Public Assessment Report Decentralised Procedure

PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Public Assessment Report
Decentralised Procedure
Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
UK licence no: PL 04569/1118
Generics (UK) Limited
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
LAY SUMMARY
On 6 Septemeber 2011, the Medicine and Healthcare products Regulatory Agency (MHRA)
granted Generics (UK) Limited a Marketing Authorisation (licence) for the medicinal
product Cefixime 100 mg/5 mL Powder for Oral Suspension (PL 04569/1118). This licence
was granted via the decentralised procedure (UK/H/2828/001/DC). This is a prescriptiononly medicine.
Cefixime 100 mg/5 mL Powder for Oral Suspension contains the active ingredient cefixime
and belongs to a group of medicines called cephalsporins which are used for treating bacterial
infections. Cefixime can be used to treat:
•
•
•
•
•
•
•
Infection of the middle ear
Sinus infection
Throat infection
Infection causing sudden worsening of long standing bronchitis
Serious lung infections (such as pneumonia) acquired outside the hospital
Infections in the urinary tract
Kidney infection
No new or unexpected safety concerns arose from this application and it was therefore judged
that the benefits of taking Cefixime 100 mg/5 mL Powder for Oral Suspension outweighs the
risks and a Marketing Authorisation was granted.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
TABLE OF CONTENTS
Module 1: Information about initial procedure
Page 4
Module 2: Summary of Product Characteristics
Page 5
Module 3: Product Information Leaflets
Page 12
Module 4: Labelling
Page 18
Module 5: Scientific Discussion
Page 22
Module 6
I Introduction
II About the product
III.1 Quality aspects
III.2 Non-clinical aspects
III.3 Clinical aspects
IV Overall Conclusion and Benefit:Risk Assessment
Page 22
Page 24
Page 25
Page 27
Page 28
Page 31
Steps taken after initial procedure
Page 32
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Module 1
Product Name
Cefixime 100 mg/5 mL Powder for Oral Suspensin
Type of Application
Generic Application, Article 10(1)
Active Substance
Cefixime
Form
Powder for oral suspension
Strength
100mg/5ml
Marketing
Authorisation Holder
Generics (UK) Limited
Station Close
Potters Bar, Hertsfordshire EN6 1TL UK
UK
Reference Member
State (RMS)
Concerned Member
State (CMS)
Italy
Procedure Number
UK/H/2828/001/DC
End of Procedure
3 August 2011
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Module 2
SUMMARY OF PRODUCT CHARACTERISTICS
The UK Summary of Product Characteristics (SmPC) for Cefixime 100 mg/5 mL Powder for
Oral Suspension (PL 04569/1118) is as follows:
1
NAME OF THE MEDICINAL PRODUCT
Cefixime 100 mg/5 ml Powder for Oral Suspension
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5 ml of reconstituted suspension contains 111.917 mg of cefixime trihydrate equivalent to 100
mg of cefixime (anhydrous).
Excipient(s): Each 5 ml of reconstituted suspension contains 2.43 g of sucrose.
For a full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
Powder for oral suspension.
Off-white to pale yellow coloured powder with characteristic odour and gives a cream colour to pale
yellow coloured viscous suspension after reconstitution with water.
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4.1
CLINICAL PARTICULARS
Therapeutic indications
Cefixime is indicated for the treatment of the following infections when caused by susceptible
organisms (see sections 4.4 and 5.1)
Acute exacerbations of chronic bronchitis
Community-acquired Pneumonia
Lower urinary tract infections
Pyelonephritis
In the treatment of:
Otitis media
Sinusitis
Pharyngitis
The use of Cefixime should be reserved for infections where the causative organism is known or
suspected to be resistant to other commonly used antibiotics, or where treatment failure may carry
significant risk.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2
Posology and method of administration
Adults and children over 10 years of age (body weight is greater than 50 kg)
The recommended dose is 200-400 mg daily according to the severity of the infection, given either as a
single dose or in two divided doses.
Elderly patients
Elderly patients may be given the same dose as recommended for adults. Renal function should be
assessed and dosage should be adjusted in severe impairment (See dosage for renal impairment and
section 4.4).
Children younger than 10 years of age (body weight is lower than 50 kg) – Paediatric Oral
Suspension
The recommended dosage for children is 8 mg/kg/day administered as a single dose or in two divided
doses. As a general guide for prescribing in children the following daily doses in terms of quantity and
volume of paediatric oral suspension are suggested:
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Weight (kg)/Age
6 months upto 1 year
Children aged 1 – 4 years
Daily dose (mg)
75 mg
100 mg
Daily dose (ml)
3.75 ml
5 ml
Children aged 5 – 10 years
200 mg
10 ml
Children weighing more than 50 kg or older than 10 years should be treated with the recommended
adult dose (200 -400 mg daily), depending on the severity of the infection.
