Prescription Drugs

CLINICAL PHARMACOLOGY Sulfamethoxazole and Trimethoprim Oral Suspension is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N -acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1 - and 3 - oxides and the 3' - and 4' - hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole. Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 μg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 μg/mL and 68.0 μg/mL, respectively. These steadystate levels were achieved after three days of drug administration.1 Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N4-acetylated metabolite.2 When administered together, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid, and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in breast milk. Microbiology: Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, this combination blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. In vitro studies have shown that bacterial resistance develops more slowly with this combination than with either sulfamethoxazole or trimethoprim alone. In vitro serial dilution tests have shown that the spectrum of antibacterial activity of sulfamethoxazole and trimethoprim includes the common urinary tract pathogens with the exception of Pseudomonas aeruginosa. The following organisms are usually susceptible: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and indole-positive Proteus species including Proteus vulgaris. The usual spectrum of antimicrobial activity of sulfamethoxazole and trimethoprim includes the following bacterial pathogens isolated from middle ear exudate and from bronchial secretions: Haemophilus influenzae, including ampicillin-resistant strains, and Streptococcus pneumoniae. Shigella flexneri and Shigella sonnei are usually susceptible. The usual spectrum also includes enterotoxigenic strains of Escherichia coli (ETEC) causing bacterial gastroenteritis. REPRESENTATIVE MINIMUM INHIBITORY CONCENTRATION VALUES FOR SULFAMETHOXAZOLE AND TRIMETHOPRIM SUSCEPTIBLE ORGANISMS (MIC-μg/mL) Bacteria TMP Alone SMX Alone TMP/SMX (1:20) TMP SMX Escherichia coli 0.05-1.5 1.0-245 0.05-0.5 0.95-9.5 Escherichia coli (enterotoxigenic strains) 0.015-0.15 0.285- > 950 0.005-0.15 0.095-2.85 Proteus species (indole positive) 0.5-5.0 7.35-300 0.05-1.5 0.95-28.5 Morganella morganii 0.5-5.0 7.35-300 0.05-1.5 0.95-28.5 Proteus mirabilis 0.5-1.5 7.35-30 0.05-0.15 0.95-2.85 Klebsiella species 0.15-5.0 2.45-245 0.05-1.5 0.95-28.5 Enterobacter species 0.15-5.0 2.45-245 0.05-1.5 0.95-28.5 Haemophilus influenzae 0.15-1.5 2.85-95 0.015-0.15 0.285-2.85 Streptococcus pneumoniae 0.15-1.5 7.35-24.5 0.05-0.15 0.95-2.85 Shigella flexneri† < 0.01-0.04 < 0.16- > 320 < 0.002-0.03 0.04-0.625 Shigella sonnei† 0.02-0.08 0.625- > 320 0.004-0.06 0.08-1.25 TMP = Trimethoprim; SMX = Sulfamethoxazole †Rudoy RC, Nelson JD, Haltalin KC, Antimicrob Agents Chemother. May 1974:5:439-443. Susceptibility Testing The recommended quantitative disc susceptibility method may be used for estimating the susceptibility of bacteria to sulfamethoxazole and trimethoprim.3,4 With this procedure, a report from the laboratory of “Susceptible to trimethoprim and sulfamethoxazole” indicates that the infection is likely to respond to therapy with this product. If the infection is confined to the urine, a report of “Intermediate susceptibility to trimethoprim and sulfamethoxazole” also indicates that the infection is likely to respond. A report of “Resistant to trimethoprim and sulfamethoxazole” indicates that the infection is unlikely to respond to therapy with this product. REFERENCES 1. Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J. Clin Pharmacol. Feb-Mar 1974; 14:112-117. 2. Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis. Nov 1973; 128(Suppl): S547-S555. 3. Federal Register. 1972; 37:20527-20529. 4. Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic Susceptibility Testing by Standardized Single Disk Method. Am J Clin Path. Apr 1966; 45:493-496.

