Amoxycillin + Clavulanate potassium AUGMENTIN SUSPENSION 228 mg/5 mL and 457 mg/5 mL – Mixed fruit flavour Amoxicillin trihydrate – Potassium clavulanate QUALITATIVE AND QUANTITATIVE COMPOSITION AUGMENTIN suspension 228 mg/5 mL: When reconstituted each 5 mL contains 200 mg amoxicillin (as amoxicillin trihydrate) and 28.5 mg clavulanic acid (as potassium clavulanate). AUGMENTIN suspension 457 mg/5 mL: When reconstituted each 5 mL contains 400 mg amoxicillin (as amoxicillin trihydrate) and 57 mg clavulanic acid (as potassium clavulanate). PHARMACEUTICAL FORM A white to off-white dry powder for reconstitution in water to form an off-white mixedfruit flavoured suspension. CLINICAL PARTICULARS Indications AUGMENTIN should be used in accordance with local official antibiotic prescribing guidelines and local susceptibility data. AUGMENTIN suspension (228 mg/5 mL and 457mg/5 mL), for twice daily oral dosing, is indicated for short term treatment of bacterial infections at the following sites when amoxicillin resistant beta-lactamase producing strains are suspected as the cause. In other situations, amoxicillin alone should be considered. Upper respiratory tract infections (including ENT) e.g. recurrent tonsillitis, sinusitis, otitis media. Lower respiratory tract infections e.g. acute exacerbations of chronic bronchitis, lobar and bronchopneumonia. Urinary tract infections e.g. cystitis, urethritis, pyelonephritis. Skin and soft tissue infections e.g. cellulitis, animal bites. Susceptibility to AUGMENTIN will vary with geography and time (see Pharmacological Properties, Pharmacodynamics for further information). Local susceptibility data should be consulted where available, and microbiological sampling and susceptibility testing performed where necessary. Mixed infections caused by amoxicillin-susceptible organisms in conjunction with AUGMENTIN susceptible beta-lactamase producing organisms may be treated with AUGMENTIN suspension 228 mg/5mL and 457 mg/5 mL. These infections should not require the addition of another antibiotic resistant to beta-lactamases. Dosage and Administration Dosage depends on the age, weight and renal function of the patient and the severity of the infection. Dosages are expressed throughout in terms of amoxicillin/clavulanate content except when doses are stated in terms of an individual component. To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of AUGMENTIN is optimised when taken at the start of a meal. Treatment should not exceed 14 days without review. Therapy can be started parenterally and continued with an oral preparation. AUGMENTIN bottle presentations for suspension may be supplied with a plastic dosing device. For preparation of the suspensions, see Instructions for Use/Handling. The usual recommended daily dosage is: • 25/3.6 mg/kg/day in mild to moderate infections (upper respiratory tract infections e.g. recurrent tonsillitis, lower respiratory infections and skin and soft tissue infections). • 45/6.4 mg/kg/day for the treatment of more serious infections (upper respiratory tract infections e.g. otitis media and sinusitis, lower respiratory tract infections e.g. bronchopneumonia and urinary tract infections). No clinical data are available on doses above 45/6.4 mg/kg/day in children under 2 years. There are no clinical data for AUGMENTIN suspension 228 mg/5 mL and 457 mg/5 mL to make dosage recommendations for children under 2 months old. The tables below give dosage guidance for children. Children 2 years and over 25/3.6 mg/kg/day 2 - 6 years (13 - 21 kg) 5.0 ml AUGMENTIN suspension 228 mg/5 ml twice daily or 2.5 ml AUGMENTIN suspension 457 mg/5 ml twice daily. 7 - 12 years (22 - 40 kg) 10.0 ml AUGMENTIN suspension 228 mg/ 5 ml twice daily or 5.0 ml AUGMENTIN suspension 457 mg/5 ml twice daily. 45/6.4 mg/kg/day 2 - 6 years (13 - 21 kg) 10.0 ml AUGMENTIN suspension 228 mg/5 ml twice daily or 5.0 ml AUGMENTIN suspension 457 mg/5 ml twice daily. 