Label: SULFAMETHOXAZOLE AND TRIMETHOPRIM tablet

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.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 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

Microbiology

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 vitrostudies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone.

Antimicrobial Activity

Sulfamethoxazole and trimethoprim have been shown to be active against most isolates of the following microorganisms, both in vitroand in clinical infections as described in the  INDICATIONS AND USAGEsection.

Aerobic gram-positive bacteria

Streptococcus pneumoniae

Aerobic gram-negative bacteria

Escherichia coli(including susceptible enterotoxigenic strains implicated in traveler’s diarrhea)

Klebsiellaspecies

Enterobacterspecies

Haemophilus influenzae

Morganella morganii

Proteus mirabilis

Proteus vulgaris

Shigella flexneri

Shigella sonnei

Other Microorganisms

Pneumocystis jirovecii

Susceptibility Testing

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.fda.gov/STIC.

Urinary Tract Infections

For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiellaspecies, Enterobacterspecies, Morganella morganii, Proteus mirabilisand 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.

Acute Otitis Media

For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniaeor Haemophilus influenzaewhen 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 tablets in pediatric patients under two years of age. Sulfamethoxazole and trimethoprim tablets are not indicated for prophylactic or prolonged administration in otitis media at any age.

Acute Exacerbations of Chronic Bronchitis in Adults

For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniaeor Haemophilus influenzaewhen a physician deems that  sulfamethoxazole and trimethoprim tablets could offer some advantage over the use of a single antimicrobial agent.

Shigellosis

For the treatment of enteritis caused by susceptible strains of Shigella flexneriand Shigella sonneiwhen antibacterial therapy is indicated.

Pneumocystis jiroveciiPneumonia

For the treatment of documented Pneumocystis jiroveciipneumonia and for prophylaxis against P.jiroveciipneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing P. jiroveciipneumonia.

Traveler's Diarrhea in Adults

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

Development of Drug Resistant Bacteria

Prescribing   sulfamethoxazole and trimethoprim tablets 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.

Folate Deficiency

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.

Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure. These effects are reversible by folinic acid therapy (see  PRECAUTIONS,  Geriatric Use).

Hemolysis

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

Hypoglycemia

Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen rarely, 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.

Impaired Phenylalanine Metabolism

The 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.

Porphyria and Hypothyroidism

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.

Potential Risk in the Treatment of PneumocystisjiroveciiPneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS)

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 P. jiroveciipneumonia has been reported to be increased compared with the incidence normally associated with the use of sulfamethoxazole and trimethoprim in non-AIDS patients. If a patient develops skin rash, fever, leukopenia or any sign of adverse reaction, reevaluate benefit-risk of continuing therapy or re-challenge with sulfamethoxazole and trimethoprim (see WARNINGS).

Avoid coadministration of sulfamethoxazole and trimethoprim and leucovorin during treatment of P. jiroveciipneumonia (see WARNINGS).

Electrolyte Abnormalities 

Hyperkalemia: High dosage of trimethoprim, as used in patients with P. jiroveciipneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients. Even treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly. Close monitoring of serum potassium is warranted in these patients.

Hyponatremia: Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole and trimethoprim, particularly for the treatment of P. jiroveciipneumonia. Evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent   life-threatening complications.

Crystalluria:During treatment, ensure adequate fluid intake and urinary output to prevent crystalluria. Patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides.

Information for Patients

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 healthcare provider as soon as possible (see  WARNINGS and ADVERSE REACTIONS).

Antibacterial Resistance: Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When sulfamethoxazole and trimethoprim tablets are 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 tablets 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 or 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.

Laboratory Tests

Complete blood counts and clinical chemistry testing should be done frequently in patients receiving sulfamethoxazole and trimethoprim. Perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function. Discontinue sulfamethoxazole and trimethoprim if a significant electrolyte abnormality, renal insufficiency or reduction in the count of any formed blood element is noted.

Drug Interactions

Potential forSulfamethoxazole and Trimethoprimto Affect Other Drugs

Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor of CYP2C9. Avoid coadministration of sulfamethoxazole and trimethoprim with drugs that are substrates of CYP2C8 and 2C9 or OCT2.

Drug/Laboratory Test Interactions

Sulfamethoxazole and trimethoprim, specifically the trimethoprim component, can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).

The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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 twice a day).

Mutagenesis

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

Sulfamethoxazole alone was positive in an in vitroreverse mutation bacterial assay and in in vitromicronucleus assays using cultured human lymphocytes.

Trimethoprim alone was negative in in vitroreverse mutation bacterial assays and in in vitrochromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation. In in vitroComet, 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.

Impairment of Fertility

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.

Pregnancy

Nursing Mothers

Levels of sulfamethoxazole and trimethoprim in breast milk are approximately 2 to 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.

Pediatric Use

Sulfamethoxazole and trimethoprim is contraindicated for infants younger than 2 months of age (see  INDICATIONS AND USAGE and  CONTRAINDICATIONSsections).

Geriatric Use

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 WARNINGSand 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. 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 0.45 mg sodium (0.02 mEq) of sodium per tablet. Sulfamethoxazole and trimethoprim DS tablets contain 0.9 mg (0.04 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 trimethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL PHARMACOLOGY: Geriatric Pharmacokinetics).

Acute

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.

Chronic

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.

Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children

Adults:The usual adult dosage in the treatment of urinary tract infections is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets 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:

For Patients with Impaired Renal Function

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

Acute Exacerbations of Chronic Bronchitis in Adults

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.

PneumocystisjiroveciiPneumonia

Treatment

Adults and Children:

The recommended dosage for treatment of patients with documented Pneumocystis jiroveciipneumonia 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. 12The following table is a guideline for the upper limit of this dosage:

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/day sulfamethoxazole with 150 mg/m 2/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. 14The following table is a guideline for the attainment of this dosage in children:

Traveler's Diarrhea in Adults

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.