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1. Co-Trimoxazole 80/400mg Tablets
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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-Trimoxazole 80/400mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

3 PHARMACEUTICAL FORM

Tablet

White round flat bevel edged tablets with an approximate diameter of 12.5mm, marked “COT 480” on one side and a cross break line on the other.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-trimoxazole is an antibacterial agent. Co-trimoxazole is effective in vitro against a wide range of gram-positive and gram-negative organisms. It is not active against

Mycobacterium tuberculosis, mycoplasma or Treponema pallidum, Pseudomonas aeruginosa is usually insensitive.

•    Co-trimoxazole is indicated for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

Treatment and prophylaxis (primary and secondary) of Pneumocytosis carinii (Pneumocytosis jiroveci) pneumonitis in adults and children.

•    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:

•    Treatment of urinary tract infections

•    Treatment of acute exacerbations of chronic bronchitis

•    Treatment of acute otitis media in children

Consideration should be given to official

4.2 Posology and method of administration

Posology

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

Adults

Standard dosage	2 tablets twice daily
For severe infections:	3 tablets twice daily

Paediatric population A more appropriate dosage formulation should be used.

Over 12 years	As for adults
6-12 years	1 tablet twice daily
6 weeks-5 months	120 mg twice daily
6 months-5 years:	240 mg twice daily

This dosage approximates to 6 mg trimethoprim and 30 mg sulfamethoxazole per kilogram body weight per 24 hours.

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 of therapy, the patient should be reassessed.

Where dosage is expressed as “tablets”, this refers to the adult tablet, i.e. 80mg Trimethoprim and 400mg Sulfamethoxazole. If other formulations are to be used, appropriate adjustments should be made.

Special dosage recommendations:

Unless stated, standard dosage applies.

As an alternative to standard therapy for acute uncomplicated lower urinary tract infections, short-term therapy of one to three days duration has been shown to be effective.

Impaired hepatic function:

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

Impaired renal function:

Adults and children over 12 years

If Co-trimoxazole is given to patients with renal impairment then the following dosage scheme is suggested (no information is available for children under 12 years of age with renal failure).

>30	Men <265 Women <175	Standard dosage
15 to 30	Men 265-620 Women 175-400	Half the standard dosage
<15	Men >620 Women >400	Not recommended

Measurements of plasma concentrations of sulfamethoxazole at intervals of two to three days are recommended in samples obtained 12 hours after administration of Co-trimoxazole. If the concentration of total sulfamethoxazole exceeds 150 mcg/ml, then treatment should be interrupted until the value falls below 120 mcg/ml.

Long-term prophylaxis of recurrent or suppression of chronic infection following sterilisation of the urine:

Adults and children over 12 years:

1 tablet nightly

Children under 12 years

A single nightly dose of 2 mg trimethoprim and 10 mg sulfamethoxazole per kg body weight.

Treatment may be continued for 3 to 12 months or more as appropriate.

Chronic Prostatitis:

It may be advisable to use a higher than standard dose initially. The course of treatment should last for three months to reduce the risk of relapse.

Pneumocystis carinii (Pneumocytosis jiroveci) pneumonitis:

Treatment: A higher dosage is recommended, using 20 mg trimethoprim and 100 mg sulfamethoxazole per kg body weight per day in two or more divided doses for two weeks. The steady state of serum level of trimethoprim should be maintained at 5 mcg/ml or higher for maximum efficacy (verified in patients receiving 1-hour infusions of intravenous Co-trimoxazole) (see section 4.8).

Prevention:

Adults: Standard dosage for the duration of the period at risk. The following dose schedules may be used:

Two tablets (total of 160mg trimethoprim/800mg sulfamethoxazole) daily for seven days or

Two tablets (total of 160mg trimethoprim/800mg sulfamethoxazole) daily three times a week on alternate days or

Two tablets (total of 160mg trimethoprim/800mg sulfamethoxazole) twice a day three times a week on alternate days

Children: The following dose schedules may be used for the duration of the period at risk (see standard dosage recommendations for acute infections subsection of 4.2):

•    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.

