Summary of medicine characteristics - RESPILLIN 125 MG / 5ML, AMOXICILLIN ORAL SUSPENSION BP 125 MG / 5ML
1 NAME OF THE MEDICINAL PRODUCT
1. Arnoxicillin Oral Suspension BP 125 mg/5 ml
2. Respillin 125 mg/5 ml (OPD Pharmaceuticals Ltd)
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 3 mg sodium per 5 ml.
Contains 1.54 g of sorbitol.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for oral suspension.
An off-white powder for oral suspension, which, on reconstitution with water, produces a white, lime 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 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:
For less severe infections the usual adult dose is 250 mg three times daily. In more severe conditions the dosage may be doubled.
High-dosage therapy
(Maximum recommended oral dosage 6 g daily in divided doses):
A dosage of 3 g twice daily is recommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract.
Short-course therapy
In simple, acute urinary tract infection in adults: two 3 g doses with 10 – 12 hours between the doses.
A single dose of 3g is recommended for the treatment of gonorrhoea.
Dental abscess: two 3 g doses with 8 hours between the doses.
| Indication* | Dose* |
| Acute bacterial sinusitis | 250 mg to 500 mg every 8 hours or 750 mg to 1 g every 12 hours For severe infections 750 mg to 1 g every 8 hours Acute cystitis may be treated with 3 g twice daily for one day |
| Asymptomatic bacteriuria in pregnancy | |
| Acute pyelonephritis | |
| Dental abscess with spreading cellulitis | |
| Acute cystitis | |
| Acute otitis media Acute streptococcal tonsillitis and pharyngitis Acute exacerbations of chronic bronchitis | 500 mg every 8 hours, 750 mg to 1 g every 12 hours For severe infections 750 mg to 1 g every 8 hours for 10 days |
| Community acquired pneumonia | 500 mg to 1 g every 8 hours |
| Typhoid and paratyphoid fever | 500 mg to 2 g every 8 hours |
| Prosthetic joint infections | 500 mg to 1 g every 8 hours |
| Prophylaxis of endocarditis | 2 g orally, single dose 30 to 60 minutes before procedure |
| Helicobacter pylori eradication | 750 mg to 1 g twice daily in combination with a proton pump inhibitor (e.g. omeprazole, lansoprazole) and another antibiotic (e.g. clarithromycin, metronidazole) for 7 days |
| Lyme disease (see section 4.4) | Early stage: 500 mg to 1 g every 8 hours up to a maximum of 4 g/day in divided doses for 14 days (10 to 21 days) Late stage (systemic involvement): 500 mg to 2 g every 8 hours up to a maximum of 6 g/day in divided doses for 10 to 30 days |
| Consideration should be given to the official treatment guidelines for each indication | |
Children < 40 kg
Children may be treated with Amoxicillin capsules, dispersible tablets suspensions or sachets.
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:
| Indication+ | Dose+ |
| Acute bacterial sinusitis | 20 to 90 mg/kg/day in divided doses |
| Acute otitis media | |
| Community acquired pneumonia | |
| Acute cystitis | |
| Acute pyelonephritis | |
| Dental abscess with spreading cellulitis | |
| Acute streptococcal tonsillitis and pharyngitis | 40 to 90 mg/kg/day in divided doses* |
| Typhoid and paratyphoid fever | 100 mg/kg/day in three divided doses |
| Prophylaxis of endocarditis | 50 mg/kg orally, single dose 30 to 60 minutes before procedure |
| Lyme disease (see section 4.4) | Early stage: 25 to 50 mg/kg/day in three divided doses for 10 to 21 days Late stage (systemic involvement): 100 mg/kg/day in three divided doses for 10 to 30 days |
| Tonsillitis | 50mg/kg/day in two divided doses |
| +Consideration should be given to the official treatment guidelines for each indication. *Twice daily dosing regimens should only be considered when the dose is in the upper range In areas with high prevalence of pneumococci with reduced susceptibility to penicillins, dosage regimens should be guided by national/local recommendations. In severe or recurrent acute otitis media, especially where compliance may be a problem, 750 mg twice a day for two days may be used as an alternative course of treatment in children aged 3 to 10 years. | |
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
| GFR (ml/min) | Adults and children > 40 kg | Children < 40 kg# |
| greater than 30 | No adjustment necessary | No adjustment necessary |
| 10 to 30 | Maximum 500 mg twice daily | 15 mg/kg given twice daily (maximum 500 mg twice daily) |
| less than 10 | Maximum 500mg/day. | 15 mg/kg given as a single daily dose (maximum 500 mg) |
| # In the majority of cases, parenteral therapy is pref | erred. | |
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 Oral Suspension may be removed from the circulation by haemodialysis.