Children younger than 6 months of age
The safety and efficacy of cefixime has not been established in children less than 6 months.
Renal impairment
Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule
may be given in patients with creatinine clearance of 20 ml/ min or greater. In patients whose
creatinine clearance is less than 20 ml/min, it is recommended that a dose of 200 mg once daily should
not be exceeded. The dose and regimen for patients who are maintained on chronic ambulatory dialysis
or haemodialysis should follow the same recommendation as that for patients with creatinine clearance
of less than 20 ml/min.
Method of administration
Cefixime powder for oral suspension is for oral administration only.
The absorption of cefixime is not significantly affected by the presence of food. Hence it can be
administered with or without food.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
Duration of treatment
The usual course of treatment is 7 days. In severe cases, this can be extended to 14 days.
4.3
Contraindications
Patients with known hypersensitivity to cefixime, other cephalosporin antibiotics or to any of the
excipients.
Cefixime is also contraindicated in patients with previous, immediate and/or severe hypersensitivity to
penicillin or any beta-lactam antibiotics and preterm and term newborn infants (0-27 days).
4.4
Special warnings and precautions for use
Cefixime should be given with caution to patients who have shown hypersensitivity to other drugs.
Cephalsporins should be given with caution to penicillin-sensitive patients, as there is some evidence
of partial cross-allerginicity between penicillin and cephalsporins.
Patients have had severe reactions (including anaphylaxis) to both classes of drugs. Special care is
indicated in patients who have experienced any allergic reaction to penicillins or any beta-lactam
antibiotics as cross-reactions may occur (see section 4.3).
If severe hypersensitivity reactions or anaphylactic reactions occur after administration of Cefixime,
the medicine should be discontinued immediately and appropriate emergency measures should be
initiated.
Prolonged use of cefixime may result in the overgrowth of non-susceptible organisms.
Treatment with a broad spectrum of antibiotics alters the normal flora of the colon and may permit the
overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary
cause for antibiotic-associated diarrhoea. Pseudomembranous colitis is associated with the use of
broad-spectrum antibiotics (including macrolides, semi-synthetic penicillins, lincosamides and
cephalsporins). It is therefore important to consider its diagnosis in patients who develop diarrhoea in
association with the use of antibiotics.
In patients who develop severe diarrhoea during or after use of cefixime, the risk of life threatening
pseudo-membranous colitis should be taken into account (see section 4.8). The use of cefixime should
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
be discontinued and appropriate treatment measures should be established. Management of
pseudomembranous colitis should include sigmoidoscopy, appropriate bacteriologic studies, fluids,
electrolyte and protein supplementation. If the colitis does not improve after the drug has been
discontinued or if the symptoms are severe, oral vancomycin is the drug of choice for antibioticassociated pseudomembreanous colitis produced by C. Difficile. Other causes of colitis should be
excluded. The use of medicinal products inhibiting the intestinal peristalsis is contra-indicated.
Cefixime contains sucrose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use of Nifedipine, a calcium channel blocker, may increase bioavailability of Cefixime upto 70%.
Renal insufficiency
Cefixime should be administered with caution in adult patients with creatinine clearance <20ml/min
(see sections 4.2 and 5.2). There are insufficient data regarding use of cefixime in the pediatric and
adolescent age group in the presence of renal insufficiency: the use of cefixime in these patient-groups
is not recommended.
4.5
Interaction with other medicinal products and other forms of interaction
The administration of cephalsporins may interfere with the results of some laboratory tests.
A false positive reaction for glucose in the urine may occur with the Benedict’s or Fehling’s solutions
or with copper sulphate test tablets, but not with tests based on enzymatic glucose oxidase reactions.
A false positive direct Coombs’test has been reported during treatment with cephalosporin antibiotics,
therefore it should be recognised that a positive Coombs’ test may be due to the drug.
In common with other cephalsporins, increases in prothrombin times have been noted in a few patients.
Care should therefore be taken in patients receiving anticoagulation therapy.
In use with Nifedipine, a calcium channel blocker, may increase bioavailability of Cefixime upto 70%.
4.6
Fertility, pregnancy and lactation
Pregnancy
For cefixime, no clinical data on exposed pregnancies are available. Animal studies do not indicate
direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition
or postnatal development (see section 5.3).
Caution should be exercised when prescribing to pregnant women. Cefixime should not be used in
pregnant mothers unless considered essential by the physician.
