Included as part of the "PRECAUTIONS" Section
Some epidemiologic studies suggest that exposure to BACTRIM during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If BACTRIM is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus [see Use In Specific Populations].
Hypersensitivity And Other Fatal Reactions
Fatalities associated with the administration of sulfonamides, 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 products such as BACTRIM, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. Clinical signs, such as rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura or jaundice may be early indications of serious reactions. A skin rash may be followed by more severe reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis or serious blood disorder. Complete blood counts should be done frequently in patients receiving sulfonamides. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.
BACTRIM-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Monitor patients for hematologic toxicity. Thrombocytopenia usually resolves within a week upon discontinuation of BACTRIM.
Streptococcal Infections And Rheumatic Fever
Avoid use of BACTRIM in the treatment of streptococcal pharyngitis. Clinical studies have documented that patients with group A β-hemolytic streptococcal tonsillopharyngitis have a greater incidence of bacteriologic failure when treated with BACTRIM than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area. Therefore, BACTRIM will not prevent sequelae such as rheumatic fever.
Clostridium Difficile-Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTRIM, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
BACTRIM 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. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.
Benzyl Alcohol Toxicity In Pediatric Patients (“Gasping Syndrome”)
BACTRIM contains benzyl alcohol as a preservative. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved formulations in infusion solutions, including BACTRIM. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. BACTRIM is contraindicated in pediatric patients less than two months of age [see CONTRAINDICATIONS].
When prescribing BACTRIM in pediatric patients (two months of age and older), consider the combined daily metabolic load of benzyl alcohol from all sources including BACTRIM (contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol.
The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use In Specific Populations].
Risk Associated With Concurrent Use Of Leucovorin For Pneumocystis Jirovecii Pneumonia
Treatment failure and excess mortality were observed when BACTRIM was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jirovecii pneumonia in a randomized placebo controlled trial.4 Avoid coadministration of BACTRIM and leucovorin during treatment of Pneumocystis jirovecii pneumonia.
Avoid use of BACTRIM in patients with impaired renal or hepatic function, in 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 in those with severe allergies or bronchial asthma.
Hematologic changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy [see Use In Specific Populations].
In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.
Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with BACTRIM. If these occur the infusion should be discontinued and restarted at another site.
Cases of hypoglycemia in non-diabetic patients treated with BACTRIM have been seen, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of BACTRIM are particularly at risk.
Impaired Phenylalanine Metabolism
Trimethoprim, component of BACTRIM, has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.
Porphyria And Hypothyroidism
Like other drugs containing sulfonamides, BACTRIM can precipitate porphyria crisis and hypothyroidism. Avoid use of BACTRIM in patients with porphyria or thyroid dysfunction.
Potential Risk In The Treatment Of Pneumocystis Jirovecii Pneumonia In Patients With Acquired Immunodeficiency Syndrome (AIDS)
AIDS patients may not tolerate or respond to BACTRIM in the same manner as non-AIDS patients. The incidence of adverse reactions, particularly rash, fever, leukopenia, and elevated aminotransferase (transaminase) values, with BACTRIM therapy in AIDS patients who are being treated for Pneumocystis jirovecii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of BACTRIM in non-AIDS patients. If a patient develops skin rash or any sign of an adverse reaction, reevaluate therapy with BACTRIM [see Hypersensitivity And Other Fatal Reactions].
Avoid coadministration of BACTRIM and leucovorin during treatment of Pneumocystis jirovecii pneumonia [see Risk Associated With Concurrent Use Of Leucovorin For Pneumocystis Jirovecii Pneumonia].
High dosage of trimethoprim, as used in patients with P. jirovecii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients.
Severe and symptomatic hyponatremia can occur in patients receiving BACTRIM, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.
During treatment, ensure adequate fluid intake and urinary output to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides.
Monitoring Of Laboratory Tests
Complete blood counts should be done frequently in patients receiving BACTRIM. Discontinue BACTRIM if a significant reduction in the count of any formed blood element is noted. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function.
Development Of Drug-Resistant Bacteria
Prescribing BACTRIM in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d. (twice a day).
In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.
Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes.
Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded.
Impairment Of Fertility
No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim, doses roughly two times the recommended human daily dose on a body surface area basis.
Use In Specific Populations
BACTRIM may cause fetal harm if administered to a pregnant woman. Some epidemiologic studies suggest that exposure to BACTRIM during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot [see Human Data].
One of 3 rat studies showed cleft palate at doses approximately 5 times the recommended human dose on a body surface area basis; the other 2 studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately 6 times the human dose on a body surface area basis [see Animal Data].
The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Advise pregnant women of the potential harm of BACTRIM to the fetus [see Clinical Considerations].
Disease-associated Maternal and/or Embryo/Fetal Risk
Urinary tract infection in pregnancy is associated with adverse perinatal outcomes such as preterm birth, low birth weight, and pre-eclampsia, and increased mortality to the pregnant woman. P. jirovecii pneumonia in pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman. BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
While there are no large, prospective, well-controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to BACTRIM with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons.
Alternatively, other epidemiologic studies did not detect statistically significant associations between BACTRIM exposure and specific malformations. Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. 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 trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester.
In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.
In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.
Levels of BACTRIM in breast milk are approximately 2 to 5% of the recommended daily dose for pediatric patients over two months of age. There is no information regarding the effect of BACTRIM on the breastfed infant or the effect on milk production. Because of the potential risk of bilirubin displacement and kernicterus on the breastfed child [see CONTRAINDICATIONS], advise women to avoid breastfeeding during treatment with BACTRIM.
BACTRIM is contraindicated in pediatric patients younger than two months of age because of the potential risk of bilirubin displacement and kernicterus [see CONTRAINDICATIONS].
Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received benzyl alcohol as a preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.
When prescribing BACTRIM in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including BACTRIM (BACTRIM contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see WARNINGS AND PRECAUTIONS].
Clinical studies of BACTRIM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
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, generalized bone marrow suppression [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS], a specific decrease in platelets (with or without purpura), and hyperkalemia 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. Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored [see DRUG INTERACTIONS].
Hematologic changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions [see DOSAGE AND ADMINISTRATION].
The trimethoprim component of BACTRIM may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of BACTRIM treatment is recommended to help lower potassium serum levels.
Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects [see CLINICAL PHARMACOLOGY].
4. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. Oct 1994;170(4):912-7.
10. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973;128 (Suppl): S657-S663.