SULFAMETHOXAZOLE AND TRIMETHOPRIM- sulfamethoxazole and trimethoprim_tablet

Sulfamethoxazole and trimethoprim is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N 4 4 4 4 via in vitro DOSAGE AND ADMINISTRATION 1 4 2 Pharmacokinetics in Pediatric Patients A simulation conducted with data from a pharmacokinetic study in 153 infants and children demonstrated that mean steady state AUC and maximum plasma concentration of trimethoprim and sulfamethoxazole would be comparable between pediatric patients 2 months to 18 years receiving 8/40 (trimethoprim/ sulfamethoxazole) mg/kg/day divided every 12 hours and adult patients receiving 320/1600 (trimethoprim/ sulfamethoxazole) mg/day. Pharmacokinetics in Geriatric Patients The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78. 6 years) and 6 young healthy subjects (mean age: 29. 3 years) using a non-U. approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects. 3 Mechanism of Action Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para- aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. Resistance In vitro Antimicrobial Activity Sulfamethoxazole and trimethoprim have been shown to be active against most isolates of the following microorganisms, both in vitro INDICATIONS AND USAGE Aerobic gram-positive bacteria Streptococcus pneumoniae Aerobic gram-negative bacteria Escherichia coli Klebsiella Enterobacter Haemophilus influenzae Morganella morganii Proteus mirabilis Proteus vulgaris Shigella flexneri Shigella sonnei Other Microorganisms Pneumocystis jirovecii For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim tablets and other antibacterial drugs, sulfamethoxazole and trimethoprim tablets 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. For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella Enterobacter Morganella morganii, Proteus mirabilis Proteus vulgaris. For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae Haemophilus influenzae For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae Haemophilus influenzae For the treatment of enteritis caused by susceptible strains of Shigella flexneri Shigella sonnei Pneumocystis jirovecii Pneumocystis jirovecii P. jirovecii P. jirovecii For the treatment of traveler's diarrhea due to susceptible strains of enterotoxigenic E.

Sulfamethoxazole and trimethoprim tablets are contraindicated in pediatric patients less than 2 months of age. Adults: Children: Children 2 months of age or older: Weight Doseen dashevery 12 hours lb kg Tablets 22 10 en dash 44 20 1 66 30 1½ 88 40 2 or 1 DS tablet When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Clearance (mL/min) Recommended Dosage Regimen Above 30 Usual standard regimen 15en dash30 ½ the usual regimen Below 15 Use not recommended The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 14 days. Pneumocystis jirovecii Treatment The recommended dosage for treatment of patients with documented Pneumocystis jirovecii 12 Weight Dose-every 6 hours lb kg Tablets 18 8 en dash 35 16 1 53 24 1½ 70 32 2 or 1 DS tablet 88 40 2½ 106 48 3 or 1½ 141 64 4 or 2 DS tablets 176 80 5 or 2½ DS tablets For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table. Prophylaxis Adults: The recommended dosage for prophylaxis in adults is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet daily. 13 Children: For children, the recommended dose is 750 mg/m 2 2 14 Body Surface Area Dose-every 12 hours (m 2 Tablets 0. 26 en dash 0. 06 1 For the treatment of traveler’s diarrhea, the usual adult dosage is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 5 days.

The following adverse reactions associated with the use of 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, 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 (see WARNINGS ). Hematologic: Allergic Reactions: WARNINGS Gastrointestinal: Genitourinary: Metabolic and Nutritional: PRECAUTIONS: Electrolyte Abnormalities Neurologic: Psychiatric: Endocrine: Musculoskeletal: Respiratory: WARNINGS Cardiovascular System: torsades de pointes WARNINGS . Miscellaneous:

Sulfamethoxazole and trimethoprim tablets are contraindicated in the following situations: known hypersensitivity to trimethoprim or sulfonamides history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides documented megaloblastic anemia due to folate deficiency pediatric patients less than 2 months of age marked hepatic damage severe renal insufficiency when renal function status cannot be monitored concomitant administration with dofetilide (see PRECAUTIONS

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 PRECAUTIONS ADVERSE REACTIONS 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 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. Clostridioides difficile Associated Diarrhea Clostridioides difficile C. difficile C. difficile C. difficile If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile C. difficile, Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii 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 4 P jirovecii
OVERDOSAGE
The amount of a single dose of sulfamethoxazole and trimethoprim that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported. Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage. Use of sulfamethoxazole and trimethoprim at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored.
REFERENCES
Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J Clin Pharmacol Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis Varoquaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii J Infect Dis Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol Moh R, et al. Haematological changes in adults receiving a zidovudine-containing HAART regimen in combination with cotrimoxazole in Côte d’Ivoire. Antivir Ther. Al-Khatib SM, LaPointe N, Kramer JM, Califf RM. What Clinicians Should Know About the QT Interval. JAMA. Boyer EW, Stork C, Wang RY. Review: The Pharmacology and Toxicology of Dofetilide. Int J Med Toxicol. Kosoglou T, Rocci ML Jr, Vlasses PH. Trimethoprim alters the disposition of procainamide and N Clin Pharmacol Ther. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis Masur H. Prevention and treatment of Pneumocystis N Engl J Med Recommendations for prophylaxis against Pneumocystis carinii MMWR. CDC Guidelines for prophylaxis against Pneumocystis carinii MMWR Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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