AMOXICILLIN CAPSULES 500 MG, DEDOXIL CAPSULES 500 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

DEDOXIL/Amoxicillin capsules 500 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains Amoxicillin Trihydrate BP 500 mg

(equivalent to Amoxicillin anhydrous)

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Opaque Capsules

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

DEDOXIL/Amoxicillin is indicated for the treatment of the following infection:

Acute bacterial sinusitis

Acute Otitis media,

Acute streptococcal tonsillitis and pharyngitis

Acute exacerbations and chronic bronchitis,

Community acquired pneumonia,

Acute cystitis,

Asymptomatic bacteriuria in pregnancy,

Acute pyelonephritis

Typhoid and paratyphoid fever,

Dental abscess) with spreading cellulitis

Prosthetic joint infections

Helicobacter pylori eradication

Lyme disease

DEDOXIL/Amoxicillin is also indicated for the prophylaxis of endocarditis

Consideration should be given to official guidance (e.g. national requirements) on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

The dose of Dedoxil/Amoxicillin 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 duration of therapy should be determined by the type of infection and the response of the patient, and should generally be as short as possible. Some infections require longer periods of treatment (see section 4.4 regarding prolonged therapy).

Adults and children >40 kg

Children <40 kg

Children weighing 40 kg or more should be prescribed the adult dosage. Recommended doses:

Elderly

No dose adjustment is considered necessary.

Renal impairment

In patients receiving haemodialysis

Amoxicillin may be removed from the circulation by haemodialysis.

In patients receiving peritoneal dialysis

Amoxicillin maximum 500 mg/day.

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals (see sections 4.4 and 4.8).

Amoxicillin is for oral use

Absorption of Amoxicillin is unimpaired by food.

Swallow with water without opening capsule.

4.3 Contraindications

DEDOXIL is a penicillin and should not be given to penicillin-sensitive patients, Hypersensitivity to the active substance or to any of the excipients listed in the section 6.1.

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

4.4 Special warnings and precautions for use

Hypersensitivity reactions

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

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of hypersensitivity to beta-lactam antibiotics, (see section 4.3) and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and appropriate alternative therapy instituted

Non-susceptible microorganisms

Amoxicillin is not suitable for the treatment of some types of infection unless the pathogen is already documented and known to be susceptible or there is a very high likelihood that the pathogen would be suitable for treatment with amoxicillin (see section 5.1). This particularly applies when considering the treatment of patients with urinary tract infections and severe infections of the ear, nose and throat.

Convulsions

Convulsions may occur in patients with impaired renal function or in those receiving high doses or in patients with predisposing factors (e.g. history of seizures, treated epilepsy or meningeal disorders (see section 4.8).

Renal Impairment

Dosage should be adjusted in patients with renal impairment as the rate of excretion of amoxicillin will be reduced depending on the degree of impairment, (see section 4.2).

Skin reactions

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

Amoxicillin 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.

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction has been seen following amoxicillin treatment of Lyme disease (see section 4.8). It results directly from the bactericidal activity of amoxicillin on the causative bacteria of Lyme disease, the spirochaete Borrelia burgdorferi. Patients should be reassured that this is a common and usually selflimiting consequence of antibiotic treatment of Lyme disease

Overgrowth of non-susceptible microorganisms

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

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 should immediately be discontinued, a physician consulted and an appropriate therapy initiated. Antiperistaltic medicinal products are contra-indicated in this situation.

Prolonged therapy

Periodic assessment of organ system functions; including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Elevated liver enzymes and changes in blood counts have been reported (see section 4.8).

Anticoagulants

Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin. 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).

Crystalluria

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 4.8 and 4.9).

Interference with diagnostic tests

Elevated serum and urinary levels of amoxicillin are likely to affect certain laboratory tests. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.

It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used.

The presence of amoxicillin may distort assay results for oestriol in pregnant women

Precaution should be taken in premature children and during the neonatal period: renal, hepatic and haematological functions should be monitored.

4.5 Interaction with other medicinal products and other forms of interaction

Probenicid

Renal tubular excretion of penicillins is reduced by probenicid. Concurrent use with amoxicillin may result in increased and prolonged blood levels of amoxicillin.

