Trimol Paediatric Suspension is indicated in children aged 12 years and under (infants (>6 weeks to <2 years old) and children (>2 to <12 years old) for the treatment of the following infections when owing to sensitive organisms (see section 5.1) :

§ Urinary tract infections: For simple urinary tract infections, trimethoprim alone or another single antimicrobial agent is the preferred treatment. Since trimethoprim is also as efficacious as co-Trimoxazole for the prophylaxis of recurrent urinary tract infections, co-Trimoxazole is not indicated for prophylactic use.  

§ Respiratory tract infections: Co-Trimoxazole may be used as second line therapy in chronic obstructive airways disease or other respiratory tract infections, including acute otitis media where sensitivity has been demonstrated or is highly probable.

(Co-Trimoxazole is not indicated for prophylactic or prolonged administration in otitis media).

§ Treatment and prevention of Pneumocystis jirovecii pneumonitis (PJP).

§ Co-Trimoxazole may be used in the management of other serious conditions such as nocardiasis, toxoplasmosis and brucellosis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology:

Standard dosage recommendations for acute infections

Children aged 12 years and under (infants (>6 weeks to <2 years old) and children (>2 to <12 years old)

The standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulphamethoxazole per kg body weight per day, given in two equally divided doses. The schedules for children are according to the child's age and provided in the table below:

Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 days. If clinical improvement is not evident after 7 days therapy, the patient should be reassessed.

As an alternative to Standard Dosage for acute uncomplicated lower urinary tract infections, short-term therapy of 1 to 3 days duration has been shown to be effective.

Impaired hepatic function:

No data are available relating to dosage in patients with impaired hepatic function.

Impaired renal function:

Dosage recommendation:

Adults (>18 years old) and children over 12 years old (>12 to <18 years old):

No information available for children aged 12 years and under with renal failure. See section 5.2 for the pharmacokinetics in the paediatric population with normal renal function of both components of Co-Trimoxazole .

Measurements of plasma concentration of sulphamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of Co-Trimoxazole. If the concentration of total sulphamethoxazole exceeds 150 microgram/ml then treatment should be interrupted until the value falls below 120 microgram/ml.

Pneumocystis jirovecii pneumonitis:

Treatment - Children aged 12 years and under (infants (>6 weeks to <2 years old) and children (>2 to <12 years old):

A higher dosage is recommended, using 20 mg trimethoprim and 100 mg sulphamethoxazole per kg of body weight per day (see table below) in two or more divided doses for two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Co-Trimoxazole) (see section 4.8).

Prevention - Children aged 12 years and under (infants (>6 weeks to <2 years old) and children (>2 to <12 years old):

The daily dose given on a treatment day approximates to 150 mg trimethoprim/m²/day and 750 mg sulphamethoxazole/m²/day. The total daily dose should not exceed 320 mg trimethoprim and 1600 mg sulphamethoxazole.

Nocardiosis

There is no consensus on the most appropriate dosage. Adult doses of 480 mg trimethoprim/2400 mg sulphamethoxazole to 640 mg trimethoprim/3200 mg sulphamethoxazole daily for up to three months have been used.

Brucellosis

It may be advisable to use a higher than standard dosage initially. Treatment should continue for a period of at least four weeks and repeated courses may be beneficial. Co-trimoxazole should be given in combination with other agents in line with national treatment guidelines.

Toxoplasmosis

There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. Doses of 480 mg or 960 mg of trimethoprim - sulphamethoxazole twice daily for three months have been used for prophylaxis and 40 mg/kg/day or 120 mg/kg/day for a mean of 25 days for the treatment of toxoplasmosis in patients with HIV.

Method of administration

Oral

It may be preferable to take co-trimoxazole with some food or drink to minimise the possibility of gastrointestinal disturbances.

Fatalities, although very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

Life threatening adverse reaction

§ Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of co-trimoxazole.

§ Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

§ If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, co-trimoxazole treatment should be discontinued (see section 4.8).

