Sulfamethoxazole/Trimethoprim (Sulfatrim)

1. Health Canada Product Monograph — Sulfamethoxazole/Trimethoprim

• Sulfamethoxazole/trimethoprim treats acute uncomplicated urinary tract infections caused by susceptible bacteria.
• It treats acute exacerbations of chronic bronchitis due to susceptible organisms.
• It treats and prevents Pneumocystis jirovecii pneumonia, particularly in immunosuppressed patients.
• It treats traveler's diarrhea and bacillary dysentery caused by susceptible Shigella strains.
• It is used as an adjunct to fluid and electrolyte replacement in cholera caused by susceptible Vibrio cholerae.
• It treats uncomplicated gonorrhea and nocardiosis caused by susceptible organisms.
• It serves as second-line therapy for brucellosis when combined with gentamicin or rifampicin.
• It is not effective against infections caused by Pseudomonas, Mycoplasma, or viruses, and should not be used for group A streptococcal pharyngitis.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Sulfamethoxazole/trimethoprim is contraindicated in pregnancy because both components cross the placenta, and trimethoprim, a folate antagonist, has been linked to fetal abnormalities including cleft palate in animal studies.
• Use near the time of delivery can worsen newborn jaundice and raise the risk of kernicterus, since sulfamethoxazole competes with bilirubin for protein binding.
• If use in pregnancy cannot be avoided, folate supplementation should be considered.

• Sulfamethoxazole/trimethoprim passes into breast milk and should be avoided while breastfeeding, particularly if the mother or infant has, or is at risk of, high bilirubin levels.
• It should not be given to infants younger than eight weeks of age because of their increased susceptibility to jaundice.

• Older adults face a higher risk of severe adverse reactions, including severe skin reactions and bone marrow suppression, especially when other health conditions are present.
• Older adults taking thiazide diuretics alongside sulfamethoxazole/trimethoprim have a higher reported rate of low platelet counts.
• Dose adjustment is required for reduced kidney function, which is more common in older adults.
• Folate supplementation should be considered in older adults who may have borderline folate stores.

• Sulfamethoxazole/trimethoprim is not recommended for infants younger than two months of age because safety and effectiveness have not been established.
• Safety and effectiveness have been established for children from two months to twelve years of age using weight-based dosing.
• Adolescents aged 12 to 17 years should receive the standard adult dose.

• For most bacterial infections in adults and children over 12, the usual dose is 2 regular-strength tablets (or 1 double-strength tablet) twice daily for at least 5 days or until symptom-free for 48 hours; children 12 and under are dosed at 15 mg/kg sulfamethoxazole and 3 mg/kg trimethoprim twice daily.
• For severe bacterial infections, the dose increases to 3 regular-strength tablets (or 1.5 double-strength tablets) twice daily, continued until urine is sterile for urinary infections.
• For Pneumocystis jirovecii pneumonia, the dose is 25 mg/kg sulfamethoxazole and 5 mg/kg trimethoprim four times daily for at least 14 days.
• For uncomplicated gonorrhea, the dose is 2 regular-strength tablets (or 1 double-strength tablet) four times daily for two days.
• For salmonella prophylaxis or carrier states, the dose is 1 regular-strength tablet (or half a double-strength tablet) twice daily, continued until stool cultures are negative.
• In patients with reduced kidney function, the dose is halved when creatinine clearance is 15-25 mL/min, and the drug is not recommended when creatinine clearance falls below 15 mL/min.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Overdose can cause loss of appetite, nausea, vomiting, dizziness, headache, drowsiness, and confusion.
• Severe overdose may progress to bone marrow suppression, blood cell abnormalities, and jaundice, which can appear as delayed effects.
• Crystals may appear in the urine (crystalluria), along with blood in the urine and fever.
• There is no specific antidote for the sulfonamide component, but calcium folinate (leucovorin) is an effective antidote for trimethoprim's effects on the bone marrow.
• Treatment involves generous oral or intravenous fluids, urine acidification to speed trimethoprim elimination, and monitoring of blood counts and electrolytes; hemodialysis removes only a moderate amount of the drug.

• Loss of appetite may occur.
• Headache may occur.
• Nausea, vomiting, or diarrhea may occur.
• Weakness, fatigue, or trouble sleeping may occur.
• Skin rash or hives may occur.
• Sensitivity to sunlight may occur.
• Yeast overgrowth (thrush) may occur.
• Dizziness or vertigo may occur.
• Ringing in the ears may occur.
• Tooth or tongue discoloration may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Sulfamethoxazole/trimethoprim can cause life-threatening skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, presenting as blistering, peeling skin, and mouth or eye sores.
• It can cause DRESS syndrome, a severe reaction involving fever, rash, and abnormal liver or blood tests.
• It can cause fulminant liver necrosis, presenting as jaundice, right upper abdominal pain, and vomiting.
• It can cause agranulocytosis and aplastic anemia, presenting as fever, chills, sore throat, or unusual bruising.
• It can cause life-threatening immune thrombocytopenia, presenting as easy bruising, pinpoint red spots on the skin, or bleeding gums.
• It can cause a severe allergic lung and airway reaction, presenting as difficulty breathing, cough, and chest tightness.
• Aseptic meningitis, presenting as sudden headache, neck stiffness, fever, and light sensitivity, has been reported and can recur with re-exposure.
• Severe hypersensitivity reactions, including circulatory shock with fever and confusion, can occur within minutes to hours of re-exposure in previously sensitized patients.
• Seizures have been reported.
• Seek urgent medical attention for any rash with blistering or peeling, yellowing of the skin or eyes, unexplained bruising or bleeding, severe difficulty breathing, or signs of severe allergic reaction.

