Label Changes for:

Septra and Septra DS (Trimethoprim and Sulfamethoxazole) Tablets

September 2013

Changes have been made to the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

 

September 2013

CONTRAINDICATIONS

  • In patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides…

WARNINGS

  • Embryofetal Toxicity - 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…
  • 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…
  • Thrombocytopenia - Sulfamethoxazole/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/trimethoprim.
  • Streptococcal Infections and Rheumatic Fever (header added)
  • Clostridium difficile associated diarrhea (header added)
  • Adjunctive Treatment with Leucovorin for Pneumocystis jiroveci pneumonia - 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…

PRECAUTIONS

  • Development of drug resistant bacteria (header added)
  • Folate deficiency (header added)
  • Hemolysis (header added)
  • Hypoglycemia – Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole/trimethoprim are seen rarely, usually occurring after a few days of therapy…
  • 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 and Prophylaxis for Pneumocystis jiroveci Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS):
  • AIDS patients may not tolerate or respond to Septra in the same manner as non-AIDS patients.
  • Co-administration of Septra and leucovorin should be avoided with Pneumocystis jiroveci pneumonia
  • Electrolyte Abnormalities - High dosage of trimethoprim, as used in patients with P. jiroveci pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients…
 
Drug Interactions:
  • Potential for Septra to Affect Other Drugs
  • 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.
  • 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 co-administration of Septra and cyclosporine in renal transplant recipients.
  • Increased digoxin blood levels can occur with concomitant Septra 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 Septra is prescribed.
  • 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). Additional monitoring of blood glucose may be warranted.
  • 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.
  • 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.
Carcinogenesis, Metagenesis, 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 b.i.d.).
Mutagenesis:
  • In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination…
Pregnancy
Impairment of Fertility:
  • doses roughly two times the recommended human daily dose on a body surface area basis.
Teratogenic Effects: Pregnancy Category D
  • 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/trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot…
  • 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…
Nursing Mothers
  • Levels of trimethoprim/sulfamethoxazole in breast milk are approximately 2-5% of the recommended daily dose for infants over 2 months of age…
     
Pediatric Use
  • Septra is contraindicated for pediatric patients younger than 2 months of age

ADVERSE REACTIONS

Genitourinary
  • and nephrotoxicity in association with cyclosporine.
Musculoskeletal
  • Isolated cases of rhabdomyolyosis have been reported with SEPTRA, mainly in AIDS patients.
Miscellaneous
Postmarketing Experience
  • The following adverse reactions have been identified during post-approval use of trimethoprim-sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
  • Thrombotic thrombocytopenia purpura
  • Idiopathic thrombocytopenic purpura
  • QT prolongation resulting in ventricular tachycardia and torsade de pointes

 

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