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INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim tablets, USP and other antibacterial drugs, sulfamethoxazole and trimethoprim tablets, USP 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 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 pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim tablets offer 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 tablets, USP in pediatric patients under two years of age. Sulfamethoxazole and trimethoprim tablets, USP are 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 a physician deems that sulfamethoxazole and trimethoprim tablets, USP could offer 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 jiroveci Pneumonia For the treatment of documented Pneumocystis jiroveci pneumonia and for prophylaxis against P. jiroveci pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing P. jiroveci pneumonia. Traveler's Diarrhea in Adults For the treatment of traveler's diarrhea due to susceptible strains of enterotoxigenic E. coli.

DOSAGE AND ADMINISTRATION Sulfamethoxazole and trimethoprim tablets are contraindicated in pediatric patients less than 2 months of age. Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children Adults The usual adult dosage in the treatment of urinary tract infections is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets 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 this dosage: Children 2 months of age or older: Weight Dose–every 12 hours lb kg Tablets 22 44 66 88 10 20 30 40 – 1 1½ 2 or 1 DS tablet 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 15–30 Below 15 Usual standard regimen ½ the usual regimen Use not recommended Acute Exacerbations of Chronic Bronchitis in Adults The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 14 days. Pneumocystis Jiroveci Pneumonia Treatment Adults and Children The recommended dosage for treatment of patients with documented Pneumocystis jiroveci 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. 11 The following table is a guideline for the upper limit of this dosage: Weight Dose–every 6 hours lb kg Tablets 18 35 53 70 88 106 141 176 8 16 24 32 40 48 64 80 – 1 1½ 2 or 1 DS tablet 2½ 3 or 1½ DS tablets 4 or 2 DS tablets 5 or 2½ DS tablets 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 1 sulfamethoxazole and trimethoprim DS (double strength) tablet daily. 12 Children For children, the recommended dose is 750 mg/m 2 /day sulfamethoxazole with 150 mg/m 2 /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. 13 The following table is a guideline for the attainment of this dosage in children: Body Surface Area Dose–every 12 hours (m 2 ) Tablets 0.26 0.53 1.06 – ½ 1 Traveler's Diarrhea in Adults For the treatment of traveler’s diarrhea, the usual adult dosage is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 5 days.

CONTRAINDICATIONS Sulfamethoxazole and trimethoprim tablets are contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole and trimethoprim tablets are contraindicated in pediatric patients less than 2 months of age. Sulfamethoxazole and trimethoprim tablets are also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored.

WARNINGS Embryofetal Toxicity Some epidemiologic studies suggest that exposure to sulfamethoxazole and 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 and 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 and 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 and 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 and trimethoprim. Streptococcal Infections and Rheumatic Fever The sulfonamides should not be used for treatment of group A β-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 sulfamethoxazole and trimethoprim, 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.

Drug Interactions Potential for Sulfamethoxazole and Trimethoprim 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 sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when sulfamethoxazole and trimethoprim 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 (a CYP2C9 substrate). 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 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 sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients. Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim 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 sulfamethoxazole and trimethoprim is prescribed. The efficacy of tricyclic antidepressants can decrease when coadministered with sulfamethoxazole and trimethoprim. Sulfamethoxazole and trimethoprim 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 and 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 and trimethoprim and an angiotensin converting enzyme inhibitor. 8,9

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. 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 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, hyponatremia ( see PRECAUTIONS: Electrolyte Abnormalities ). 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 sulfamethoxazole and trimethoprim, mainly in AIDS patients. Respiratory Cough, shortness of breath and pulmonary infiltrates (see WARNINGS ). Miscellaneous Weakness, fatigue, insomnia. Postmarketing Experience The following adverse reactions have been identified during post-approval use of trimethoprim-sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Thrombotic thrombocytopenia purpura Idiopathic thrombocytopenic purpura QT prolongation resulting in ventricular tachycardia and torsade de pointes

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, sulfamethoxazole and trimethoprim 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 and 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 and 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.