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Trimethoprim

Last reviewed on RxList: 12/25/2016
Drug Description

TRIMETHOPRIM
(trimethoprim) Tablet

DESCRIPTION

Trimethoprim (trimethoprim tablet) is a synthetic antibacterial available as 100 mg tablets for oral administration.

Trimethoprim (trimethoprim tablet) is 2,4-Diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. It is a white to cream colored, odorless, bitter compound. The structural formula is represented below:

Trimethoprim Structural Formula Illustration

Trimethoprim (trimethoprim) Tablets USP, 100 mg contain the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, sodium starch glycolate and stearic acid.

Indications & Dosage

INDICATIONS

For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of the following organisms: Escherichiacoli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species and coagulase-negative Staphylococcus species, including S. saprophyticus.

Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to trimethoprim (trimethoprim (trimethoprim tablet) tablet) . Therapy may be initiated prior to obtaining the results of these tests.

DOSAGE AND ADMINISTRATION

The usual oral adult dosage is 100 mg of trimethoprim every 12 hours or 200 mg trimethoprim (trimethoprim (trimethoprim tablet) tablet) (two 100 mg tablets) every 24 hours, each for 10 days. The use of trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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, the dose should be 50 mg every 12 hours.

HOW SUPPLIED

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) Tablets USP, 100 mg are scored, oval-shaped, white tablets imprinted DAN DAN and 5571 supplied in bottles of 100.

Dispense in a tight, light-resistant container with child-resistant closure.

Store at 20°-25°C (68°-77°F) in a dry place. [See USP controlled room temperature.]

Watson Laboratories, Inc., Corona, CA 92880, USA. Revised: June 2006. FDA rev date: 5/1/2002

Side Effects & Drug Interactions

SIDE EFFECTS

The adverse effects encountered most often with trimethoprim (trimethoprim (trimethoprim tablet) tablet) were rash and pruritus.

Dermatologic

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 (trimethoprim (trimethoprim tablet) tablet) , 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.

Hypersensitivity

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

Gastrointestinal

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.

Hematologic

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

Metabolic

Hyperkalemia, hyponatremia.

Neurologic

Aseptic meningitis has been rarely reported.

Miscellaneous

Fever, and increases in BUN and serum creatinine levels.

DRUG INTERACTIONS

Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim (trimethoprim (trimethoprim tablet) tablet) , 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.

Drug/Laboratory Test Interactions

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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 (trimethoprim (trimethoprim tablet) tablet) 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.

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Warnings & Precautions

WARNINGS

Serious hypersensitivity reactions have been reported rarely in patients on trimethoprim (trimethoprim (trimethoprim tablet) tablet) therapy. Trimethoprim (trimethoprim (trimethoprim tablet) tablet) has been reported rarely to interfere with hematopoiesis, especially when administered in large doses and/or for prolonged periods.

The presence of clinical signs such as sore throat, fever, pallor or purpura may be early indications of serious blood disorders (see OVERDOSAGE: Chronic). Complete blood counts should be obtained if any of these signs are noted in a patient receiving trimethoprim (trimethoprim (trimethoprim tablet) tablet) and the drug discontinued if a significant reduction in the count of any formed blood element is found.

PRECAUTIONS

General

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate carcinogenic potential have not been conducted with trimethoprim.

Mutagenesis

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) was demonstrated to be nonmutagenic in the Ames assay. In studies at two laboratories, no chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma levels; at concentrations approximately 1000 times human plasma levels in these same cells, a low level of chromosomal damage was induced at one of the laboratories. No chromosomal abnormalities were observed in cultured human leukocytes at concentrations of trimethoprim (trimethoprim (trimethoprim tablet) tablet) up to 20 times human steady-state plasma levels. No chromosomal effects were detected in peripheral lymphocytes of human subjects receiving 320 mg of trimethoprim (trimethoprim (trimethoprim tablet) tablet) in combination with up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.

Impairment of Fertility

No adverse effects on fertility or general reproductive performance were observed in rats given trimethoprim (trimethoprim (trimethoprim tablet) tablet) in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.

Pregnancy

Teratogenic Effects

Pregnancy Category C. Trimethoprim (trimethoprim (trimethoprim tablet) tablet) has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.

While there are no large, well-controlled studies on the use of trimethoprim (trimethoprim (trimethoprim tablet) tablet) in pregnant women, Brumfitt and Pursell,3 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or trimethoprim (trimethoprim (trimethoprim tablet) tablet) in combination with sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim (trimethoprim (trimethoprim tablet) tablet) and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received trimethoprim (trimethoprim (trimethoprim tablet) tablet) and sulfamethoxazole at the time of conception or shortly thereafter.

Because trimethoprim may interfere with folic acid metabolism, trimethoprim (trimethoprim (trimethoprim tablet) tablet) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

The oral administration of trimethoprim (trimethoprim (trimethoprim tablet) tablet) to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

Clinical studies of trimethoprim (trimethoprim (trimethoprim tablet) tablet) tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience4,5 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 (trimethoprim (trimethoprim tablet) tablet) 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.

REFERENCES

3. Brumfitt W, Pursell R. Trimethoprim (trimethoprim (trimethoprim tablet) tablet) -sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis. 1973; 128 (suppl):S657-S663.

4. Lacey RW, Simpson MHC, Fawcett C, et al. Comparison of single-dose trimethoprim (trimethoprim (trimethoprim tablet) tablet) with a five-day course for the treatment of urinary tract infections in the elderly. Age and Ageing 10: 179-185, 1981.