Breast-feeding
It is unknown whether cefixime is excreted in human milk and non-clinical studies have shown
excretion of cefixime in animalmilk. A decision on whether to continue/discontinue breast-feeding or
to continue/discontinue therapy with cefixime should be made taking into account the benefit of breastfeeding to the child and the benefit of cefixime therapy to the woman. However, until further clinical
experience is available, cefixime should not be prescribed to breast-feeding mothers.
Fertility
Animal studies do not indicate any harmful effects with respect to fertility, however, no clinical data
are available
4.7
Effects on ability to drive and use machines
Cefixime has no known influence on the ability to drive and use machines. However, side effects may
occur (see section 4.8), which may influence the ability to drive and use machines.
4.8
Undesirable effects
Cefixime, like other cephalsporin antibiotics, may be associated with adverse events.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following undesirable effects have been divided in the following categories:
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
Very common:
Common:
Uncommon:
Rare:
Very rare:
Not known:
>1/10
>1/100 to <1/10
>1/1,000 to <1/100
>1/10,000 to <1/1,000
<1/10,000
cannot be estimated from the available data
MedDRA System Organ Class
Infections and infestations
Blood and lymphatic system
disorders
Immune system disorders
Metabolism and nutrition
disorders
Nervous system disorders
Gastrointestinal disorders
Hepatobiliary disorders
Skin and subcutaneous
disorders
Renal and urinary disorders
General disorders and
administration site conditions
Investigations
4.9
UK/H/2828/001/DC
Adverse Reaction
Superinfection bacterial,
superinfection fungal
Antibiotic-associated colitis (see
section
Eosinophilia
Leucopenia, agranulocytosis,
pancytopenia, thrombocytopenia,
haemolytic anaemia
Hypersensitivity
Anaphylactic shock, serum
sickness
Anorexia
Frequency
Rare
Very rare
Rare
Very rare
Rare
Very rare
Rare
Headache
Vertigo, dizziness
Psychomotor hyperactivity
Diarrhoea
Abdominal pain, nausea,
vomiting
Flatulence
Cases of pseudomembraneous
colitis
Hepatitis, cholestatic jaundice
Rash
Angioneurotic oedema, pruritus
Stevens-Johnson Syndrome, toxic
epidermal necrolysis, Lyell
syndrome
Interstitial nephritis
Mucosal inflammation, pyrexia
Uncommon
Rare
Very rare
Common
Uncommon
Hepatic enzyme increased
(transaminase, alkaline
phosphatase)
Blood urea increased
Blood creatinine increased
Uncommon
Rare
Very rare
Very rare
Uncommon
Rare
Very rare
Very rare
Rare
Rare
Very rare
Overdose
There is no experience with overdoses with Cefixime.
Adverse reactions seen at dose levels up to 2 g of cefixime in normal subjects did not differ from the
profile seen in patients treated at the recommended doses. Gastric lavage may be indicated in
overdosage. No specific antidote exists. Cefixime is not removed from the circulation in significant
quantities by dialysis.
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5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: antibacterial for systemic use, belonging to the class of cephalsporins,
ATC code: J01DD08.
Mode of action
Cefixime is an antibiotic belonging to the third generation cephalosporin group.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Like other cephalsporins, cefixime exerts antibacterial activity by binding to and inhibiting the action
of penicillin-binding proteins involved in the synthesis of bacterial cell walls. This leads to bacterial
cell lysis and cell death.
PK/PD Relationship
The time that the plasma concentration of cefixime exceeds the MIC of the infecting organism has
been shown to best correlate with efficacy in PK/PD studies.
Mechanism of resistance
Bacterial resistance to cefixime may be due to one or more of the following mechanisms:
•
•
•
•
Hydrolysis by extended-spectrum beta-lactamases and/or by chromosomally-encoded (AmpC)
enzymes that may be induced or de-repressed in certain aerobic gram- negative bacterial species
Reduced affinity of penicillin-binding proteins
Reduced permeability of the outer membrane of certain gram-negative organisms restricting access to
penicillin-binding proteins
Drug efflux pumps
More than one of these mechanisms of resistance may co-exist in a single bacterial cell. Depending on
the mechanism(s) present, bacteria may express cross-resistance to several or all beta-lactams and/or
antibacterial drugs of other classes.