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).

Allopurinol

Concurrent administration of allopurinol may increase the likelihood of allergic skin reactions.

Tetracyclines

Tetracyclines and other bacteriostatic drugs may interfere with the bactericidal effects of amoxicillin.

Methotrexate

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

4.6 Fertility, pregnancy and lactation

Pregnancy:

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Limited data on the use of amoxicillin during pregnancy in humans do not indicate an increased risk of congenital malformations. When antibiotic therapy is required during pregnancy, DEDOXIL may be considered appropriate when the potential benefits of the drug outweigh the possible hazards to the foetus.

Breastfeeding

Amoxicillin may be given during lactation. With the exception of the risk of sensitisation associated with the excretion of trace quantities of amoxicillin in breast milk, there are no known detrimental effects for the breast-fed infant.

Amoxicillin should only be used during breast-feeding after benefit/risk assessment by the physician in charge

Fertility

There are no data on the effects of amoxicillin on fertility in humans. Reproductive studies in animals have shown no effects on fertility.

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 skin rash. The following convention has been utilised for the classification of undesirable effects:-

Very common (>1/10), Common (>1/100, <1/10),

Uncommon (>1/1000, <1/100), Rare (>1/10,000, <1/1000), Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Infections and infestations

Very Rare: Mucocutaneous candidiasis

Blood and lymphatic system disorders

Very rare:    Reversible leucopenia (including severe neutropenia or

agranulocytosis),

Reversible thrombocytopenia and haemolytic anaemia.

Prolongation of bleeding time and prothrombin, (see Section 4.5)

Immune system disorders

Very rare:     As with other antibiotics, severe allergic reactions, including

angioneurotic

oedema, anaphylaxis, serum sickness and hypersensitivity vasculitis (see

Section 4.4),

If a hypersensitivity reaction is reported, the treatment must be discontinued.

(See also Skin and subcutaneous tissue disorders) and subcutaneous tissue

disorders)

Not known Jarisch-Herxheimer reaction (see section 4.4).

Nervous system disorders

Very rare:     Hyperkinesia, dizziness and convulsions.

Convulsions may occur in patients with impaired renal function or in those

receiving high doses.

Gastrointestinal disorders

Clinical trial data

* Common:   Diarrhoea and nausea.

* Uncommon: Vomiting.

Very rare: Antibiotic associated colitis (including pseudomembraneous colitis and

haemorrhagic colitis).

Black hairy tongue

Superficial tooth discolouration has been reported in children. Good oral

hygiene may help to prevent tooth discolouration as it can usually be

removed by brushing.

Hepato-biliary disorders

Very rare:    Hepatitis and cholestatic jaundice. A moderate rise in AST and/or

ALT

The significance of a rise in AST and/or ALT is unclear.

Skin and subcutaneous tissue disorders

* Common:   Skin rash

* Uncommon: Urticaria and pruritus

Very rare: Skin reactions such as erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP) (see section 4.4) and drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary tract disorders

Very rare:     Interstitial nephritis Crystalluria (see Section 4.9 Overdose)

* The incidence of these AEs was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms and signs of overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea and disturbance of the fluid and electrolyte balances may be evident. Large overdosage will produce very high urinary concentrations with crystalluria a possibility, (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses (see sections 4.4 and 4.8).

Treatment of intoxication

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

Adequate fluid intake and urinary output should be maintained.

In patients with impaired renal function the antibiotic is removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: penicillins with extended spectrum; ATC code: J01CA04.

Mechanism 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.

Pharmacokinetic/phar­macodynamic 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 main mechanisms of resistance to amoxicillin are:

Inactivation by bacterial beta-lactamases.

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 are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) version 5.0.___________­________________________­_________

1Wild type Enterobacteriaceae are categorised as susceptible to aminopenicillins. Some countries prefer to categorise wild type isolates of E. coli and P. mirabilis as intermediate.

When this is the case, use the MIC breakpoint S < 0.5 mg/L

2Most staphylococci are penicillinase producers, which are resistant to amoxicillin.

Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents.

