Sulfadiazine – Trimethoprim
Action And Clinical Pharmacology: Tetrahydrofolic acid is an essential metabolic co-factor in the biosynthesis of purines and thymine compounds which are ultimately utilized in the synthesis of DNA and RNA. The amino acids, serine and methionine, also require tetrahydrofolic acid for their biosynthesis.
Cotrimazine exerts its antibacterial effect by interfering with 2 consecutive steps in the biosynthesis of tetrahydrofolic acid. Sulfadiazine inhibits bacterial production of dihydrofolic acid by competing with para-aminobenzoic acid. Trimethoprim inhibits the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the enzyme, dihydrofolate reductase. Trimethoprim has only a very weak affinity for the human enzyme in comparison to bacterial forms.
Indications And Clinical Uses: Treatment of acute, chronic and recurrent urinary tract infections, including asymptomatic bacteriuria, cystitis and pyelonephritis, when these are caused by susceptible strains of bacteria including E. coli, P. mirabilis, P. vulgaris and Klebsiella-Enterobacter species.
Contra-Indications: Patients known to have hypersensitivity to sulfonamides or trimethoprim; marked parenchymal liver damage or blood dyscrasias and also in patients with marked renal impairment when repeated measurements of the plasma drug concentration cannot be performed.
Children, Pregnancy and Lactation: Cotrimazine should not be given to women who are pregnant or breast-feeding, nor to premature infants or neonates during the first 12 weeks of life.
Manufacturers’ Warnings In Clinical States: With the administration of sulfonamides, hypersensitivity reactions, agranulocytosis, aplastic anemia and other blood dyscrasias have been reported. In some instances, these complications have been fatal.
Experience with the use of trimethoprim alone is not extensive but the drug has been reported to interfere with hematopoiesis in some patients. In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.
During therapy with cotrimazine, patients should be carefully evaluated for clinical evidence of serious blood disorders. If signs such as unexplained infection, fever, pallor, bleeding or jaundice appear, cotrimazine administration should be discontinued immediately and appropriate hematological investigations should be conducted.
Hematological changes related to impairment of folic acid metabolism have been reported in a few patients taking other combinations of a sulfonamide and trimethoprim. When these have occurred, they have been reversible with folinic acid therapy. Blood counts should be performed at appropriate intervals in patients on long-term therapy, in those predisposed to folate deficiency (i.e., the elderly, chronic alcoholics and rheumatoid arthritics), in malabsorption syndromes, malnutrition states, or during the treatment of epilepsy with anticonvulsant drugs such as phenytoin, primidone or barbiturates. If significant hematological abnormalities are noted, cotrimazine administration should be discontinued immediately and appropriate hematological investigations should be conducted.
Precautions: Cotrimazine should be given with caution to patients having impaired renal or hepatic function, to those with possible folate deficiency and to those with severe allergy or bronchial asthma. Therapy should be discontinued when rash or allergy develops.
In glucose-6-phosphate dehydrogenase deficiency, hemolysis may be exacerbated by cotrimazine owing to the sulfonamide component and this effect is frequently dose related.
When cotrimazine therapy is undertaken, it is recommended, as with all sulfonamide-containing agents, that adequate fluid intake be maintained in order to minimize the risk of crystalluria and stone formation.
Urinalysis with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. In individuals with renal impairment, a reduced dosage of cotrimazine is indicated to avoid accumulation of its components. In these patients, measurements of the plasma concentrations of the drugs are advisable. Cotrimazine should not be used when the serum creatinine concentration exceeds 2 mg/100 mL.
The sulfonamides are chemically similar to some goitrogens, diuretics such as acetazolamide and the thiazides, and oral hypoglycemics. Goiter, diuresis, and hypoglycemia may occur occasionally. Cross-sensitivity may exist with these agents.
Drug Interactions: No drug interactions with cotrimazine have been reported to date. However, as is the case with all sulfonamide-containing compounds, cotrimazine should be used with caution in patients receiving coumarin anticoagulants and oral sulfonylurea hypoglycemic agents, as sulfonamides have been reported to enhance the activity of these drugs.
