Document 6471427

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Document 6471427

UKPAR Levofloxacin 250mg and 500mg Film-coated Tablets
PL 24668/0102-5
LEVOFLOXACIN 250MG FILM-COATED TABLETS
PL 24668/0102 and 0104
PL 24668/0103 and 0105
UKPAR
TABLE OF CONTENTS
Lay Summary
Page 2
Scientific discussion
Page 3
Steps taken for assessment
Page 13
Steps taken after authorisation – summary
Page 14
Summary of Product Characteristics
Page 15
Product Information Leaflet
Page 16
Labelling
Page 17
Annex 1
Page 30
1
PL 24668/0102-5
PL 24668/0102 & 0104
PL 24668/0103 & 0105
LAY SUMMARY
On 8th January 2010, the MHRA granted Caduceus Pharma Limited Marketing Authorisations (licences)
for the medicinal products Levofloxacin 250mg and 500mg Film-coated tablets (PL 24668/0102-5).
These are prescription-only medicines.
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class.
Levofloxacin is used to treat infections caused by bacteria against which the medicine is active.
Infections which the tablets can be used to treat include infections of the sinuses, infection of the lungs,
urinary tract infections, skin infections and infection of the prostate.
No new or unexpected safety concerns arose from these applications and it was, therefore, judged that
the benefits of taking Levofloxacin 250mg and 500mg Film-coated tablets outweigh the risks. Hence
Marketing Authorisations have been granted.
A subsequent Change of Ownership (CoA) was granted for Levofloxacin 250mg and 500mg
Film-coated tablets (PL 24668/104-105) on 26 May 2012, to change the Marketing Authorisation Holder
to Aptil Pharma Limited (PL 40378/0019-0020).
2
PL 24668/0102-5
PL 24668/0102 & 0104
PL 24668/0103 & 0105
SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
Introduction
Page 4
Pharmaceutical assessment
Page 5
Preclinical assessment
Page 8
Clinical assessment (including statistical assessment)
Page 9
Overall conclusion and risk benefit assessment
Page 12
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PL 24668/0102-5
INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the UK granted Marketing
Authorisations for the medicinal products Levofloxacin 250mg and 500mg Film-coated tablets (PL
24668/0102-5) on the 8th January 2010. These products are prescription-only medicines (POM).
These are National abridged complex and standard applications for Levofloxacin 250 mg and 500 mg
film coated tablets submitted under article 10 (1) of Directive 2001/83/EC, as amended. The application
claims the products to be generic medicinal products of Tavanic 250mg and 500mg, authorised to
Hoechst Marion Roussel, (PL 13402/0011-0012) in 1997.
Levofloxacin is the S-(-)-isomer of the fluoroquinolone antibacterial ofloxacin. Levofloxacin is generally
considered to be about twice as active as ofloxacin, the racemic substance. Usual doses range from 250
to 500 mg once or twice daily for 7 to 14 days depending on the severity and nature of the infection.
Levofloxacin is indicated for the following infections:
250mg
• Acute sinusitis
• Acute exacerbations of chronic bronchitis
• Community-acquired pneumonia
• Uncomplicated urinary tract infections
• Complicated urinary tract infections including pyelonephritis
• Chronic bacterial prostatitis.
• Skin and soft tissue infections.
500mg
• Acute sinusitis
• Acute exacerbations of chronic bronchitis
• Community-acquired pneumonia
• Complicated urinary tract infections including pyelonephritis
• Chronic bacterial prostatitis.
• Skin and soft tissue infections.
A subsequent Change of Ownership (CoA) was granted for Levofloxacin 250mg and 500mg Filmcoated tablets (PL 24668/104-105) on 26 May 2012, to change the Marketing Authorisation Holder to
Aptil Pharma Limited (PL 40378/0019-0020).
4
PL 24668/0102-5
PHARMACEUTICAL ASSESSMENT
DRUG SUBSTANCE
Nomenclature
rINN: Levofloxacin hemihydrate
Chemical names:
(-)-(s)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7Hpyrido[1,2,3-de]-1,4 benzoxazine-6-carboxylic acid hemihydrate.
