Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Sulfamethoxazole and Trimethoprim Injection, USP is supplied as follows: NDC Numbers Sulfamethoxazole, USP Strength Trimethoprim, USP Strength Pack Size 0703-9514-83 800 mg/10 mL (80 mg/mL) 160 mg/10 mL (16 mg/mL) 10 mL multiple-dose amber vials packaged 10 per carton. 0703-9526-81 2400 mg/30 mL (80 mg/mL) 480 mg/30 mL (16 mg/mL) 30 mL multiple-dose amber vials packaged individually. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. DO NOT REFRIGERATE.; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 0703-9514-83 Sulfamethoxazole and Trimethoprim Injection, USP Sulfamethoxazole 800 mg/10 mL (80 mg/mL) Trimethoprim 160 mg/10 mL (16 mg/mL) For Intravenous Infusion Only Must be diluted with 5% dextrose injection prior to administration. Rx only 10 mL Multiple-Dose Vial 10 Vials 1; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 0703-9526-81 Sulfamethoxazole and Trimethoprim Injection, USP Sulfamethoxazole 2400 mg/30 mL (80 mg/mL) Trimethoprim 480 mg/30 mL (16 mg/mL) For Intravenous Infusion Only Must be diluted with 5% dextrose injection prior to administration. Rx only 30 mL Multiple-Dose Vial 1
- 16 HOW SUPPLIED/STORAGE AND HANDLING Sulfamethoxazole and Trimethoprim Injection, USP is supplied as follows: NDC Numbers Sulfamethoxazole, USP Strength Trimethoprim, USP Strength Pack Size 0703-9514-83 800 mg/10 mL (80 mg/mL) 160 mg/10 mL (16 mg/mL) 10 mL multiple-dose amber vials packaged 10 per carton. 0703-9526-81 2400 mg/30 mL (80 mg/mL) 480 mg/30 mL (16 mg/mL) 30 mL multiple-dose amber vials packaged individually. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. DO NOT REFRIGERATE.
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 0703-9514-83 Sulfamethoxazole and Trimethoprim Injection, USP Sulfamethoxazole 800 mg/10 mL (80 mg/mL) Trimethoprim 160 mg/10 mL (16 mg/mL) For Intravenous Infusion Only Must be diluted with 5% dextrose injection prior to administration. Rx only 10 mL Multiple-Dose Vial 10 Vials 1
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 0703-9526-81 Sulfamethoxazole and Trimethoprim Injection, USP Sulfamethoxazole 2400 mg/30 mL (80 mg/mL) Trimethoprim 480 mg/30 mL (16 mg/mL) For Intravenous Infusion Only Must be diluted with 5% dextrose injection prior to administration. Rx only 30 mL Multiple-Dose Vial 1
Overview
Sulfamethoxazole and Trimethoprim Injection USP, a clear, colorless to slight yellow, sterile solution for intravenous infusion only, is a combination of sulfamethoxazole USP, a sulfonamide antimicrobial, and trimethoprim USP, a dihydrofolate reductase inhibitor antibacterial. Each mL contains: sulfamethoxazole, USP 80 mg; trimethoprim, USP 16 mg; benzyl alcohol 10 mg (1.0% v/v and 1.0% w/v) as a preservative; diethanolamine 3 mg (0.3% v/v and 0.3% w/v); ethyl alcohol 100 mg (12.3% v/v and 10.0% w/v); propylene glycol 400 mg (38.6% v/v and 40.0% w/v); sodium metabisulfite 1 mg as an antioxidant; water for injection q.s.; air replaced with nitrogen; pH adjusted with sodium hydroxide and/or hydrochloric acid if necessary. pH: 9.5 to 10.5. Trimethoprim, USP is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.32 and the following structural formula: C 14 H 18 N 4 O 3 M.W. 290.32 Sulfamethoxazole, USP is N 1 -(5-methyl-3-isoxazolyl) sulfanilamide. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: C 10 H 11 N 3 O 3 S M.W. 253.28 Trim sulfa
Indications & Usage
Sulfamethoxazole and Trimethoprim Injection is a combination of sulfamethoxazole, a sulfonamide antimicrobial, and trimethoprim, a dihydrofolate reductase inhibitor antibacterial, indicated in adults and pediatric patients two months of age and older for treatment of 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 Sulfamethoxazole and Trimethoprim Injection is indicated in the treatment of Pneumocystis jirovecii pneumonia in adults and pediatric patients two months of age and older. 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. 1.1 Pneumocystis jirovecii Pneumonia Sulfamethoxazole and Trimethoprim Injection is indicated in the treatment of Pneumocystis jirovecii pneumonia in adults and pediatric patients two months of age and older. 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.
