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ACTAVIS PHARMA/
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00591557101

trimethoprim 100 mg tablet

Generic
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Uses

Acute Otitis Media

Trimethoprim has been used for treatment of acute otitis media (AOM) caused by Streptococcus pneumoniae and Haemophilus influenzae. Because Moraxella catarrhalis is resistant to trimethoprim, the drug should not be used if M. catarrhalis is suspected.

The manufacturer states that trimethoprim is not indicated for treatment of AOM in adults or in children younger than 6 months of age. In addition, the drug should not be used for prophylaxis of AOM and should not be given for prolonged periods for treatment of AOM in any age group.

When anti-infective therapy is indicated for treatment of AOM, the American Academy of Pediatrics (AAP) recommends high-dose amoxicillin or amoxicillin and clavulanate potassium as the drugs of first choice for initial treatment and certain cephalosporins (cefdinir, cefpodoxime, cefuroxime, ceftriaxone) as alternatives for initial treatment in penicillin-allergic patients who do not have a history of severe and/or recent penicillin-allergic reactions. Although the fixed combination containing trimethoprim and sulfamethoxazole has been used for treatment of AOM, substantial resistance to the drug has been reported in S. pneumoniae and AAP states that it should not be used as an alternative in patients who do not respond to amoxicillin.

Urinary Tract Infections

Trimethoprim is used for treatment of initial episodes of acute, uncomplicated urinary tract infections caused by susceptible Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter, or coagulase-negative Staphylococcus (including S. saprophyticus).

Although trimethoprim has been used for treatment of acute, uncomplicated cystitis, the value of trimethoprim alone for treatment of acute, uncomplicated urinary tract infections has been questioned because of emergence of an increasing number of trimethoprim-resistant organisms. The fixed combination containing trimethoprim and sulfamethoxazole is used for treatment of urinary tract infections, and has been recommended as a good choice for empiric treatment of acute, uncomplicated cystitis. However, uropathogens with resistance to trimethoprim (with or without sulfamethoxazole) have been reported with increasing frequency.

Prior to initiation of trimethoprim for treatment of acute, uncomplicated urinary tract infections, specimens should be collected for culture and in vitro susceptibility tests; the drug may be initiated before obtaining results. Some clinicians also recommend obtaining follow-up urine cultures after discontinuance of anti-infective therapy to determine whether the bacteria have been eliminated.

Pneumocystis jirovecii Pneumonia

Treatment of Pneumocystis jirovecii Pneumonia

Trimethoprim is used in conjunction with dapsone as an alternative for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP). Animal studies suggest that trimethoprim alone is ineffective for treatment of PCP.

The fixed combination containing trimethoprim and sulfamethoxazole is the drug of choice for treatment of mild, moderate, or severe PCP, including PCP in adults, adolescents, and children with human immunodeficiency virus (HIV) infection.

The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that alternative regimens for treatment of mild to moderate PCP in HIV-infected adults and adolescents when co-trimoxazole cannot be used are dapsone in conjunction with trimethoprim, primaquine in conjunction with clindamycin, or atovaquone alone. These experts state that dapsone in conjunction with trimethoprim may be as effective as co-trimoxazole for treatment of mild to moderate PCP and has fewer adverse effects, but is less convenient because of higher pill burden. Although efficacy and safety data are limited regarding use of dapsone in conjunction with trimethoprim for treatment of PCP in children, some clinicians also recommend the regimen as an alternative for treatment of mild to moderate PCP in children when co-trimoxazole cannot be used. The dapsone and trimethoprim regimen is not included in recommendations for treatment of severe PCP.

Dosage and Administration

Administration

Trimethoprim is administered orally. Trimethoprim also is administered orally or IV as a fixed-combination preparation with sulfamethoxazole.

Dosage

Acute Otitis Media

For treatment of acute otitis media (AOM) in children 6 months of age or older, the manufacturer recommends that the oral solution containing 50 mg of trimethoprim per 5 mL be given in a dosage of 10 mg/kg daily in 2 divided doses every 12 hours for 10 days.

Urinary Tract Infections

For treatment of acute, uncomplicated urinary tract infections, the usual adult dosage of trimethoprim is 100 mg every 12 hours or 200 mg once daily for 10 days.

Pneumocystis jirovecii Pneumonia

When used as an alternative for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) in adults and adolescents 13 years of age or older, including those with human immunodeficiency virus (HIV) infection, trimethoprim is given in a dosage of 5 mg/kg 3 times daily for 21 days in conjunction with oral dapsone (100 mg once daily for 21 days).

Although efficacy and safety data are limited in children, some clinicians state that trimethoprim can be given in a dosage of 5 mg/kg 3 times daily for 21 days in conjunction with oral dapsone (2 mg/kg [up to 100 mg] once daily for 21 days) as an alternative for treatment of mild to moderate PCP in children younger than 13 years of age.

