Sulfamethoxazole and trimethoprim

Overdose

Since there has been no extensive experience in humans with single doses of Sulfamethoxazole And Trimethoprim in excess of 25 mL (400 mg trimethoprim and 2000 mg sulfamethoxazole), the maximum tolerated dose in humans is unknown.

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.

Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression.

General principles of treatment include the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

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.

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. Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion, and bone marrow depression.

General principles of treatment include the institution of gastric lavage or emesis; forcing oral fluids; and the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

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 leucovorin daily has been recommended by some investigators.

Contraindications

Sulfamethoxazole And Trimethoprim is contraindicated in the following:

• Known hypersensitivity to trimethoprim or sulfonamides
• History of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides
• Patients with documented megaloblastic anemia due to folate deficiency
• Pediatric patients less than two months of age
• Marked hepatic damage
• Severe renal insufficiency when renal function status cannot be monitored
• Concomitant administration with dofetilide2,3

Sulfamethoxazole And Trimethoprim is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole And Trimethoprim is contraindicated in pediatric patients less than 2 months of age. Sulfamethoxazole And Trimethoprim is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored.

Pharmaceutical form

Undesirable effects

The following serious adverse reactions are described elsewhere in the labeling:

• Embryo-fetal Toxicity
• Hypersensitivity and Other Fatal Reactions
• Thrombocytopenia
• Clostridium difficile-Associated Diarrhea
• Sulfite Sensitivity
• Risk Associated with Concurrent Use of Leucovorin for Pneumocystis jirovecii Pneumonia
• Infusion Reactions
• Hypoglycemia
• Electrolyte Abnormalities

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, and anorexia) and allergic skin reactions (such as rash and urticaria).

Local reaction, pain and slight irritation on intravenous (IV) administration are infrequent. Thrombophlebitis has been observed.

Table 3: Adverse Reactions Reported with Sulfamethoxazole And Trimethoprim

The following adverse reactions have been identified during post-approval use of Sulfamethoxazole And Trimethoprim. 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

The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). 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, OTHER BLOOD DYSCRASIAS, AND HYPERSENSITIVITY OF THE RESPIRATORY TRACT (SEE WARNINGS).

Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.

Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch- Schonlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria, and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.

Hepatitis, including cholestatic jaundice and hepatic necrosis, elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.

Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria, and nephrotoxicity in association with cyclosporine.

Hyperkalemia, hyponatremia (see PRECAUTIONS: Electrolyte Abnormalities).

Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.

Hallucinations, depression, apathy, nervousness.

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides.

Arthralgia and myalgia. Cases of rhabdomyolysis have been reported with Sulfamethoxazole And Trimethoprim, mainly in AIDS patients.

Cough, shortness of breath, and pulmonary infiltrates (see WARNINGS).

Weakness, fatigue, insomnia.

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

Therapeutic indications

Sulfamethoxazole And Trimethoprim is indicated in the treatment of Pneumocystis jirovecii pneumonia in adults and pediatric patients two months of age and older.

Sulfamethoxazole And Trimethoprim is indicated in the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei in adults and pediatric patients two months of age and older.

Sulfamethoxazole And Trimethoprim is indicated in the treatment of severe or complicated urinary tract infections in adults and pediatric patients two months of age and older due to susceptible strains of Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii and Proteus species when oral administration of Sulfamethoxazole And Trimethoprim is not feasible and when the organism is not susceptible to single-agent antibacterials effective in the urinary tract.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Sulfamethoxazole And Trimethoprim and other antibacterial drugs, Sulfamethoxazole And Trimethoprim 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.

Although appropriate culture and susceptibility studies should be performed, therapy may be started while awaiting the results of these studies.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Sulfamethoxazole And Trimethoprim and other antibacterial drugs, Sulfamethoxazole And Trimethoprim 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.

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.

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, Sulfamethoxazole And Trimethoprim offers some advantage over the use of other antimicrobial agents. To date, there is limited data on the safety of repeated use of Sulfamethoxazole And Trimethoprim in pediatric patients under two years of age. Sulfamethoxazole And Trimethoprim is not indicated for prophylactic or prolonged administration in otitis media at any age.

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

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

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

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.

