Co-Trimoxazole Pharmc 160 mg/800 mg/80 mg/400 mg/40 mg/200 mg

Co-trimoxazole is effective against a wide range of Gram-positive and Gram-negative organisms. It is indicated for:

• Upper and lower respiratory tract infections e.g., acute, and chronic bronchitis, bronchiectasis, tonsillitis, sinusitis and pharyngitis, otitis media, pneumonia and pneumocystis carinii pneumonitis (see also section 4.8 Pneumocystis jirovecii Pneumonitis (PJP)).
• Renal and urinary tract infections e.g., pyelitis, pyelonephritis, urethritis, acute and chronic cystitis and cystopyelitis, including prostatitis.
• Gastrointestinal tract infections e.g., enteritis, typhoid and paratyphoid fever, typhoid carriage, bacillary dysentery and cholera. (as an adjunct to fluid and electrolyte replacement).
• Genital tract infections: both male and female including gonococcal infections.
• Skin infections e.g., pyoderma, boils, furuncles, abscesses.
• Other bacterial infections: acute brucellosis, mycetoma except those caused by true fungi, nocardiosis, acute and chronic osteomyelitis.

Posology

CO-TRIMOXAZOLE DS PHARMC

Adults and children over 12 years

The usual dose is one CO-TRIMOXAZOLE DS PHARMC tablet every 12 hours after meals. The maximum dose (for particularly severe cases) is one and a half CO-TRIMOXAZOLE DS PHARMC tablets every 12 hours. The minimum dosage for long term treatment (more than 14 days) is half a CO-TRIMOXAZOLE DS PHARMC tablet every 12 hours.

CO-TRIMOXAZOLE PHARMC

Adults and children over 12 years

The usual dose is two CO-TRIMOXAZOLE PHARMC tablets every 12 hours after meals. The maximum dose (for particularly severe cases) is three CO-TRIMOXAZOLE PHARMC tablets every 12 hours. The minimum dosage for long term treatment is one CO-TRIMOXAZOLE PHARMC tablet every 12 hours.

CO-TRIMOXAZOLE PAED PHARMC (Bottle to be shaken before use)

Infants and children 6 weeks to 5 months: Half (2,5 mL) a medicine measure twice daily.

6 months to 5 years: One (5 mL) medicine measure twice daily.

6 to 12 years: Two (10 mL) medicine measures twice daily.

In the treatment of acute infections CO-TRIMOXAZOLE PHARMC should be administered for at least 5 days or for at least 2 days after the symptoms have disappeared. If clinical improvement is not evident after 7 days therapy, the patient should be reassessed.

Special populations

Renal Impairment

If CO-TRIMOXAZOLE PHARMC is indicated for patients with renal impairment, the following dosage scheme, based on creatinine clearance is suggested:

• Above 25 mL/min: Standard dosage
• 15 u2013 25 mL/min: Standard dosage for a maximum of 3 days followed by half the standard daily dosage.
• Below 15 mL/min: Not to be administered unless haemodialysis facilities are available when half the standard daily dosage may be given.

Measurements of plasma concentrations of sulfamethoxazole at intervals of 2 days are recommended in samples obtained 12 hours after administration of CO-TRIMOXAZOLE PHARMC. If the concentration of total sulfamethoxazole exceeds 150 ug/mL then treatment should be interrupted until the value falls below 120 ug/mL. No Information is available for children with renal failure.

Method of administration

The tablets and suspension must be taken by mouth, after food. The tablets must be swallowed with a drink of water.

• Hypersensitivity to sulfamethoxazole, trimethoprim, sulfonamides or to any of the excipients listed in section 6.1.
• Patients suffering from porphyria
• Liver parenchymal damage
• Megaloblastic anaemia due to folic acid deficiency
• Severe renal insufficiency
• Pregnancy, in women prior to delivery or by nursing mothers.
• Infants during the first 6 weeks of life.

Immunocompromised patients

A high incident of side-effects occurs in immunocompromised patients such as those suffering from AIDS or patients receiving immunosuppressive therapy. The adverse effects include skin rash, recurrent fever, neutropenia, thrombocytopenia and raised liver enzyme values.

Life threatening skin adverse reactions

CO-TRIMOXAZOLE PHARMC may cause the occurrence of erythema multiforme, toxic dermal necrolysis and allergic vasculitis. Treatment should be discontinued immediately when a rash appears because the danger of severe allergic reactions.

Folate

CO-TRIMOXAZOLE PHARMC should be given with caution to patients with actual or possible folate deficiency because of possible interference with human folate metabolism by trimethoprim as in CO-TRIMOXAZOLE PHARMC. Administration of folinic acid could be considered.