Sulfatrim (sulfamethoxazole and trimethoprim) Oral Suspension USP To reduce the development of drug-resistant bacteria and maintain the effectiveness of Sulfamethoxazole and Trimethoprim Oral Suspension and other antibacterial drugs, Sulfamethoxazole and Trimethoprim Oral Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION Sulfamethoxazole and Trimethoprim Oral Suspension is a synthetic antibacterial combination product. Sulfamethoxazole is N1 -(5-methyl-3- isoxazolyl) sulfanilamide. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.32, and the following structural formula: EACH 5 mL (ONE TEASPOONFUL) OF SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION USP CONTAINS 200 mg sulfamethoxazole and 40 mg trimethoprim. Inactive Ingredients: alcohol (less than 0.5%), carboxymethylcellulose sodium, citric acid, FD&C Red #40, FD&C Yellow #6, flavor, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, propylene glycol, propylparaben, purified water, saccharin sodium, simethicone emulsion, sucrose.

INDICATIONS To reduce the development of drug-resistant bacteria and maintain the effectiveness of Sulfamethoxazole and Trimethoprim Oral Suspension and other antibacterial drugs, Sulfamethoxazole and Trimethoprim Oral Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Urinary Tract Infections For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination. Acute Otitis Media For the treatment of acute otitis media in children due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician this combination offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of sulfamethoxazole and trimethoprim in children under two years of age. This product is not indicated for prophylactic or prolonged administration in otitis media at any age. Acute Exacerbations Of Chronic Bronchitis In Adults For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician, this combination offers some advantage over the use of a single antimicrobial agent. Shigellosis For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated. Pneumocystis Carinii Pneumonia For the treatment of documented Pneumocystis carinii pneumonia. For prophylaxis against Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis carinii pneumonia. Travelers' Diarrhea In Adults For the treatment of travelers' diarrhea due to susceptible strains of enterotoxigenic E. coli. DOSAGE AND ADMINISTRATION Not recommended for us e in infants les s than 2 months of age. Urinary Tract Infections And Shigellos is In Adults And Children And Acute Otitis Media In Children Adults The usual adult dosage in the treatment of urinary tract infections is 4 teaspoonfuls (20 mL) of the suspension every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. Children The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of his dosage: Children: 2 months of age or older. Weight Dose -every 12 hours Teaspoonfuls lb kg 22 10 1 (5 mL) 44 20 2 (10 mL) 66 30 3 (15 mL) 88 40 4 (20 mL) For Patients With Impaired Renal Function When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Clearance (mL/min) Recommended Dosage Regimen Above 30 Usual standard regimen 15 - 30 ½ the usual regimen Below 15 Use not recommended Acute Exacerbations Of Chronic Bronchitis In Adults The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 4 teaspoonfuls (20 mL) of the suspension every 12 hours for 14 days. Pneumocystis Carinii Pneumonia Treatment Adults and children The recommended dosage for treatment of patients with documented Pneumocystis carinii pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.7 The following table is a guideline for the upper limit of this dosage. Weight Dose - every 6 hours Teaspoonfuls lb kg 18 8 1 (5 mL) 35 16 2 (10 mL) 53 24 3 (15 mL) 70 32 4 (20 mL) 88 40 5 (25 mL) 106 48 6 (30 mL) 141 64 8 (40 mL) 176 80 10 (50 mL) For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. Prophylaxis Adults The recommended dosage for prophylaxis in adults is 800 mg sulfamethoxazole and 160 mg trimethoprim daily.8 Children For children, the recommended dose is 750 mg/m²/day sulfamethoxazole with 150 mg/m²/day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.9 The following table is a guideline for the attainment of this dosage in children: Body Surface Dose - every Area(m²) 12 hours Teaspoonfuls 0.26 ½ (2.5 mL) 0.53 1 (5 mL) 1.06 2 (10 mL) Travelers' Diarrhea In Adults For the treatment of travelers' diarrhea, the usual adult dosage is 4 teaspoonfuls (20 mL) of the suspension every 12 hours for 5 days. HOW SUPPLIED Sulfamethoxazole and Trimethoprim Oral Suspension USP, containing 200 mg sulfamethoxazole and 40 mg trimethoprim per teaspoonful (5 mL), is a fruit-licorice flavored suspension available in pint (473 mL) bottles. Sulfamethoxazole and Trimethoprim Oral Suspension USP (Pediatric), containing 200 mg sulfamethoxazole and 40 mg trimethoprim per teaspoonful (5 mL), is a cherry flavored suspension available in 100 mL and pint (473 mL) bottles. Shake well before using. Store at controlled room temperature 15°-30°C (59°-86°F). Protect from light. Dispense in a tight, light-resistant container as defined in the USP. REFERENCES 7. Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med. 1992; 327:1853-1880. 8. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR. 1992; 41(RR-4): 1-11. 9. CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR. 1991; 40(RR-2); 1-13. Manufactured by: Actavis Mid Atlantic LLC, 7205 Windsor Blvd., Baltimore, MD 21244 USA. Revised: Mar 2006

