Xeroprim 80 mg & 400 mg Tablets.

The treatment of infections of the upper and lower respiratory tract, the urinary tract and the alimentary and genital tract in both sexes, and skin infections caused by sensitive organisms. Xeroprim 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

Adults and children older than 12 years: Two tablets every 12 hours for a period of 10 to 14 days.

Special populations

Renal Impairment

If XEROPRIM is indicated for patients with renal impairment, the following dosage scheme, based on creatinine clearance is suggested:

• Above 25 ml/min: Standard dosage
• 15 - 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 XEROPRIM. If the concentration of total sulfamethoxazole exceeds 150 u03bcg/ml then treatment should be interrupted until the value falls below 120 u03bcg/ml. No Information is available for children with renal failure.

Paediatric population

Cotrimoxazole paediatric formulations to be used in children under 12 years.

Method of administration

For oral use. Tablets must be swallowed with a sufficient quantity of liquid.

• XEROPRIM is contraindicated in patients with known hypersensitivity to sulphonamide, sulphamethoxazole, trimethoprim or to any of the excipients listed in section 6.1.
• Patients who are suffering from porphyria.
• It should not be used in patients suffering from liver parenchyma damage.
• Severe renal insufficiency.
• Co-trimoxazole should not be used during pregnancy and lactation.
• Use of the substance in premature or new-born infants during the first two months of life, is contraindicated.
• Should not be given to patients with megaloblastic anaemia or blood dyscrasias.
• Contraindicated in the presence of vitamin b 12 and folic acid deficiency state.

Life threatening skin adverse reactions

Erythema multiforme, toxic dermal necrolysis and allergic vasculitis may occur. Treatment should be discontinued immediately when a rash appears because the danger of severe allergic reactions.

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.

Folate

XEROPRIM is contraindicated in patients with actual or possible folate deficiency because of possible interference with human folate metabolism by trimethoprim as in XEROPRIM (see Section 4.3).

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 XEROPRIM should be given regular blood examinations.

Renal impairment

XEROPRIM 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 XEROPRIM and chemically related compounds such as some diuretics, particularly acetazolamide and thiazides, and the sulfonylurea hypoglycaemic medicines. Direct exposure to sunlight should be avoided as it facilitates development of sensitisation dermatitis. XEROPRIM should be used with caution in patients with allergic conditions or bronchial asthma. High doses of XEROPRIM may have a hypoglycaemic effect. Thyroid tests must be carried out in patients with thyroid disorders.

Excipients with known effect

XEROPRIM contains Nipastat, a mixture of parahydroxybenzoate esters. It may cause allergic reactions (possibly delayed).

Paediatric population

Not recommended for children under 12 years (see section 4.2).

Diuretics

Previous or simultaneous administration of diuretics with co-trimoxazole may cause an increased risk of thrombocytopenia, especially in elderly patients with heart failure; death may occur.

Paraldehyde

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

p-aminobenzoic acid

XEROPRIM may be antagonized by p-aminobenzoic acid and compounds derived from it.

Protein binding, anticoagulants and methotrexate

Sulfamethoxazole is strongly bound to proteins. Patients receiving anticoagulants of the coumarin group or methotrexate concomitantly should therefore be carefully monitored.

Sulphonylureas

Sulfamethoxazole increases the hypoglycaemic action of sulphonylureas in diabetic patients.

Pyrimethamine or immunosuppressive therapy

XEROPRIM should be used with caution in patients receiving pyrimethamine or immunosuppressive therapy. Patients receiving pyrimethamine may develop megaloblastic anaemia due to the trimethoprim component in XEROPRIM.

Phenytoin

Trimethoprim prolongs the half-life of phenytoin.

Digoxin, procainamide and tolbutamide

XEROPRIM may interact with the following medicines by interfering with their clearance: digoxin, procainamide and tolbutamide.

Diagnostic tests

Sulfamethoxazole has been reported to interfere with some diagnostic tests including those for urea, creatinine, urinary glucose and urobilinogen. Trimethoprim may interfere with some diagnostic tests including serum methotrexate assay and the jaffu00e9 reaction for creatinine.

Ciclosporin

Reversible deterioration in renal function has been reported in patients given trimethoprim as in XEROPRIM and cyclosporine following renal transplantation.

Zidovudine

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

Lamivudine

Administration of trimethoprim /sulfamethoxazole 160 mg/800 mg 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 XEROPRIM. This has been observed in Pneumocystis jirovecii pneumonia prophylaxis and treatment.

Contraceptives

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

Pregnancy

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

Breastfeeding

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

Fertility

No data available.

It is not always possible to predict to what extent XEROPRIM may interfere with the daily activities of a patient. XEROPRIM 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 XEROPRIM affects them.

a. Summary of the safety profile

Hypersensitivity reactions particularly involving the skin are among the most common adverse effects of XEROPRIM 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 list of adverse reactions

Sulfamethoxazole and Trimethoprim

Symptoms and signs

Nausea, vomiting, cyanosis, heamaturia, oliguria, or anuria and allergic skin reactions (skin rashes, anaphylaxis, etc.) (see also section 4.8). Bone marrow depression has been reported in acute trimethoprim overdosage.

Treatment

Treatment is supportive and symptomatic. If vomiting has not occurred, induction of vomiting may be desirable. 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.