SYNTOCLAV Powder for solution for injection or infusion Ref.[28257] Active ingredients: Amoxicillin Clavulanic acid

In moderate to severe renal impairment dosage adjustment is required (see section 4.2).

Caution should be exercised in administration to patients with hepatic impairment or evidence of hepatic dysfunction. In some patients there have been changes in liver function tests, the clinical significance of which is unknown.

There are rare reports of cholestatic jaundice, sometimes severe, usually reversible, the signs and symptoms of which did not appear until several weeks after therapy cessation.

In patients with reduced urine output, crystalluria has been observed very rarely, predominately with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria.

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy. These reactions are more likely in patients with a history of penicillin sensitivity. The possibility of cross sensitivity in patients known to be hypersensitive to cephalosporins should be considered.

Syntoclav should be administered with extreme caution to patients with asthma, infectious mononucleosis or chronic lymphoid leukaemia due to the increased risk of erythematous rash developing. Erythematous rashes have been associated with glandular fever in patients receiving amoxicillin.

There have been reports of prolongation of bleeding time and prothrombin time in some patients on anticoagulant therapy. Caution should be exercised in such patients and the bleeding time monitored.

Prolonged usage of Syntoclav, as with any antibiotic, may result in the overgrowth of non susceptible micro-organisms.

If the parenteral administration of high doses is necessary, the sodium content must be taken into account in patients on a sodium restricted diet.

Amoxicillin has been reported to precipitate in bladder catheters after intravenous administration of large doses. A regular check of patency should be maintained.

The presence of clavulanic acid in Syntoclav may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Other bacterial agents: There is a possibility that the antibacterial action of amoxicillin could be antagonised on co-administration with macrolides, tetracyclines, sulphonamides or chloramphenicol.

Drugs

Allopurinol: concurrent use with amoxicillin may increase the possibility of allergic skin reactions.

Anticoagulants: There have been reports of prolongation of the bleeding time and prothrombin time in some patients. Caution should be exercised in administration to patients on anticoagulation therapy.

Oral contraceptives: The efficacy of oral contraceptives may be reduced during Syntoclav therapy. Patients should be cautioned and advised to use additional non hormonal contraception.

Probenecid: Concurrent administration with Syntoclav may result in elevated and prolonged serum levels of amoxicillin due to a decrease in the renal tubular secretion of amoxicillin.

Tetracycline antibiotics: The bactericidal activity of amoxicillin is decreased with concurrent administration of tetracycline antibiotics.

Methotrexate: Concomitant administration with methotrexate may lead to an increase in toxicity of methotrexate.

Laboratory tests

Glucose in urine: False positive results may be obtained using test methods relying on copper sulphate reagent.

The presence of clavulanic acid in Syntoclav may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Pregnancy

Although reproductive studies in rodents gave no evidence of toxicity such studies are not always predictive of behaviour in man.

In a single study in women with preterm, premature rupture of the foetal membrane, it was reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use of Syntoclav in pregnancy should be avoided, especially in the first trimester, unless the clinical benefits outweigh the potential unknown risk to the foetus.

Breastfeeding

Small quantities of amoxicillin are excreted in milk. Due to the risk of sensitisation of the infant, caution should be exercised in the administration of Syntoclav during lactation.

There are no known effects on the ability to drive/operate machines.

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.

The ADRs derived from clinical studies and post-marketing surveillance with amoxicillin/clavulanic acid, sorted by MedDRA System Organ Class are listed below. The following terminologies have been used in order to classify the occurrence of undesirable effects: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1000 to <1/100), Rare (>1/10,000 to <1/1000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).

Infections and infestations

Common: Mucocutaneous candidiasis

Blood and lymphatic system disorders

Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia

Very rare: Reversible agranulocytosis and haemolytic anaemia.

Prolongation of bleeding time and prothrombin time (see section 4.5)

Immune system disorders

Very rare: As with other antibiotics, severe allergic reactions, including angioneurotic oedema, anaphylaxis, serum sickness-like syndrome and hypersensitivity vasculitis.

If hypersensitivity reaction is reported, the treatment must be discontinued.

Nervous system disorders

Uncommon: Dizziness, headache

Very rare: Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Vascular disorders

Rare: Thrombophlebitis at the site of injection

Gastrointestinal disorders

Common: Diarrhoea

Uncommon: Nausea, vomiting, indigestion

Very rare: Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis), less likely to occur after parenteral administration.

Hepato-biliary disorders

Uncommon: Moderate rise in AST and/or ALT, the significance is unknown.

Very rare: Hepatitis and cholestatic jaundice

Hepatic events have been reported predominately in males and elderly patients and may be associated with prolonged treatment.

Signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported.

Skin and subcutaneous tissue disorders

Uncommon: Skin rash, pruritus, urticaria

Rare: Erythema multiforme

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, Bullous exfoliative-dermatitis, acute generalised exanthemous pustulosis (AGEP)

Not known: Drug reaction with eosinophilia and systemic symptoms (DRESS)

If any hypersensitivity dermatitis reaction is reported, the treatment must be discontinued.

Renal and urinary disorders

Very rare: Interstitial nephritis, crystalluria (see Section 4.4 and 4.9)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

Syntoclav should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions.

If Syntoclav is prescribed concurrently with an aminoglycoside, the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because loss of activity of the aminoglycoside can occur under these conditions.