TRIMETHOPRIM TABLETS, USP Rx Only

Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. This binding is much stronger for the bacterial enzyme than for the corresponding mammalian enzyme. Thus, trimethoprim selectively interferes with bacterial biosynthesis of nucleic acids and proteins.

In vitro serial dilution tests have shown that the spectrum of antibacterial activity of trimethoprim includes the common urinary tract pathogens with the exception of Pseudomonas aeruginosa.

The dominant non-Enterobacteriaceae fecal organisms, Bacteroides spp. and Lactobacillus spp., are not susceptible to trimethoprim concentrations obtained with the recommended dosage.

Trimethoprim has 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.

Staphylococcus species (coagulase-negative strains, including S. saprophyticus)

Enterobacter species
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis

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 method1,7 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trimethoprim powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae and Staphylococcus spp.:

A report of “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.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard trimethoprim^a powder should provide the following MIC values:

^a Very medium-dependent.

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 procedure^2,7 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg trimethoprim to test the susceptibility of microorganisms to trimethoprim.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg trimethoprim disk should be interpreted according to the following criteria:

For testing Enterobacteriaceae and Staphylococcus spp.:

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 of trimethoprim.

As with standardized dilution techniques, diffusion methods require the use of the laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 mcg trimethoprim disk^b should provide the following zone diameters in these laboratory test quality control strains:

^b Mueller-Hinton agar should be checked for excessive levels of thymidine. 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 trimethoprim/ sulfamethoxazole disks. A zone of inhibition ≥ 20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

Prescribing trimethoprim tablets, USP 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.

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. Trimethoprim should also be given with caution to patients with impaired renal or hepatic function (see CLINICAL PHARMACOLOGYand DOSAGE AND ADMINISTRATION).

Patients should be counseledthat antibacterial drugs includingtrimethoprim tablets, USP shouldonly be used to treat bacterialinfections. They do not treat viralinfections (e.g., the common cold).When trimethoprim tablets, USPare prescribed to treat a bacterialinfection, patients should be told thatalthough it is common to feel betterearly in the course of therapy, themedication should be taken exactlyas directed. Skipping doses or notcompleting the full course of therapymay (1) decrease the effectivenessof the immediate treatment and (2)increase the likelihood that bacteriawill develop resistance and will notbe treatable by trimethoprim tablets,USP or other antibacterial drugsin the future.

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.

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.

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 Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Trimethoprim is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism, caution should be exercised when trimethoprim is administered to a nursing woman.

Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of trimethoprim as a single agent has not been established in pediatric patients under 12 years of age.

Clinical studies of trimethoprim tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience^4,5 has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been published.6 Trimethoprim is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor potassium concentrations and to monitor renal function by calculating creatinine clearance.

Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg q.d., 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.

Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell Syndrome), and anaphylaxis have been received

Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.

Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.

Hyperkalemia, hyponatremia.

Aseptic meningitis has been rarely reported.

Fever, and increases in BUN and serum creatinine levels.

To report SUSPECTED ADVERSE EVENTS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression (see Chronicsubsection).

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

Use of 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, trimethoprim should be discontinued and the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.