Acute Exacerbations of Chronic Bronchitis in Adults:    For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae.

Travelers' Diarrhea in Adults:    For the treatment of travelers' diarrhea due to susceptible strains of enterotoxigenic E. coli. Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei.

Pneumocystis Carinii Pneumonia:    For the treatment of documented Pneumocystis carinii pneumonia. For prophylaxis against Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis carinii pneumonia.

CONTRAINDICATIONS:

Co-trimoxazole is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides and in patients with documented megaloblastic anemia due to folate deficiency. Co-trimoxazole is also contraindicated in pregnant patients at term and in nursing mothers. Co-Trimoxazole is contraindicated in pediatric patients less than 2 months of age.

DESCRIPTION: Trimethoprim and sulfamethoxazole is a synthetic antibacterial combination product. Each Adult Tablet contains 80 mg trimethoprim and 400 mg sulfamethoxazole. Each Pediatric Tablet contains 20 mg trimethoprim and 100 mg sulfamethoxazole.

CLINICAL PHARMACOLOGY: Co-trimoxazole 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. The metabolism of sulfamethoxazole occurs predominately by N ₄ -acetylation although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 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. 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. Detectable amounts of trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration. 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. 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.

Microbiology:    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.

The usual spectrum of antimicrobial activity of Co-trimoxazole includes bacterial pathogens isolated from middle ear exudate and from bronchial secretions ( Haemophilus influenzae , including ampicillin-resistant strains, and Streptococcus pneumoniae ), and enterotoxigenic strains of Escherichia coli (ETEC) causing bacterial gastroenteritis. Shigella flexneri and Shigella sonnei are also usually susceptible.

WARNINGS:

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 TRIMETHOPRIM/SULFAMETHOXAZOLE, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION.

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

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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including trimethoprim/sulfamethoxazole, and may range in severity from mild to life-threatening.

PRECAUTIONS:

General:    Co-trimoxazole 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 dehydrognase-deficient individuals, hemolysis may occur.

Use in the Elderly:  There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist.

Information for Patients:    Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.

Pregnancy: Pregnancy Category C.  

Pediatric Use:    Co-trimoxazole is not indicated for pediatric patients younger than 2 months of age.

Drug Interactions:   

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

It has been reported that Co-trimoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin.

Co-trimoxazole may inhibit the hepatic metabolism of phenytoin.

Sulfonamides can also displace methotrexate from plasma protein binding sites.

SIDE EFFECTS:

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

Hematologic:    Agranulocytosis, aplastic anemia, thrombocytopenia, eucopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.

Allergic:    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. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.

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

Genitourinary:    Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria.

Metabolic:    Hyperkalemia, hyponatremia.

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

Psychiatric:    Hallucinations, depression, apathy, nervousness.

Endocrine:    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.

Musculoskeletal:    Arthralgia and myalgia.

Respiratory System:    Cough, shortness of breath, and pulmonary infiltrates.

Miscellaneous:    Weakness, fatigue, insomnia.

FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FLUMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA, OTHER BLOOD DYSCRASIAS, AND HYPERSENSITIVITY OF THE RESPIRATORY TRACT.

OVERDOSAGE:

Acute:  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.

Chronic:    Use of Co-trimoxazole at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia.

DOSAGE AND ADMINISTRATION:

Contraindicated in pediatric patients less than 2 months of age.

Adults:    The usual adult dosage in the treatment of urinary tract infections is one two Co-trimoxazole tablets every 12 hours for 10 to 14 days.

Pediatric Patients:    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.

For Patients With Impaired Renal Function:    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

15-30

¹ / ₂ the Usual Regimen

Below 15

Use Not Recommended

Acute Exacerbations of Chronic Bronchitis in Adults:    The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is two Co-trimoxazole

 tablets every 12 hours for 14 days.

Travelers' Diarrhea in Adults:    For the treatment of travelers' diarrhea, the usual adult dosage is two Co-trimoxazole tablets, every 12 hours for 5 days.

Pneumocystis Carinii Pneumonia: Treatment:

Adults and Pediatric Patients:

The recommended dosage for treatment of patients with documented Pneumocystis carinii 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.

Prophylaxis:

Adults: The recommended dosage for prophylaxis in adults is two Co-trimoxazole

tablet daily.

Pediatric Patients: For pediatric patients, the recommended dose is 150 mg/m ² /day trimethoprim with 750 mg/m ² /day sulfamethoxazole given orally in equally divided doses twice a day, on 3 consecutive days per week.

How Supplied: Each pack of Ruz-Cotrimoxazole adult or pediatric tablets contains 100 tablets in 10 blisters.

storage: Stored at 15° to 25°C in a dry place and protect from light.

For more information please refer to:

           PDR 2000, page 2614-6

                  USPDI for Professional Health Care, 2004, Page 2583-6