• Use with caution in patients with impaired kidney or liver function, adjusting the dose as needed.
• Use with caution in patients at risk of folate deficiency, including older adults, chronic alcohol users, and those with malabsorption, since folate supplementation may be needed.
• Use with caution in patients with severe allergies or bronchial asthma.
• Use with caution in patients at risk of hyperkalemia or hyponatremia, particularly those on high doses, with monitoring of electrolytes and kidney function.
• Use with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, due to the risk of hemolysis.
• Use with caution in patients with or at risk of acute porphyria, since exacerbations have been reported.
• Use with caution in HIV-positive patients being treated for Pneumocystis jirovecii pneumonia, who experience a higher rate of side effects including rash, fever, and blood count changes.
• Use with caution and maintain adequate fluid intake to reduce the risk of crystals forming in the urine.

• Contraindicated in patients with known hypersensitivity to sulfamethoxazole, trimethoprim, or any ingredient in the formulation.
• Contraindicated in patients with a history of drug-induced immune thrombocytopenia related to trimethoprim or sulfonamides.
• Contraindicated in patients with documented megaloblastic anemia caused by folate deficiency.
• Contraindicated in patients with marked kidney impairment where drug levels cannot be regularly monitored.
• Contraindicated in pregnant patients and nursing mothers.
• Contraindicated in premature infants and full-term infants younger than two months of age.
• Contraindicated in patients with acute porphyria.
• Contraindicated in combination with dofetilide, due to the risk of dangerous heart rhythm disturbances.

• Combining with dofetilide is contraindicated because trimethoprim raises dofetilide blood levels, increasing the risk of dangerous heart rhythm disturbances.
• Warfarin's blood-thinning effect may be enhanced, requiring closer monitoring of clotting time.
• Phenytoin levels may rise because sulfamethoxazole/trimethoprim slows its breakdown in the liver.
• Methotrexate's free blood levels may increase because sulfonamides displace it from protein binding sites, raising toxicity risk.
• Digoxin blood levels may rise in elderly patients taking trimethoprim concurrently.
• Cyclosporine combined with sulfamethoxazole/trimethoprim after kidney transplant has been linked to reversible declines in kidney function.
• Drugs that raise potassium levels, such as ACE inhibitors, angiotensin receptor blockers, and potassium-sparing diuretics like spironolactone, increase the risk of dangerously high potassium when combined with sulfamethoxazole/trimethoprim.
• Thiazide diuretics combined with sulfamethoxazole/trimethoprim in older adults raise the risk of low platelet counts.
• Pyrimethamine doses above 25 mg weekly combined with sulfamethoxazole/trimethoprim may cause megaloblastic anemia.
• Zidovudine combined with sulfamethoxazole/trimethoprim may increase the risk of blood cell abnormalities, warranting monitoring.
• Lamivudine blood levels rise by about 40% when combined with sulfamethoxazole/trimethoprim due to the trimethoprim component.
• Rifampicin shortens the half-life of trimethoprim, though this is not considered clinically significant.
• Repaglinide exposure may increase, raising the risk of low blood sugar.
• Folinic acid supplementation can interfere with the antimicrobial effectiveness of sulfamethoxazole/trimethoprim, particularly during PJP treatment.
• Azathioprine combined with sulfamethoxazole/trimethoprim has been linked to serious blood abnormalities in some reports.

• Sulfamethoxazole/trimethoprim can be taken with or without food; taking it with food may help reduce stomach upset.
• Plenty of fluids should be taken throughout treatment to reduce the risk of crystals forming in the urine.

• Doses are typically spaced 12 hours apart (or spread through the day for four-times-daily regimens) and can be taken with or without regard to meals.

• Store sulfamethoxazole/trimethoprim tablets at room temperature between 15°C and 30°C, protected from light.

• Sulfamethoxazole/trimethoprim is an antibiotic combination used to treat a range of bacterial infections and to prevent or treat Pneumocystis pneumonia.
• Complete the full course as prescribed, even if symptoms improve early, to reduce the risk of resistant bacteria.
• Report any rash, especially with blistering, peeling, or mouth sores, right away, as this can signal a serious reaction.
• Drink plenty of fluids while taking this medication.
• Tell your healthcare provider about all other medications, since sulfamethoxazole/trimethoprim interacts with several common drugs including warfarin, phenytoin, and methotrexate.