| Haemodialysis | |
| Adults and children > 40 kg | 15 mg/kg/day given as a single daily dose. Prior to haemodialysis one additional dose of 15 mg/kg should be administered. In order to restore circulating drug levels, another dose of 15 mg/kg should be administered after 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
| Condition | Adult’s dosage (including elderly) | Children’s dosage (<40kg) | Notes | |
| Dental procedures: Prophylaxis for patients undergoing extraction, scaling or surgery involving gingival tissues and who have not received a penicillin in the previous month. (N.B. Patients with prosthetic heart valves should be referred to hospital – see below). | Patient not having general anaesthetic | 3 g amoxicillin orally, 1 hour before procedure. A second dose may be given 6 hours later, if considered necessary. | 50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure | Note 1. If prophylaxis with amoxicillin is given twice within one month, emergence of resistant streptococci is unlikely to be a problem. Alternative antibiotics are recommended if more frequent prophylaxis is required, or if the patient has received a course of treatment with a penicillin during |
| Patient having general anaesthetic: if oral antibiotics considered to be appropriate. | Initially 3 g amoxicillin orally 4 hours prior to anaesthesia, followed by 3 g orally (or 1 g IV or IM if oral dose not | |||
| Condition | Adult’s dosage (including elderly) | Children’s dosage (<40kg) | Notes | |
| tolerated) as soon as possible after the operation. | the previous month. Note 2. To minimise pain on injection, amoxicillin may be given as two injections of 500 mg dissolved in sterile 1% lidocaine solution (See Method of administration) | |||
| Patient having general anaesthetic: if oral antibiotics not appropriate. | 1 g amoxicillin IV or IM immediately before induction; with 500 mg orally, 6 hours later. | |||
| Dental procedures : patients for whom referral to hospital is recommended: a) Patients to be given a general anaesthetic who have been given a penicillin in the previous month. b) Patients to be given a general anaesthetic who have a prosthetic heart valve. c) Patients who have had one or more attacks of endocarditis. | Initially: 1 g amoxicillin IV or IM with 120 mg gentamicin IV or IM immediately prior to anaesthesia (if given) or 15 minutes prior to dental procedure. Followed by (6 hours later): 500 mg amoxicillin orally. | 50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure | See Note 2. Note 3. Amoxicillin and gentamicin should not be mixed in the same syringe. Note 4. Please consult the appropriate data sheet for full prescribing information on gentamicin. | |
| Genitourinary surgery or instrumentation : prophylaxis for patients who have no urinary tract infection and who are to | Initially: 1 g amoxicillin IV or IM with 120 mg | See Notes 2, 3 and 4 above. | ||
| Condition | Adult’s dosage (including elderly) | Children’s dosage (<40kg) | Notes | |
| 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. | gentamicin IV or IM, immediately before induction. Followed by (6 hours later): 500 mg amoxicillin orally or IV or IM according to clinical condition. | |||
| Surgery or instrumentation of the upper respiratory tract | Patients other than those with prosthetic heart valves. | 1 g amoxicillin IV or IM immediately before induction; 500 mg amoxicillin IV or IM 6 hours later. | 50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure | See Note 2 above. 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. | |
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 A 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 allergens (see section 4.3 and 4.8).
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individual with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and appropriate alternative therapy institute.
Erythematous (morbilliform) rashes have been associated with glandular fever in patients receiving amoxicillin.
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 (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 selflimiting 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 contraindicated 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.
Paediatric population
Precaution should be taken in premature children and during the neonatal period: renal, hepatic and haematological functions should be monitored.
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.
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.
Methotrexate
Penicillins may reduce the excretion of methotrexate causing a potential increase in risk of 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 congential 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.
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)
Mot known (cannot be estimated from the available data).
The majority of adverse events listed below are not unique to amoxicillin and may occur when using other penicillins.
Unless otherwise stated, the frequency of adverse events has been derived from more than 30 years of post-marketing reports.
| Infections and infestations | |
| Very rare | Mucocutaneous candidiasis |
| Blood and lymphatic system disorders: | |
| Very rare | Reversible leucopenia (including severe neutropenia and agranulocytosis), reversible thrombocytopenia and haemolytic anaemia have been reported. Prolongation of bleeding time and prothrombin time (see section 4.4). |
| Immune system disorders | |
| Very rare | Severe allergic reactions including angioneurotic oedema, anaphylaxis, serum sickness and hypersensitivity vasculitis (see section 4.4). If a hypersensitivity reaction occurs, the treatment must be discontinued (see also skin and subcutaneous tissue disorders). |
| Not Known | Jarisch-Herxheimer reaction (see section 4.4). |
| Nervous system disorders | |
| Very rare | Hyperkinesia, dizziness and convulsions (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses. |
| Post-marketing data | |
| Not known | Aseptic meningitis |
| Gastrointestinal disorders | |
| Clinical trial data | |
| Common | Diarrhoea and nausea |
| Uncommon | Vomiting |
| Post-marketing data | |
| Very rare | Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis have been reported (see section 4.4). Black hairy tongue Superficial tooth discolouration# |
| Hepatobiliary disorders | |
| Very rare | Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT, but the significance of this is unclear. |
| Skin and subcutaneous tissue disorders | |
| Clinical trial data | |
| *Common: | Skin rash |
| *Uncommon: | Urticaria and pruritus. |
| Post-marketing data | |
| Very rare | Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (see section 4.4). |
| Renal and urinary tract disorders | |
| Very rare | Interstitial nephritis Crystalluria (see section 4.4 and 4.9 Overdose) can occur. |
| *The incidence of these AEs was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin. #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 of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: penicillins with extended spectrum; ATC Code: JO1CA04.