3Susceptibility to amoxicillin can be inferred from ampicillin

4The susceptibility of streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin susceptibility.

breakpoints relate only to non-meningitis isolates. For isolates categorised as intermediate to ampicillin avoid oral treatment with amoxicillin. Susceptibility inferred from the MIC of

ampicillin.

breakpoints are based on intravenous administration. Beta-lactamase positive isolates should be reported resistant.

beta lactamase producers should be reported resistant

8Susceptibility to amoxicillin can be inferred from benzylpenicillin.

9The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility.

10The non-species related breakpoints are based on doses of at least 0.5 g x 3or 4 doses daily (1.5 to 2 g/day).

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.

In vitro susceptibility of micro-organisms to Amoxicillin

Commonly Susceptible Species

Gram-positive aerobes:

Enterococcus faecalis

Beta-hemolytic streptococci (Groups A, B, C and G)

Species for which acquired resistance may be a. problem

Gram-negative aerobes:

Escherichia coli

Haemophilus influenzae

Helicobacter pylori

Proteus mirabilis

Salmonella typhi

Gram-positive aerobes:

Coagulase negative staphylococcus

Staphylococcus aureus£

Streptococcus pneumoniae

Viridans group streptococcus

Gram-positive anaerobes:

Clostridium spp.

Gram-negative anaerobes:

Fusobacterium spp.

Other:

Borrelia burgdorferi

Inherently resistant organisms^

Gram-positive aerobes:

Enterococcus faecium f

Gram-negative aerobes:

Acinetobacter spp. Enterobacter spp. Klebsiella spp.

Pseudomonas spp.

Gram-negative anaerobes:

Bacteroides spp. (many strains of Bacteroides fragilis are resistant).

Others: Chlamydia spp. Mycoplasma spp. Legionella spp.

' Natural intermediate susceptibility in the absence of acquired mechanism of resistance.

£ Almost all S.aureus are resistant to amoxilcillin due to production of penicillinase. In addition, all methicillin-resistant strains are resistant to amoxicillin.

5.2 Pharmacokinetic properties

Absorption

Amoxicillin fully dissociates in aqueous solution at physiological pH. It is rapidly and well absorbed by the oral route of administration. Following oral administration, amoxicillin is approximately 70% bioavailable. The time to peak plasma concentration (Tmax) is approximately one hour.

The pharmacokinetic results for a study, in which an amoxicillin dose of 250 mg three times daily was administered in the fasting state to groups of healthy volunteers are presented below.

In the range 250 to 3000 mg the bioavailability is linear in proportion to dose (measured as Cmax and AUC). The absorption is not influenced by simultaneous food intake.

Haemodialysis can be used for elimination of amoxicillin.

Distribution

About 18% of total plasma amoxicillin is bound to protein and the apparent volume of distribution is around 0.3 to 0.4 l/kg.

Following intravenous administration, amoxicillin has 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. Amoxicillin, like most penicillins, can be detected in breast milk (see section 4.6).

Amoxicillin has 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.

Elimination

The major route of elimination for amoxicillin is via the kidney.

Amoxicillin has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/hour in healthy subjects. Approximately 60 to 70% of the amoxicillin is excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg dose of amoxicillin. Various studies have found the urinary excretion to be 50–85% for amoxicillin over a 24 hour period.

Concomitant use of probenecid delays amoxicillin excretion (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/ to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of amoxicillin.

Renal impairment

The total serum clearance of amoxicillin decreases proportionately with decreasing renal function (see sections 4.2 and 4.4).

Hepatic impairment

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

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Carcinogenicity studies have not been conducted with amoxicillin.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Magnesium stearate Gelatin

Yellow iron oxide Titanium dioxide Red iron oxide

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store in a dry place below 25°C. Keep container well closed.

6.5 Nature and contents of container

High density polystyrene with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polyurethane/po­lythene inserts.

PVC/Aluminium blister packs.

Pack sizes for both types of packaging: 7, 14, 15, 21, 28, 30, 56, 60, 100 and 500.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited

11 Boumpoulinas,

Nicosia 1060,

Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 33414/0128

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/06/1985

29/02/1996

10