5. Ewer TC, Bailey RR, Gilchrist NL, et al. Comparative study of norfloxacin and trimethoprim (trimethoprim (trimethoprim tablet) tablet) for the treatment of elderly patients with urinary tract infection. NZ Med J 101: 537-539, 1988.

6. Marinella MA. Trimethoprim (trimethoprim (trimethoprim tablet) tablet) -induced hyperkalemia: An analysis of reported cases. Gerontology 45: 209-212, 1999.

Overdosage & Contraindications

OVERDOSE

Acute

Signs of acute overdosage with trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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 Chronic subsection).

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

Chronic

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

CONTRAINDICATIONS

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) tablets are contraindicated in individuals hypersensitive to trimethoprim (trimethoprim (trimethoprim tablet) tablet) and in those with documented megaloblastic anemia due to folate deficiency.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound and metabolized forms. Ten to twenty percent of trimethoprim (trimethoprim (trimethoprim tablet) tablet) is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. The principal metabolites of trimethoprim (trimethoprim (trimethoprim tablet) tablet) are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free form is considered to be the therapeutically active form. Approximately 44% of trimethoprim (trimethoprim (trimethoprim tablet) tablet) is bound to plasma proteins.

Mean peak plasma concentrations of approximately 1 mcg/mL occur 1 to 4 hours after oral administration of a single 100 mg dose. A single 200 mg dose will result in serum levels approximately twice as high. The half-life of trimethoprim (trimethoprim (trimethoprim tablet) tablet) ranges from 8 to 10 hours. However, patients with severely impaired renal function exhibit an increase in the half-life of trimethoprim (trimethoprim (trimethoprim tablet) tablet) , which requires either dosage regimen adjustment or not using the drug in such patients (see DOSAGE AND ADMINISTRATION). During a 13-week study of trimethoprim (trimethoprim (trimethoprim tablet) tablet) administered at a daily dosage of 200 mg (50 mg q.i.d.), the mean minimum steady-state concentration of the drug was 1.1 mcg/mL. Steady-state concentrations were achieved within 2 to 3 days of chronic administration, and were maintained throughout the experimental period.

Excretion of trimethoprim (trimethoprim (trimethoprim tablet) tablet) is primarily by the kidneys through glomerular filtration and tubular secretion. Urine concentrations of trimethoprim (trimethoprim (trimethoprim tablet) tablet) are considerably higher than are the concentrations in the blood.

After a single oral dose of 100 mg, urine concentrations of trimethoprim (trimethoprim (trimethoprim tablet) tablet) ranged from 30 to 160 mcg/mL during the 0- to 4-hour period and declined to approximately 18 to 91 mcg/mL during the 8- to 24-hour period. A 200 mg single oral dose will result in trimethoprim (trimethoprim (trimethoprim tablet) tablet) urine levels approximately twice as high. After oral administration, 50% to 60% of trimethoprim (trimethoprim (trimethoprim tablet) tablet) is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim (trimethoprim (trimethoprim tablet) tablet) .

Since normal vaginal and fecal flora are the source of most pathogens causing urinary tract infections, it is relevant to consider the distribution of trimethoprim into these sites. Concentrations of trimethoprim (trimethoprim (trimethoprim tablet) tablet) in vaginal secretions are consistently greater than those found simultaneously in the serum, being typically 1.6 times the concentrations of simultaneously obtained serum samples. Sufficient trimethoprim (trimethoprim (trimethoprim tablet) tablet) is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora.

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) also passes the placental barrier and is excreted in human milk.

Microbiology

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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 (trimethoprim (trimethoprim tablet) tablet) selectively interferes with bacterial biosynthesis of nucleic acids and proteins.

In vitroserial dilution tests have shown that the spectrum of antibacterial activity of trimethoprim (trimethoprim (trimethoprim tablet) tablet) includes the common urinary tract pathogens with the exception of Pseudomonas aeruginosa.

The dominant non-Entero-bacteriaceae fecal organisms, Bacteroides spp. and Lactobacillusspp., are not susceptible to trimethoprim (trimethoprim (trimethoprim tablet) tablet) concentrations obtained with the recommended dosage.

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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.

Aerobic gram-positive microorganisms

Staphylococcusspecies (coagulase-negative strains, including S. saprophyticus)

Aerobic gram-negative microorganisms

Enterobacter species
Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Susceptibility Testing Methods

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal 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 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trimethoprim (trimethoprim (trimethoprim tablet) tablet) powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteri-aceae and Staphylococcus spp.:

MIC (mcg/mL) Interpretation
≤ 8 Susceptible (S)
≥ 16 Resistant (R)

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 (trimethoprim (trimethoprim tablet) tablet) a powder should provide the following MIC values:

Microorganism MIC (mcg/mL)
E. coli ATCC 25922 0.5 - 2.0
S. aureus ATCC 29213 1.0 - 4.0
aVery 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 procedure2 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 (trimethoprim (trimethoprim tablet) tablet) .

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

For testing Enterobacteri-aceae and Staphylococcus spp.:

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

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 trimethoprim (trimethoprim (trimethoprim tablet) tablet) .

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 5 mcg trimethoprim (trimethoprim (trimethoprim tablet) tablet) diskb should provide the following zone diameters in these laboratory test quality control strains.

Microorganism MIC (mcg/mL)
E. coli ATCC 25922 0.5 - 2.0
Microorganism Zone Diameter (mm)
E. coli ATCC 25922 21 - 28
S. aureus ATCC 25923 19 - 26

bMueller-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 (trimethoprim (trimethoprim tablet) tablet) /sulfamethoxazole disks. A zone of inhibition ≥ 20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 3rd ed.; Approved Standard. NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.

Medication Guide

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

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