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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amoxicillin Oral Suspension BP 125 mg/5 ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of suspension contains Amoxicillin Trihydrate Ph.Eur equivalent to 125 mg amoxicillin.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral suspension.

Appearance: Off-white powder for oral suspension, which when constituted with water forms a yellow, lemon flavoured suspension.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of infection:

Amoxicillin is a broad spectrum antibiotic indicated for the treatment of commonly occurring bacterial infections such as:

Upper respiratory tract infection Otitis media

Acute and chronic bronchitis Chronic bronchial sepsis Lobar and bronchopneumonia 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 Osteomyelitis

Dental abscess (as an adjunct to surgical management)

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

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

Prophylaxis of endocarditis:

Amoxicillin 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 (see section 5.1).

4.2 Posology and method of administration Posology

Treatment of infection

Adult dosae (including elderly patients):

Standard dosage :

For less severe infections the usual adult dose is 250 mg three times daily. In more severe conditions the dosage may be doubled.

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.

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

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

Children’s dosage (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.

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, 750mg twice a day for two days may be used as an alternative course of treatment in children ages 3 to 10 years.

Early Lyme disease (isolates erythema migrans):

50mg/kg/day in three divided doses, over 14-21 days.

Dosage in impaired renal function:

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).

Adults (including elderly patients).

Glomerular filtration rate >30ml/min: No adjustment necessary Glomerular filtration rate 10-30ml/min: Amoxicillin max. 500mg BID Glomerular filtration rate <10ml/min: Amoxicillin max. 500mg/day In case of hemodialysis: 500mg should be administered at the end of the procedure.

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)

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

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

(Omeprazole 40mg daily, Amoxicillin 1g BID, Clarithromycin 500mg BID) x 7 days Or

(Omeprazole 40mg daily, Amoxicillin 750mg-1g BID, Metronidazole 400mg TID) x 7days

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

Prophylaxis of endocarditits:

Condition		Adult’s dosage (including elderly)	Children’s dosage (<40kg)	Notes
Dental procedures: Prophylaxis for patients undergoing extraction, scaling or surgery involving gingival tissues and who have not received a penicillin in the previous month. (N.B. Patients with prosthetic heart valves should be referred to hospital -see below).	Patient not having general anaesthetic	3 g amoxicillin orally, 1 hour before procedure. A second dose may be given 6 hours later, if considered necessary.	50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure	Note 1. If prophylaxis with amoxicillin is given twice within 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. Note 2. To minimise pain on injection, amoxicillin may be given as two injections of 500 mg dissolved in sterile 1% lidocaine solution (See Method of administration)
	Patient having general anaesthetic: if oral antibiotics considered to be appropriate.	Initially 3 g amoxicillin orally 4 hours prior to anaesthesia, followed by 3 g orally (or 1 g IV or IM if oral dose not tolerated) as soon as possible after the operation.
	Patient having general anaesthetic: if oral antibiotics not appropriate.	1 g amoxicillin IV or IM immediately before induction; with 500 mg orally, 6 hours later.

Condition		Adult’s dosage (including elderly)	Children’s dosage (<40kg)	Notes
Dental procedures: patients for whom referral to hospital is recommended: a)    Patients to be given a general anaesthetic who have been given a penicillin in the previous month. b)    Patients to be given a general anaesthetic who have a prosthetic heart valve. c)    Patients who have had one or more attacks of endocarditis.		Initially: 1 g amoxicillin IV or IM with 120 mg gentamicin IV or IM immediately prior to anaesthesia (if given) or 15 minutes prior to dental procedure. Followed by (6 hours later): 500 mg amoxicillin orally.	50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure	See Note 2. Note 3. Amoxicillin and gentamicin should not be mixed in the same syringe. Note 4. Please consult the appropriate data sheet for full prescribing information on gentamicin.
Genitourinary surgery or instrumentation: prophylaxis for patients who have no urinary tract infection and who are to have genito-urinary surgery or instrumentation under general anaesthesia. In the case of obstetric and gynaecological procedures and gastrointestinal procedures- routine prophylaxis is recommended only for patients with prosthetic heart valves.		Initially: 1 g amoxicillin IV or IM with 120 mg gentamicin IV or IM, immediately before induction. Followed by (6 hours later): 500 mg amoxicillin orally or IV or IM according to clinical condition.		See Notes 2, 3 and 4 above.
Surgery or instrumentatio n of the upper respiratory tract	Patients other than those with prosthetic heart valves.	1 g amoxicillin IV or IM immediately before induction; 500 mg amoxicillin IV or IM 6	50 mg amoxicillin/kg body weight given as a	See Note 2 above. Note 5. The second dose of
		hours later.	single dose one hour preceding the surgical	amoxicillin may be administered orally as amoxicillin

