RESPILLIN 125 MG / 5ML ORAL SUSPENSION SUGAR FREE BP, AMOXICILLIN 125 MG / 5ML ORAL SUSPENSION SUGAR FREE BP - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amoxicillin 125 mg/5 ml Oral Suspension Sugar Free BP and

Respillin 125 mg/5 ml Oral Suspension Sugar Free BP

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

When reconstituted, every 5 ml of oral suspension contains amoxicillin trihydrate

B.P. equivalent to 125 mg amoxicillin (25 mg per ml)

Excipients with known effect

Contains 4.82 mg sodium benzoate per 5 ml.

Contains sorbitol.

For the full list of excipients, see section 6.1.

Powder for oral suspension.

Pale yellow powder for reconstitution as suspension.

4.1 Therapeutic indications

Amoxicillin Oral Suspension Sugar Free is indicated for the treatment of the following infections in adults and children (see section 4.2, 4.4 and 5.1) such as:

Acute bacterial sinusitis

Acute Otitis media

Acute streptococcal tonsillitis and pharyngitis

Acute exacerbation 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 Oral Suspension Sugar Free 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

Dose with caution and monitor hepatic function at regular intervals (see sections 4.4 and 4.8).

Method of administration

Amoxicillin Oral Suspension Sugar Free is for oral use.

Absorption of Amoxicillin Oral Suspension Sugar Free 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, 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. a cephalosporin, 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 on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity 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 accordingly 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 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 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 sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

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 in newborn babies.

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 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.

Methotrexate

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

Oral typhoid vaccine

The oral typhoid vaccine is inactivated by antibacterials.

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).

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.

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

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).

Infections and infestations

Renal and urinary tract disorders

*The incidence of these AEs was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin. #Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing

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

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 may be removed from the circulation by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: penicillins with extended spectrum; ATC Code: JO1CA04

Mechanism of action

Amoxicillin is a semi-synthetic penicillin, 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

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.

T 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 (T ) 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 Cmax and AUC). The absorption in 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

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

Sodium Benzoate (E211)

Disodium Edetate

Sodium Citrate

Citric Acid Monohydrate

Colloidal Anhydrous Silica

Sorbitol (E420)

Saccharin Sodium

Orange Bramble Flavour

Quinoline Yellow (E104)

Xanthan Gum (E415)

6.2 Incompati­bilities

Not applicable.

6.3 Shelf life

Dry Powder: 30 months

Reconstituted suspension: 14 days

Reconstituted suspensions: At 2°C-8°C in a refrigerator.

6.4 Special precautions for storage

Do not store above 25°C.

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

6.5 Nature and contents of container

High density polyethylene bottles with tamper-evident and child-resistant cap of the appropriate size to accommodate 100ml.

May also contain:

5ml Opaque spoon

Or

A dosing syringe with bottle neck adaptor

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Check cap seal is intact before use.

Invert and shake bottle to loosen powder.

To prepare add 84ml of potable water and shake until all contents are dispersed.

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