Amoxicillin Oral Suspension BP 125 mg/5 ml – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Amoxicillin Oral Suspension BP 125 mg/5 ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

When reconstituted, every 5 ml of oral suspension contains amoxicillin trihydrate Ph.Eur equivalent to 125 mg amoxicillin (25 mg per ml).

Excipients with known effect

Contains 2.59 g sucrose per 5 ml.

Contains 6.1 mg of sodium per 5 ml.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder for oral suspension.

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Amoxicillin Oral Suspension is indicated for the treatment of the following infections in adults and children (see section 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, urethritis
• Asymptomatic bacteriuria in pregnancy
• Acute pyelonephritis
• 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) with spreading cellulitis
• Prosthetic joint infections
• Helicobacter pylori eradication in peptic (duodenal and gastric) ulcer disease
• Lyme disease

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

Amoxicillin Oral Suspension is also indicated for the prophylaxis of endocarditis.

Prophylaxis of endocarditis:

Amoxicillin Oral Suspension 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 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

The dose of Amoxicillin Oral Suspension 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 ≥ 40kg

Standard dosage

250 mg three times daily by the oral route. In cases of severe infection 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 weighing < 40 kg

Children may be treated with Amoxicillin capsules, dispersible tablets suspensions or sachet.

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

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

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.

Recommended doses:

Elderly

No dose adjustment is considered necessary

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).

Renal impairment

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 streptococci in order to achieve eradication of the organism.

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).

Prophylaxis of endocarditis

if oral

antibiotics considered to be

appropriate.

anaesthesia, followed by 3 g orally (or 1 g IV or IM if oral dose

Method of administration

Amoxicillin Oral Suspension is for oral use.

Absorption of Amoxicillin Oral Suspension is unimpaired by food. Therapy can be started parenterally according to the dosing recommendations of the intravenous formulation and continued with an oral preparation.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance, other 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. ampicillin, cephalosporins, carbapenem or monobactam).

4.4 Special warnings and precautions for use

Hypersensitivity reactions

Before initiating therapy with any penicillin careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see section 4.3 and 4.8). Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients receiving beta-lactam antibiotics (see section 4.3). These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to Amoxicillin (see section 4.8). If an allergic reaction occurs, amoxicillin therapy must be discontinued and appropriate alternative therapy instituted.

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

Drug-induced enterocolitis syndrome (DIES) has been reported mainly in children receiving amoxicillin (see section 4.8). DIES is an allergic reaction with the leading symptom of protracted vomiting (1-4 hours after drug intake) in the absence of allergic skin or respiratory symptoms. Further symptoms could comprise abdominal pain, diarrhoea, hypotension or leucocytosis with neutrophilia. There have been severe cases including progression to shock.

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 accordingly to the degree of impairment (see section 4.2).

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.

Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.

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

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 (AGEP, 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 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. Anti-peristaltic 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 (including acute renal injury) 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.

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).

Important Information about excipients

This medicinal product contains sucrose. 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.

This medicinal product contains sodium benzoate (E211) which is a mild irritant to the eyes, skin and mucous membrane. 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

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.

Methotrexate

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

Tetracyclines

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

Oral typhoid vaccine

The oral typhoid vaccine is inactivated by antibacterials

Sulfinpyrazone

Excretion of penicillins is reduced by

sulfinpyrazone. 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).

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

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.

The suitability of amoxicillin for use in human pregnancy has been well documented in clinical studies since 1972. Amoxicillin may be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment. Anti-infectives should not be used during pregnancy unless considered essential by the physician.

Breastfeeding

Amoxicillin is excreted into the 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 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 teratogenic 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 or use machines (see section 4.8).

4.8 Undesirable effects

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

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).

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.

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 or by searching for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms and signs of overdose

Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).

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: JO1CA04

Mechanism of action

Amoxicillin is a semi-synthetic 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, which is acid-resistant and has a similar antibacterial spectrum to ampicillin.

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. 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

MIC breakpoints for amoxicillin are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) version 11.0.

¹ Beta-lactamase positive isolates can be reported resistant to ampicillin, amoxicillin and piperacillin without inhibitors. Tests based on a chromogenic cephalosporin can be used to detect the beta-lactamase.

² Most M. catarrhalis produce beta-lactamase, although beta-lactamase production is slow and may give weak results with in vitro tests. Beta-lactamase producers should be reported resistant to penicillins and aminopenicillins without inhibitors.

