SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL    PRODUCT

Co-Trimoxazole Tablets B.P. (400/80)

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Sulfamethoxazole    400mg

Trimethoprim    80mg

For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Uncoated Tablets for oral administration

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 Tablets are indicated:

-    In the treatment and primary and secondary prophylaxis of Pneumocystis jiroveci (P. carinii) pneumonitis in both adults and children.

-    In the treatment and prophylaxis of toxoplasmosis and the treatment of nocardia.

-    The treatment of urinary tract infections and acute exacerbations of chronic bronchitis, where there is bacterial evidence of Co-Trimoxazole sensitivity and a good reason to use the combination product rather than a single antibiotic.

-    The treatment of otitis media in children, again where there is a good reason to prefer the combination product.

4.2    Posology and method of administration

Method of administration: Oral

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

Acute Infections

Adults and Children over 12 years Two tablets every 12 hours

Children aged 6 to 12 years One tablet every 12 hours

Co-trimoxazole tablets are not recommended for children under 6 years of age.

Treatment should be continued until the patient has been 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 the above dosage, in the treatment of acute uncomplicated lower urinary tract infections, short term therapy of 1-3 days duration has been shown to be effective.

Use in the elderly

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.

Special dosage recommendations

Impaired Renal function

Adults and children over 12 years

Creatinine clearance    Recommended dosage

(ml/min)

>30    Two tablets every 12 hours

15 to 30    One tablet every 12 hours

<15    Not recommended

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

Pneumocystis jiroveci (P.carinii) pneumonitis

Treatment

A higher dosage is recommended using 20mg trimethoprim and 100mg sulfamethoxazole per kg of body weight per day in two or more divided doses for two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim greater or equal to 5 microgram/ml

Prevention

Adults

The following dosage schedules may be used:

-    two tablets daily 7 days per week

-    two tablets three times per week on alternate days

-    four tablets per day in two divided doses three times a week on alternate days

Children aged 6 to 12 years

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

-    one tablet taken twice    a    day seven days    a week

-    one tablet taken twice    a    day three times    per week on    alternate days

-    one tablet taken twice    a    day three times    per week on    consecutive days

-    two tablets taken as a    single dose three times per week on consecutive days

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

Nocardiasis: 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 the prevention of Pneumocystis jiroveci (P.carinii) pneumonia may be appropriate.

4.3 Contraindications

Co-Trimoxazole Tablets should not be given if there is a history of hypersensitivity to sulphonamide, trimethoprim or co-trimoxazole or any of the excipients of co-trimoxazole tablets.

Co-trimoxazole tablets are contra-indicated in patients with liver parenchymal damage, serious haematological disorders except under careful supervision (see section 4.8 Undesirable Effects) and in severe renal insufficiency where repeated measurements of plasma concentration cannot be performed. Co-trimoxazole has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

Co-trimoxazole should not be given to premature babies nor to full-term infants during the first 6 weeks of life except for the treatment / prophylaxis of Pneumocystis jiroveci (P.carinii) pneumonia in infants 4 weeks of age or greater.

4.4 Special warnings and precautions for use

Patients receiving pyrimethamine in excess of 25 mg weekly should have blood pictures monitored due to occurrence of megaloblastic anaemia.

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

Co-trimoxazole tablets should be discontinued at the first appearance of skin rash.

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 renal and/or liver function and /or concomitant use of other drugs.

Special care should be exercised in treating elderly or susceptible folate-deficient patients: folate supplementation should be considered.

An adequate urinary output should be maintained at all times as sulphonamide crystals have been noted in the cooled urine of some patients and the risk may be increased in patients suffering from malnutrition.

Regular monthly blood counts are advisable if co-trimoxazole is given for long periods and a folate supplement should be considered with prolonged high dosage.

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

Co-trimoxazole should be given with caution to 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.

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

Administration of Co-trimoxazole to patients with known or suspected to be at risk of acute porphyria should be avoided. Trimethoprim and sulphonamides but not specifically sulfamethoxazole have been associated with clinical exacerbation of porphyria.

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

Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of PCP (see also Section 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

There may be an increased risk of thrombocytopenia with or without purpura in elderly patients concurrently receiving diuretic (mainly thiazides)

Pyrimethamine - see Section 4.4 Special Precautions and Warnings

In some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole.

