Sulfamethoxazole

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim oral suspension, USP and other antibacterial drugs, sulfamethoxazole and trimethoprim oral suspension, 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 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 oral suspension, USP in pediatric patients under two years of age. Sulfamethoxazole and trimethoprim oral suspension, USP 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 oral suspension, 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 Dosage Guidelines For Adults and Pediatric Patients (Two Months of Age and Older) Infection Total Daily Dose (based on trimethoprim content) Frequency Duration Pneumocystis jirovecii Pneumonia 15 to 20 mg/kg (in 3 or 4 equally divided doses) Every 6 to 8 hours 14 days Severe Urinary Tract Infections 8 to 10 mg/kg (in 2 to 4 equally divided doses) Every 6, 8 or 12 hours 14 days Shigellosis 8 to 10 mg/kg (in 2 to 4 equally divided doses) Every 6, 8 or 12 hours 5 days For patients with impaired renal function, a reduced dosage should be employed. ( 2.2 ) Sulfamethoxazole and Trimethoprim Injection must be given by intravenous infusion over a period of 60 to 90 minutes. Rapid infusion or bolus injection must be avoided. ( 2.3 ) Sulfamethoxazole and Trimethoprim Injection must be diluted in 5% dextrose in water solution prior to administration. ( 2.4 ) Do not mix Sulfamethoxazole and Trimethoprim Injection with other drugs or solutions. ( 2.4 ) 2.1 Dosage in Adults and Pediatric Patients (Two Months of Age and Older) The maximum recommended daily dose is 60 mL (960 mg trimethoprim) per day. Table 1: Dosage in Adults and Pediatric Patients (Two Months of Age and Older) by Indication Dosage Guidelines Infection Total Daily Dose (based on trimethoprim content) Frequency Duration Pneumocystis jirovecii Pneumonia * 15 to 20 mg/kg (in 3 or 4 equally divided doses) Every 6 to 8 hours 14 days Severe Urinary Tract Infections 8 to 10 mg/kg (in 2 to 4 equally divided doses) Every 6, 8 or 12 hours 14 days Shigellosis 8 to 10 mg/kg (in 2 to 4 equally divided doses) Every 6, 8 or 12 hours 5 days * A total daily dose of 10 to 15 mg/kg was sufficient in 10 adult patients with normal renal function in a published literature. 1 2.2 Dosage Modifications in Patients with Impaired Renal Function When renal function is impaired, a reduced dosage should be employed, as shown in Table 2 . Table 2: Impaired Renal Function Dosage Guidelines Creatinine Clearance (mL/min) Recommended Dosage Regimen Above 30 Usual standard dosage regimen 15 to 30 ½ the usual dosage regimen Below 15 Use not recommended 2.3 Important Administration Instructions Administer the solution by intravenous infusion over a period of 60 to 90 minutes. Avoid administration by rapid infusion or bolus injection. Do NOT administer Sulfamethoxazole and Trimethoprim Injection intramuscularly. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit. 2.4 Method of Preparation Dilution of Single- and Multiple-Dose Vials Sulfamethoxazole and Trimethoprim Injection must be diluted. Each 5 mL should be added to 125 mL of 5% dextrose in water. After diluting with 5% dextrose in water, the solution should not be refrigerated and should be used within 6 hours. If a dilution of 5 mL per 100 mL of 5% dextrose in water is desired, it should be used within 4 hours. In those instances where fluid restriction is desirable, each 5 mL may be added to 75 mL of 5% dextrose in water. Under these circumstances the solution should be mixed just prior to use and should be administered within 2 hours. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared. Do NOT mix Sulfamethoxazole and Trimethoprim Injection in 5% dextrose in water with drugs or solutions in the same container. Multiple-dose Vials (Handling) After initial entry into the vial, the remaining contents must be used within 48 hours. Infusion Systems for Intravenous Administration The following infusion systems have been tested and found satisfactory: unit-dose glass containers; unit-dose polyvinyl chloride and polyolefin containers. No other systems have been tested and therefore no others can be recommended.

