Sulfamethoxazole and Trimethoprim

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat 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. Azithromycin is a macrolide antibacterial drug indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Recommended dosages and durations of therapy in adult and pediatric patient populations vary in these indications. [see Dosage and Administration (2) ] Azithromycin is a macrolide antibacterial drug indicated for mild to moderate infections caused by designated, susceptible bacteria: macrolide antibacterial drug indicated for mild to moderate infections caused by designated, susceptible bacteria: Pneumocystis jirovecii Pneumonia (1.1) Shigellosis (1.2) Urinary Tract Infections (1.3) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Sulfamethoxazole and trimethoprim injection and other antibacterial drugs, Sulfamethoxazole and trimethoprim injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.4) 1.1 Pneumocystis jirovecii Pneumonia Limitation of Use: Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors. (1.3) To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria 1.2 Shigellosis Sulfamethoxazole and trimethoprim injection is indicated in the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei in adults and pediatric patients two months of age and older. 1.3 Urinary Tract Infections Sulfamethoxazole and trimethoprim injection is indicated in the treatment of severe or complicated urinary tract infections in adults and pediatric patients two months of age and older due to susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii , Proteus mirabilis and Proteus vulgaris when oral administration of sulfamethoxazole and trimethoprim injection is not feasible and when the organism is not susceptible to single-agent antibacterials effective in the urinary tract. 1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim injection and other antibacterial drugs, sulfamethoxazole and trimethoprim injection 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. Although appropriate culture and susceptibility studies should be performed, therapy may be started while awaiting the results of these studies.

2 DOSAGE AND ADMINISTRATION 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* 15-20 mg/kg (in 3 or 4 equally divided doses) Every 6 to 8 hours 14 days Severe Urinary Tract Infections 8-10 mg/kg (in 2 to 4 equally divided doses) Every 6, 8 or 12 hours 14 days Shigellosis 8-10 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 – 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.

5 WARNINGS AND PRECAUTIONS Embryo-fetal Toxicity: Increased risk of congenital malformations. Advise patient of the potential hazards to the fetus. (5.1) Hypersensitivity and Other Serious or Fatal Reactions: Discontinue at first appearance of skin rash or any sign of adverse reaction. (5.2) Hemophagocytic Lymphohistiocytosis (HLH): Cases of HLH have been reported in patients treated with sulfamethoxazole-trimethoprim. If HLH is suspected, discontinue sulfamethoxazole and trimethoprim injection immediately and institute appropriate management. (5.3) Thrombocytopenia: Monitor for hematologic toxicity. (5.4) Streptococcal Infections and Rheumatic Fever: Do not use for the treatment of group A beta-hemolytic streptococcal infections. (5.5) Clostridioides difficile- Associated Diarrhea: Evaluate if diarrhea occurs. (5.6) Sulfite Sensitivity: May cause allergic-type reactions. (5.7) Benzyl Alcohol Toxicity: Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates. (5.8) Increased mortality with adjunctive leucovorin for Pneumocystis jirovecii pneumonia: Avoid concurrent use. (5.9) Propylene glycol toxicity: Hyperosmolarity with lactic or non-gap metabolic acidosis can occur. Monitor for total intake of propylene glycol and for acid-base disturbances. (5.10) 5.1 Embryo-fetal Toxicity Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim injection 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 injection 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 Use in Specific Populations (8.1)]. 5.2 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 injection [see Adverse Reactions (6.1)]. 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. Other severe pulmonary adverse reactions occurring within days to week of sulfamethoxazole and trimethoprim injection 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 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 injection, in patients with history of recent (days to weeks) exposure to sulfamethoxazole and trimethoprim. Sulfamethoxazole and trimethoprim injection 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 more severe reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AFND, AGEP, hepatic necrosis or serious blood disorder. Clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, pur…

4 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)

7 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 contraindicate…

8.1 Pregnancy Risk Summary Sulfamethoxazole and trimethoprim injection may cause fetal harm if administered to a pregnant woman. Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim injection during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot (see Human Data). One of 3 rat studies showed cleft palate at doses approximately 5 times the recommended human dose on a body surface area basis; the other 2 studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately 6 times the human dose on a body surface area basis ( see Animal Data). The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Advise pregnant women of the potential harm of sulfamethoxazole and trimethoprim injection to the fetus ( see Clinical Considerations). Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Urinary tract infection in pregnancy is associated with adverse perinatal outcomes such as preterm birth, low birth weight, and pre-eclampsia, and increased mortality to the pregnant woman. P. jirovecii pneumonia in pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman. Sulfamethoxazole and trimethoprim injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data 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 injection 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 injection exposure and specific malformations. Brumfitt and Pursell, 10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter. 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…

6 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 Serious or 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 Somerset Therapeutics, LLC at 1-800-417-9175 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 c…