Public Assessment Report
Decentralised Procedure
AMOXICILLIN 125 MG/ 5 ML POWDER FOR ORAL SUSPENSION
AMOXICILLIN 250 MG/ 5 ML POWDER FOR ORAL SUSPENSION
Procedure No: UK/H/3242/001-2/DC
UK Licence No: PL 25298/0003-4
LAY SUMMARY
On 14 December 2011, the Netherlands and the UK agreed to grant Marketing Authorisations
to Brown & Burk UK Ltd for the medicinal products Amoxicillin 125 mg/ 5 ml and
Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension (PL 25298/0003-4;
UK/H/3242/001-2/DC). The licences were granted via the Decentralised Procedure (DCP), with the UK as
Reference Member State (RMS). After a subsequent national phase, Marketing
Authorisations were granted in the UK on 13 January 2012.
These are prescription-only medicines (POM) used in adults and children above the age of 6
months to treat infections of the chest (bronchitis or pneumonia) and ears (acute otitis media)
and cystitis. They can also be used as part of treatment to prevent infections of the heart
lining (endocarditis).
Amoxicillin belongs to a group of antibiotics called “penicillins”. Penicillins work by killing
the bacteria that can cause infections.
No new or unexpected safety concerns arose from these applications and it was, therefore,
judged that the benefits of taking Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml Powder for
Oral Suspension outweigh the risks, hence Marketing Authorisations have been granted.
TABLE OF CONTENTS
Module 1: Information about initial
procedure Page
4
Module 2: Summary of Product Characteristics
Page 5
Module 3: Product Information Leaflet
Page 23
Module
4:
Labelling
Page
25
Module
5:
Scientific
Discussion
Page
29
1
Introduction
2
Quality
aspects
3
Non-clinical
aspects
4
Clinical
aspects
5
Overall
conclusions
Module 6: Steps taken after initial procedure
Page 37
Module 1
Product Name Amoxicillin 125 mg/ 5 ml Powder for Oral Suspension Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension
Type of Application Generic, Article 10 (1)
Active Substances Amoxicillin
Form Powder for oral suspension
Strength 125 mg/ 5 ml and 250 mg/ 5 ml
MA Holder Brown & Burk UK Ltd, 5, Marryat Close, Hounslow West Middlesex, TW4 5DQ, UK
Reference Member State (RMS)
UK
Concerned Member State (CMS)
The Netherlands
Procedure Number UK/H/3242/001-2/DC
Timetable Day 208 – 14 December 2011
Module 2
Summary of Product Characteristics
1 NAME OF THE MEDICINAL PRODUCT
Amoxicillin 125 mg/ 5 ml Powder for Oral Suspension
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Amoxicillin suspension contains 125 mg amoxicillin per 5 ml dose. The amoxicillin is present as the trihydrate.
Contains 295 mg /5 ml sorbitol (E420) For excipients see 6.1.
3 PHARMACEUTICAL FORM
Powder for oral suspension
White to pale yellow free flowing powder for oral suspension.
4 CLINICAL PARTICULARS 4.1 Therapeutic indications
Amoxicillin Suspension is indicated for the treatment of the following infections caused by susceptible bacteria in adults and children above the age of 6 months (see sections 4.2, 4.4 and 5.1):
Acute otitis media
Acute exacerbations of chronic bronchitis Community acquired pneumonia
Cystitis
Endocarditis: Prophylaxis of endocarditisassociated with procedures such as dental extraction, where
indicated in patients at risk of developing bacterial endocarditis.
Consideration should be given to official guidelines on the appropriate use of antibacterial agents.
4.2 Posology and method of administration Treatment of Infection:
Adult dosage (including elderly patients):
Oral:
Standard adult dosage: 250 mg-500 mg three times daily, increasing to 1 g three times daily for more
severe infections.
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: Simple acute urinary tract infection: two 3 g doses with 10-12 hours between the
doses.
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 a reduction in the total daily dose by an increase in the dosage interval and/or a reduction in subsequent doses is recommended (see section 4.4 and 5.2). The following adjustments are recommended:
Glomerular filtration rate > 30 ml/min: No adjustment necessary. Glomerular filtration rate 10-30 ml/min: Amoxicillin. max. 500 mg b.d
Glomerular filtration rate < 10 ml/min: Amoxicillin. max. 500 mg/day
In case of hemodialysis: 500 mg should be administered at the end of the procedure.
Dosage in impaired hepatic function:
Dose with caution and monitor hepatic function at regular intervals
Prophylaxis for endocarditis
3g amoxicillin given as a single dose one hour preceding the surgical procedure. National guidelines should be followed.
