4.1. Therapeutic indications

Co-Trimoxazole Forte tablets are indicated in adults and children over 12 years for the treatment of the following infections when owing to sensitive organisms (see section 5.1).

• Treatment and prevention of Pneumocystis jirovecii pneumonitis or “PJP”.

• 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:

• Acute uncomplicated urinary tract infection.

• Acute otitis media.

• Acute exacerbation of chronic bronchitis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

General dosage recommendations

Where dosage is expressed as "tablets" this refers to the adult Forte tablet, i.e 160 mg Trimethoprim BP and 800 mg Sulfamethoxazole BP. If other formulations are to be used appropriate adjustment should be made.

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. If clinical improvement is not evident after 7 days' therapy, the patient should be reassessed.

Adults and children over 12 years:

STANDARD DOSAGE: 1 tablet every 12 hours

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.

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.

Elderly patients:

See Special Warnings and Precautions for Use (section 4.4). 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:

Adults and children over 12 years:

Creatinine Clearance (ml/min)

Recommended Dosage

> 30

1 tablet every 12 hours

15 to 30

1 tablet per day

<15

Not recommended

No information is available for children aged 12 years and under with renal failure. See section 5.2 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.

Pneumocystis jirovecii pneumonitis

Treatment - Adults and children over 12 years:

A higher dosage is recommended using 20 mg trimethoprim and 100 mg 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 of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Co-Trimoxazole). (See section 4.8).

Prevention - Adults and children over 12 years:

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 alternative days.

320 mg trimethoprim/1600 mg sulfamethoxazole per day in two divided doses three times per week on alternative days.

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 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 (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

Oral.

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

4.3. Contraindications

• Hypersensitivity to the active substance(s) sulphonamides, trimethoprim, co-trimoxazole or to any of the excipients listed in section 6.1.

• Contra-indicated in 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.

• First trimester of pregnancy (see section 4.6).

4.4. 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.

• Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS),toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms have been reported with the use of Co-Trimoxazole (see section 4.8).

• 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, TEN (e.g. progressive skin rash often with blisters or mucosal lesions) or DRESS (e.g. fever, eosinophilia) are present, Co-Trimoxazole treatment should be discontinued (see section 4.8) and an alternative treatment considered (as appropriate).

• 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, the treatment must not be re-started in this patient at any time.

• At the start of treatment, the occurrence of a generalised febrile erythema associated with pustules, should raise the suspicion of acute generalised exanthematous pustulosis (AGEP) (see section 4.8); 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. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of an excessive systemic inflammation (e.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.

Elderly patients

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.

Patients with renal impairment

For patients with known renal impairment special measures should be adopted (see section 4.2).

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. Supplementation with folinic acid may be considered during treatment but this should be initiated with caution due to possible interference with antimicrobial efficacy (see section 4.5).

Patients with glucose-6-phosphate dehydrogenase deficiency

In glucose-6-phosphate 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 phenylketonuric 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 and sodium 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.

Patients with serious haematological disorders

Except under careful supervision Co-Trimoxazole should not be given to patients with serious haematological disorders (see section 4.8). 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.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction with 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.

Zidovudine: in some situations, 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.

Cyclosporin: reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and cyclosporin following renal transplantation.

Rifampicin: concurrent use of rifampicin and Co-Trimoxazole results in 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.

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.

Diuretics (thiazides): in elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Pyrimethamine: occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co- trimoxazole be prescribed concurrently.

Warfarin: 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.

Phenytoin: co-trimoxazole prolongs the half-life of phenytoin and if co-administered could result in excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.

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

Methotrexate: 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 (see section 4.4).

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.

Lamivudine: administration of trimethoprim/sulfamethoxazole 160 mg/800 mg (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.

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

Hyperkalaemia: caution should be exercised in patients taking any other drugs that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulfamethoxazole (co-trimoxazole) may result in clinically relevant hyperkalaemia.

Repaglinide: trimethoprim may increase the exposure of repaglinide which may result in hypoglycaemia.

Folinic acid: folinic acid supplementation has been shown to interfere with the antimicrobial efficacy of trimethoprim-sulfamethoxazole. This has been observed in Pneumocystis jirovecii pneumonia prophylaxis and treatment.

Contraceptives: oral contraceptive failures have been reported with antibiotics. The mechanism of this effect has not been elucidated. Women on treatment with antibiotics should temporarily use a barrier method in addition to the oral contraceptive, or choose another method of contraception.

Azathioprine: There are conflicting clinical reports of interactions between azathioprine and trimethoprim-sulfamethoxazole, resulting in serious haematological abnormalities.

4.6. Fertility, pregnancy and lactation

Pregnancy

Trimethoprim is contraindicated during the first trimester of pregnancy (see section 4.3). Studies in animals have shown a teratogenic effect.

Epidemiological studies have shown an increased risk of spontaneous abortion and congenital malformations, in particular neural tube defects, oral clefts and cardiovascular defects, in children of mothers treated with trimethoprim during the first trimester of pregnancy. The presumed mechanism of action is thought to be interference with folates.

In the second and third trimesters, use should be avoided, unless clinically necessary.

Trimethoprim and sulfamethoxazole cross the placenta and their safety in pregnant women 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.

Trimethoprim is a folate antagonist 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.

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 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.

Breast-feeding

The components of Co-Trimoxazole (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

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 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

Summary of the safety profile

As co-trimoxazole 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 reaction

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.

System Organ Class

Frequency

Side effects

Infections and infestations

Common

Overgrowth fungal.

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 reactions,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.

Metabolism and nutrition disorders

Very common

Hyperkalaemia.

Very rare

Hypoglycaemia, hyponatraemia, decreased appetite, metabolic acidosis

Psychiatric disorders

Very rare

Depression, hallucination.

Not known

Psychotic disorder.

Nervous system disorders

Common

Headache.

Very rare

Meningitis aseptic *, seizure, neuropathy peripheral, ataxia, dizziness.

Ear and Labyrinth disorders

Very rare

Vertigo, tinnitus

Eye disorders

Very rare

Uveitis.

Vascular disorders

Not known

Circulatory shock*

Respiratory, thoracic and mediastinal disorders

Very rare

Cough*, dyspnoea*, lung infiltration*.

Gastrointestinal disorders

Common

Nausea, diarrhoea.

Uncommon

Vomiting.

Very rare

Glossitis, stomatitis, pancreatitis.

Hepatobiliary disorders

Very rare

Jaundice cholestatic *, hepatic necrosis*.

Transaminases increased, blood bilirubin increased.

Skin and subcutaneous tissue disorders*

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).

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.

* 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 (see section 4.4).

Hepatobiliary disorders

Jaundice cholestatic and hepatic necrosis may be fatal.

Severe cutaneous adverse reactions (SCARs)

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported to be life-threatening (see section 4.4)

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. Very rare cases of acute generalised exanthematous pustulosis (AGEP) have been observed (see section 4.4).

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 co-trimoxazole, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving co-tromixazole 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms:

Nausea, vomiting, dizziness and confusion are likely signs/symptoms of overdosage. Bone marrow depression has been reported in acute trimethoprim overdosage.

Treatment:

If vomiting has not occurred, induction of vomiting may be desirable. Gastric lavage may be useful, though absorption from the gastrointestinal tract is normally very rapid and complete within approximately two hours. 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.

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