FECTRIM TABLETS STANDARD, CO-TRIMOXAZOLE 80/400 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

FECTRIM/Co-Trimoxazole 80/400 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole For the full list of excipients, see section 6.1

Tablet

White, capsule shaped tablets, engraved ‘160’ and ‘800’on the scored side.

The tablet can be divided into equal doses.

4.1 Therapeutic indications

Co-trimoxazole is indicated in adults and children over 12 years for treatment of the following infections when owing to sensitive organisms (see section

5.1):

Treatment and prophylaxis of Pneumocystis jirovecii pneumonia in adults and children.

Treatment and prophylaxis of toxoplasmosis

Treatment of nocardiosis

The following infections in adults and children over 12 years may be treated with Co-trimoxazole where there is bacterial evidence of sensitivity to Co-trimoxazole and good reason to prefer this combination of antibiotics in Co-trimoxazole to a single antibiotic.

Acute uncomplicated urinary tract infections

Acute exacerbations of chronic bronchitis

Acute otitis media

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

4.2 Posology and method of administration

Posology:

Adults and children over 12 years:

Standard dosage for acute infections: 2 tablets every 12 hours.

The dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kilogram body weight per day.

The dosage regime should be continued until the patient has become symptom-free for 2 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.

Pneumocystis jirovecii pneumonitis:

Treatment:

A higher dosage is recommended, using up to 120 mg (20 mg Trimethoprim and 100 mg Sulfamethoxazole) per kg bodyweight per day in 2 or more divided doses for 2 weeks. For maximum efficacy and minimum toxicity the steady state peak plasma or serum level of Trimethoprim should be maintained at 5 micrograms per ml.

Prophylaxis:

Adults:

The following dosing schedules may be used:

– 160 mg trimethoprim/800 mg sulfamethoxazole daily, 7 days per week.

– 160 mg trimethoprim/800 mg sulfamethoxazole three times a week on

alternate days.

– 320 mg trimethoprim/1600 mg sulfamethoxazole per day in two divided doses three times a week on alternate days.

Children (over 12 years):

The following dose schedules may be used for the duration of the period at risk

– Standard dosage taken in two divided doses, seven days per week

– Standard dosage taken in two divided doses, three times per week on alternate days

– Standard dosage taken in two divided doses, three times per week on consecutive days

– Standard dosage taken as a single dose, three times per week on consecutive days

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.

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.

Elderly:

Treatment should commence with one tablet twice daily and increased, if necessary, to the standard adult dosage.

Renal Impairment:

Doses of Co-trimoxazole should be reduced in patients with renal impairment.

The following recommendations for adults and children over 12 years of age based on creatinine clearance (CC):

– CC above 30 ml/minute: Standard dose

– CC 15 to 30 ml/minute: Half the standard dose

– CC below 15 ml/minute: Not recommended

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

Hepatic Impairment:

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

Method of administration: Oral.

FECTRIM should be taken with food or drink to minimise the possibility of gastro-intestinal disturbances.

4.3 Contraindications

Fectrim should not be given to patients with a history of hypersensitivity to sulfonamides, trimethoprim, co-trimoxazole or to any of the excipients of Fectrim listed in section 6.1

Contra-indicated in patients showing marked liver parenchymal change.

Contra-indicated in patients with severe renal insufficiency where repeated measurement of the plasma concentration cannot be performed.

Co-trimoxazole is contra-indicated in patients with megaloblastic anaemia due to folate deficiency.

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

4.4 Special warnings and precautions before use

An adequate urinary output should be maintained in cases with renal impairment, and a reduced or more widely spaced dosage interval should be used so as to avoid accumulation of the drug. Evidence of crystalluria in vivo is rare, although sulfonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased. An adequate fluid intake should be maintained to reduce the risk of crystalluria, but alkalinisation of the urine, although it increases urinary excretion of the sulfamethoxazole component, decreases urinary trimethoprim excretion.

Hypersensitivity reactions may require treatment with steroids. Calcium folinate, 3 to 6 mg intramuscularly for five to seven days may be given to counteract the effect of Trimethoprim on haemopoiesis

Fatalities, although very rare, may occur due to severe reactions including Stevens Johnson syndrome (SJS), Lyell syndrome/toxic epidermal necrolysis (TEN), fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias, hypersensitivity of respiratory tract.

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, Fectrim treatment should be discontinued (see 4.8 Undesirable Effects).

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 Fectrim, Fectrim must not be re-started in this patient at any time.

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. Dosage adjustment may be necessary.

Haemolysis may occur in glucose-6-phosphate dehydrogenase deficiency patients.

Fectrim should be given with caution in patients with severe allergy and bronchial asthma.

Fectrim should not be use 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.

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

The administration of Fectrim to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulfonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

Regular monthly blood counts are advised for patients on prolonged treatment, 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. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the antibacterial activity.

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

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

The combination of antibiotics in Fectrim 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.

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.