Structure
Molecular formula: C18H20FN3O4.½H2O
Molecular Mass: 370.38
Physical Description: Light yellowish-white odourless powder.
Solubility: Sparingly soluble in methanol, aqueous solubility decreases with increase in pH
The drug substance is the subject of a European Drug Master File (EDMF). A letter of access has been
provided by the drug substance manufacturer.
Synthesis of the drug substance from the designated starting material has been adequately described and
appropriate in-process controls and intermediate specifications are applied. Satisfactory specifications
are in place for all starting materials and reagents and these are supported by relevant Certificates of
Analysis.
An appropriate specification based on the European Pharmacopoeia has been provided.
Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with
the relevant specifications.
Levofloxacin hemihydrate is stored in appropriate packaging. The specifications and typical analytical
test reports are provided and are satisfactory.
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PL 24668/0102-5
Batch analysis data are provided and comply with the proposed specification.
Satisfactory Certificates of Analysis have been provided for working standards used by the drug
substance manufacturer and finished product manufacturer during validation studies.
Appropriate stability data have been generated, supporting a suitable retest period when the drug
substance is stored in the packaging proposed.
DRUG PRODUCT
Other ingredients
Other ingredients consist of pharmaceutical excipients, namely colloidal anhydrous silicon dioxide,
titanium dioxide, silicified microcrystalline cellulose, copovidone, crospovidone, lactose monohydrate,
HPMC 2910 15CPS, sodium stearyl fumarate, glycerol triacetate, iron oxide red K 5609 and iron oxide
yellow 17268E172.
All excipients used comply with their respective European Pharmacopoeia monograph with the
exception of iron oxide red K 5609 and iron oxide yellow 17268E172 which complies with national
formulae. Satisfactory Certificates of Analysis have been provided for all excipients.
Confirmation has been given that the sodium stearyl fumarate used in the tablets is of vegetable origin.
Pharmaceutical development
Suitable pharmaceutical development data have been provided for these applications. Comparable
dissolution and impurity profile are provided for these products versus the originator product.
Manufacture
A description and flow-chart of the manufacturing method have been provided. In-process controls are
satisfactory based on process validation data and controls on the finished product. Process validation has
been carried out on batches of the product. The results appear satisfactory.
Finished product specification
The finished product specification is satisfactory. Test methods have been described and adequately
validated, as appropriate. Batch data have been provided and comply with the release specification.
Certificates of Analysis have been provided for any working standards used.
Container Closure System
Product is packaged in aluminium/PVC blister packs and HDPE container with LDPE lid. Specifications
and Certificates of Analysis for all packaging types used have been provided. These are satisfactory. All
primary product packaging complies with EU legislation regarding contact with food.
Stability
Finished product stability studies have been conducted in accordance with current guidelines. Based on
the results, a shelf-life of 2 years is set and this is acceptable.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling
The SmPC, PIL and labelling are pharmaceutically satisfactory.
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.
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PL 24668/0102-5
MAA Form
The MAA form is pharmaceutically satisfactory.
Expert Report
The pharmaceutical expert report is written by an appropriately qualified person and is a suitable
summary of the pharmaceutical aspects of the dossier.
Conclusion
It is recommended that Marketing Authorisations are granted for these applications.
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PL 24668/0102-5
PRECLINICAL ASSESSMENT
The pharmacodynamic, pharmacokinetic and toxicological properties of the product are well-known.
Thus, the applicant has not provided additional studies and further studies are not required.
A preclinical expert report has been provided, written by an appropriately qualified person. This is
satisfactory.
A suitable justification has been provided for non-submission of an Environmental Risk Assessment.
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PL 24668/0102-5
CLINICAL ASSESSMENT
TOXICOLOGY
No new preclinical data have been submitted and none are required for these applications.