Administration of trimethoprim/sulfamethoxazole 160/800mg (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.

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

Co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin. Careful control of anticoagulant therapy during co-trimoxazole treatment is advised.

Co-trimoxazole prolongs the half life of phenytoin and if co-administered could result in excessive phenytoin effect. Close monitoring of the patients condition and serum phenytoin levels are advised.

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

Simultaneous administration of trimethoprim with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine) may lead to an increase in plasma concentration of one or both of the drugs.

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

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

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

If co-trimoxazole is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered.

4.6 Pregnancy and lactation

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

Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when co-trimoxazole is administered to the mother near to 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.

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

4.7 Effects on ability to drive and use machines

As co-trimoxazole can cause dizziness, tinnitus, ataxia and vertigo, patients should make sure they are not affected before driving or operating machines.

4.8 Undesirable effects

The frequency categories associated with 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 effects in terms of frequency:- very common >1/10, common > 1/100, and <1/10, uncommon > 1 /1000 and <1/100, rare >1/10,000 and < 1/1000, very rare <1/10,000

Infections and infestations:

Common: monilial overgrowth.

Blood and 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.

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 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).

Immune system disorders:

Very rare: serum sickness, anaphylaxis, allergic myocarditis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus.

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.

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, shortness of breath, pulmonary infiltrates.

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

Gastro-intestinal disorders:

Common: nausea, diarrhoea.

Uncommon: vomiting.

Very rare: glossitis, stomatitis, pseudomembranous colitis, pancreatitis. Hepatobiliary disorders:

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

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,

Stevens-Johnson syndrome, Lyells’s syndrome (toxic epidermal necrolysis). Lyell's syndrome carries a high mortality.

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.

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.

An increased risk of rhabdomyolysis has been seen in patients with HIV infection, particularly in those who received treatment with co-trimoxazole for P.jiroveci pneumonia (see Section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms are nausea, vomiting abdominal pain, dizziness, confusion. Bone marrow depression has been reported in acute trimethoprim overdosage.

Treatment should be gastric lavage within one hour or increased fluid intake if later. Administer calcium folinate orally or IV for 5 to 7 days. Both trimethoprim and sulfamethoxazole are moderately dialysable by haemodialysis. Peritoneal dialysis is not effective.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: sulphonamides and trimethoprim ATC code: J01EE01.

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

Trimethoprim binds to plasmodial DHFR but less tightly than to the bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme. Many of 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 be noted that satisfactory sensitivity testing is achieved only with recommended media free from inhibitory substances especially thymidine and thymine.

5.2 Pharmacokinetic properties

After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose. Steady state levels in adults are reached after dosing for 2-3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.

Trimethoprim is a weak base with a pKa of 7.4. It is lipophilic. Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (intestinal) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum.

Approximately 50% of trimethoprim in the plasma is protein bound. The 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 10ml/minute. There appears to be no significant difference in the elderly compared with young patients.

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

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% of sulfamethoxazole in the plasma is protein bound. The half-life in man is approximately 9 to 11 hours in the presence of normal renal function. There is no change in the half-life of active 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 25ml/minute.

The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In elderly patients there is a reduced renal clearance of sulfamethoxazole.

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

Starch

Magnesium Stearate Colloidal Silica Sodium Starch Glycollate

6.2    Incompatibilities

Rare

6.3    Shelf life

Three years

6.4    Special precautions for storage

Protect from heat, light and moisture

6.5    Nature and contents of container

There are four pack sizes: 28’s, 100's, 500's and 1,000's and all are packed in securitainers

6.6 Special precautions for disposal

The tablets should be taken as shown in paragraph 4.2.

There are no special requirements regarding handling.

All medicines should be stored in a safe place out of the reach of children.

7    MARKETING AUTHORISATION HOLDER

Chemidex Pharma Limited

T/A Essential Generics or Chemidex Generics

Chemidex House

Egham Business Village

Egham Surrey

TW20 8RB

United Kingdom

8    MARKETING AUTHORISATION NUMBER

PL 17736/0079

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/02/2005    / 04/12/2008

10 DATE OF REVISION OF THE TEXT

15/10/2015