PRIMSOL- trimethoprim hydrochloride solution

Primsol by

Drug Labeling and Warnings

Primsol by is a Prescription medication manufactured, distributed, or labeled by FSC Laboratories, Inc. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

DESCRIPTION

PRIMSOL (trimethoprim hydrochloride oral solution) is a solution of the synthetic antibacterial trimethoprim in water prepared with the aid of hydrochloric acid. Each 5 mL for oral administration contains trimethoprim hydrochloride equivalent to 50 mg trimethoprim and the inactive ingredients bubble gum flavor, fructose, glycerin, methylparaben, monoammonium glycyrrhizinate, povidone, propylparaben, propylene glycol, saccharin sodium, sodium benzoate, sorbitol, water and hydrochloric acid and/or sodium hydroxide to adjust pH to a range of 3.0 - 5.0. Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. Trimethoprim is a white to cream-colored, odorless, bitter compound with a molecular formula of C14H18N4O3 and a molecular weight of 290.32 and the following structural formula:

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 principal metabolites of trimethoprim 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 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 plasma concentrations approximately twice as high. The mean half-life of trimethoprim is approximately 9 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 (see DOSAGE AND ADMINISTRATION section). During a 13-week study of trimethoprim tablets administered at a dosage of 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 two to three days of chronic administration and were maintained throughout the experimental period.

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. After a single oral dose of 100 mg, urine concentrations of trimethoprim 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 urine concentrations approximately twice as high. After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim.

Trimethoprim half-life, clearance, and volume of distribution vary with age. Excluding newborns, an apparent trend of increasing half-life, volume of distribution, and decreasing clearance is observed with increasing age until adulthood.

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 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 is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora. The dominant non-Enterobacteriaceae fecal organisms, Bacteroides spp. and Lactobacillus spp., are not susceptible to trimethoprim concentrations obtained with the recommended dosage.

Trimethoprim also concentrates into middle ear fluid (MEF) very efficiently. In a study in children aged 1 to 12 years, administration of a single 4 mg/kg dose resulted in a mean peak MEF concentration of 2.0 mcg/mL.

Trimethoprim also passes the placental barrier and is excreted in breast milk.

Microbiology

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

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.

Aerobic gram-positive microorganisms

• Staphylococcus species: (coagulase-negative strains, including S. saprophyticus)
• Streptococcus pneumoniae: (penicillin-susceptible strains)

Aerobic gram-negative microorganisms

• Haemophilus influenzae: (excluding beta-lactamase negative, ampicillin resistant strains)

NOTE: Moraxella catarrhalis isolates were found consistently resistant to trimethoprim.

Susceptibility Tests

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's 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 powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms isolated from urinary tract infections:

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

When testing Haemophilus influenzae 1

MIC (mcg/mL)	Interpretation
≤ 0.5	Susceptible (S)
1-2	Intermediate (I)
≥ 4	Resistant (R)

When testing Streptococcus pneumoniae 2

MIC (mcg/mL)	Interpretation
≤ 2	Susceptible (S)
≥ 4	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 trimethoprim3 powder should provide the following MIC values:

Microorganism		MIC (mcg/mL)
* Range applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1 † Range applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1
Escherichia coli	ATCC 25922	0.5 - 2
Haemophilus influenzae*	ATCC 49247	0.06 - 0.5
Staphylococcus aureus	ATCC 29213	1 - 4
Streptococcus pneumoniae†	ATCC 49619	1 - 4

1 Interpretive criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1

2 Interpretive criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1

3 Trimethoprim 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 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.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg trimethoprim4 disk should be interpreted according to the following criteria:

For testing aerobic microorganisms isolated from urinary tract infections:

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

For testing Haemophilus influenzae 5:

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

Note:

Diffusion techniques are not recommended for determining susceptibility of Streptococcus pneumoniae to trimethoprim.

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.

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 trimethoprim4 disk should provide the following zone diameters in this laboratory test quality control strain:

Microorganism		Zone Diameter (mm)
* Range applicable only to tests performed by disk diffusion method using Haemophilus Test Medium (HTM).2
Escherichia coli	ATCC 25922	21 - 28
Haemophilus influenzae*	ATCC 49247	27 - 33
Staphylococcus aureus	ATCC 25923	19 - 26

Note:

Diffusion techniques are not recommended for determining susceptibility of Streptococcus pneumoniae to trimethoprim.

4 Blood-containing media (except for lysed horse blood) are generally not suitable for testing trimethoprim. 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.

5 Interpretative criteria applicable only to tests performed by disk diffusion method using Haemophilus Test Medium (HTM).2