Pharmacokinetic properties

Following a 1-hour intravenous infusion of a single dose of 160 mg trimethoprim and 800 mg sulfamethoxazole to 11 patients whose weight ranged from 105 lbs to 165 lbs (mean, 143 lbs), the peak plasma concentrations of trimethoprim and sulfamethoxazole were 3.4 ± 0.3 μg/mL and 46.3 ± 2.7 μg/mL, respectively. Following repeated intravenous administration of the same dose at 8-hour intervals, the mean plasma concentrations just prior to and immediately after each infusion at steady state were 5.6 ± 0.6 μg/mL and 8.8 ± 0.9 μg/mL for trimethoprim and 70.6 ± 7.3 μg/mL and 105.6 ± 10.9 μg/mL for sulfamethoxazole. The mean plasma half-life was 11.3 ± 0.7 hours for trimethoprim and 12.8 ± 1.8 hours for sulfamethoxazole. All of these 11 patients had normal renal function, and their ages ranged from 17 to 78 years (median, 60 years).11

Pharmacokinetic studies in children and adults suggest an age-dependent half-life of trimethoprim, as indicated in Table 5. 12

Table 5: Half-life of Trimethoprim (TMP) in Pediatric Patients and Adults

Patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment.

Both trimethoprim and sulfamethoxazole exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form.

Approximately 44% of trimethoprim and 70% of sulfamethoxazole are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.

Both trimethoprim and sulfamethoxazole distribute to sputum and vaginal fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in breast milk.

Metabolism

Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N4-acetyl-, N4-hydroxy-, 5methylhydroxy-, N4-acetyl-5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formation of N4-hydroxy metabolite is mediated via CYP2C9.

Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 1- and 3-oxides and the 3- and 4hydroxy derivatives.

The free forms of trimethoprim and sulfamethoxazole are considered to be the therapeutically active forms. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein.

Excretion

Excretion of trimethoprim and sulfamethoxazole is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both trimethoprim and sulfamethoxazole are considerably higher than are the concentrations in the blood. The percent of dose excreted in urine over a 12-hour period following the intravenous administration of the first dose of 240 mg of trimethoprim and 1200 mg of sulfamethoxazole on day 1 ranged from 17% to 42.4% as free trimethoprim; 7% to 12.7% as free sulfamethoxazole; and 36.7% to 56% as total (free plus the N4-acetylated metabolite) sulfamethoxazole. When administered together as Sulfamethoxazole And Trimethoprim, neither trimethoprim nor sulfamethoxazole affects the urinary excretion pattern of the other.

REFERENCES

3. Varoqaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985; 20: 575-581.

7. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994 Oct; 170(4): 912-7.

8. Marinella MA. Trimethoprim - induced hyperkalemia: An analysis of reported cases. Gerontology 45: 209-212, 1999.

9. Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis. 1973;128 (suppl):S657-S663.

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. Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion, and bone marrow depression.

General principles of treatment include the institution of gastric lavage or emesis; forcing oral fluids; and the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

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 leucovorin daily has been recommended by some investigators.

Sulfamethoxazole And Trimethoprim is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. Sulfamethoxazole And Trimethoprim is contraindicated in pediatric patients less than 2 months of age. Sulfamethoxazole And Trimethoprim is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored.

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 N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxysulfamethoxazole metabolites, and an N-glucuronide conjugate. The formation of N4-hydroxy metabolite is mediated via CYP2C9.

Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 1- and 3-oxides and the 3- and 4-hydroxy derivatives.

The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of Pglycoprotein.

Approximately 44% of trimethoprim and 70% of sulfamethoxazole are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.

Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION). Detectable amounts of trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration. During administration of 160 mg trimethoprim and 800 mg sulfamethoxazole b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state minimal plasma levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68.0 mcg/mL, respectively. These steady-state levels were achieved after 3 days of drug administration.1

Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N -acetylated metabolite.2 When administered together as Sulfamethoxazole And Trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.

Both trimethoprim and sulfamethoxazole distribute to sputum, vaginal fluid, and middle ear fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in human milk.

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-US 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 an average 19% lower in geriatric subjects compared with young adult subjects.3

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.

In vitro studies have shown that bacterial resistance develops more slowly with Sulfamethoxazole And Trimethoprim than with either trimethoprim or sulfamethoxazole alone.

REPRESENTATIVE MINIMUM INHIBITORY CONCENTRATION VALUES FOR ORGANISMS SUSCEPTIBLE TO Sulfamethoxazole And Trimethoprim (MICμg/mL)

Sulfamethoxazole And Trimethoprim have been shown to be active against most strains of the following microorganisms, bothi n vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Streptococcus pneumoniae

Escherichia coli
Klebsiella species
Enterobacter species
Haemophilus influenzae
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Shigella flexneri
Shigella sonnei

Pneumocystis jiroveci

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar)4,5. The MIC values should be interpreted according to the criteria provided in Table 1.

