ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS (SEE WARNINGS SECTION). Local reaction, pain and slight irritation on IV administration are infrequent. Thrombophlebitis has rarely been observed.. Hematologic. Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.. Allergic Reactions. Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, conjunctival and scleral injection, photosensitivity, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.. Gastrointestinal. Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.. Genitourinary. Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria.. Metabolic and Nutritional. HyperkalemiaSee PRECAUTIONS, Use in the Treatment of Pneumocystis Jiroveci Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS). Neurologic. Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.. Psychiatric. Hallucinations, depression, apathy, nervousness.. Endocrine. The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides.. Musculoskeletal. Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported with sulfamethoxazole and trimethoprim, mainly in AIDS patients.. Respiratory. Pulmonary infiltrates.. Miscellaneous. Weakness, fatigue, insomnia.. Postmarketing Experience. The following adverse reactions have been identified during post-approval use of trimethoprim and sulfamethoxazole. Because these reactions were reported voluntarily from population of uncertain size, it is not possible to reliably estimate their frequency or establish causal relationship to drug exposure:Thrombotic thrombocytopenia purpuraIdiopathic thrombocytopenic purpura. Thrombotic thrombocytopenia purpura. Idiopathic thrombocytopenic purpura.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis. Long-term studies in animals to evaluate carcinogenic potential have not been conducted with sulfamethoxazole and trimethoprim. Mutagenesis. Bacterial mutagenic studies have not been performed with sulfamethoxazole and trimethoprim in combination. Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. No chromosomal damage was observed in human leukocytes cultured in vitro with sulfamethoxazole and trimethoprim alone or in combination; the concentrations used exceeded blood levels of these compounds following therapy with sulfamethoxazole and trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities. Impairment of Fertility. No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Following 1 hour intravenous infusion of single dose of 800 mg sulfamethoxazole and 160 mg trimethoprim to 11 patients whose weight ranged from 105 lbs to 165 lbs (mean, 143 lbs) the peak plasma concentrations of sulfamethoxazole and trimethoprim were 46.3 +- 2.7 mcg/mL and 3.4 +- 0.3 mcg/mL, respectively. Following repeated intravenous administration of the same dose at hour intervals, the mean plasma concentrations just prior to and immediately after each infusion at steady state were 70.6 +- 7.3 mcg/mL and 105.6 +- 10.9 mcg/mL for sulfamethoxazole and 5.6 +- 0.6 mcg/mL and 8.8 +- 0.9 mcg/mL for trimethoprim. The mean plasma half-life was 12.8 +- 1.8 hours for sulfamethoxazole and 11.3 +- 0.7 hours for trimethoprim. All of these 11 patients had normal renal function, and their ages ranged from 17 to 78 years (median, 60 years).1 Pharmacokinetic studies in children and adults suggest an age-dependent half-life of trimethoprim, as indicated in the following table.2 Age(years)No. ofPatientsMean TMPHalf-life (hours)< 127.671 to 1095.4910 to 2058.1920 to 63612.82Patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION section).Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N4-acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 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. 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.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 percent of dose excreted in urine over 12 hour period following the intravenous administration of the first dose of 1200 mg of sulfamethoxazole and 240 mg of trimethoprim on day ranged from 7% to 12.7% as free sulfamethoxazole and 17% to 42.4% as free trimethoprim; and 36.7% to 56% as total (free plus the N4-acetylated metabolite) sulfamethoxazole. When administered together, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum and vaginal fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in breast milk.. 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 microorganismsStreptococcus pneumoniaeAerobic gram-negative microorganismsEscherichia coli (including susceptible enterotoxigenic strains implicated in travelers diarrhea) Klebsiella species Enterobacter species Haemophilus influenzae Morganella morganii Proteus mirabilis Proteus vulgaris Shigella flexneri Shigella sonnei Other OrganismsPneumocystis jiroveciSusceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Sulfamethoxazole and trimethoprim are contraindicated in patients with known hypersensitivity to trimethoprim or sulfonamides, in patients with history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole and trimethoprim are also contraindicated in pregnant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Sulfamethoxazole and trimethoprim are contraindicated in pediatric patients less than months of age.

