CO-TRIMOXAZOLE 40 MG / 200 MG PER 5 ML PAEDIATRIC SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Co-Trimoxazole 40 mg/200 mg per 5 ml Paediatric Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml contains 40 mg Trimethoprim and 200 mg Sulfamethoxazole

Excipient(s) with known effect:

This product contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

Also contains 3.25 g sorbitol per 5 ml, less than 100 mg of ethanol per 5 ml and methyl hydroxybenzoate.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral suspension

Off white in colour.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-Trimoxazole 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):

Treatment and prevention of Pneumocystis jirovecii pneumonitis (PJP).

Treatment and prophylaxis of toxoplasmosis.

Treatment of nocardiosis.

The following infections may be treated with Co-Trimoxazole where there is bacterial evidence of sensitivity to Co-Trimoxazole and good reason to prefer the combination of antibiotics in Co-Trimoxazole to a single antibiotic:

Acute uncomplicated urinary tract infection.

Acute otitis media.

Acute exacerbation of chronic bronchitis.

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

4.2 Posology and method of administration

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 sulfamethoxazole 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 is 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 TMP and SMZ.

Measurements of plasma concentration of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of Co-Trimoxazole. If the concentration of total sulfamethoxazole 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 sulfamethoxazole 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 standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg body weight per day, given in two equally divided doses. The schedules according to the child’s age that may be used for the duration of the period at risk are provided in the table below:

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

Nocardiosis:

There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used (one tablet contains 400 mg sulfamethoxazole and 80 mg trimethoprim).

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.

For prophylaxis, however, the dosages suggested for prevention of Pneumocystis jirovecii pneumonitis may be appropriate.

Method of administration:

Oral

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

4.3 Contraindications

Hypersensitivity to the active substance(s) sulphonamides, trimethoprim, co-trimoxazole or to any of the excipients listed in section 6.1.

Severe impairment of liver. Patients with severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

Co-Trimoxazole should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides.

Co-Trimoxazole should not be given to patients with acute porphyria.

Co-Trimoxazole should not be given to infants during the first 6 weeks of life.

4.4 Special warnings and precautions for use

Life threatening adverse reactions

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 cutaneous reactions Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) 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, TEN (e.g. progressive skin rash often with blisters or

mucosal lesions) or DRESS (e.g. fever, eosinophilia) are present, Co-Trimoxazole treatment should be discontinued (see section 4.8).

The best results in managing SJS, TEN and DRESS 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, TEN and DRESS with the use of Co-Trimoxazole,

Co-Trimoxazole must not be re-started in this patient at any time.

At the start of treatment, the occurrence of a generalised febrile erythema associated with pustules, should raise the suspicion of acute generalised exanthematous pustulosis (AGEP) (see section 4.8); it requires cessation of treatment and contraindicates any new administration of Co-Trimoxazole alone or in combination with other drugs.

Haemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported very rarely in patients treated with co-trimoxazole. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of an excessive systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyce­ridaemia, hypofibrinoge­naemia, high serum ferritin, cytopenias and haemophagocytosis). Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, co-trimoxazole treatment should be discontinued.

Respiratory toxicity

Very rare, severe cases of respiratory toxicity, sometimes progressing to Acute Respiratory Distress Syndrome (ARDS), have been reported during co-trimoxazole treatment. The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function may be preliminary signs of ARDS. In such circumstances, co-trimoxazole should be discontinued and appropriate treatment given.

Elderly patients

Particular care is always advisable when treating older 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 malnutrition 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 older patients; 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 beta-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 sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

Patients with hyperkalaemia and hyponatraemia

Close monitoring of serum potassium and sodium 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.

The combination of antibiotics in Co-Trimoxazole should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial a­gent.

Excipients

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

This medicinal product contains methyl hydroxybenzoate, which may cause allergic reactions (possibly delayed).

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction with laboratory tests: 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%. The creatinine clearance is reduced: the renal tubular secretion of creatinine is decreased from 23% to 9% whilst the glomerular filtration remains unchanged.

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.

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

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.

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.

Diuretics (thiazides): in older 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.

Warfarin: co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole 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 could result in excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.

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

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

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 radioimmuno assay.

Lamivudine: administration of trimethoprim/sul­famethoxazole 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 sulfamethoxazole.

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

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-sulfamethoxazole (co-trimoxazole) may result in clinically relevant hyperkalaemia.

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-sulfamethoxazole. This has been observed in Pneumocystis jirovecii 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.

Azathioprine: There are conflicting clinical reports of interactions between azathioprine and trimethoprim-sulfamethoxazole, resulting in serious haematological abnormalities.

4.6 Fertility, pregnancy and lactation

Pregnancy

Trimethoprim and sulfamethoxazole cross the placenta and their safety in pregnant women has not been established. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans.

Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see section 5.3).

Co-Trimoxazole should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Co-Trimoxazole is used in pregnancy.

Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly 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

The components of Co-Trimoxazole (trimethoprim and sulfamethoxazole) 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.

4.7 Effects on ability to drive and use machines

There have been no studies to investigate the effect of Co-Trimoxazole on driving performance or the ability to operate machinery. Further a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless the clinical status of the patient and the adverse events profile of Co-Trimoxazole should be borne in mind when considering the patients ability to operate machinery.

4.8 Undesirable effects

Summary of the safety profile

As co-trimoxazole contains trimethoprim and a sulfonamide 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.

