CO-TRIMOXAZOLE

e. 80 mg Trimethoprim BP and 400 mg Sulfamethoxazole BP. If other formulations are to be used appropriate adjustment should be made.

Standard dosage recommendations for acute infections Adults (>18 years old):

STANDARD DOSAGE Age Tablets >18 years old 2 tablets every 12 hours Children over 12 years old (>12 to <18 years old): The standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg body weight per day, given in two equally divided doses.

The schedules for children are according to the child's age provided in the table below: Age Tablets >12 to <18 years old 2 tablets every 12 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. 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.

4). Unless otherwise specified standard dosage applies.

Impaired hepatic function:

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

Impaired renal function:

Dosage recommendation: Children (>12 to <18 years old) and adults (>18 years old): Creatinine Clearance (ml/min) Recommended Dosage >30 2 tablets every 12 hours 15 to 30 1 tablet every 12 hours <15 Not recommended No information available for children aged 12 years and under with renal failure.

2 for the pharmacokinetics in the paediatric population with normal renal function of both components of co-trimoxazole, TMP and SMZ. Measurements of plasma concentration of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of co- trimoxazole.

If the concentration of total sulfamethoxazole exceeds 150 microgram/ml then treatment should be interrupted until the value falls below 120 microgram/ml.

Pneumocytosis jiroveci pneumonitis:

Treatment - Children (>12 to <18 years old) and adults (>18 years old): 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 aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous co-trimoxazole).

8).

Prevention - Adults (>18 years old):

The following dose schedules may be used: • 160mg trimethoprim/800mg sulfamethoxazole daily for 7 days per week. • 160mg trimethoprim/800mg sulfamethoxazole three times a week on alternate days. • 320 mg trimethoprim/1600 mg sulfamethoxazole per day in two divided doses three times per week on alternate days.

Prevention - Children (>12 to <18 years old):

The standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg body weight per day, given in two equally divided doses.

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

Age Tablets >12 to <18 years old 2 tablets every 12 hours, seven days per week >12 to <18 years old 2 tablets every 12 hours, three times per week on alternative days >12 to <18 years old 2 tablets every 12 hours, three times per week on consecutive days >12 to <18 years old 4 tablets once a day, 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 - Adults (>18 years old):

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 jiroveci pneumonitis may be appropriate.

Method of administration:

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

Summary of the safety profile 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.

Tabulated list of adverse reaction The following convention has been used for the classification of adverse events in terms of frequency: Very common (≥1/10), common (≥1/100 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 Very rare Pseudomembranous colitis Blood and lymphatic system disorders Very rare Leukopenia, neutropenia, thrombocytopenia, agranulocytosis, anaemia megaloblastic, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, eosinophilia, purpura, haemolysis in certain susceptible G- 6-PD deficient patients.

Immune system disorders Very rare Serum sickness, anaphylactic reaction, allergic myocarditis, hypersensitivity vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus. Severe hypersensitivity reactions associated with PJP*, rash, pyrexia, neutropenia, thrombocytopenia, hepatic enzyme increased, hyperkalaemia, hyponatraemia, rhabdomyolysis.

Psychiatric disorders Not known Psychotic disorder. Nervous system disorders Very rare Meningitis aseptic *, convulsions/seizures, neuropathy peripheral, ataxia, dizziness. Ear and labrynth disorders Very rare Vertigo, tinnitus Eye disorders Very rare Uveitis.

Respiratory, thoracic and mediastinal disorders Very rare Cough *, dyspnoea*, lung infiltration*. Common Nausea, diarrhoea. Uncommon Vomiting. Gastrointestinal disorders Very rare Glossitis, stomatitis, pancreatitis. Hepatobiliary disorders* Very rare Transaminases increased, blood bilirubin increased, cholestatic jaundice, hepatic necrosis.

Common Rash. Very rare Photosensitivity reaction, angiodema, dermatitis exfoliative, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome (SJS) *, toxic epidermal necrolysis (TEN) *. Acute generalised exanthematous pustulosis (AGEP).