DESCRIPTION SECTION.

DESCRIPTION. Sulfamethoxazole and Trimethoprim Injection USP, sterile solution for intravenous infusion only, is synthetic antibacterial combination product. 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 preservative; diethanolamine 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 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.Sulfamethoxazole, USP is N1 -(5-methyl-3-isoxazolyl)sulfanilamide. It is an almost white, odorless, tasteless compound with the following structural formula:C10H11N3O3S M.W. 253.28Trimethoprim, USP is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine. It is white to light yellow, odorless, bitter compound with the following structural formula:C14H18N4O3 M.W. 290.3. Sulfamethoxazole Structural Formula. Trimethoprim Structural Formula.

LABORATORY TESTS SECTION.

Laboratory Tests. Complete blood counts should be done frequently in patients receiving sulfamethoxazole and trimethoprim; if significant reduction in the count of any formed blood element is noted, sulfamethoxazole and trimethoprim should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function.

NONTERATOGENIC EFFECTS SECTION.

Nonteratogenic Effects. See CONTRAINDICATIONS section.

NURSING MOTHERS SECTION.

Nursing Mothers. See CONTRAINDICATIONS section.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION IS CONTRAINDICATED IN PEDIATRIC PATIENTS LESS THAN MONTHS OF AGE. CAUTION--SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION MUST BE DILUTED IN 5% DEXTROSE IN WATER SOLUTION PRIOR TO ADMINISTRATION. DO NOT MIX SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION WITH OTHER DRUGS OR SOLUTIONS. RAPID INFUSION OR BOLUS INJECTION MUST BE AVOIDED.. Dosage. Children and Adults. Pneumocystis Jiroveci Pneumonia. Total daily dose is 15 to 20 mg/kg (based on the trimethoprim component) given in or equally divided doses every to hours for up to 14 days. One investigator noted that total daily dose of 10 to 15 mg/kg was sufficient in 10 adult patients with normal renal function.8 Severe Urinary Tract Infections and Shigellosis. Total daily dose is to 10 mg/kg (based on the trimethoprim component) given in or equally divided doses every 6, or 12 hours for up to 14 days for severe urinary tract infections and days for shigellosis. The maximum recommended daily dose is 60 mL per day.. For Patients With Impaired Renal Function. When renal function is impaired, reduced dosage should be employed using the following table: CreatinineClearance (mL/min)RecommendedDosage RegimenAbove 30Usual standard regimen15 to 301/2 the usual regimenBelow 15Use not recommended. Method of Preparation. Sulfamethoxazole and trimethoprim injection must be diluted. EACH 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 hours. If dilution of mL per 100 mL of 5% dextrose in water is desired, it should be used within hours. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and fresh solution prepared.. Multidose Vials. After initial entry into the vial, the remaining contents must be used within 48 hours.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.. Dilution. EACH ML OF SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION SHOULD BE ADDED TO 125 ML OF 5% DEXTROSE IN WATER. Note: In those instances where fluid restriction is desirable, each 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 hours. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and fresh solution prepared.DO NOT MIX SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION 5% DEXTROSE IN WATER WITH DRUGS OR SOLUTIONS IN THE SAME CONTAINER. Administration. The solution should be given by intravenous infusion over period of 60 to 90 minutes. Rapid infusion or bolus injection must be avoided. Sulfamethoxazole and trimethoprim injection should not be given intramuscularly. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

Drug/Laboratory Test Interactions. Sulfamethoxazole and trimethoprim, specifically the trimethoprim component, can interfere with serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by radioimmunoassay (RIA). The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

DRUG INTERACTIONS SECTION.

Drug Interactions. In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when sulfamethoxazole and trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin. Sulfamethoxazole and trimethoprim, given at common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.There have been reports of marked but reversible nephrotoxicity with coadministration of sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients.Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored.Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if sulfamethoxazole and trimethoprim is prescribed.The efficacy of tricyclic antidepressants can decrease when coadministered with sulfamethoxazole and trimethoprim.Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim potentiates the effect of oral hypoglycemics.In the literature, single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole and trimethoprim and amantadine.In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole and trimethoprim and an angiotensin converting enzyme inhibitor.5,.

