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1.    Name of the Medicinal Product

Amoxicillin 250 mg Capsules

2.    Qualitative and Quantitative Composition

Each capsule contains Amoxicillin Trihydrate equivalent to 250 mg Amoxicillin (anhydrous).

For the full list of excipients, see section 6.1.

3.    Pharmaceutical Form

Capsule, hard

Amoxicillin 250 mg Capsules are hard gelatine capsules with a red cap and a yellow body, marked “AX250” and “G” in black ink.

4.1.    Therapeutic Indications

Treatment of Infections

Amoxicillin is a broad spectrum antibiotic indicated for the treatment of commonly occurring bacterial infections where a sensitive organism is suspected or proven. For example:

Lower respiratory tract - acute and chronic bronchitis, lobar and bronchopneumonia.

Upper respiratory tract - bacterial pharyngitis, otitis media and chronic bronchial sepsis.

Genito-urinary tract - acute cystitis, urethritis, pyelonephritis for sensitive infections, gonorrhoea (in combination with probenecid).

Gastro-intestinal tract - typhoid and paratyphoid fever

Gynaecological infections - including puerperal sepsis and septic abortion.

Other - Bacteriuria in pregnancy, skin and soft tissue infections, dental abscess (as an adjunct to surgical management), intra-abdominal sepsis, peritonitis, septicaemia (in combination with an aminoglycoside or metronidazole) and Helicobacter pylori eradication in peptic (duodenal and gastric) ulcer disease.

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.

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

Amoxicillin is inactivated by penicillinases including those produced by Staph. aureus and gram negative bacteria such as E. coli.

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

Method of Administration For oral administration.

Posology

Treatment of Infection

For adults, including older patients

Standard dosage:

250 mg every 8 hours increasing to 500 mg every 8 hours for more severe infections.

High dosage therapy:

Note: The maximum recommended dosage is 6 g daily, in divided doses.

In appropriate cases a recommended dosage is 3 g twice daily. This dosage is suitable for the treatment of severe or recurrent purulent infection of the respiratory tract.

Short course therapy:

For simple acute urinary tract infection : Two 3 g doses. A 10-12 hour interval should elapse between the doses.

For dental abscess : Two 3 g doses. An 8 hour interval should elapse between the doses.

For gonorrhoea : A single 3 g dose.

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 sections 4.4 and 5.2).

Glomerular filtration rate >30 ml/min - no adjustment necessary Glomerular filtration rate 10 - 30 ml/min - maximum 500 mg twice daily

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Glomerular filtration rate <10 ml/min - maximum 500 mg daily

For Helicobacter eradication in peptic (duodenal and gastric) ulcer disease: Amoxicillin is recommended at a twice daily dose in association with a proton pump inhibitor and antimicrobial agents, as detailed below:

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

Omeprazole 40 mg daily, Amoxicillin 750 mg - 1 g twice daily, Metronidazole 400 mg three times a day for 7 days.

Paediatric population

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.

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

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.

Condition		Adult Dosage (including the elderly)	Children
Dental Procedures	Patients not having general	3 g Amoxicillin orally, 1 hour	50 mg am
	anaesthetic.	before procedure	given as a
Prophylaxis for patients	Patients having general	A second dose may be given 6 hours later if considered necessary. Initially 3 g Amoxicillin orally 4	preceding
undergoing extraction, scaling or	anaesthetic:	hours prior to anaesthesia,
surgery involving gingival tissues, and who have not received a	If oral antibiotics are considered to	followed by 3 g orally (or 1 g IM or IV if oral dose not tolerated) as
penicillin in the previous month.	be appropriate.	soon as possible after the
Note : Patients with prosthetic heart	Patients having general anaesthetic:	operation. 1 g Amoxicillin IM or IV
valves should be referred to hospital - see below	Oral antibiotics not appropriate	immediately before induction: with 500 mg orally 6 hours later.
Dental procedures Patients for whom referral to hospitals is recommended:		Initially 1 g Amoxicillin IM or IV	50 mg am given as a
a) Patients to be given a general anaesthetic who have been given a		with 120mg gentamicin IM or IV immediately prior to anaesthesia	preceding
penicillin in the previous month.		(if given) or 15 minutes prior to
b) Patients to be given a general anaesthetic who have a prosthetic		dental procedures followed by (6 hours later) 500 mg Amoxicillin
heart valve c) Patients who have had one or more attacks of endocarditis.		orally.

Condition		Adult Dosage (including the elderly)	Children’s Dosage	Notes
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.	50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure.	See notes 2, 3 and 4 above
Surgery or Instrumentation of the Upper	Patients other than those with prosthetic	1 g Amoxicillin IV or IM immediately before	50 mg amoxicillin/kg	See Note 2 above.

Respiratory Tract	heart valves.	induction; 500 mg Amoxicillin IV or IM 6 hours later.	body weight given as a single dose one hour preceding the surgical procedure.	Note 5. The second dose of Amoxicillin may be administered orally as Amoxicillin 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.

4.3.    Contraindications

Amoxicillin is a penicillin and should not be given to penicillin-sensitive patients. Attention should be paid to possible cross-sensitivity with other beta-lactam antibiotics e.g. cephalosporins.