Breakpoints
Clinical minimum inhibitory concentration (MIC) breakpoints established by EUCAST (May 2009) for
cefixime are:
Breakpoints (MIC, mg/L)
Microorganism Susceptible (≤)
Susceptible (≤)
Resistant (>)
Haemophilus influenzae
0.12 mg/L
0.12 mg/L
Moraxella catarrhalis
0.5 mg/L
1.0 mg/L
Neisseria gonorrhoeae
0.12 mg/L
0.12 mg/L
Enterobacteriaceae
1.0 mg/L
1.0 mg/L
Enterobacteriaceae: For uncomplicated urinary tract infections only. The breakpoints for
Enterobacteriaceae will detect reduced susceptibility mediated by most clinically
important beta-lactamases in Enterobacteriaceae. Occassional ESBL-producing strains will
be reported susceptible. For purposes of infection control, epidemiology and surveillance,
laboratories may wish to use specific tests to screen for and confirm ESBL-production.
Non-species related breakpoints
Insufficient data
Susceptibility
The prevalence of resistance may vary geographically and over time for selected species and local
information on resistance is desirable, particularly when treating severe infections. As necessary,
expert advice should be sought when local prevalence if resistance is such that the utility of the agent
in at least some types of infections is questionable.
Category 1: Commonly Susceptible organisms
Aerobes, Gram-positive
Streptococcus pneumoniae (penicillin-susceptible)
Streptococcus pyogenes
Aerobes, Gram-negative
Escherichia Coli%
Haemophilus influenzae
Klebsiella species%
Morexella catarrhalis
Proteus mirabilis%
Category 2: Organisms for which acquired resistance may be problematic
Enterobacter species
Category 3: Resistant organisms
Clostridium difficile
Bacteroides fragilis
Enterococci
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Pseudomonas species
Staphylococcus aureus+
Streptococcus pneumoniae (Penicillin resistant)
% Extended spectrum beta-lactamase (ESBL) producing isolates are always resistant
+ Cefixime has poor activity against staphylococci (regardless of susceptibility to
methicillin)
5.2
Pharmacokinetic properties
Absorption
The absolute bioavailability of cefixime is in the range of 22-54%. Absorption is not significantly
modified by the presence of food. Cefixime may therefore be given without regard for meals.
Distribution
Serum protein binding is well characterised for human and animal sera; cefixime is almost exclusively
bound to the albumin fraction, the mean free fraction being approximately 30%. Protein binding of
cefixime is only concentration dependent in human serum at very high concentrations which are not
seen following clinical dosing.
From in vitro studies, serum or urine concentrations of 1 mg/L or greater were considered to be
adequate for most common pathogens against which cefixime is active. Typically, the peak serum
levels following the recommended adult or paediatric doses are between 1.5 and 3 mg/L. Little or no
accumulation of cefixime occurs following multiple dosing.
Metabolism and elimination
Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is
considered the predominant mechanism. Metabolites of cefixime have not been isolated from human
serum or urine.
Transfer of 14C-labelled cefixime from lactating rats to their nursing offspring through breast milk was
quantitatively small (approximately 1.5% of the mothers' body content of cefixime in the pup). No data
are available on secretion of cefixime in human breast milk. Placental transfer of cefixime was small in
pregnant rats dosed with labelled cefixime.
Special age groups
The pharmacokinetics of cefixime in healthy elderly (aged > 64 years) and young volunteers (11-35)
compared the administration of 400 mg doses once daily for 5 days. Mean Cmax and AUC values were
slightly greater in the elderly. Elderly patients may be given the same dose as the general population
(see section 4.2).
5.3
Preclinical safety data
There are no findings from chronic toxicity investigations suggesting that any side effects unknown to
date could occur in humans. Furthermore, in vivo and in vitro studies did not yield any indication of a
potential to cause mutagenicity. Long-term studies on carcinogenicity have not been conducted.
Reproduction studies have been performed in mice and rats at does up to 400 times the human dose
and have revealed no evidence of impaired fertility or harm to the foetus due to cefixime. In the rabbit,
at doses up to 4 times the human dose, there was no evidence of a teratogenic effect; there was a high
incidence of abortion and maternal death, which is an expected consequence of the known
hypersensitivity of rabbits to antibiotic-induced changes in the population of the microflora of the
intestine.
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6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Xanthum gum
Sodium benzoate
Silica colloidal, anhydrous
Sucrose
Flavour strawberry (maltodextrin, triethyl acetate –E1505, propylene glycol – E1520)
6.2
Incompatibilities
Not applicable.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
6.3
Shelf life
Unopened: 2 years. Do not store above 25oC.
After reconstitution: The reconstituted suspension may be stored for 14 days below 25oC.
6.4
Special precautions for storage
Unopened: This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted medicinal product, see section 6.3.
After reconstitution, the suspension can be stored below 25º C for 14 days without significant loss of
potency. Do not freeze. Keep bottles tightly closed and shake well before use. Discard any unused
portion after 14 days. Dilution of the suspension is not recommended.
