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Trimethoprim

Pronunciation

Pronunciation

(trye METH oh prim)

Index Terms

  • TMP

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral [strength expressed as base]:

Primsol: 50 mg/5 mL (473 mL) [alcohol free, dye free; contains methylparaben, propylene glycol, propylparaben, saccharin sodium, sodium benzoate]

Tablet, Oral:

Generic: 100 mg

Brand Names: U.S.

  • Primsol

Pharmacologic Category

  • Antibiotic, Miscellaneous

Pharmacology

Inhibits folic acid reduction to tetrahydrofolate by reversible inhibition of dihydrofolate reductase, inhibiting bacterial synthesis of nucleic acids and proteins

Absorption

Oral: Readily and extensively absorbed

Distribution

Widely into body tissues and fluids (middle ear, prostate, bile, aqueous humor, CSF); mean peak middle ear fluid concentration in children 1 to 12 years of 2 mcg/mL after a single 4 mg/kg dose; Vd:

Newborns: 2.7 L/kg (range: 1.3 to 4.1 hours) (Springer 1982)

Infants: 1.5 L/kg (Hoppu 1989)

Children (Hoppu 1987):

1 to 3 years: 0.86 L/kg

8 to 10 years: 1 L/kg

Adults: ~1.3 L/kg (Hoppu 1987)

Metabolism

Partially hepatic (10% to 20%) via demethylation, oxidation, and hydroxylation

Excretion

Urine (50% to 60%; 80% as unchanged drug); feces

Time to Peak

Serum: 1 to 4 hours

Half-Life Elimination

Prolonged with renal impairment

Newborns: 19 hours; range: 11 to 27 hours (Springer 1982)

Infants 2 months to 1 year: 4.6 hours; range: 3 to 6 hours (Hoppu 1989)

Children (Hoppu 1987): 1 to 3 years: 3.7 hours; 8 to 10 years: 5.4 hours

Adults, normal renal function: 8 to 10 hours

Protein Binding

~44%

Special Populations: Renal Function Impairment

Half-life is prolonged.

Use: Labeled Indications

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.

Use: Unlabeled

Alternative agent for Pneumocystis jirovecii pneumonia (in combination with dapsone)

Contraindications

Hypersensitivity to trimethoprim or any component of the formulation; megaloblastic anemia due to folate deficiency

Dosing: Adult

Urinary tract infection (uncomplicated), treatment: Oral: 100 mg every 12 hours or 200 mg every 24 hours for 10 days; alternative duration of 3 days has been recommended (Gupta 2011)

Pneumocystis pneumonia (PCP), treatment (off-label use): Oral: 15 mg/kg/day in 3 divided doses in combination with dapsone for 21 days (HHS [adult] 2015)

Urinary tract infection (uncomplicated), prophylaxis (off-label use): Oral: 100 mg once daily (Brumfitt 1983; Kasanen 1974; Stamm 1980)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Otitis media, acute: Infants ≥6 months, Children, and Adolescents: Oral: 10 mg/kg/day in divided doses every 12 hours for 10 days

Urinary tract infection (uncomplicated), treatment (off-label population): Infants ≥2 months, Children, and Adolescents: Oral: 4 to 6 mg/kg/day in divided doses every 12 hours (Schleiss 2016); Note: Preferred therapy is sulfamethoxazole and trimethoprim combined product (AAP 2011).

Pneumocystis pneumonia (PCP), treatment (off-label use): Children and Adolescents: Oral: 15 mg/kg/day in 3 divided doses for 21 days; in combination with dapsone; data in children is limited (HHS [adult] 2015; HHS [pediatric] 2014])

Dosing: Renal Impairment

Manufacturer’s labeling:

CrCl >30 mL/minute: No dosage adjustments necessary; use with caution.

CrCl 15 to 30 mL/minute: Administer 50% of recommended dose.

CrCl <15 mL/minute: Use is not recommended.

Alternate recommendations (Aronoff 2007):

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl 10 to 30 mL/minute: 100 mg every 18 hours.

CrCl <10 mL/minute: 100 mg every 24 hours.

Intermittent Hemodialysis: Moderately dialyzable (20% to 59%). Dose after dialysis

Peritoneal dialysis: 100 mg every 24 hours

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Extemporaneously Prepared

Note: Commercial oral solution is available (10 mg/mL [dye free, ethanol free; contains propylene glycol, sodium benzoate; bubblegum flavor])

A 10 mg/mL oral suspension may be made with tablets. Crush ten 100 mg tablets in a mortar and reduce to a fine powder. Add 20 mL of a 1:1 mixture of Simple Syrup, NF, and Methylcellulose 1% and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 100 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Label "shake well" and "refrigerate". Stable for 91 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer without regard to food; may administer with milk or food if GI upset occurs.

Dietary Considerations

May cause folic acid deficiency, supplements may be needed.

Storage

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.