Elderly patients

Adverse effects on the blood may be more severe in malnourished or elderly patients: there also appears to be an increased risk of thrombocytopenia in elderly patients concurrently receiving diuretics, mainly thiazides.

Prolonged treatment

All patients receiving prolonged treatment with CO-TRIMOXAZOLE PHARMC should be given regular blood examinations.

Renal impairment

CO-TRIMOXAZOLE PHARMC should be used cautiously and in reduced dosage in patients with impaired renal function (see section 4.2). Because of the risk of crystalluria, an adequate fluid intake should be maintained, and the administration of alkalis may be necessary if very large doses are used.

Cross-sensitivity

Cross-sensitivity has been observed between sulfamethoxazole as in CO-TRIMOXAZOLE PHARMC and chemically related compounds such as some diuretics, particularly acetazolamide and thiazides, and the sulfonylurea hypoglycaemic medicines.

Excipients with known effect

CO-TRIMOXAZOLE PHARMC contains Nipastat, a mixture of parahydroxybenzoate esters. It may cause allergic reactions (possibly delayed). CO-TRIMOXAZOLE PAED PHARMC contains alcohol 0,025 mg of alcohol (ethanol) in each 5 mL which is equivalent to 0,5 % v/v alcohol (ethanol). The amount in 5 mL of this medicine is equivalent to 0,5 mL of bear and less than 0,5 mL of wine. The small amount of alcohol in this medicine will not have any noticeable effects. CO-TRIMOXAZOLE PAED PHARMC contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take CO-TRIMOXAZOLE PAED PHARMC. The sucrose content of 2 500 mg per 5 mL should be taken into account in patients with diabetes mellitus.

Oral anticoagulants, methotrexate and phenytoin

Sulfamethoxazole as in CO-TRIMOXAZOLE PHARMC may potentiate the effects of some medicines such as oral anticoagulants, methotrexate, phenytoin; this may be due to displacement of the compound from plasma protein binding sites or to inhibition of metabolism.

Trimethoprim as in CO-TRIMOXAZOLE PHARMC may potentiate the anticoagulant effect of warfarin. It also prolongs the half-life of phenytoin.

Sulfonylurea compounds

High doses of sulfamethoxazole as in CO-TRIMOXAZOLE PHARMC may have a hypoglycaemic effect. The antidiabetic effect of the sulfonylurea compounds may be enhanced by the concomitant administration of sulfamethoxazole.

Para-aminobenzoic acid and compounds

The action of sulfamethoxazole as in CO-TRIMOXAZOLE PHARMC may be antagonised by para-aminobenzoic acid and compounds derived from it, particularly the procaine group of local anaesthetics.

Paraldehyde has been reported to increase the acetylation of sulfamethoxazole with subsequent increased risk of crystalluria.

Diagnostic tests

Sulfamethoxazole as in CO-TRIMOXAZOLE PHARMC may interfere with some diagnostic tests including those for urea, creatinine, and urinary glucose and urobilinogen. Trimethoprim as in CO-TRIMOXAZOLE PHARMC may interfere with some diagnostic tests including serum methotrexate assay where dihydrofolate reductase is used, and the Jaffe reaction for creatinine.

Digoxin, procainamide, and tolbutamide

Trimethoprim has been reported to interact with a number of other medicines by interfering with their clearance; such medicines include digoxin, procainamide, and tolbutamide.

Cyclosporine

Reversible deterioration in renal function has been reported in patients given trimethoprim as in CO-TRIMOXAZOLE PHARMC and cyclosporine following renal transplantation.

Pyrimethamine

Patients receiving pyrimethamine may develop megaloblastic anaemia due to the trimethoprim component in CO-TRIMOXAZOLE PHARMC.

Zidovudine

Concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to CO-TRIMOXAZOLE PHARMC. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.

Lamivudine

Administration of trimethoprim /sulfamethoxazole 160 mg/800 mg as in CO-TRIMOXAZOLE DS PHARMC causes a 40 % increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.

Hyperkalaemia

Caution should be exercised in patients taking any other medicines 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 as in CO-TRIMOXAZOLE PHARMC. This has been observed in Pneumocystis jirovecii pneumonia prophylaxis and treatment.

Contraceptives

Oral contraceptive failures have been reported with antibiotics, such as CO-TRIMOXAZOLE PHARMC. The mechanism of this effect has not been elucidated. Women on CO-TRIMOXAZOLE PHARMC treatment 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 as in CO-TRIMOXAZOLE PHARMC, resulting in serious haematological abnormalities.

Pregnancy

Trimethoprim and sulfamethoxazole as in CO-TRIMOXAZOLE PHARMC cross the placenta and their safety in pregnant women has not been established. CO-TRIMOXAZOLE PHARMC should not be used during pregnancy (see section 4.3).