Tabulated list of adverse reaction

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,

Not Known – cannot be estimated from the available data

* 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.

Hepatobiliary disorders

Jaundice cholestatic and hepatic necrosis may be fatal.

Severe cutaneous adverse reactions (SCARs)

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported to be lifethreatening (see section 4.4).

As with any other drug, allergic reactions such as an itchy rash and hives may occur in patients with hypersensitivity to the components of the drug. Very rare cases of acute generalised exanthematous pustulosis (AGEP) have been observed (see section 4.4).

Effects associated with Pneumocystis jirovecii Pneumonitis (PJP) management

Severe hypersensitivity reactions, rash, pyrexia, neutropenia, thrombocytopenia, hepatic enzyme increased, hyperkalaemia, hyponatraemia and rhabdomyolysis

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 co-trimoxazole, 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms and Signs

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

Treatment

If vomiting has not occurred, induction of vomiting may be desirable. Gastric lavage may be useful, though absorption from the gastrointestinal tract is normally very rapid and complete within approximately two hours. This may not be the case in gross overdosage. Dependant on the status of renal function administration of fluids is recommended if urine output is low.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use – Sulfonamides and trimethoprim, incl. derivatives; ATC code: J01EE01

Mechanism of action

Sulfamethoxazole 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 sulfamethoxazole 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. Its affinity 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 sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.

Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out- compete with sulfamethoxazole 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 sulfamethoxazole 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.

Pharmacodynamic effects

Many common pathogenic bacteria are susceptible in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must be noted that satisfactory susceptibility testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.

Susceptibility testing breakpoints

EUCAST (European Committee on Antimicrobial Susceptibility Testing) limits

Enterobacteriaceae: S< 2 R> 4

.S' maltophilia: S< 4 R> 4

Acinetobacter: S< 2 R> 4

Staphylococcus: S< 2 R> 4

Enterococcus: S< 0.032 R> 1

Streptococcus ABCG: S< 1 R> 2

Streptococcus pneumoniae: S< 1 R> 2

Hemophilus influenza: S< 0.5 R> 1

Moraxella catarrhalis: S<0.5 R >1

Psuedomonas aeruginosa and other non-enterobacteriaceae: S< 2* R> 4*

S = susceptible, R = resistant. *These are CLSI breakpoints since no EUCAST breakpoints are currently available for these organisms.

Trimethoprim: sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as trimethoprim concentration.

Antibacterial Spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to trimethoprim/sul­famethoxazole or not.

Trimethoprim/sul­famethoxazole susceptibilities against a number of bacteria are shown in the table below:

Commonly susceptible species:_________­_______________

Gram-positive aerobes:

Staphylococcus aureus

Staphylococcus saprophyticus

Streptococcus pyogenes_________­________________________

Gram-negative aerobes:

Enterobacter cloacae

Haemophilus influenzae

Klebsiella oxytoca

Moraxella catarrhalis

Salmonella spp.

Stenotrophomonas maltophilia

Yersinia spp.___________­________________________­_____________

Species for which acquired resistance may be a problem:

Gram-positive aerobes:

Enterococcus faecalis

Enterococcus faecium

Nocardia spp.

Staphylococcus epidermidis

Streptococcus pneumoniae___________­__________________

Gram-negative aerobes:

Citrobacter spp.

Enterobacter aerogenes

Escherichia coli

Klebsiella pneumoniae

Klebsiella pneumonia

Proteus mirabilis

Proteus vulgaris

Providencia spp.

Serratia marcesans___________­________________________­__

Inherently resistant organisms:

Gram-negative aerobes:

Pseudomonas aeruginosa

Shigella spp. Vibrio cholera

5.2 Pharmacokinetic properties

Absorption:

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 2–3 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 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 to 50% of the plasma concentration.

Biotransformation

Renal excretion of intact sulfamethoxazole 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. 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 drug. 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, TMP and SMZ are age dependent. Elimination of TMP-SMZ 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).

Elderly patients

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

5.3 Preclinical safety data

At doses in excess of recommended human therapeutic dose, trimethoprim and sulfamethoxazole 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 administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sorbitol solution 70% (non crystallising) (E420 ii)

Glycerol (E422)

Dispersible Cellulose (E460)

Sodium Carmellose

Polysorbate 80 (E433)

Methyl Hydroxybenzoate (E218)

Sodium Benzoate (E211)

Saccharin Sodium (E954)

Ethanol (96%)

Flavour, Banana 81.605P

Flavour, Vanilla 407

Purified Water to 5 ml

6.2 Incompatibilities

None Known

6.3 Shelf life

36 months.

6.4 Special precautions for storage Store below 25°C.

Protect from light.

6.5 Nature and contents of container

Amber glass bottles, with plastic child resistant closures (CRC) made of polypropylene with a polyethylene liner and a polypropylene double ended spoon. Pack size: 100 and 30 ml

A double-ended 5 ml/2.5 ml measuring spoon is included.

Paper/Aluminium foil/ionomer resin sachet

Pack size: 5 ml

6.6 Special precautions for disposal and other handling

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 radioimmuno 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 inhibition of the renal tubular secretion of creatinine may product a spurious fall in the estimated rate of creatinine clearance.

7. Marketing Authorisation Holder

Aspen Pharma Trading Limited

3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland.

8 MARKETING AUTHORISATION NUMBER(S)

PL 39699/ 0037

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

17/10/2006