Co-amoxiclav 400 / 57mg / 5ml Powder for Oral Suspension (Sandoz Limited)

1. Name Of The Medicinal Product

Co-amoxiclav 400/57mg/5ml Powder for Oral Suspension

2. Qualitative And Quantitative Composition

1 ml reconstituted suspension (corresponding to 0.160 g powder) contains:

Amoxicillin trihydrate corresponding to 80 mg amoxicillin.

Potassium clavulanate corresponding to 11.4 mg clavulanic acid.

Excipient(s):

1 ml reconstituted suspension contains 1.7 mg of aspartame.

1 ml reconstituted suspension contains sorbitol

1 ml reconstituted suspension contains glucose

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Powder for oral suspension:

Off-white powder

4. Clinical Particulars

4.1 Therapeutic Indications

Co-amoxiclav 400/57mg/5ml Powder for Oral Suspension 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

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 400/57mg/5ml Powder for Oral Suspension 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 400/57mg/5ml Powder for Oral Suspension (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 adults and children

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

Recommended doses:

• standard dose: (for all indications) 875 mg/125 mg two times a day;

• higher dose - (particularly for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections): 875 mg/125 mg three times a day.

Children < 40 kg

Children may be treated with Co-amoxiclav 400/57mg/5ml Powder for Oral Suspension 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 400/57mg/5ml Powder for Oral Suspension 7:1 formulations regarding doses higher than 45 mg/6.4 mg/kg per day in children under 2 years.

There are no clinical data for Co-amoxiclav 400/57mg/5ml Powder for Oral Suspension 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 adjustment in dose 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 400/57mg/5ml Powder for Oral Suspensionpresentations 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 400/57mg/5ml Powder for Oral Suspension 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 the 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).

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 sections 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 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 400/57mg/5ml Powder for Oral Suspension is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or 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 400/57mg/5ml Powder for Oral Suspension 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 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 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 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 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 non-enzymatic methods.

The presence of Clavulanic acid in Co-amoxiclav 400/57mg/5ml Powder for Oral Suspension 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 400/57mg/5ml Powder for Oral Suspension contains 1.7 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria.

Patients with rare heriditary problems of fructose intolerance or glucose-galactose malabsorption should not take this medicine.

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.

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 400/57mg/5ml Powder for Oral Suspension, 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 (

Common (

Uncommon (

Rare (

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 disorders10
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
Convulsions2	Not known
Gastrointestinal disorders
Diarrhoea	Common
Nausea3	Common
Vomiting	Common
Indigestion	Uncommon
Antibiotic-associated colitis4	Not known
Black hairy tongue	Not known
Tooth discoloration11	Not known
Hepatobiliary disorders
Rises in AST and/or ALT5	Uncommon
Hepatitis6	Not known
Cholestatic jaundice6	Not known
Skin and subcutaneous tissue disorders 7
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)9	Not known
Renal and urinary disorders
Interstitial nephritis	Not known
Crystalluria8	Not known
1 See section 4.4 2 See section 4.4 3 Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking Co-amoxiclav 400/57mg/5ml Powder for Oral Suspension at the start of a meal. 4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4) 5 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. 6 These events have been noted with other penicillins and cephalosporins (see section 4.4). 7 If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4). 8 See section 4.9 9 See section 4.4 10 See sections 4.3 and 4.4 11 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.

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: J01CR02.

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 (µg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae1		-	> 1
Moraxella catarrhalis1		-	> 1
Staphylococcus aureus 2		-	> 2
Coagulase-negative staphylococci 2			> 0.25
Enterococcus1		8	> 8
Streptococcus A, B, C, G5		-	> 0.25
Streptococcus pneumoniae3		1-2	> 2
Enterobacteriaceae1,4	-	-	> 8
Gram-negative Anaerobes1		8	> 8
Gram-positive Anaerobes1		8	> 8
Non-species related breakpoints1		4-8	> 8
1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l. 2 The reported values are Oxacillin concentrations. 3 Breakpoint values in the table are based on Ampicillin breakpoints. 4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant. 5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive micro-organisms Enterococcus faecalis Gardnerella vaginalis Staphylococcus aureus (methicillin-susceptible)£ Coagulase-negative staphylococci (methicillin-susceptible) Streptococcus agalactiae Streptococcus pneumoniae1 Streptococcus pyogenes and other beta-haemolytic streptococci Streptococcus viridans group Aerobic Gram-negative micro-organisms Capnocytophaga spp. Eikenella corrodens Haemophilus influenzae2 Moraxella catarrhalis Pasteurella multocida Anaerobic micro-organisms Bacteroides fragilis Fusobacterium nucleatum Prevotella spp.