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 (see PRECAUTIONS). Hypersensitivity and Other Serious or Fatal Reactions Fatalities and serious adverse reactions including severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (AFND), acute generalized erythematous pustulosis (AGEP); fulminant hepatic necrosis; agranulocytosis, aplastic anemia and other blood dyscrasias; acute and delayed lung injury; anaphylaxis and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim (see ADVERSE REACTIONS). Hypersensitivity Reactions of the Respiratory Tract Cough, shortness of breath and pulmonary infiltrates potentially representing hypersensitivity reactions of the respiratory tract have been reported in association with sulfamethoxazole and trimethoprim treatment. Respiratory Failure Other severe pulmonary adverse reactions occurring within days to week of sulfamethoxazole and trimethoprim initiation and resulting in prolonged respiratory failure requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO), lung transplantation or death have also been reported in patients and otherwise healthy individuals treated with sulfamethoxazole and trimethoprim products. Circulatory Shock Circulatory shock with fever, severe hypotension, and confusion requiring intravenous fluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim, in patients with history of recent (days to weeks) exposure to sulfamethoxazole and trimethoprim. Management of Hypersensitivity and Other Serious Reactions Sulfamethoxazole and trimethoprim should be discontinued at the first appearance of skin rash or any sign of a serious adverse reaction. A skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AFND, AGEP, hepatic necrosis, or serious blood disorders (see PRECAUTIONS and ADVERSE REACTIONS). Clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice may be early indications of serious reactions. Hemophagocytic Lymphohistiocytosis Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in patients treated with sulfamethoxazole-trimethoprim. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. Signs and symptoms of HLH may include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver enzyme and coagulation abnormalities. If HLH is suspected, discontinue sulfamethoxazole and trimethoprim immediately and institute appropriate management. 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 Aβ-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. Clostridioides difficile Associated Diarrhea Clostridioides 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. Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia Treatment failure and excess mortality were observed when sulfamethoxazole and trimethoprim was used concomitantly with leucovorin for the treatment of HIV positive patients with P. jirovecii pneumonia in a randomized placebo-controlled trial. 4 Avoid coadministration of sulfamethoxazole and trimethoprim and leucovorin during treatment of P. jirovecii pneumonia. PRECAUTIONS Development of Drug Resistant Bacteria Prescribing 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 Avoid use of sulfamethoxazole and trimethoprim in patients with impaired renal or hepatic function, in 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 in 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 (see PRECAUTIONS, Geriatric Use). Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related. Hypoglycemia Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole and trimethoprim are particularly at risk. Impaired Phenylalanine Metabolism The trimethoprim component of sulfamethoxazole and trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction. Porphyria and Hypothyroidism Like other drugs containing sulfonamides, sulfamethoxazole and trimethoprim can precipitate porphyria crisis and hypothyroidism. Avoid use of sulfamethoxazole and trimethoprim in patients with porphyria or thyroid dysfunction. Potential Risk in the Treatment of Pneumocystis jirovecii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS) AIDS patients may not tolerate or respond to sulfamethoxazole and trimethoprim in the same manner as non-AIDS patients. The incidence of adverse reactions, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with sulfamethoxaz