Children weighing < 40 kg:
The daily dosage for children is 40 - 90 mg/kg/day in two to three divided doses* (not exceeding 3 g/day) depending on the indication, severity of the disease and the susceptibility of the pathogen (see special dosage recommendations below and sections 4.4, 5.1 and 5.2).
*PK/PD data indicate that dosing three times daily is associated with enhanced efficacy, thus twice daily dosing is only recommended when the dose is in the upper range.
Children weighing more than 40 kg should be given the usual adult dosage.
Special dosage recommendation
Indication Dose regimen and duration of treatment
Acute otitis media In areas with high prevalence of pneumococci with reduced
susceptibility to penicillins, dosage regimens should be guided by national/local recommendations.
Prophylaxis for
endocarditis 50 mg amoxicillin/kg body weight given as a single dose, one hour preceding the surgical procedure.
Renal impairment in children under 40 kg:
Creatinine clearance ml/min
Dose Interval between
administration
> 30 Usual dose No adjustment necessary
10 – 30 Half of
usual dose 12 h
< 10 Half of
usual dose 24 h
In case of haemodialysis: one usual dose should be administered at the end of the procedure.
Administration: Oral
Treatment should be continued for 2 to 3 days following the disappearance of symptoms. It is recommended that atleast 10 days treatment be given for any infection caused by beta-haemolytic streptococci in order to achieve eradication of the organism.
Parenteral therapy is indicated if the oral route is considered impracticable or unsuitable, and particularly for the urgent treatment of severe infection.
For instructions on reconstitution of the medicinal product before administration see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.
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
Before treatment with amoxicillin is started, thorough enquiries should be made concerning earlier hypersensitivity reactions to penicillins and cephalosporins (see sections 4.3 and 4.8).
The possibility of cross-sensitivity (10-15%) with cephalosporins should be taken into account. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and alternative therapy instituted.
Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).
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.
Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.
Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
Treatment of urinary tract infections may be a problem due to a very high resistance rate of Escherichia coli reported for amoxicillin in some European countries (see section 5.1).
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 4.9). 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.
Dosage should be adjusted in patients with renal impairment (see 4.2).
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 of amoxicillin.
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/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation.
Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.
Precaution should be taken in premature children and during the neonatal period: renal, hepatic and haematological functions should be monitored.
Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. 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).
This medicine contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance
should not take this medicine.
This medicine also contains sodium benzoate (E211), which may increase the risk of jaundice in newborn babies.
4.5 Interaction with other medicinal products and other forms of interaction
In common with other broad spectrum antibiotics, amoxicillin may reduce the efficacy of oral contraceptives and patients should be warned accordingly.
Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.
It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.
There have been cases of increased international normalised ratio in patients treated with
acenocoumarol or warfarin when receiving concurrent treatment with amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Adjustments in the dose of oral anticoagulants may be necessary.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Amoxicillin passes the placenta and foetal plasma concentrations are approximately 25-30% of the maternal plasma concentrations. Data on a limited number of exposed pregnancies indicate no adverse effects of amoxicillin on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Caution should be exercised when prescribing to pregnant women.
Lactation:
Amoxicillin diffuses into the breast milk (approx. 10% of the corresponding serum concentration) and in rare cases this can lead to diarrhoea and/or fungal colonisation of the mucosa in the infant. The possibility of sensitisation of the infant to beta-lactam drugs should also be considered. A decision must be made as to whether to discontinue breast-feeding, or to discontinue/abstain from Amoxicillin suspension therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility:
No fertility data are available.
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 following convention has been utilised for the classification of undesirable effects:-
Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000,<1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000).
The majority of side effects listed below are not unique to amoxicillin and may occur when using other pencillins.
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 or
agranulocytosis), reversible thrombocytopenia and haemolytic anaemia.
Prolongation of bleeding time and prothrombin (see Section 4.4)
Immune system disorders
Very rare: Severe allergic reactions, including angioneurotic oedema, anaphylaxis (see Section 4.4), serum sickness and hypersensitivity vasculitis.
Nervous system disorders
Very rare: Hyperkinesia, dizziness and
convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Gastrointestinal disorders
Clinical Trial Data
*Common: Diarrhoea and nausea.
*Uncommon: Vomiting.
Post-marketing Data
Very rare: Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis). Black hairy tongue
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.
Hepato-biliary disorders
Very rare: Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT. The significance of a rise in AST and/or ALT is unclear.
Skin and subcutaneous tissue disorders
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 also Immune system disorders).
Renal and urinary tract disorders
Very rare: Interstitial nephritis.
Very rare: Crystalluria (see Section 4.9).
*The incidence of these AE's was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin.
4.9 Overdose
Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically with attention to the water/electrolyte balance. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Section 4.4). Amoxicillin has been reported to
precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4)
Amoxicillin may be removed from the circulation by haemodialysis.