Species for which acquired resistance may be a problem

Aerobic Gram-positive micro-organisms Enterococcus faecium $ Aerobic Gram-negative micro-organisms Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Proteus mirabilis Proteus vulgaris

Inherently resistant organisms

Aerobic Gram-negative micro-organisms Acinetobacter sp. Citrobacter freundii Enterobacter sp. Legionella pneumophila Morganella morganii Providencia spp. Pseudomonas sp. Serratia sp. Stenotrophomonas maltophilia Other micro-organisms Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetti Mycoplasma pneumoniae

$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid 1Streptococcus pneumoniae that are resistant to penicillin should not be treated with this presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4). 2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.

5.2 Pharmacokinetic Properties

Absorption

Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour.

The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (875 mg/125 mg tablets given twice daily) was administered in the fasting state to groups of healthy volunteers are presented below.

Mean (± SD) pharmacokinetic parameters
Active substance(s) administered	Dose	Cmax	Tmax *	AUC (0-24h)	T 1/2
(mg)	(µg/ml)	(h)	(µg.h/ml)	(h)
Amoxicillin
AMX/CA 875/125 mg	875	11.64 ± 2.78	1.50 (1.0-2.5)	53.52 ± 12.31	1.19 ± 0.21
Clavulanic acid
AMX/CA 875 mg/125 mg	125	2.18 ± 0.99	1.25 (1.0-2.0)	10.16 ± 3.04	0.96 ± 0.12
AMX – amoxicillin, CA – clavulanic acid * Median (range)

Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

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).

Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (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 single Co-amoxiclav 400/57mg/5ml Powder for Oral Suspension 250 mg/125 mg or 500 mg/125 mg tablets. 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.

Gender

Following oral administration of amoxicillin/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.

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 demonst

Elidel 10mg / g cream (Meda Pharmaceuticals )

1. Name Of The Medicinal Product

Elidel® 10mg/g cream.

2. Qualitative And Quantitative Composition

1 g of cream contains 10 mg of pimecrolimus.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Cream.

Whitish and homogeneous.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of patients aged 2 years and over with mild or moderate atopic dermatitis where treatment with topical corticosteroids is either inadvisable or not possible. This may include:

• Intolerance to topical corticosteroids

• Lack of effect of topical corticosteroids

• Use on the face and neck where prolonged intermittent treatment with topical corticosteroids may be inappropriate

4.2 Posology And Method Of Administration

Elidel should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis.

Elidel can be used in the short term for the treatment of the signs and symptoms of atopic eczema and intermittently in the long term for the prevention of progression to flares.

Elidel treatment should begin at the first appearance of signs and symptoms of atopic dermatitis. Elidel should only be applied to areas affected with atopic dermatitis. Elidel should be used for as short period as possible during flares of disease. The patient or caregiver should stop using Elidel when signs and symptoms resolve. Treatment should be intermittent, short-term and not continuous. Elidel should be applied thinly to the affected areas twice daily.

Data from clinical studies support intermittent treatment with Elidel for up to 12 months.

If no improvement occurs after 6 weeks, or in case of disease exacerbation, Elidel should be stopped. The diagnosis of atopic dermatitis should be re-evaluated and further therapeutic options considered.

Adults

Apply a thin layer of Elidel to the affected skin twice daily and rub in gently and completely. Each affected region of the skin should be treated with Elidel until clearance occurs and then treatment should be discontinued.

Elidel may be used on all skin areas, including the head and face, neck and intertriginous areas, except on mucous membranes. Elidel should not be applied under occlusion (see section 4.4).

In the long-term management of atopic dermatitis (eczema), Elidel treatment should begin at first appearance of signs and symptoms of atopic dermatitis to prevent flares of the disease. Elidel should be used twice daily. Emollients can be applied immediately after using Elidel.