GERIATRIC USE SECTION.

Geriatric Use. Clinical studies of sulfamethoxazole and trimethoprim did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of sulfamethoxazole and trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of sulfamethoxazole and trimethoprim treatment is recommended to help lower potassium serum levels. Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY).

HOW SUPPLIED SECTION.

HOW SUPPLIED. Sulfamethoxazole and Trimethoprim Injection USP, 80 mg and 16 mg are supplied as follows:NDC NumbersSulfamethoxazole, USPTrimethoprim, USPSize0703-9503-0380 mg/mL16 mg/mL5 mL Single dose vial0703-9514-0380 mg/mL16 mg/mL10 mL Multiple dose vial0703-9526-0180 mg/mL16 mg/mL30 mL Multiple dose vial5 mL single dose amber vials packaged 10 per carton.10 mL multiple dose amber vials packaged 10 per carton.30 mL multiple dose amber vials packaged individually. Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].DO NOT REFRIGERATE.

INDICATIONS & USAGE SECTION.

INDICATIONS AND 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.. Pneumocystis Jiroveci Pneumonia. Sulfamethoxazole and trimethoprim injection is indicated in the treatment of Pneumocystis jiroveci pneumonia in children and adults.. Shigellosis. Sulfamethoxazole and trimethoprim injection is indicated in the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei in children and adults.. Urinary Tract Infections. Sulfamethoxazole and trimethoprim injection is indicated in the treatment of severe or complicated urinary tract infections due to susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii and Proteus species when oral administration of sulfamethoxazole and trimethoprim is not feasible and when the organism is not susceptible to single-agent antibacterials effective in the urinary tract.Although appropriate culture and susceptibility studies should be performed, therapy may be started while awaiting the results of these studies.

OVERDOSAGE SECTION.

OVERDOSAGE. Acute. Since there has been no extensive experience in humans with single doses of sulfamethoxazole and trimethoprim injection in excess of 25 mL (2000 mg sulfamethoxazole and 400 mg trimethoprim), the maximum tolerated dose in humans is unknown. Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage.Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression.General principles of treatment include the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.. Chronic. Use of sulfamethoxazole and trimethoprim injection at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin to 15 mg daily until normal hematopoiesis is restored.. Animal Toxicity. The LD50 of sulfamethoxazole and trimethoprim injection in mice is 700 mg/kg or 7.3 mL/kg; in rats and rabbits the LD50 is 500 mg/kg or 5.2 mL/kg. The vehicle produced the same LD50 in each of these species as the active drug.The signs and symptoms noted in mice, rats and rabbits with sulfamethoxazole and trimethoprim or its vehicle at the high IV doses used in acute toxicity studies included ataxia, decreased motor activity, loss of righting reflex, tremors or convulsions, and/or respiratory depression.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. image. image. Sulfamethoxazole 80 mg/mL and Trimethoprim 16 mg/mL Injection USP, 10 5 mL Single Dose Vial Carton Text. NDC 0703-9503-03 Rx onlySulfamethoxazole and TrimethoprimInjection USPSulfamethoxazole 400 mg/5 mL (80 mg/mL) Trimethoprim 80 mg/5 mL (16 mg/mL)For IV Infusion Only mL Single Dose Vial 10 Vials Must be diluted with 5% dextrose injection prior to administration. TEVA.

PEDIATRIC USE SECTION.

Pediatric Use. Sulfamethoxazole and trimethoprim is contraindicated for infants younger than months of age (see CONTRAINDICATIONS section).

PRECAUTIONS SECTION.

