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 of fertility. 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.
Pediatric Use
Sulfamethoxazole; trimethoprim is not recommended for infants
younger than 2 months of age (see INDICATIONS AND USAGE
and CONTRAINDICATIONS).
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