Paediatric patients

The use of Elidel in patients under 2 years of age is not recommended until further data become available.

For children (2-11 years) and adolescents (12-17 years) the posology and method of administration are the same as for adults.

Elderly patients

Atopic dermatitis (eczema) is rarely observed in patients aged 65 and over. Clinical studies with Elidel did not include a sufficient number of patients in this age range to determine whether they respond differently from younger patients.

4.3 Contraindications

Hypersensitivity to pimecrolimus, other macrolactams or to any of the excipients (see section 6.1).

4.4 Special Warnings And Precautions For Use

Elidel cream should not be used in patients with congenital or acquired immunodeficiencies or in patients on therapy that causes immunosuppression.

Long-term effect on the local skin immune response and on the incidence of skin malignancies is unknown. Elidel should not be applied to potentially malignant or pre-malignant skin lesions.

Elidel should not be applied to areas affected by acute cutaneous viral infections (herpes simplex, chicken pox).

Elidel has not been evaluated for its efficacy and safety in the treatment of clinically infected atopic dermatitis. Before commencing treatment with Elidel, clinical infections at treatment sites should be cleared.

While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum (Kaposi's varicelliform eruption), treatment with Elidel may be associated with an increased risk of skin herpes simplex virus infection, or eczema herpeticum (manifesting as rapid spread of vesicular and erosive lesions). In the presence of herpes simplex skin infection, Elidel treatment at the site of infection should be discontinued until the viral infection has cleared.

Patients with severe atopic dermatitis may have an increased risk of skin bacterial infections (impetigo) during treatment with Elidel.

Use of Elidel may cause mild and transient reactions at the site of application, such as a feeling of warmth and/or burning sensation. If the application site reaction is severe, the risk-benefit of treatment should be re-evaluated.

Care should be taken to avoid contact with eyes and mucous membranes. If accidentally applied to these areas, the cream should be thoroughly wiped off and/or rinsed off with water.

Physicians should advise patients on appropriate sun protection measures, such as minimisation of the time in the sun, use of sunscreen product and covering the skin with appropriate clothing (see section 4.5).

Elidel contains cetyl alcohol and stearyl alcohol which may cause local skin reactions. Elidel also contains propylene glycol, which may cause skin irritation.

Elidel contains the active substance pimecrolimus, a calcineurin inhibitor. In transplant patients, prolonged systemic exposure to intense immunosuppression following systemic administration of calcineurin inhibitors has been associated with an increased risk of developing lymphomas and skin malignancies.

Cases of malignancies, including cutaneous and other types of lymphoma, and skin cancers have been reported in patients using pimecrolimus cream (see section 4.8). However, patients with atopic dermatitis treated with Elidel have not been found to have significant systemic pimecrolimus levels.

In clinical studies, 14/1,544 (0.9%) cases of lymphadenopathy were reported while using Elidel 10mg/g cream. These cases of lymphadenopathy were usually related to infections and noted to resolve upon appropriate antibiotic therapy. Of these 14 cases, the majority had either a clear etiology or were known to resolve. Patients who receive Elidel 10mg/g cream and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, Elidel 10mg/g cream should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.

Populations with potentially higher risk of systemic exposure.

Elidel has not been studied in patients with Netherton's syndrome. Due to the potential for increased systemic absorption of pimecrolimus, Elidel is not recommended in patients with Netherton's syndrome.

As the safety of Elidel has not been established in erythrodermic patients, the use of the product in this patient population cannot be recommended.

The use of Elidel under occlusion has not been studied in patients. Occlusive dressings are not recommended.

In patients with severely inflamed and/or damaged skin, the systemic concentrations may be higher.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Potential interactions between Elidel and other medicinal products have not been systematically evaluated. Pimecrolimus is exclusively metabolised by CYP 450 3A4. Based on its minimal extent of absorption, interactions of Elidel with systemically administered medicinal products are unlikely to occur (see section 5.2).

The present data indicate that Elidel can be used simultaneously with antibiotics, antihistamines and corticosteroids (oral/nasal/inhaled).