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, 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.
Mechanism 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 5.0.
| Organism | MIC breakpoint (mg/L) | |
| Susceptible < | Resistant > | |
| Enterobacteri aceae | 1 8 | 8 |
| Staphylococcus spp. | 2 Note | 2 Note |
| 3 Enterococcus spp. | 4 | 8 |
| Streptococcus groups A, B, C and G | 4 Note | 4 Note |
| Streptococcus pneumoniae | 5 Note | 5 Note |
| Viridans group steprococci | 0.5 | 2 |
| Haemophilus influenzae | 6 2 | 6 2 |
| Moraxella catarrhalis | 7 Note | 7 Note |
| Neisseria meningitidis | 0.125 | 1 |
| Gram positive anaerobes except 8 Clostridium difficile | 4 | 8 |
| 8 Gram negative anaerobes | 0.5 | 2 |
| Helicobacter pylori | 9 0.125 | 9 0.125 |
| Pasteurella multocida | 1 | 1 |
| 10 Non- species related breakpoints | 2 | 8 |
| 1 Wild type Enterobacteriaceae are categorised as susceptible to aminopenicillins. Some countries prefer to categorise wild type isolates of E. coli and P. mirabilis as intermediate. When this is the case, use the MIC breakpoint S < 0.5 mg/L | ||
7----------------------------------------------------------------------
Most staphylococci are penicillinase producers, which are resistant to amoxicillin. Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents.
3
Susceptibility to amoxicillin can be inferred from ampicillin
4
The susceptibility of streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin susceptibility.
5
Breakpoints relate only to non-meningitis isolates. For isolates categorised as intermediate to ampicillin avoid oral treatment with amoxicillin.
Susceptibility inferred from the MIC of ampicillin.
6
Breakpoints are based on intravenous administration. Beta-lactamase positive isolates should be reported resistant.
7
Beta lactamase producers should be reported resistant
8
Susceptibility to amoxicillin can be inferred from benzylpenicillin.
9
The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility.
10
The non-species related breakpoints are based on doses of at least 0.5 g x 3or 4 doses daily (1.5 to 2 g/day)
Susceptibility:
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
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
Brucella species
Neisseria gonorrhoeae
Neisseria meningitides
Vibrio cholerae
Gram-positive aerobes:
Coagulase negative staphylococcus
£
Staphylococcus aureus
Streptococcus pneumoniae
Viridans group streptococcus
Corynebacterium species
Bacillus anthracis
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 (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.
| Cmax | Tmax * | AUC (0–24h) | T */2 |
| (gg/ml) | (h) | ((pg.h/ml) | (h) |
| 3.3 ± 1.12 | 1.5 (1.0–2.0) | 26.7 ± 4.56 | 1.36 ± 0.56 |
| *Median (range) | |||
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.
Peak plasma amoxicillin concentrations of about 5^g per ml have been observed 1 to 2 hours after a dose of 250mg with detectable amounts present for up to 8 hours. Doubling the dose can produce double the concentrations. The presence of food in the stomach does not appear to diminish absorption significantly.
Distribution:
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).
Amoxicillin gives good penetration into bronchial secretions and high urinary concentrations of unchanged antibiotic.Therapeutic drug levels are rapidly achieved in serum, lung tissue, bronchial secretions, middle ear fluid, bile and urine. In healthy meninges amoxicillin diffuses badly in liquor cerebrospinalis. Amoxicillin crosses the placenta and a small percentage is excreted into the breast milk.
Biotransformation
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.
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
5.3 Preclinical safety dataNon-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.
6.1 List of excipients
Saccharin Sodium,
Sodium Benzoate (E211)
Sodium Citrate Anhydrous
Lime Flavour
Microcrystalline Cellulose
Carboxymethylcellulose Sodium
Disodium Edetate
Sorbitol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Dry Powder: 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. White polyethylene bottle with child resistant cap.
2. Clear glass bottle with white polypropylene cap.
Pack sizes: 60 ml and 100 ml
6.6 Special precautions for disposal and other handling
6.6 Special precautions for disposal and other handlingCheck 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
ATHLONE PHARMACEUTICALS LIMITED
BALLYMURRAY
ROSCOMMON
COUNTY ROSCOMMON
IRELAND
8 MARKETING AUTHORISATION NUMBER(S)
PL 30464/0009
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
First Authorisation: 26 March 1993
Renewal: 13 March 2009