AMOXICILLIN 250 MG / 5ML POWDER FOR ORAL SUSPENSION - summary of medicine characteristics

Amoxicillin 250 mg/5 ml powder for oral suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml reconstituted suspension contain 57.4 mg amoxicillin trihydrate, corresponding to 250 mg amoxicillin/5 ml.

Excipient(s) with known effect

5 ml reconstituted suspension contains 8.5 mg aspartame (E 951), up to 3 mg of benzyl alcohol, up to 0.44 mg of benzyl benzoate, 0.14 mg of sorbitol (E 420), 0.1 micrograms of sulphur dioxide (E 220), 0.68 mg of glucose and 7.1mg sodium benzoate (E 211).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral suspension

White to slightly yellowish powder with characteristic fruity odour.

4.1 Therapeutic indications

Amoxicillin 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

Acute otitis media

Acute streptococcal tonsillitis and pharyngitis

Acute exacerbations of 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

Amoxicillin is also indicated for the prophylaxis of endocarditis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

4.3 Contraindications

Hypersensitivity to the active substance, to any of the penicillins or to any of the    excipients listed in section 6.1.

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta- lactam agent (e.g. 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 penicillin 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

In patients with renal impairment, the dose should be adjusted according to 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 self-limiting consequence of antibiotic treatment of Lyme disease.

Overgrowth of non-susceptible microorganisms

Prolonged use may 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.

Important information about excipients

This medicinal product contains 8.5mg aspartame in each dose. Aspartame is a source of phenylalanine. This medicinal product should be used with caution in patients with phenylketonuria. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

This medicinal product contains 7.1 mg sodium benzoate which is a mild irritant to the eyes, skin and mucous membrane. This medicinal product contains up to 0.44 mg benzyl benzoate in each dose. Benzyl benzoate and sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to

4 weeks old).

This medicinal product contains up to 3 mg benzyl alcohol in each dose. Benzyl alcohol may cause allergic reactions.

Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called “gasping syndrome”) in young children.

High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

This medicinal product contains small amounts of ethanol, less than 100 mg per dose.

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially sodium free.

This medicinal product contains 0.14 mg sorbitol in each dose.

This medicinal product contains 0.1 micrograms sulphur dioxide in each dose. May rarely cause severe hypersensitivity reactions and bronchospasm.

This medicinal product contains 0.68 mg glucose in each dose. Patients with rare glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Allopurinol

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

Tetracyclines

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

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. Amoxicillin may be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

Breast-feeding

Amoxicillin is excreted into breast milk in small quantities with the possible risk of sensitisation. 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 should only be used during breastfeeding 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 ADRs derived from clinical studies and post-marketing surveillance with amoxicillin, presented 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 (>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)

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 (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in Google play or Apple App store.

4.9 Overdose

Symptoms and signs of overdose:

Gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed. 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.

Amoxicillin can be removed from the circulation by haemodialysis.

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.___________­_____________

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)

Listeria monocytogenes

Gram-negative aerobes:

Escherichia coli

Haemophilus influenzae

Helicobater pylori

Proteus mirabilis

Salmonella typhi

Salmonella paratyphi

Pasteurella multocida

Gram-positive aerobes:

Coagulase negative styphylococcus

£

Staphylococcus aureus

Streptococcus pneumoniae

Viridans group streptococcus

Gram-positive anaerobes:

Clostridium spp.

Gram-negative anaerobes:

Fusobacterium spp.

Other:

Borrelia burgdorferi

Inherently resistant organismsf

Gram-positive aerobes:

Enterococcus faecium f

Gram-negative aerobes:

Acinetobacter spp

Enterobacter spp

Klebsiella spp

Pseudomonas spp

Gram-negarive anaerobes:

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

Others:

Chlamydia spp

Mycoplasma spp

Legionella spp.

f Natural intermediate susceptibility in the absence of acquired mechanism of resistance £

Almost all S.aureus are resistant to amoxicillin 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

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid anhydrous Sodium Benzoate Aspartame

(E 330)

(E 211)

(E 951)

Talc                                    (E

Trisodium citrate, anhydrous               (E

Guar                                  (E

Silicon dioxide, precipitated                (E

Lemon flavouring, powdered (containing among others: sorbitol, sulphur dioxide, glucose)

Peach-apricot flavouring, powdered (containing among others: sorbitol, sulphur dioxide, ethanol,

Orange flavouring, powdered (containing among others: benzyl alcohol)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Powder for oral suspension: 3 years

In use shelf life after reconstitution: 14 days

6.4 Special precautions for storage

Powder for oral suspension: Do not store above 25 °C. Keep the bottle tightly closed in order to protect from moisture.

In use storage condition after reconstitution:

Store in a refrigerator (2oC – 8oC).

6.5 Nature and contents of container

Amber glass bottles containing 6.6 g powder for 60 ml oral suspension respectively containing 11 g powder for 100 ml oral suspension with polypropylene screw closure (press + turn) and sealing membrane.

The packaged measuring spoon with filling marks at 1.25 ml, 2.5 ml and 5.0 ml is made of polypropylene.

Individual packs of 60 ml and 100 ml bottles in carton box

Hospital packs of 10×60 ml, 20×60 ml, 40×60 ml,

10×100 ml and 40×100 ml bottles in carton box

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The reconstitution of the suspension is carried out by the doctor or pharmacist.

After opening of the screw cap, ensure that the bottle cap seal is intact and tightly attached to the bottle rim. Do not use if not intact. Shake bottle to loosen powder. To reconstitute the suspension fill the bottle with fresh tap water approx. 1 cm below the filling mark, close and shake well at once.

After the foam has settled slowly add fresh tap water exactly to the filling mark (55 ml water for 60 ml, 92 ml water for 100 ml suspension). Shake vigorously again.

The white to slightly yellowish suspension with fruity odour is now ready for use.

Shake the bottle well before taking each dose.

This medicinal product should not be used if lumps of powder are visible in the bottle before reconstitution.

After reconstitution the product should not be used if the colour of the reconstituted product is different from the one described before.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Sandoz Limited

Park View, Riverside Way Watchmoor Park

Camberley, Surrey

GU15 3YL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04416/0485

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/09/2010