To reduce the development of drug-resistant bacteria and maintain the effectiveness of SEPTRA and other antibacterial drugs, SEPTRA 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 the empiric selection of  therapy.

Urinary Tract Infections:

• For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, and Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination.

Acute Otitis Media:

• For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when, in the judgment of the physician, SEPTRA offers some advantage over the use of other antimicrobial agents. To date, there is limited data on the safety of repeated use of SEPTRA in pediatric patients under two years of age. SEPTRA is not indicated for prophylactic or prolonged administration in otitis media at any age.

Acute Exacerbations of Chronic Bronchitis in Adults:

• For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when, a physician deems that, SEPTRA could offer some advantage over the use of a single antimicrobial agent.

Travelers’ Diarrhea in Adults:

• For the treatment of travelers’ diarrhea due to susceptible strains of enterotoxigenic E. coli.

Shigellosis:

• For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated.

Pneumocystis jiroveci Pneumonia:

• For the treatment of documented Pneumocystis jiroveci pneumonia. For prophylaxis against Pneumocystis jiroveci pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis jiroveci pneumonia.

SEPTRA is contraindicated in patients:

• with a known hypersensitivity to trimethoprim or sulfonamides
• with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides
• with documented megaloblastic anemia due to folate deficiency
• pediatric patients less than 2 months of age
• severe renal insufficiency when renal function status cannot be monitored
• concomitant administration with dofetilide

The sulfonamides should not be used for the treatment of group A beta-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Patients should be counseled that antibacterial drugs including SEPTRA should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).

Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and acute febrile neutrophilic dermatosis (AFND), fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias

Sulfonamides, including sulfonamide containing products such as sulfamethoxazole/trimethoprim, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

Severe cases of thrombocytopenia that are fatal or life threatening have been reported.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including SEPTRA, and may range in severity from mild diarrhea to fatal colitis.

Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial. Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.

SEPTRA 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 allergy or bronchial asthma.

In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur. This reaction is frequently dose-related.

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

As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.

AIDS patients may not tolerate or respond to SEPTRA it the same manner as non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia, and elevated aminotransferase (transaminase) values in AIDS patients who are being treated with SEPTRA for P. jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of SEPTRA in non-AIDS patients.

Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole/trimethoprim, particularly for the treatment of P. jiroveci pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.

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.

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

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

Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Caution is recommended when SEPTRA is co-administered with drugs that are substrates of CYP2C8 and 2C9 or OCT2.

In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. In the literature, two cases of hyperkalemia in elderly patients have been reported after concomitant intake of trimethoprim/sulfamethoxazole and an angiotensin converting enzyme inhibitor. Avoid concurrent use of diuretics.

It has been reported that SEPTRA may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin (a CYP2C9 substrate). This interaction should be kept in mind when SEPTRA is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

SEPTRA may inhibit the hepatic metabolism of phenytoin (a CYP2C9 substrate). SEPTRA, 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.

Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations. Avoid concurrent use with methotrexate.

There have been reports of marked but reversible nephrotoxicity with co-administration of SEPTRA and cyclosporine in renal transplant recipients. Avoid concurrent use with cyclosporine.

Increased digoxin blood levels can occur with concomitant SEPTRA therapy, especially in elderly patients. 

Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin. Avoid concurrent use with indomethacin.

Patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if SEPTRA is prescribed. Avoid concurrent use with pyrimethamine.

The efficacy of tricyclic antidepressants can decrease when co-administered with SEPTRA.

SEPTRA potentiates the effect of oral hypoglycemics 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). 

In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other OCT2 substrates, memantine and metformin, have also been reported. Avoid concurrent use with amantadine.

In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor. Avoid concurrent use with angiotensin converting enzyme inhibitor.

Zidovudine and SEPTRA are known to induce hematological abnormalities. Hence, there is potential for an additive myelotoxicity when co-administered.

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. Concurrent administration is contraindicated.

Trimethoprim increases the plasma concentrations of procainamide and its active N-acetyl metabolite (NAPA) when trimethoprim and procainamide are co-administered. The increased procainamide and NAPA plasma concentrations that resulted from the pharmacokinetic interaction with trimethoprim are associated with further prolongation of the QTc interval.

SEPTRA, 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 trimethoprim and sulfamethoxazole may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Some epidemiologic studies suggest that exposure to sulfamethoxazole/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/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.

Levels of trimethoprim/sulfamethoxazole in breast milk are approximately 2-5% of the recommended daily dose for infants over 2 months of age. Caution should be exercised when SEPTRA 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.

GoToSource

• Use in patients under the age of 2 months. GoToSource

• Prophylactic or prolonged administration in otitis media. GoToSource

• Group A beta-hemolytic streptococcal infections. GoToSource

• Recurrent nephrogenic adenoma. GoToSource

• Cat scratch disease. GoToSource

• Listeria meningitis and bacteremia. GoToSource

• Pyelonephritis. GoToSource

• Uncomplicated skin abscesses. GoToSource

⚠️  Hemolysis may occur in patients with G6PD gene variation.

Stevens-johnson syndrome (severe skin reaction) and drug-induced aseptic meningitis (inflammation of lining of brain and spinal cord). GoToSource

Thrombotic thrombocytopenic purpura (blood clots form in small blood vessels in body), urticarial rash (hives) and leukopenia (low white blood cell count). GoToSource

Agitation, visual and auditory hallucinations, hypersensitivity reactions and bone marrow suppression. GoToSource

Hyperkalemia (high blood potassium level) and hyponatremia (low blood sodium level). GoToSource

Thrombocytopenia (low blood platelet count). GoToSource

Oral erythema multiforme (skin disorder or reaction occurring in lips and mucous membranes in the mouth). GoToSource

Drug rash with eosinophilia and systemic symptoms (potentially life-threatening drug-induced hypersensitivity reaction). GoToSource

Drug-induced lupus erythematosus (inflammatory autoimmune disease). GoToSource

Lactic acidosis (too much lactic acid in the body). GoToSource

Myositis (muscle inflammation) and rhabdomyolysis (breakdown of skeletal muscle). GoToSource

Pancreatitis (inflammation of pancreas). GoToSource

Methemoglobinemia (elevated methemoglobin blood level, a form of hemoglobin). GoToSource

Reactivation of human herpes virus. GoToSource

Toxic epidermal necrolysis (potentially life-threatening skin reaction). GoToSource

Hypoglycemia (low blood sugar). GoToSource

Pseudomembranous colitis (swelling or inflammation of large intestine). GoToSource

Acute fibrinous organising pneumonia (diffuse infiltrative pulmonary disease). GoToSource

Liver injury and fulminant hepatic failure. GoToSource

Agranulocytosis (decreased number of granulocytes, a type of white blood cell). GoToSource

Hemolytic anemia (red blood cells destroyed faster than they can be made). GoToSource

Clostridium difficile associated diarrhea. GoToSource

Kidney injury. GoToSource

Lawsuits filed for stevens-johnson syndrome.