Based on the minimal extent of absorption, a potential systemic interaction with vaccination is unlikely to occur. However, this interaction has not been studied. Therefore, in patients with extensive disease, it is recommended to administer vaccinations during treatment-free intervals.

There is no experience with concomitant use of immunosuppressive therapies given for atopic eczema such as UVB, UVA, PUVA, azathioprine and cyclosporin A.

Elidel has no photocarcinogenic potential in animals (see section 5.3.). However, since the relevance to man is unknown excessive exposure of the skin to ultraviolet light including light from a solarium, or therapy with PUVA, UVA or UVB should be avoided during treatment with Elidel.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Elidel in pregnant women. Animal studies using dermal application do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Studies in animals after oral application have shown reproductive toxicity (see section 5.3). Based on the minimal extent of pimecrolimus absorption after topical application of Elidel (see section 5.2), the potential risk for humans is considered limited. However, Elidel should not be used during pregnancy.

Lactation

Animal studies on milk excretion after topical application were not conducted and the use of Elidel in breastfeeding women has not been studied. It is not known whether pimecrolimus is excreted in the milk after topical application.

However, based on the minimal extent of pimecrolimus absorption after topical application of Elidel, (see section 5.2), the potential risk for humans is considered limited. Caution should be exercised when Elidel is administered to breastfeeding women.

Breastfeeding mothers may use Elidel but should not apply Elidel to the breast in order to avoid unintentional oral uptake by the newborn.

4.7 Effects On Ability To Drive And Use Machines

Elidel has no known effect on the ability to drive and use machines.

4.8 Undesirable Effects

The most common adverse events were application site reactions which were reported by approximately 19% of the patients treated with Elidel and 16% of patients in the control groups. These reactions generally occurred early in treatment, were mild/moderate and were of short duration.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (

Skin and subcutaneous tissue disorders
Common	Skin infections (folliculitis)
Uncommon	Furuncle, impetigo, herpes simplex, herpes zoster, herpes simplex dermatitis (eczema herpeticum), skin papilloma and condition aggravated
Rare	Allergic reactions (e.g. rash, urticaria, angiooedema), skin discoloration (e.g hypopigmentation, hyperpigmentation)
Metabolism and nutrition disorders
Rare	Alcohol intolerance (in most cases, flushing, rash, burning, itching or swelling occurred shortly after the intake of alcohol)
Infections and infestations
Uncommon	Molluscum contagiosum
General disorders and administration site conditions
Very common	Application site burning
Common	Application site reactions (irritation, pruritus and erythema)
Uncommon	Application site disorders (rash, pain, paraesthesia, desquamation, dryness, oedema)
Immune system disorders
Very rare	Anaphylactic reactions, including severe forms

Post marketing: Cases of malignancy, including cutaneous and other types of lymphoma, and skin cancers, have been reported in patients using pimecrolimus cream (see Section 4.4) .

4.9 Overdose

There has been no experience of overdose with Elidel.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AH02

Non-clinical pharmacology

Pimecrolimus is a lipophilic anti-inflammatory ascomycin macrolactam derivative and a cell selective inhibitor of the production and release of pro-inflammatory cytokines.

Pimecrolimus binds with high affinity to macrophilin-12 and inhibits the calcium-dependent phosphatase calcineurin. As a consequence, it blocks the synthesis of inflammatory cytokines in T cells.

Pimecrolimus exhibits high anti-inflammatory activity in animal models of skin inflammation after topical and systemic application. In the pig model of allergic contact dermatitis, topical pimecrolimus is as effective as potent corticosteroids. Unlike corticosteroids, pimecrolimus does not cause skin atrophy in pigs and does not affect Langerhans´cells in murine skin.

Pimecrolimus neither impairs the primary immune response nor affects lymph nodes in murine allergic contact dermatitis. Topical pimecrolimus penetrates similarly into, but permeates much less through human skin than corticosteroids, indicating a very low potential of pimecrolimus for systemic absorption.

In conclusion, pimecrolimus has a skin-selective pharmacological profile different from corticosteroids.