5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties
General properties
Pharmacotherapeutic Group: Penicillins with extended spectrum, ATC classification: J01CA04
Mode of action
Amoxicillin is bactericidal against susceptible organisms during the stage of active multiplication. It acts through the inhibition of one or more enzymes (often referred to as penicillin-binding proteins, PBP’s) in the biosynthetic pathway of bacterial peptidoglycan, an integral structural component of the bacterial cell wall.
PK/PD relationship
Amoxicillin demonstrates a time-dependent pattern of bactericidal activity (%T > MIC is considered to be the major determinant of efficacy).
Mechanisms of resistance
Bacteria may be resistant to amoxicillin owing to:
• production of beta-lactamases that hydrolyse aminopenicillins
• alterations in penicillin-binding proteins
• impermeability of the bacteria to the drug
• drug efflux pumps.
• Complete cross-resistance occurs with ampicillin and amoxicillin
Breakpoints (EUCAST)
Organism Susceptibility Breakpoints (μg/ml)
Susceptible Intermediate Resistant Haemophilus influenzae ≤ 1 - > 1 Moraxella catharrhalis ≤ 1 - > 1 Enterococcus ≤ 4 8 > 8 Streptococcus A, B, C, G1 ≤ 0.25 - > 0.25 Streptococcus pneumoniae2 ≤ 0.5 1-2 > 2 Enterobacteriaceae3 - - > 8 Gram-negative anaerobes ≤ 0.5 - > 2 Gram-positive Anaerobes ≤ 4 8 > 8 Non-species related breakpoints ≤ 2 4-8 > 8
1Breakpoint values in the table are based on Benzylpenicillin breakpoints.
2 Breakpoint values in the table are based on ampicillin breakpoints.
3 The resistant breakpoint of R>8 mg/L ensures that all isolates with resistance mechanisms are reported resistant.
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.
Commonly susceptible species
Aerobic Gram-positive
Enterococcus faecalis $
Streptococcus agalactiae Streptococcus bovis
Streptococcus pyogenes *
Staphylococcus aureus (penicillin-sensitive strains only) Anaerobes
Peptostreptococci Others
Borrelia
Species for which acquired resistance may be a problem
Aerobic Gram-positive Corynebacterium spp Enterococcus faecium $ Streptococcus pneumoniae * + Streptococcus viridans Aerobic Gram-negative Escherichia coli + Haemophilus influenzae * Haemophilus para-influenzae * Moraxella catarrhalis + Proteus mirabilis Anaerobes Prevotella Fusobacterium spp
Inherently resistant organisms
Aerobic Gram-negative Acinetobacter spp Citrobacter spp Enterobacter spp Klebsiella spp Legionella Morganella morganii Proteus vulgaris Providencia spp Pseudomonas spp Serratia spp Anaerobes Bacteroides fragilis Others Chlamydia Mycoplasma Rickettsia
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications + pathogens resistance prevalence is > 50%
$ Naturally intermediate species
5.2 Pharmacokinetic properties
Absorption:
After oral administration, amoxicillin is rapidly and almost completely (85-90%) absorbed. The absorption of amoxicillin is unaffected by taking with food. Maximum plasma concentrations are reached after 1-2 hours. Bioavailability (as assessed by pharmacokinetic parameters AUC and / or recovery in urine) is linearly proportional to the dose of amoxicillin between 250 mg and 750 mg. Distribution:
Protein binding for amoxicillin is approximately 17%. Therapeutic drug levels are rapidly achieved in serum, lung tissue, bronchial secretions, middle ear fluid, bile and urine. Amoxicillin can penetrate inflamed meninges and enter the cerebrospinal fluid. Amoxicillin crosses the placenta and a small percentage is excreted into the breast milk.
Biotransformation:
About 7 - 25% of the administered dose is metabolised to inactive penicilloic acid. Elimination:
Excretion is primarily via the kidneys, mostly (approx. 80%) by tubular secretion, the rest (20%) by glomerular filtration.
The plasma half-life of amoxicillin is 1 to 1.5 hours with normal renal function, in premature infants, newborns and infants up to 6 months 3-4 hours. In impaired renal function (creatinine clearance 15 ml / min. or below) the half-life increase, to 8.5 hours in anuria. Hepatic impairment does not affect the half-life.
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 inulin clearance (GFR) in this population. Following oral administration, the absorption pattern and the bioavailability of amoxicillin in small children may be different to that of adults. Consequently, due to the decreased CL, the exposure is expected to be elevated in this group of patients, although this increase in exposure may in part be diminished by decreased bioavailability when given orally.
5.3 Preclinical safety data
There are no non clinical data of relevance to the prescriber which are additional to that already included in other sections of this SPC.
