rial 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 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 pediatric patients under two years of age. sulfamethoxazole and trimethoprim 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 a physician deems that sulfamethoxazole and trimethoprim 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 .

. 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 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.

y 12 hours lb kg tablets 22 10 - 44 20 1 66 30 1 ½ 88 40 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 usual standard regimen 15 to 30 1/2 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 1 sulfamethoxazole and trimethoprim double strength tablet, usp, or 2 sulfamethoxazole and trimethoprim single strength tablets, usp, 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, usp and 15 to 20 mg/kg trimethoprim, usp 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 8 - 35 16 1 53 24 1 ½ 70 32 2 or 1 ds tablet 88 40 2 ½ 106 48 3 or 1 ½ ds tablets 141 64 4 or 2 ds tablets 176 80 5 or 2 ½ ds tablets for the lower limit dose (75 mg/kg sulfamethoxazole, usp and 15 mg/kg trimethoprim, usp 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, usp daily. 12 children: for children, the recommended dose is 750 mg/m 2 /day sulfamethoxazole, usp with 150 mg/m 2 /day trimethoprim, usp 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, usp and 320 mg trimethoprim, usp. 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 ½ 1.06 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, usp or 2 sulfamethoxazole and trimethoprim single strength tablets, usp every 12 hours for 5 days.

ction, 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 to report suspected adverse reactions contact avkare, inc. at 1-855-361-3993; email drugsafety@avkare.com ; or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

ot a substrate of p-glycoprotein. 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 mcg/ml. the steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 mcg/ml and 68 mcg/ml, respectively. these steady-state 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 of sulfamethoxazole and trimethoprim 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 n 4 -acetylated metabolite. 2 when administered together as sulfamethoxazole and trimethoprim, 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 human milk. geriatric pharmacokinetics: the pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-us approved formulation. pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. the mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 ml/h/kg vs. 55 ml/h/kg). however, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects. 3 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, sulfamethoxazole and trimethoprim 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 both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both i n vitro and in clinical infections as described in the indications and usage section. aerobic gram-positive microorganisms: streptococcus pneumoniae aerobic gram-negative microorganisms: escherichia coli (including susceptible enterotoxigenic strains implicated in traveler’s diarrhea) klebsiella species enterobacter species haemophilus influenzae morganella morganii proteus mirabilis proteus vulgaris shigella flexneri shigella sonnei other organisms: pneumocystis jiroveci susceptibility testing methods when available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. these reports should aid the physician in selecting an antibacterial drug for treatment. dilution techniques: quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (mics). these mics provide estimates of the susceptibility of bacteria to antimicrobial compounds. the mics should be determined using a standardized test method (broth or agar) 4,15 . the mic values should be interpreted according to the criteria provided in table 1. diffusion techniques: quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. the zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. the zone size should be determined using a standardized test method 14,15 . this procedure uses paper disks impregnated with 1.25/23.75 mcg of trimethoprim/sulfamethoxazole to test the susceptibility of microorganisms to trimethoprim/sulfamethoxazole. the disc diffusion interpretive criteria are provided in table 1. table 1: susceptibility test interpretive criteria for trimethoprim/sulfamethoxazole minimal inhibitory concentration zone diameter bacteria (mcg/ml) (mm) s i r s i r enterobacteriaceae ≤ 2/38 - ≥ 4/76 ≥ 16 11 to 15 ≤ 10 haemophilus influenzae ≤ 0.5/9.5 1/19 to 2/38 ≥ 4/76 ≥ 16 11 to 15 ≤ 10 streptococcus pneumoniae ≤ 0.5/9.5 1/19 to 2/38 ≥ 4/76 ≥ 19 16 to 18 ≤ 15 a report of susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. a report of intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. this category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. this category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. a report of resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. quality control standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test 4, 14, 15 . standard trimethoprim/sulfamethoxazole powder should provide the following range of mic values noted in table 2. for the diffusion technique using the 1.25/23.75 mcg trimethoprim/sulfamethoxazole disk the criteria in table 2 should be achieved. table 2: acceptable quality control ranges for susceptibility testing for trimethoprim/sulfamethoxazole qc strain minimal inhibitory zone diameter concentration (mcg/ml) (mm) escherichia coli atcc 25922 ≤ 0.5/9.5 23 to 29 haemophilus influenzae atcc 49247 0.03/0.59 to 0.25/4.75 24 to 32 streptococcus pneumoniae atcc 49619 0.12/2.4 to 1/19 20 to 28