Sulfamethoxazole warnings and precautions

# Warnings
Embryofetal Toxicity
Some epidemiologic studies suggest that exposure to sulfamethoxazole/trimethoprim 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 sulfamethoxazole/trimethoprim 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.
Hypersensitivity and Other Fatal Reactions
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 products 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 disorders (see PRECAUTIONS). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions.
Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.
Thrombocytopenia
Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim.
Streptococcal Infections and Rheumatic Fever
The sulfonamides should not be used for treatment of group A -hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Adjunctive treatment with Leucovorin for Pneumocystis jiroveci pneumonia
Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial.6 Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.

# Precautions
Development of drug resistant bacteria
Prescribing Bactrim (sulfamethoxazole and trimethoprim) tablets 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.
Folate deficiency
BACTRIM 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 allergies or bronchial asthma.
Hematological 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.
Hemolysis
In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Hypoglycemia
Cases of hypoglycemia in non-diabetic patients treated with BACTRIM are seen rarely, 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.
Phenylalanine metabolism
Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.
Porphyria and Hypothyroidism
As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.
Use in the Treatment of and Prophylaxis for Pneumocystis jiroveci 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 side effects, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with BACTRIM therapy in AIDS patients who are being treated for P. jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of BACTRIM in non-AIDS patients. Adverse effects are generally less severe in patients receiving BACTRIM for prophylaxis. A history of mild intolerance to BACTRIM in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis.7 However, if a patient develops skin rash or any sign of adverse reaction, therapy with BACTRIM should be reevaluated (see WARNINGS).
Co-administration of BACTRIM and leucovorin should be avoided with P. jiroveci pneumonia (see WARNINGS).
Electrolyte Abnormalities
High dosage of trimethoprim, as used in patients with P. jiroveci 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. jiroveci pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.
During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria. Patients who are "slow acetylators" may be more prone to idiosyncratic reactions to sulfonamides.
Information for Patients: Patients should be counseled that antibacterial drugs including Bactrim (sulfamethoxazole and trimethoprim) tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Bactrim (sulfamethoxazole and trimethoprim) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bactrim (sulfamethoxazole and trimethoprim) tablets or other antibacterial drugs in the future.
Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Laboratory Tests: Complete blood counts should be done frequently in patients receiving BACTRIM; if a significant reduction in the count of any formed blood element is noted, BACTRIM 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.
Drug Interactions:
Potential for BACTRIM to Affect Other Drugs
Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when Bactrim is co-administered with drugs that are substrates of CYP2C8 and 2C9 or OCT2.
In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.
It has been reported that BACTRIM may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when BACTRIM is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.
BACTRIM may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). BACTRIM, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.
There have been reports of marked but reversible nephrotoxicity with coadministration of BACTRIM and cyclosporine in renal transplant recipients.
Increased digoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderly patients. Serum digoxin levels should be monitored.
Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin.
Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if BACTRIM is prescribed.
The efficacy of tricyclic antidepressants can decrease when coadministered with BACTRIM.
BACTRIM potentiates the effect of oral hypoglycemics that are metabolized by CYP2C8 (e.g., pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g., glipizide and glyburide) or eliminated renally via OCT2 (e.g., metformin). Additional monitoring of blood glucose may be warranted.
In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported.
In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.8,9
Drug/Laboratory Test Interactions: BACTRIM, 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 and 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, Impairment of Fertility:
Carcinogenesis: 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 2.4-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d.).
Mutagenesis: 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.
Pregnancy:
While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and 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 and trimethoprim. 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 sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter.
Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, BACTRIM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Teratogenic Effects: Pregnancy Category D.
Human Data:
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 sulfamethoxazole/trimethoprim 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 sulfamethoxazole/trimethoprim exposure and specific malformations.
Animal Data:
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.
Nonteratogenic Effects: See CONTRAINDICATIONS section.
Nursing Mothers: Levels of trimethoprim/sulfamethoxazole in breast milk are approximately 25% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when BACTRIM is administered to a nursing woman, especially when breastfeeding, jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus.
Pediatric Use: BACTRIM is contraindicated for infants younger than 2 months of age (see INDICATIONS and CONTRAINDICATIONS sections).
Geriatric Use: 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, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), 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. Hematological 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 section). 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. Bactrim Tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet. Bactrim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet.
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: Geriatric Pharmacokinetics).