Hypersensitivity to any of the excipients listed in section 6.1.

4.4.    Special Warnings and Precautions for Use

Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins or other beta-lactam antibiotics such as 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.

Erythematous (morbilliform) rashes have been associated with glandular fever in patients receiving amoxicillin. The treatment should be discontinued if a rash appears and should be changed to an alternative non-penicillin antibiotic.

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).

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).

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).

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

4.5.    Interactions with other Medicaments and other forms of Interaction

Oral courses of broad spectrum anti-bacterials may affect thehyprothrombinaemic response to oral anticoagulants. 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)

Methotrexate excretion is reduced by penicillins. Patients should be monitored carefully for signs of methotrexate toxicity.

Probenecid decreases the renal excretion of penicillins. Plasma concentrations are enhanced if probenecid is given concomitantly.

In common with other antibiotics, amoxicillin may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. Patients should be warned of this.

Concurrent administration of allopurinol during treatment with amoxicillin can 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.    Fertility, Pregnancy and Lactation

Pregnancy

Animal studies with amoxicillin have shown no teratogenic effects. Amoxicillin has been in extensive clinical use and suitability in human pregnancy has been well documented in clinical studies. When antibiotic therapy is required during pregnancy, Amoxicillin may be considered appropriate when the potential benefits outweigh the potential risks associated with treatment.

Lactation

Breastfeeding is not contraindicated with amoxicillin. 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

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

Very common (< 1/10), common (< 1/100, < 1/10), uncommon (< 1/1,000, < 1/100), rare (< 1/10, 000, < 1/1,000), very rare (< 1/10,000)

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

SOC	Frequency
	Very common	Common	Uncommon	Rare	Very rare
Infections and infestations					Mucocutaneous candidiasis
Blood and lymphatic system disorders					Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin (see section 4.4)
Immune system disorders					As with other antibiotics, severe allergic reactions, including angioneurotic oedema, anaphylaxis (see section 4.4 special warnings and precautions for use), serum sickness and hypersensitivity vasculitis. If a hypersensitivity reaction is reported, the treatment must be discontinued. (See also skin and subcutaneous tissue disorders).
Nervous system disorders					Hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.

SOC	Frequency
	Very common	Common	Uncommon	Rare	Very rare
Gastrointestinal disorders		Diarrhoea and nausea	Vomiting		Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis). Black hairy tongue Superficial tooth discolouration has been reported in children. Good overall hygiene may help to prevent tooth discolouration as it can usually be removed by brushing.
Hepato-biliary disorders					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		Skin rash	Urticaria and pruritus		Skin reactions such as erythema multiforme, Steven Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (See also immune system disorders).
Renal and urinary disorders					Interstitial nephritis, crystalluria (see section 4.9)

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 internet 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).

Amoxicillin may be removed from the circulation by haemodialysis.

5. Pharmacological Properties

5.1.    Pharmacodynamic Properties

Pharmacotherapeutic group: Amoxicillin is a broad spectrum antibiotic and is rapidly bactericidal. ATC code: J01CA04

Amoxicillin acts by inhibiting cell wall synthesis, probably by acylation of membrane-bound transpeptidase enzymes. This prevents cross linkage of peptidoglycan chains which is necessary for bacterial cell wall strength and rigidity. Also, cell division and growth are inhibited and lysis and elongation of susceptible bacteria frequently occur. Rapidly dividing bacteria are most susceptible to the action of penicillins.

5.2.    Pharmacokinetic Properties

Amoxicillin is well absorbed by the oral route (75-90%) and produces high serum levels which are not affected by the presence of food in the stomach. Amoxicillin readily penetrates into bronchial secretions and is evenly distributed throughout most body tissues and with the exception of the kidneys and liver, tissue concentration are lower than simultaneous plasma levels in healthy individuals. Amoxicillin exhibits low plasma protein binding (1718%). 28-50% of an amoxicillin dose undergoes hepatic biotransformation and about 58-68% is excreted unchanged in the urine.

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.

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5.3.    Preclinical Safety Data

There are no preclinical safety data of relevance to the prescriber which are additional to those already included in other sections of the SmPC.

6    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

The core capsule contains talc, magnesium stearate, sodium starch glycollate, microcrystalline cellulose.

The capsule body shell contains erythrosine (E127), quinoline yellow (E104), titanium dioxide (E171) and gelatine.

The capsule cap shell contains erythrosine (E127), red iron oxide, titanium dioxide (E171) and gelatine.

The printing ink contains iron oxide black (E172), shellac, isopropyl alcohol, n-butyl alcohol, propylene glycol and ammonium hydroxide.

6.2    Incompatibilities None known.

6.3    Shelf life 48 months

6.4.    Special Precautions for Storage

Store in a dry place, below 25°C and protected from light.

6.5 Nature and contents of container

Polypropylene containers with polyethylene caps (with optional polyethylene ullage filler), Glass containers with a screw cap closure, PVC Aluminium foil blisters and High density polyethylene (HDPE) containers with polyethylene snap closures in packs of 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 50, 56, 60, 84, 90, 100, 250, 500 capsules.

6.6. Special precautions for disposal and other handling

No special requirements

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