alcohol (less than 0.5%), carboxymethylcellulose sodium, citric acid, FD&C Red #40, FD&C Yellow #6, cherry flavor, methylparaben, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, propylene glycol, propylparaben, purified water, saccharin sodium, simethicone emulsion, sucrose.

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.S. 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 lowered 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 both sulfamethoxazole trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone.

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

Aerobic gram-positive microorganisms:
Streptococcus pneumoniae

Aerobic gram-negative microorganisms:
Escherichis coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea)

Klebsiella species

Enterobacter species

Haemophilus influenzae

Morganella morganii

Proteus mirabilis

Proteus vulgaris

Shigella flexneri

Shigella sonnei

Other Organisms:

Pneumocystis carinii

Susceptibility Testing Methods:

Dilution Techniques:

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 procedure. Standardized procedures are based on a dilution method⁴ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of sulfamethoxazole/trimethoprim powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae:

MIC (μg/mL)	Interpretation
≤2/38	Susceptible (S)
≥4/76	Resistant (R)

When testing either Haemophilus influenzae ^a or Streptococcus pneumoniae ^b:

MIC (μg/mL	Interpretationb
≤0.5/9.5	Susceptible (S)
1/19 - 2/38	Intermediate (I)
≥4/76	Resistant (R)

a. These interpretative standards are applicable only to broth microdilution susceptibility tests with Haemophilus influenzae using Haemophilus Test Medium (HTM).⁴

b.  These interpretative standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.⁴

A report "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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 which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.  Standard sulfamethoxazole/trimethoprim powder should provide the following range of values:

Microorganism		MIC (μg/mL)
Escherichia coli	ATCC 25922	≤0.5/9.5
Haemophilus influenzae c	ATCC 49247	0.03/0.59 - 0.25/4.75
Streptococcus pneumoniae d	ATCC 49619	0.12/2.4 - 1/19

c. This quality control range is applicable only to Haemophilus influenzae ATCC 49247 tested by broth microdilution procedure using Haemophilus Test Medium (HTM).⁴

d. This quality control range is applicable to tests performed by the broth microdilution method only using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.⁴

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure5 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 1.25/23.75 μg of sulfamethoxazole/trimethoprim to test the susceptibility of microorganisms to sulfamethoxazole/trimethoprim.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 1.25/23.75 mcg of sulfamethoxazole/trimethoprim disk should be interpreted
according to the following criteria:

For testing either Enterobacteriaceae or Haemophilus influenzae ^e:

Zone Diameter (mm)	Interpretation
≥16	Susceptible (S)
11-15	Intermediate (I)
≤10	Resistant (R)

e. These zone diameter standards are applicable only for disk diffusion testing with Haemophilus influenzae and Haemophilus Test Medium (HTM).⁵

When testing Streptococcus pneumoniae ^f:

Zone Diameter (mm)	Interpretation
≥19	Susceptible (S)
16-18	Intermediate (I)
≤15	Resistant (R)

f. These zone diameter interpretative standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood when incubated 5% CO₂.⁵

Interpretation should be as stated above for results using dilution techniques.  Interpretation involves correlation of the diameter obtained in the disk test with the MIC for sulfamethoxazole/trimethoprim.

Quality Control

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures.  For the diffusion technique, the 1.25/23.75 μg sulfamethoxazole/trimethoprim disk* should provide the following zone diameters in these laboratory test quality control strains:

Microorganism		Zone Diameter  Range (mm)
Escherichia coli	ATCC 25922	23-29
Haemophilus influenzae g	ATCC 49247	24-32
Streptococcus pneumoniaeh	ATCC 49619	20-28

*Mueller-Hinton agar should be checked for excessive levels of thymidine or thymine.  To determine whether Mueller-Hinton medium has sufficiently low levels of thymidine and thymine, an Enterococcus faecalis (ATCC 29212 or ATCC 33186) may be tested with sulfamethoxazole/trimethoprim disks.  A zone of inhibition ≥20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

g.  This quality control range is applicable only to Haemophilus influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM).⁵

h. This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood incubated in 5% CO₂.⁵

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 are 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 in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of a single antimicrobial agent.