§ The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

§ If the patient has developed SJS or TEN with the use of co-trimoxazole, co-trimoxazole must not be re-started in this patient at any time.

Elderly patients

Particular care is always advisable when treating elderly patients because, as a group, they are more susceptible to adverse reactions and more likely to suffer serious effects as a result particularly when complicating conditions exist, e.g. impaired kidney and/or liver function and/or concomitant use of other drugs.

Patients with renal impairment

For patients with known renal impairment special measures should be adopted (see section 4.2).

Urinary output

An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from hypoalbuminaemia the risk may be increased.

Folate

Regular monthly blood counts are advisable when co-trimoxazole is given for long periods, or to folate deficient patients or to the elderly; since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate. Supplementation with folinic acid may be considered during treatment but this should be initiated with caution due to possible interference with antimicrobial efficacy (see section 4.5).

Patients with glucose-6-phosphate dehydrogenase deficiency

In glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients, haemolysis may occur.

Patients with severe atopy or bronchial asthma

Co-trimoxazole should be given with caution to patients with severe atopy or bronchial asthma.

Treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci

Co-trimoxazole should not be used in the treatment of streptococcal pharyngitis due to Group A β-haemolytic streptococci; eradication of these organisms from the oropharynx is less effective than with penicillin.

Phenylalanine metabolism

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

Patients with or at risk of porphyria

The administration of co-trimoxazole to patients known or suspected to be at risk of porphyria should be avoided. Both trimethoprim and sulphonamides (although not specifically sulphamethoxazole) have been associated with clinical exacerbation of porphyria.

Patients with hyperkalaemia and hyponatraemia

Close monitoring of serum potassium is warranted in patients at risk of hyperkalaemia and hyponatraemia.

Metabolic acidosis 

Co-trimoxazole has been associated with metabolic acidosis when other possible underlying causes have been excluded. Close monitoring is always advisable when metabolic acidosis is suspected.

Patients with serious haematological disorders

Except under careful supervision co-trimoxazole should not be given to patients with serious haematological disorders (see section 4.8). Co-trimoxazole has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

Patients with rare hereditary problems of fructose intolerance should not take this medicine (see section 2).

Trimol Suspension contains:

§ Methyl paraben and propyl paraben, which may cause allergic reactions (possibly delayed).

Diuretics (thiazides): in elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Pyrimethamine: occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co-trimoxazole be prescribed concurrently.

Zidovudine: in some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.

Lamivudine: administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole.

Warfarin: co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulphamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Co-trimoxazole is advisable.

Phenytoin: co-trimoxazole prolongs the half-life of phenytoin and if co-administered excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.

Rifampicin: concurrent use of rifampicin and Co-trimoxazole results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is not thought to be of clinical significance.

Cyclosporin: reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and cyclosporin following renal transplantation.

When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

Digoxin: concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.

Hyperkalaemia: caution should be exercised in patients taking any other drugs that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulphamethoxazole (co-trimoxazole) may result in clinically relevant hyperkalaemia. Azathioprine: There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and co-trimoxazole.

Methotrexate: co-trimoxazole may increase the free plasma levels of methotrexate. If Co-trimoxazole is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered. (see section 4.4)

Repaglinide: trimethoprim may increase the exposure of repaglinide which may result in hypoglycaemia.

Folinic acid: folinic acid supplementation has been shown to interfere with the antimicrobial efficacy of trimethoprim-sulphamethoxazole. This has been observed in Pneumocystis jiroveci pneumonia prophylaxis and treatment.

Contraceptives: oral contraceptive failures have been reported with antibiotics. The mechanism of this effect has not been elucidated. Women on treatment with antibiotics should temporarily use a barrier method in addition to the oral contraceptive, or choose another method of contraception.

Interaction with laboratory tests:

Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radio-immune assay.

Trimethoprim may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine of the order of 10%.