6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients
The powder contains: Di-sodium Edetate Sodium Benzoate (E211) Sodium Saccharin (E954) Colloidal Silicon Dioxide (E551) Xanthan Gum (E415)
Orange Flavour Raspberry Flavour Golden Caramel Sorbitol (E420) 6.2 Incompatibilities Not applicable. 6.3 Shelf life
24 months (once reconstituted: 14 days)
6.4 Special precautions for storage
Store powder in a dry place. Once dispensed, Amoxicillin Suspension should be used within 14 days. If dilution of the reconstituted product is required, water should be used.
6.5 Nature and contents of container
150 ml HDPE bottle containing 100ml of product.
150 ml HDPE bottle containing powder for suspension and a dosing syringe of 5 ml.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Add sufficient quantity of water (approx. 92.0 mL) to reconstitute the product. Close the cap securely. Shake the bottle vigorously to dissolve the content. The product appears pale yellow to yellow colored suspension with fruity aromatic odor after reconstitution.
7 MARKETING AUTHORISATION HOLDER
Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex TW4 5DQ UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 25298/0003
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/01/2012
10 DATE OF REVISION OF THE TEXT
13/01/2012
1 NAME OF THE MEDICINAL PRODUCT
Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Amoxicillin suspension contains 250 mg amoxicillin per 5 ml dose. The amoxicillin is present as the trihydrate.
Contains 590 mg /5 ml sorbitol (E420) For excipients see 6.1.
3 PHARMACEUTICAL FORM
Powder for oral suspension
White to pale yellow free flowing powder for oral suspension.
4 CLINICAL PARTICULARS 4.1 Therapeutic indications
Amoxicillin Suspension is indicated for the treatment of the following infections caused by susceptible bacteria in adults and children above the age of 6 months (see sections 4.2, 4.4 and 5.1):
Acute otitis media
Acute exacerbations of chronic bronchitis Community acquired pneumonia
Cystitis
Endocarditis: Prophylaxis of endocarditisassociated with procedures such as dental extraction, where
indicated in patients at risk of developing bacterial endocarditis.
Consideration should be given to official guidelines on the appropriate use of antibacterial agents.
4.2 Posology and method of administration Treatment of Infection:
Adult dosage (including elderly patients):
Oral:
Standard adult dosage: 250 mg-500 mg three times daily, increasing to 1 g three times daily for more
severe infections.
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: Simple acute urinary tract infection: two 3 g doses with 10-12 hours between the
doses.
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 a reduction in the total daily dose by an increase in the dosage interval and/or a reduction in subsequent doses is recommended (see section 4.4 and 5.2). The following adjustments are recommended:
Glomerular filtration rate > 30 ml/min: No adjustment necessary. Glomerular filtration rate 10-30 ml/min: Amoxicillin. max. 500 mg b.d Glomerular filtration rate < 10 ml/min: Amoxicillin. max. 500 mg/day
In case of hemodialysis: 500 mg should be administered at the end of the procedure.
Dosage in impaired hepatic function
Dose with caution and monitor hepatic function at regular intervals
Prophylaxis for endocarditis
3g amoxicillin given as a single dose one hour preceding the surgical procedure. National guidelines should be followed.
Children weighing < 40 kg:
The daily dosage for children is 40 - 90 mg/kg/day in two to three divided doses* (not exceeding 3 g/day) depending on the indication, severity of the disease and the susceptibility of the pathogen (see special dosage recommendations below and sections 4.4, 5.1 and 5.2).
*PK/PD data indicate that dosing three times daily is associated with enhanced efficacy, thus twice daily dosing is only recommended when the dose is in the upper range.
Children weighing more than 40 kg should be given the usual adult dosage.
Special dosage recommendation
Indication Dose regimen and duration of treatment
Acute otitis media In areas with high prevalence of pneumococci with reduced
susceptibility to penicillins, dosage regimens should be guided by national/local recommendations.
Prophylaxis for
endocarditis 50 mg amoxicillin/kg body weight given as a single dose, one hour preceding the surgical procedure.
Renal impairment in children under 40 kg:
Creatinine clearance ml/min
Dose Interval between
administration
> 30 Usual dose No adjustment necessary
10 – 30 Half of
usual dose 12 h
< 10 Half of
usual dose 24 h
In case of haemodialysis: one usual dose should be administered at the end of the procedure.
Administration: Oral
Treatment should be continued for 2 to 3 days following the disappearance of symptoms. It is recommended that atleast 10 days treatment be given for any infection caused by beta-haemolytic streptococci in order to achieve eradication of the organism.
Parenteral therapy is indicated if the oral route is considered impracticable or unsuitable, and particularly for the urgent treatment of severe infection.