Skin and subcutaneous tissue disorders* Not known Acute febrile neutrophilic dermatosis (Sweet's syndrome), Drug reaction with eosinophilia and systemic symptoms (DRESS)* Musculoskeletal and connective tissue disorders Very rare Arthralgia, myalgia.

Renal and urinary disorders Very rare Renal impairment (sometimes reported as renal failure), tubulointerstitial nephritis and uveitis syndrome, renal tubular acidosis Vascular disorders Not known Circulatory shock * see description of selected adverse reactions Description of selected adverse reactions Aseptic meningitis Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.

Pulmonary hypersensitivity reactions Cough, dyspnoea and lung infiltration may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal. Hepatobiliary disorders Jaundice cholestatic and hepatic necrosis may be fatal.

4). As with any other drug, allergic reactions such as an itchy rash and hives may occur in patients with hypersensitivity to the components of the drug. 4). Effects associated with Pneumocystis jirovecii Pneumonitis (PJP) management Very rare: Severe hypersensitivity reactions, rash, pyrexia, neutropenia, thrombocytopenia, hepatic enzyme increased, hyperkalaemia, hyponatraemia, rhabdomyolysis.

At the high dosages used for PJP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. Severe hypersensitivity reactions have been reported in PJP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days.

Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of PJP. Circulatory shock Cases of circulatory shock, often accompanied by fever and not responding to standard treatment for hypersensitivity, have been reported with sulfamethoxazole + trimethoprim, mainly in immunocompromised patients.

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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Life threatening adverse reactions Fatalities, although very rare have occurred due to severe reactions including Stevens- Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

• Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of co-trimoxazole. • Patients should be advised of the signs and symptoms and monitored closely for skin reactions.

The highest risk for occurrence of SJS or TEN is within the first weeks of treatment. g. g. 8). • The best results in managing SJS, TEN and DRESS come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

• If the patient has developed SJS, TEN or DRESS with the use of co-trimoxazole, co-trimoxazole must not be re-started in this patient at any time. 8); it requires cessation of treatment and contraindicates any new administration of co-trimoxazole alone or in combination with other drugs.

Haemophagocytic lymphohistiocytosis (HLH) Cases of HLH have been reported very rarely in patients treated with co-trimoxazole. g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis).

Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, co-trimoxazole treatment should be discontinued. Respiratory toxicity Very rare, severe cases of respiratory toxicity, sometimes progressing to Acute Respiratory Distress Syndrome (ARDS), have been reported during co-trimoxazole treatment.

The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function may be preliminary signs of ARDS. In such circumstances, co- trimoxazole should be discontinued and appropriate treatment given.

g. impaired kidney and/or liver function and/ or concomitant use of other drugs. 2). Urinary output An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients.

In patients suffering from malnutrition the risk may be increased. Folate Regular monthly blood counts are advisable when co-trimoxazole is given for long periods, or to folate deficient patients or to the elderly; since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate.

5). Patients with glucose-6-phosphate dehydrogenase deficiency In glucose-6-phosphatase dehydrogenase (G-6-PD) deficient patients, haemolysis may occur. Patients with severe atopy or bronchial asthma Co-trimoxazole should be given with caution to patients with severe atopy or bronchial asthma.

Treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci Co-trimoxazole should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci; eradication of these organisms from the oropharynx is less effective than with penicillin.

Phenylalanine metabolism Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenyl ketonuric patients on appropriate dietary restriction. Patients with or at risk of porphyria The administration of co-trimoxazole to patients known or suspected to be at risk of porphyria should be avoided.

Both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria. Patients with hyperkalaemia and hyponatraemia Close monitoring of serum potassium is warranted in patients at risk of hyperkalaemia and hyponatraemia.

Metabolic acidosis Co-trimoxazole has been associated with metabolic acidosis when other possible underlying causes have been excluded. Close monitoring is always advisable when metabolic acidosis is suspected. 8). Co-trimoxazole has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

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

Co-Trimoxazole contains Sodium This medicine contains less than 1 mmol sodium (23mg) per […]

1. • Co-trimoxazole should not be given to patients with severe impairment of liver function. • Contra-indicated in patients with severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

• Co-trimoxazole should not be given to infants during the first 6 weeks of life. • Co-trimoxazole should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides.

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