7 - 12 years 10.0 ml AUGMENTIN suspension 457 mg/5 ml twice daily. Children aged 2 months to under 2 years Children under 2 years should be dosed according to body weight. AUGMENTIN suspension 457 mg/5 mL Body Weight (kg) Lower dose at 25/3.6 mg/kg/day (mL every 12 hours) Higher dose at 45/6.4 mg/kg/day (mL every 12 hours) 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0.3 0.5 0.6 0.8 0.9 1.1 1.3 1.4 1.6 1.7 1.9 2.0 2.2 2.3 0.6 0.8 1.1 1.4 1.7 2.0 2.3 2.5 2.8 3.1 3.4 3.7 3.9 4.2 Renal Impairment No adjustment in dose is required in patients with creatinine clearance greater than 30 mL/min. AUGMENTIN suspension 228 mg/5 mL and 457 mg/5 mL are not recommended in patients with a creatinine clearance of less than 30 mL/min. Hepatic Impairment Dose with caution; monitor hepatic function at regular intervals. There is, as yet, insufficient evidence on which to base a dosage recommendation. Contraindications AUGMENTIN is contraindicated in patients with a history of hypersensitivity to betalactams, e.g. penicillins and cephalosporins. AUGMENTIN is contraindicated in patients with a previous history of AUGMENTINassociated jaundice/hepatic dysfunction. Warnings and Precautions Before initiating therapy with AUGMENTIN, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. 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 to occur in individuals with a history of penicillin hypersensitivity (see Contraindications). If an allergic reaction occurs, AUGMENTIN therapy must be discontinued and appropriate alternative therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous (i.v.) steroids and airway management (including intubation) may also be required. AUGMENTIN 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. Prolonged use may also occasionally 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. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further. Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving AUGMENTIN and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. Changes in liver function tests have been observed in some patients receiving AUGMENTIN. The clinical significance of these changes is uncertain but AUGMENTIN should be used with caution in patients with evidence of hepatic dysfunction. Cholestatic jaundice, which may be severe, but is usually reversible, has been reported rarely. Signs and symptoms may not become apparent for up to six weeks after treatment has ceased. In patients with renal impairment AUGMENTIN suspension 228 mg/5 mL and 457 mg/5 mL are not recommended. In patients with reduced urine output, crystalluria 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 (see Overdose). AUGMENTIN 228 mg/5 mL and 457 mg/5mL suspensions contain 12.5 mg aspartame per 5 mL dose and therefore care should be taken in patients with phenylketonuria. Interactions Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use with AUGMENTIN may result in increased and prolonged blood levels of amoxicillin but not of clavulanate. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of AUGMENTIN and allopurinol. In common with other antibiotics, AUGMENTIN may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. In the literature there are rare cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If coadministration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of AUGMENTIN. In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid 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. Pregnancy and Lactation Reproduction studies in animals (mice and rats) with orally and parenterally administered AUGMENTIN have shown no teratogenic effects. In a single study in women with preterm, premature rupture of the foetal membrane (pPROM), it was reported that prophylactic treatment with AUGMENTIN may be associated with an increased risk of necrotising enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, especially during the first trimester, unless considered essential by the physician. AUGMENTIN may be administered during the period of lactation. With the exception of the risk of sensitisation, associated with the excretion of trace quantities in breast milk, there are no detrimental effects for the infant. Effects on Ability to Drive and Use Machines Adverse effects on the ability to drive or operate machinery have not been observed. Adverse Reactions Data from large clinical trials were used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e., those occurring at <1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency. The following convention has been used for the classification of frequency: 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. 