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method5,6. This procedure uses paper disks impregnated with 1.25/23.75 μg of trimethoprim/sulfamethoxazole to test the susceptibility of microorganisms to Sulfamethoxazole And Trimethoprim. The disc diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Trimethoprim/Sulfamethoxazole

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test4-6. Standard trimethoprim/sulfamethoxazole powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 1.25/23.75 μg trimethoprim/sulfamethoxazole disk the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Trimethoprim/Sulfamethoxazole

REFERENCES

1. Kremers P, Duvivier J, Heusghem C. Pharmacokinetic studies of co-trimoxazole in man after single and repeated doses.J Clin Pharmacol. 1974;14:112-117.

2. Kaplan SA, Weinfeld RE, Abruzzo CW, McFaden K, Jack ML, Weissman L. Pharmacokinetic profile of trimethoprimsulfamethoxazole in man. J Infect Dis. 1973;128(suppl):S547-S555.

3. Varoqaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985; 20: 575-581.

4. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

5. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twentythird Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

6. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

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.

Fatalities associated with the administration of sulfonamides, have occurred due to severe reactions, including, Stevens-Johnson Syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.

Sulfonamides, including sulfonamide-containing products such as Sulfamethoxazole And Trimethoprim, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. Clinical signs, such as rash, sore throat, fever, arthralgia, cough, shortness of breath, pallor, purpura or jaundice may be early indications of serious reactions. A skin rash may be followed by more severe reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis or serious blood disorder. Complete blood counts should be done frequently in patients receiving sulfonamides. Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

Sulfamethoxazole And Trimethoprim-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.

Avoid use of Sulfamethoxazole And Trimethoprim 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 than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area. Therefore, Sulfamethoxazole And Trimethoprim will not prevent sequelae such as rheumatic fever.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Sulfamethoxazole And Trimethoprim, 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.

Sulfamethoxazole And Trimethoprim 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.

Sulfamethoxazole And Trimethoprim 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. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. Sulfamethoxazole And Trimethoprim is contraindicated in pediatric patients less than two months of age.

When prescribing Sulfamethoxazole And Trimethoprim 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 (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.

Treatment failure and excess mortality were observed when Sulfamethoxazole And Trimethoprim was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jirovecii pneumonia in a randomized placebo controlled trial.4 Avoid coadministration of Sulfamethoxazole And Trimethoprim and leucovorin during treatment of Pneumocystis jirovecii pneumonia.

Avoid use of Sulfamethoxazole And Trimethoprim 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.

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

Local irritation and inflammation due to extravascular infiltration of the infusion have been observed with Sulfamethoxazole And Trimethoprim. If these occur the infusion should be discontinued and restarted at another site.

Cases of hypoglycemia in non-diabetic patients treated with Sulfamethoxazole And Trimethoprim 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 are particularly at risk.

Trimethoprim, component of Sulfamethoxazole And Trimethoprim, has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

Like other drugs containing sulfonamides, Sulfamethoxazole And Trimethoprim can precipitate porphyria crisis and hypothyroidism. Avoid use of Sulfamethoxazole And Trimethoprim in patients with porphyria or thyroid dysfunction.

AIDS patients may not tolerate or respond to Sulfamethoxazole And Trimethoprim 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 therapy in AIDS patients who are being treated for Pneumocystis jirovecii pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of Sulfamethoxazole And Trimethoprim in non-AIDS patients. If a patient develops skin rash or any sign of an adverse reaction, reevaluate therapy with Sulfamethoxazole And Trimethoprim.

Avoid coadministration of Sulfamethoxazole And Trimethoprim and leucovorin during treatment of Pneumocystis jirovecii pneumonia.

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.

Severe and symptomatic hyponatremia can occur in patients receiving Sulfamethoxazole And Trimethoprim, particularly for the treatment of P. jirovecii pneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.

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.

Complete blood counts should be done frequently in patients receiving Sulfamethoxazole And Trimethoprim. Discontinue Sulfamethoxazole And Trimethoprim if a significant 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.

Prescribing Sulfamethoxazole And Trimethoprim 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.

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-fold the human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d. (twice a day).

In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.

Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes.

Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded.

No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day trimethoprim, doses roughly two times the recommended human daily dose on a body surface area basis.

Sulfamethoxazole And Trimethoprim may cause fetal harm if administered to a pregnant woman. 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 abnormalities, urinary tract defects, oral clefts, and club foot.

One of 3 rat studies showed cleft palate at doses approximately 5 times the recommended human dose on a body surface area basis; the other 2 studies did not show teratogenicity at similar doses. Studies in pregnant rabbits showed increased fetal loss at approximately 6 times the human dose on a body surface area basis.

