Side Effects of Primsol (trimethoprim)

Primsol (trimethoprim) is an antibiotic used to treat uncomplicated urinary tract infections (UTIs) due to susceptible bacteria such as

• Escherichia coli,
• Proteus mirabilis,
• Klebsiella pneumoniae,
• Enterobacter species, and
• coagulase-negative Staphylococcus species, including S. saprophyticus.

Primsol interferes with the production of tetrahydrofolic acid, a chemical necessary for bacteria and human cells to produce proteins.

Primsol inhibits production of tetrahydrofolic acid by inhibiting the enzyme responsible for making tetrahydrofolic acid from dihydrofolic acid.

Primsol inhibits the bacterial enzyme more than the human enzyme.

Therefore, Primsol has less effect on the production of tetrahydrofolic acid by humans. Because of the frequent development of resistance to Primsol, it is more effective when combined with another antibiotic, sulfamethoxazole (Azo-Gantanol), and is rarely used alone.

Common side effects of Primsol include

• loss of appetite,
• nausea,
• vomiting,
• diarrhea,
• abdominal pain,
• abnormal taste,
• swelling of the tongue,
• skin rash (rarely, may progress to peeling or blistering),
• itching, and
• sensitivity to sunlight. 

Serious side effects of Primsol include

• serious allergic reactions,
• exfoliative dermatitis,
• Stevens-Johnson syndrome,
• phototoxicity,
• cholestatic jaundice,
• C. difficile diarrhea,
• anemia due to a deficiency of folic acid,
• low platelet counts,
• low white blood cell counts, and
• other toxic effects on the blood cells.

Drug interactions of Primsol include amantadine, which can result in changes in a patient's mental status.

• Blood levels of phenytoin may be increased by treatment with Primsol which may lead to side effects of phenytoin such as dizziness, and reduced attention.
• Primsol also may increase blood levels of digoxin and warfarin and lead to serious toxic effects.
• Anemia, due to a reduction in folic acid, can occur in persons receiving trimethoprim in combination with divalproex, valproic acid, methotrexate, pyrimethamine, triamterene, or trimetrexate.
• The combination of Primsol and cyclosporine can increase the risk of kidney damage from cyclosporine.
• When Primsol and dapsone are used together, increased blood concentrations of both drugs can occur, sometimes with side effects that include a toxic condition of the blood called methemoglobinemia.
• Rifampin can increase the elimination of Primsol by the kidneys and may reduce the effectiveness of Primsol.

Although there are no human studies that have examined the effects of Primsol on the fetus, animal studies have shown adverse effects. The potential risks to the fetus must be weighed against the potential benefits to the mother when considering Primsol therapy for pregnant women.

Primsol is secreted into breast milk in high concentrations. Use of Primsol by mothers who are breastfeeding should be avoided.

The most common side effects associated with Primsol involve the gastrointestinal (GI) tract, such as:

• Loss of appetite
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Abnormal taste
• Swelling of the tongue

Other important side effects are:

• Skin rash
• Itching

Rarely, the skin rash can progress to peeling or blistering. Some patients have photosensitivity reactions, that is, they develop skin rashes on parts of their body that are exposed to the sun.

Serious side effects include:

• Serious allergic reactions
• Exfoliative dermatitis
• Stevens-Johnson syndrome
• Phototoxicity
• Cholestatic jaundice
• C. Difficile diarrhea

Primsol may cause anemia due to a deficiency of folic acid. The anemia usually is mild and resolves when the Primsol is stopped.

Patients who are folate-deficient, such as malnourished, alcoholic, geriatric, or pregnant females, may be at greater risk for developing anemia with Primsol. Warning signs of anemia include white or bluish fingernails and unusual tiredness and weakness.

Prolonged therapy can result in low platelet counts, low white blood cell counts, and other toxic effects on the blood cells.

To report suspected adverse reactions, contact FSC Laboratories , Inc. at 1-866-764- 7822, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Adverse Events Reported During Pediatric Clinical Trials With Primsol

The following table lists those drug-related adverse events reported most frequently during the clinical trials in pediatric patients aged 6 months to 12 years.

Most of these events were determined to be mild. The incidence of drug-related adverse events was significantly lower for Primsol, which was most apparent for those events related to skin/appendages as a body system.

An increase in lymphocytes and eosinophils was noted in some pediatric patients following treatment with Primsol or sulfamethoxazole + trimethoprim oral suspension.

Adverse Reactions Reported For Trimethoprim

In addition to the adverse events listed above which have been observed in pediatric patients receiving Primsol, the following adverse reactions and altered laboratory tests have been previously reported for trimethoprim and therefore, may occur with Primsol therapy:

Dermatologic reactions: pruritus and exfoliative dermatitis. At the recommended adult dosage regimens of 100 mg b.i.d., or 200 mg q.d., each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies, which employed high doses of trimethoprim in adults, an elevated incidence of rash was noted. These rashes were

• maculopapular,
• morbilliform,
• pruritic and
• generally mild to moderate, appearing 7 to 14 days after the initiation of therapy.

Gastrointestinal reactions: Epigastric distress, nausea, and glossitis.

Hematologic reactions: Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia and methemoglobinemia.

Metabolic reactions: Hyperkalemia, hyponatremia.

Miscellaneous reactions: Fever, elevation of serum transaminase and bilirubin, and increases in BUN and serum creatinine levels.

Primsol may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%.

When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Drug/Laboratory Test Interactions

Trimethoprim can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein.

No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).

The presence of trimethoprim may also interfere with the Jaffé alkaline picrate reaction assay for creatinine resulting in overestimations of about 10% in the range of normal values.