6.5
Nature and contents of container
Nature of container: Type III molded, amber coloured, round glass bottle with 100ml ring mark and
with a plastic child resistant cap with induction seal liner.
Contents of container: Bottle of size 100 ml.
Bottles are supplied with a single 5 ml plastic dosing pipette (plunger, barrel and piston).
6.6
Special precautions for disposal
Instructions for the preparation of the oral suspension:
Cefixime 100 mg/5 ml Powder for
Oral Suspension
Bottle size
Directions for Reconstitution
100 mg/ 5 ml
100 ml
Add 68 ml of water in two portions to the
dry mixture in the bottle. Shake well after
each addition.
Any unused product or waste material should be disposed of in accordance with local requirements.
7
MARKETING AUTHORISATION HOLDER
Generics [UK] Ltd t/a Mylan
Station Close,
Potters Bar,
EN6 1AG
United Kingdom
8
MARKETING AUTHORISATION NUMBER(S)
PL 04569/0118
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
06/09/2011
10
DATE OF REVISION OF THE TEXT
06/09/2011
AUTHORISATION
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Module 3
Product Information Leaflet
The text version of the PIL was provided and approved as part of this application. In accordance with medicines legislation,
this product shall not be marketed in the UK until the PIL mock-up has been submitted to and approved by the competent
authority.
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Module 4
Labelling
The text version of the labelling has been provided and approved as part of this application. No label mock-ups
have been provided. In accordance with medicines legislation, this product shall not be marketed in the UK until
approval of the label mock-ups has been obtained.
Carton
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Module 5
Scientific discussion during initial procedure
I
INTRODUCTION
On 3 August 2011, Italy and the UK agreed to grant a Marketing Authorisation (MA) to
Generics (UK) Limited for the medicinal product Cefixime 100 mg/5 mL Powder for Oral
Suspension. The MA was granted via a Decentralised Procedure (DCP), with the UK as
Reference Member State (UK/H/2828/001/DC). After the national phase, a licence was
granted in the UK on 6 September 2011 (PL 04569/1118).
This is a generic application for Cefixime 100 mg/5 mL Powder for Oral Suspension,
submitted under Article 10.1 of Directive 2001/83/EC, as amended. The application refers to
Suprax Powder Paediatric 100 mg/5 mL Powder for Oral Suspension, first authorised to
Sanofi-Aventis Ireland Ltd in Ireland on 5 January 1989. The period of exclusivity has
expired.
Cefixime is an oral third-generation cephalosporin. It exerts its bactericidal effect by
attaching to penicillin-binding proteins and inhibiting peptidoglycan synthesis, thus causing
damage to the bacterial cell wall. Cefixime has marked in-vitro bactericidal activity against
a wide variety of gram-positive and gram-negative organisms.
It exhibits a broad spectrum of antibacterial activity with minimum inhibitory concentrations
similar to or less than those for other oral cephalosporins against many Gram-negative and
Gram-positive microorganisms. It is approved for the treatment of upper and lower
respiratory tract infections and urinary tract infections.
No new non-clinical or clinical efficacy studies were conducted for this application, which is
acceptable given that the application was for a generic version of a product that have been
licensed for over 10 years.
The application is supported by a bioequivalence study comparing the pharmacokinetic
profile of the test product, Cefixime 100 mg/5 mL Powder for Oral Suspension, to that of the
reference product, Suprax powder for Paediatric Oral Suspension (Sanofi-Aventis). The
bioequivalence study was carried out in accordance with Good Clinical Prcatice (GCP).
The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP)
are in place for these product types at all sites responsible for the manufacture and assembly
of these products. Evidence of compliance with GMP has been provided for the named
manufacturing and assembly sites. For manufacturing sites within the Community, the RMS
has accepted copies of current manufacturer authorisations issued by inspection services of
the competent authorities as certification that acceptable standards of GMP are in place at
those sites.
For manufacturing sites outside the community, the RMS has accepted copies of current
GMP certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange
of information’ issued by the inspection services of the competent authorities (or those
countries with which the EEA has a Mutual Recognition Agreement for their own territories)
as certification that acceptable standards of GMP are in place at those non-Community sites.
The RMS considers that the pharmacovigilance system, as described by the MAH, fulfils the
requirements and provides adequate evidence that the MAH has the services of a qualified
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
person responsible for pharmacovigilance and has the necessary means for the notification of
any adverse reaction suspected of occurring either in the Community or in a third country.
The Marketing Authorisation Holder has provided adequate justification for not submitting a
Risk Management Plan (RMP). As the application is for a generic version of an already
authorised reference product, for which safety concerns requiring additional risk
minimisation have not been identified, a risk minimisation system is not considered
necessary. The reference product has been in use for many years and the safety profile of the
active substances is well established.