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,

competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

Anti-epileptics:

The antifolate effect and plasma concentration of phenytoin is increased by co-trimoxazole. Co-trimoxazole prolongs the half-life of phenytoin and if coadministered could result in excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.

Angiotensin-converting enzyme inhibitors:

Concurrent use of an ACE inhibitor or an angiotensin-II receptor antagonist with co-trimoxazole might increase the risk of hyperkalaemia and/or sudden death.

Diuretics:

The concurrent use of spironolactone and co-trimoxazole might increase the risk of hyperkalaemia. Hyponatraemia (excessively low sodium levels) have been seen in patients taking hydrochlorothiazide with amiloride or triamterene when they were given co-trimoxazole.

Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia.

In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Anti-virals:

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.

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.

Bone marrow suppressants:

Use of trimethoprim with other depressants of bone marrow function may increase the likelihood of myelosuppression.

Combined hormonal contraceptives

The failure of oral combined hormonal contraceptives has been attributed to antibacterials, including co-trimoxazole.

Local anaesthetics:

The action of sulfonamides may be antagonised by the procaine group of local anaesthetics.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are not any adequate data from the use of Fectrim in pregnant women. 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 5.3 Preclinical Safety Data). Fectrim should not be given during pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Fectrim 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 Fectrim 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.

Lactation

The components of Fectrim (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of Fectrim 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 Fectrim 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 Fectrim 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 Fectrim should be borne in mind when considering the patients ability to operate machinery.

4.8 Undesirable effects

The frequency categories associated with the adverse events below are estimates. For most events, suitable data for estimating incidence were not available. In addition, adverse events may vary in their incidence depending on the indication.

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.

The following convention has been used for the classification of adverse events in terms of frequency: Very common >1/10, common >1/100 and 01/10, uncommon >1/1000 and 01/100, rare >1/10,000 and 01/1000, very rare 01/10,000.

Infections and Infestations

Common:    Monilial overgrowth

Blood and lymphatic system disorders

Very rare:    Thrombocyto­penia, purpura, leucopenia, neutropenia,

agranulocytosis, megaloblastic anaemia, aplastic anaemia, haemolytic anaemia, methaemoglobi­naemia, eosinophilia, haemolysis in certain susceptible glucose-6-phosphate dehydrogenase (G6PD) deficient patients

The majority of haematological changes are mild and reversible when treatment is stopped. Most of the changes cause no clinical symptoms although they may become severe in isolated cases, especially in the elderly, in those with hepatic or renal dysfunction or in those with poor folate status. Fatalities have been recorded in at-risk patients and these patients should be observed carefully (see 4.3 Contra-indications).

A blood count should be determined when treatment has continued for 4 weeks or longer.

Immune system disorders

Very rare: Serum sickness, anaphylaxis, allergic myocarditis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, peri-arteritis nodosa, systemic lupus erythematosus (SLE)

Metabolism and nutrition disorders

Very common:      Hyperkalaemia

Very rare: Hypoglycaemia, hyponatraemia, anorexia

Close supervision is recommended when co-trimoxazole is used in elderly patients or in patients taking high doses of co-trimoxazole as these patients may be more susceptible to hyperkalaemia and hyponatraemia.

Psychiatric disorders

Very rare:     Depression, hallucinations

Nervous system disorders

Common:   Headache

Very rare: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, dizziness

Frequency unknown: Drowsiness

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.

Respiratory, thoracic and mediastinal disorders

Very rare: Cough, dyspnoea, pulmonary infiltrates

Cough, shortness of breath and pulmonary infiltrates may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Gastrointestinal disorders

Common:    Nausea, diarrhoea

Uncommon: Vomiting

Very rare:     Glossitis, stomatitis, pseudomembranous colitis, pancreatitis

Eye Disorders

Very rare:    Uveitis

Cardiac disorders

Frequency unknown: Myocarditis

Vascular disorders:

Frequency unknown: Vasculitis

Hepatobiliary disorders

Very rare: Elevated serum transaminases, elevation of bilirubin levels, cholestatic jaundice, hepatic necrosis

Cholestatic jaundice and hepatic necrosis which may be fatal.

Skin and subcutaneous tissue disorders

Common:    Skin rashes

Very rare:     Photosensi­tivity, exfoliative dermatitis, fixed drug eruption,

erythema multiforme, severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4)

Frequency unknown: pruritus

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia, myalgia

Renal and urinary disorders

Very rare: Impaired renal function (sometimes reported as renal failure), interstitial nephritis

Frequency unknown: Crystalluria

General disorders and administration site conditions

Frequency unknown: Fever, fatigue

Effects associated with Pneumocystis  jirovecii Pneumonitis (PCP) management.

Very rare: Severe hypersensitivity reactions, rash, fever, neutropenia, thrombocytopenia, raised liver enzymes, hyperkalaemia, hyponatraemia

At the high dosages used for PCP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5–10 mg/day). Severe hypersensitivity reactions have been reported in PCP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days.

