Bactrim

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.
Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.
Use in the Elderly: There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, eg, impaired kidney and/or liver function, or concomitant use of other drugs.

Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections) 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 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. Close monitoring of serum potassium is warranted in these patients. Discontinuation of Bactrim treatment is recommended to help lower potassium serum levels.

Use in the Treatment of and Prophylaxis for Pneumocystis Carinii 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 Pneumocystis carinii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of Bactrim in non-AIDS patients.

The incidence of hyperkalemia appears to be increased in AIDS patients receiving Bactrim.
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.

However, if a patient develops skin rash or any sign of adverse reaction, therapy with Bactrim should be reevaluated (see WARNINGS ).

High dosage of trimethoprim, as used in patients with Pneumocystis carinii 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.

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.

The efficacy of tricyclic antidepressants can decrease when coadministered with Bactrim.
Like other sulfonamide-containing drugs, Bactrim potentiates the effect of oral hypoglycemics.
In the literature, a single case of toxic delirium has been reported after concomitant intake of trimethoprim/sulfamethoxazole and amantadine.

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 trimethoprim and sulfamethoxazole may also interfere with the Jaff? alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis Long-term studies in animals to evaluate carcinogenic potential have not been conducted with Bactrim.
Mutagenesis Bacterial mutagenic studies have not been performed with sulfamethoxazole and trimethoprim in combination. Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. No chromosomal damage was observed in human leukocytes cultured in vitro with sulfamethoxazole and trimethoprim alone or in combination; the concentrations used exceeded blood levels of these compounds following therapy with Bactrim.

Observations of leukocytes obtained from patients treated with Bactrim revealed no chromosomal abnormalities.
Impairment of Fertility: 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.

These doses are 10.9-fold higher than the recommended human dose for trimethoprim and sulfamethoxazole.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In rats, oral doses of 533 mg/kg sulfamethoxazole (16.7-fold higher than the recommended human dose) or 200 mg/kg trimethoprim (31.3-fold higher than the recommended human dose) produced teratologic effects manifested mainly as cleft palates.

The highest dose which did not cause cleft palates in rats was 512 mg/kg sulfamethoxazole (16-fold higher than the recommended human dose) or 192 mg/kg trimethoprim (30-fold higher than the recommended human dose) when administered separately.

In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole (16-fold higher than the recommended human dose) was used in combination with 128 mg/kg of trimethoprim (20-fold higher than the recommended human dose).

In one study, however, cleft palates were observed in one litter out of 9 when 355 mg/kg of sulfamethoxazole (11.1-fold higher than the recommended human dose) was used in combination with 88 mg/kg of trimethoprim (13.8-fold higher than the recommended human dose).

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 trimethoprim and sulfamethoxazole in pregnant women, Brumfitt and Pursell, 7 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or 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.

Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, Bactrim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: See CONTRAINDICATIONS section.
Nursing Mothers: See CONTRAINDICATIONS section.

Pediatric Use: Bactrim is not recommended for pediatric patients younger than 2 months of age (see INDICATIONS and CONTRAINDICATIONS sections).

ADVERSE REACTIONS: The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). 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 (SEE WARNINGS SECTION

Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia, pancytopenia, purpura.

Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schonlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.
Gastrointestinal Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.

Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine.

Metabolic and Nutritional: Hyperkalemia (see PRECAUTIONS : Use in the Elderly and Use in the Treatment of and Prophylaxis for Pneumocystis Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome [AIDS] ).

Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.

Psychiatric: Hallucinations, depression, apathy, nervousness.

Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides.

Musculoskeletal: Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported with Bactrim, mainly in AIDS patients.
Respiratory Cough, shortness of breath, and pulmonary infiltrates (see WARNINGS ).

Miscellaneous: Weakness, fatigue, insomnia.

OVERDOSAGE
Acute: The amount of a single dose of Bactrim that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported. Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage.

Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression.

General principles of treatment include the institution of gastric lavage or emesis, forcing oral fluids, and the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

Chronic: Use of Bactrim at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored.

DOSAGE AND ADMINISTRATION
Not recommended for use in pediatric patients less than 2 months of age.