Treatment of Nocardiosis: There is no consensus on the most appropriate dosage. Adult doses of six to eight tablets daily for up to 3 months have been used.

Treatment and prophylaxis of 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 jiroveci (P. carinii) pneumonitis may be appropriate.

Gonorrhoea

In uncomplicated cases 4 tablets every 12 hours for two days or 5 tablets followed by a further dose of 5 tablets eight hours later.

Acute Brucellosis:

It may be advisable to use a higher than standard dose initially. Treatment should continue for a period of at least four weeks and repeated courses may be beneficial.

Typhoid and Paratyphoid Carriage:

Treatment should be continued for at least 1-3 months.

Older People:

No specific studies have been carried out in the elderly, although Co-trimoxazole has been widely used in older people. However, care is advised when treating the elderly because, as a group, they are more susceptible to adverse reactions and more likely to suffer effects as a result particularly when complicating conditions exist e.g. impaired kidney and/or liver function and/or concomitant use of other drugs. Unless otherwise specified standard dosage applies (see section 4.4).

Method of administration:

For oral administration.

4.3 Contraindications

•    Hypersensitivity to sulphonamide, trimethoprim or to any of the excipients listed in section 6.1.

•    Severe hepatic failure, marked liver parenchymal damage or jaundice.

•    Severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

•    Co-trimoxazole should not be given to premature babies, infants under six weeks, except for the treatment/prophylaxis (primary or secondary) of Pneumocystis carinii (Pneumocystis jiroveci) pneumonitis when treatment can be given in infants of four weeks of age or greater.

• Pregnancy - especially in the period prior to birth (see section 4.6).

4.4 Special warnings and precautions for use

Fatalities although very rare, have occurred due to severe reactions including fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias, hypersensitivity of respiratory tract.

•    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 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, then it must not be re-started in this patient at any time.

In cases with renal impairment a modified dosage schedule as described above is indicated (see Section 4.2). In such patients, measurements of the plasma concentration of the drug is advisable.

Special care should always be taken 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 renal and/or hepatic function and/or concomitant use of other drugs.

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. The risk of crystalluria is increased in patients suffering from malnutrition.

If Co-trimoxazole treatment is prolonged, especially in patients with suspected impairment of folate metabolism or to the elderly, it is suggested that complete blood counts including thrombocytes be performed at monthly intervals; 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 5 to 10mg folinic acid per day without interfering with the antibacterial activity.

Patients with glucose-6-phosphatase dehydrogenase deficiency may be at risk of haemolytic reactions.

Care is generally advisable in patients with severe allergy or bronchial asthma.

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.

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction. Co-trimoxazole can be used in phenylketonuria patients on diet.

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

There is a small risk of kericterus in jaundiced infants and haemolysis in G6PD-deficient infants (due to sulfamethoxazole).

Serum potassium and sodium levels should be monitored closely in those patients at risk of hyperkalaemia and hyponaturaemia.

Except in certain circumstances it should not be given to patients with serious haematological disorders and porphyria (see section 4.8). The combination has been administered to patients receiving cytotoxic agents without evidence of an adverse 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.

4.5 Interaction with other medicinal products and other forms of interaction

Anticoagulants

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.

The effect of acencoumarol may also be enhanced.

Anticonvulsants

Co-trimoxazole prolongs the half-life of phenytoin and if co-administered could result in excessive phenytoin effect of these drugs. Close monitoring of the patient’s condition and serum levels are advisable.

Clozapine: avoid concomitant use; increased risk of fatal agranulocytosis.

Digoxin

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

Antidiabetic Agents

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

Methotrexate

Co-trimoxazole may increase the free plasma levels of methotrexate. 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.

If Co-trimoxazole is considered to be appropriate therapy in patients receiving methotrexate or other antifolate drugs, a folate supplement should be considered (see section 4.4)

Cytotoxic Agents

There is an increased risk of haematological toxicity with azathioprine and mercaptopurine.