PRECAUTIONS. Development of Drug Resistant Bacteria. Prescribing sulfamethoxazole and trimethoprim injection in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.. General. Folate Deficiency. Sulfamethoxazole and trimethoprim injection should be given with caution to patients with impaired renal or hepatic function, to 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 to 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.. Hemolysis. In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).. Infusion Reactions. Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with sulfamethoxazole and trimethoprim. If these occur the infusion should be discontinued and restarted at another site.. Hypoglycemia. Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen rarely, usually occurring after few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole and trimethoprim are particularly at risk.. Phenylalanine Metabolism. Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.. Porphyria and Hypothyroidism. As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.. Use in the Treatment of Pneumocystis Jiroveci 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 side effects, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with sulfamethoxazole and trimethoprim therapy in AIDS patients who are being treated for Pneumocystis jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of sulfamethoxazole and trimethoprim in non-AIDS patients. The incidence of hyperkalemia appears to be increased in AIDS patients receiving sulfamethoxazole and trimethoprim. Adverse effects are generally less severe in patients receiving sulfamethoxazole and trimethoprim for prophylaxis. history of mild intolerance to sulfamethoxazole and trimethoprim in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis.4 However, if patient develops skin rash or any sign of adverse reaction, therapy with sulfamethoxazole and trimethoprim should be reevaluated (see WARNINGS).Coadministration of sulfamethoxazole and trimethoprim and leucovorin should be avoided with Pneumocystis jiroveci pneumonia (see WARNINGS).High dosage of trimethoprim, as used in patients with Pneumocystis jiroveci pneumonia, induces progressive but reversible increase of serum potassium concentrations in 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.During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria. Patients who are slow acetylators may be more prone to idiosyncratic reactions to sulfonamides.. Information for Patients. Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim injection should only be used to treat bacterial infections. It does not treat viral infections (e.g., the common cold). Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.Diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.. Laboratory Tests. Complete blood counts should be done frequently in patients receiving sulfamethoxazole and trimethoprim; if significant reduction in the count of any formed blood element is noted, sulfamethoxazole and trimethoprim should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function.. Drug Interactions. In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when sulfamethoxazole and trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin. Sulfamethoxazole and trimethoprim, given at common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.There have been reports of marked but reversible nephrotoxicity with coadministration of sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients.Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored.Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if sulfamethoxazole and trimethoprim is prescribed.The efficacy of tricyclic antidepressants can decrease when coadministered with sulfamethoxazole and trimethoprim.Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim potentiates the effect of oral hypoglycemics.In the literature, single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole and trimethoprim and amantadine.In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole and trimethoprim and an angiotensin converting enzyme inhibitor.5, . Drug/Laboratory Test Interactions. Sulfamethoxazole and trimethoprim, specifically the trimethoprim component, can interfere with serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by radioimmunoassay (RIA). The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis. Long-term studies in animals to evaluate carcinogenic potential have not been conducted with sulfamethoxazole and trimethoprim. Mutagenesis. Bacterial mutagenic studies have not been performed with sulfamethoxazole and trimethoprim in combination. Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. No chromosomal damage was observed in human leukocytes cultured in vitro with sulfamethoxazole and trimethoprim alone or in combination; the concentrations used exceeded blood levels of these compounds following therapy with sulfamethoxazole and trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities. Impairment of Fertility. No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim.. Pregnancy. Teratogenic Effects. Pregnancy Category C. In rats, oral doses of 533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates.The highest dose which did not cause cleft palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg trimethoprim when administered separately. 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 one study, however, cleft palates were observed in one litter out of when 355 mg/kg of sulfamethoxazole was used in combination with 88 mg/kg of trimethoprim.In some rabbit studies, an overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses of trimethoprim six times the human therapeutic dose. While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,7 in retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and trimethoprim. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethoxazole and trimethoprim. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter.Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, sulfamethoxazole and trimethoprim injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects. See CONTRAINDICATIONS section.. Nursing Mothers. See CONTRAINDICATIONS section.. Pediatric Use. Sulfamethoxazole and trimethoprim is contraindicated for infants younger than months of age (see CONTRAINDICATIONS section).. Geriatric Use. Clinical studies of sulfamethoxazole and trimethoprim did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of sulfamethoxazole and trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of sulfamethoxazole and trimethoprim treatment is recommended to help lower potassium serum levels. Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY).

REFERENCES SECTION.