Drug Interactions

ACE Inhibitors: Trimethoprim may enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Amantadine: Trimethoprim may enhance the adverse/toxic effect of Amantadine. Specifically, the risk of myoclonus and/or delirium may be increased. Amantadine may increase the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Amantadine. Monitor therapy

Amodiaquine: Trimethoprim may enhance the neutropenic effect of Amodiaquine. Trimethoprim may increase the serum concentration of Amodiaquine. Avoid combination

Angiotensin II Receptor Blockers: Trimethoprim may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Antidiabetic Agents (Thiazolidinedione): Trimethoprim may decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Monitor therapy

AzaTHIOprine: Trimethoprim may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapsone (Systemic): Trimethoprim may increase the serum concentration of Dapsone (Systemic). Dapsone (Systemic) may increase the serum concentration of Trimethoprim. Monitor therapy

Dapsone (Topical): Trimethoprim may enhance the adverse/toxic effect of Dapsone (Topical). More specifically, trimethoprim may increase the risk for hemolysis Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Digoxin: Trimethoprim may increase the serum concentration of Digoxin. Monitor therapy

Dofetilide: Trimethoprim may decrease the excretion of Dofetilide. Avoid combination

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: Trimethoprim may enhance the hyperkalemic effect of Eplerenone. Monitor therapy

Fosphenytoin: May decrease the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Fosphenytoin. Management: Consider alternatives to this combination when possible, to avoid potential decreased trimethoprim efficacy and increased phenytoin concentrations/effects. Monitor patients receiving this combination closely for both of these possible effects. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

LamiVUDine: Trimethoprim may decrease the excretion of LamiVUDine. Monitor therapy

Leucovorin Calcium-Levoleucovorin: May diminish the therapeutic effect of Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with trimethoprim (plus sulfamethoxazole) for Pneumocystis jiroveci pneumonia. If trimethoprim is used for another indication, monitor closely for reduced efficacy. Avoid combination

Memantine: Trimethoprim may enhance the adverse/toxic effect of Memantine. Specifically, the risk of myoclonus and/or delirium may be increased. Trimethoprim may increase the serum concentration of Memantine. Memantine may increase the serum concentration of Trimethoprim. Monitor therapy

Mercaptopurine: Trimethoprim may enhance the myelosuppressive effect of Mercaptopurine. Monitor therapy

MetFORMIN: Trimethoprim may increase the serum concentration of MetFORMIN. Monitor therapy

Methotrexate: Trimethoprim may enhance the adverse/toxic effect of Methotrexate. Management: Consider avoiding concomitant use of methotrexate and either sulfamethoxazole or trimethoprim. If used concomitantly, monitor for the development of signs and symptoms of methotrexate toxicity (e.g., bone marrow suppression). Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Phenytoin: Trimethoprim may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Trimethoprim. Management: Consider alternatives to this combination when possible, to avoid potential decreased trimethoprim efficacy and increased phenytoin concentrations/effects. Monitor patients receiving this combination closely for both of these possible effects. Consider therapy modification

PRALAtrexate: Trimethoprim may increase the serum concentration of PRALAtrexate. More specifically, trimethoprim may decrease excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum level and/or possible toxicity with concomitant use of trimethoprim. Monitor for decreased pralatrexate levels with discontinuation of trimethoprim. Monitor therapy

Procainamide: Trimethoprim may increase serum concentrations of the active metabolite(s) of Procainamide. Trimethoprim may increase the serum concentration of Procainamide. Consider therapy modification

Repaglinide: Trimethoprim may decrease the metabolism of Repaglinide. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Spironolactone: Trimethoprim may enhance the hyperkalemic effect of Spironolactone. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Varenicline: Trimethoprim may increase the serum concentration of Varenicline. Management: Monitor for increased varenicline adverse effects with concomitant use of trimethoprim, particularly in patients with severe renal impairment. International product labeling recommendations vary. Consult appropriate labeling. Monitor therapy

Test Interactions

May falsely increase (~10%) creatinine determination measured by the Jaffé alkaline picrate assay; may interfere with determination of serum methotrexate when measured by methods that use a bacterial dihydrofolate reductase as the binding protein (eg, the competitive binding protein technique); does not interfere with RIA for methotrexate

Adverse Reactions

Frequency not defined.

Central nervous system: Aseptic meningitis (rare), fever

Dermatologic: Maculopapular rash (3% to 7% at 200 mg/day; incidence higher with larger daily doses), erythema multiforme (rare), exfoliative dermatitis (rare), pruritus (common), phototoxic skin eruptions, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare)

Endocrine & metabolic: Hyperkalemia, hyponatremia

Gastrointestinal: Epigastric distress, glossitis, nausea, vomiting

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

Hepatic: Cholestatic jaundice (rare), liver enzymes increased

Renal: BUN and creatinine increased

Miscellaneous: Anaphylaxis, hypersensitivity reactions

Warnings/Precautions

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.

Monitoring Parameters

CBC with differential, platelet count, liver enzyme tests, bilirubin, serum potassium, serum creatinine, and BUN periodically during long-term therapy

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Trimethoprim crosses the placenta and can be detected in the fetal serum and amniotic fluid (Reid 1975). Adverse events may be associated with trimethoprim use during pregnancy (Andersen 2012; Andersen 2013; Mølgaard-Nielsen 2012). Untreated urinary tract infections may cause adverse pregnancy outcomes (Nicolle 2005); because safer options are available for the treatment of UTIs in pregnant women, use of TMP containing products in the first trimester should be avoided (Lee 2008). Studies evaluating the effects of trimethoprim administration in pregnancy have also been conducted with Sulfamethoxazole and Trimethoprim (see the Sulfamethoxazole and Trimethoprim monograph for details).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, nausea, or vomiting. Have patient report immediately to prescriber signs of methemoglobinemia (blue or gray color of the lips, nails, or skin; abnormal heartbeat; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), chills, pharyngitis, pale skin, bruising, bleeding, purple patches on skin or mouth, or signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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