Document: spc-doc_PL 00289-1572 change

• spc-doc_PL 00289-1572
• spc-doc_PL 29831-0043
• spc-doc_PL 30306-0612
• spc-doc_PL 31745-0025

---

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-amoxiclav 1000mg/200mg powder for solution for injection or infusion

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each vial contains 1000mg amoxicillin (as sodium) and 200mg clavulanic acid (as potassium).

For reconstitution as an intravenous injection or infusion For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Powder for solution for injection or infusion.

White to almost white crystalline powder.

4    CLINICAL PARTICULARS

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):

•    Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections, epiglottitis, and sinusitis when accompanied by severe systemic signs and symptoms)

•    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

•    Intra-abdominal infections

•    Female genital infections.

Prophylaxis against infections associated with major surgical procedures in adults, such as those involving the:

•    Gastrointestinal tract

•    Pelvic cavity

•    Head and neck

•    Biliary tract surgery.

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

4.2 Posology and method of administration

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).

This Co-amoxiclav powder for solution for injection or infusion provides a total daily dose of 3000 mg amoxicillin and 600 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 an alternative intravenous formulation of Co-amoxiclav is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid.

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). Consideration should be given to local guidelines on appropriate dosing frequencies for amoxicillin/clavulanic acid.

Adults and children > 40 kg

For treatment of infections as indicated in section 4.1: 1000 mg/ 200 mg every 8 hours

Children < 40 kg Recommended doses:

•    Children aged 3 months and over: 25 mg/5 mg per kg every 8 hours

•    Children aged less than 3 months or weighing less than 4 kg: 25 mg/5 mg per kg every 12 hours.

Elderly

No dose adjustment is considered necessary.

Renal impairment

Dose adjustments are based on the maximum recommended level of amoxicillin.

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

Adults and children £40 kg

CrCl: 10-30 ml/min	Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given twice daily
CrCl < 10 ml /min	Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given every 24 hours
Haemodialysis	Initial dose of 1000 mg/200 mg and then followed by 500 mg/100 mg every 24 hours, plus a dose of 500 mg/100 mg at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)

Children < 40 kg

CrCl < 10 ml /min	25 mg/5 mg per kg given every 24 hours
Haemodialysis	25 mg/5 mg per kg given every 24 hours, plus a dose of 12.5 mg/2.5 mg per kg at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased).

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 intravenous use.

Co-amoxiclav may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. Co-amoxiclav is not suitable for intramuscular administration.

Children aged less than 3 months should be administered Co-amoxiclav by infusion only.

Treatment with Co-amoxiclav may be initiated by the use of an intravenous preparation and completed with an appropriate oral presentation as considered appropriate for the individual patient.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.

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 section 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin/clavulanic acid therapy should 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 may not be 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. As no specific data for T>MIC are available and the data for comparable oral presentations are borderline, this presentation (without additional amoxicillin) may not be suitable for the treatment of 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 pustule 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, Co-amoxiclav should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Antiperistaltic drugs are contra-indicated 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 section 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 has been observed very rarely, predominantly with parenteral therapy. During 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 section 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 nonenzymatic 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.

1000 mg/200 mg powder for solution for injection or infusion

This medicinal product contains 62.9 mg (2.7 mmol) of sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

1000 mg/200 mg powder for solution for injection or infusion This medicinal product contains 39.3 mg (1.0 mmol) of potassium per vial. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

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 coadministration 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.

4.6 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.

Lactation

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. 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

Common: Mucocutaneous candidosis

Not known: Overgrowth of non-susceptible organisms

Blood and lymphatic system disorders

Rare: Reversible leucopenia (including neutropenia), Thrombocytopenia

Not known: Reversible agranulocytosis, Haemolytic anaemia, Prolongation of

bleeding time and prothrombin time¹

Immune system disorders¹⁰

Not known: Angioneurotic oedema, Anaphylaxis, Serum sickness-like syndrome, Hypersensitivity vasculitis

Nervous system disorders

Uncommon: Dizziness, Headache

2

Not known: Convulsions

Vascular disorders

Rare: Thrombophlebitis³

Gastrointestinal disorders

Common: Diarrhoea

Uncommon: Nausea, Vomiting, Indigestion Not known: Antibiotic-associated colitis⁴