For instructions on reconstitution of the medicinal product before administration see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.
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
Before treatment with amoxicillin is started, thorough enquiries should be made concerning earlier hypersensitivity reactions to penicillins and cephalosporins (see sections 4.3 and 4.8).
The possibility of cross-sensitivity (10-15%) with cephalosporins should be taken into account. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and alternative therapy instituted.
Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).
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.
Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.
Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
Treatment of urinary tract infections may be a problem due to a very high resistance rate of Escherichia coli reported for amoxicillin in some European countries (see section 5.1).
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 4.9). 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.
Dosage should be adjusted in patients with renal impairment (see 4.2).
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 of amoxicillin.
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/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation.
Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.
Precaution should be taken in premature children and during the neonatal period: renal, hepatic and haematological functions should be monitored.
Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. 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).
This medicine contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance
should not take this medicine.
This medicine also contains sodium benzoate (E211), which may increase the risk of jaundice in newborn babies.
4.5 Interaction with other medicinal products and other forms of interaction
In common with other broad spectrum antibiotics, amoxicillin may reduce the efficacy of oral contraceptives and patients should be warned accordingly.
Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.
It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.
There have been cases of increased international normalised ratio in patients treated with
acenocoumarol or warfarin when receiving concurrent treatment with amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Adjustments in the dose of oral anticoagulants may be necessary.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Amoxicillin passes the placenta and foetal plasma concentrations are approximately 25-30% of the maternal plasma concentrations. Data on a limited number of exposed pregnancies indicate no adverse effects of amoxicillin on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Caution should be exercised when prescribing to pregnant women.
Lactation:
Amoxicillin diffuses into the breast milk (approx. 10% of the corresponding serum concentration) and in rare cases this can lead to diarrhoea and/or fungal colonisation of the mucosa in the infant. The possibility of sensitisation of the infant to beta-lactam drugs should also be considered. A decision must be made as to whether to discontinue breast-feeding, or to discontinue/abstain from Amoxicillin suspension therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility:
No fertility data are available.
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 following convention has been utilised for the classification of undesirable effects:-
Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000,<1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000).
The majority of side effects listed below are not unique to amoxicillin and may occur when using other pencillins.
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 or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia.
Prolongation of bleeding time and prothrombin (see
Section 4.4)
Immune system disorders
Very rare: Severe allergic reactions, including angioneurotic oedema, anaphylaxis (see Section 4.4), serum sickness and hypersensitivity vasculitis.
Nervous system disorders
Very rare: Hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Gastrointestinal disorders
Clinical Trial Data
*Common: Diarrhoea and nausea.
*Uncommon: Vomiting.
Post-marketing Data
Very rare: Antibiotic associated colitis (including
pseudomembraneous colitis and haemorrhagic colitis). Black hairy tongue
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.
Hepato-biliary disorders
Very rare: Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT.
The significance of a rise in AST and/or ALT is unclear.
Skin and subcutaneous tissue disorders
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 also Immune system disorders).
Renal and urinary tract disorders
Very rare: Interstitial nephritis.
Very rare: Crystalluria (see Section 4.9).
*The incidence of these AE's was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin.
4.9 Overdose
Gastrointestinal effects such as nausea, vomiting and diarrhoea may be evident and should be treated symptomatically with attention to the water/electrolyte balance. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see Section 4.4). Amoxicillin has been reported to
precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained (see section 4.4)
Amoxicillin may be removed from the circulation by haemodialysis.
5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties
General properties
Pharmacotherapeutic Group: Penicillins with extended spectrum, ATC classification: J01CA04
Mode of action
Amoxicillin is bactericidal against susceptible organisms during the stage of active multiplication. It acts through the inhibition of one or more enzymes (often referred to as penicillin-binding proteins, PBP’s) in the biosynthetic pathway of bacterial peptidoglycan, an integral structural component of the bacterial cell wall.
PK/PD relationship
Amoxicillin demonstrates a time-dependent pattern of bactericidal activity (%T > MIC is considered to be the major determinant of efficacy).
Mechanisms of resistance
Bacteria may be resistant to amoxicillin owing to:
• production of beta-lactamases that hydrolyse aminopenicillins
• alterations in penicillin-binding proteins
• impermeability of the bacteria to the drug
• drug efflux pumps.
