Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2781
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TREXIMET (Tablet)
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TREXIMET is a fixed combination containing
doses of sumatriptan (85 mg) and naproxen sodium (500 mg)
within the approved dosage ranges of the individual components (25
to 100 mg of sumatriptan and 220 to 825 mg of naproxen sodium).
TREXIMET contains a dose of sumatriptan higher than the lowest effective
dose. Individuals may vary in response to doses of sumatriptan. The
choice of the dose of sumatriptan, and of the use of a fixed dose
combination such as in TREXIMET should therefore be made on an individual
basis, weighing the possible benefit of a higher dose of sumatriptan
with the potential for a greater risk of adverse events. Carefully
consider the potential benefits and risks of TREXIMET and other treatment
options when deciding to use TREXIMET. The recommended dose is 1 tablet. In controlled clinical trials,
single doses of TREXIMET were effective for the acute treatment of
migraine in adults (see CLINICAL TRIALS). The
efficacy of taking a second dose has not been established. Do not
take more than 2 TREXIMET tablets in 24 hours. Dosing of tablets should
be at least 2 hours apart. The safety of treating an average
of more than 5 migraine headaches in a 30-day period has not been
established. TREXIMET may be administered
with or without food. Tablets should not be split, crushed,
or chewed. The combined use of TREXIMET with
MAO-A inhibitors or use of TREXIMET within 2 weeks of discontinuation
of MAO-A inhibitor therapy is contraindicated (see CONTRAINDICATIONS,
CLINICAL PHARMACOLOGY: Drug Interactions, PRECAUTIONS: Drug Interactions). TREXIMET and any ergotamine-containing or ergot-type
medication (like dihydroergotamine or methysergide) should not be
used within 24 hours of each other. TREXIMET and other 5-HTagonists should not be administered within 24 hours
of each other (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions). TREXIMET is contraindicated in patients with hepatic
impairment (see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Special
Populations). TREXIMET is not recommended for
use in patients with creatinine clearance less than 30 mL/min
(see CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS: Renal
Effects).
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| dailymed-instance:descripti... |
TREXIMET contains sumatriptan (as the succinate),
a selective 5-hydroxytryptamine(5-HT) receptor subtype agonist, and naproxen sodium, a member
of the arylacetic acid group of nonsteroidal anti-inflammatory drugs
(NSAIDs). 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. Naproxen sodium is chemically
designated as (S)-6-methoxy-��-methyl-2-naphthaleneacetic acid,
sodium salt, and it has the following structure: The empirical formula is CHNaO, representing a molecular weight of 252.23.
Naproxen sodium is a white-to-creamy white crystalline solid, freely
soluble in water at neutral pH. Each TREXIMET
Tablet for oral administration contains 119 mg of sumatriptan
succinate equivalent to 85 mg of sumatriptan and 500 mg
of naproxen sodium. Each tablet also contains the inactive ingredients
croscarmellose sodium, dextrose monohydrate, dibasic calcium phosphate,
FD&C Blue No. 2, lecithin, magnesium stearate, maltodextrin, microcrystalline
cellulose, povidone, sodium bicarbonate, sodium carboxymethylcellulose,
talc, and titanium dioxide.
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Mechanism of Action: TREXIMET contains sumatriptan,
a 5-HTreceptor agonist that mediates vasoconstriction
of the human basilar artery and vasculature of human dura mater, which
correlates with the relief of migraine headache. It also contains
naproxen, an NSAID that inhibits the synthesis of inflammatory mediators.
Therefore, sumatriptan and naproxen contribute to the relief of migraine
through pharmacologically different mechanisms of action. Sumatriptan is a 5-HTreceptor agonist that
binds with high affinity to 5-HTand 5-HTreceptors. Sumatriptan has only a weak affinity for 5-HT, 5-HT, and 5-HTreceptors and no significant
affinity (as measured using standard radioligand binding assays) or
pharmacological activity at 5-HT, 5-HTor
5-HTreceptor subtypes or at alpha-, alpha-, or beta-adrenergic; dopamine; dopamine; muscarinic; or benzodiazepine receptors. 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
carotid arterial blood flow with little or no effect on arterial blood
pressure or total peripheral resistance. Naproxen
sodium is an NSAID with analgesic and antipyretic properties. The
sodium salt of naproxen has been developed as a more rapidly absorbed
formulation of naproxen for use as an analgesic. The mechanism of
action of the naproxen anion, like that of other NSAIDs, is not completely
understood but may be related to prostaglandin synthetase inhibition.<br/>Pharmacokinetics: TREXIMET is a formulation of 85 mg
of sumatriptan (as sumatriptan succinate) and 500 mg of naproxen
sodium with a distinct pharmacokinetic profile. Cfor sumatriptan following administration of TREXIMET occurs
at approximately 1 hour (median, range 0.3 to 4.0 hours).