Antibacterial Agents

Concurrent use of rifampicin and Co-trimoxazole results in increased rifampicin serum levels and 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. Serum levels of dapsone and Co-trimoxazole are possibly raised by the presence of the other. Be alert for dapsone toxicity causing methaemoglobinaemia. Increased risk of crystalluria when sulphonamides given with methenamine.

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.

Ciclosporine

Reversible deterioration in renal function has been observed in patients treated with Co-trimoxazole and ciclosporine following renal transplantation.

Antimalarial Agents

Occasional reports suggest that patients receiving pyrimethamine as malarial prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anaemia should Co-trimoxazole be prescribed concurrently.

Diuretics

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

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

ACE Inhibitors

Risk of severe hyperkalaemia.

Anaesthetics

Increased risk of methaemoglobinaemia when sulphonamides given with prilocaine.

Antiarrhythmics

Co-trimoxazole increases the risk of ventricular arrhythmias with amiodarone. Plasma levels of dofetilide increased markedly by co-administration with Co-trimoxazole resulting in the increase dofetilide-induced QT prolongation and the risk of arrhythmias.

Antivirals

Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg (Co-trimoxazole) causes a 40% increase in plasma concentrations of lamivudine because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. Avoid concomitant high dose Co-trimoxazole.

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.

Zalcitabine plasma concentrations possibly increased by Co-trimoxazole.

Potassium aminobenzoate: effects of sulphonamides inhibited.

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.

Trimethoprim and sulphonamides have been reported to interfere with diagnostic tests, including urea, urinary glucose and urobilinogen tests.

4.6 Fertility, pregnancy and lactation

Pregnancy:

The safety of Co-trimoxazole in human pregnancy 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.

Co-trimoxazole should not be given during pregnancy, particularly in the first trimester, unless clearly necessary.

Co-trimoxazole interferes with folate metabolism and, in animal studies, both agents have been shown to cause foetal abnormalities (see section 5.3). Folate supplementation should be considered if Co-trimoxazole is used in pregnancy.

Animal studies have shown teratogenic effects typical of a folate antagonist in rats but not in rabbits at high doses; these were prevented by administration of dietary folates.

Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persists for several days in the newborn, there may be risk of precipitating hyperbilirubinaemia with associated risk of kernicterus when 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 or those with glucose-6-phosphate dehydrogenase deficiency.

The usual caution is prescribing any drug for women of child-bearing age should be exercised with Co-trimoxazole.

Breast-feeding:

Both sulfamethoxazole and trimethoprim are excreted in breast milk. Administration of Co-trimoxazole should be avoided in late pregnancy and 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, as Co-trimoxazole can cause dizziness, drowsiness, tinnitus, insomnia and hallucinations, 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

As Co-trimoxazole contains trimethoprim and a sulphonamide, the type and frequency of adverse effects 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.

The following convention has been used for the classification of adverse events in terms of frequency: Very common (>1/10), common (>1/100 to < 1/10), uncommon (>1/1,000 to < 1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

• Infections and Infestations

Common:	Monilial overgrowth
• Blood and the lymphatic system disorders
Very rare	Leucopenia, neutropenia, thrombocytopenia, agranulocytosis, megaloblastic anaemia, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, eosinophilia, purpura, haemolysis in certain susceptible G-6-PD deficient patients, bone marrow depression.

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 section 4.3).

• Immune system disorders

• Metabolism and nutrition disorders

Very common:	Hyperkalaemia
Very rare:	Hypoglycaemia, hyponatraemia, anorexia
Frequency not known	Electrolyte disturbances, metabolic acidosis

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

Nervous system disorders

Common:	Headache
Very rare:	Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, dizziness
Frequency not known	Drowsiness, fatigue, and insomnia

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

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

• Gastrointestinal disorders-

Common:	Nausea, diarrhoea
Uncommon:	Vomiting
Very rare:	Glossitis, stomatitis, pseudomembranous colitis, pancreatitis
Frequency not known	Sore mouth

• Eye Disorders

Hepato-biliary disorders

Cholestatic jaundice and hepatic necrosis 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)

• Musculoskeletal and connective tissue disorders

• Renal and urinary disorders

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

During long-term therapy, isolated cases of megaloblastic changes in the bone marrow have been reported; these are reversible by folinic acid therapy.