Clinical data

The efficacy and safety profile of Elidel has been evaluated in more than 2,000 patients including infants (

Short-term (acute) treatment:

Children and adolescents: Two 6-week, vehicle-controlled trials were conducted including a total of 403 paediatric patients aged 2 to 17 years. Patients were treated twice daily with Elidel. The data of both studies were pooled.

Infants: A similar 6-week study was conducted in 186 patients aged 3-23 months.

In these three 6-week studies, the efficacy results at endpoint were as follows:

		Children and adolescents	Infants
Endpoint	Criteria	Elidel 1% (N=267)	Vehicle (N=136)	p-value	Elidel 1% (N=123)	Vehicle (N=63)	p-value
IGA*:	Clear or almost clear 1	34.8%	18.4%	<0.001	54.5%	23.8%	<0.001
IGA*	Improvement 2	59.9%	33%	not done	68%	40%	Not done
Pruritus:	Absent or mild	56.6%	33.8%	<0.001	72.4%	33.3%	<0.001
EASI°:	Overall (mean % change)3	-43.6	-0.7	<0.001	-61.8	+7.35	<0.001
EASI°:	Head/Neck (mean % change)3	-61.1	+0.6	<0.001	-74.0	+31.48	<0.001
* Investigators Global Assessment ° Eczema Area Severity Index (EASI): mean % change in clinical signs (erythema, infiltration, excoriation, lichenification) and body surface area involved 1: p-value based on CMH test stratified by centre 2 Improvement=lower IGA than at baseline 3: p-value based on ANCOVA model of EASI at Day 43 endpoint, with centre and treatment as factors and baseline (Day 1) EASI a covariate;

A significant improvement in pruritus was observed within the first week of treatment in 44% of children and adolescents and in 70% of infants.

Adults: Elidel was less effective than 0.1% betamethasone-17-valerate in the short-term treatment (3 weeks) of adults with moderate to severe atopic dermatitis.

Long-term treatment

Two double-blind studies of long-term management of atopic dermatitis were undertaken in 713 children and adolescents (2-17 years) and 251 infants (3-23 months). Elidel was evaluated as foundation therapy.

Elidel was used at first signs of itching and redness to prevent progression to flares of atopic dermatitis. Only in case of a flare of severe disease not controlled by Elidel, treatment with medium potency topical corticosteroids was initiated. When corticosteroid therapy was initiated for the treatment of flares, Elidel therapy was discontinued. The control group received Elidel vehicle in order to maintain blinding.

Both studies showed a significant reduction in the incidence of flares (p<0.001) in favour of Elidel treatment; Elidel treatment showed better efficacy in all secondary assessments (Eczema Area Severity Index, Investigators Global Assessment, subject assessment); pruritus was controlled within a week with Elidel. More patients treated with Elidel completed 6 months [children (61% Elidel vs 34% control), infants (70% Elidel vs 33% control)] and 12 months with no flare [children (51% Elidel vs 28% control), infants (57% Elidel vs 28% control)].

Elidel had a sparing effect on the use of topical corticosteroids: more patients treated with Elidel did not use corticosteroids in 12 months [children (57% Elidel vs 32% control), infants (64% Elidel vs 35% control)]. The efficacy of Elidel was maintained over time.

A 6-month randomized, double-blind, parallel group, vehicle-controlled study of similar design was performed in 192 adults with moderate to severe atopic dermatitis. Topical corticosteroid medication was used on 14.2 ± 24.2% of the days of the 24-week treatment period in Elidel group and on 37.2 ± 34.6% of the days in the control group (p<0.001). A total of 50.0% of the patients treated with Elidel did not experience any flare compared with 24.0% of the patients randomized to the control group.

A one year double-blind study in adults with moderate to severe atopic dermatitis was conducted to compare Elidel to 0.1% triamcinolone acetonide cream (for trunk and extremities) plus 1% hydrocortisone acetate cream (for face, neck and intertriginous areas). Both Elidel and topical corticosteroids were used without restrictions. Half of the patients in the control group received topical corticosteroids for more than 95% of study days. Elidel was less effective than 0.1% triamcinolone acetonide cream (for trunk and extremities) plus 1% hydrocortisone acetate cream (for face, neck and intertriginous areas) in the long-term treatment (52 weeks) of adults with moderate to severe atopic dermatitis.