REFERENCES. Grose WE, Bodey GP, Loo TL. Clinical Pharmacology of Intravenously Administered Trimethoprim-Sulfamethoxazole. Antimicrob Agents Chemother. Mar 1979;15:447-451. Siber GR, Gorham C, Durbin W, Lesko L, Levin MJ. Pharmacology of Intravenous Trimethoprim-Sulfamethoxazole in Children and Adults. Current Chemotherapy and Infectious Diseases, American Society for Microbiology, Washington, D.C., 1980, Vol. 1, pp. 691-692. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. Infect Dis. 1994 Oct;170(4):912-7. Hardy DW, et al. controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Engl Med. 1992; 327: 1842-1848.Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol. 45:209-212.Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410-414.Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. Infect Dis. Nov 1973;128 (Suppl):S657-S663. Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim- Sulfamethoxazole for the Treatment of Pneumocystis carinii pneumonia. Ann Intern Med. June 1980;92:762-769.Rev. 4/2019Manufactured In Israel By:Teva Pharmaceutical Ind. Ltd.Kfar Saba, 44102, IsraelManufactured For:Teva Pharmaceuticals USA, Inc.North Wales, PA 19454. Grose WE, Bodey GP, Loo TL. Clinical Pharmacology of Intravenously Administered Trimethoprim-Sulfamethoxazole. Antimicrob Agents Chemother. Mar 1979;15:447-451. Siber GR, Gorham C, Durbin W, Lesko L, Levin MJ. Pharmacology of Intravenous Trimethoprim-Sulfamethoxazole in Children and Adults. Current Chemotherapy and Infectious Diseases, American Society for Microbiology, Washington, D.C., 1980, Vol. 1, pp. 691-692. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. Infect Dis. 1994 Oct;170(4):912-7. Hardy DW, et al. controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Engl Med. 1992; 327: 1842-1848.. Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol. 45:209-212.. Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410-414.. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. Infect Dis. Nov 1973;128 (Suppl):S657-S663. Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprim- Sulfamethoxazole for the Treatment of Pneumocystis carinii pneumonia. Ann Intern Med. June 1980;92:762-769.

SPL UNCLASSIFIED SECTION.

Rx onlyTo 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 bacteria.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy Category C. In rats, oral doses of 533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates.The highest dose which did not cause cleft palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg trimethoprim when administered separately. 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 one study, however, cleft palates were observed in one litter out of when 355 mg/kg of sulfamethoxazole was used in combination with 88 mg/kg of trimethoprim.In some rabbit studies, an overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses of trimethoprim six times the human therapeutic dose. While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,7 in retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and trimethoprim. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethoxazole and trimethoprim. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter.Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, sulfamethoxazole and trimethoprim injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

WARNINGS SECTION.

