COTRIM

Clinical safety rating: caution

Comprehensive clinical and safety monograph for COTRIM (COTRIM).

How it works

COTRIM is a combination of trimethoprim and sulfamethoxazole; sulfamethoxazole inhibits dihydropteroate synthase, and trimethoprim inhibits dihydrofolate reductase, sequentially blocking bacterial folate synthesis.

What the body does with it

Metabolism	Trimethoprim is primarily metabolized by the liver via CYP450 enzymes (CYP3A4, CYP1A2) and excreted in urine; sulfamethoxazole undergoes N-acetylation and glucuronidation, also excreted renally.
Excretion	Renal: 50-70% unchanged sulfamethoxazole, 15-30% N4-acetylated metabolite; trimethoprim: 50-60% unchanged, 10-20% metabolites. Biliary/fecal: minimal.
Half-life	Sulfamethoxazole: 9-11 hours (normal renal function); trimethoprim: 8-10 hours. Extended in renal impairment (SMX up to 30h, TMP up to 24h).
Protein binding	Sulfamethoxazole: 70% bound to albumin; trimethoprim: 44% bound to alpha-1 acid glycoprotein and albumin.
Volume of Distribution	Sulfamethoxazole: 0.2-0.3 L/kg; trimethoprim: 1.3-2.0 L/kg. TMP distributes extensively into tissues, including CNS (50% of serum concentration).
Bioavailability	Oral: 85-100% for both components; IV: 100%.
Onset of Action	Oral: 1-4 hours; IV: 30-60 minutes.
Duration of Action	12-24 hours; clinical effect persists for duration of therapy. Half-life determines dosing interval (usually q12h).

Classification & Brands

Dosing & administration

1 double-strength tablet (160 mg trimethoprim + 800 mg sulfamethoxazole) orally every 12 hours for 5-14 days; 15-20 mg/kg/day (based on trimethoprim) IV divided every 6-8 hours for severe infections.

Dosage form	TABLET
Renal impairment	CrCl >30 mL/min: no adjustment; CrCl 15-30 mL/min: reduce dose by 50%; CrCl <15 mL/min: contraindicated unless for prophylaxis against Pneumocystis jirovecii, in which case use 50% dose.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: use with caution, monitor liver function; Child-Pugh C: contraindicated due to risk of hepatotoxicity.
Pediatric use	Pneumocystis jirovecii pneumonia: 15-20 mg/kg/day (based on trimethoprim) IV divided every 6-8 hours for 21 days; mild infections: 8-12 mg/kg/day oral divided every 12 hours; maximum: 640 mg/day trimethoprim.
Geriatric use	Assess renal function; CrCl >30 mL/min: standard adult dosing; reduce dose or extend interval if CrCl 15-30 mL/min; avoid if CrCl <15 mL/min; monitor for electrolyte abnormalities and hypersensitivity.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for COTRIM (COTRIM).

Breastfeeding	Small amounts excreted in breast milk; M/P ratio unknown. May cause kernicterus in jaundiced infants or hemolysis in G6PD deficiency. Consider risks vs benefits; alternative agents preferred.
Teratogenic Risk	Pregnancy category C/D. First trimester: Folate antagonist; neural tube defects, cardiovascular malformations, cleft palate reported. Second/third trimester: Kernicterus risk in neonate due to bilirubin displacement; hemolytic anemia in G6PD deficiency. Avoid near term.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Fatal hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS); agranulocytosis, aplastic anemia, and other blood dyscrasias; use in patients with G6PD deficiency may cause hemolytic anemia.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to sulfonamides or trimethoprim; severe hepatic injury; marked renal impairment (CrCl <15 mL/min) unless dialysis; megaloblastic anemia due to folate deficiency; pregnancy (especially first trimester) and lactation; infants <2 months of age; concurrent use with dofetilide (risk of QT prolongation).

Clinical Precautions

Precautions

Monitor for hypersensitivity reactions; avoid use in elderly with renal impairment due to risk of sulfonamide-induced blood dyscrasias; monitor renal function and electrolytes (hyperkalemia with high doses); caution in folate deficiency; use with other drugs prolonging QT interval; monitor for neutropenia with prolonged therapy.

Clinical Tips & Counseling

Drug interactions

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COTRIM

Clinical safety rating: caution

Comprehensive clinical and safety monograph for COTRIM (COTRIM).

How it works

What the body does with it

Metabolism	Trimethoprim is primarily metabolized by the liver via CYP450 enzymes (CYP3A4, CYP1A2) and excreted in urine; sulfamethoxazole undergoes N-acetylation and glucuronidation, also excreted renally.
Excretion	Renal: 50-70% unchanged sulfamethoxazole, 15-30% N4-acetylated metabolite; trimethoprim: 50-60% unchanged, 10-20% metabolites. Biliary/fecal: minimal.
Half-life	Sulfamethoxazole: 9-11 hours (normal renal function); trimethoprim: 8-10 hours. Extended in renal impairment (SMX up to 30h, TMP up to 24h).
Protein binding	Sulfamethoxazole: 70% bound to albumin; trimethoprim: 44% bound to alpha-1 acid glycoprotein and albumin.
Volume of Distribution	Sulfamethoxazole: 0.2-0.3 L/kg; trimethoprim: 1.3-2.0 L/kg. TMP distributes extensively into tissues, including CNS (50% of serum concentration).
Bioavailability	Oral: 85-100% for both components; IV: 100%.
Onset of Action	Oral: 1-4 hours; IV: 30-60 minutes.
Duration of Action	12-24 hours; clinical effect persists for duration of therapy. Half-life determines dosing interval (usually q12h).

Classification & Brands

Dosing & administration

1 double-strength tablet (160 mg trimethoprim + 800 mg sulfamethoxazole) orally every 12 hours for 5-14 days; 15-20 mg/kg/day (based on trimethoprim) IV divided every 6-8 hours for severe infections.

Dosage form	TABLET
Renal impairment	CrCl >30 mL/min: no adjustment; CrCl 15-30 mL/min: reduce dose by 50%; CrCl <15 mL/min: contraindicated unless for prophylaxis against Pneumocystis jirovecii, in which case use 50% dose.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: use with caution, monitor liver function; Child-Pugh C: contraindicated due to risk of hepatotoxicity.
Pediatric use	Pneumocystis jirovecii pneumonia: 15-20 mg/kg/day (based on trimethoprim) IV divided every 6-8 hours for 21 days; mild infections: 8-12 mg/kg/day oral divided every 12 hours; maximum: 640 mg/day trimethoprim.
Geriatric use	Assess renal function; CrCl >30 mL/min: standard adult dosing; reduce dose or extend interval if CrCl 15-30 mL/min; avoid if CrCl <15 mL/min; monitor for electrolyte abnormalities and hypersensitivity.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for COTRIM (COTRIM).

Breastfeeding	Small amounts excreted in breast milk; M/P ratio unknown. May cause kernicterus in jaundiced infants or hemolysis in G6PD deficiency. Consider risks vs benefits; alternative agents preferred.
Teratogenic Risk	Pregnancy category C/D. First trimester: Folate antagonist; neural tube defects, cardiovascular malformations, cleft palate reported. Second/third trimester: Kernicterus risk in neonate due to bilirubin displacement; hemolytic anemia in G6PD deficiency. Avoid near term.
Fetal Monitoring