³ Most S. aureus are penicillinase producers and some are methicillin resistant. Either mechanism renders them resistant to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. Isolates that test susceptible to benzylpenicillin and cefoxitin can be reported susceptible to all penicillins. Isolates that test resistant to benzylpenicillin but susceptible to cefoxitin are susceptible to β- lactam β-lactamase inhibitor combinations, the isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin) and nafcillin. For agents given orally, care to achieve sufficient exposure at the site of the infection should be exercised. Isolates that test resistant to cefoxitin are resistant to all penicillins.

⁴ Most coagulase-negative staphylococci are penicillinase producers and some are methicillin resistant. Either mechanism renders them resistant to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. No currently available method can reliably detect penicillinase production in coagulase- negative staphylococci but methicillin resistance can be detected with cefoxitin as described.

⁵ Ampicillin susceptible S. saprophyticus are mecA-negative and susceptible to ampicillin, amoxicillin and piperacillin (without or with a beta-lactamase inhibitor).

⁶ Aminopenicillin breakpoints in enterococci are based on intravenous administration. For oral administration the breakpoints are relevant for urinary tract infections only.

⁷ Susceptibility to ampicillin, amoxicillin and piperacillin (with and without beta- lactamase inhibitor) can be inferred from ampicillin. Ampicillin resistance is uncommon in E. faecalis (confirm with MIC) but common in E. faecium.

⁸ The susceptibility of streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin susceptibility (indications other than meningitis) with the exception of phenoxymethylpenicillin and isoxazolylpenicillins for streptococcus group B.

⁹ The oxacillin 1 μg disk screen test or a benzylpenicillin MIC test shall be used to exclude beta-lactam resistance mechanisms. When the screen is negative (oxacillin inhibition zone ^≥20 mm, or benzylpenicillin MIC ^≤0.06 mg/l) all beta-lactam agents for which clinical breakpoints are available, can be reported susceptible without further testing, except for cefaclor, which if reported, should be reported as “susceptible, increased exposure” (I). When the screen is positive (inhibition zone <20 mm, or benzylpenicillin MIC >0.06 mg/l), refer to EUCAST flow chart.

¹⁰ Aminopenicillin breakpoints in Enterobacterales are based on intravenous administration. For oral administration the breakpoints are relevant for urinary tract infections only. Breakpoints for other infections are under review.

¹¹ Susceptibility to ampicillin, amoxicillin, piperacillin and ticarcillin can be inferred from susceptibility to benzylpenicillin.

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

Species for which acquired resistance may be a problem

Gram-negative aerobes:

Escherichia coli

Haemophilus influenzae

Helicobacter pylori

Proteus mirabilis

Salmonella typhi

Salmonella paratyphi

Pasteurella multocida

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†

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 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 2½ times as high as from the same dose of ampicillin. Peak plasma amoxicillin concentrations of about 5µg 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.

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

Haemodialysis can be used for elimination of amoxicillin.

Distribution

Amoxicillin gives good penetration into bronchial secretions and high urinary concentrations of unchanged antibiotic.

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:

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 half-life 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.

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.

Paediatric 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.

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

Saccharin Sodium

Sodium Benzoate (E211)

Sodium Citrate Anhydrous

Colloidal Anhydrous Silica

Microcrystalline Cellulose

Carboxymethylcellulose Sodium

Lemon Flavour (84260-51)

Quinoline Yellow 14031 (E104)

Sucrose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Dry Powder: 3 years

Foil sachets: 2 years

Reconstituted suspension: 14 days

Reconstituted suspensions: Do not store above 25°C.

6.4 Special precautions for storage

Do not store above 25°C.

Protect from light.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

1. 1.

   White polyethylene bottle with child resistant cap.

   Pack sizes: 60 ml and 100 ml.

2. 2.

   Clear glass bottle with white polypropylene cap.

   Pack sizes: 60 ml and 100 ml

3. 3.

   Foil sachets.

   Pack size: A single dose of 125 mg.

6.6 Special precautions for disposal

Check cap seal is intact before use.

Invert and shake bottle to loosen powder.

Fill the bottle with water to just below the mark on the bottle label. Invert and shake well, then top up with water to the mark. Invert and shake again.

Shake well before taking each dose.

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

7 MARKETING AUTHORISATION HOLDER

Kent Pharmaceuticals Limited,

Connect 38,

1, Dover Place,

Ashford,

Kent,

United Kingdom.

TN23 1FB

8 MARKETING AUTHORISATION NUMBER(S)

PL 08215/0167

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date granted: 18 December 1985

Last renewal date: 04 February 2009

10 DATE OF REVISION OF THE TEXT

30/09/2025

11 DOSIMETRY (IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF

RADIOPHARMACEUTICALS (IF APPLICABLE)