Trimethoprim may possibly potentiate the action of other agents such as methotrexate and pyrimethamine, that interfere with folate metabolism.
Sulfonamides are known to interfere with the plasma protein binding of numerous other drugs. These agents, in turn, may compete with the sulfonamides for available binding sites. The net result depends on the relative concentrations of the agents involved and their binding affinities but, in theory, the plasma level of free sulfonamide or other drug may be altered with enhancement of its action or toxicity, whenever a sulfonamide is used concurrently with another agent that is markedly protein bound. Among the most widely recognized interactions of this type are the displacement of the coumarin anticoagulants, penicillin and phenytoin by sulfonamides and the displacement of sulfonamides by salicylates, sulfinpyrazone, phenylbutazone and certain other nonsteroidal antiarthritic agents. These interactions would seem unlikely to be of clinical significance with the administration of Coptin owing to the relatively small dose of sulfadiazine involved.
Para-aminobenzoic acid antagonizes the antibacterial action of sulfonamides and should not be administered concurrently with cotrimazine.
Adverse Reactions: Cotrimazine is usually well tolerated at the recommended dosage. However, gastrointestinal and allergic reactions can occur. The most common adverse reactions to sulfonamides and trimethoprim are listed below though they may not have all been reported with Coptin.
Gastrointestinal: nausea, abdominal pain, emesis, diarrhea, glossitis, somatitis and pancreatitis.
Allergic: erythema multiforme, the Stevens-Johnson syndrome, generalized skin eruptions, epidermal necrolysis, urticaria, serum sickness, pruritus, exfoliative dermatitis, anaphylactoid reactions, periorbital edema, conjunctival and scleral infection, photosensitization arthralgia, allergic myocarditis, drug fever, chills, lupus erythematous phenomena and periarteritis nodosa.
CNS: headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations, tinnitus, vertigo, insomnia, apathy, fatigue, muscle weakness and nervousness.
Renal: toxic nephrosis with oligurion, anuria and crystaluria, functional kidney changes resulting in elevated serum urea, creatinine and protein levels.
Hepatic: hepatitis as seen by elevated serum conjugated bilirubin levels. Liver changes such as increase in alkaline phosphatase and serum transaminase levels.
Blood Dyscrasias: agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, purpura, hypoprothrombinemia and methemoglobinemia.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Symptomatic. It may include gastric lavage and forced diuresis. Alkalinization of the urine may help to minimize the risk of sulfadiazine crystal formation. In patients with impaired renal function, both trimethoprim and sulfadiazine may be removed from the blood by dialysis. Calcium folinate (3 to 6 mg i.m. for 5 to 7 days) can be a useful antidote for the adverse hematological effects of trimethoprim.
Dosage And Administration: Adults and children over 12 years: 2 Coptin tablets or 20 mL of oral suspension as a single dose administered every 24 hours.
Children 12 years and under: 14 mg sulfadiazine/kg/day+3 mg trimethoprim/kg/day divided in 2 equal doses administered every 12 hours.
Cotrimazine is not recommended for children less than 3 months of age.
SuppliedSupplied: Oral Suspension: Each 5 mL teaspoonful of banana-flavored oral suspension contains: sulfadiazine 205 mg and trimethoprim 45 mg. Nonmedicinal ingredients: colloidal silicone dioxide, essence of banana, Keltrol, methylparaben, propylparaben, sodium citrate, sodium hydroxide and sorbitol solution. Bottles of 50 and 100 mL.
Tablets: Each white, scored tablet identified with monogram “C 500” on the scored side and “J” on the reverse side, contains: sulfadiazine 410 mg and trimethoprim 90 mg. Nonmedicinal ingredients: cornstarch, magnesium stearate and povidone. Bottles of 100. (Shown in Product Recognition Section)
COPTIN® Axcan Pharma Sulfadiazine – Trimethoprim Antibacterial