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 carinii pneumonia and for prophylaxis against Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis carinii pneumonia.

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

Hypersensitivity and Other Serious Reactions: Advise patients to stop taking Sulfamethoxazole and Trimethoprim immediately if they experience any clinical signs such as rash, pharyngitis, fever, arthralgia, cough, chest pain, dyspnea, pallor, purpura, or jaundice and to contact their health care provider as soon as possible (see WARNINGS and ADVERSE REACTIONS).

Antibacterial Resistance: Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim oral suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When sulfamethoxazole and trimethoprim oral suspension is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by sulfamethoxazole and trimethoprim oral suspension or other antibacterial drugs in the future.

Crystalluria and Stone Formation: Advise patients to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.

Diarrhea: Advise patients that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with and without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.

It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when sulfamethoxazole and trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.

Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin. Sulfamethoxazole and trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.

There have been reports of marked but reversible nephrotoxicity with coadministration of sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients.

Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients. Serum digoxin levels should be monitored. Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin.

Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if sulfamethoxazole and trimethoprim is prescribed.

The efficacy of tricyclic antidepressants can decrease when coadministered with sulfamethoxazole and trimethoprim.

Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim potentiates the effect of oral hypoglycemics.

In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine.

In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.^7,8

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-Schönlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash, periarteritis nodosa, systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized erythematous pustulosis (AGEP), and acute febrile neutrophilic dermatosis (AFND) (see WARNINGS ).

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 (see PRECAUTIONS: Use in the Treatment of and Prophylaxis for Pneumocystis Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS) .

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. Isolated cases of rhabdomyolysis have been reported with sulfamethoxazole and trimethoprim, mainly in AIDS patients.

Cough, shortness of breath, pulmonary infiltrates, acute eosinophilic pneumonia, acute and delayed lung injury, interstitial lung disease, acute respiratory failure (see WARNINGS ).

Circulatory shock (see WARNINGS ), QT prolongation resulting in ventricular tachycardia and torsades de pointes.

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

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 sulfamethoxazole and trimethoprim.

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 usual adult dosage in the treatment of urinary tract infections is four teaspoonfuls (20mL) Sulfamethoxazole and trimethoprim oral suspension every 12 hours for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis.

Children

The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim 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:

Children 2 months of age or older:

Weight		Dose - every 12 hours Teaspoonfuls
lb	kg
22	10	1 (5 mL)
44	20	2 (10 mL)
66	30	3 (15 mL)
88	40	4 (20 mL)

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

Creatinine Clearance (mL/min)	Recommended Dosage Regimen
Above 30	Use standard regimen
15 to 30	1/2 the usual regimen
Below 15	Use not recommended

The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is four teaspoonfuls (20 mL) sulfamethoxazole and trimethoprim oral suspension every 12 hours for 14 days.

Treatment

Adults and Children:  The recommended dosage for treatment of patients with documented Pneumocystis carinii pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.¹⁰

The following table is as a guideline for the upper limit of this dosage:

Weight		Dose - every 6 hours Teaspoonfuls
lb	kg
18	8	1 (5 mL)
35	16	2 (10 mL)
53	24	3 (15 mL)
70	32	4 (20 mL)
88	40	5 (25 mL)
106	48	6 (30 mL)
141	64	8 (40 mL)
176	80	10 (50 mL)

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.

Adults

The recommended dosage for prophylaxis in adults is four teaspoonfuls (20 mL) of the oral suspension daily.¹¹

For children, the recommended dose is 750 mg/m²/day sulfamethoxazole with 150 mg/m²/day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.¹² The following table is a guideline for the attainment of this dosage in children:

Body Surface Area	Dose every 12 hours
(m2)	Teaspoonfuls
0.26	1/2 (2.5 mL)
0.53	1 (5 mL)
1.06	2 (10 mL)

For the treatment of travelers' diarrhea, the usual adult dosage is four teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension every 12 hours for 5 days.