signs persist, and for at least 10 hours. 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 (Injection)
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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: Risk of Myocardial Ischemia and/or Infarction and Other Adverse
Cardiac Events, and PRECAUTIONS: General). Significant
hypertensive episodes, including hypertensive crises, have been reported on
rare occasions in patients with or without a history of hypertension (see
WARNINGS: Increase in Blood Pressure). Among patients
in clinical trials of subcutaneous IMITREX Injection (N = 6,218),
up to 3.5% of patients withdrew for reasons related to adverse events.<br/>Incidence in Controlled Clinical Trials of Migraine Headache: Table 4 lists adverse events that occurred in 2 large US,
Phase III, placebo-controlled clinical trials in migraine patients following
either a single 6-mg dose of IMITREX Injection or placebo. Only events that
occurred at a frequency of 2% or more in groups treated with IMITREX Injection
6 mg and occurred at a frequency greater than the placebo group are included
in Table 4. The sum of the percentages
cited is greater than 100% because patients may experience more than 1 type
of adverse event. Only events that occurred at a frequency of 2% or more in
groups treated with IMITREX Injection and occurred at a frequency greater
than the placebo groups are included. 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/>Incidence in Controlled Trials of Cluster Headache: In the controlled clinical trials assessing sumatriptan's
efficacy as a treatment for cluster headache, no new significant adverse events
associated with the use of sumatriptan were detected that had not already
been identified in association with the drug's use in migraine. Overall,
the frequency of adverse events reported in the studies of cluster headache
were generally lower. Exceptions include reports of paresthesia (5% IMITREX,
0% placebo), nausea and vomiting (4% IMITREX, 0% placebo), and bronchospasm
(1% IMITREX, 0% placebo).<br/>Other Events Observed in Association With the Administration of IMITREX
Injection: 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 Injection 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
the quantitative frequency estimates provided. Event
frequencies are calculated as the number of patients reporting an event divided
by the total number of patients (N = 6,218) exposed to subcutaneous
IMITREX Injection. 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: 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/>Cardiovascular: Infrequent were hypertension, hypotension, bradycardia,
tachycardia, palpitations, pulsating sensations, 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 syncope. Rare were pallor, arrhythmia, abnormal pulse, vasodilatation,
and Raynaud syndrome.<br/>Endocrine and Metabolic: Infrequent was thirst. Rare were polydipsia and dehydration.<br/>Eye: Frequent was vision alterations. Infrequent was irritation
of the eye.<br/>Gastrointestinal: Frequent were abdominal discomfort and dysphagia. Infrequent
were gastroesophageal reflux and diarrhea. Rare were peptic ulcer, retching,
flatulence/eructation, and gallstones.<br/>Musculoskeletal: Frequent were muscle cramps. Infrequent were various joint
disturbances (pain, stiffness, swelling, ache). Rare were muscle stiffness,
need to flex calf muscles, backache, muscle tiredness, and swelling of the
extremities.<br/>Neurological: Frequent was anxiety. Infrequent were mental confusion,
euphoria, agitation, relaxation, chills, sensation of lightness, tremor, shivering,
disturbances of taste, prickling sensations, paresthesia, stinging sensations,
facial pain, photophobia, and lacrimation. Rare were transient hemiplegia,
hysteria, globus hystericus, intoxication, depression, myoclonia, monoplegia/diplegia,
sleep disturbance, difficulties in concentration, disturbances of smell, hyperesthesia,
dysesthesia, simultaneous hot and cold sensations, tickling sensations, dysarthria,
yawning, reduced appetite, hunger, and dystonia.<br/>Respiratory: Infrequent was dyspnea. Rare were influenza, diseases of
the lower respiratory tract, and hiccoughs.<br/>Skin: Infrequent were erythema, pruritus, and skin rashes and
eruptions. Rare was skin tenderness.<br/>Urogenital: Rare were dysuria, frequency, dysmenorrhea, and renal calculus.<br/>Miscellaneous: Infrequent were
miscellaneous laboratory abnormalities, including minor disturbances in liver
function tests,���serotonin agonist effect,���and hypersensitivity
to various agents. Rare was fever.<br/>Other Events Observed in the Clinical Development of IMITREX: The following adverse events occurred in clinical trials
with IMITREX Tablets 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/>Breasts: Breast swelling, cysts, disorder of breasts, lumps, masses
of breasts, nipple discharge, primary malignant breast neoplasm, and tenderness.<br/>Cardiovascular: Abdominal aortic
aneurysm, angina, atherosclerosis, cerebral ischemia, cerebrovascular lesion,
heart block, peripheral cyanosis, phlebitis, thrombosis, and transient myocardial
ischemia.<br/>Ear, Nose, and Throat: Allergic rhinitis; disorder of nasal cavity/sinuses; ear,
nose, and throat hemorrhage; ear infection; external otitis; feeling of fullness
in the ear(s); hearing disturbances; hearing loss; Meniere disease; nasal
inflammation; otalgia; sensitivity to noise; sinusitis; tinnitus; and upper
respiratory inflammation.<br/>Endocrine and Metabolic: Elevated thyrotropin stimulating hormone (TSH) levels; endocrine
cysts, lumps, and masses; fluid disturbances; galactorrhea; hyperglycemia;
hypoglycemia; hypothyroidism; weight gain; and weight loss.<br/>Eye: Accommodation disorders, blindness and low vision, conjunctivitis,
