WARNINGS
FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF
SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS,
INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS,
FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA, AND
OTHER BLOOD DYSCRASIAS.
SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCS
SUCH AS SULFAMETHOXAZOLE; TRIMETHOPRIM SHOULD BE DISCONTINUED AT
THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION.
In rare instances, a skin rash may be followed by a more severe
reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis,
hepatic necrosis and serious blood disorder (see PRECAUTIONS ).
Clinical signs, such as rash, sore throat, fever,
arthralgia, pallor, purpura or jaundice may be early indications
of serious reactions.
The sulfonamides should not be used for the treatment
of group A beta-hemolytic streptococcal infections. In an established
infection, they will not eradicated the streptococcus and, therefore,
will not prevent sequelae such as rheumatic fever.
Pseudomembranous colitis has been reported with nearly
all antibacterial agents, including sulfamethoxazole; trimethoprim,
and may range in severity from mild to life-threatening. Therefore,
it is important to consider this diagnosis in patients who present
with diarrhea subsequent to the administration of antibacterial
agents.
Treatment with antibacterial agents alters the normal
flora of the colon and may permit overgrowth of clostridia. Studies
indicate that a toxin produced by Clostridium difficile is one primary
cause of "antibiotic-associated colitis."
After the diagnosis of pseudomembranous colitis has
been established, therapeutic measures should be initiated. Mild
cases of pseudomembranous colitis usually respond to drug discontinuation
alone. In moderate to severe cases, consideration should be given
to management with fluids and electrolytes, protein supplementation,
and treatment with an antibacterial drug effective against C. difficile.
Additional Information for IV Infusion: Contains
sodium metabisulfite, a sulfite that may cause allergic-type reactions,
including anaphylactic symptoms and life-threatening or less severe
asthmatic episodes in certain susceptible people. The overall prevalence
of sulfite sensitivity in the general population is unknown and
probably low. Sulfite sensitivity is seen more frequently in asthmatic
than in nonasthmatic people.Contains benzyl alcohol. In newborn
infants, benzyl alcohol has been associated with an increased incidence
of neurological and other complications which are sometimes fatal.
PRECAUTIONS
General
Sulfamethoxazole; trimethoprim should be given with
caution to patients with impaired renal or hepatic function, to
those with possible folate deficiency (e.g., the elderly, chronic
alcoholics, patients receiving anticonvulsant therapy, patients
with malabsorption syndrome, and patients in malnutrition states),
and to those with severe allergy or bronchial asthma. In glucose-6-phosphate
dehydrogenase deficient individuals, hemolysis may occur. This reaction
is frequently dose-related (see CLINICAL PHARMACOLOGY).
Additional Information for IV Infusion: Adequate
fluid intake must be maintained in order to prevent crystalluria
and stone formation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Local iritation and inflammation due to extravascular
infiltration of the infusion has been observed with sulfamethoxazole;
trimethoprim IV infusion. If these occur, the infusion should be
discontinued and restarted at another site.
Geriatric Use
There may be an increased risk of severe adverse
reactions in elderly patients, particularly when complicating conditions
exist, (e.g., impaired kidney and/or liver function, or concomitant
use of other drugs). Severe skin reactions, or generalized bone
marrow suppression (see
WARNINGS
and ADVERSE REACTIONS), or a specific decrease in platelets (with
or without purpura) are the most frequently reported severe adverse
reactions in elderly patients. In those concurrently receiving certain
diuretics, primarily thiazides, an increased incidence of thrombocytopenia
with purpura has been reported. Appropriate dosage adjustments should
be made for patients with impaired kidney function (see DOSAGE AND
ADMINISTRATION).
Use in the Treatment of and Prophylaxis for Pneumocystis
Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome
(AIDS)
The incidence of side effects, particularly rash,
fever, leukopenia and elevated aminotransferase (transaminase) values
in AIDS patients who are being treated with sulfamethoxazole; trimethoprim
for Pneumocystis carinii pneumonia has been reported to be greatly
increased compared with the incidence normally associated with the
use of sulfamethoxazole; trimethoprim in non-AIDS patients. The
incidence of hyperkalemia and hyponatremia appears to be increased
in AIDS patients receiving sulfamethoxazole; trimethoprim. Additional
Information for Tablets and Suspensions Only: Adverse effects are
generally less severe in patients receiving sulfamethoxazole; trimethoprim
for prophylaxis. A history of mild intolerance to sulfamethoxazole;
trimethoprim in AIDS patients does not appear to predict intolerance
of subsequent secondary prophylaxis.5 However, if a patient develops
skin rash or any sign of adverse reaction, therapy with sulfamethoxazole;
trimethoprim should be re-evaluated (see WARNINGS ).
