Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Innovata Pharmaceuticals (Pty) LTD, 100 Northern Parkway Rd, Crownwood Office, Block D, Ground Floor, Ormonde, 2091
Pharmacological classification: A 20.2.1 Antimicrobial (Chemotherapeutic) agents (other than antibiotics)
Pharmacotherapeutic group: Antibacterials for systemic use – Sulfonamides and trimethoprim, incl. derivatives
ATC code: J01EE01
Co-trimoxazole exerts its bacterial action by the sequential blockade of two enzymes intervening in the biosynthesis of folinic acid in the micro-organism. Co-trimoxazole is bactericidal at concentrations at which the active ingredients trimethoprim and sulfamethoxazole are usually bacteriostatic. It is therefore often active against organisms resistant to one of the active ingredients thereby minimising the risk of bacterial resistance.
After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose. Steady state levels in adults are reached after dosing for 2 to 3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.
Approximately 50% of trimethoprim in the plasma is protein bound. Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions. Levels in the aqueous humour, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (intestinal) fluid are adequate for antibacterial activity.
Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum. Approximately 66% of sulfamethoxazole in the plasma is protein bound.
The concentration of active sulfamethoxazole in amniotic fluid, aqueous humour, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial) fluids is of the order of 20–50% of the plasma concentration.
Renal excretion of intact sulfamethoxazole accounts for 15–30% of the dose. This medicine is more extensively metabolised than trimethoprim, via acetylation, oxidation or glucuronidation. Over a 72 hour period, approximately 85% of the dose can be accounted for in the urine as unchanged medicine plus the major (N4-acetylated) metabolite.
The half-life of trimethoprim in man is in the range 8,6–17 hours in the presence of normal renal function. It is increased by a factor of 1,5 to 3,0 when the creatinine clearance is less than 10 mL/minute. There appears to be no significant difference in older patients compared with young patients.
The principal route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged medicine. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.
The half-life of sulfamethoxazole in man is approximately 9 to 11 hours in the presence of normal renal function. There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 mL/minute.
The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In older patients there is a reduced renal clearance of sulfamethoxazole.
The pharmacokinetics in the paediatric population with normal renal function of both components of Co-Trimoxazole, MP and SMZ are age dependent. Elimination of TMPSMZ is reduced in neonates, during the first two months of life, thereafter both TMP and SMZ show a higher elimination with a higher body clearance and a shorter elimination half-life. The differences are most prominent in young infants (>1,7 months up to 24 months) and decrease with increasing age, as compared to young children (1 year up to 3,6 years), children (7,5 years and <10 years) and adults (see section 4.2).
The elimination half-life of trimethoprim is increased by a factor of 1,5–3,0 when the creatinine clearance is less than 10 mL/minute. When the creatinine clearance falls below 30 mL/min the dosage of Co-trimoxazole should be reduced (see section 4.2).
In elderly patients, a slight reduction in renal clearance of sulfamethoxazole but not trimethoprim has been observed.
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