The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Advise pregnant women of the potential harm of Sulfamethoxazole And Trimethoprim to the fetus.

Disease-associated Maternal and/or Embryo/Fetal Risk

Urinary tract infection in pregnancy is associated with adverse perinatal outcomes such as preterm birth, low birth weight, and pre-eclampsia, and increased mortality to the pregnant woman. P. jirovecii pneumonia in pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman. Sulfamethoxazole And Trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 And Trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons.

Alternatively, other epidemiologic studies did not detect statistically significant associations between Sulfamethoxazole And Trimethoprim exposure and specific malformations. Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester.

In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.

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. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.

Levels of Sulfamethoxazole And Trimethoprim in breast milk are approximately 2 to 5% of the recommended daily dose for pediatric patients over two months of age. There is no information regarding the effect of Sulfamethoxazole And Trimethoprim on the breastfed infant or the effect on milk production. Because of the potential risk of bilirubin displacement and kernicterus on the breastfed child , advise women to avoid breastfeeding during treatment with Sulfamethoxazole And Trimethoprim.

Sulfamethoxazole And Trimethoprim is contraindicated in pediatric patients younger than two months of age because of the potential risk of bilirubin displacement and kernicterus.

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received benzyl alcohol as a preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

When prescribing Sulfamethoxazole And Trimethoprim in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including Sulfamethoxazole And Trimethoprim (Sulfamethoxazole And Trimethoprim 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.

Clinical studies of Sulfamethoxazole And Trimethoprim did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, or concomitant use of other drugs.

Severe skin reactions, generalized bone marrow suppression , a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients.

In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant Sulfamethoxazole And Trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored.

Hematologic changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions.

The trimethoprim component of Sulfamethoxazole And Trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of Sulfamethoxazole And Trimethoprim treatment is recommended to help lower potassium serum levels.

Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects.

REFERENCES

4. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. Oct 1994;170(4):912-7.

10. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973;128 (Suppl): S657-S663.

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.

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.

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 (see PRECAUTIONS). Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions.

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

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.

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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Sulfamethoxazole And Trimethoprim, 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.

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.7 Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.

Prescribing Sulfamethoxazole And Trimethoprim 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.

Sulfamethoxazole And Trimethoprim 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 (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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 Sulfamethoxazole And Trimethoprim are particularly at risk.

Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

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

AIDS patients may not tolerate or respond to Sulfamethoxazole And Trimethoprim 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 Sulfamethoxazole And Trimethoprim for P. jiroveci pneumonia has been reported to be greatly increased compared with the incidence normally associated with the use of Sulfamethoxazole And Trimethoprim in non-AIDS patients. Adverse effects are generally less severe in patients receiving Sulfamethoxazole And Trimethoprim for prophylaxis. A history of mild intolerance to Sulfamethoxazole And Trimethoprim in AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis. However, if a patient develops skin rash or any sign of adverse reaction, therapy with Sulfamethoxazole And Trimethoprim should be re-evaluated (see WARNINGS).

Co-administration of Sulfamethoxazole And Trimethoprim and leucovorin should be avoided with P. jiroveci pneumonia (see WARNINGS).

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. 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.

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.

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 Sulfamethoxazole And Trimethoprim; if a significant reduction in the count of any formed blood element is noted, Sulfamethoxazole And Trimethoprim should be discontinued. Urinalyses with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function.

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.).

In vitro reverse mutation bacterial tests according to the standard protocol have not been performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no chromosomal abnormalities.

Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro micronucleus assays using cultured human lymphocytes.

Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes, trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded.

No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 70 mg/kg/day trimethoprim plus 350 mg/kg/day sulfamethoxazole, doses roughly two times the recommended human daily dose on a body surface area basis.

While there are no large, well-controlled studies on the use of trimethoprim and sulfamethoxazole in pregnant women, Brumfitt and Pursell,9 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.

Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, Sulfamethoxazole And Trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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. These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders. These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings. Lastly, outcome measures varied between studies, limiting cross-study comparisons. Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole/trimethoprim exposure and specific malformations.

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. These doses are approximately 5 and 6 times the recommended human total daily dose on a body surface area basis. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.

See CONTRAINDICATIONS section.

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 Sulfamethoxazole And Trimethoprim 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.

Sulfamethoxazole And Trimethoprim is contraindicated for pediatric patients younger than 2 months of age (see INDICATIONS AND USAGE and CONTRAINDICATIONS).