Functional inhibitation of the renal tubular secretion of creatinine may produce a spurious fall in the estimated rate of creatinine clearance.

Pregnancy

Trimethoprim and sulphamethoxazole cross the placenta and their safety in human pregnancy has not been established. Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see section 5.3). Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans. Therefore Co-trimoxazole should be avoided in pregnancy, particularly in the first trimester, unless the potential benefit to the mother outweighs the potential risk to the foetus; folate supplementation should be considered if Co-trimoxazole is used in pregnancy

Sulphamethoxazole competes with bilirubin for binding to plasma albumin. As significant maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Co-trimoxazole is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6- phosphate dehydrogenase deficiency.

Breast Feeding

Trimethoprim and sulphamethoxazole are excreted in breast milk. Administration of Co-trimoxazole should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. Additionally, administration of Co-trimoxazole should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia

Effects on the ability to drive and operate machinery in patients taking this medicine have not been studied.

As co-trimoxazole contains trimethoprim and a sulphonamide the type and frequency of adverse reactions associated with such compounds are expected to be consistent with extensive historical experience.

Data from large published clinical trials were used to determine the frequency of very common to rare adverse events. Very rare adverse events were primarily determined from post-marketing experience data and therefore refer to reporting rate rather than a "true" frequency. In addition, adverse events may vary in their incidence depending on the indication.

The following convention has been used for the classification of adverse events in terms of frequency:

§ Very common ≥1/10,

§ Common ≥1/100 and <1/10,

§ Uncommon ≥1/1000 and <1/100,

§ Rare ≥1/10,000 and <1/1000,

§ Very rare <1/10,000.

* see description of selected adverse reactions

Description of selected adverse reactions

Aseptic meningitis

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.

Pulmonary hypersensitivity reactions 

Cough, dyspnoea and lung infiltration may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Severe cutaneous adverse reactions (SCARs)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4).

Hepatobiliary disorders

Jaundice cholestatic and hepatic necrosis may be fatal.

Effects associated with Pneumocystis jirovecii (P. carinii) Pneumonitis (PJP) management

At the high dosages used for PJP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. Severe hypersensitivity reactions have been reported in PJP patients on re-exposure to trimethoprim-sulphamethoxazole, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of PJP.

To report any side effect(s):

·  Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)

Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2340

Reporting Hotline: 19999

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

·  Other GCC States: Please contact the relevant competent authority

Symptoms

Nausea, vomiting, dizziness and confusion are likely signs/symptoms of overdose. Bone marrow depression has been reported in acute trimethoprim overdose.

Management

Dependent on the status of renal function administration of fluids is recommended if urine output is low.

Both trimethoprim and active sulphamethoxazole are moderately dialysable by haemodialysis. Peritoneal dialysis is not effective.

In cases of known, suspected or accidental overdose, stop therapy.

Acidification of the urine will increase the elimination of trimethoprim. Inducing diuresis plus alkalinisation of urine will enhance the elimination of sulphamethoxazole. Alkalinisation will reduce the rate of elimination of trimethoprim. Calcium folinate (5 to 10 mg/day) will reverse any folate deficiency effect of trimethoprim on the bone marrow should this occur. General supportive measures are recommended

Pharmacotherapeutic group: antibacterials for systemic use – sulfonamides and trimethoprim Combinations of sulfonamides and trimethoprim, incl. derivatives;

ATC code: J01EE01

Mechanism of action

Sulphamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme active in the folate metabolic pathway converting dihydrofolate to tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulphamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.

Trimethoprim binds to plasmodial DHFR but less tightly than to the bacterial enzyme. The affinity of trimethoprim for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Resistance

In vitro studies have shown that bacterial resistance can develop more slowly with both sulphamethoxazole and trimethoprim in combination that with either sulphamethoxazole or trimethoprim alone.

Resistance to sulphamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulphamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulphamethoxazole compared to the wild-type enzyme.

Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.