WARNINGS. Hypersensitivity and Other Fatal Reactions. FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA, AND OTHER BLOOD DYSCRASIAS.SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS SULFAMETHOXAZOLE AND TRIMETHOPRIM INJECTION, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION. In rare instances, skin rash may be followed by more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice may be early indications of serious reactions.Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.. Thrombocytopenia. Sulfamethoxazole and trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within week upon discontinuation of sulfamethoxazole and trimethoprim.. Streptococcal Infections and Rheumatic Fever. The sulfonamides should not be used for the treatment of group beta-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.. Clostridium Difficile Associated Diarrhea. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.C. difficile produces toxins and 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.. Sulfite Sensitivity. Sulfamethoxazole and trimethoprim injection contains sodium metabisulfite, 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 and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.. Benzyl Alcohol. Contains benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal.. Adjunctive Treatment With Leucovorin for Pneumocystis Jiroveci Pneumonia. Treatment failure and excess mortality were observed when trimethoprim and sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in randomized placebo controlled trial.3 Coadministration of trimethoprim and sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Sulfamethoxazole and Trimethoprim Injection USP, is clear, colorless to slight yellow, sterile solution available as an injection containing:400 mg/5 mL (80 mg/mL) of sulfamethoxazole, USP and 80 mg/5 mL (16 mg/mL) of trimethoprim, USP in mL single dose vials.800 mg/10 mL (80 mg/mL) of sulfamethoxazole, USP and 160 mg/10 mL (16 mg/mL) of trimethoprim, USP in 10 mL multiple dose vials.2400 mg/30 mL (80 mg/mL) of sulfamethoxazole, USP and 480 mg/30 mL (16 mg/mL) of trimethoprim, USP in 30 mL multiple dose vials.. 400 mg/5 mL (80 mg/mL) of sulfamethoxazole, USP and 80 mg/5 mL (16 mg/mL) of trimethoprim, USP in mL single dose vials.. 800 mg/10 mL (80 mg/mL) of sulfamethoxazole, USP and 160 mg/10 mL (16 mg/mL) of trimethoprim, USP in 10 mL multiple dose vials.. 2400 mg/30 mL (80 mg/mL) of sulfamethoxazole, USP and 480 mg/30 mL (16 mg/mL) of trimethoprim, USP in 30 mL multiple dose vials.. Injection: (3)400 mg/5 mL (80 mg/mL) of sulfamethoxazole and 80 mg/5 mL (16 mg/mL) of trimethoprim in mL single dose vials.800 mg/10 mL (80 mg/mL) of sulfamethoxazole and 160 mg/10 mL (16 mg/mL) of trimethoprim in 10 mL multiple dose vials.2400 mg/30 mL (80 mg/mL) of sulfamethoxazole and 480 mg/30 mL (16 mg/mL) of trimethoprim in 30 mL multiple dose vials. 400 mg/5 mL (80 mg/mL) of sulfamethoxazole and 80 mg/5 mL (16 mg/mL) of trimethoprim in mL single dose vials.. 800 mg/10 mL (80 mg/mL) of sulfamethoxazole and 160 mg/10 mL (16 mg/mL) of trimethoprim in 10 mL multiple dose vials.. 2400 mg/30 mL (80 mg/mL) of sulfamethoxazole and 480 mg/30 mL (16 mg/mL) of trimethoprim in 30 mL multiple dose vials.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Embryo-fetal ToxicityAdvise female patients of reproductive potential that Sulfamethoxazole and Trimethoprim Injection can cause fetal harm and to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)].Hypersensitivity and Other Serious or Fatal ReactionsAdvise patients to stop taking Sulfamethoxazole and Trimethoprim Injection immediately if they experience any clinical signs such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].LactationAdvise nursing women to avoid breastfeeding during treatment with Sulfamethoxazole and Trimethoprim Injection.Antibacterial ResistanceCounsel patients that antibacterial drugs including Sulfamethoxazole and Trimethoprim Injection should only be used to treat bacterial infections. It does not treat viral infections (e.g., the common cold).Instruct patients to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. DiarrheaAdvise patients that diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.Manufactured In Israel By: Teva Pharmaceutical Ind. Ltd. Kfar Saba, 44102, IsraelManufactured For: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454Rev. 9/2022.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryLevels of sulfamethoxazole and trimethoprim in breast milk are approximately 2% to 5% of the recommended daily dose for pediatric patients over two months of age. There is no information regarding the effect of Sulfamethoxazole and Trimethoprim Injection on the breastfed infant or the effect on milk production. Because of the potential risk of bilirubin displacement and kernicterus on the breastfed child [see Contraindications (4)], advise women to avoid breastfeeding during treatment with Sulfamethoxazole and Trimethoprim Injection.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Sulfamethoxazole and Trimethoprim Injection is an antimicrobial drug [see Microbiology (12.4)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisSulfamethoxazole was not carcinogenic when assessed in 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2-fold the human systemic exposure (at daily dose of 800 mg sulfamethoxazole twice day).MutagenesisIn vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes.Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded. Impairment of FertilityNo adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim, doses roughly two times the recommended human daily dose on body surface area basis.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following 1-hour intravenous infusion of single dose of 160 mg trimethoprim and 800 mg sulfamethoxazole to 11 patients whose weight ranged from 105 lbs to 165 lbs (mean, 143 lbs), the peak plasma concentrations of trimethoprim and sulfamethoxazole were 3.4 +- 0.3 mcg/mL and 46.3 +- 2.7 mcg/mL, respectively. Following repeated intravenous administration of the same dose at 8-hour intervals, the mean plasma concentrations just prior to and immediately after each infusion at steady state were 5.6 +-0.6 mcg/mL and 8.8 +- 0.9 mcg/mL for trimethoprim and 70.6 +- 7.3 mcg/mL and 105.6 +- 10.9 mcg/mL for sulfamethoxazole. The mean plasma half-life was 11.3 +- 0.7 hours for trimethoprim and 12.8 +- 1.8 hours for sulfamethoxazole. All of these 11 patients had normal renal function, and their ages ranged from 17 to 78 years (median, 60 years).11 Pharmacokinetic studies in children and adults suggest an age-dependent half-life of trimethoprim, as indicated in Table 5.12 Table 5: Half-life of Trimethoprim (TMP) in Pediatric Patients and Adults Age (years) No. of Patients