Long-term controlled clinical trials were 1 year in duration. There is clinical data in pediatric patients for up to 24 months.

Frequency of application greater than twice daily has not been studied.

Special studies

Tolerability studies demonstrated that Elidel has not shown contact sensitising, phototoxic or photosensitising potential, nor did they show any cumulative irritation.

The atrophogenic potential of Elidel in humans was tested in comparison to medium and highly potent topical steroids (betamethasone-17-valerate 0.1% cream, triamcinolone acetonide 0.1% cream) and vehicle in sixteen healthy volunteers treated for 4 weeks. Both topical corticosteroids induced a significant reduction in skin thickness measured by echography, as compared to Elidel and vehicle, which did not induce a reduction of skin thickness.

5.2 Pharmacokinetic Properties

Data in animals

The bioavailability of pimecrolimus in mini-pigs following a single dermal dose (applied for 22h under semi-occlusion) was 0.03%. The amount of active substance-related material in the skin at the application site (almost exclusively unchanged pimecrolimus) remained practically constant for 10 days.

Data in humans

Absorption in adults

Systemic exposure to pimecrolimus was investigated in 12 adults with atopic dermatitis who were treated with Elidel twice daily for 3 weeks. The affected body surface area (BSA) ranged from 15-59%. 77.5% of pimecrolimus blood concentrations were below 0.5 ng/ml and 99.8% of the total samples were below 1 ng/ml. The highest pimecrolimus blood concentration was 1.4 ng/ml in one patient.

In 40 adult patients treated for up to 1 year with Elidel, having 14-62% of their BSA affected at baseline, 98% of pimecrolimus blood concentrations were below 0.5 ng/ml. A maximum blood concentration of 0.8 ng/ml was measured in only 2 patients in week 6 of treatment. There was no increase in blood concentration over time in any patient during the 12 months of treatment. In 8 adult atopic dermatitis patients, in which AUC levels could be quantified, the AUC _(0-12h) values ranged from 2.5 to 11.4 ng h/ml.

Absorption in children

Systemic exposure to pimecrolimus was investigated in 58 paediatric patients aged 3 months to 14 years. The affected BSA ranged from 10-92%. These children were treated with Elidel twice daily for 3 weeks and five out of them were treated for up to 1 year on a “as needed” basis.

Pimecrolimus blood concentrations were consistently low regardless of the extent of lesions treated or duration of therapy. They were in a range similar to that measured in adult patients. Around 60% of pimecrolimus blood concentrations were below 0.5 ng/ml and 97% of all samples were below 2 ng/ml. The highest blood concentrations measured in 2 paediatric patients aged 8 months to 14 years were 2.0 ng/ml.

In infants (aged 3 to 23 months), the highest blood concentration measured in one patient was 2.6 ng/ml. In the 5 children treated for 1 year, blood concentrations were consistently low (maximum blood concentration was 1.94 ng/ml in 1 patient). There was no increase in blood concentration over time in any patient during the 12 months of treatment.

In 8 paediatric patients aged 2-14 years, AUC _(0-12h) ranged from 5.4 to 18.8 ng h/ml. AUC ranges observed in patients with <40% BSA affected at baseline were comparable to those in patients with

The maximum body surface area treated was 92% in clinical pharmacology studies and up to 100% in Phase III trials.

Distribution

Consistent with its skin selectivity, after topical application, pimecrolimus blood levels are very low. Therefore pimecrolimus metabolism could not be determined after topical administration.

In vitro plasma protein binding studies have shown that 99.6% of pimecrolimus in plasma is bound to proteins. The major fraction of pimecrolimus in plasma is bound to different lipoproteins.

Metabolism

After single oral administration of radiolabeled pimecrolimus in healthy subjects, unchanged pimecrolimus was the major active substance-related component in blood and there were numerous minor metabolites of moderate polarity that appeared to be products of O-demethylations and oxygenation.

No metabolism of pimecrolimus was observed in human skin in vitro.

Excretion

Active substance-related radioactivity was excreted principally via the faeces (78.4%) and only a small fraction (2.5%) was recovered in urine. Total mean recovery of radioactivity was 80.9%. Parent compound was not detected in urine and less than 1% of radioactivity in faeces was accounted for by unchanged pimecrolimus.

