ACTIMENTIN Powder for oral suspension Ref.[51179] Active ingredients: Amoxicillin Clavulanic acid

Prescribers must adhere to the principles of antibiotic stewardship.

Serious allergic reactions, including anaphylaxis

Before initiating therapy with ACTIMENTIN 600 BD, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, beta-lactam medicines or other allergens (see sections 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) angioneurotic oedema have been reported in patients on penicillin therapy, including amoxicillin/clavulanic acid. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity, who have experienced severe reactions when treated with cephalosporins.

If an allergic reaction occurs, ACTIMENTIN 600 BD must be discontinued, and appropriate alternative therapy instituted. Serious anaphylactic reactions require emergency treatment with epinephrine (adrenaline).

Hepatic dysfunction

Use ACTIMENTIN 600 BD with caution in patients with evidence of hepatic dysfunction (see sections 4.3 and 4.8).

Changes in liver function tests have been observed in some patients receiving amoxicillin/clavulanic acid. It should be used with care in patients with evidence of severe hepatic dysfunction and hepatic function should be monitored at regular intervals (see section 4.2). Transient hepatitis and cholestatic jaundice have been reported.

Hepatic events may be severe and fatal. It has been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been reported less frequently in children. In all populations, 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. It has been reported that such hepatic events most frequently occurred in patients with serious underlying disease or taking concomitant medication known to have the potential for hepatic effects (see section 4.8).

Antibiotic-associated diarrhoea

Prolonged use may result in overgrowth of non-susceptible organisms. Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, ACTIMENTIN 600 BD treatment should be discontinued immediately and the patient investigated further. Anti-peristaltic medicines are contraindicated in this situation.

Mononucleosis

Since ACTIMENTIN 600 BD contains amoxicillin, an aminopenicillin, it is not the treatment of choice in patients presenting with sore throat or pharyngitis because of the possibility that the underlying cause is infectious mononucleosis, in the presence of which there is a high incidence of rash if amoxicillin is used. ACTIMENTIN 600 BD should be avoided if infectious mononucleosis is suspected.

Prothrombin time

Abnormal prolongation of prothrombin time (increased international normalised ratio (INR)) has been reported in patients receiving an amoxicillin/clavulanic acid combination with oral anticoagulants (see sections 4.5 and 4.8).

Crystalluria

In patients with reduced urine output, crystalluria has been observed less frequently, predominantly with parenteral therapy. During the administration of high doses or overdosage of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output to reduce the possibility of amoxicillin crystalluria (see section 4.9). In patients with bladder catheters, a regular check of patency should be maintained.

Potential for microbial overgrowth

Prolonged use may also result in overgrowth of non-susceptible organisms. The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Aerobacter, Pseudomonas or Candida), ACTIMENTIN 600 BD should be discontinued and / or appropriate therapy instituted.

Sensitivity testing / susceptibility data

ACTIMENTIN 600 BD use may lead to resistant strains of organisms and, therefore, sensitivity testing should be carried out whenever possible to demonstrate the appropriateness of therapy. In the case that an infection is proven to be due to amoxicillinsusceptible organisms(s), consideration should be given to switching from ACTIMENTIN 600 BD acid to an amoxicillin only medicine in accordance with official guidance. ACTIMENTIN 600 BD should be used in accordance with local official antibiotic-prescribing guidelines and local susceptibility data. Susceptibility to ACTIMENTIN 600 BD will vary with geography and time. Local susceptibility data should be consulted where available, and microbiological sampling and susceptibility testing performed where necessary.

Convulsions

Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).

Concomitant allopurinol use

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions (see section 4.5).

Acute generalised exanthemous pustulosis (AGEP)

The occurrence of a feverish generalised erythema associated with pustula at treatment initiation may be a symptom of AGEP (see section 4.8). This reaction requires treatment discontinuation and contraindicates any subsequent administration of amoxicillin.

Organ system functions

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged treatment.

Leukaemia

ACTIMENTIN 600 BD should be given with caution to patients with lymphatic leukaemia since such patients are especially susceptible to amoxicillin-induced skin rashes.

Interference with laboratory test

Urine glucose

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine due to false positive results which may occur with non-enzymatic methods.

Coombs test

The presence of clavulanic acid in ACTIMENTIN 600 BD may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

Bio-Rad Laboratories Platelia Aspergillus EIA

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients taking ACTIMENTIN 600 BD should be interpreted cautiously and confirmed by other diagnostic methods.

Maltodextrin

ACTIMENTIN 600 BD contains maltodextrin (glucose) as an ingredient of the flavourant. Patients with rare glucose-galactose malabsorption should not take this medicine.

Probenecid

Concurrent use of probenecid with ACTIMENTIN 600 BD is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin but does not affect clavulanic acid excretion. Concomitant use of probenecid with ACTIMENTIN 600 BD may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.

Allopurinol

The concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. It is reported that the concurrent administration of allopurinol and ampicillin could substantially increase the incidence of skin rashes in patients receiving both medicines, as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricaemia present in these patients. There are no data on the combination of amoxicillin and potassium clavulanate used concurrently with allopurinol.

Oral anticoagulants

Abnormal prolongation of prothrombin time (increased INR) has been reported in patients receiving amoxicillin-clavulanate with oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with ACTIMENTIN 600 BD (or during addition or treatment withdrawal). Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections 4.4 and 4.8).

Oral contraceptives

ACTIMENTIN 600 BD may affect the gut flora, leading to lower estrogen re-absorption and, subsequently, reduced efficacy of combined oral contraceptives. Patients should be warned accordingly.

Methotrexate

Penicillin antibiotics may reduce the excretion of methotrexate causing a potential increase in toxicity.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) of approximately 50 % has been reported following commencement of oral amoxicillin plus clavulanic acid treatment. The change in pre-dose level may not accurately represent changes in overall MPA exposure. (2, 4) Therefore, a change in the dose of mycophenolate mofetil should normally not be required in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed with concurrent use and shortly after antibiotic treatment.

Alcohol

No information is available about the concurrent use of the amoxicillin/clavulanic acid combination, as contained in ACTIMENTIN 600 BD, and alcohol. However, the ingestion of alcohol whilst being treated with some other β-lactam antibiotics has precipitated a disulfiramlike reaction in some patients. Therefore, the ingestion of alcohol should be avoided during and for several days after treatment with ACTIMENTIN 600 BD.

Pregnancy

Use should be avoided during pregnancy, as safety in pregnancy has not been established. Results from a single study in women with preterm, premature rupture of the foetal membrane (pPROM) reported that prophylactic treatment with amoxicillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates.

Breastfeeding

Both amoxicillin and clavulanic acid are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breastfed infant). Consequently, candidiasis and skin rash are possible in breastfed infants. Mothers on treatment with ACTIMENTIN 600 BD should not breastfeed their infants.

There are no data available from studies on the effects on the ability to drive and use machines. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

Summary of the safety profile

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

Tabulated list of adverse reactions

^A Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, it may be reduced by taking ACTIMENTIN 600 BD at the start of a meal.
^B Superficial tooth discolouration has been reported less frequently in children. Good oral hygiene may help to prevent tooth discolouration and can usually be removed by brushing.
^C A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown.
^D These events have been noted with other penicillins and cephalosporins (see section 4.4).
^E If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4).
^* Reported post marketing and therefore, the frequency of occurrence is unknown as it cannot be estimated from available data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.