disorders of sclera, external ocular muscle disorders, eye edema and swelling,
eye hemorrhage, eye itching, eye pain, keratitis, mydriasis, and visual disturbances.<br/>Gastrointestinal: Abdominal distention, colitis, constipation, dental pain,
dyspeptic symptoms, feelings of gastrointestinal pressure, gastric symptoms,
gastritis, gastroenteritis, gastrointestinal bleeding, gastrointestinal pain,
hematemesis, hypersalivation, hyposalivation, intestinal obstruction, melena,
nausea and/or vomiting, oral itching and irritation, pancreatitis, salivary
gland swelling, and swallowing disorders.<br/>Hematological Disorders: Anemia.<br/>Mouth and Teeth: Disorder of mouth and tongue (e.g., burning of tongue, numbness
of tongue, dry mouth).<br/>Musculoskeletal: Acquired musculoskeletal deformity, arthralgia and articular
rheumatitis, arthritis, intervertebral disc disorder, muscle atrophy, muscle
tightness and rigidity, musculoskeletal inflammation, and tetany.<br/>Neurological: Apathy, aggressiveness, bad/unusual taste, bradylogia, cluster
headache, convulsions, depressive disorders, detachment, disturbance of emotions,
drug abuse, facial paralysis, hallucinations, heat sensitivity, incoordination,
increased alertness, memory disturbance, migraine, motor dysfunction, neoplasm
of pituitary, neuralgia, neurotic disorders, paralysis, personality change,
phobia, phonophobia, psychomotor disorders, radiculopathy, raised intracranial
pressure, rigidity, stress, syncope, suicide, and twitching.<br/>Respiratory: Asthma, breathing disorders, bronchitis, cough, and lower
respiratory tract infection.<br/>Skin: Dry/scaly skin, eczema, herpes, seborrheic dermatitis, skin
nodules, tightness of skin, and wrinkling of skin.<br/>Urogenital: Abnormal menstrual cycle, abortion, bladder inflammation,
endometriosis, hematuria, increased urination, inflammation of fallopian tubes,
intermenstrual bleeding, menstruation symptoms, micturition disorders, urethritis,
and urinary infections.<br/>Miscellaneous: Contusions, difficulty in walking, edema, hematoma, hypersensitivity,
fever, fluid retention, lymphadenopathy, overdose, speech disturbance, swelling
of extremities, swelling of face, and voice disturbances.<br/>Pain and Other Pressure Sensations: Chest pain and/or heaviness, neck/throat/jaw pain/tightness/pressure,
and pain (location specified).<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 IMITREX Injection 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:
Hypersensitivity]), photosensitivity. Following subcutaneous administration
of sumatriptan, pain, redness, stinging, induration, swelling, contusion,
subcutaneous bleeding, and, on rare occasions, lipoatrophy (depression in
the skin) or lipohypertrophy (enlargement or thickening of tissue) have been
reported.<br/>Urogenital: Acute renal failure.
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IMITREX Injection should only
be used where a clear diagnosis of migraine or cluster headache has been established.
The prescriber should be aware that cluster headache patients often possess
one or more predictive risk factors for coronary artery disease (CAD).<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 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 aredetermined to have a satisfactory cardiovascular evaluation, it is strongly
recommended that administration of the first dose of sumatriptan injection
take place in the setting of a physician's office or similar medically
staffed and equipped facility.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 Injection, 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. In considering this recommendation for periodic
cardiovascular evaluation, it is noted that patients with cluster headache
are predominantly male and over 40 years of age, which are risk factors
for CAD. 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 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 patientswith 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 CAD, the relationship is uncertain.<br/>Premarketing Experience With Sumatriptan: 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. 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
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.<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, the majority 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 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/>Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake
Inhibitors and Serotonin Syndrome: Cases of life threatening serotonin syndrome have been reported
during combined use of selective serotonin reuptake inhibitors (SSRIs) or
serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant
treatment with IMITREX Injection is clinically warranted, careful observation
of the patientis 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 nearly double those
obtained under other conditions. Accordingly, the coadministration of sumatriptan
and an MAO-A inhibitor is not generally recommended. If such therapy is clinically
warranted, however, suitable dose adjustment and appropriate observation of
the patient is advised (see CLINICAL PHARMACOLOGY: Drug Interactions: Monoamine Oxidase Inhibitors).<br/>Use in Women of Childbearing Potential: (see PRECAUTIONS: Pregnancy)<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 Injection is
indicated for 1) the acute treatment of migraine attacks with or without aura
and 2) the acute treatment of cluster headache episodes. IMITREX
Injection is not for use in the management of hemiplegic or basilar migraine
(see CONTRAINDICATIONS).
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| dailymed-instance:name |
IMITREX
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