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1. NAME OF THE MEDICINAL PRODUCT

DEDOXIL/Amoxicillin capsules 500 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Amoxicillin Trihydrate BP 500 mg (equivalent to amoxicillin anhydrous)

3.    PHARMACEUTICAL FORM

Capsule

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of infection: Upper respiratory tract infections, otitis media, acute and chronic bronchitis, lobar and bronco-pneumonia, cystitis, urethritis, pyelonephritis bacteriuria in pregnancy, gynaecological infections including puerperal sepsis and septic abortion, gonorrhoea, peritonitis, intra-abdominal sepsis, septicaemia, bacterial endocarditis, typhoid and paratyphoid fever, skin and soft tissue infections, dental abscess (as an adjunct to surgical management) and Helicobacter pylori eradication in peptic (duodenal and gastric) ulcer disease.

In children with urinary tract infection the need for investigation should be considered.

Oral prophylaxis of endocarditis; DEDOXIL may be used for the prevention of bacteraemia, associated with procedures such as dental extraction in patients at risk of developing bacterial endocarditis.

Consideration should be given to official local guidance (e.g. national requirements) on the appropriate use of antibacterial agents. “Susceptibility of the causative organisms to the treatment should be tested (if possible), although the therapy may be initiated before the results are available.”

4.2 Posology and method of administration

To be taken orally.

Treatment of infections:

Adult dosage (including the elderly):

•    Standard adult dosage: 250 mg three times a day. In more severe infections doses should be increased to 500 mg three times daily.

•    High dosage therapy (maximum recommended oral dosage 6 g daily in divided doses): A dosage of 3 g twice daily is recommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract.

• Short course therapy: In simple, acute urinary tract infection in adults, two 3 g doses with 10-12 hours between the doses.

Dental abscess: two 3 g doses with 8 hours between the doses.

A single 3 g dose of DEDOXIL is recommended for the treatment of gonorrhoea.

In renal impairment:

The dose should be reduced in patients with severe renal function impairment. In patients with a creatinine clearance of less than 30 ml/min an increase in the dosage interval and a reduction in the total daily dose is recommended (see section 4.4 and 5.2):

Glomerular filtration rate > 30 ml/min:    No adjustment necessary

Glomerular filtration rate 10-30 ml/min:    Amoxicillin max. 500 mg twice daily

Glomerular filtration rate < 10 ml/min:    Amoxicillin max. 500 mg daily

Helicobacter eradication in peptic (duodenal and gastric) ulcer disease:

Amoxicillin is recommended at a dose of twice daily in association with a proton pump inhibitor and antimicrobial agents as detailed below:

Omeprazole 40 mg daily, Amoxicillin 1 g twice daily, Clarithromycin 500mg twice daily, for 7days or

Omeprazole 40mg daily, Amoxicillin750mg-1g twice daily, Metronidazole 400mg three times daily, for 7 days

Children weighing < 40 kg

The daily dosage for children is 40 - 90 mg/kg/day in two to three divided doses* (not exceeding 3 g/day) depending on the indication, severity of the disease and the susceptibility of the pathogen (see special dosage recommendations below and sections 4.4, 5.1 and 5.2).

*PK/PD data indicate that dosing three times daily is associated with enhanced efficacy, thus twice daily dosing is only recommended when the dose is in the upper range.

Children weighing more than 40 kg should be given the usual adult dosage.

Renal impairment in children under 40 kg:

Creatinine clearance mL/min	Dose	Interval between administration
> 30	Usual dose	No adjustment necessary
10 - 30	Usual dose	12 h (corresponding to 2/3 of the dose)
< 10	Usual dose	24 h (corresponding to 1/3 of the dose)

Amoxicillin Paediatric Suspension is recommended for children under six months of age.

Special dosage recommendation Tonsillitis: 50 mg/kg/day in two divided doses.

Acute otitis media: In areas with high prevalence of pneumococci with reduced susceptibility to penicillins, dosage regimens should be guided by national/local recommendations. In severe or recurrent acute otitis media, especially where compliance may be a problem, 750 mg twice a day for two days may be used as an alternative course of treatment in children aged 3 to 10 years.

Early Lyme disease (isolated erythema migrans): 50 mg/kg/day in three divided doses, over 14 - 21 days.

Treatment should be continued for 2 to 3 days following the disappearance of symptoms. It is recommended that at least 10 days treatment be given for any infection caused by beta-haemolytic streptococci in order to achieve eradication of the organism.

Prophylaxis of endocarditis:

See table on next page;

Notes:

1.    If prophylaxis with amoxicillin is given twice in one month, emergence of resistant streptococci is unlikely to be a problem. Alternative antibiotics are recommended if more frequent prophylaxis is required, or if the patient has received a course of treatment with a penicillin during the previous month.

2.    Please consult the appropriate data sheet for full prescribing information on gentamicin.

For patients undergoing surgery or Instrumentation of the upper respiratory tract, intravenous antibiotic prophylaxis is recommended. Please refer to the relevant product literature and guidelines.

4.3 Contraindications

DEDOXIL is a penicillin and should not be given to penicillin-sensitive patients, or those sensitive to any of the excipients.

Attention should be given to the possibility of cross-sensitivity with other beta-lactams eg: cephalosporins.

4.4 Special warnings and precautions for use

Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins.