Cfor naproxen following administration
of TREXIMET occurs at approximately 5 hours (median, range 0.3
to 12 hours). The sumatriptan half-life is approximately 2 hours
(15% to 43% CV) and the naproxen half-life is approximately 19 hours
(13% to 15% CV). The mean Cfor sumatriptan
when given as TREXIMET is similar to that of sumatriptan when given
as IMITREX Tablets 100 mg alone.The median
sumatriptan Tis only slightly different
(1 hour for TREXIMET and 1.5 hours for IMITREX). The Cfor naproxen is approximately 36% lower,
and the Toccurs approximately 4 hours
later from TREXIMET than from ANAPROX DS (naproxen sodium tablets) 550 mg. AUC values for sumatriptan
and for naproxen are similar for TREXIMET compared to IMITREX or ANAPROX
DS, respectively. In a crossover study in 16 patients, the pharmacokinetics
of both components administered as TREXIMET were similar during a
migraine attack and during a migraine-free period.<br/>Absorption and Bioavailability: Bioavailability of sumatriptan
is approximately 15%, primarily due to presystemic (first-pass) metabolism
and partly due to incomplete absorption. Naproxen
is rapidly and completely absorbed from the gastrointestinal tract
with an in vivo bioavailability of 95%.<br/>Food Effects: Food had no significant effect on the bioavailability
of sumatriptan or naproxen administered as TREXIMET, but slightly
delayed the Tof sumatriptan by about 0.6 hour. These data indicate that TREXIMET may be administered
without regard to food.<br/>Distribution: The volume of distribution of sumatriptan is 2.4 L/kg.
Plasma protein binding is 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 protein binding. The volume of distribution of naproxen is 0.16 L/kg.
At therapeutic levels naproxen is greater than 99% albumin bound.
At doses of naproxen greater than 500 mg/day, there is a less
than proportional increase in plasma levels due to an increase in
clearance caused by saturation of plasma protein binding at higher
doses (average trough C= 36.5, 49.2, and 56.4 mg/L
with 500, 1,000, and 1,500 mg daily doses of naproxen, respectively).
However, the concentration of unbound naproxen continues to increase
proportionally to dose.<br/>Metabolism: Most of a radiolabeled dose of sumatriptan excreted
in the urine is the major metabolite indole acetic acid (IAA) or the
IAA glucuronide, both of which are inactive. Three percent of the
dose can be recovered as unchanged sumatriptan. In vitro studies with
human microsomes suggest that sumatriptan is metabolized by monoamine
oxidase (MAO), predominantly the A isoenzyme, and inhibitors of that
enzyme may alter sumatriptan pharmacokinetics to increase systemic
exposure (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions: Monoamine Oxidase-A Inhibitors). No
significant effect was seen with an MAO-B inhibitor. Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and
both parent and metabolites do not induce metabolizing enzymes.<br/>Elimination: RadiolabeledC-sumatriptan administered
orally is largely renally excreted (about 60%), with about 40% found
in the feces. The elimination half-life of sumatriptan is approximately
2 hours. The clearance of naproxen is 0.13 mL/min/kg.
Approximately 95% of the naproxen from any dose is excreted in the
urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen
(less than 1%), or their conjugates (66% to 92%). The plasma half-life
of the naproxen anion in humans is approximately 19 hours. The
corresponding half-lives of both metabolites and conjugates of naproxen
are shorter than 12 hours, and their rates of excretion have
been found to coincide closely with the rate of naproxendisappearance
from the plasma. In patients with renal failure, metabolites may accumulate
(see PRECAUTIONS: Renal Effects).<br/>Special Populations:<br/>Renal Impairment: TREXIMET is not recommended for use in patients
with creatinine clearance less than 30 mL/min (see PRECAUTIONS:
Renal Effects). The effect of renal impairment on the pharmacokinetics
of TREXIMET has not been studied. Minimal change
in clinical effect would be expected with regard to sumatriptan as
it is largely metabolized to an inactive substance. Since naproxen and its metabolites and conjugates are primarily
excreted by the kidney, the potential exists for naproxen metabolites
to accumulate in the presence of renal insufficiency. Elimination
of naproxen is decreased in patients with severe renal impairment.<br/>Hepatic Impairment: Because TREXIMET is a fixed-dose combination
that cannot be adjusted for this patient population, it is contraindicated
in patients with hepatic impairment (see CONTRAINDICATIONS
and PRECAUTIONS: Hepatic Effects). The effect of hepatic impairment
on the pharmacokinetics of TREXIMET has not been studied. Sumatriptan is contraindicated in patients with severe hepatic impairment
and the dose is limited to 50 mg in patients with liver disease.<br/>Age: The effect of age (elderly or pediatric patients)
on the pharmacokinetics of TREXIMET has not been studied. Elderly
patients are more likely to have decreased hepatic function and decreased
renal function (see PRECAUTIONS: Geriatric Use). 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).<br/>Gender: In a pooled analysis of 5 pharmacokinetic studies,
there was no effect of gender on the systemic exposure of TREXIMET.
