4.1. Therapeutic indications

Co-amoxiclav is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1):

• Acute bacterial sinusitis (adequately diagnosed)

• Acute otitis media

• Acute exacerbations of chronic bronchitis (adequately diagnosed)

• Community acquired pneumonia

• Cystitis

• Pyelonephritis

• Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis.

• Bone and joint infections, in particular osteomyelitis.

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

4.2. Posology and method of administration

White to off-white powder which on reconstitution with water gives white to off-white suspension with fruity aromatic odor

Posology

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.

The dose of Co-amoxiclav that is selected to treat an individual infection should take into account:

• The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)

• The severity and the site of the infection

• The age, weight and renal function of the patient as shown below.

The use of alternative presentations of Co-amoxiclav (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary (see sections 4.4 and 5.1).

For children < 40 kg, this formulation of Co-amoxiclav provides a maximum daily dose of 1000-2800 mg amoxicillin/143-400 mg clavulanic acid, when administered as recommended below. If it is considered that a higher daily dose of amoxicillin is required, it is recommended that another preparation of Co-amoxiclav is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid (see sections 4.4 and 5.1).

The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review (see section 4.4 regarding prolonged therapy).

Adults and Children ≥ 40 kg should be treated with the adult formulations of Co-amoxiclav.

Children < 40 kg

Children may be treated with Co-amoxiclav tablets, suspensions or paediatric sachets.

Recommended doses:

• 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses;

• up to 70 mg/10 mg/kg/day given as two divided doses may be considered for some infections (such as otitis media, sinusitis and lower respiratory tract infections).

No clinical data are available for Co-amoxiclav 7:1 formulations regarding doses higher than 45 mg/6.4 mg per kg per day in children under 2 years.

There are no clinical data for Co-amoxiclav 7:1 formulations for patients under 2 months of age. Dosing recommendations in this population therefore cannot be made.

Elderly

No dose adjustment is considered necessary.

Renal impairment

No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.

In patients with creatinine clearance less than 30 ml/min, the use of Co-amoxiclav presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose adjustments are available.

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals (see sections 4.3 and 4.4).

Method of administration

Co-amoxiclav is for oral use.

Administer at the start of a meal to minimise potential gastrointestinal intolerance and optimise absorption of amoxicillin/clavulanic acid.

Therapy can be started parenterally according to the SmPC of the IV formulation and continued with an oral preparation.

Shake to loosen powder, add water as directed, invert and shake.

Shake the bottle before each dose (see section 6.6).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in section 6.1.

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).

History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section 4.8).

4.4. Special warnings and precautions for use

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. Drug-induced enterocolitis syndrome (DIES) has been reported mainly in children receiving amoxicillin/clavulanic acid (see section 4.8). DIES is an allergic reaction with the leading symptom of protracted vomiting (1-4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Further symptoms could comprise abdominal pain, diarrhoea, hypotension or leucocytosis with neutrophilia. There have been severe cases including progression to shock. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted.

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s), then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.

This presentation of Co-amoxiclav is not suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation should not be used to treat penicillin-resistant S. pneumoniae.

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

Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AGEP) (see section 4.8). This reaction requires Co-amoxiclav discontinuation and contra-indicates any subsequent administration of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see sections 4.2, 4.3 and 4.8).

Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported 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. Hepatic events may be severe and in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8).

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin 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. Should antibiotic-associated colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contraindicated in this situation.

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

Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see sections 4.5 and 4.8).

In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).

In patients with reduced urine output, crystalluria (including acute renal injury) has been observed very rarely, predominantly 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. In patients with bladder catheters, a regular check of patency should be maintained (see sections 4.8 and 4.9).

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

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

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 receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

Co-amoxiclav Sugar Free 400 mg/57 mg/5 mL Powder for Oral Suspension contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicinal product should be used with caution in patients with phenylketonuria. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

The flavouring in Co-amoxiclav contains traces of benzyl alcohol. Benzyl alcohol may cause allergic reactions.

This medicinal product contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicinal product.

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

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary (see sections 4.4 and 4.8).

Methotrexate

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

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.

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. The change in pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

4.6. Fertility, pregnancy and lactation

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. 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 should be avoided during pregnancy, unless considered essential by the physician.

Breastfeeding

Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. The possibility of sensitisation should be taken into account. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. 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).

4.8. Undesirable effects

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

The ADRs derived from clinical studies and post-marketing surveillance with Co-amoxiclav, 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 (≥ 1/1 000 to <1/100)

Rare (≥ 1/10 000 to <1/1 000)

Very rare (<1/10 000)

Not known (cannot be estimated from the available data)

Infections and infestations

Mucocutaneous candidosis

Common

Overgrowth of non-susceptible organisms

Not known

Blood and lymphatic system disorders

Reversible leucopenia (including neutropenia)

Rare

Thrombocytopenia

Rare

Reversible agranulocytosis

Not known

Haemolytic anaemia

Not known

Prolongation of bleeding time and prothrombin time1

Not known

Immune system disorders8

Angioneurotic oedema

Not known

Anaphylaxis

Not known

Serum sickness-like syndrome

Not known

Hypersensitivity vasculitis

Not known

Nervous system disorders

Dizziness

Uncommon

Headache

Uncommon

Reversible hyperactivity

Not known

Convulsions1

Not known

Aseptic meningitis

Not known

Gastrointestinal disorders

Diarrhoea

Common

Nausea2

Common

Vomiting

Common

Indigestion

Uncommon

Antibiotic-associated colitis3

Not known

Black hairy tongue

Not known

Tooth discolouration9

Not known

Drug-induced enterocolitis syndrome

Not known

Pancreatitis acute

Not known

Hepatobiliary disorders

Rises in AST and/or ALT4

Uncommon

Hepatitis5

Not known

Cholestatic jaundice5

Not known

Cardiac disorders

Kounis syndrome

Not known

Skin and subcutaneous tissue disorders6

Skin rash

Uncommon

Pruritus

Uncommon

Urticaria

Uncommon

Erythema multiforme

Rare

Stevens-Johnson syndrome

Not known

Toxic epidermal necrolysis

Not known

Bullous exfoliative-dermatitis

Not known

Acute generalised exanthemous pustulosis (AGEP)1

Not known

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Not known

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) (baboon syndrome)

Not known

Linear IgA disease

Not known

Renal and urinary disorders

Interstitial nephritis

Not known

Crystalluria (including acute renal injury)7

Not known

1 See section 4.4

2 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid at the start of a meal.

3 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4)

4 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.

5 These events have been noted with other penicillins and cephalosporins (see section 4.4).

6 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4).

7 See section 4.9

8 See sections 4.3 and 4.4

9 Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisations 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 and signs of overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).

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

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4)

Treatment of intoxication

Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.