Trimethoprim

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

• fever, chills, body aches, flu symptoms, sores in your mouth and throat;

• pale skin, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling); or

• severe headache with muscle cramps, confusion, weakness, loss of coordination, feeling unsteady, and weak or shallow breathing.

Other common side effects may include:

• stomach pain, vomiting, diarrhea;

• sore or swollen tongue; or

• mild itching or skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Antibacterial; dihydrofolate reductase inhibitor.106 124 Commercially available alone106 124 or in fixed combination with sulfamethoxazole.135 186

Absorption

Bioavailability

Rapidly absorbed from GI tract.106 124

Steady-state concentrations attained within 2–3 days.124 Peak serum concentrations attained within 1–4 hours after a dose.106 124 b

Distribution

Extent

Widely distributed into body tissues and fluids, including aqueous humor, middle ear fluid, saliva, lung tissue, sputum, seminal fluid, prostatic tissue and fluid, vaginal secretions, bile, and bone.106 124 b

Distributed into CSF.b In patients with uninflamed meninges receiving oral trimethoprim, CSF concentrations are approximately 13–34% of concurrent serum concentrations.b CSF concentrations somewhat higher if meninges are inflamed.b

Readily crosses placenta;106 124 b amniotic fluid concentrations are 80% of concurrent maternal serum concentrations.b

Distributed into milk106 124 b in concentrations approximately 125% those of concurrent maternal serum concentrations.b

Plasma Protein Binding

42–46% bound to plasma proteins.106 124 b

Elimination

Metabolism

10–20%106 of a dose is metabolized in the liver to oxide and hydroxylated metabolites.106 124 b

Elimination Route

Eliminated in urine via glomerular filtration and tubular secretion.106 124 b Only small amounts excreted in feces via biliary elimination.b

In adults with normal renal function, approximately 50–60 and 56–70% of an oral dose is excreted in urine within 24 and 72 hours, respectively.106 b Approximately 80% of amount recovered in urine is unchanged drug.106 124 b

Hemodialysis is only moderately effective in removing trimethoprim;106 not removed by peritoneal dialysis.106

Half-life

8–11 hours in adults with normal renal function.106 b

7.7 hours in children <1 year of age and 5.5 hours in children 1–10 years of age.b

Special Populations

Half-life is prolonged in patients with renal impairment.124 b Half-life is 15 hours in adults with Clcr 10–30 mL/minute and may increase to >26 hours in those with Clcr ≤10 mL/minute.b

Storage

Oral

15–25°C in tight, light-resistant container.124

20–25°C in tight, light-resistant container in a dry place.106

It is important that your doctor check your progress at regular visits if you will be taking trimethoprim for a long time. This will allow your doctor to check for any unwanted effects that may be caused by trimethoprim.

If your symptoms do not improve within a few days, or if they become worse, check with your doctor.

If trimethoprim causes anemia, your doctor may want you to take folic acid (a vitamin) every day to help clear up the anemia. If so, it is important to take folic acid every day along with trimethoprim; do not miss any doses.

Trimethoprim may cause blood problems. These problems may result in a greater chance of certain infections, slow healing, and bleeding of the gums. Therefore, you should be careful when using regular toothbrushes, dental floss, and toothpicks. Dental work should be delayed until your blood counts have returned to normal. Check with your medical doctor or dentist if you have any questions about proper oral hygiene (mouth care) during treatment.

Some people who take trimethoprim may become more sensitive to sunlight than they are normally. Exposure to sunlight, even for brief periods of time, may cause severe sunburn or skin rash, redness, itching, or discoloration. When you begin taking trimethoprim:

• Stay out of direct sunlight, especially between the hours of 10:00 a.m. and 3:00 p.m., if possible.
• Apply a sun block product that has a skin protection factor (SPF) of at least 15. Some patients may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your health care professional.
• Do not use a sunlamp or tanning bed or booth.

If you have a severe reaction from the sun, check with your doctor.

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 3ʹ- and 4ʹ-hydroxy derivatives. The free form is considered to be the therapeutically active form. Approximately 44% of Trimethoprim is bound to plasma proteins.

Mean peak serum 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 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 (see DOSAGEAND ADMINISTRATION). During a 13 week study of Trimethoprim 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. Steadystate concentrations were achieved within 2 to 3 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 levels 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.

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.

Trimethoprim also passes the placental barrier and is excreted in human 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 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.

Aerobic gram-positive microorganisms

Staphylococcus species (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 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 Trimethoprima 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 procedure2,7 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 diskb 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.

Trimethoprim tablets, USP, 100 mg are scored, oval-shaped, white tablets imprinted DAN DAN and

5571 supplied in bottles of 100.

Store at 20° to 25°C (68° to 77°F) in a dry place. [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required).

Otitis media, acute (oral solution): Treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae and Haemophilus influenzae.

Urinary tract infection (uncomplicated), treatment (tablets, oral solution): Treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species and coagulase-negative Staphylococcus species, including S. saprophyticus.

Solution: Store between 15°C to 25°C (59°F to 77°F). Protect from light.

Tablets: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Frequency not always defined.

Dermatologic: Maculopapular rash (200 mg/day: 3% to 7%; incidence higher with larger daily doses), phototoxicity, pruritus (common)

Endocrine & metabolic: Hyperkalemia, hyponatremia

Gastrointestinal: Epigastric distress, glossitis, nausea, vomiting

Hematologic & oncologic: Leukopenia, megaloblastic anemia, methemoglobinemia, neutropenia, thrombocytopenia

Hepatic: Increased liver enzymes

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Renal: Increased blood urea nitrogen, increased serum creatinine

Miscellaneous: Fever

1% (Limited to important or life-threatening): Aseptic meningitis, cholestatic jaundice, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Concerns related to adverse effects:

• Hematologic effects: May rarely interfere with hematopoiesis, especially with large doses or long term therapy; monitor patients on long term therapy for signs/symptoms of hematologic disorders.

• Hyperkalemia: May cause hyperkalemia; potential risk factors include high dosage (20 mg/kg/day), renal impairment, older age, hypoaldosteronism, and concomitant use of medications causing or exacerbating hyperkalemia (Perazella 2000).

• Hypersensitivity: Serious hypersensitivity reactions have been reported (rarely).

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Elderly patients may be at risk for hyperkalemia with trimethoprim use and are at an increased risk for severe and potentially life-threatening hyperkalemia when trimethoprim is used concomitantly with medications known to cause or exacerbate hyperkalemia, such as spironolactone, ACE inhibitors, or ARBs (Antoniou 2010; Antoniou 2011; Antoniou 2015).

• Patients with potential for folate deficiency: Use with caution in patients with potential folate deficiency (malnourished, chronic anticonvulsant therapy, or elderly).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar 2007).

Other warnings/precautions:

• Appropriate use: Otitis media: Not indicated for prophylactic or prolonged administration in otitis media at any age.

12 TO 18 YEARS OF AGE:
Recommended dose:
100 mg orally every 12 hours for 10 days or 200 mg orally every 24 hours for 10 days

Comments:
-Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to this drug.
-Therapy may be initiated prior to obtaining the results of susceptibility tests.

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

Peritoneal dialysis is not effective and hemodialysis only moderately effective in eliminating this drug.