Breastfeeding

The components of CO-TRIMOXAZOLE PHARMC (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of CO-TRIMOXAZOLE PHARMC should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinemia. CO-TRIMOXAZOLE PHARMC should not be given to the new-born infant during the first weeks of life (see section 4.3).

It is not always possible to predict to what extent CO-TRIMOXAZOLE PHARMC may interfere with the daily activities of a patient. CO-TRIMOXAZOLE PHARMC can cause hallucinations, headache, dizziness and vertigo (see section 4.8). Patients should ensure that they do not engage in the above activities until they are aware of the measure to which CO-TRIMOXAZOLE PHARMC affects them.

a. Summary of the safety profile

Hypersensitivity reactions particularly involving the skin are among the most common adverse effects of CO-TRIMOXAZOLE PHARMC and are usually due to the sulfamethoxazole component. The Stevens-Johnson and Lyell's syndromes have been reported. Adverse effects on the gastro-intestinal tract may also occur fairly frequently.

b. Tabulated summary of adverse reactions

System Organ Class Frequency Adverse reactions

Infections and infestations Frequent Overgrowth fungal Less frequent Pseudomembranous colitis

Blood and lymphatic system disorders Less frequent Agranulocytosis, aplastic anaemia, thrombocytopenia, leukopenia, hypoprothrombinaemia, eosinophilia, methaemoglobinaemia, acute haemolytic anaemia often associated with glucose-6-phosphate dehydrogenase deficiency, neutropenia

Immune system disorders Less frequent Anaphylaxis, serum sickness, allergic myocarditis, hypersensitivity vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus, severe hypersensitivity reactions associated with PJP*

Endocrine disorders Frequency unknown Hypothyroidism

Metabolism and nutrition disorders Frequent Hyperkalaemia Less frequent Hypoglycaemia, hyponatraemia, decreased appetite, metabolic acidosis

Psychiatric disorders Less frequent Depression, hallucination Frequency unknown Psychotic disorder

Nervous system disorders Frequent Headache Less frequent Meningitis aseptic, * ataxia, dizziness, fatigue, insomnia, peripheral neuritis, seizure

Eye disorders Less frequent Optic neuropathy, transient myopia, uveitis

Ear and labyrinth disorders Less frequent Vertigo, tinnitus

Respiratory, thoracic and mediastinal disorders Less frequent Cough*, dyspnoea*, lung infiltration* Frequency unknown Cyanosis due to methaemoglobinaemia or sulphaemoglobinaemia

Gastrointestinal disorders Frequent Nausea, diarrhoea Less frequent Vomiting, glossitis, stomatitis, pancreatitis

Hepato-biliary disorders Less frequent Jaundice cholestatic *, hepatic necrosis,* increased transaminases, increased blood bilirubin

Skin and subcutaneous tissue disorders Frequent Rash Less frequent Photosensitivity reactions, exfoliative dermatitis, angioedema, fixed drug eruption, erythema multiforme, Steven-Johnson syndrome (SJS)*, toxic epidermal necrolysis (Lyell's syndrome) (TEN), acute generalised exanthematous pustulosis (AGEP)

Frequency unknown Acute febrile neutrophilic dermatosis (Sweet's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS)*

Musculoskeletal, connective tissue and bone disorders Less frequent Arthralgia, myalgia

Renal and urinary disorders Less frequent Renal failure, lumbar pain, haematuria, oliguria, and anuria may also occur due to crystallisation in the urine, tubulointerstitial nephritis and uveitis syndrome, renal tubular acidosis

* See below section c.

c. Description of selected adverse reactions

Aseptic meningitis Aseptic meningitis was rapidly reversible on withdrawal of the medicine, but recurred in a number of cases on re-exposure to either CO-TRIMOXAZOLE PHARMC 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.

Severe cutaneous adverse reactions (SCARs) Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and medicine reaction with eosinophilia and systemic symptoms (DRESS) have been reported to be life-threatening (see section 4.4) Allergic reactions such as an itchy rash and hives may occur in patients with hypersensitivity to the components of CO-TRIMOXAZOLE PHARMC. 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-trimoxazole for prophylaxis or treatment of PJP.

Symptoms and Signs

Nausea, vomiting, dizziness and confusion are likely signs/symptoms of overdosage (see also section 4.8). Bone marrow depression has been reported in acute trimethoprim overdosage.

Treatment

No specific antidote is available for overdose with sulfamethoxazole and/or trimethoprim. Treatment is symptomatic and supportive, including general supportive measures such as monitoring of vital signs, as well as observation of the clinical status of the patient. Monitoring of blood counts and appropriate blood chemistries, including electrolytes is advisable. 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.