CLINICAL PHARMACOLOGY
BIOEQUIVALENCE (STUDY NO.: 901/06)
A randomised, single dose, randomized, 2-period, 2-way crossover study to assess the pharmacokinetics
of the test product Levofloxacin 250mg Film-coated tablets versus the reference product Tavanic
250mg, in healthy fasted volunteers. 28 healthy male Indians with age range from 18 to 42 years were
included in the study. Inclusion and exclusion criteria were presented. All volunteers completed both
study phases. Subjects were housed in the clinical facility at the evening before drug administration until
24 hours after drug administration. Study drug was administered after an overnight fast with 240 ml
water. 21 blood samples were collected at 0, 0.25, 0.5, 0.67, 0.83, 1, 1.167, 1.33, 1.5, 1.75, 2, 2.25, 2.5,
3, 4, 6, 8, 12, 16, 24 and 36 hours post dose with washout period of 7 days between study periods.
One of the predose samples (period 2, Subject 7) contained levofloxacin (<5% of Cmax). One subject
(Subject 12) vomited 4 hours after administration of test product.
Results
All study subjects (n=28) completed both study phases and were included in statistical analysis.
Pharmacokinetic parameters for the Test product (A) and Reference product (B) are given below.
No significant differences were observed in mean Tmax values between test (1 h) and reference
(1.16 h).
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PL 24668/0102-5
Assessor' s Conclusion on Bioequivalence
Clinical part of the Bioequivalence study was conducted in line with EMEA current guidance.
Standard single dose BE study was conducted with 250 mg tablets. BE was shown based on point
estimates and 90%CI of the log-transformed PK parameters.
The applicant is seeking Marketing Authorisation for 250 mg and 500 mg strengths. Biowaiver to the
500 mg strength can be granted since the pharmacokinetics of levofloxacin is linear, pharmaceutical
composition of both strength is proportionally similar, both products are manufactured by the same
process and dissolution profiles with 250 mg and 500 mg were similar. According to the EMEA
guideline on the Investigation of BA &BE, a bioequivalence study with the highest strength should have
been conducted. The bioequivalence between the two formulations of 250mg products was demonstrated
with a very narrow CI. Biowaiver to the 500 mg could be considered therefore acceptable.
EFFICACY
No new efficacy data have been submitted and none are required for these applications.
SAFETY
No new safety data have been submitted and none are required for these applications.
EXPERT REPORT
A clinical expert report has been written by clinical consultant to the pharmaceutical industry. The report
is satisfactory.
SUMMARY OF PRODUCT CHARACTERISTICS (SmPC)
Clinically satisfactory
PATIENT INFORMATION LEAFLET
This is satisfactory
LABELLING
These are satisfactory.
MARKETING AUTHORISATION FORM
These are satisfactory.
10
PL 24668/0102-5
DISCUSSION
The applicant has conducted a bioequivalent study comparing the applicant’s product with the cross
referred medicinal product. The study has confirmed that both products are bioequivalent and therefore
would exhibit the same efficacy and safety profile.
CONCLUSION
The grant of Marketing Authorisations is recommended.
11
PL 24668/0102-5
OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of Levofloxacin 250mg and 500mg Film-coated tablets 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.
PRECLINICAL
No new preclinical data were submitted and none are required for applications of this type.
EFFICACY
No new data have been submitted and none are required for an application of this type.
Levofloxacin 250mg and 500mg Film-coated tablets are the generic versions of Tavanic 250mg and
500mg (Hoechst Marion Roussel). The use of the reference product is well-established in the UK. Both
products contain the same quantitative and qualitative composition of the active ingredients,
levofloxacin hemihydrate.
The 90% confidence intervals for the test/reference lie within the acceptance criteria specified in the
CPMP/EWP/QWP/1401/98 Notes for Guidance on the Investigation of Bioavailability and
Bioequivalence. Bioequivalence of the test product to the reference formulation has been satisfactorily
demonstrated in accordance with CHMP criteria.
No new safety data are supplied or required for these generic applications. Levofloxacin hemihydrate
have well-established side-effect profiles and are generally well-tolerated.
The SmPC, PIL and labelling are satisfactory.