The Marketing Authorisation Holder has provided adequate justification for not submitting
an Environmental Risk Assessment (ERA). This was an application for a generic product and
there is no reason to conclude that the marketing of this product will change the overall use
pattern of the existing market.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
II.
UK/H/2828/001/DC
ABOUT THE PRODUCT
Name of the product in the Reference Member
State
Name(s) of the active substance(s) (INN)
Pharmacotherapeutic classification
(ATC code)
Pharmaceutical form and strength(s)
Reference numbers for the Decentralised
Procedure
Reference Member State
Member States concerned
Marketing Authorisation Number(s)
Name and address of the
authorisation holder
Cefixime 100mg/5ml Powder for oral suspension
Cefixime
J01DD08 (Third generation Cephalosporin)
Powder for oral suspension
100mg/5ml
UK/H/2828/001/DC
United Kingdom
Italy
PL 04569/1118
Generics (UK) Limited
Station Close
Potters Bar, Hertsfordshire EN6 1TL UK
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
III
SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 QUALITY ASPECTS
DRUG SUBSTANCE
Cefixime
INN: Cefixime
Chemical name:
(6R, 7R0-7-[[(2Z)-(2-amino-4thioazolyl)[(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboylic acid.
Structure:
Molecular formula:
C16H15N5O7S2.3H20
Molecular weight:
507.5
General Properties
Description:
A white or almost white powder, slightly hygroscopic.
Solubility:
Soluble in methanol, slightly soluble in water and ethanol and practically insoluble in ethyl
acetate.
Cefixime is the subject of a European Pharmacopoeia (Eur Ph.) monograph.
Manufacture
All aspects of the manufacture and control of the active substance cefixime are covered by a
European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.
DRUG PRODUCT
Description and Composition
Cefixime 100 mg/5 mL Powder for Oral Suspension is presented as off-white to pale yellow
coloured powder with characteristic odour and gives a cream colour to pale yellow coloured
viscous suspension after reconstitution with water. Each 5 mL of reconstituted suspension
contains 111.917 mg of cefixime trihydrate equivalent to 100 mg of the active ingredient,
cefixime (anhydrous).
Other ingredients consist of the pharmaceutical excipients, xanthum gum, sodium benzoate,
silica colloidal, anhydrous, sucrose and flavour strawberry (maltodextrin, triethyl acetateE1505, propylene glycol-E1520). All the ingredients in the tablets comply with their relevant
Ph.Eur monographs with the exception of the strawberry flavour which complies with an inhouse specification which is satisfactory.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Appropriate justification for the inclusion of each of the excipients has been provided.
Satisfactory Certificates of Analysis for each of the excipients have been presented. The
applicant has provided a declaration confirming that there are no materials of human or
animal origin contained in the product, or used in the manufacturing process. Furthermore, no
genetically modified organisms are used in the manufacture of the excipients.
Pharmaceutical Development
Details of the pharmaceutical development of the medicinal product have been supplied and
are satisfactory. The aim was to develop a stable, robust, generic dosage form of Cefixime
100 mg/5 mL Powder for Oral Suspension, which is pharmaceutically equivalent to the
reference product Suprax 100 mg/5 mL Powder for Oral Suspension (Sanofi-Aventis).
Comparative dissolution data were provided for bio-batches of the test and reference
products. The dissolution profiles were satisfactory.
Manufacture
A description and flow-chart of the manufacturing method has been provided.
In-process controls are appropriate considering the nature of the product and the method of
manufacture. Process validation studies have been conducted on two pilot-scale batches and
the results were satisfactory. The validation data demonstrated consistency of the
manufacturing process. A commitment has been made by the MAH that full process
validation will be conducted on commercial scale batches in accordance with the process
validation protocol.
Finished Product Specification
Finished product specifications are provided for both release and shelf–life, and are
satisfactory. These provide an assurance of the quality and consistency of the finished
product. Acceptance limits have been justified with respect to conventional pharmaceutical
requirements and, where appropriate, safety. Test methods have been described and
adequately validated, as appropriate. Batch data are provided, which comply with the release
specifications. Certificates of Analysis have been provided for all working standards used.
Container Closure System
The finished product is licensed for marketing in Type III moulded, amber coloured, round
glass bottles with 100 mL ring mark and with a plastic child resistant cap with induction seal
liner. Each bottle is supplied with a single 5 mL plastic dosing pipette (plunger, barrel and
piston) and packed with the Patient Information Leaflet (PIL) into a cardboard outer carton.