The concomitatnt use of leucovorin with oral and
IV infusion sulfamethoxazole; trimethoprim for the acute treatment
of Pneumocystis carinii pneumonia in patients with HIV infection
was associated with increased rates of treatment failure and morbidity
in a placebo-controlled study.
Information for the Patient
Tablets and Suspensions Only: Patients should be
instructed to maintain an adequate fluid intake in order to prevent
crystalluria and stone formation.
Laboratory Tests
Complete blood counts should be done frequently in
patients receiving sulfamethoxazole; trimethoprim; if a significant
reduction in the count of any formed blood element is noted, sulfamethoxazole;
trimethoprim should be discontinued. Urinalyses with careful microscopic
examination and renal function tests should be performed during
therapy, particularly for those patients with impaired renal function.
Additional Information for IV Infusion: Appropriate culture and
susceptibility studies should be performed before and throughout
treatment.
Drug/Laboratory Test Interactions
Sulfamethoxazole; trimethoprim, specifically the
trimethoprim component, can interfere with a serum methotrexate
assay as determined by the competitive binding protein technique
(CBPA) when a bacterial dihydrofolate reductase is used as the binding
protein. No interference occurs, however, if methotrexate is measured
by a radioimmunoassay (RIA).
The presence of sulfamethoxazole; trimethoprim may
also interfere with the Jaffe alkaline picrate reaction assay for
creatinine, resulting in overestimations of about 10% in the range
of normal values.
Carcinogenesis, Mutagenesis, and Impairment
of Fertility
Carcinogenesis: Long-term studies in animals to evaluate
carcinogenic potential have not been conducted with sulfamethoxazole;
trimethoprim.
Mutagenesis: Bacterial mutagenic studies have not
been performed with sulfamethoxazole; trimethoprim in combination.
Trimethoprim was demonstrated to be non-mutagenic in the Ames assay.
In studies at two laboratories, no chromosomal damage was detected
in cultured Chinese hamster ovary cells at concentrations approximately
500 times human plasma levels; at concentrations approximately 1000
times human plasma levels in these same cells, a low level of chromosomal
damage was induced at one of the laboratories. No chromosomal abnormalities
were observed in cultured human leukocytes at concentrations of
trimethoprim up to 20 times human steady-state plasma levels. No
chromosomal effects were dettected in peripheral lymphocytes of
human subjects receiving 320 mg of trimethoprim in combination with
up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.
Impairment of Fertility: Tablets and Suspensions:
No adverse effects on fertility or general reproductive performance
were observed in rats given oral dosages as high as 70 mg/kg/day
trimethoprim plus 350 mg/kg/day sulfamethoxazole. IV Infusion: Sulfamethoxazole;
trimethoprim IV infusion has not been studied in animals for evidence
of impairment offertility. However, studies in rats at oral dosages
as high as 70 mg/kg trimethoprim plus 350 mg/kg sulfamethoxazole
daily showed no adverse effects on fertility or general reproductive
performance.
Pregnancy, Teratogenic Effects, Pregnancy
Category C
In rats, oral doses of 533 mg/kg sulfamethoxazole
or 200 mg/kg trimethoprim produced teratologic effects manifested
mainly as cleft palates. The highest dose which did not cause cleft
palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg trimethoprim
when administered separately. In two studies in rats, no teratogenicity
was observed when 512 mg/kg of sulfamethoxazole was used in combination
with 128 mg/kg of trimethoprim. In one study, however, cleft palates
were observed in one litter out of 9 when 355 mg/kg of sulfamethoxazole
was used in combination with 88 mg/kg of trimethoprim.
In some rabbit studies, an overall increase in fetal
loss (dead and resorbed and malformed conceptuses) was associated
with doses of trimethoprim 6 times the human therapeutic dose.
While there are no large, well-controlled studies
on the use of sulfamethoxazole; trimethoprim in pregnant women,
Brumfitt and Pursell,5 in a retrospective study, reported the outcome
of 186 pregnancies during which the mother received either placebo
or oral sulfamethoxazole; trimethoprim. The incidence of congenital
abnormalities was 4.5% (3 of 66) in those who received placebo and
3.3% (4 of 120) in those receiving sulfamethoxazole; trimethoprim.
There were no abnormalities in the 10 pediatric patients whose mothers
received the drug during the first trimester. In a separate survey,
Brumfitt and Pursell also found no congenital abnormalities in 35
pediatric patients whose mothers had received oral sulfamethoxazole;
trimethoprim at the time of conception or shortly thereafter.
Because sulfamethoxazole; trimethoprim may interfere
with folic acid metabolism, sulfamethoxazole; trimethoprim should
be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.Nonteratogenic Effects: See CONTRAINDICATIONS.
Nursing Mothers
See CONTRAINDICATIONS.
Sulfamethoxazole; trimethoprim is not recommended
for infants younger than 2 months of age (see INDICATIONS AND USAGE
and CONTRAINDICATIONS).
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