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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-trimoxazole Forte 160mg/800mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 160 mg of trimethoprim and 800 mg of sulfamethoxazole For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet.

White oblong shaped tablets with an approximate diameter of 10mm x 19mm, marked "COT 960"on one side and a 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 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.

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 nocardoasis.

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 guidance on the appropriate use of antibacterial agents.

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:	1 tablet twice daily
For severe infections:	1/ tablets twice daily

Paediatric population

Over 12 years:	As for adults
Under 12 years:	Not recommended

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.

Pneumocystis carinii (Pneumocytosis jiroveci) pneumonitis:

Treatment: A higher dosage is recommended, using 20mg trimethoprim and 100mg sulfamethoxazole per kg body weight per day in two or more divided doses for two weeks. The steady state or 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: The following dose schedules may be used:

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

•    160 mg trimethoprim/800 mg sulfamethoxazole three times per week on alternate days.

•    320 mg trimethoprim/1600 mg sulfamethoxazole per day in two divided doses three times per 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/m 2 /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.

Special Populations:

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.

Patients with renal impairment:

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).

Creatinine clearance	Serum creatinine(pmol/l)		Dosage
(ml/min)
>30	Men	<265	Standard dosage
	Women	<175
15 to 30	Men	265-620	Half the standard dosage
	Women	175-400
<15	Men	>620	Not recommended
	Women	>400

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

Older people

See section 4.4. Unless otherwise specified standard dosage applies.

Method of administration

For oral administration

4.3 Contraindications

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

•    Severe hepatic impairment, particularly those showing marked liver parenchymal damage, 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 from four weeks of age.

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

4.4 Special warnings and precautions for use

Co-trimoxazole should be discontinued if a skin rash appears or blood disorder develops.

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 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. 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.

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 10 mg 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 treatment of infections due to Group A beta-haemolytic streptococci such as streptococcal pharyngitis; 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

ACE Inhibitors

Risk of severe hyperkalaemia

Anaesthetics

Increased risk of methaemoglobinaemia when sulphonamides given with prilocaine

Antiarrythmics

Co-trimoxazole increases the risk of ventricular arrhythmias with amiodarone. Concomitant use should be avoided. 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.

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.

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 possibly be enhanced.

Antidiabetic Agents

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

Anticonvulsants

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.

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

Antimalarial Agents

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

Antivirals

Concomitant treatment with zidovudine may increase the risk of haematological 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 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.

Cytotoxic Agents

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

Digoxin

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

Diuretics

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

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).

Ciclosporine

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

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

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 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.

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.
Immune system disorders
Very rare:	Serum sickness, anaphylaxis, allergic myocarditis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus (SLE)
Metabolism and nutrition disorders
Very Common	Hyperkalaemia
Very rare	Hypoglycaemia, hyponatraemia, anorexia
Frequency Not Known	Electrolyte disturbances, metabolic acidosis
Psychiatric disorders
Very rare	Depression, hallucinations
Nervous System disorders
Common	Headache
Very Rare	Aseptic meningitis1, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, dizziness
Frequency Not Known	Drowsiness, fatigue, and insomnia
Respiratory, thoracic and mediastinal disorders
Very Rare	Cough, dyspnoea, pulmonary infiltrates2
Gastrointestinal disorders
Common	Nausea, diarrhoea
Uncommon	Vomiting
Very rare	Glossitis,, stomatitis, pseudomembranous colitis, pancreatitis
Frequency not known	Sore mouth
Eye Disorders
Very rare	Uveitis

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 5-10mg daily will counteract any adverse effects of trimethoprim on bone marrow or Calcium folinate (3-6 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 byhaemodialysis. Peritoneal dialysis is not effective.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

ATC code: J01EE

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-aminobenzoid acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme that converts dihydrofolate to tetrahydrofolate and blocks the production of tetrahydrofolate. Depending on the conditions the effect may be bactericidal. sulfamethoxazole and trimethoprim 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. Both substances are employed in the treatment of bacterial infections.

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 the bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Most common pathogenic bacteria are sensitive 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 not be noted that satisfactory sensitivity testing is achieved only with the 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:

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.

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 pKa of 7.4. It is lopophilic. 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 concentration 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.

Sulphamethoxazole is a weak acid with a pKa of 6.0. The concentration of active sulphamethoxazole in a variety of body fluids is of the order of 20 to 50% of the plasma concentration. About 66% is bound to plasma albumin.

Biotransformation

The half-life of trimethoprim is about 8.6 to 17 hours when renal function is normal.

It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10ml/minute. There appears to be no significant difference in elderly compared with young patients.

The plasma half-life of sulfamethoxazole is approximately 9 to 11 hours. 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 2g 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 the half-life of the major acetylated metabolite is increased when creatinine clearance is below 25ml/minute. In elderly patients, there clearance of sulfamethoxazole is reduced.

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

Sta-Rx 1500 HSE (Pregelatinised Starch)

Starch

Nipastat

Hydrogenated Vegetable Oil

Magnesium Stearate

Sodium Starch Glycollate (Primojel)

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for    storage

Store in a cool dry place.

Store in the original package in order to protect from heat, light and moisture

6.5    Nature and contents    of    container

PVC/Aluminium blister pack

HDPE round, tear strip tamper evident container containing white absorbent cotton BP and an HDPE pilfer proof lock ring cap.

Pack sizes: 2, 4, 6, 8, 10, 14, 100, 250, 500 or 1000 tablets per blister pack/container. Not all pack sizes may be marketed

Special precautions for disposal and other handling

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited

3 Howard Road

Eaton Socon

St. Neots

Cambridgeshire

PE19 8ET

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0354

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of first authorisation: 17/03/2006 Date of latest renewal: 14/12/2008

10 DATE OF REVISION OF THE TEXT

11/09/2015