CONTRAINDICATIONS Sulfamethoxazole and Trimethoprim Injection is contraindicated in the following situations: Known hypersensitivity to trimethoprim or sulfonamides [see Warnings and Precautions ( 5.2 )] History of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides [see Warnings and Precautions ( 5.4 )] Documented megaloblastic anemia due to folate deficiency [see Warnings and Precautions ( 5.11 )] Pediatric patients less than two months of age [see Use in Specific Populations ( 8.4 )] Marked hepatic damage [see Warnings and Precautions ( 5.11 , 5.14 )] Severe renal insufficiency when renal function status cannot be monitored [see Warnings and Precautions ( 5.11 , 5.14 )] Concomitant administration with dofetilide 2,3 [see Drug Interactions ( 7 )] Known hypersensitivity to trimethoprim or sulfonamides ( 4 ) History of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides ( 4 ) Documented megaloblastic anemia due to folate deficiency ( 4 ) Pediatric patients less than two months of age ( 4 ) Marked hepatic damage ( 4 ) Severe renal insufficiency when renal function status cannot be monitored ( 4 ) Concomitant administration with dofetilide ( 4 )

DRUG INTERACTIONS Potential for Sulfamethoxazole and Trimethoprim Injection to Affect Other Drugs Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Avoid coadministration of Sulfamethoxazole and Trimethoprim Injection with drugs that are substrates of CYP2C8 and 2C9 or OCT2. Table 4: Drug Interactions with Sulfamethoxazole and Trimethoprim Injection Drug(s) Recommendation Comments Diuretics Avoid concurrent use In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Warfarin Monitor prothrombin time and INR It has been reported that Sulfamethoxazole and Trimethoprim Injection 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 Injection is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Phenytoin Monitor serum phenytoin levels Sulfamethoxazole and Trimethoprim Injection may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Sulfamethoxazole and Trimethoprim Injection, 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. Methotrexate Avoid concurrent use Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. Cyclosporine Avoid concurrent use There have been reports of marked but reversible nephrotoxicity with coadministration of Sulfamethoxazole and Trimethoprim Injection and cyclosporine in renal transplant recipients. Digoxin Monitor serum digoxin levels Increased digoxin blood levels can occur with concomitant Sulfamethoxazole and Trimethoprim Injection therapy, especially in elderly patients Indomethacin Avoid concurrent use Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. Pyrimethamine Avoid concurrent use Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if Sulfamethoxazole and Trimethoprim Injection is prescribed. Tricyclic Antidepressants (TCAs) Monitor therapeutic response and adjust dose of TCA accordingly The efficacy of tricyclic antidepressants can decrease when coadministered with Sulfamethoxazole and Trimethoprim Injection. Oral hypoglycemics Monitor blood glucose more frequently Like other sulfonamide-containing drugs, Sulfamethoxazole and Trimethoprim Injection potentiates the effect of oral hypoglycemic 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. Amantadine Avoid concurrent use In the literature, a single case of toxic delirium has been reported after concomitant intake of Sulfamethoxazole and Trimethoprim Injection and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported. Angiotensin Converting Enzyme Inhibitors Avoid concurrent use In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of Sulfamethoxazole and Trimethoprim Injection and an angiotensin converting enzyme inhibitor. 6,7 Zidovudine Monitor for hematologic toxicity Zidovudine and Sulfamethoxazole and Trimethoprim Injection are known to induce hematological abnormalities. Hence, there is potential for an additive myelotoxicity when coadministered. 8 Dofetilide Concurrent administration is contraindicated Elevated plasma concentrations of dofetilide have been reported following concurrent administration of trimethoprim and dofetilide. Increased plasma concentrations of dofetilide may cause serious ventricular arrhythmias associated with QT interval prolongation, including torsade de pointes . 2,3 Procainamide Closely monitor for clinical and ECG signs of procainamide toxicity and/or procainamide plasma concentration if available Trimethoprim increases the plasma concentrations of procainamide and its active N -acetyl metabolite (NAPA) when trimethoprim and procainamide are coadministered. The increased procainamide and NAPA plasma concentrations that resulted from the pharmacokinetic interaction with trimethoprim are associated with further prolongation of the QTc interval. 