5.3 Preclinical Safety Data

Conventional studies of repeated dose toxicity, reproductive toxicity and carcinogenicity using oral administration produced effects at exposures sufficiently in excess of those in man to be of negligible clinical significance. Pimecrolimus had no genotoxic, antigenic, phototoxic, photoallergenic or photocarcinogenic potential. Dermal application in embryo/fetal developmental studies in rats and rabbits and in carcinogenicity studies in mice and rats were negative.

Effects on reproductive organs and altered sex hormone functions were seen in male and female rats in repeated dose toxicity studies after oral administration of 10 or 40 mg/kg/day (= 20 to 60 times the maximum human exposure after dermal application). This is reflected by the findings from the fertility study. The No Observed Adverse Effect Level (NOAEL) for female fertility was 10 mg/kg/day (= 20 times the maximum human exposure after dermal application). In the oral embryotoxicity study in rabbits, a higher resorption rate associated with maternal toxicity was observed at 20 mg/kg/day (= 7 times the maximum human exposure after dermal application); the mean number of live fetuses was not affected.

Dose-dependent increases in the incidence of lymphomas were observed at all doses in a 39 week monkey oral toxicity study. Signs of recovery and/or at least partial reversibility of the effects were noted upon cessation of dosages in a few animals. Failure to derive a NOAEL precludes an assessment of the margin of safety between a non-carcinogenic concentration in the monkey and exposures in patients. The systemic exposure at the LOAEL of 15mg/kg/day was 31 times the highest maximum exposure observed in a human (paediatric patient). The risk for humans cannot be completely ruled out as the potential for local immunosuppression with the long-term use of pimecrolimus cream is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Medium chain triglycerides

Oleyl alcohol

Propylene glycol

Stearyl alcohol

Cetyl alcohol

Mono-and di-glycerides

Sodium cetostearyl sulphate

Benzyl alcohol

Citric acid anhydrous

Sodium hydroxide

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years. After first opening the container: 12 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not freeze.

6.5 Nature And Contents Of Container

Aluminium tube with a phenol-epoxy protective inner lacquer and polypropylene screw cap.

Tubes of 5, 15, 30, 60 and 100 grams.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Emollients can be applied together with Elidel (see ection 4.2).

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

United Kingdom

8. Marketing Authorisation Number(S)

PL 15142/0250

9. Date Of First Authorisation/Renewal Of The Authorisation

1 August 2011

10. Date Of Revision Of The Text

1 August 2011

Augmentin XR Extended-Release Tablets

Pronunciation: a-MOX-i-SIL-in/KLAV-ue-la-nate
Generic Name: Amoxicillin/Clavulanate
Brand Name: Augmentin XR

Augmentin XR Extended-Release Tablets are used for:

Treating infections caused by certain bacteria.

Augmentin XR Extended-Release Tablets are a penicillin antibiotic. It works by killing sensitive bacteria.

Do NOT use Augmentin XR Extended-Release Tablets if:

• you are allergic to any ingredient in Augmentin XR Extended-Release Tablets or another penicillin antibiotic (eg, ampicillin)


• you have a history of liver problems or yellowing of the eyes or skin caused by Augmentin XR Extended-Release Tablets


• you have severe kidney problems or are on dialysis


• you have infectious mononucleosis (mono)


• you have recently received or will be receiving a live oral typhoid vaccine

Contact your doctor or health care provider right away if any of these apply to you.

Before using Augmentin XR Extended-Release Tablets:

Some medical conditions may interact with Augmentin XR Extended-Release Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of allergies, asthma, hay fever, or hives


• if you have had a severe allergic reaction (eg, severe rash, hives, breathing difficulties, dizziness) to a cephalosporin (eg, cephalexin) or another beta-lactam antibiotic (eg, imipenem)


• if you have kidney problems or gonorrhea


• if you have a history of liver problems or yellowing of the eyes or skin


• if you are on a low-salt (sodium) diet

Some MEDICINES MAY INTERACT with Augmentin XR Extended-Release Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticoagulants (eg, warfarin) because the risk of bleeding may be increased