Susceptibility testing breakpoints

Testing of trimethoprim sulphamethoxazole was performed using the common dilution series to assess the Minimum Inhibitory Concentration (MIC). The MIC breakpoints for resistance are those recommended by CLSI (Clinical and Laboratory Standards Institute – formerly the National Committee for Clinical Laboratory Standards (NCCLS) and EUCAST guidelines.

Pharmacodynamic effects

The majority of common pathogenic bacteria are sensitive in vitro to trimethoprim and sulphamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antimicrobial agents in vitro activity does not necessarily imply that clinical efficacy had been demonstrated. These organisms include:

Many strains of Bacteroides fragilis are sensitive. Some strains of Campylobacter fetus subsp. Jejuni and chlamydia are sensitive without evidence of synergy. Some varieties of non-tuberculous mycobacteria are sensitive to sulphamethoxazole but not trimethoprim. Mycoplasmas, Ureaplasma urealyticum, Mycobacterium tuberculosis and Treponema pallidum are insensitive.

Satisfactory sensitivity testing is achieved only with recommended media free from inhibitory substances especially thymidine and thymine.

5.2 Pharmacokinetic properties

Absorption:

After oral administration trimethoprim and sulphamethoxazole 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 2-3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.

Distribution:

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 humor, 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 sulphamethoxazole in the plasma is protein bound.

The concentration of active sulphamethoxazole in amniotic fluid, aqueous humour, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial) fluid is of the order of 20-50% of the plasma concentration.

Biotransformation

Renal excretion of intact sulphamethoxazole accounts for 15-30% of the dose. This drug 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 drug plus the major (N4-acetylated) metabolite.

Elimination

The half-life of trimethoprim in man is in the range 8.6 to 17 hours in the presence of normal renal function. There appears to be no significant difference in the elderly compared with young patients.

The principle route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentration of trimethoprim varies widely.

The half-life of sulphamethoxazole in man is approximately 9-11 hours in the presence of normal renal function. There is no change in the half-life of active sulphamethoxazole 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 principle route of excretion of sulphamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form.

Special patient populations

Renal impairment

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).

Hepatic impairment

Caution should be exercised when treating patients with severe hepatic impairment as there may be changes in the absorption and biotransformation of trimethoprim and sulphamethoxazole

Older patients

In older patients, a slight reduction in renal clearance of sulphamethoxazole but not trimethoprim has been observed.

Paediatric population

The pharmacokinetics in the paediatric population with normal renal function of both components of suspension, trimethoprim and sulphamethoxazole are age dependent. Elimination of trimethoprim - sulphamethoxazole is reduced in neonates, during the first two months of life, thereafter both trimethoprim and sulphamethoxazole 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).

After oral administration trimethoprim and sulphamethoxazole  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 2-3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.

Trimethoprim is a weak base with a pKa of 7.4. It is lipophilic. 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 humor, 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 50% of trimethoprim in the plasma is protein bound. The half-life in man is in the range 8.6 to 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 the elderly 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 drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.

Sulphamethoxazole  is a weak acid with a pKa of 6.0. The concentration of active sulphamethoxazole  in a variety of body fluids is of the order of 20 to 50% of the plasma concentration.

Approximately 66% of sulphamethoxazole  in the plasma is protein bound and the principal route of excretion of sulphamethoxazole  is renal. The half-life 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 sulphamethoxazole  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 principle route of excretion of sulphamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In elderly patients there is a reduced renal clearance of sulphamethoxazole .

At doses generally in excess of recommended human therapeutic dose, trimethoprim and sulphamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by co-administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.

None known

Store below 30ºC. After opening, use within one month.

§ Pack of 50mL: Suspension packed in an Amber coloured glass bottle provided with CRC cap, packed in a printed carton along with a leaflet.

§ Pack of 100mL: Suspension packed in an Amber coloured glass bottle provided with CRC cap, packed in a printed carton along with a leaflet.

Not applicable