CO-TRIMOXAZOLE

Posology:

Standard dosage recommendations for acute infections Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 days. For severe infections in all age groups, dosage may be increased by 50%.

Adults and children over 12 years old:

STANDARD DOSAGE Age Solution for Infusion >12 years old 2 ampoules (10 ml) every 12 hours Children aged 12 years and under (>6 weeks to <12 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.

25 ml every 12 hours. 0 ml every 12 hours.

Elderly patients:

See section

Summary of the safety profile As Co-trimoxazole for Infusion contains trimethoprim and a sulphonamide, the type and frequency of adverse reactions 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.

In addition, adverse events may vary in their incidence depending on the indication. Tabulated list of adverse reactions The following convention has been used for the classification of adverse events 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, 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.

Nervous system disorders Very rare Meningitis aseptic *, Seizure, neuropathy peripheral, ataxia,dizziness. Ear and labyrinth 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 Jaundice cholestatic *, hepatic necrosis*. Transaminases increased, blood bilirubin increased.

Common Rash. Very rare Photosensitivity reaction, dermatitis exfoliative, angioedema, 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 trimethoprim-sulfamethoxazole 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 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 trimethoprim-sulfamethoxazole, sometimes after a dosage interval of a few days.

Rhabdomyolysis has been reported in HIV positive patients receiving trimethoprim-sulfamethoxazole for prophylaxis or treatment of PJP. For the management of the hypersensitivity reactions associated with Co- Trimoxazole therapy concomitant administration of intravenous diphenhydramine may permit continued infusion when Co-trimoxazole for Infusion is used for the 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.

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

Impaired renal function:

Dosage recommendation: Adults (>18 years old) and Children over 12 years old (>12 to <18 years old): Creatinine Clearance (ml/min) Recommended Dosage > than 30 2 ampoules (10 ml) every 12 hours 15-30 1 ampoule (5 ml) every 12 hours < 15 Not recommended.

No information is 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 for Infusion, TMP and SMZ. Caution should be exercised when treating patients with severe hepatic impairment as there may be changes in the absorption and biotransformation of trimethoprim and sulfamethoxazole.

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 16 mg/80 mg per ml for Infusion If the concentration of total sulfamethoxazole exceeds 150 micrograms/ml then treatment should be interrupted until the value falls below 120 micrograms/ml.

Pneumocystis jirovecii pneumonitis:

Treatment : 15-20 mg trimethoprim and 75-100 mg sulfamethoxazole per kg of bodyweight per day in two or more divided doses. Therapy should be changed to the oral route as soon as possible and continued for a total treatment period of 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: Standard dosage as described under acute infections for the duration of the period at risk.

Nocardiosis:

There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used (one tablet contains 400 mg sulfamethoxazole and 80 mg trimethoprim).

Toxoplasmosis:

There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. For prophylaxis, however, the dosages suggested for prevention of Pneumocystis jirovecii pneumonitis may be appropriate.

Method of administration:

Co-trimoxazole for Infusion is for administration only by the intravenous route and must be diluted before administration. It is intended that Co-trimoxazole for Infusion should be used only during such a period as the patient is unable to accept oral therapy, where initiation of treatment is particularly urgent or for convenience if the patient is already receiving intravenous fluids.

Although Co-trimoxazole for Infusion is useful in critically ill patients, there may be no therapeutic advantage over oral preparation. 6. 1. • Co-trimoxazole for Infusion is contra-indicated in patients with severe impairment of liver function • Co-trimoxazole for Infusion is contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

• Co-trimoxazole for Infusion should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides. • Co-trimoxazole for Infusion should not be given to patients with acute porphyria.

• Co-trimoxazole for Infusion should not be given to infants during the first 6 weeks of life. 4 Special warnings and precautions for use 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.

Severe cutaneous adverse reactions (SCARs) Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia with 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 or 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. , fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis).

Patients who develop early manifestations of pathologic […]

1. • Co-trimoxazole for Infusion is contra-indicated in patients with severe impairment of liver function • Co-trimoxazole for Infusion is contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

• Co-trimoxazole for Infusion should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides. • Co-trimoxazole for Infusion should not be given to patients with acute porphyria.

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