RISK BENEFIT ASSESSMENT
The quality of the product is acceptable and no new preclinical or clinical safety concerns have been
identified. The bioequivalence study supports the claim that the applicant’s product and the innovator
product are interchangeable. Extensive clinical experience with Levofloxacin 250mg and 500mg
Film coated tablets is considered to have demonstrated the therapeutic value of the compound. The risk
benefit is, therefore, considered to be positive.
12
PL 24668/0102-5
PL 24668/0102 and 0104
PL 24668/0103 and 0105
STEPS TAKEN FOR ASSESMENT
1
The MHRA received the Marketing Authorisation applications on 8th August
2007
2
Following standard checks and communication with the applicant the MHRA
considered the applications valid on 29th October 2007
3
Following assessment of the applications the MHRA requested further
information relating to the quality dossier on 31st October 2008.
4
The applicant responded to the MHRA’s requests, providing further information
to the quality section on 13th March 2009
5
The applications were determined on 8th January 2010
13
PL 24668/0102-5
PL 24668/0102 and 0104
PL 24668/0103 and 0105
STEPS TAKEN AFTER AUTHORISATION – SUMMARY
The following table lists a non-safety update to the Marketing Authorisations for Levofloxacin 250mg
and 500mg Film coated tablets (PL 40378/0019-0020 previously PL 24688/0104-0105) that has been
approved by the MHRA since the products were first licensed. The table includes an update that has
been added as an annex to this PAR. This is not a complete list of the post-authorisation changes that
have been made to these Marketing Authorisations.
Date
Application
submitted type
Scope
Outcome
27
January
2014
To update sections 4
(Clinical particulars) and 5
(Pharmacological properties)
of the Summary of Product
Characteristics (SmPC) and,
consequentially, the Patient
Information Leaflet (PIL) in
line with the outcome of
Article 30 referral.
Approved 06 March
2014
Type 1B
14
PL 24668/0102-5
Summary of Product Characteristics
In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for
products granted Marketing Authorisations at a national level are available on the MHRA website.
15
PL 24668/0102-5
PATIENT INFORMATION LEAFLET
In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted
Marketing Authorisations at a national level are available on the MHRA website.
16
PL 24668/0102-5
LABELLING
The following text is the approved label text. No label mock-ups have been provided. In
accordance with medicines legislation, the products shall not be marketed in the UK until
approval of the label mock-ups has been obtained
17
PL 24668/0102-5
18
PL 24668/0102-5
19
PL 24668/0102-5
20
PL 24668/0102-5
21
PL 24668/0102-5
22
PL 24668/0102-5
23
PL 24668/0102-5
24
PL 24668/0102-5
25
PL 24668/0102-5
26
PL 24668/0102-5
27
PL 24668/0102-5
28
PL 24668/0102-5
Annex 1
Our Reference:
Product:
Marketing Authorisation Holder:
Active Ingredient(s):
PL 40378/0019, Application 12
Levofloxacin 250 mg film-coated tablets
Aptil Pharma Limited
Levofloxacin hemihydrate
Type of Procedure:
Submission Type:
Submission Category:
Submission Complexity:
EU Procedure Number (if applicable):
National
Variation
Type IB
Standard
Reason:
To update sections 4 (Clinical particulars) and 5 (Pharmacological properties) of the Summary of
Product Characteristics (SmPC) and, consequentially, the Patient Information Leaflet (PIL) in line with
the outcome of Article 30 referral.
Linked / Related Variation(s) or Case(s):
The Assessment Report refers to the Collection ID 148625 and covers the following submissions
PL40378/0020, Application 0012.
Supporting Evidence
Revised SmPC fragments and the PIL have been provided.
Evaluation
Adequate clinical information has been provided.
The updated sections of the SmPC and the updated PIL are satisfactory.
Conclusion
The amendments to the SmPC and PIL are acceptable and there are no objections to approval.
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient
Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are
available on the MHRA website.
Decision – Approved 06 March 2014
29

Document 6471427

Transcription

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