• Effects associated with Pneumocystis jiroveci (P.carinii) 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

Symptoms

Symptoms of acute overdosage are likely to be nausea, vomiting, abdominal pain, dizziness, rashes, headache, ataxia, drowsiness, dysuria, swelling of the face, weakness and confusion. Symptoms of bone marrow depression may develop. Bone marrow depression has been reported in acute trimethoprim overdosage.

Management

If vomiting has not occurred, induction of vomiting may be desirable. Treatment should consist of gastric lavage if within an hour of ingestion. Absorption of trimethoprim from the gastrointestinal tract is normally complete in approximately 2 hours, but 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. Increased fluid intake will increase the elimination of sulfamethoxazole. Alkalinisation of the urine will also increase the elimination of sulfamethoxazole but decrease that of the trimethoprim. Calcium Leucovirin 5-10 mg daily will counteract any adverse effects of trimethoprim on bone marrow or Calcium folinate (36 mg/day) given orally or intramuscularly for five to seven days should reverse any folate deficiency effect of trimethoprim. Generally supportive measures are recommended. Observe the patient for at least four hours and monitor U&Es and full blood count in symptomatic cases.

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

5 PHARMACOLOGICAL PROPERTIES

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

ATC code: J01E

Mechanism of Action

Co-trimoxazole is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim binds to and reversibly inhibits bacterial dihydrofolate reductase (DHFR) and blocks the production of 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.

Mechanism of resistance

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

Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase in 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.

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

Trimethoprim is readily absorbed from the gastro-intestinal tract and peak concentrations in the circulation occur about 3 hours after an oral dose is taken.

Sulfamethoxazole is readily absorbed from the gastro-intestinal tract and peak plasma concentrations are reached within 4 hours. Doses of 1 g twice daily should produce blood concentrations of unconjugated sulfamethoxazole in excess of 50 pg/mL.

After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption. 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.

When Co-trimoxazole is administered, plasma concentrations of trimethoprim and sulfamethoxazole are generally in the ratio of 1:20; in urine this ratio may vary from 1:1 to 1:5.

Distribution

Trimethoprim is a weak base with a pKa of 7.4. It is lipophilic. Approximately 50% 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 but concentrations in the cerebro-spinal fluid are about one-half of those in the blood. 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.

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. Approximately 66% is bound to plasma albumin.

Biotransformation

The half-life of trimethoprim is about 8.6 to 17 hours. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 mL/min. There appears to be no significant difference in the elderly compared with young patients.

The plasma half-life of sulfamethoxazole is approximately 9 to 11 hours in man. About 15% of sulfamethoxazole in the blood is present as the acetyl derivative.

Elimination

The principal route of excretion of trimethoprim is renal and about 40 - 50% of a dose is excreted unchanged in the urine within 24 hours, together with metabolites. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely. Trimethoprim appears in breast milk.

Sulfamethoxazole elimination in the urine is dependent on pH. The principal route of excretion of sulfamethoxazole is renal, about 25% of a single 2 g dose of sulfamethoxazole has been reported to be excreted in the urine within 8 hours, about 60% being in the form of 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/min. In elderly patients there is a reduced renal clearance of sulfamethoxazole.

When Co-trimoxazole is administered, about 50% of administered trimethoprim and 50% of sulfamethoxazole is excreted in the urine in 24 hours; a larger proportion of sulfamethoxazole appears as inactive metabolite.

5.3 Preclinical safety data

Reproductive toxicology: 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

Microcrystalline Cellulose Starch Pregelatinised Maize Starch Nipastat

Hydrogenated Castor Oil

Magnesium Stearate

Sodium Starch Glycollate (Primojel)

Purified Water

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

10 DATE OF REVISION OF THE TEXT

11/06/2008