warnings
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. 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. 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 generalized exanthematous pustulosis (AGEP) and acute febrile neutrophilic dermatosis (AFND), fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias, acute and delayed lung injury, anaphylaxis, and circulatory shock have occurred with the administration of trimethoprim-sulfamethoxazole including SEPTRA (see PRECAUTIONS and 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 trimethoprim-sulfamethoxazole treatment. Respiratory Failure Other severe pulmonary adverse reactions occurring within days to week of SEPTRA 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 trimethoprim-sulfamethoxazole 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 trimethoprim-sulfamethoxazole in patients with history of recent (days to weeks) exposure to sulfamethoxazole-trimethoprim. Management of Hypersensitivity and Other Serious Reactions SEPTRA should be discontinued at the first appearance of skin rash or any sign of a serious adverse reaction. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AGEP, or AFND, hepatic necrosis, and serious blood disorders (see PRECAUTIONS and ADVERSE REACTIONS ). Clinical signs, such as rash, pharyngitis, fever, cough, arthralgia, 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 trimethoprim-sulfamethoxazole. 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 SEPTRA immediately and institute appropriate management. Thrombocytopenia Trimethoprim-sulfamethoxazole-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 trimethoprim-sulfamethoxazole. Streptococcal Infections and Rheumatic Fever SEPTRA should not be used for the treatment of group A beta-hemolytic streptococcal infections. In an established infection, SEPTRA 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 SEPTRA, 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 of Failure and Excess Mortality with Leucovorin Use for Pneumocystis jirovecii Pneumonia Treatment Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jirovecii pneumonia in a randomized placebo controlled trial. 4 Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jirovecii pneumonia should be avoided.