CONTRAINDICATIONS: Trimethoprim is contraindicated in individuals hypersensitive to Trimethoprim and in those with documented megaloblastic anemia due to folate deficiency.

DESCRIPTION: Trimethoprim is a synthetic antibacterial available in scored, tablets, each containing 100 mg Trimethoprim. 

CLINICAL PHARMACOLOGY:

 Trimethoprim is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound and metabolized forms. Ten to twenty percent of Trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. The free is considered to be the therapeutically active form. Approximately 44% of Trimethoprim is to plasma proteins.

Mean peak plasma concentrations of approximatelly 1.0 μg/mL occur 1 to 4 hours after result in plasma concentrations approximately twice as high. The half-life of Trimethoprim ranges from 8 to 10 hours. However, patients with severely impaired

renal function exhibit an increase in the half-life of Trimethoprim, which requires either dosage regimen adjustment or not using the drug in such patients

Excretion of Trimethoprim is primarily by the kidneys through glomerular

Filtration and tubular secretion. Urine concentrations of  Trimethoprim

are considerably higher than are the concentrations in the blood.

Concentrations of Trimethoprim in vaginal secretions are consistently greater than those found simultaneously in the serum, being typically 1.6 times the concentrations of simultaneously obtained samples. Trimethoprim also passes the placental

barrier and is excreted in breast milk. 

WARNINGS:

Experience with trimethoprim alone is limited, but it has been reported rarely to interfere with hematopolesis, especially when administered in large doses and/or for prolonged periods. The presence of clinical signs such as throat, fever, pallor or purpura

 may be early indications of serious blood disorders.

PRECAUTIONS:

 General

Trimethoprim should be given with caution to patients with possible folate deficiency. Folates may be administered concomitantly without interfering with the antibacterial

action of trimethoprim. Trimethioprim should also be given with caution to patients with impaired or hepatic function. If any clinical signs of a disorder are noted in a patient receiving trimethoprim, a complete blood should be obtained and the discontinued if a significant reduction in the count of any formed element is found.

Drug/Laboratory Test Interactions

Trimethoprim 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 trimethoprim may also interfere with the Jaffé alkaline picrate reaction

assay for creatinine, resulting in over estimations of about 10% in the range of normal values.

Nursing Mothers: Trimethoprim is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism, caution should be exercised when Trimethoprim Tablets are ad ministered to a nursing woman.

Pediatric Use: The safety of trimethoprim in infants under two months of has not been demonstrated. The effectiveness trimethoprim has not been established in children under 12 years of age.

Drug Interactions: Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

SIDE EFFECTS: The adverse effects encountered most often with trimethoprim were rash and pruritus. Other adverse effects reported involved the gastrointestinal and hematopoietic systems.

Dermatologic Reactions: Rash, pruritus and exfoliative dermatitis. At the recommended dosage regimens of 100 mg bid or 200 mg qd, each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies which employed high doses of trimethoprim, an elevated incidence of rash was noted. These rashes were maculopapular, morbilliform, pruritic and generally mild to moderate, appearing 7 to 14 days after the initiation of therapy.

Gastrointestinal Reactions: Epigastric distress, nausea, vomiting and glossitis.

Hematologic Reactions: Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia and methemoglobinemia.

Metabolic Reactions: Hyperkalemia, hyponatremia.

Miscellaneous Reactions: Fever, elevation of serum transaminase and bilirubin and increases in BUN and serum creatinine levels. 

OVERDOSAGE:

Acute Signs of overdosage with trimethoprim may appear following

ingestion of 1 gram or more of the and include nausea, vomiting, dizziness, headaches, mental depression, confusion and marrow depression

Treatment consists of gastric lavage  and general supportive measures. Acidification of the urine increase renal elimination of trimethoprim. Peritoneal dialysis is not effective and hemodialysis only moderately effective in eliminating the drug.

Chronic

Use of trimethoprim at high doses and/or for extended periods of

may cause marrow depression manifested as thrombocytopenia, leukopenia

and/or megaloblastic anemia. If signs of bone marrow depression occur,

trimethoprim should be discontinued and the patient should be given leucovorin 3 to 6 mg intramuscularly daily for three days or as required to restore normal hematopoiesis.

DOSAGE AND ADMINISTRATION: The usual adult dosage is 100 mg every 12 hours or 200 mg every 24 hours, each for 10 days. The use of trimethoprim in patients with a creatinine clearance of less than 15 mL/min is not recommended. For patients with a creatinine clearance of 15 to 30 mL/min, it should be 50 mg every 12 hours.

The effectiveness of trimethoprim has not been established in children under 12 years of age.

How Supplied: Pack of 100 tablets in 10 blisters.

storage: Store at controlled room temperature 15°-30° C. Protect from moisture and light. Dispense in a tight, light-resistant container.

Reference: USPDI for Professional Health Care, 2004, Page 2751-4

                  Martindale 2005, Page 272-4