Dosage in Renal Impairment

If trimethoprim is used for treatment of acute, uncomplicated urinary tract infections in adults with creatinine clearances of 15-30 mL/minute, dosage of the drug should be reduced to 50 mg every 12 hours. The drug is not recommended in patients with creatinine clearances less than 15 mL/minute.

For information on dosage of the fixed combination containing trimethoprim and sulfamethoxazole, see Co-trimoxazole 8:12.20.

Cautions

Dermatologic and Sensitivity Reactions

The most frequent adverse effects of trimethoprim are rash and pruritus. Rash generally is maculopapular, morbilliform, and pruritic. Mild to moderate rash appearing 7-14 days after initiation of trimethoprim has occurred in 2.9-6.7% of patients receiving a dosage of 200 mg daily. Rash has been reported to occur in up to 24% of patients receiving a dosage of 400 mg or more for 14 days. Photosensitivity (e.g., erythematous phototoxic eruptions with subsequent hyperpigmentation of sun-exposed skin) also has occurred.

Serious hypersensitivity reactions have been reported rarely in patients receiving trimethoprim. Exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, and Stevens-Johnson syndrome have been reported. Anaphylaxis also has occurred rarely.

GI Effects

Adverse GI reactions reported in patients receiving trimethoprim include epigastric discomfort, nausea, diarrhea, vomiting, glossitis, and abnormal taste sensation.

Hepatic Effects

Elevated serum aminotransferase and bilirubin concentrations have been reported in patients receiving trimethoprim, but the clinical importance is not known. Cholestatic jaundice has been reported rarely.

Hematologic Effects

Hematologic toxicity, resulting from trimethoprim-induced inhibition of dihydrofolate reductase, has resulted rarely in thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia. Mild, reversible hematologic toxicity, including thrombocytopenia, megaloblastic anemia, and leukopenia has occurred with a trimethoprim dosage of 1 g daily for 1 month.

Hematologic toxicity may occur with increased frequency in folate-depleted patients including geriatric, malnourished, alcoholic, pregnant, or debilitated patients; in patients receiving folate antimetabolites (e.g., phenytoin); in patients with hemolysis or impaired renal function; and in patients receiving high doses of trimethoprim for prolonged periods (e.g., longer than 6 months). Hematologic abnormalities usually resolve following administration of leucovorin (folinic acid).

Other Adverse Effects

Other adverse effects of trimethoprim occurring rarely include fever, aseptic meningitis, elevated BUN and serum creatinine concentrations, hyperkalemia, and hyponatremia.

Precautions and Contraindications

Trimethoprim is contraindicated in patients with known hypersensitivity to the drug or with documented megaloblastic anemia secondary to folate deficiency.

Trimethoprim should be used with caution in patients with impaired renal or hepatic function. The drug is not recommended in patients with creatinine clearances less than 15 mL/minute.

Trimethoprim should be used with caution in patients with possible folate deficiency. Folates, such as leucovorin, may be administered during trimethoprim therapy and will not interfere with the drug's antibacterial effect.

If signs of bone marrow depression occur, trimethoprim should be discontinued and leucovorin administered as required to restore normal hematopoiesis.

Clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders. A complete blood count (CBC) should be obtained if these signs and symptoms occur in a patient receiving trimethoprim, and the drug should be discontinued if any clinically important reduction in formed blood elements is noted.

Pediatric Precautions

Safety and efficacy of trimethoprim oral solution or tablets have not been established in infants younger than 2 months of age.

Safety and efficacy of trimethoprim oral solution have not been established for treatment of acute otitis media (AOM) in infants younger than 6 months of age.

Efficacy of trimethoprim tablets when used as a single agent have not been established for treatment of acute, uncomplicated urinary tract infections in children younger than 12 years of age.

It has been suggested that trimethoprim should be used with caution in children who have the fragile X chromosome associated with mental retardation, because folate depletion may worsen the psychomotor regression associated with the disorder.

Geriatric Precautions

Clinical studies of trimethoprim did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. While other clinical experience has not revealed age-related differences in response, dosage of the drug for geriatric patients generally should be selected carefully, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Hyperkalemia has been reported in geriatric patients receiving the fixed combination of trimethoprim and sulfamethoxazole (co-trimoxazole).

Trimethoprim is substantially eliminated by the kidneys, and the risk of adverse effects is increased in patients with renal impairment. Because geriatric patients are more likely to have decreased renal function, consideration should be given to monitoring potassium concentrations and renal function in this age group.

Mutagenicity and Carcinogenicity

Trimethoprim did not exhibit mutagenic activity in the Ames test, and no chromosomal damage was observed in human leukocytes cultured in vitro with trimethoprim concentrations exceeding those attained in blood during therapy with the drug. Long-term animal studies to determine carcinogenic potential of the drug have not been performed to date.

