SULFAMETHOXAZOLE: 4,239 Adverse Event Reports & Safety Profile

DESCRIPTION Sulfamethoxazole and Trimethoprim Oral Suspension, USP is a synthetic antibacterial combination product with each teaspoonful (5 mL) containing 200 mg sulfamethoxazole and 40 mg trimethoprim. Sulfamethoxazole is N 1 -(5-methyl-3-isoxazolyl) sulfanilamide; the molecular formula is C 10 H 11 N 3 O 3 S. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine; the molecular formula is C 14 H 18 N 4 O 3 . It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3 and the following structural formula: Each teaspoonful (5 mL) of sulfamethoxazole and trimethoprim oral suspension (cherry flavor) is an opaque pinkish orange suspension with a cherry aroma and contains 40 mg trimethoprim and 200 mg sulfamethoxazole and the inactive ingredients alcohol not more than 0.5%; methylparaben 0.1% and sodium benzoate 0.1% (added as preservatives), artificial wild cherry flavor, citric acid anhydrous, FD&C Red #40, FD&C Yellow #6, glycerin, microcrystalline cellulose, polysorbate 80, purified water, saccharin sodium, sodium carboxymethylcellulose, sodium citrate dihydrate, and sorbitol solution. image description image description

AND 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.

AND ADMINISTRATION Dosage Guidelines For Adults and Pediatric Patients (Two Months of Age and Older)

Infection Total Daily

Dose (based on trimethoprim content)

Frequency Duration

Pneumocystis jirovecii Pneumonia 15 to 20 mg/kg (in 3 or 4 equally divided doses)

Every

6 to 8 hours 14 days Severe Urinary Tract Infections 8 to 10 mg/kg (in 2 to 4 equally divided doses)

Every

6, 8 or 12 hours 14 days Shigellosis 8 to 10 mg/kg (in 2 to 4 equally divided doses)

Every

6, 8 or 12 hours 5 days For patients with impaired renal function, a reduced dosage should be employed. ( 2.2 ) Sulfamethoxazole and Trimethoprim Injection must be given by intravenous infusion over a period of 60 to 90 minutes. Rapid infusion or bolus injection must be avoided. ( 2.3 ) Sulfamethoxazole and Trimethoprim Injection must be diluted in 5% dextrose in water solution prior to administration. ( 2.4 ) Do not mix Sulfamethoxazole and Trimethoprim Injection with other drugs or solutions. ( 2.4 )

2.1 Dosage in Adults and Pediatric Patients (Two Months of Age and Older) The maximum recommended daily dose is 60 mL (960 mg trimethoprim) per day.

Table

1: Dosage in Adults and Pediatric Patients (Two Months of Age and Older) by Indication Dosage Guidelines Infection Total Daily Dose (based on trimethoprim content)

Frequency Duration

Pneumocystis jirovecii Pneumonia * 15 to 20 mg/kg (in 3 or 4 equally divided doses)

Every

6 to 8 hours 14 days Severe Urinary Tract Infections 8 to 10 mg/kg (in 2 to 4 equally divided doses)

Every

6, 8 or 12 hours 14 days Shigellosis 8 to 10 mg/kg (in 2 to 4 equally divided doses)

Every

6, 8 or 12 hours 5 days * A total daily dose of 10 to 15 mg/kg was sufficient in 10 adult patients with normal renal function in a published literature. 1

2.2 Dosage Modifications in Patients with Impaired Renal Function When renal function is impaired, a reduced dosage should be employed, as shown in Table 2 .

Table

2: Impaired Renal Function Dosage Guidelines Creatinine Clearance (mL/min)

Recommended Dosage Regimen Above

30 Usual standard dosage regimen 15 to 30 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.

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 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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

WARNINGS Embryofetal Toxicity​ Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If sulfamethoxazole and trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus (see PRECAUTIONS). Hypersensitivity and Other Serious or Fatal Reactions Fatalities and serious adverse reactions including severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (AFND), acute generalized erythematous pustulosis (AGEP); fulminant hepatic necrosis; agranulocytosis, aplastic anemia and other blood dyscrasias; acute and delayed lung injury; anaphylaxis and circulatory shock have occurred with the administration of sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim (see ADVERSE REACTIONS).

Hypersensitivity

Reactions of the Respiratory Tract Cough, shortness of breath and pulmonary infiltrates potentially representing hypersensitivity reactions of the respiratory tract have been reported in association with sulfamethoxazole and trimethoprim treatment.

Respiratory Failure

Other severe pulmonary adverse reactions occurring within days to week of sulfamethoxazole and trimethoprim initiation and resulting in prolonged respiratory failure requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO), lung transplantation or death have also been reported in patients and otherwise healthy individuals treated with sulfamethoxazole and trimethoprim products.