Condition		Adult’s dosage (including elderly)	Children’s dosage (<40kg)	Notes
			procedure	syrup SF/DF.
	Patients with prosthetic heart valves.	Initially: 1 g amoxicillin IV or IM with 120 mg gentamicin IV or IM, immediately before induction; followed by (6 hours later) 500 mg amoxicillin IV or IM.	50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure	See Notes 2, 3, 4 and 5 above.

Method of administration:

Oral route.

4.3 Contraindications

Hypersensitivity to the active substance, other penicillins or to any of the excipients in section 6.1. Attention should be paid to possible cross-sensitivity with other beta-lactam e.g. semi-synthetic penicillins, ampicillin or cephalosporins.

4.4 Special warnings and precautions for use

Before initiating therapy with any penicillin careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.

In patients with renal impairment, the rate of excretion of amoxicillin will be reduced depending on the degree of impairment and it may be necessary to reduce the total daily unit amoxicillin dosage accordingly (see section 4.2).

Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in persons with a history of hypersensitivity to beta-lactam antiobiotics (see section 4.3) and/ or a history of sensitivity to multiple allergens

Erythematous (morbilliform) rashes have been associated with glandular fever in patients receiving amoxicillin.

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

In patients with reduced urine output crystalluria has been observed very rarely predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria (see section 4.9).

In patients with renal impairment, the rate of excretion of amoxicillin will be reduced depending on the degree of impairment and it may be necessary to reduce the total daily unit amoxicillin dosage accordingly (see section 4.2).

Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxicillin and oral anticoagulants. 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 sections 4.5 and 4.8).

This medicinal product contains sucrose and sodium benzoate. Sucrose is broken down in the digestive system, by substances called enzymes, into glucose and fructose and thus is unsuitable for patients who suffer from fructose intolerance, glucose-galactose malabsorption syndrome(faulty absorption from the digestive tract) or a deficiency in the enzyme which breaks down sucrose.

Sodium benzoate may increase the risk of jaundice (yellowing of the skin or the whites of the eyes) in newborn babies.

Paediatric population

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

When administered concurrently, the following drugs may interact with amoxicillin: Oral contraceptives

In common with other broad spectrum antibiotics, amoxicillin may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

Bacteriostatic antibiotics

Chloramphenicol, erythromycins, sulfonamides or tetracyclines may interfere with the bactericidal effects of penicillins. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.

Probenecid

Probenecid may decrease the renal tubular secretion of amoxicillin resulting in increased blood levels and/or amoxicillin toxicity.

Allopurinol

Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

Methotrexate

Excretion of methotrexate is reduced by penicillins; increased risk of toxicity.

Oral typhoid vaccine

The oral typhoid vaccine is inactivated by antibacterials

Sulfinpyrazone

Excretion of penicillins is reduced by sulfinpyrazone.

Anticoagulants

In the literature there are rare cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin (see sections 4.4 and 4.8).

Muscle relaxants

Piperacillin (and possibly other penicillins) enhance the effects of non-depolarising muscle relaxants and suxamethonium.