Mean TMP Half-life (hours) <1 7.67 to 10 5.49 10 to 20 8.19 20 to 63 12.82Patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment [see Dosage and Administration (2.2)]. DistributionBoth trimethoprim and sulfamethoxazole exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form.Approximately 44% of trimethoprim and 70% of sulfamethoxazole 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. Both trimethoprim and sulfamethoxazole distribute to sputum and vaginal fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in breast milk. EliminationMetabolismSulfamethoxazole is metabolized in humans to at least metabolites: the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy-sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formation of N4-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 trimethoprim and sulfamethoxazole are considered to be the therapeutically active forms. In vitro studies suggest that trimethoprim is substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not substrate of P-glycoprotein. ExcretionExcretion of trimethoprim and sulfamethoxazole is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both trimethoprim and sulfamethoxazole are considerably higher than are the concentrations in the blood. The percent of dose excreted in urine over 12-hour period following the intravenous administration of the first dose of 240 mg of trimethoprim and 1200 mg of sulfamethoxazole on day ranged from 17% to 42.4% as free trimethoprim; 7% to 12.7% as free sulfamethoxazole; and 36.7% to 56% as total (free plus the N4-acetylated metabolite) sulfamethoxazole. When administered together as Sulfamethoxazole and Trimethoprim Injection, neither trimethoprim nor sulfamethoxazole affects the urinary excretion pattern of the other.Specific PopulationsGeriatric Patients: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in six geriatric subjects (mean age: 78.6 years) and six young healthy subjects (mean age: 29.3 years) using non-US approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummarySulfamethoxazole and Trimethoprim Injection may cause fetal harm if administered to 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 rat studies showed cleft palate at doses approximately times the recommended human dose on body surface area basis; the other studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately times the human dose on 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 ConsiderationsDisease-associated Maternal and/or Embryo/Fetal RiskUrinary 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.DataHuman DataWhile 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 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 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 DataIn 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 and times the recommended human total daily dose on 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 times the human therapeutic dose based on body surface area.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Sulfamethoxazole and Trimethoprim Injection may cause fetal harm to the fetus. Use only if potential benefit justifies potential risk to the fetus. (8.1)Lactation: Avoid breastfeeding during treatment with Sulfamethoxazole and Trimethoprim Injection because of potential risk of bilirubin displacement and kernicterus. (8.2). Pregnancy: Sulfamethoxazole and Trimethoprim Injection may cause fetal harm to the fetus. Use only if potential benefit justifies potential risk to the fetus. (8.1). Lactation: Avoid breastfeeding during treatment with Sulfamethoxazole and Trimethoprim Injection because of potential risk of bilirubin displacement and kernicterus. (8.2). 8.1 Pregnancy. Risk SummarySulfamethoxazole and Trimethoprim Injection may cause fetal harm if administered to 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 rat studies showed cleft palate at doses approximately times the recommended human dose on body surface area basis; the other studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately times the human dose on 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 ConsiderationsDisease-associated Maternal and/or Embryo/Fetal RiskUrinary 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.DataHuman DataWhile 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 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 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 DataIn 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 and times the recommended human total daily dose on 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 times the human therapeutic dose based on body surface area.. 8.2 Lactation. Risk SummaryLevels of sulfamethoxazole and trimethoprim in breast milk are approximately 2% to 5% of the recommended daily dose for pediatric patients over two months of age. There is no information regarding the effect of Sulfamethoxazole and Trimethoprim Injection on the breastfed infant or the effect on milk production. Because of the potential risk of bilirubin displacement and kernicterus on the breastfed child [see Contraindications (4)], advise women to avoid breastfeeding during treatment with Sulfamethoxazole and Trimethoprim Injection.. 8.4 Pediatric Use. Sulfamethoxazole and Trimethoprim Injection is contraindicated in pediatric patients younger than two months of age because of the potential risk of bilirubin displacement and kernicterus [see Contraindications (4)].Serious adverse reactions including fatal reactions and the gasping syndrome occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received benzyl alcohol as preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.When prescribing Sulfamethoxazole and Trimethoprim Injection in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including Sulfamethoxazole and Trimethoprim Injection (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 Warnings and Precautions (5.7)]. 8.5 Geriatric Use. Clinical studies of Sulfamethoxazole and Trimethoprim Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression [see Warnings and Precautions (5.10), Adverse Reactions (6.1)], specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients.In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant Sulfamethoxazole and Trimethoprim Injection therapy, especially in elderly patients. Serum digoxin levels should be monitored [see Drug Interactions (7)].Hematologic changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions [see Dosage and Administration (2.2)].The trimethoprim component of Sulfamethoxazole and Trimethoprim Injection may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of Sulfamethoxazole and Trimethoprim Injection treatment is recommended to help lower potassium serum levels.Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