In a study comparing the pharmacokinetics of sumatriptan in females
and males, no differences were observed between genders for AUC, C, T, and T.<br/>Race: The effect of race on the pharmacokinetics of TREXIMET
has not been studied. The systemic clearance and Cof
sumatriptan were similar in black (n = 34) and Caucasian
(n = 38) healthy male subjects.<br/>Drug Interactions: No formal drug interaction studies have been conducted
with TREXIMET.<br/>Monoamine Oxidase Inhibitors: TREXIMET is contraindicated in patients
taking MAO-A inhibitors (see CONTRAINDICATIONS and PRECAUTIONS:
Drug Interactions). Treatment with MAO-A inhibitors generally leads
to an increase of sumatriptan plasma levels. This interaction has
not been seen with an MAO-B inhibitor.<br/>Alcohol: The effect of alcohol consumption on the pharmacokinetics
of TREXIMET has not been studied. Alcohol consumed 30 minutes
prior to sumatriptan ingestion had no effect on the pharmacokinetics
of sumatriptan.
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Cardiac, Cerebrovascular, or Peripheral
Vascular Disease: TREXIMET 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 TREXIMET, nor should patients who have had coronary artery
bypass graft (CABG) surgery. Ischemic cardiac syndromes include, but
are notlimited 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: Cardiovascular Effects).<br/>Uncontrolled Hypertension: TREXIMET should not be
given to patients with uncontrolled hypertension because the components
have been shown to increase blood pressure.<br/>Monoamine Oxidase-A Inhibitors: Concurrent administration
of MAO-A inhibitors or use of TREXIMET within 2 weeks of discontinuation
of MAO-A inhibitor therapy is contraindicated (see CLINICAL PHARMACOLOGY:
Drug Interactions and PRECAUTIONS: Drug Interactions).<br/>Ergotamine-Containing or Ergot-Type
Medications: TREXIMET and any ergotamine-containing
or ergot-type medication (like dihydroergotamine or methysergide)
should not be used within 24 hours of each other (see PRECAUTIONS:
Drug Interactions).<br/>Other 5-HTAgonists: Since TREXIMET contains
sumatriptan, it should not be administered within 24 hours of another
5-HTagonist.<br/>Hemiplegic or Basilar Migraine: TREXIMET should not be
administered to patients with hemiplegic or basilar migraine.<br/>Hepatic Impairment: TREXIMET is contraindicated
in patients with hepatic impairment (see CLINICAL PHARMACOLOGY: Special
Populations, PRECAUTIONS: Hepatic Effects, and PRECAUTIONS: Geriatric
Use).<br/>Allergy to Naproxen/Asthma, Nasal
Polyps, Urticaria, and Hypotension Associated With Nonsteroidal Anti-inflammatory
Drugs: TREXIMET is contraindicated
in patients who have had allergic reactions to prescription as well
as to over-the-counter products containing naproxen. It is also contraindicated
in patients in whom aspirin or other nonsteroidal anti-inflammatory/analgesic
drugs induce the syndrome of asthma, rhinitis, and nasal polyps. Anaphylactic/anaphylactoid
reactions to naproxen, whether of the true allergic type or the pharmacologic
idiosyncratic type (e.g., aspirin hypersensitivity syndrome), usually
but not always occur in patients with a known history of such reactions.
Both types of reactions have the potential of being fatal. Therefore,
careful questioning of patients for medical conditions such as asthma,
nasal polyps, urticaria, and hypotension associated with NSAIDs before
starting therapy is important. In addition, if such symptoms occur
during therapy, treatment should be discontinued (see WARNINGS: Anaphylactic/Anaphylactoid
Reactions and PRECAUTIONS: Preexisting Asthma).<br/>Hypersensitivity to Sumatriptan or
Naproxen: TREXIMET is contraindicated
in patients with hypersensitivity to sumatriptan, naproxen, or any
other component of the product.
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TREXIMET contains 119 mg of sumatriptan succinate
equivalent to 85 mg of sumatriptan and 500 mg of naproxen
sodium and is supplied as blue film-coated tablets debossed on one
side with GS YYG in compact containers of 9 tablets with a specially
formulated, non-removable desiccant (NDC 0173-0750-00). Store at 25��C (77��F);
excursions permitted to 15��-30��C (59��-86��F) [see
USP Controlled Room Temperature]. Do not repackage; dispense and store
in original container.
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WARNINGS:<br/>Cardiovascular Risk: TREXIMET may cause an
increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase
with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk (see WARNINGS:
Cardiovascular Effects).<br/>Gastrointestinal Risk: TREXIMET contains a nonsteroidal
anti-inflammatory drug (NSAID). NSAID-containing products cause an
increased risk of serious gastrointestinal adverse events including
bleeding, ulceration, and perforation of the stomach or intestines,
which can be fatal. These events can occur at any time during use
and without warning symptoms. Elderly patients are at greater risk
for serious gastrointestinal events (see WARNINGS: Risk of Gastrointestinal
Ulceration, Bleeding, and Perforation With Nonsteroidal Anti-inflammatory
Drug Therapy).