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. Immune system disorders Very rare Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis. Nervous system disorders Uncommon Dizziness, headache Very rare Reversible hyperactivity, aseptic meningitis, convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses. Gastrointestinal disorders Adults: Very common Diarrhoea Common Nausea, vomiting Children: Common Diarrhoea, nausea, vomiting All populations: Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking AUGMENTIN at the start of a meal. Uncommon Indigestion Very rare Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis – see Warnings and Precautions). Black hairy tongue 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. Hepatobiliary disorders Uncommon 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. Very Rare Hepatitis and cholestatic jaundice. These events have been noted with other penicillins and cephalosporins. 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. 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. 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 exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued. Renal and urinary disorders Very rare Interstitial nephritis, crystalluria (see Overdose) Overdose Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Gastrointestinal symptoms may be treated symptomatically with attention to the water-electrolyte balance. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Warnings and Precautions). AUGMENTIN can be removed from the circulation by haemodialysis. PHARMACOLOGICAL PROPERTIES Pharmacodynamics Resistance to many antibiotics is caused by bacterial enzymes which destroy the antibiotic before it can act on the pathogen. The clavulanate in AUGMENTIN suspension anticipates this defence mechanism by blocking the beta-lactamase enzymes, thus rendering the organisms sensitive to amoxicillin's rapid bactericidal effect at concentrations readily attainable in the body. Clavulanate by itself has little antibacterial activity; however, in association with amoxicillin as AUGMENTIN it produces an antibiotic agent of broad spectrum with wide application in hospital and general practice. In the list below, organisms are categorised according to their in vitro susceptibility to AUGMENTIN. In vitro susceptibility of micro-organisms to AUGMENTIN Where clinical efficacy of AUGMENTIN has been demonstrated in clinical trials this is indicated with an asterisk (*). Organisms that do not produce beta-lactamase are identified (with † ). If an isolate is susceptible to amoxicillin, it can be considered susceptible to AUGMENTIN. Commonly susceptible species Gram-positive aerobes: Bacillius anthracis Enterococcus faecalis Gardnerella vaginalis Listeria monocytogenes Streptococcus pneumoniae*† Streptococcus pyogenes*† Streptococcus agalactiae*† Viridans group streptococcus† Streptococcus spp. (other beta-hemolytic)*† Staphylococcus aureus (methicillin susceptible)* Staphylococcus saprophyticus (methicillin susceptible) Coagulase negative staphylococcus (methicillin susceptible) Gram-negative aerobes: Bordetella pertussis Haemophilus influenzae* Helicobacter pylori Moraxella catarrhalis* Neisseria gonorrhoeae Pasteurella multocida Vibrio cholerae Gram-positive anaerobes: Clostridium spp. Peptococcus niger Peptostreptococcus magnus Peptostreptococcus micros Peptostreptococcus spp. Gram-negative anaerobes: Bacteroides fragilis Bacteroides spp. Fusobacterium nucleatum Fusobacterium spp. Species for which acquired resistance may be a problem Gram-negative aerobes: Escherichia coli* Klebsiella oxytoca Klebsiella pneumoniae* Klebsiella spp. Proteus mirabilis Proteus vulgaris Proteus spp. Salmonella spp. Shigella spp. Gram-positive aerobes: Corynebacterium spp. Enterococcus faecium Inherently resistant organisms Gram-negative aerobes: Acinetobacter spp. Citrobacter freundii Enterobacter spp. Hafnia alvei Legionella pneumophila Morganella morganii Providencia spp. Pseudomonas spp. Serratia spp. Stenotrophomas maltophilia Yersinia enterolitica Others: Chlamydia pneumoniae Chlamydia psittaci Chlamydia spp. Coxiella burnetti Mycoplasma spp. Infections caused by amoxicillin-susceptible organisms are amenable to AUGMENTIN treatment due to its amoxicillin content. Mixed infections caused by amoxicillinsusceptible organisms in conjunction with AUGMENTIN-susceptible beta-lactamase producing organisms may therefore be treated with AUGMENTIN. Pharmacokinetics Absorption The two components of AUGMENTIN suspension 228 mg/5 mL and 457 mg/5 mL, amoxicillin and clavulanate, are each fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of AUGMENTIN is optimised when taken at the start of a meal. The mean AUC values for amoxicillin are essentially the same following twice a day dosing with the AUGMENTIN 875/125 mg tablet or three times a day dosing with the AUGMENTIN 500/125 