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)Thrombocytopenia: Monitor for hematologic toxicity. (5.3)Streptococcal Infections and Rheumatic Fever: Do not use for the treatment of group beta-hemolytic streptococcal infections. (5.4)Clostridioides difficile-Associated Diarrhea: Evaluate if diarrhea occurs. (5.5)Sulfite Sensitivity: May cause allergic-type reactions. (5.6)Benzyl Alcohol Toxicity: Serious and fatal adverse reactions including gasping syndrome can occur in neonates. (5.7)Increased mortality with adjunctive leucovorin for Pneumocystis jirovecii pneumonia: Avoid concurrent use. (5.8)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. (5.9). 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). Thrombocytopenia: Monitor for hematologic toxicity. (5.3). Streptococcal Infections and Rheumatic Fever: Do not use for the treatment of group beta-hemolytic streptococcal infections. (5.4). Clostridioides difficile-Associated Diarrhea: Evaluate if diarrhea occurs. (5.5). Sulfite Sensitivity: May cause allergic-type reactions. (5.6). Benzyl Alcohol Toxicity: Serious and fatal adverse reactions including gasping syndrome can occur in neonates. (5.7). Increased mortality with adjunctive leucovorin for Pneumocystis jirovecii pneumonia: Avoid concurrent use. (5.8). 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. (5.9). 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 serious adverse reaction. 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 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 week upon discontinuation of Sulfamethoxazole and Trimethoprim Injection. 5.4 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 -hemolytic streptococcal tonsillopharyngitis have 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. 5.5 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 and 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.. 5.6 Sulfite Sensitivity. Sulfamethoxazole and Trimethoprim Injection contains sodium metabisulfite, 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.. 5.7 Benzyl Alcohol Toxicity in Pediatric Patients (Gasping Syndrome). Sulfamethoxazole and Trimethoprim Injection contains benzyl alcohol as 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)].. 5.8 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 randomized placebo-controlled trial.4 Avoid coadministration of Sulfamethoxazole and Trimethoprim Injection and leucovorin during treatment of P. jirovecii pneumonia.. 5.9 Propylene Glycol Toxicity. Sulfamethoxazole and Trimethoprim Injection contains propylene glycol as 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)]. 5.10 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)].. 5.11 Hemolysis. In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.. 5.12 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. 5.13 Hypoglycemia. Cases of hypoglycemia in non-diabetic patients treated with Sulfamethoxazole and Trimethoprim Injection have been seen, usually occurring after 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. 5.14 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. 5.15 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. 5.16 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 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 (5.8)].. 5.17 Electrolyte Abnormalities. HyperkalemiaHigh dosage of trimethoprim, as used in patients with P. jirovecii pneumonia, induces progressive but reversible increase of serum potassium concentrations in 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.HyponatremiaSevere 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.CrystalluriaDuring 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.. 5.18 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 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.. 5.19 Development of Drug-Resistant Bacteria. Prescribing Sulfamethoxazole and Trimethoprim Injection in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.