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dailymed-ingredient:FD&C_Blue_No._2,
dailymed-ingredient:croscarmellose_sodium,
dailymed-ingredient:dextrose_monohydrate,
dailymed-ingredient:dibasic_calcium_phosphate,
dailymed-ingredient:lecithin,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:maltodextrin,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:povidone,
dailymed-ingredient:sodium_bicarbonate,
dailymed-ingredient:sodium_carboxymethylcellulose,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide
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Naproxen-Containing Products: TREXIMET and other naproxen-containing
products should not be used concomitantly since they all circulate
in the plasma as the naproxen anion.<br/>Chest, Jaw, or Neck Pain/Discomfort: Chest discomfort and jaw or neck tightness have
been reported following use of sumatriptan. 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 TREXIMET should be
evaluated for the presence of CAD or a predisposition to Prinzmetal
variant angina before receiving additional doses of TREXIMET 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 TREXIMET should be evaluated
for atherosclerosis or predisposition to vasospasm (see WARNINGS:
Cardiovascular Effects).<br/>Diseases That May Alter the Absorption,
Metabolism, or Excretion of Drugs: TREXIMET should also be administered with caution
to patients with diseases that may alter the absorption, metabolism,
or excretion of drugs, such as impaired renal function.<br/>Seizures: TREXIMET should be used with caution in patients
with a history of epilepsy or conditions associated with a lowered
seizure threshold. There have been reports of seizure following administration
of sumatriptan.<br/>Other Potentially Serious Neurologic
Conditions: 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 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 TREXIMET, the diagnosis of migraine should be reconsidered before
administration of a second dose.<br/>Hepatic Effects: TREXIMET is contraindicated
in patients with hepatic impairment (see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY). A patient with symptoms and/or signs
suggesting liver dysfunction or in whom an abnormal liver test has
occurred should be evaluated for evidence of the development of a
more severe hepatic reaction while on therapy with TREXIMET. Borderline
elevations of 1 or more liver tests may occur in up to 15% of patients
who take NSAID-containing products. These abnormalities may progress,
may remain essentially unchanged, or may be transient with continued
therapy. Notable (3 times the upper limit of normal) elevations of
SGPT (ALT) or SGOT (AST) have been reported in approximately 1% of
patients in clinical trials with NSAIDs. In addition, cases of severe
hepatic reactions, including jaundice and fatal fulminant hepatitis,
liver necrosis, and hepatic failure, some of them with fatal outcomes,
have been reported with NSAIDs. A patient with symptoms and/or signs
suggesting liver dysfunction, or in whom an abnormal liver test has
occurred, should be evaluated for evidence of the development of a
more severe hepatic reaction while on therapy with TREXIMET. If clinical
signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash), TREXIMET should be
discontinued.<br/>Binding to Melanin-Containing Tissues: In rats treated with a single subcutaneous dose
(0.5 mg/kg) or oral dose (2 mg/kg) of radiolabeled sumatriptan,
the elimination half-life of radioactivity from the eye was 15 and
23 days, respectively, suggesting that sumatriptan and/or its
metabolites bind to the melanin of the eye. Because there could be
an accumulation in melanin-rich tissues over time, sumatriptan could
possibly 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 (see ANIMAL TOXICOLOGY). Adverse
eye findings have also been observed in animal studies with some NSAIDs.