9 CYP2C8, CYP2C9 or OCT2 substrates: Use with caution when coadministering with Sulfamethoxazole and Trimethoprim Injection. ( 7 ) Warfarin: Monitor prothrombin time and INR. ( 7 ) Phenytoin: Monitor serum phenytoin levels. ( 7 ) Digoxin: Concomitant use may increase digoxin blood levels, especially in elderly patients. Monitor serum digoxin levels. ( 7 ) Oral hypoglycemics: Concomitant use may potentiate hypoglycemic effects. Monitor blood glucose more frequently. ( 7 ) Zidovudine: Monitor for hematologic toxicity. ( 7 ) Procainamide: Monitor for signs of procainamide toxicity. ( 7 ) 7.1 Interactions with Laboratory or Diagnostic Testing Sulfamethoxazole and Trimethoprim Injection, 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 Injection may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Embryo-fetal Toxicity [see Warnings and Precautions ( 5.1 )] Hypersensitivity and Other Fatal Reactions [see Warnings and Precautions ( 5.2 )] Thrombocytopenia [see Warnings and Precautions ( 5.4 )] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.6 )] Sulfite Sensitivity [see Warnings and Precautions ( 5.7 )] Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia [see Warnings and Precautions ( 5.9 )] Propylene Glycol Toxicity [see Warnings and Precautions ( 5.10 )] Infusion Reactions [see Warnings and Precautions ( 5.13 )] Hypoglycemia [see Warnings and Precautions ( 5.14 )] Electrolyte Abnormalities [see Warnings and Precautions ( 5.18 )] The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, and anorexia) and allergic skin reactions (such as rash and urticaria). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following adverse reactions associated with the use of Sulfamethoxazole and Trimethoprim Injection or sulfamethoxazole and trimethoprim were identified in clinical trials, postmarketing or published reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, and anorexia) and allergic skin reactions (such as rash and urticaria). Fatalities and serious adverse reactions, including severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (AFND), acute generalized erythematous pustulosis (AGEP); fulminant hepatic necrosis; agranulocytosis, aplastic anemia and other blood dyscrasias; acute and delayed lung injury; anaphylaxis and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including Sulfamethoxazole and Trimethoprim Injection [see Warnings and Precautions ( 5.2 )] . Local reaction, pain and slight irritation on intravenous (IV) administration are infrequent. Thrombophlebitis has been observed. Table 3: Adverse Reactions Reported with Sulfamethoxazole and Trimethoprim Injection Body System Adverse Reactions Hematologic Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura. Allergic/Immune 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, rash, periarteritis nodosa, hemophagocytic lymphohistiocytosis (HLH), systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized erythematous pustulosis (AGEP), and acute febrile neutrophilic dermatosis (AFND) [see Warnings and Precautions ( 5.2 and 5.3 )] . 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, renal insufficiency, oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine. Metabolic and Nutritional Hyperkalemia, hyponatremia [see Warnings and Precautions ( 5.18 )], metabolic acidosis. 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. Musculoskeletal Arthralgia, myalgia, rhabdomyolysis. Respiratory Cough, shortness of breath and pulmonary infiltrates, acute eosinophilic pneumonia, acute and delayed lung injury, interstitial lung disease, acute respiratory failure [see Warnings and Precautions ( 5.2 )] . Cardiovascular System QT prolongation resulting in ventricular tachycardia and torsades de pointes, circulatory shock [see Warnings and Precautions ( 5.2 )] . Miscellaneous Weakness, fatigue, insomnia. Eye Disorders Uveitis 5

CLINICAL PHARMACOLOGY Sulfamethoxazole and trimethoprim 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. Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N 4 -acetyl-, N 4 -hydroxy-, 5-methylhydroxy-, N 4 -acetyl-5-methylhydroxy-sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formulation of N 4 -hydroxy metabolite is mediated via CYP2C9. Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 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. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not 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-U.S. 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 in 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 and sulfamethoxazole to test the susceptibility of microorganisms to trimethoprim and sulfamethoxazole. The disc diffusion interpretive criteria are provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Trimethoprim and Sulfamethoxazole Bacteria Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) S I R S I R Enterobacteriaceae ≤ 2/38 - ≥ 4/76 ≥ 16 11 – 15 ≤ 10 Haemophilus influenzae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 16 11 – 15 ≤ 10 Streptococcus pneumoniae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 19 16 – 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