PATIENT INFORMATION Patients should be counseled that antibacterial drugs including Sulfamethoxazole and Trimethoprim Oral Suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Sulfamethoxazole and Trimethoprim Oral Suspension is 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 Sulfamethoxazole and Trimethoprim Oral Suspension 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.

OVERDOSE Acute The amount of a single dose of sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim. Chronic Use of sulfamethoxazole and trimethoprim 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. CONTRAINDICATIONS Sulfamethoxazole and Trimethoprim Oral Suspension is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole and Trimethoprim Oral Suspension is also contraindicated in pregnant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Sulfamethoxazole and Trimethoprim Oral Suspension is contraindicated in infants less than 2 months of age.

SIDE EFFECTS 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. Allergic Reactions Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein 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 pains, diarrhea, anorexia. Genitourinary Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria. 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. Respiratory Pulmonary infiltrates. Miscellaneous Weakness, fatigue, insomnia. DRUG INTERACTIONS In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when sulfamethoxazole and trimethoprim oral suspension is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin. Sulfamethoxazole and trimethoprim, 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, thus increasing free methotrexate concentrations. Drug/Laboratory Test Interactions This combination product, 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 Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

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. SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION 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. In rare instances 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. SULFAMETHOXAZOLE AND TRIMETHOPRIM ORAL SUSPENSION SHOULD NOT BE USED 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 this combination than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area. PRECAUTIONS General Prescribing Sulfamethoxazole and Trimethoprim Oral Suspension 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. Sulfamethoxazole and Trimethoprim Oral Suspension 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. In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related. Use In The Elderly 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 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 (see DOSAGE AND ADMINISTRATION section). 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 sulfamethoxazole and trimethoprim oral suspension in the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leucopenia and elevated aminotransferase (transaminase) values with sulfamethoxazole and trimethoprim therapy in AIDS patients who are being treated for Pneumocystic carinii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of sulfamethoxazole and trimethoprim in non-AIDS patients. Adverse effects are generally less severe in patients receiving sulfamethoxazole and trimethoprim for prophylaxis. A history of mild intolerance to sulfamethoxazole and 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 and trimethoprim oral suspension should be reevaluated (see WARNINGS). Laboratory Tests Complete blood counts should be done frequently in patients receiving sulfamethoxazole and trimethoprim; if a significant reduction in the count of any formed blood element is noted, this drug product should be discontinued. Urinalysis with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. REFERENCES 5. Hardy DW, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1992; 327:1842-1848. Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Long-term studies in animals to evaluate carcinogenic potential have not been conducted with sulfamethoxazole and trimethoprim. 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 in vitro with sulfamethoxazole and trimethoprim alone or in combination; the concentrations used exceeded blood levels of these compounds following therapy with sulfamethoxazole and trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim 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. Pregnancy Teratogenic Effects Pregnancy Category C. In rats, oral doses of 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratological 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 teratology 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 and trimethoprim in pregnant women, Brumfitt and Pursell6, 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, this product 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 Sulfamethoxazole and Trimethoprim Oral Suspension is not recommended for pediatric patients younger than 2 months of age (see INDICATIONS AND USAGE and CONTRAINDICATIONSsections). REFERENCES 6. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov. 1973; 128(Suppl): S657-S663.