Patients were not systematically evaluated for these changes in clinical
trials. However, since the animal findings raise the possibility that
adverse effects on the eye may occur in humans, it is recommended
that ophthalmic studies be carried out if any change or disturbance
in vision occurs.<br/>Renal Effects: Caution is recommended in patients with preexisting
kidney disease or dehydration (see WARNINGS: Renal Effects). Naproxen
and its metabolites are eliminated primarily by the kidneys; therefore,
TREXIMET should be used with caution in patients with significantly
impaired renal function, and monitoring of serum creatinine and/or
creatinine clearance is advised in these patients. TREXIMET is not
recommended for use in patients with creatinine clearance less than
30 mL/min (see CLINICAL PHARMACOLOGY: Special Populations).<br/>Hematological Effects: Patients on long-term treatment with NSAIDs,
including TREXIMET, should have
their hemoglobin or hematocrit checked if they exhibit any signs or
symptoms of anemia. Anemia is sometimes seen in patients receiving
NSAIDs. This may be due to fluid retention, occult or gross gastrointestinal
blood loss, or an incompletely described effect upon erythropoiesis. Patients receiving TREXIMET who may be adversely affected
by alterations in platelet function, such as those with coagulation
disorders or patients receiving anticoagulants, should be carefully
monitored. NSAID-containing products inhibit platelet aggregation
and have been shown to prolong bleeding time in some patients. Unlike
aspirin, their effect on platelet function is quantitatively less,
of shorter duration, and reversible.<br/>Preexisting Asthma: Patients with asthma
may have aspirin-sensitive asthma. The use of aspirin in patients
with aspirin-sensitive asthma has been associated with severe bronchospasm
that can be fatal. Since cross reactivity, including bronchospasm,
between aspirin and other NSAIDs has been reported in such aspirin-sensitive
patients, TREXIMET should not be administered to
patients with this form of aspirin sensitivity
and should be used with caution in patients with preexisting asthma.<br/>Information for Patients: Patients should be informed of the following information
before initiating therapy with TREXIMET and periodically during the
course of ongoing therapy. Patients should also be encouraged to read
the Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious gastrointestinal tract ulcerations
and bleeding can occur without warning symptoms, physicians should
monitor for signs or symptoms of gastrointestinal bleeding. If clinical
signs and symptoms consistent with liver or renal disease develop,
systemic manifestations occur (e.g., eosinophilia, rash), orabnormal
liver tests persist or worsen, TREXIMET should be discontinued.<br/>Drug Interactions:<br/>Monoamine Oxidase-A Inhibitors: The use of TREXIMET in patients receiving MAO-A
inhibitors is contraindicated (see CLINICAL PHARMACOLOGY: Drug Interactions
and CONTRAINDICATIONS). MAO-A inhibitors reduce sumatriptan clearance,
significantly increasing systemic exposure. In patients taking MAO-A
inhibitors, sumatriptan plasma levels attained after treatment with
recommended doses are 7-fold higher following oral administration
than those obtained under other conditions.<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 (e.g., dihydroergotamine, methysergide) and
TREXIMET within 24 hours of each other should be avoided (see
CONTRAINDICATIONS).<br/>Methotrexate: Caution should be used if TREXIMET is administered
concomitantly with methotrexate. Naproxen sodium and other NSAIDs
have been reported to reduce the tubular secretion of methotrexate
in an animal model, possibly increasing the toxicity of methotrexate.
Concomitant administration of some NSAIDs with high-dose methotrexate
therapy has been reported to elevate and prolong serum methotrexate
levels, resulting in deaths from severe hematologic and gastrointestinal
toxicity.<br/>Aspirin: When naproxen is administered with aspirin,
its protein binding is reduced, although the clearance of free naproxen
is not altered. The clinical significance of this interaction is not
known; however, as with other NSAID-containing products, concomitant
administration of TREXIMET and aspirin is not generally
recommended because of the potential of increased adverse effects.<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: Serotonin Syndrome).<br/>Angiotensin-Converting Enzyme
Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive
effect of ACE inhibitors. The use of TREXIMET in patients who are
receiving ACE inhibitors may potentiate renal disease states (see
WARNINGS: Renal Effects).<br/>Furosemide: Clinical studies, as well as postmarketing observations,
have shown that NSAIDs can reduce the natriuretic effect of furosemide
and thiazides in some patients. This response has been attributed
to inhibition of renal prostaglandin synthesis. During concomitant
therapy with NSAIDs, the patient should be observed closely for signs
of renal failure (see WARNINGS: Renal Effects), as well as to assure
diuretic efficacy.<br/>Lithium: NSAIDs have produced an elevation of plasma lithium
levels and a reduction in renal lithium clearance. The mean minimum
lithium concentration increased 15%, and the renal clearance was decreased
by approximately 20%. These effects have been attributed to inhibition
of renal prostaglandin synthesis by the NSAID. Thus, when TREXIMET
and lithium are administered concurrently, patients should be observed
carefully for signs of lithium toxicity.<br/>Probenecid: Probenecid given concurrently increases naproxen
anion plasma levels and extends its plasma half-life significantly.<br/>Propranolol and Other Beta-Blockers: Propranolol 80 mg given twice daily had no