• Complete cross-resistance occurs with ampicillin and amoxicillin
Breakpoints (EUCAST)
Organism Susceptibility Breakpoints (μg/ml)
Susceptible Intermediate Resistant Haemophilus influenzae ≤ 1 - > 1 Moraxella catharrhalis ≤ 1 - > 1 Enterococcus ≤ 4 8 > 8 Streptococcus A, B, C, G1 ≤ 0.25 - > 0.25 Streptococcus pneumoniae2 ≤ 0.5 1-2 > 2 Enterobacteriaceae3 - - > 8 Gram-negative anaerobes ≤ 0.5 - > 2 Gram-positive Anaerobes ≤ 4 8 > 8 Non-species related breakpoints ≤ 2 4-8 > 8
1Breakpoint values in the table are based on Benzylpenicillin breakpoints.
2 Breakpoint values in the table are based on ampicillin breakpoints.
3 The resistant breakpoint of R>8 mg/L ensures that all isolates with resistance mechanisms are reported
resistant.
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.
Commonly susceptible species
Aerobic Gram-positive Enterococcus faecalis $ Streptococcus agalactiae Streptococcus bovis Streptococcus pyogenes * 19
Commonly susceptible species
Staphylococcus aureus (penicillin-sensitive strains only) Anaerobes
Peptostreptococci Others
Borrelia
Species for which acquired resistance may be a problem
Aerobic Gram-positive Corynebacterium spp Enterococcus faecium $ Streptococcus pneumoniae * + Streptococcus viridans Aerobic Gram-negative Escherichia coli + Haemophilus influenzae * Haemophilus para-influenzae * Moraxella catarrhalis + Proteus mirabilis Anaerobes Prevotella Fusobacterium spp
Inherently resistant organisms
Aerobic Gram-negative Acinetobacter spp Citrobacter spp Enterobacter spp Klebsiella spp Legionella Morganella morganii Proteus vulgaris Providencia spp Pseudomonas spp Serratia spp Anaerobes Bacteroides fragilis Others Chlamydia Mycoplasma Rickettsia
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications
+ pathogens resistance prevalence is > 50%
$ Naturally intermediate species
5.2 Pharmacokinetic properties
Absorption:
After oral administration, amoxicillin is rapidly and almost completely (85-90%) absorbed. The absorption of amoxicillin is unaffected by taking with food. Maximum plasma concentrations are reached after 1-2 hours. Bioavailability (as assessed by pharmacokinetic parameters AUC and / or recovery in urine) is linearly proportional to the dose of amoxicillin between 250 mg and 750 mg. Distribution:
Protein binding for amoxicillin is approximately 17%. Therapeutic drug levels are rapidly achieved in serum, lung tissue, bronchial secretions, middle ear fluid, bile and urine. Amoxicillin can penetrate inflamed meninges and enter the cerebrospinal fluid. Amoxicillin crosses the placenta and a small percentage is excreted into the breast milk.
Biotransformation:
About 7 - 25% of the administered dose is metabolised to inactive penicilloic acid.
Elimination:
Excretion is primarily via the kidneys, mostly (approx. 80%) by tubular secretion, the rest (20%) by glomerular filtration.
The plasma half-life of amoxicillin is 1 to 1.5 hours with normal renal function, in premature infants, newborns and infants up to 6 months 3-4 hours. In impaired renal function (creatinine clearance 15 ml / min. or below) the half-life increase, to 8.5 hours in anuria. Hepatic impairment does not affect the half-life.
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 inulin clearance (GFR) in this population. Following oral administration, the absorption pattern and the bioavailability of amoxicillin in small children may be different to that of adults. Consequently, due to the decreased CL, the exposure is expected to be elevated in this group of patients, although this increase in exposure may in part be diminished by decreased bioavailability when given orally.
5.3 Preclinical safety data
There are no non clinical data of relevance to the prescriber which are additional to that already included in other sections of this SPC.
6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients
The powder contains: Di-sodium Edetate Sodium Benzoate (E211) Sodium Saccharin (E954) Colloidal Silicon Dioxide (E551) Xanthan Gum (E415)
Orange Flavour Raspberry Flavour Golden Caramel Sorbitol (E420) 6.2 Incompatibilities Not applicable. 6.3 Shelf life
24 months (once reconstituted: 14 days)
6.4 Special precautions for storage
Store powder in a dry place. Once dispensed, Amoxicillin Suspension should be used within 14 days. If dilution of the reconstituted product is required, water should be used.
6.5 Nature and contents of container
150 ml HDPE bottle containing 100ml of product.
150 ml HDPE bottle containing powder for suspension and a dosing syringe of 5 ml. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Add sufficient quantity of water (approx. 92.0 mL) to reconstitute the product. Close the cap securely. Shake the bottle vigorously to dissolve the content. The product appears pale yellow to yellow colored suspension with fruity aromatic odor after reconstitution.