Antibacterials

Absorption of phenoxymethylpenicillin (and possibly other penicillins) reduced by neomycin.

Drug/laboratory test interactions

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 Fertility, pregnancy and lactation Pregnancy

There have been no teratogenic effects with amoxicillin in animal studies.

The suitability of amoxicillin for use in human pregnancy has been well documented in clinical studies since 1972. When antibiotic therapy is required during human pregnancy, amoxicillin may be considered appropriate when the potential benefits outweigh the potential risks associated with treatment.

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

Amoxicillin has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Side effects, as with other penicillins, are uncommon and mainly of a mild and transitory nature.

The following convention has been utilised for the classification of undesirable effects:

Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).The majority of adverse events listed below are not unique to amoxicillin and may occur when using other penicillins.

Unless otherwise stated, the frequency of adverse events has been derived from more than 30 years of post-marketing reports.

Infections and infestations

Very rare:    Mucocutaneous candidiasis

Blood and lymphatic system disorders:

Very rare:    Reversible leucopenia (including severe neutropenia and

agranulocytosis), reversible thrombocytopenia and haemolytic anaemia have been reported.

Prolongation of bleeding time and prothrombin time (see also sections 4.4 and 4.5).

Immune system disorders

Very rare:    Hypersensitivity reactions:

Severe allergic reactions including angioneurotic oedema, anaphylaxis (see section 4.4), serum sickness and hypersensitivity vasculitis

If a hypersensitivity reaction occurs, the treatment must be discontinued. (See also skin 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.

Post marketing data

Not known:    Aseptic meningitis

Gastrointestinal disorders:

Clinical trial data

*Common:    Diarrhoea and nausea

*Uncommon: Vomiting Post-marketing data

Very rare:    Antibiotic associated colitis including pseudomembranous colitis and

haemorrhagic colitis have been reported Black hairy tongue

Superficial tooth discolouration has been reported in children. This can usually be removed by brushing.

Hepatobiliary disorders:

Very rare:    Hepatitis and cholestatic jaundice.

Moderate rise in AST and/or ALT, but the significance of this is unclear.

Skin and subcutaneous tissue disorders

Clinical trial data *Common:    Skin rash,

*Uncommon: Pruritus and urticaria.

Post-marketing data

Very rare:    Skin reactions such as erythema multiforme and 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) can occur

*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

Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically with attention to the water/electrolyte balance. Amoxicillin crystalluria, in some cases leading to renal failure has been observed (see section 4.4)

Gross overdosage will produce high urinary concentrations. Problems are unlikely if adequate fluid intake and urinary output are maintained.More specific measures may be necessary in patients with impaired renal function: the antibiotic is removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties ATC Code: JO1CA04

Pharmacotherapeutic group: Beta-lactam antibacterials, penicillins with extended spectrum.

Mode of action: Amoxicillin is a broad spectrum semi-synthetic penicillin, which is acid-resistant and has a similar antibacterial spectrum to ampicillin.

PK/PD relationship

For amoxicillin, time above MIC (T>MIC) is the key pharmacodynamics parameter in predicting a successful clinical and bacteriological outcome.

Mechanism of resistance: Amoxicillin is better absorbed after oral administration, yielding blood levels approximately twice as high as those obtained with similar doses of ampicillin.

Amoxicillin is used for the same purposes as ampicillin and is especially suitable for the treatment of infections of the urinary and respiratory tracts by ampicillin-sensitive organisms. It is rapidly bactericidal and possesses the safety profile of a penicillin.

Bacteria may be resistant to amoxicillin due to production of beta-lactamases which hydrolyse aminopenicillins, due to alteration in penicillin-binding proteins, due to impermeability to the drug, or due to drug efflux pumps. One or more of these mechanisms may co-exist in the same organism, leading to a variable and unpredictable cross-resistance to other beta-lactams and to antibacterial drugs of other classes.