significant effect on sumatriptan pharmacokinetics. Naproxen and other
NSAIDs can reduce the antihypertensive effect of propranolol and other
beta-blockers.<br/>Warfarin: The effects of warfarin and NSAIDs on gastrointestinal
bleeding are synergistic, such that patients taking both drugs have
a higher risk of serious gastrointestinal bleeding than patients taking
either drug alone.<br/>Drug/Laboratory Test Interactions: The ability of TREXIMET to interfere with commonly
employed clinical laboratory tests has not been investigated. Sumatriptan is not known to interfere with commonly employed
clinical laboratory tests. Naproxen may decrease platelet aggregation
and prolong bleeding time. This effect should be kept in mind when
bleeding times are determined. The administration
of naproxen sodium may result in increased urinary values for 17-ketogenic
steroids because of an interaction between the drug and/or its metabolites
with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid
measurements (Porter-Silber test) do not appear to be artifactually
altered, it is suggested that therapy with naproxen be temporarily
discontinued 72 hours before adrenal function tests are performed
if the Porter-Silber test is to be used. Naproxen
may interfere with some urinary assays of 5-hydroxy indoleacetic acid
(5HIAA).<br/>Carcinogenesis, Mutagenesis, Impairment
of Fertility:<br/>Carcinogenesis: The carcinogenic potential of TREXIMET has not been
studied. The carcinogenic potential of sumatriptan
was evaluated in oral carcinogenicity studies in mice (78 weeks)and rats (104 weeks). The highest dose administered to mice and
rats (160 mg/kg/day) is approximately 9 and 18 times, respectively,
the recommended human oral daily dose of 85 mg sumatriptan on
a mg/mbasis. There was no evidence of an increase in
tumors in either species related to sumatriptan administration. The carcinogenic potential of naproxen sodium was evaluated
in a 2-year oral carcinogenicity study in rats at doses of 8, 16,
and 24 mg/kg/day and in another 2-year oral carcinogenicity study
in rats at a dose of 8 mg/kg/day. No evidence of tumorigenicity
was found in either study, at doses up to approximately 0.5 times
the recommended human oral daily dose of 500 mg/day naproxen
sodium on a mg/mbasis.<br/>Mutagenesis: Sumatriptan and naproxen sodium tested alone and
in combination were negative in an in vitro bacterial reverse mutation
assay, and in an in vivo micronucleus assay in mice. The combination of sumatriptan and naproxen sodium was negative
in an in vitro mouse lymphoma tk assay in the presence and absence
of metabolic activation. However, in separate in vitro mouse lymphoma
tk assays, naproxen sodium alone was reproducibly positive in the
presence of metabolic activation. Naproxen
sodium alone and in combination with sumatriptan was positive in an
in vitro clastogenicity assay in mammalian cells in the presence and
absence of metabolic activation. The clastogenic effect for the combination
was reproducible within this assay and was greater than observed with
naproxen sodium alone. Sumatriptan alone was negative in these assays. Chromosomal aberrations were not induced in
peripheral blood lymphocytes following 7 days of twice-daily dosing
with TREXIMET in human volunteers. In previous studies, sumatriptan alone was not mutagenic in 2 gene
mutation assays (the Ames test and the in vitro Chinese Hamster V79/HGPRT
assay) and was not clastogenic in 2 cytogenetics assays (the in vitro
human lymphocyte assay and the in vivo rat micronucleus assay).<br/>Impairment of Fertility: The effect of TREXIMET on fertility in animals has
not been studied. 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 0.5 times the recommended
human oral daily dose of 85 mg sumatriptan 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 of sumatriptan
by the subcutaneous route there was no evidence of impaired fertility
at doses up to 60 mg/kg/day.<br/>Pregnancy: Pregnancy Category C. In developmental toxicity
studies in rabbits, oral treatment with sumatriptan combined with
naproxen sodium (5/9, 25/45, or 50/90 mg/kg/day sumatriptan/naproxen
sodium) or each drug alone (50/0 or 0/90 mg/kg/day sumatriptan/naproxen
sodium) resulted in decreased fetal body weight in all treated groups
and in increased embryofetal death at the highest dose of naproxen,
alone and in combination with sumatriptan. Naproxen sodium, alone
and in combination with sumatriptan, increased the total incidences
of fetal abnormalities at all doses and increased the incidences of
specific malformations (cardiac interventricular septal defect in
the 50/90-mg/kg/day group, fused caudal vertebrae in the 50/0- and
0/90-mg/kg/day groups) and variations (absent intermediate lobe of
the lung, irregular ossification of the skull, incompletely ossified
sternal centra) in the 50/0- and 0/90-mg/kg/day groups. A no-effect
dose for development toxicity in rabbits was not established. The
lowest effect dose was 5/9 mg/kg/day sumatriptan/naproxen sodium,
which was associated with plasmaexposures (AUC) to sumatriptan and
naproxen that were 1.4 and 0.14 times, respectively, those attained
at the maximum recommended human oral daily dose of 85 mg sumatriptan
and 500 mg naproxen sodium. In previous
developmental toxicity studies in rats and rabbits, oral treatment
with sumatriptan was associated with embryolethality, fetal abnormalities,
and pup mortality. Oral treatment of pregnant rats with sumatriptan
during the period of organogenesis resulted in an increased incidence
of fetal blood vessel (cervicothoracic and umbilical) abnormalities
and decreased pup survival at doses of 250 mg/kg/day or higher.