Pregnancy, Fertility, and Lactation

Pregnancy

Trimethoprim has been shown to be teratogenic in rats when given in doses 40 times the usual human dose; in rabbits, an overall increase in fetal loss was associated with trimethoprim doses 6 times the usual human dose. Although there are no adequate and controlled studies to date using trimethoprim in humans, a retrospective study that reported the outcome of 186 pregnancies suggested that the incidence of congenital abnormalities in those who received the fixed combination containing trimethoprim and sulfamethoxazole (co-trimoxazole) was similar to that in those who received a placebo.Because trimethoprim may interfere with folic acid metabolism, the drug should be used during pregnancy only when potential benefits justify possible risks to the fetus.

Fertility

Reproduction studies in rats using oral trimethoprim dosages up to 70 mg/kg daily in males and 14 mg/kg daily in females have not revealed evidence of impaired fertility.

Lactation

Trimethoprim is distributed into milk. Because trimethoprim may interfere with folic acid metabolism, the drug should be used with caution in nursing women.

Drug Interactions

Dapsone

Concomitant use of dapsone and trimethoprim may increase serum dapsone concentrations and potentially increase the risk of adverse effects associated with dapsone. In a study in adults with acquired immunodeficiency syndrome (AIDS) who received oral dapsone (100 mg once daily) alone or in conjunction with oral trimethoprim (20 mg/kg daily) for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP), plasma dapsone concentrations were 40% higher with the combined regimen than with dapsone alone and methemoglobinemia occurred more frequently with the combined regimen (67%) than with dapsone alone (11%). There also is some evidence that dapsone may increase plasma trimethoprim concentrations, but an increased risk of trimethoprim-associated adverse effects was not identified in this study.

Periodic monitoring for potential toxicity (e.g., methemoglobinemia) is recommended in patients receiving dapsone in conjunction with trimethoprim.

Phenytoin

Trimethoprim appears to inhibit hepatic metabolism of phenytoin. When the drugs are administered concomitantly, the metabolic clearance of phenytoin is substantially decreased and its elimination half-life is substantially increased. If trimethoprim is administered concomitantly with phenytoin, the patient should be observed closely for signs of phenytoin toxicity and dosage of phenytoin reduced if necessary.

Pharmacokinetics

Absorption

Trimethoprim is readily and almost completely absorbed from the GI tract. Peak serum concentrations of approximately 1, 1.6, and 2 mcg/mL are reached in 1-4 hours after single 100-, 160-, and 200-mg oral doses of trimethoprim. Following multiple-dose oral administration, steady-state peak serum concentrations of trimethoprim usually are 50% greater than those obtained after single-dose administration of the drug. Steady-state trough serum concentrations range from 1.2-3.2 mcg/mL following oral administration of 160 mg of trimethoprim every 12 hours in adults with normal renal function.

Distribution

Trimethoprim is widely distributed into body tissues and fluids including the aqueous humor, middle ear fluid, saliva, lung tissue, sputum, seminal fluid, prostatic tissue and fluid, vaginal secretions, bile, bone, and CSF. The apparent volume of distribution of trimethoprim in adults with normal renal function ranges from 100-120 L. In patients with uninflamed meninges, trimethoprim concentrations in CSF are approximately 20-44 and 13-34% of concurrent trimethoprim serum concentrations following IV and oral administration of the drug, respectively. If the meninges are inflamed, a somewhat higher concentration of the antibiotic is found in CSF. Trimethoprim concentrations in middle ear fluid, prostatic fluid, and vaginal secretions are approximately 75, 200, and 160%, respectively, of concurrent trimethoprim serum concentrations.

Trimethoprim is 42-46% bound to plasma proteins.

Trimethoprim readily crosses the placenta, and amniotic fluid concentrations are reported to be 80% of concurrent maternal serum concentrations.

Trimethoprim is distributed into milk in concentrations approximately 125% those of concurrent maternal serum concentrations.

Elimination

Trimethoprim has a serum half-life of approximately 8-11 hours in adults with normal renal function. In adults with creatinine clearances of 10-30 or 0-10 mL/minute, serum half-life of the drug may increase to 15 hours or greater than 26 hours, respectively. Trimethoprim serum half-lives of about 7.7 and 5.5 hours have been reported in children less than 1 year of age and between 1 and 10 years of age, respectively.

Trimethoprim is metabolized in the liver to oxide and hydroxylated metabolites. The drug is rapidly excreted in urine via glomerular filtration and tubular secretion. In adults with normal renal function, approximately 50-60 and 56-70% of an oral dose of trimethoprim is excreted in urine within 24 and 72 hours, respectively. Approximately 80% of the amount recovered in urine is unchanged drug. In adults with normal renal function, urinary concentrations of trimethoprim range from 30-160 and 18-91 mcg/mL at 0-4 and 8-24 hours, respectively, after administration of a single 100-mg dose of the drug. Urinary concentrations of the drug are decreased in patients with impaired renal function.

Only small amounts of trimethoprim are excreted in feces via biliary elimination. Trimethoprim is only moderately removed by hemodialysis, and is not removed by peritoneal dialysis.

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