Breakpoints (EUCAST)

Organism	Susceptibility Breakpoints (pg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae	< 1	-	> 1
Moraxella catharrhalis	< 1	-	> 1
Enterococcus	< 4	8	> 8
Streptococcus A, B, C, G1	< 0.25	-	> 0.25
Streptococcus pneumoniae2	< 0.5	1-2	> 2
Enterobacteriaceae’3	-	-	> 8
Gram-negative anaerobes	< 0.5	-	> 2
Gram-positive Anaerobes	< 4	8	> 8
Non-species related breakpoints	< 2	4-8	> 8
1 Breakpoint values in the table are based on Benzylpenicillin breakpoints.
2 Breakpoint values in the table are based on ampicillin breakpoints.
3 The resistant breakpoint of R>8 mg/L ensures that all isolates with resistance mechanisms are reported resistant.

Susceptibility:

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.

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications

+ pathogens resistance prevalence is > 50%

$ Naturally intermediate species

5.2 Pharmacokinetic properties

Absorption:

Amoxicillin trihydrate is resistant to inactivation by the acid of gastric secretions and is rapidly absorbed when given by mouth. It is more completely absorbed than ampicillin and is reported to produce peak antibiotic plasma concentrations that are up to 2‘A times as high as from the same dose of ampicillin.

Peak plasma amoxicillin concentrations of about 5pg per ml have been observed 1 to 2 hours after a dose of 250mg with detectable amounts present for up to 8 hours. Doubling the dose can produce double the concentrations. The presence of food in the stomach does not appear to diminish absorption significantly.

Distribution:

Amoxicillin gives good penetration into bronchial secretions and high urinary concentrations of unchanged antiobiotic. Protein binding for amoxicillin is approximately 17%. Therapeutic drug levels are rapidly achieved in serum, lung tissue, bronchial secretions, middle ear fluid, bile and urine. In healthy meninges amoxicillin diffuses badly in liquor cerebrospinalis. Amoxicillin crosses the placenta and a small percentage is excreted into the breast milk.

Biotransformation and elimination:

The main route of excretion of amoxicillin is the kidney. About 60-80% of an oral dose of amoxicillin are excreted in unchanged active form in the urine within 6 hours of administration, and a small fraction is excreted in the bile. Approximately 7 - 25% of the administered dose is metabolised to inactive penicilloic acid. The serum halflife in patients with normal renal function is approximately 1 - 1.5 hour. In patients with end-stage renal failure the half-life ranges between 5 to 20 hours. The substance is haemodialysable.

Pediatric population:

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 from 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

Saccharin sodium, sodium benzoate (E211), sodium citrate anhydrous, colloidal anhydrous silica, microcrystalline cellulose and carboxymethylcellulose sodium, lemon flavour (84260-51), quinoline yellow 14031 (E104), sucrose.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

Bottles:    3 years

Foil sachets: 2 years

6.4 Special precautions for storage

Store below 25°C in a dry place. Protect from light.

6.5 Nature and contents of container

1.    White polyethylene bottle with child resistant cap. Pack sizes: 60 ml and 100 ml.

2.    Clear glass bottle with white polypropylene cap. Pack sizes: 60 ml and 100 ml

3. Foil sachets.

Pack size: A single dose of 125 mg.

6.6 Special precautions for disposal

Add 62 ml of water to constitute. Loosen powder, add about half the water and shake well. Add the remaining water and shake to complete suspension.

7 MARKETING AUTHORISATION HOLDER

ATHLONE PHARMACEUTICALS LIMITED

BALLYMURRAY

ROSCOMMON

COUNTY ROSCOMMON

IRELAND

8    MARKETING AUTHORISATION NUMBER(S)

PL 30464/0011

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date granted:    18 December 1985

Last renewal date: 18 December 2002

10 DATE OF REVISION OF THE TEXT

18/05/2015

11 DOSIMETRY (IF APPLICABLE)

INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)