The highest no-effect dose was approximately 60 mg/kg/day, which
is approximately 7 times the recommended human oral daily dose
of 85 mg sumatriptan 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 at a dose of 50 mg/kg/day and embryolethality
at 100 mg/kg/day. The highest no-effect dose for embryotoxicity
in rabbits was 15 mg/kg/day, or approximately 3 times the
recommended human oral daily dose of 85 mg sumatriptan on a mg/mbasis. Inhibitors of prostaglandin
synthesis (including naproxen) are known to delay parturition. Because
of this and the known effects of drugs of this class on the human
fetal cardiovascular system (closure of the ductus arteriosus), use
during third trimester should be avoided. There
are no adequate and well-controlled studies in pregnant women. TREXIMET should not be used during pregnancy unless the
potential benefit justifies the potential risk to the fetus.<br/>Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed
to TREXIMET, GlaxoSmithKline maintains a TREXIMET Pregnancy Registry.
Physicians are encouraged to register patients as soon as possible
after they become pregnant and (if possible) before the outcome of
the pregnancy is known by calling (800) 336-2176.<br/>Labor and Delivery: In rat studies with NSAIDs, as with other drugs
known to inhibit prostaglandin synthesis, an increased incidence of
dystocia, delayed parturition, and decreased pup survival occurred.
Naproxen-containing products are not recommended in labor and delivery
because, through its prostaglandin synthesis inhibitory effect, naproxen
may adversely affect fetal circulation and inhibit uterine contractions,
thus increasing the risk of uterine hemorrhage.<br/>Nursing Mothers: Both active components of TREXIMET, sumatriptan
and naproxen sodium, have been reported to be excreted in human breast
milk. Because of the possible adverse effects of these drugs on neonates,
use of TREXIMET in nursing mothers should be avoided.<br/>Pediatric Use: Safety and effectiveness of TREXIMET in pediatric
patients have not been established.<br/>Geriatric Use: TREXIMET is contraindicated for use in elderly patients
who have abnormal hepatic function, and is not recommended for use
in elderly patients who have decreased renal function, higher risk
for unrecognized CAD, and increases in blood pressure that may be
more pronounced in the elderly (see CONTRAINDICATIONS: Hepatic Impairment,
WARNINGS: Cardiovascular Effects and CLINICAL PHARMACOLOGY: Pharmacokinetics).
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| dailymed-instance:overdosag... |
Because strategies for the management of overdose
are continually evolving, it is advisable to contact a Poison Control
Center to determine the latest recommendations for the management
of an overdose of any drug. There have been
no reports of overdosage with TREXIMET. Since sumatriptan and naproxen
have pharmacologically different actions, it is difficult to predict
how an individual will respond to an overdosage with TREXIMET. Patients (N = 670) have received single oral
doses of 140 to 300 mg of sumatriptan without significant adverse
effects. Volunteers (N = 174) have received single oral
doses of 140 to 400 mg without serious adverse events. Overdose
of sumatriptan 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. Significant naproxen overdosage
may be characterized by lethargy, dizziness, drowsiness, epigastric
pain, abdominal discomfort, heartburn, indigestion, nausea, transient
alterations in liver function, hypoprothrombinemia, renal dysfunction,
metabolic acidosis, apnea, disorientation, or vomiting. Gastrointestinal
bleeding can occur. Hypertension, acute renal failure, respiratory
depression, and coma may occur, but are rare. Anaphylactoid reactions
have been reported with therapeutic ingestion of NSAIDs, and may occur
following an overdose. Because naproxen sodium may be rapidly absorbed,
high and early blood levels should be anticipated. A few patients
have experienced seizures, but it is not clear whether or not thesewere drug related. It is not known what dose of the drug would be
life threatening. In animals 0.5 g/kg
of activated charcoal was effective in reducing plasma levels of naproxen.
Patients should be managed by symptomatic and supportive care. There
are no specific antidotes. Hemodialysis does not decrease the plasma
concentration of naproxen because of the high degree of its protein
binding. It is unknown what effect hemodialysis or peritoneal dialysis
has on the serum concentrationsof sumatriptan. Emesis and/or activated
charcoal (60 to 100 g in adults, 1 to 2 g/kg in children)
and/or osmotic cathartic may be indicated in patients seen within
4 hours of ingestion with symptoms or following a large overdose.
Forced diuresis, alkalinization of urine, or hemoperfusion may not
be useful due to high protein binding.