Circulatory Shock

Circulatory shock with fever, severe hypotension, and confusion requiring intravenous fluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with sulfamethoxazole and trimethoprim products, including sulfamethoxazole and trimethoprim, in patients with history of recent (days to weeks) exposure to sulfamethoxazole and trimethoprim. Management of Hypersensitivity and Other Serious Reactions Sulfamethoxazole and trimethoprim should be discontinued at the first appearance of skin rash or any sign of a serious adverse reaction. A skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AFND, AGEP, hepatic necrosis, or serious blood disorders (see PRECAUTIONS and ADVERSE REACTIONS). Clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura or jaundice may be early indications of serious reactions.

Hemophagocytic Lymphohistiocytosis

Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in patients treated with sulfamethoxazole-trimethoprim. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. Signs and symptoms of HLH may include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver enzyme and coagulation abnormalities. If HLH is suspected, discontinue sulfamethoxazole and trimethoprim immediately and institute appropriate management.

Thrombocytopenia

Sulfamethoxazole and trimethoprim-induced thrombocytopenia may be an immune-mediated disorder. Severe cases of thrombocytopenia that are fatal or life threatening have been reported. Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole and trimethoprim.

Streptococcal

Infections and Rheumatic Fever The sulfonamides should not be used for treatment of group Aβ-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever. Clostridioides difficile Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Risk

Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia Treatment failure and excess mortality were observed when sulfamethoxazole and trimethoprim was used concomitantly with leucovorin for the treatment of HIV positive patients with P. jirovecii pneumonia in a randomized placebo-controlled trial. 4 Avoid coadministration of sulfamethoxazole and trimethoprim and leucovorin during treatment of P. jirovecii pneumonia.

Precautions

Development of Drug Resistant Bacteria Prescribing sulfamethoxazole and trimethoprim tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Folate Deficiency

Avoid use of sulfamethoxazole and trimethoprim in patients with impaired renal or hepatic function, in those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and in those with severe allergies or bronchial asthma. Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy (see PRECAUTIONS, Geriatric Use). Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.

Hypoglycemia

Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole and trimethoprim are particularly at risk.

Impaired Phenylalanine Metabolism

The trimethoprim component of sulfamethoxazole and trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction. Porphyria and Hypothyroidism Like other drugs containing sulfonamides, sulfamethoxazole and trimethoprim can precipitate porphyria crisis and hypothyroidism. Avoid use of sulfamethoxazole and trimethoprim in patients with porphyria or thyroid dysfunction.

Potential

Risk in the Treatment of Pneumocystis jirovecii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS) AIDS patients may not tolerate or respond to sulfamethoxazole and trimethoprim in the same manner as non-AIDS patients. The incidence of adverse reactions, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with sulfamethoxazole and trimethoprim 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 in non-AIDS patients. If a patient develops skin rash, fever, leukopenia or any sign of adverse reaction, reevaluate benefit-risk of continuing therapy or re-challenge with sulfamethoxazole and trimethoprim (see WARNINGS). Avoid coadministration of sulfamethoxazole and trimethoprim and leucovorin during treatment of P. jirovecii pneumonia (see WARNINGS).

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, 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. Information for Patients Hypersensitivity and Other Serious Reactions: Advise patients to stop taking sulfamethoxazole and trimethoprim 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 ADVERSE REACTIONS).

Antibacterial

Resistance: Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When sulfamethoxazole and trimethoprim tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by sulfamethoxazole and trimethoprim tablets or other antibacterial drugs in the future. Crystalluria and Stone Formation: Advise patients to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. Diarrhea: Advise patients that diarrhea is a 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 and clinical chemistry testing should be done frequently in patients receiving sulfamethoxazole and trimethoprim. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function. Discontinue sulfamethoxazole and trimethoprim if a significant electrolyte abnormality, renal insufficiency or reduction in the count of any formed blood element is noted.

Drug Interactions

Potential for Sulfamethoxazole and Trimethoprim 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 with drugs that are substrates of CYP2C8 and 2C9 or OCT2.

Table

1: Drug Interactions with Sulfamethoxazole and Trimethoprim Table 1: Drug Interactions with Sulfamethoxazole and Trimethoprim (continued)

Drug/Laboratory

Test Interactions Sulfamethoxazole and trimethoprim, 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 may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2.4-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole twice a day). Mutagenesis In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An invitro chromosomal aberration test in human lymphocytes with sulfamethoxazole and trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole and trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole and 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 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, doses roughly two times the recommended human daily dose on a body surface area basis.

Pregnancy

While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,11 in a 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 a 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects Human Data

While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole and trimethoprim 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 exposure and specific malformations.

Animal

Data In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.

Nonteratogenic Effects

See CONTRAINDICATIONS section.

Nursing Mothers

Levels of sulfamethoxazole and trimethoprim in breast milk are approximately 2 to 5% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when sulfamethoxazole and trimethoprim is administered to a nursing woman, especially when breastfeeding, jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus.

Pediatric Use

Sulfamethoxazole and trimethoprim is contraindicated for infants younger than 2 months of age (see INDICATIONS AND USAGE and CONTRAINDICATIONS sections).