7 MARKETING AUTHORISATION HOLDER
Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex
TW4 5DQ UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 25298/0004
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/01/2012
10 DATE OF REVISION OF THE TEXT
13/01/2012
Module 3
Module 4
Labelling
Carton:
Bottle label:
Carton:
28
Module 5
Scientific discussion during initial procedure
I
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the Member States considered
that the applications for Amoxicillin 125 mg/ 5 ml and 250 mg/ 5 ml Powder for Oral
Suspension (PL 25298/0003-4; UK/H/3242/001-2/DC) could be approved. These
applications were submitted via the Decentralised Procedure (DCP), with the UK as
Reference Member State (RMS), and the Netherlands as Concerned Member State (CMS).
The products are prescription-only medicines (POM) indicated for the treatment of the
following infections caused by susceptible bacteria in adults and children above the age of 6
months:
•
acute otitis media
•
acute exacerbations of chronic bronchitis
•
community acquired pneumonia
•
cystitis
•
Endocarditis: Prophylaxis of endocarditis associated with procedures such as dental
extraction, where indicated in patients at risk of developing bacterial endocarditis.
These applications were submitted under Article 10(1) of Directive 2001/83/EC, as amended,
cross referring to the reference products Amoxil Syrup Sucrose Free/Dye Free 125 mg/5 ml
and Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK) which have
been authorised in the UK since 14 May 1985.
Amoxicillin is an aminopenicillin and belongs to a group of medicines called Beta-lactam
antibiotics. It is bactericidal against susceptible organisms during the stage of active
multiplication. It acts through the inhibition of one or more enzymes (often referred to as
penicillin-binding proteins or PBPs) in the biosynthetic pathway of bacterial peptidoglycan,
an integral structural component of the bacterial cell wall.
No new non-clinical studies were conducted, which is acceptable given that the applications
were based on being generic medicinal products of originator products that have been
licensed for over 10 years.
One bioequivalence study (single dose) was submitted to support these applications,
comparing the test product Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension (Brown &
Burk Ltd) with the reference product Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml
(GlaxoSmithKline, UK).
With the exception of the bioequivalence study, no new clinical studies were conducted,
which is acceptable given that the applications were for products that are being considered as
generic medicinal products of an originator product that have been licensed for over 10 years.
The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP)
The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP)
are in place for this product type at all sites responsible for the manufacture, assembly and
batch release of this products.
The RMS and CMS considered that the applications could be approved with the end of
procedure (Day 208) on 14 December 2011. After a subsequent national phase, the licences
were granted in the UK on 13 January 2012.
II.
ABOUT THE PRODUCT
Name of the product in the Reference Member State Amoxicillin 125 mg/ 5 ml Powder for Oral
Suspension
Amoxicillin 250 mg/ 5 ml Powder for Oral Suspension
Name(s) of the active substance(s) (INN) Amoxicillin
Pharmacotherapeutic classification (ATC code) Penicillins with extended spectrum
(ATC code:J01CA04)
Pharmaceutical form and strength(s) Powder for oral suspension, 125 mg/ 5 ml and
250 mg/ 5 ml.
Reference numbers for the Decentralised procedure UK/H/3242/001-2/DC
Reference Member State (RMS) United Kingdom
Concerned Member State (CMS) The Netherlands.
Marketing Authorisation Number(s) PL 25298/003-4
Name and address of the authorisation holder Brown & Burk UK Ltd, 5, Marryat Close,
Hounslow West, Middlesex, TW4 5DQ, UK.
III
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS
S.
Active substance
INN:
Amoxicillin
trihydrate
Chemical name:
(2S,5R,6R)-6-[[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]-
amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic
acid trihydrate
Structure:
Molecular formula: C16H19N3O5S * 3H20
Molecular mass:
419.1
Appearance:
Amoxicillin trihydrate is a white or almost white, crystalline powder. It
is slightly soluble in water, very slightly soluble in ethanol, practically
insoluble in fatty oils and dissolves in dilute acids and dilute solutions
of alkali hydroxides.
Amoxicillin trihydrate is the subject of a European Pharmacopoeia monograph.
All aspects of the manufacture and control of the active substance amoxicillin trihydrate are
covered by a European Directorate for the Quality of Medicines (EDQM) certificate of
suitability.
P.
Medicinal Product
Other Ingredients
Other ingredients consist of the pharmaceutical excipients di-sodium edentate, sodium
benzoate (E211), sodium saccharin (E954), colloidal silicon dioxide (E551), xanthan gum
(E415), orange flavour, raspberry flavour, golden caramel and sorbitol (E420).
All excipients used comply with their respective European Pharmacopoeia monograph with
the exception of orange flavour, raspberry flavour and golden caramel which are controlled to
suitable in-house specifications. Satisfactory Certificates of Analysis have been provided for
all excipients.
None of the excipients are of animal or human origin. No genetically modified organisms
(GMO) have been used in the preparation of these products.