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| dailymed-instance:genericMe... |
sumatriptan succinate and naproxen sodium
|
| dailymed-instance:fullName |
TREXIMET (Tablet)
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| dailymed-instance:adverseRe... |
The adverse reactions reported below are specific
to the clinical trials with TREXIMET. See also the full prescribing
information for naproxen and sumatriptan products.<br/>Incidence in Controlled Clinical
Trials: Table 2 lists adverse events that occurred in 2
placebo-controlled clinical trials evaluating patients who took at
least 1 dose of study drug. Only events that occurred at a frequency
of 2% or more with TREXIMET and were more frequent than in the placebo
group are included in Table 2. The events cited reflect experience
gained under closely monitored conditions of clinical trials in a
highly selected patient population. In actual clinical practice or
in other clinical trials, these frequency estimates may not apply,
as the conditions of use, reporting behavior, and the kinds of patients
treated may differ. Other events that occurred in more than 1% of
patients receiving TREXIMET and occurred at a frequency greater than
the placebo group included asthenia, feeling hot, muscle tightness,
and palpitations. TREXIMET was generally well
tolerated. Most adverse reactions were mild and transient. The incidence
of adverse events in controlled clinical trials was not affected by
gender or age of the patients. There were insufficient data to assess
the impact of race on the incidence of adverse events.<br/>Other Events Observed in Migraine
Clinical Trials Associated With the Administration of TREXIMET: The occurrence of less commonly reported adverse
clinical events is presented in this section. Because the reports
include events observed in an open-label, long-term safety study in
which TREXIMET was used as needed for up to 12 months, the role
of TREXIMET cannot be reliably determined. Furthermore, variability
associated with adverse event reporting, the terminology used to describe
adverse events, etc., limit the value of quantitative frequency estimates
provided. Event frequencies are calculated as the number of patients
who used TREXIMET and reported an event divided by the total number
of patients (N = 3,302) exposed to TREXIMET. Events listed
in the previous table and text are not included below. Those events
described too generally to be informative or those unlikely to be
associated with the use of TREXIMET are excluded. Events are further
classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse
events are 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/>Blood and Lymphatic Disorders: Infrequent was lymphadenopathy. Rare were anemia,
ecchymosis, leukopenia.<br/>Cardiac Disorders: Infrequent was tachycardia. Rare were acute coronary
syndrome, cardiac flutter, congestive cardiac failure, right ventricular
failure, ventricular extrasystoles.<br/>Ear and Labyrinth Disorders: Infrequent were ear pain, tinnitus. Rare were motion
sickness, vertigo.<br/>Endocrine, Metabolic, and
Nutrition Disorders: Rare were diabetes mellitus, goiter, hypoglycemia,
hypothyroidism.<br/>Eye Disorders: Infrequent was conjunctivitis. Rare were cataract,
conjunctival hemorrhage, visual disturbance.<br/>Gastrointestinal Disorders: Frequent was abdominal pain. Infrequent were abdominal
distention, constipation, diarrhea, dysgeusia, dysphagia, flatulence,
gastritis, gastroesophageal reflux disease, vomiting. Rare were colitis,
diverticulitis, gastric ulcer, irritable bowel syndrome, oral mucosal
blistering, swollen tongue.<br/>General Disorders: Frequent was fatigue. Infrequent were feeling jittery,
lethargy, malaise, peripheral edema, pyrexia, temperature intolerance,
thirst. Rare was difficulty in walking.<br/>Hepatobiliary Disorders: Rare was biliary colic.<br/>Infections and Infestations: Rare were kidney infection, pneumonia, sepsis, staphylococcal
infection, viral myocarditis.<br/>Musculoskeletal and Connective
Tissue: Infrequent were arthralgia, back pain, muscular
weakness, myalgia, sensation of heaviness.<br/>Nervous System Disorders: Infrequent were burning sensation, disturbance of
attention, insomnia, mental impairment, tremor. Rare were aphasia,
facial palsy, impairment of psychomotor skills, sedation.<br/>Psychiatric Disorders: Infrequent were anxiety, depression, irritability,
nervousness. Rare were disorientation, panic attack.<br/>Renal and Urinary Disorders: Infrequent was nephrolithiasis. Rare was renal insufficiency.<br/>Respiratory, Thoracic, and
Mediastinal: Infrequent were asthma, cough, dyspnea, oropharyngeal
swelling. Rare was pleurisy.<br/>Skin and Subcutaneous Disorders: Infrequent were facial swelling, hyperhydrosis,
pruritus, rash, urticaria. Rare was systemic lupus erythematosus.<br/>Vascular Disorders: Infrequent were flushing, hot flush, hypertension.
Rare were epistaxis, peripheral coldness.
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| dailymed-instance:warning |
Cardiovascular Risk: TREXIMET may cause an
increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase
with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk (see WARNINGS:
Cardiovascular Effects).<br/>Gastrointestinal Risk: TREXIMET contains a nonsteroidal
anti-inflammatory drug (NSAID). NSAID-containing products cause an
increased risk of serious gastrointestinal adverse events including
bleeding, ulceration, and perforation of the stomach or intestines,
which can be fatal. These events can occur at any time during use
and without warning symptoms. Elderly patients are at greater risk
for serious gastrointestinal events (see WARNINGS: Risk of Gastrointestinal
Ulceration, Bleeding, and Perforation With Nonsteroidal Anti-inflammatory
Drug Therapy).
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| dailymed-instance:indicatio... |
TREXIMET is indicated for the acute treatment of
migraine attacks with or without aura in adults. Carefully consider
the potential benefits and risks of TREXIMET and other treatment options
when deciding to use TREXIMET. TREXIMET 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 TREXIMET have not been established for
cluster headache.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
TREXIMET
|