• Probenecid because it may increase the amount of Augmentin XR Extended-Release Tablets in your blood


• Chloramphenicol, macrolide antibiotics (eg, erythromycin), sulfonamides (eg, sulfamethoxazole), or tetracycline antibiotics (eg, doxycycline) because they may decrease Augmentin XR Extended-Release Tablets's effectiveness


• Allopurinol because the risk of rash may be increased


• Methotrexate because the risk of its side effects may be increased by Augmentin XR Extended-Release Tablets


• Live oral typhoid vaccine or hormonal birth control (eg, birth control pills) because their effectiveness may be decreased by Augmentin XR Extended-Release Tablets

This may not be a complete list of all interactions that may occur. Ask your health care provider if Augmentin XR Extended-Release Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Augmentin XR Extended-Release Tablets:

Use Augmentin XR Extended-Release Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Augmentin XR Extended-Release Tablets by mouth at the start of a meal.


• Swallow Augmentin XR Extended-Release Tablets whole. Do not break, crush, or chew before swallowing. If you have difficulty swallowing the whole tablet, this tablet may be broken in half.


• To clear up your infection completely, take Augmentin XR Extended-Release Tablets for the full course of treatment. Keep taking it even if you feel better in a few days.


• If you miss a dose of Augmentin XR Extended-Release Tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Augmentin XR Extended-Release Tablets.

Important safety information:

• Augmentin XR Extended-Release Tablets may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Augmentin XR Extended-Release Tablets with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Augmentin XR Extended-Release Tablets only works against bacteria; it does not treat viral infections (eg, the common cold).


• Be sure to use Augmentin XR Extended-Release Tablets for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Long-term or repeated use of Augmentin XR Extended-Release Tablets may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.


• Mild diarrhea is common with antibiotic use. However, a more serious form of diarrhea (pseudomembranous colitis) may rarely occur. This may develop while you use the antibiotic or within several months after you stop using it. Contact your doctor right away if stomach pain or cramps, severe diarrhea, or bloody stools occur. Do not treat diarrhea without first checking with your doctor.


• Hormonal birth control (eg, birth control pills) may not work as well while you are using Augmentin XR Extended-Release Tablets. To prevent pregnancy, use an extra form of birth control (eg, condoms).


• Augmentin XR Extended-Release Tablets has sodium in it. If you are on a low-salt (sodium) diet, include this when you count your daily intake of sodium.


• Brown, yellow, or gray tooth discoloration has occurred rarely in some patients taking Augmentin XR Extended-Release Tablets. It occurred most often in children. The discoloration was reduced or removed by brushing or dental cleaning in most cases. Contact your doctor if you experience this effect.


• Diabetes patients - Augmentin XR Extended-Release Tablets may cause the results of some tests for urine glucose to be wrong. Ask your doctor before you change your diet or the dose of your diabetes medicine.


• Lab tests, including liver function, kidney function, and complete blood cell counts, may be performed if you use Augmentin XR Extended-Release Tablets for a long period of time. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Augmentin XR Extended-Release Tablets with caution in the ELDERLY; they may be more sensitive to its effects, especially patients with kidney problems.


• Augmentin XR Extended-Release Tablets should be used with extreme caution in CHILDREN weighing less than 40 kilograms (88 pounds); safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Augmentin XR Extended-Release Tablets while you are pregnant. Augmentin XR Extended-Release Tablets are found in breast milk. If you are or will be breast-feeding while you use Augmentin XR Extended-Release Tablets, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Augmentin XR Extended-Release Tablets:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); bloody stools; confusion; dark urine; fever, chills, or persistent sore throat; red, swollen, blistered, or peeling skin; seizures; severe or persistent diarrhea; stomach pain or cramps; unusual bruising or bleeding; vaginal discharge or irritation; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Augmentin XR side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include decreased urination; severe nausea, vomiting, or diarrhea; stomach pain; unusual drowsiness.

Proper storage of Augmentin XR Extended-Release Tablets:

Store at or below 77 degrees F (25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Augmentin XR Extended-Release Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about Augmentin XR Extended-Release Tablets, please talk with your doctor, pharmacist, or other health care provider.


• Augmentin XR Extended-Release Tablets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Augmentin XR Extended-Release Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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