warnings and cautions
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) Hemophagocytic Lymphohistiocytosis (HLH): Cases of HLH have been reported in patients treated with sulfamethoxazole-trimethoprim. If HLH is suspected, discontinue sulfamethoxazole and trimethoprim injection immediately and institute appropriate management. (5.3) Thrombocytopenia: Monitor for hematologic toxicity. (5.4) Streptococcal Infections and Rheumatic Fever: Do not use for the treatment of group A beta-hemolytic streptococcal infections. (5.5) Clostridioides difficile- Associated Diarrhea: Evaluate if diarrhea occurs. (5.6) Sulfite Sensitivity: May cause allergic-type reactions. (5.7) Benzyl Alcohol Toxicity: Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates. (5.8) Increased mortality with adjunctive leucovorin for Pneumocystis jirovecii pneumonia: Avoid concurrent use. (5.9) 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. (5.10) 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 a serious adverse reaction. A 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 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 injection immediately and institute appropriate management. 5.4 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 a week upon discontinuation of sulfamethoxazole and trimethoprim injection. 5.5 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 A β-hemolytic streptococcal tonsillopharyngitis have a 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. 5.6 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 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 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. 5.7 Sulfite Sensitivity Sulfamethoxazole and trimethoprim injection contains sodium metabisulfite, a 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. 5.8 Benzyl Alcohol Toxicity in Pediatric Patients ("Gasping Syndrome") Sulfamethoxazole and trimethoprim injection contains benzyl alcohol as a 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)]. 5.9 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 a randomized placebo -controlled trial. 4 Avoid coadministration of sulfamethoxazole and trimethoprim injection and leucovorin during treatment of P. jirovecii pneumonia. 5.10 Propylene Glycol Toxicity Sulfamethoxazole and trimethoprim injection contains propylene glycol as a solvent (40% 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)]. 5.11 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)]. 5.12 Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related. 5.13 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. 5.14 Hypoglycemia Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim injection have been seen, usually occurring after a 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. 5.15 Impaired Phenylalanine Metabolism 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. 5.16 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. 5.17 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 a 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 Pneumocystis jirovecii pneumonia [see Warnings and Precautions (5.9)] 5.18 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 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. 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. 5.19 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 a 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. 5.20 Development of Drug-Resistant Bacteria Prescribing sulfamethoxazole and trimethoprim injection 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.