Satisfactory specifications and Certificates of Analysis for all packaging components used
have been provided. . All primary product packaging complies with EU legislation, Directive
2002/72/EC (as amended), and is suitable for contact with foodstuffs. The glass components
used have been provided. The glass bottles comply with Ph Eur requirements and are suitable
for contact with oral solution products; the caps comply with child resistant packaging
legislation.
Stability
Finished product stability studies have been conducted in accordance with current guidelines
and results were within the proposed specification limits. Based on the results, a shelf-life of
2 years has been set, when the bottle is unopened, which is satisfactory. The storage
conditions are ‘Do not store above 25oC’.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
An ‘in-use’ product stability study was carried out on Cefixime 100 mg/5 mL Powder for
Oral Suspension to establish the time period over which the product could be used after the
bottle has been opened. Please refer to Section 6.3 and 6.4 for shelf-life and storage
conditions of the product after reconstitution.
Quality Overall Summary
A satisfactory quality overview is provided and has been prepared by an appropriately
qualified expert. The curriculum vitae of the expert has been provided.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),
Labels
The SmPC, PIL and labelling are acceptable from a pharmaceutical perspective. The
labelling is satisfactory and fulfils the statutory requirements for Braille. Text versions of the
PILs and labels have been provided and are satisfactory. In accordance with medicines
legislation, the Marketing Authorisation Holder (MAH) has provided a commitment that the
product shall not be marketed in the UK until approval of the PIL and label mock-ups has
been obtained.
The applicant has submitted results of PIL user testing. The results indicate that the PIL is
well-structured and organised, easy to understand and written in a comprehensive manner.
The test shows that the patients/users are able to act upon the information that it contains.
MAA Form
The MAA forms are satisfactory from a pharmaceutical perspective.
Conclusion
The test product has been demonstrated to be equivalent pharmaceutically to the reference
product, which has been licensed in the UK for over 10 years.
There are no objections to the approval of Cefixime 100 mg/5 mL Powder for Oral Solution
from a pharmaceutical point of view.
III.2 NON-CLINICAL ASPECTS
Pharmacodynamic, pharmacokinetic and toxicological properties of cefixime are well known.
As this is a widely used, well-known active substance, the applicant has not provided
additional studies and further studies are not required. Overview based on literature review
is, thus, appropriate.
Environmental risk assessment
No formal Environmental Risk Assessment has been provided. The applicant has justified
the absence adequately. As a generic product, the use of this product is not expected to
increase the overall use of cefixime and so no additional increase in environmental risk has
been identified.
Non-Clinical Overview
The non-clinical overview was written by a suitably qualified person and is satisfactory. The
curriculum vitae of the expert has been provided.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Summary of Product Characteristics (SmPC)
Section 4.6 and 5.3 are satisfactory from a non-clinical viewpoint.
There are no objections to approval of Cefixime 100 mg/5 mL Powder for Oral Suspensiont
from a non-clinical point of view.
III.3
CLINICAL ASPECTS
Indications
Cefixime 100 mg/5 mL Powder for Oral Suspension is indicated in the treatment of:
• infection of the middle ear
• sinus infection
• throat infection
• infection causing sudden worsening of long-standing bronchitis
• serious lung infections (such as pneumonia) acquired outside hospital
• urinary tract infections
• kidney infection
The indications are in-line with thos for the reference product and are satisfactory.
Posology and Method of Administration
The recommended dose in adults and children over 10 years of age (body weight greater than
50kg) is 200-400 mg daily according to the severity of the infection, given either as a single
dose or in two divided doses. For elderly patients and children younger than 10 years the
dose may vary and details these patients can be found in the SmPC.
Full details concerning the posology are provided in the SmPC. The posology is consistent
with that for the reference product and is satisfactory.
Pharmacokinetics- bioequivalence study
The application is supported by the bioequivalence study presented by the applicant
comparing the pharmacokinetic profile of the test product, Cefixime 100 mg/5 mL
Powder for Oral Suspension, to that of the reference product, Suprax Powder for
Paediatric Oral Suspension (Sanofi-Aventis). The tudy was of an appropriate design and
was conducted to principles of Good Clinical Practice (GCP). Certificates of Analysis
were provided for both the test and reference products. The UK reference product,
Suprax Powder for Paediatric Oral Suspension (Sanofi-Aventis) is considered to be
equivalent to the originator and clinical reference product Suprax Powder for Paediatric
100mg/5 mL (Sanofi-Aventis Ireland Ltd).
This was a randomised open label, two treatment, two period, two sequence, single dose
crossover bioequivalence study conducted in adult male subjects under fasting conditions. A
single dose of the investigational products was administered orally to each subject in each
period. A satisfactory washout period of 7 days was maintained between the dosing days in
each group.