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of sulfonamides and trimethoprim, incl. derivatives; ATC code: J01EE01

Mode of Action

Fectrim is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. The two components block two consecutive steps in the bacterial biosynthesis of tetrahydrofolic acid, an essential stage in the production of thymidine, purines and, subsequently, nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.

Sulfamethoxazole, like the other sulfonamides, competitively inhibits the utilisation of p-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis.

Trimethoprim binds to and reversibly inhibits the action of bacterial dihydrofolate reductase (DHFR) and prevents the synthesis of tetrahydrofolic acid from dihydrofolic acid; although this stage also occurs in man, Trimethoprim is much less active against the mammalian enzyme. Depending on the conditions the effect may be bactericidal.

Enhanced antibacterial activity has been reported when Sulfamethoxazole and Trimethoprim are used together in vitro although there is doubt as to whether sequential blockage of the bacterial synthetic pathway is responsible. Co-trimoxazole has a wide spectrum of activity similar to that of the sulfonamides and Trimethoprim. It is also active against pneumocystis jirovecii.

Mechanism of 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 several different mechanisms. Bacterial mutations cause an increased production 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 alteration of dihydropteroate synthetase, the enzyme inhibited by sulfonamides, to a less sensitive form, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme. Other mechanisms include; an alteration in folate biosynthesis to an alternative pathway, decreased uptake or enhanced metabolism of sulfonamides. High-level resistance is usually permanent and irreversible. There is complete crossresistance between the different sulfonamides.

Clinical 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; such genes may become incorporated into the chromosome via transposons. Resistance may also be due to overproduction of dihydrofolate reductase, changes in cell permeability, or bacterial mutants which are intrinsically resistant to trimethoprim because they depend on exogenous thymine and thymidine for growth.

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

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.

Breakpoints

EUCAST

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 susceptibility against a number of bacteria are shown in the table below:

5.2 Pharmacokinetic properties

Absorption

After oral administration Sulfamethoxazole and Trimethoprim are rapidly and nearly completely absorbed from the gastro-intestinal tract. The presence of food does not appear to delay absorption.

Distribution

When Co-trimoxazole is administered, plasma concentrations of Trimethoprim and Sulfamethoxazole are generally in the ratio of 1:20. Peak plasma concentrations are reached within between 1 and 4 hours after ingestion and the level attained is dose related. Effective plasma concentrations are maintained for up to 24 hours after an oral therapeutic dose. Doses of 1 g twice daily should produce blood concentrations of unconjugated Sulfamethoxazole in excess of 50 pg per ml. Steady state concentrations 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.

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

About 66% of sulfamethoxazole is bound to plasma albumin and the plasma half-life in man is approximately 9 to 11 hours in the presence of normal renal function. About 15% of Sulfamethoxazole in the blood is present as the acetyl derivative.

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.

Trimethoprim is a weak base with a pKa of 7.4. It is lipophilic. About 45% is bound to plasma proteins. Tissue concentrations are reported to be higher than serum concentrations, with particularly high concentrations occurring in the kidneys and lungs Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions but concentrations in the cerebrospinal fluid are about one-half of those in the blood. 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 halflife 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.

Elimination

Elimination in the urine is dependent on pH.

The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of a single dose of Sulfamethoxazole has been reported to be excreted in the urine in the active form within 8 hours, about 60% being in the form of the acetyl derivative. In elderly patients there is a reduced renal clearance of sulfamethoxazole.

The principal route of excretion of trimethoprim is renal and approximately 50% of a dose is excreted unchanged in the urine within 24 hours, together with several metabolites. Urinary concentrations of trimethoprim vary widely. Trimethoprim appears in breast milk.

Paediatric , population

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

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in the other sections of the SPC.

6.1

Povidone K25

Crospovidone

Magnesium stearate

Microcrystalline cellulose (20 mg/100 mg tablets)

6.2 Incompatibilities

None known.

6.3 Shelf life

20mg/100mg Tablets

Containers: 24 months

80mg/160mg Tablets

Containers: 36 months

PVC/Aluminium foil blisters: 24 months

160mg/800mg Tablets

Containers: 36 months

6.4 Special precautions for storage

Store below 25°C in a dry place in well closed containers.

6.5 Nature and contents of container

20mg/100mg Tablets

High density polystyrene or polypropylene containers with polythene or polypropylene lids and polyurethane/po­lythene inserts. Pack size: 100 80mg/160mg Tablets

High density polystyrene or polypropylene containers with polythene or polypropylene lids and polyurethane/po­lythene inserts. Pack sizes: 100, 500 PVC/Aluminium Foil Blister packs 250 micron PVC glass-clear/bluish rigid PVC (Pharmaceutical Grade). 20 micron hard-tempered aluminium foil coated on the pull side with 6–7 gsm heat seal lacquer and printed on the bright side. Pack Sizes: 10, 28, 30

160mg/800mg Tablets

High density polystyrene or polypropylene containers with polythene or polypropylene lids and polyurethane/po­lythene inserts. Pack size: 100

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Hualan Pharmaceuticals Limited

16/17 College Green

Dublin

D02 V078

Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 52104/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29//01/2009