Pharmaceutical Development
The objective of the programme was to develop two strengths of powder formulation for oral
suspension containing 125 mg/5ml and 250 mg/5ml amoxicillin as the active substance.
Suitable pharmaceutical development data have been provided for these applications.
Comparative
in-vitro
dissolution and impurity profiles have been provided for the proposed
and originator products
Manufacturing Process
Satisfactory batch formulae have been provided for the manufacture of the product, along
with an appropriate account of the manufacturing process. The manufacturing process has
been validated at pilot scale and has shown satisfactory results. In addition the marketing
authorisation holder has committed to conduct process validation on commercial scale
batches prior to release of the product on the market.
Finished Product Specification
The finished product specifications proposed are acceptable. Test methods have been
described and have been adequately validated. Batch data have been provided and comply
with the release specifications. Certificates of Analysis have been provided for all working
standards used.
Container-Closure System
All strengths of the finished product are packaged in:
•
150 ml high-density polyethylene (HDPE) bottles containing 100ml of product
•
150 ml high-density polyethylene (HDPE) bottles containing powder for suspension
and a dosing syringe of 5 ml.
It has been stated that not all pack sizes may be marketed, however, the marketing
authorisation holder has committed to submitting the mock-ups for any pack size to the
relevant regulatory authorities for approval before marketing.
Satisfactory specifications and Certificates of Analysis have been provided for all packaging
components. All primary packaging complies with the current European regulations
concerning materials in contact with food.
Stability of the product
Stability studies were performed in accordance with current guidelines on batches of the
finished product packed in the packaging proposed for marketing. The data from these
studies support a shelf-life of 24 months for the unopened product which reduces to 14 days
upon reconstitution with the storage conditions “Store powder in a dry place. Once
dispensed, Amoxicillin Suspension should be used within 14 days. If dilution of the
reconstituted product is required, water should be used.”
Bioequivalence/bioavailability
Satisfactory Certificates of Analysis have been provided for the test and reference batches
used in the bioequivalence studies.
Summary of Product Characteristics (SmPCs), Patient Information Leaflets (PIL),
Labels
The SmPCs, PIL and labels are acceptable.
A package leaflet has been submitted to the MHRA along with results of consultations with
target patient groups ("user testing"), in accordance with Article 59 of Council Directive
2001/83/EC, as amended. The leaflet conforms to the requirements. The test shows that the
patients/users are able to act upon the information that the leaflet contains.
MAA forms
The MAA forms are satisfactory.
Expert report
The quality overall summary has been written by an appropriately qualified person and is a
suitable summary of the pharmaceutical dossier.
Conclusion
There are no objections to the approval of these products from a pharmaceutical viewpoint.
III.2 NON-CLINICAL ASPECTS
As the pharmacodynamic, pharmacokinetic and toxicological properties of amoxicillin are
well-known, no new non-clinical studies are required and none have been provided.
The applicant’s non-clinical overview has been written by an appropriately qualified person
and is satisfactory, providing an appropriate review of the products’ pharmacology and
toxicology.
A suitable justification has been provided for non-submission of an environmental risk
assessment. As these products are intended for generic substitution with other products
already on the market they are not considered to increase the environmental risk. Thus, the
applicant’s justification is accepted.
There are no objections to the approval of these products from a non-clinical viewpoint.
III.3 CLINICAL ASPECTS
Pharmacokinetics
In support of these applications, the marketing authorisation holder has submitted the
following bioequivalence study:
An open label, randomised, single-dose, two-treatment, two-sequence, two-period,
crossover study to compare the pharmacokinetics of the test product Amoxicillin 250
mg/ 5 ml Powder for Oral Suspension (Brown & Burk UK Ltd) versus the reference
product Amoxil Syrup Sucrose Free/Dye Free 250 mg/5ml (GlaxoSmithKline, UK) in
healthy adult volunteers under fasted conditions.
All volunteers received a single oral dose of 250mg (5 ml) of either the test or reference
product administered with 240 ml of water under fasting conditions. Blood samples were
taken for the measurement of pharmacokinetic parameters at pre- and up to 12 hours post
dose. The washout period between treatment periods was at least 7 days.
The pharmacokinetic results for amoxicillin are presented below (log-transformed values;
mean, ratios and 90% confidence intervals):
Treatment AUC0-t ng/ml/h AUC0-∞ ng/ml/h Cmax ng/ml Test 20718.73 20882.65 7487.47 Reference 22314 22492.18 7859.65 *Ratio (90% CI) 93.18 (88.77-97.82%) 93.18 (88.8-97.77%) 95.71 (88.79-103.17%)
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax maximum plasma concentration
*ln-transformed values