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), a 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. Sulfamethoxazole and trimethoprim tablets contain 0.45 mg sodium (0.02 mEq) of sodium per tablet. Sulfamethoxazole and trimethoprim DS tablets contain 0.9 mg (0.04 mEq) of sodium per tablet. 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: Geriatric Pharmacokinetics). 1 1

PRECAUTIONS Development of Drug Resistant Bacteria Prescribing sulfamethoxazole and trimethoprim tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Folate Deficiency

Avoid use of sulfamethoxazole and trimethoprim tablets in patients with impaired renal or hepatic function, in those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states) and in those with severe allergies or bronchial asthma. Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy (see PRECAUTIONS , Geriatric Use ). Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.

Hypoglycemia

Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim tablets are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition or those receiving high doses of sulfamethoxazole and trimethoprim tablets are particularly at risk.

Impaired Phenylalanine Metabolism

The trimethoprim component of sulfamethoxazole and trimethoprim tablets have been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction. Porphyria and Hypothyroidism Like other drugs containing sulfonamides, sulfamethoxazole and trimethoprim tablets can precipitate porphyria crisis and hypothyroidism. Avoid use of sulfamethoxazole and trimethoprim tablets in patients with porphyria or thyroid dysfunction.

Potential

Risk in the Treatment of Pneumocystis jirovecii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS) AIDS patients may not tolerate or respond to sulfamethoxazole and trimethoprim tablets 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 tablets 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 tablets in non-AIDS patients. If a patient develops skin rash, fever, leukopenia or any sign of adverse reaction, reevaluate benefit-risk of continuing therapy or re-challenge with sulfamethoxazole and trimethoprim tablets (see WARNINGS ). Avoid coadministration of sulfamethoxazole and trimethoprim tablets and leucovorin during treatment of P. jirovecii pneumonia (see WARNINGS ).

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 tablets, 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. Information for Patients Hypersensitivity and Other Serious Reactions: Advise patients to stop taking sulfamethoxazole and trimethoprim tablets 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 ADVERSE REACTIONS ) .

Antibacterial

Resistance: Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When sulfamethoxazole and trimethoprim tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by sulfamethoxazole and trimethoprim tablets or other antibacterial drugs in the future. Crystalluria and Stone Formation: Advise patients to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. Diarrhea : Advise patients that diarrhea is a 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 and clinical chemistry testing should be done frequently in patients receiving sulfamethoxazole and trimethoprim tablets. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function. Discontinue sulfamethoxazole and trimethoprim tablets if a significant electrolyte abnormality, renal insufficiency or reduction in the count of any formed blood element is noted.

Drug Interactions

Potential for Sulfamethoxazole and Trimethoprim Tablets 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 tablets with drugs that are substrates of CYP2C8 and 2C9 or OCT2.

Table

1: Drug Interactions with Sulfamethoxazole and Trimethoprim Tablets 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 tablets 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 tablets are given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

Phenytoin

Monitor serum phenytoin levels Sulfamethoxazole and trimethoprim tablets may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). Sulfamethoxazole and trimethoprim tablets, 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 tablets and cyclosporine in renal transplant recipients.

Digoxin

Monitor serum digoxin levels Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim tablets 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 tablets are 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 tablets.

Oral Hypoglycemics

Monitor blood glucose more frequently Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim tablets 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 tablets 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 tablets and an angiotensin converting enzyme inhibitor. 5,6 Zidovudine Monitor for hematologic toxicity Zidovudine and sulfamethoxazole and trimethoprim tablets are known to induce hematological abnormalities. Hence, there is potential for an additive myelotoxicity when coadministered. 7 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 . 8,9 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. 10 Drug/Laboratory Test Interactions Sulfamethoxazole and trimethoprim tablets, 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 tablets may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2.4-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole twice a day ). Mutagenesis In 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 and trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole and trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole and 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 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, doses roughly two times the recommended human daily dose on a body surface area basis.

Pregnancy

While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell, 11 in a 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 a 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 tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects Human Data

While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole and trimethoprim 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 exposure and specific malformations.

Animal

Data In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.

Nonteratogenic Effects

See CONTRAINDICATIONS section.

Nursing Mothers

Levels of sulfamethoxazole and trimethoprim in breast milk are approximately 2–5% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when sulfamethoxazole and trimethoprim tablets are administered to a nursing woman, especially when breastfeeding jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus.

Pediatric Use

Sulfamethoxazole and trimethoprim tablets are contraindicated for infants younger than 2 months of age (see INDICATIONS AND USAGE and CONTRAINDICATIONS sections).

Geriatric Use

Clinical studies of sulfamethoxazole and trimethoprim tablets 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), a 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 tablets 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 tablets 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 tablets treatment is recommended to help lower potassium serum levels. Sulfamethoxazole and trimethoprim tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet. Sulfamethoxazole and trimethoprim DS tablets contain 3.6 mg (0.16 mEq) of sodium per tablet. 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: Geriatric Pharmacokinetics ).

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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