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 hypersensitivity to beta-lactam antibiotics, (see section 4.3).

Erythematous (morbilliform) rashes do occur in patients with infectious mononucleosis, (glandular fever), and may be more common in patients with CLL, (Chronic Lymphocytic Leukaemia).

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

At high doses relative to urinary output, adequate fluid intake and urinary output must be maintained to reduce the possibility of amoxicillin crystalluria, (see section 4.9).

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).

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

Interaction with other medicinal products and other forms of interaction

In common with other antibiotics, amoxicillin may affect the gut flora, leading to lower oestrogen reabsorption and, hence, the efficacy of oral contraceptives is reduced with concurrent administration of penicillin. Patients should take extra precautions and use a barrier method of contraception.

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

Prolongation of prothrombin time has been reported. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently.

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

It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.

4.6    Pregnancy and lactation

Pregnancy:

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.

Lactation:

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.

4.7. Effects on Ability to Drive and Use Machines

Not applicable.

4.8    Undesirable effects

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)

The majority of side effects listed below are not unique to amoxicillin and may occur when using other pencillins.

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, (see Section 4.4), serum sickness and hypersensitivity vasculitis.

If a hypersensitivity reaction is reported, the treatment must be discontinued. (See also Skin and subcutaneous tissue disorders) and subcutaneous tissue disorders)

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 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 and acute generalised exanthematous pustulosis (AGEP)

(See also Immune system disorders)

Renal and urinary tract disorders

Very rare:    Interstitial nephritis

Crystalluria (see Section 4.9 Overdose)

4.9 Overdose

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically with attention to the water/electrolyte balance.

Large overdosage will produce very high urinary concentrations with crystalluria a possibility, (see section 4.4). 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

Amoxicillin is bactericidal and has a similar mode of action to that of benzylpenicillin. It is effective against gram-positive organisms, including streptococcus faecalis, Str. pneumonia and haemolytic streptococci but, apart from Str. faecalis, it is less potent than benzylpenicillin. Listeria monocytogens is also highly sensitive. Its action is similar to that of the tetracyclines and cliloramphenicol against Gram-negative organisms, particularly Haemophilus influenzae, salmonellae, and most strains of Escherichia coli; highly resistant strains of H. influenzae have been reported. Neisseria gonorrhoea, N. meningitides, Bordetella pertussis, Proteus mirabilis, and Brucella spp. are also sensitive. Ampicillin is effective against some shigellae but strains can acquire resistance rapidly.

Minimum inhibitory concentrations for Gram-positive organisms have been reported to range from 0.02 to 5 ugh per ml and for Gram-negative organisms from 0.02 to 8 ugh per ml. It is inactive against most strains of Pseudomonas aeruginosa.

It has been reported that Amoxicillin inhibits side-wall synthesis in susceptible bacteria. Amoxicillin is inactivated by penicillinase and complete cross-resistance has been reported between Amoxicillin and Ampicillin.

5.2 Pharmacokinetic properties

Amoxicillin trihydrate is rapidly absorbed when given orally. It is widely distributed and is reported to produce peak antibiotic plasma concentrations that are up to twice as high as those from the same dose of ampicillin. Peak plasma amoxicillin concentrations of about 5 nanograms per ml have been observed two hours after a dose of 250 mg with detectable amounts present for up to eight hours. Doubling the dose can produce double the concentration.

The presence of food in the stomach does not appear to diminish absorption significantly.

Up to 20% is bound to plasma proteins in the circulation and plasma half-lives of about one hour have been reported. Amoxicillin diffuses across the placenta; little appears to be excreted in breast milk. It penetrates well into purulent and mucoid sputum and low concentrations have been found in ocular fluid. Concentrations of the antibiotic have been detected in the CSF of patients with inflamed meninges when given amoxicillin intra-venously.

About 60% of an oral dose of amoxicillin is excreted unchanged in the urine in 6 hours by glomerular filtration and tubular secretion. Urinary concentrations range from about 0.3-1.3 mg per ml after a dose of 250 mg. Up to 75% of a parenteral dose has been reported to be excreted unchanged in the urine within six hours. High concentrations have been reported in bile.

In preterm infants with gestational age 26-33 weeks, the total body clearance after intravenous dosing of amoxicillin, day 3 of life, ranged between 0.75 - 2 ml/min, very similar to the inuline clearance (GFR) in this population. Following oral administration, the absorption pattern and the bioavailability of amoxicillin in small children may be different to that of adults. Consequently, due to the decreased CL, the exposure is expected to be elevated in this group of patients, although this increase in exposure may in part be diminished by decreased bioavailability when given orally.

5.3. Preclinical Safety Data

Not applicable.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Magnesium stearate Gelatin

Yellow iron oxide Titanium dioxide Red iron oxide

6.2.    Incompatibilities

None known.

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.

Instruction for Use/Handling

Not applicable.

7    Marketing Authorisation Holder

DDSA Pharmaceuticals Limited.

T/A DDSA Pharmaceuticals 310 Old Brompton Road London SW5 9JQ

8.    MARKETING AUTHORISATION NUMBER(S)

PL 00225/0072

9.    DATE OF FIRST AUTHORISATION/RENEWAL    OF AUTHORISATION

24/06/1985    29/02/1996

10 DATE OF REVISION OF THE TEXT

22/12/2011