Dosage & 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 1/2 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 & 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 [s ee Adverse Reactions ( 6.1 )]. 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 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 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. Management of Hypersensitivity and Other Serious Reactions 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, purpura or jaundice may be early indications of serious reactions. 5.3 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 Injection immediately and institute appropriate management . 5.4 Thrombocytopenia Sulfamethoxazole and Trimethoprim Injection-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Monitor patients for hematologic toxicity. Thrombocytopenia usually resolves within a week upon discontinuation of Sulfamethoxazole and Trimethoprim Injection. 5.5 Streptococcal Infections and Rheumatic Fever Avoid use of Sulfamethoxazole and Trimethoprim Injection in the treatment of streptococcal pharyngitis. Clinical studies have documented that patients with group A β-hemolytic streptococcal tonsillopharyngitis have a greater incidence of bacteriologic failure when treated with Sulfamethoxazole and Trimethoprim Injection than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area. Therefore, Sulfamethoxazole and Trimethoprim Injection will not prevent sequelae such as rheumatic fever. 5.6 Clostridioides difficile -Associated Diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Sulfamethoxazole and Trimethoprim Injection, 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.7 Sulfite Sensitivity Sulfamethoxazole and Trimethoprim Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. 5.8 Benzyl Alcohol Toxicity in Pediatric Patients (“Gasping Syndrome”) Sulfamethoxazole and Trimethoprim Injection contains benzyl alcohol as a preservative. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved formulations in infusion solutions, including Sulfamethoxazole and Trimethoprim Injection. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. Sulfamethoxazole and Trimethoprim Injection is contraindicated in pediatric patients less than two months of age [see Contraindications ( 4 )] . When prescribing Sulfamethoxazole and Trimethoprim Injection in pediatric patients (two months of age and older), consider the combined daily metabolic load of benzyl alcohol from all sources including Sulfamethoxazole and Trimethoprim Injection (contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations ( 8.4 )] . 5.9 Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia Treatment failure and excess mortality were observed when Sulfamethoxazole and Trimethoprim Injection 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 Injection and leucovorin during treatment of P. jirovecii pneumonia. 5.10 Propylene Glycol Toxicity Sulfamethoxazole and Trimethoprim Injection contains propylene glycol as a solvent (38.6% v/v). When administered at high doses as for the treatment of P. jirovecii pneumonia and concomitantly with other products that contain propylene glycol, hyperosmolarity with anion gap metabolic acidosis, including lactic acidosis can occur. Propylene glycol toxicity can lead to acute kidney injury, CNS toxicity, and multi-organ failure. Monitor for the total daily intake of propylene glycol from all sources and for acid-base disturbances. Discontinue Sulfamethoxazole and Trimethoprim Injection if propylene glycol toxicity is suspected [see Adverse Reactions ( 6 )] . 5.11 Folate Deficiency Avoid use of Sulfamethoxazole and Trimethoprim Injection 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. Hematologic 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 Use in Specific Populations ( 8.5 )] . 5.12 Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related. 5.13 Infusion Reactions Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with Sulfamethoxazole and Trimethoprim Injection. If these occur the infusion should be discontinued and restarted at another site. 5.14 Hypoglycemia Cases of hypoglycemia in non-diabetic patients treated with Sulfamethoxazole and Trimethoprim Injection have been seen, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of Sulfamethoxazole and Trimethoprim Injection are particularly at risk. 5.15 Impaired Phenylalanine Metabolism The trimethoprim component of Sulfamethoxazole and Trimethoprim Injection has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction. 5.16 Porphyria and Hypothyroidism Like other drugs containing sulfonamides, Sulfamethoxazole and Trimethoprim Injection can precipitate porphyria crisis and hypothyroidism. Avoid use of Sulfamethoxazole and Trimethoprim Injection in patients with porphyria or thyroid dysfunction. 5.17 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 Injection in the same manner as non-AIDS patients. The incidence of adverse reactions, particularly rash, fever, leukopenia, and elevated aminotransferase (transaminase) values, with Sulfamethoxazole and Trimethoprim Injection therapy in AIDS patients who are being treated for P. jirovecii pneumonia has been reported to be increased compared with the incidence normally associated with the use of Sulfamethoxazole and Trimethoprim Injection in non-AIDS patients. If a patient develops skin rash, fever, leukopenia or any sign of an adverse reaction, reevaluate benefit-risk of continuing therapy or re-challenge with Sulfamethoxazole and Trimethoprim Injection [see Warnings and Precautions ( 5.2 )] . Avoid coadministration of Sulfamethoxazole and Trimethoprim Injection and leucovorin during treatment of P. jirovecii pneumonia [see Warnings and Precautions ( 5.9 )] . 5.18 Electrolyte Abnormalities Hyperkalemia High dosage of trimethoprim, as used in patients with P. jirovecii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients. Hyponatremia Severe and symptomatic hyponatremia can occur in patients receiving Sulfamethoxazole and Trimethoprim Injection, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications. Crystalluria During treatment, ensure adequate fluid intake and urinary output to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides. 5.19 Monitoring of Laboratory Tests Complete blood counts and clinical chemistry testing should be done frequently in patients receiving Sulfamethoxazole and Trimethoprim Injection. Discontinue Sulfamethoxazole and Trimethoprim Injection if a significant electrolyte abnormality, renal insufficiency or reduction in the count of any formed blood element is noted. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function. 5.20 Development of Drug-Resistant Bacteria Prescribing Sulfamethoxazole and Trimethoprim Injection 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.
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 )
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
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.
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