Blood samples were taken pre-dose (0.0) and at specified time points up to 24 hours after
administration of test or reference product. Plasma levels of cefixime were quanitifed by a
validated LC-MS/MS method.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
The primary pharmacokinetic parameters for this study were Cmax, AUC0-t and AUC0-∞.
Bioequivalence of the test product versus the reference product was concluded if the 90%
Confidence Intervals (CI) fell within the acceptance range, 0.80-1.25 (80.00%-125.00%), for
log-transformed Cmax, AUC0-t and AUC0-∞ for cefixime.
Results
The summary of the results of the bioequivalence study are tablulated below:
Conclusions on Bioequivalence
The results of the bioequivalence study show that the test and reference products are
bioequivalent under fasting conditions, as the confidence intervals for Cmax, AUC0-t and
AUC0-∞ for cefixime fall within the acceptance criteria ranges of 80.00-125.00% under
fasting condition, in line with current guidelines.
Clinical Efficacy
No new data have been submitted and none are required. The reference products are
established and the applications depend upon the ability to demonstrate bioequivalence.
Efficacy is reviewed in the clinical overview. The efficacy of cefixime is well-established
from its extensive use in clinical practice.
Clinical safety
No new data have been submitted and none are required for an application of this type. No
new or unexected safety concerns arose from this application. Safety is reviewed in the
clinical overview. The safety profile of cefixime is well-known.
Expert Report
A satisfactory clinical overview is provided, and has been prepared by an appropriately
qualified physician. The curriculum vitae of the expert has been provided.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),
Labels
Summary of Product Characteristics (SmPC)
The approved SmPC is consistent with that of the UK reference product and is acceptable.
Patient Information Leaflet (PIL)
The final PIL text is in line with the approved SmPC and is satisfactory. The PIL user-testing
has been evaluated and is accepted.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
Labelling
The labelling text is satisfactory.
Clinical overview
A satisfactory clinical overview is provided and has been prepared by an appropriately
qualified expert. The CV of the clinical expert has been supplied.
MAA form
The MAA form is satisfactory.
Conclusion
There are no objections to the approval of Cefixime 100 mg/5 mL powder for Oral
Suspension from a clinical point of view.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
UK/H/2828/001/DC
IV
OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT
QUALITY
The important quality characteristics of Cefixime 100 mg/5 mL Powder for Oral Suspension
are well-defined and controlled. The specifications and batch analytical results indicate
consistency from batch to batch. There are no outstanding quality issues that would have a
negative impact on the benefit/risk balance.
NON-CLINICAL
No new non-clinical data were submitted and none are required for an application of this
type.
EFFICACY
Bioequivalence has been demonstrated between the applicant’s Cefixime 100 mg/5 mL
Powder for Oral Suspension and the reference product Suprax Powder Paediatric
100 mg/5 mL Powder for Oral Suspension (Sanofi-Aventis Ireland Limited). The UK
reference product, Suprax Powder Paediatric 100 mg/5 mL Powder for Oral Suspension, is
considered to be equivalent tot eh originator and clionical reference product, Suprax Powder
Paediatric 100 mg/5 mL Powder for Oral Suspension (Sanofi-Aventis- PL 00012/0318).
No new or unexpected safety concerns arose from this application.
PRODUCT LITERATURE
The SmPC and PIL are acceptable, and consistent with those for the reference product. The
labelling is acceptable and in-line with current requirements.
A package leaflet has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The results show that the
package leaflet meets the criteria for readability as set out in the Guideline on the readability
of the label and package leaflet of medicinal products for human use.
The approved labeling text is satiactory and fulfils the stautory requirements for Braille.
The MAH has submitted text versions only for the PIL and labeling and has committed to
submitteing mock-up livery to the reevant regulatory authorities for approval before packs
are marketed.
BENEFIT/RISK ASSESSMENT
The quality of the product is acceptable, and no new non-clinical or clinical safety concerns
have been identified. The bioequivalence study and its conclusions support the claim that the
applicant’s Cefixime 100 mg/5 mL Powder for Oral Suspension is a generic version of the
reference product uprax Powder Paediatric 100 mg/5 mL Powder for Oral Suspension
(Sanofi-Aventis Ireland Limited). Extensive clinical experience with cefixime is considered
to have demonstrated the therapeutic value of the active substances. The benefit/risk ratio is
therefore considered to be positive.
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PAR Cefixime 100 mg/5 mL Powder for Oral Suspension
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Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date
submitted
Application
type
Scope
Outcome
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