mg tablet, in adults. No differences between the 875 mg twice daily and 500 mg three times daily dosing regimes are seen when comparing the amoxicillin T1/2 or Cmax after normalisation for the different doses of amoxicillin administered. Similarly, no differences are seen for the clavulanate T1/2, Cmax or AUC values after appropriate dose normalisation. The time of dosing of AUGMENTIN relative to the start of a meal has no marked effects on the pharmacokinetics of amoxicillin in adults. In a study of the AUGMENTIN 875/125 mg tablet, the time of dosing relative to ingestion of a meal had a marked effect on the pharmacokinetics of clavulanate. For clavulanate AUC and Cmax, the highest mean values and smallest inter-subject variabilities were achieved by administering AUGMENTIN at the start of a meal, compared to the fasting state or 30 or 150 minutes after the start of a meal. The mean Cmax, Tmax, T1/2 and AUC values for amoxicillin and clavulanate are given below for an 875 mg/125 mg dose of amoxicillin /clavulanic acid administered at the start of a meal. Mean Pharmacokinetic Parameters Drug Administration Dose (mg) Cmax (mg/L) Tmax* (hours) AUC (mg.h/L) T1/2 (hours) AUGMENTIN 1g Amoxicillin 875 12.4 1.5 29.9 1.36 Clavulanate 125 3.3 1.3 6.88 0.92 *Median values Amoxicillin serum concentrations achieved with AUGMENTIN are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Distribution The pharmacokinetics of the two components of AUGMENTIN are closely matched. Both clavulanate and amoxicillin have low levels of serum binding; about 70% remains free in the serum. Doubling the dosage of AUGMENTIN approximately doubles the serum levels achieved. Pre-clinical Safety Data No further information of relevance. PHARMACEUTICAL PARTICULARS List of Excipients AUGMENTIN dry powder for suspension contain xanthan gum, hydroxypropyl methylcellulose, colloidal silica, succinic acid, silicon dioxide, aspartame and dry flavours (raspberry, orange "1”, orange "2” and golden syrup). Incompatibilities None known. Shelf Life The expiry date is indicated on the packaging. Special Precautions for Storage Do not take after the expiry date shown on the pack. Store in a dry place in the original packaging to protect from moisture. Refer to pack for storage temperature. Once reconstituted, the suspension must be stored in a refrigerator (2°C to 8°C) and used within 7 days. Do not freeze. (see also Instructions for Use/Handling). Nature and Contents of Container AUGMENTIN for suspension in bottles Clear glass bottles containing powder for reconstitution. Bottles may be supplied with either an aluminium screw cap with a ring seal or a plastic child-resistant cap with a removable foil-backed seal on the bottle. Fill-lines are indicated on the bottle label. Bottles may be supplied with a plastic dosing device. Instructions for Use/Handling AUGMENTIN suspension in bottles For bottles with aluminium screw caps, check the cap ring seal is intact before using. Alternatively, for bottles with a plastic child-resistant cap, check the foil-backed bottle seal is intact before using. At time of use, the dry powder should be reconstituted to form an oral suspension, as detailed below: • Invert and shake bottle to loosen powder. • Add volume of water (indicated below). Invert and shake well. • Alternatively, fill the bottle with water to just below the mark on bottle label. Invert and shake well, then top up with water to the mark. Invert and shake again. • Allow to stand for 5 minutes to ensure full dispersion. • Shake well before taking each dose. AUGMENTIN suspension 228 mg/5 mL Fill Weight (g) Volume of water to be added to reconstitute (mL) Final volume of reconstituted oral suspension (mL) 7.7 64 70 15.4 128 140 AUGMENTIN suspension 457 mg/5 mL Fill Weight (g) Volume of water to be added to reconstitute (mL) Final volume of reconstituted oral suspension (mL) 6.3 31 35 12.6 62 70 25.2 124 140 A plastic dosing device may be supplied with the pack which can be used to measure the dose accurately. Discard any unused suspension after 7 days. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Not all presentations are available in every country. Manufactured by SmithKline Beecham Limited* Worthing, UK Or Glaxo Wellcome Production* ZI de la Peyenniere 53100 Mayenne Cedex France *Member of the GlaxoSmithKline group of companies Version number: GDS26 / IPI14(SI) Date of issue: 13 June 2019 Trade marks are owned by or licensed to the GSK group of companies [GSK logo]