Hepatobiliary disorders

Uncommon: Rises in AST and/or ALT⁵ Not known: Hepatitis⁶, Cholestatic jaundice⁶

7

Skin and subcutaneous tissue disorders

Uncommon: Skin rash, Pruritus, Urticaria Rare: Erythema multiforme

Not known: Stevens-Johnson syndrome, Toxic epidermal necrolysis, Bullous exfoliative-dermatitis, Acute generalised exanthemous pustulosis (AGEP)⁹

Renal and urinary disorders

Not known: Interstitial nephritis, Crystalluria⁸

¹See section 4.4 ²See section 4.4 ³At the site of injection

including pseudomembranous colitis and haemorrhagic colitis (see section 4.4)

⁵A 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.

⁶These events have been noted with other penicillins and cephalosporins (see section 4.4).

⁷If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4).

⁸See section 4.9 ⁹See section 4.4 ¹⁰See sections 4.3 and 4.4

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC Code: J01C R02

Mode of action

Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

PK/PD relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.

Mechanisms of resistance

The two main mechanisms of resistance to amoxicillin/clavulanic acid are:

•    Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.

•    Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Organism	Susceptibility Breakpoints (pg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae1	< 1	-	> 1
Moraxella catarrhalis1	< 1	-	> 1
Staphylococcus aureus	< 2	-	> 2
Coagulase-negative staphylococci 2	< 0.25		> 0.25
Enterococcus1	< 4	8	> 8
Streptococcus A, B, C, G5	< 0.25	-	> 0.25
Streptococcus pneumoniae3	< 0.5	1-2	> 2
Enterobacteriaceae1,4	-	-	> 8
Gram-negative Anaerobes1	< 4	8	> 8
Gram-positive Anaerobes1	< 4	8	> 8
Non-species related Breakpoints1	< 2	4-8	> 8
1The reported values are for Amoxicillin concentrations. For susceptibility testing

500 mg/100 mg
AMX/CA 1000 mg/200 mg	200 mg	28.5	0.9	27.9	63.8
AMX - amoxicillin, CA	- clavulanic acid

Distribution

About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid.

Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.

From animal studies there is no evidence for significant tissue retention of drug-derived material for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6).

Biotransformation

Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man, and eliminated in urine and faeces and as carbon dioxide in expired air.

Elimination

The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms.Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of a single 500/100 mg or a single 1000/200 mg bolus intravenous injection. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5).

Age

The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal impairment

The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).

Hepatic impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

5.3 Preclinical safety data

Nonclinical data reveal no special hazard for humans based on studies of safety pharmacology, genotoxicity and toxicity to reproduction.

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.

Carcinogenicity studies have not been conducted with Co-amoxiclav or its components.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

None.

6.2 Incompatibilities

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

If Co-amoxiclav 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.

6.3 Shelf life

Powder for injection: 2 years

From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Solutions for injection, prepared as indicated in Section 6.6, should be administered within 20 minutes of reconstitution.

Solutions for infusion should be completed within the times stated in section 6.6 (see individual infusion fluids in section 6.6).

6.4 Special precautions for storage

Do not store above 30° C. Keep container in the outer carton.

6.5 Nature and contents of container

Colourless glass vials (Ph.Eur. type II) sealed with brombutyl stopper and aluminium flip-off cap. Available in packs of 10 vials.

6.6 Special precautions for disposal

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

Preparation of solutions for intravenous injection

1000 mg/200 mg powder for solution for injection or infusion

Water for Injection Ph.Eur. is the normal solvent. Co-amoxiclav 1000 mg/200 mg should be dissolved in 20 ml of solvent. This yields approximately 20.9 ml of solution for single-dose use. A transient pink colouration may or may not develop during reconstitution. Reconstituted solutions are normally colourless or a pale straw colour.

Co-amoxiclav should be administered within 20 min of reconstitution.

Co-amoxiclav vials are not suitable for multi-dose use 1000 mg/200 mg powder for solution for injection or infusion

Co-amoxiclav should be reconstituted as described above for injection. Without delay the reconstituted solution should be added to 100 ml of infusion fluid using a minibag or in-line burette.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1572

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/10/2005 / 16/06/2010

10 DATE OF REVISION OF THE TEXT

07/04/2011