Clinical studies of Sulfamethoxazole And Trimethoprim did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant Sulfamethoxazole And Trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component of Sulfamethoxazole And Trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors.8 Close monitoring of serum potassium is warranted in these patients. Discontinuation of Sulfamethoxazole And Trimethoprim treatment is recommended to help lower potassium serum levels. Sulfamethoxazole And Trimethoprim Tablets contain 1.8 mg (0.08 mEq) of sodium per tablet. Sulfamethoxazole And Trimethoprim DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet.

Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimpethoprim was lower in geriatric subjects compared with younger subjects3 (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics:).

REFERENCES

3. Varoqaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985; 20: 575-581.

7. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994 Oct; 170(4): 912-7.

8. Marinella MA. Trimethoprim - induced hyperkalemia: An analysis of reported cases. Gerontology 45: 209-212, 1999.

9. Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis. 1973;128 (suppl):S657-S663.

Dosage (Posology) and method of administration

The maximum recommended daily dose is 60 mL (960 mg trimethoprim) per day.

Table 1: Dosage in Adults and Pediatric Patients (Two Months of Age and Older) by Indication

When renal function is impaired, a reduced dosage should be employed, as shown in Table 2.

Table 2: Impaired Renal Function Dosage Guidelines

Administer the solution by intravenous infusion over a period of 60 to 90 minutes. Avoid administration by rapid infusion or bolus injection. Do NOT administer Sulfamethoxazole And Trimethoprim intramuscularly.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever the solution and container permit.

Sulfamethoxazole And Trimethoprim must be diluted. Each 5 mL should be added to 125 mL of 5% dextrose in water. After diluting with 5% dextrose in water, the solution should not be refrigerated and should be used within 6 hours.

If a dilution of 5 mL per 100 mL of 5% dextrose in water is desired, it should be used within 4 hours.

In those instances where fluid restriction is desirable, each 5 mL may be added to 75 mL of 5% dextrose in water. Under these circumstances the solution should be mixed just prior to use and should be administered within 2 hours.

If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.

Do NOT mix Sulfamethoxazole And Trimethoprim in 5% dextrose in water with drugs or solutions in the same container.

After initial entry into the vial, the remaining contents must be used within 48 hours.

The following infusion systems have been tested and found satisfactory: unit-dose glass containers; unit-dose polyvinyl chloride and polyolefin containers. No other systems have been tested and therefore no others can be recommended.

Sulfamethoxazole And Trimethoprim is contraindicated in pediatric patients less than 2 months of age.

The usual adult dosage in the treatment of urinary tract infections is one Sulfamethoxazole And Trimethoprim DS (double strength) tablet, two Sulfamethoxazole And Trimethoprim tablets, or four teaspoonfuls (20 mL) Sulfamethoxazole And Trimethoprim Suspension every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis.

The recommended dose for pediatric patients with urinary tract infections or acute otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole per 24 hours, given in two divided doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of shigellosis. The following table is a guideline for the attainment of this dosage:

Pediatric Patients: Two Months of Age or Older

When renal function is impaired, a reduced dosage should be employed using the following table:

The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is one Sulfamethoxazole And Trimethoprim DS (double strength) tablet, two Sulfamethoxazole And Trimethoprim tablets, or four teaspoonfuls (20 mL) Sulfamethoxazole And Trimethoprim Suspension every 12 hours for 14 days.

For the treatment of travelers' diarrhea, the usual adult dosage is one Sulfamethoxazole And Trimethoprim DS (double strength) tablet, two Sulfamethoxazole And Trimethoprim tablets, or four teaspoonfuls (20 mL) of Sulfamethoxazole And Trimethoprim Suspension every 12 hours for 5 days.

Adults And Pediatric Patients

The recommended dosage for treatment of patients with documented P jiroveci pneumonia is 15 to 20 mg/kg trimethoprim and 75 to 100 mg/kg sulfamethoxazole per 24 hours given in equally divided doses every 6 hours for 14 to 21 days. The following table is a guideline for the upper limit of this dosage:

For the lower limit dose (15 mg/kg trimethoprim and 75 mg/kg sulfamethoxazole per 24 hours) administer 75% of the dose in the above table.

Adults

The recommended dosage for prophylaxis in adults is one Sulfamethoxazole And Trimethoprim DS (double strength) tablet daily.

Pediatric Patients

For pediatric patients, the recommended dose is 150 mg/m /day trimethoprim 2 with 750 mg/m²/day sulfamethoxazole given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 320 mg trimethoprim and 1,600 mg sulfamethoxazole. The following table is a guideline for the attainment of this dosage in pediatric patients: