panitaz 5, 10 and 20 micrograms/h transdermal patches
TRANSCRIPT
PAR Panitaz 5, 10 and 20 micrograms/h Transdermal Patches PL 08553/0564-0566
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Public Assessment Report
UKPAR
Panitaz 5 micrograms/h Transdermal Patches
Panitaz 10 micrograms/h Transdermal Patches
Panitaz 20 micrograms/h Transdermal Patches
(Buprenorphine)
UK Licence Number: PL 08553/0564-0566
Dr. Reddy’s Laboratories (UK) Ltd
.
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LAY SUMMARY Panitaz 5 micrograms/h Transdermal Patches
Panitaz 10 micrograms/h Transdermal Patches
Panitaz 20 micrograms/h Transdermal Patches
(Buprenorphine)
This is a summary of the Public Assessment Report (PAR) for Panitaz 5, 10 and 20 micrograms/h
Transdermal Patches (PL 08553/0564-0566). It explains how Panitaz 5, 10 and 20 micrograms/h
Transdermal Patches were assessed and their authorisation recommended, as well as the conditions of
use. It is not intended to provide practical advice on how to use Panitaz 5, 10 and 20 micrograms/h
Transdermal Patches.
These products will be referred to as Panitaz Patches in the remainder of this lay summary, for ease of
reading.
For practical information about using Panitaz Patches , patients should read the package leaflet or
contact their doctor or pharmacist.
What are Panitaz Patches and what are they used for?
Panitaz Patches are ‘hybrid generic medicines’. This means that they are similar to a reference medicine
containing the same active substance but are available in different pharmaceutical form, strength and
route of administration. The reference medicine for these products is Temgesic 400 microgram
sublingual tablets (Indivior UK Limited; PL 36699/0005).
Panitaz Patches are used to relieve moderate, longlasting pain that requires the use of a strong painkiller.
This medicine should not be used to relieve acute pain.
How do Panitaz Patches work?
Panitaz patches contain the active ingredient buprenorphine, which belongs to a group of medicines
called strong analgesics or ‘painkillers’. After application, buprenorphine passes through the skin into
the blood and helps to relieve moderate, longlasting pain.
How are Panitaz Patches used?
Panitaz patches should be applied in an area of non-irritated, intact skin of the upper arm, outer arm,
upper chest, upper back or side of the chest. Panitaz should be applied to a relatively hairless or nearly
hairless skin site. If none are available, the hair at the site should be cut with scissors. The application
site must be dry and clean.
The patient must always use this product exactly as their doctor has told them. The patient must check
with their doctor or pharmacist if they are not sure.
In adults and elderly patients, one Panitaz patch should be attached in an area of non-irritated, intact skin
and it should be changed every seventh day, preferably at the same time of day. A doctor may wish to
adjust the dose after 3-7 days until the correct level of pain control has been found. If a doctor advised
patients to take other painkillers in addition to the patch, patients should strictly follow the doctor’s
instructions, otherwise they will not fully benefit from the treatment. The patch should be worn for 3 full
days before increasing the dose; this is when the maximum effect of a given dose is established.
Panitaz patches should not be used in patients below the age of 18 years.
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In patients with kidney disease, no change in dose is necessary.
In patients with liver disease, the effects and period of action of the Panitaz patch may be affected and a
doctor will therefore check on patients more closely.
Patients should not apply more than two patches at the same time, regardless of the patch strength.
This medicine can only be obtained with a prescription from a doctor.
Please read section 3 of the package leaflet for detailed information on dosing recommendations, the
route of administration, and the duration of treatment.
What benefits of Panitaz Patches have been shown in studies?
Because Panitaz Patches are hybrid applications and are considered to be bioequivalent, to the reference
products, Norspan®
5, 10 and 20 micrograms/h transdermal patches, their benefits and risks are taken as
being the same as those of the reference medicines.
What are the possible side effects of Panitaz Patches?
Like all medicines, Panitaz Patches can cause side effects, although not everybody gets them.
The most common side effects with Panitaz Patches (which may affect more than 1 in 10 people) are
headache, dizziness, drowsiness, constipation, dry mouth, feeling or actually being sick, itchy skin,
redness and itching at application site.
The common side effects with Panitaz Patches (which may affect up to 1 in 10 people) are loss of
appetite, confusion, depression, difficulty in sleeping, nervousness, tingling or numbness, flushing of the
skin, shortness of breath, abdominal pain or discomfort, diarrhoea, indigestion, sweating, rash, skin
eruptions, tiredness, a feeling of unusual weakness, muscle weakness, pain, chest pain, swelling of
hands, ankles or feet and redness or rash at the application site.
For the full list of all side effects reported with Panitaz Patches, see section 4 of the package leaflet. For
the full list of restrictions, see the package leaflet.
Why was Panitaz Patches approved?
The MHRA decided that the benefits of Panitaz Patches are greater than their risks and recommended
that they are approved for use.
What measures are being taken to ensure the safe and effective use of Panitaz Patches?
A risk management plan (RMP) has been developed to ensure that Panitaz Patches are used as safely as
possible. Based on this plan, safety information has been included in the Summaries of Product
Characteristics and the package leaflet for Panitaz Patches including the appropriate precautions to be
followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by
patients/healthcare professionals will be monitored/reviewed continuously.
Other information about Panitaz Patches
The MHRA agreed to grant Marketing Authorisations for Panitaz Patches on 15 June 2016.
The full PAR for Panitaz Patches follows this summary. For more information about treatment with
Panitaz Patches, read the package leaflet, or contact your doctor or pharmacist.
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This summary was last updated in August 2016.
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TABLE OF CONTENTS
I Introduction Page 6
II Quality aspects Page 7
III Non-clinical aspects Page 9
IV Clinical aspects Page 9
V User consultation Page 15
VI Overall conclusion, benefit/risk assessment and
recommendation
Page 15
Table of content of the PAR update Page 22
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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products
Regulatory Agency (MHRA) granted Dr. Reddy’s Laboratories (UK) Ltd, Marketing Authorisations for
the medicinal products Panitaz 5, 10 and 20 micrograms/h Transdermal Patches (PL 08553/0564-0566).
These products are prescription only medicines (POM), used in the treatment of non-malignant pain of
moderate intensity when an opioid is necessary for obtaining adequate analgesia.
Panitaz is not suitable for the treatment of acute pain.
These applications were submitted under Article 10(3) of Directive 2001/83/EC, as amended, as hybrid
applications. The applications represent a change in pharmaceutical form, strength and route of
administration with respect to the reference product. The applicant has cross-referred to Temgesic 400
microgram sublingual tablets which were originally authorised to Reckitt & Colman (PL 00044/0109)
on 25 October 1990. Following change of ownerships this reference licence was authorised to Reckitt
Benckiser Healthcare (UK) Limited (PL 00063/0009) on 24 April 1995, then to Schering-plough
Limited (PL 00201/0244) on 20 May 1998 and to the current Marketing Authorisation Holder (MAH),
Indivior UK Limited (PL 36699/0005), on 29 September 2010.
As the pharmaceutical form of Panitaz 5, 10 and 20 micrograms/h Transdermal Patches differs from the
reference product, Temgesic 400 microgram sublingual tablets, Norspan®
transdermal patches were used
for the assessment of bioavailability (Norspan®
20 micrograms/h transdermal patches) and adhesion
performance (Norspan®
5 micrograms/h transdermal patches) of the products.
Panitaz patches contain the active ingredient buprenorphine, which is a partial agonist opioid, acting at
the mu opioid receptor. It also has antagonistic activity at the kappa opioid receptor.
The applicant has submitted two pivotal bioequivalence studies and an adhesion performance study with
these applications. The bioequivalence studies were conducted in line with the guideline on the
pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CHMP/EWP/280/96
Rev. 1).
With the exception of the above studies, no new non-clinical or clinical data were submitted, which is
acceptable given that these applications were based on the products being bioequivalent to originator
products that have been in clinical use for over 10 years.
The Marketing Authorisation holder has provided adequate justification for not submitting an
Environmental Risk Assessment (ERA).
A Risk Management Plan (RMP) and summary of the pharmacovigilance system have been provided
with these applications, and are satisfactory.
No new or unexpected safety concerns arose during the review of information provided by the
Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Panitaz 5, 10
and 20 micrograms/h Transdermal Patches outweigh the risks and Marketing Authorisations were
granted.
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II QUALITY ASPECTS
II.1 Introduction
The products are described as a transdermal delivery device containing buprenorphine in a matrix
system. It is composed of a drug-containing patch, and an oversized, beige coloured overtape. Each
transdermal patch contains 5 mg, 10 mg or 20 mg buprenorphine, as active ingredient.
Other ingredients consist of the pharmaceutical excipients:
Adhesive matrix (containing buprenorphine):
povidone K90
levulinic acid
oleyl oleate
Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl)acrylate-co-vinylacetate] (5:15:75:5)
Adhesive matrix (without buprenorphine):
Poly[(2-ethylhexyl)acrylate-co-glycidylmethacrylat-co-(2-hydroxyethyl)acrylate-co-vinylacetate]
(68:27:5:0,15)
Separating foil between adhesive matrices with and without buprenorphine: polyethylene terephthalate
(PET) film
Backing web: polyester
Release liner: PET film (to be removed before applying the patch)
Blue printing ink
All excipients comply with their respective European Pharmacopoeia monographs with the exception of
oleyl oleate which complies with the United States Pharmacopeia (USP) National Formulary as well as
with the German Pharmacopoeia (DAB). In addition, levulinic acid, acrylate polymers, polyester web
and PET film comply with in house specifications. Satisfactory Certificates of Analysis have been
provided for all excipients. Suitable batch analysis data have been provided for each excipient.
None of the excipients contain materials of animal or human origin.
No genetically modified organisms (GMO) have been used in the preparation of these products.
Each child-proof sachet is made of a composite layer material consisting of paper/PET/ polyethylene
(PE)/aluminium/surlyn. One sachet contains one transdermal patch. Each pack contains 4 individually
sealed transdermal patches.
Satisfactory specifications and Certificates of Analysis have been provided for all packaging
components.
II.2. Drug Substance
INN: Buprenorphine
Chemical name: [5-alpha, 7-alpha (S)]-6,14-ethanomorphinan-7-methanol, 17-(cyclopropyl-
methyl)-alpha-(1,1-dimethyl)-4,5-epoxy- 18,19-dihydro-3-hydroxy-6-
methoxy-alpha-methyl
(2S)-2-[17-cycloproylmethyl)-4,5-alpha-epoxy-3- hydroxy-6-methoxy-6-
alpha,14-ethano-14-alpha- morphinan-7-alpha-yl]-3,3-dimethylbutan-2-ol
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Structural formula:
Molecular formula: C29H41NO4
Molecular mass: 467.6 g/mol
Appearance: White or almost white crystalline powder.
Solubility: Buprenorphine is very slightly soluble in water; freely soluble in acetone; soluble
in methyl alcohol; slightly soluble in cyclohexane. Also dissolves in dilute
solutions of acids (Ph.Eur. monograph).
Buprenorphine is the subject of a European Pharmacopoeia monograph.
All aspects of the manufacture and control of the active substance, buprenorphine, are covered by the
European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.
II.3. Medicinal Product
Pharmaceutical Development
The objective of the development programme was to develop a drug product equivalent to the
formulation of the innovator product in qualitative and quantitative composition comprising a drug-
containing matrix patch with a desired drug release profile and an overtape with adequate adhesion
properties. A satisfactory account of the pharmaceutical development has been provided.
Comparative in vitro skin permeation experiments were conducted and comparable permeation profiles
were obtained in all experiments.
Comparative dissolution profiles have been presented for the proposed and reference products.
Manufacture of the products
Satisfactory batch formulae have been provided for the manufacture of the products, along with an
appropriate account of the manufacturing processes. The manufacturing processes have been validated at
production scale and have shown satisfactory results.
Finished Product Specifications
The finished product specifications proposed are acceptable. The test methods have been described that
have been adequately validated. Batch data have been provided that comply with the release
specifications. Certificates of Analysis have been provided for all working standards used.
Stability of the Products
Finished product stability studies were performed in accordance with current guidelines on batches of
finished product in the packaging proposed for marketing. The data from these studies support a
shelf-life of 21 months (5 and 10 micrograms/h transdermal patches) and 30 months (20 micrograms/h
transdermal patch) with a storage condition “Do not store above 25°C”.
Suitable post approval stability commitments have been provided to continue stability testing on batches
of finished products.
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II.4 Discussion on chemical, pharmaceutical and biological aspects
There are no objections to the approval of these applications from a pharmaceutical viewpoint.
III NON-CLINICAL ASPECTS III.1 Introduction
As the pharmacodynamic, pharmacokinetic and toxicological properties of buprenorphine are
well-known, no new non-clinical studies are required and none have been provided. An overview based
on the literature review is, thus, appropriate.
The Marketing Authorisation Holder’s (MAH’s) non-clinical expert report has been written by an
appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-
clinical pharmacology, pharmacokinetics and toxicology.
III.2 Pharmacology
Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.
III.3 Pharmacokinetics
Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.
III.4 Toxicology
Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.
III.5 Ecotoxicity/environmental risk assessment (ERA)
Since Panitaz 5, 10 and 20 micrograms/h Transdermal Patches are intended for generic substitution, their
use will not lead to an increased exposure to the environment. An environmental risk assessment is
therefore not deemed necessary.
III.6 Discussion on the non-clinical aspects
There are no objections to the approval of these applications from a non-clinical viewpoint.
IV CLINICAL ASPECTS IV.1 Introduction
The clinical pharmacology of buprenorphine is well-known. With the exception of data from the
bioequivalence studies and an adhesion performance study detailed below, no new pharmacodynamics
or pharmacokinetic data are provided or required for these applications.
No new efficacy or safety studies have been performed and none are required for this type of
application. A comprehensive review of the published literature has been provided by the applicant,
citing the well-established clinical pharmacology, efficacy and safety of buprenorphine.
Based on the data provided, Panitaz 5, 10 and 20 micrograms/h Transdermal Patches can be considered
bioequivalent to Norspan®
5, 10 and 20 micrograms/h transdermal patches (Mundipharma GmbH).
IV.2 Pharmacokinetics
In support of these applications, the applicant submitted two pivotal bioequivalence studies and an
adhesion performance study. Bioequivalence between the test and the reference patches with respect to
the rate and extent of buprenorphine exposure after single and multiple dose applications for the highest
strengths (20 micrograms/h) were invstigated. In addition to the bioavailability study, adhesive
behaviour of the applicant’s product was demonstrated with Norspan 5 micrograms/h transdermal patch.
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Single Dose Study
This is an open label, randomised, two-period, two-way, crossover, single dose pivotal
bioequivalence study to assess the bioequivalence, skin tolerance and adhesion performance of
Buprenorphine 20 micrograms/h transdermal patch and the reference product, Norspan®
20
micrograms/h transdermal patch, in healthy adult volunteers.
In this single dose study, 27 adult subjects received a single application of the test or the reference patch.
Following application, patches were removed after 168 hours and patients were hospitalised for 192
hours. Blood samples were collected for the pharmacokinetic comparison for 288 hours after
administration in each study period. The two applications were separated by a wash out period of 15
days.
Primary efficacy parameters, secondary parameter and %extrapolated AUC, AUC0-84.5, AUC84.5-t, T1/2,
and MRT were evaluated as additional equivalence criteria.
Results
Table 1: Pharmacokinetic parameters of buprenorphine following single application of a 20
micrograms/h transdermal patch
No significant differences in pharmacokinetic parameters were observed between the drug formulations.
Ratios and 90% confidence limits for all primary parameters were within the pre-defined acceptance
criteria specified in “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98
Rev 1/ Corr**). No significant differences between the secondary parameters were observed.
Adhesion performance and skin tolerance were evaluated as further parameters in this study. Adhesion
performance was scored using an 11-point scale (from 0 = < 50% adhesion to 10 = > 95% adhesion)
according to the Draft Guideline on Quality of Transdermal Patches (EMA/CHMP/QWP/911254/2011).
Cumulative adhesion scores (CAS) were calculated by subject and treatment over the last 24 hours
before patch removal. In order to demonstrate non-inferiority of the test versus reference, for the mean
CAS, 90% confidence interval for the difference between the CAS of Test and CAS of Reference were
calculated (see table 2).
Table 2: Mean cumulative adhesion score (CAS) analysis
As the lower limit of the 90% CI of the test (mean CASTEST - 0.8 x mean CASREFERENCE) is ≥ 0, non-inferiority can be
concluded.
The test formulation is non-inferior to the reference product with regard to adhesion performance. Mean
adherence was higher than 90% for both test and reference formulations thus demonstrating that skin
adhesion of the two study products is similar and at the same time qualitatively adequate.
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Skin tolerance was assessed at the end of the application period using an 8-point scoring system and
photographic documentation. The volunteer´s own subjective opinion regarding tolerability was scored
by the subject using a 4-point scale.
Skin irritation was generally slight and similar after both treatments, with a mean total score of 8.63 for
the test and 7.85 for the reference. A one-sided t test was performed in order to show non-inferiority of
the test to the reference (see table 3).
Table 3: Total objective irritation score analysis
As the upper limit of the 90% CI of the test (mean TEST – 1.25 x mean REFERENCE) is ≤ 0, non-inferiority can be
concluded.
The analysis of the subject’s subjective score supports the conclusion that no statistically significant
difference between the formulations can be identified with respect to the subjects’ opinions on safety or
tolerability of the two patch formulations.
Both products were well tolerated. No deaths or serious adverse events occurred during the study period.
42 (10 mild and 32 moderate) systemic adverse events were reported by 16 subjects. Subjects fully
recovered from all adverse events by the end of the study. No other clinically relevant adverse events or
laboratory changes occurred. No subject’s vital signs and electrocardiograms (ECGs) were abnormal at
the end of the study period.
Conclusion
No significant difference in the pharmacokinetic parameters was detected between the formulations.
Statistical analysis of the pharmacokinetic data proved that Buprenorphine 20 μg/h transdermal patch
and the reference product, Norspan® 20 μg/h transdermal patch, are bioequivalent after a single dose.
Analysis of adhesion scores confirmed the non-inferiority of the test buprenorphine formulation with
respect to adhesion performance. Both formulations were well tolerated. Analysis of objective and
subjective skin irritation scores obtained during the study confirmed the non-inferiority of the test
product to reference product following single application.
Multiple Dose Study
This is an open, randomised, two-period, crossover, multiple dose pivotal bioequivalence study to
assess the bioequivalence, skin tolerance and adhesion performance of Buprenorphine 20
micrograms/h transdermal patch and the reference product, Norspan®
20 micrograms/h
transdermal patch, in healthy adult volunteers.
In this multiple-dose study, 32 healthy male subjects were randomised to receive test or reference patch
for three consecutive applications of 168 hours. Each individual patch was separated with a washout
period of 18 days between removal of the last patch of the first period and the first application of the
second period.
In each period, blood samples were collected for the pharmacokinetic comparison up to 504 hours post
first application of the period. Primary efficacy parameters were (AUC0-tau)ss, Cmax.ss and Cmin.ss, Tmax.ss,
Cav.ss and peak trough fluctuation (%PTF) were evaluated as secondary criteria. 21 subjects were
included in the statistical analysis of pharmacokinetic data.
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Table 4: Pharmacokinetic parameters of buprenorphine following multiple application of a 20
micrograms/h transdermal patch
No significant differences in pharmacokinetic parameters were observed between the drug formulations.
Ratios and 90% confidence limits for all primary parameters were within the pre-defined acceptance
criteria specified in “Guideline on the Investigation of Bioequivalence” (CPMP/EWP/QWP/1401/98
Rev 1/ Corr**). No significant differences between the secondary parameters were observed.
Skin tolerance was assessed at the end of the application period of the first and second patch (168 hours
each). For the third patch skin tolerance was assessed at 168 hours, 168 hours 5 minutes and 170 hours
after application. Skin tolerance was measured using an 8-point scoring system and photographical
documentation. The volunteer’s subjective tolerability assessment was scored using a 4-point scale. Skin
irritation was generally slight and similar after both treatments, with a mean score of 10.63 for the test
and 11.33 for the reference assessed for the third patch application. A one-sided t-test was performed in
order to show non-inferiority of the test to the reference (table 5).
Table 5: Total objective irritation score analysis
As the upper limit of the 90% CI of the test (mean TEST – 1.25 x mean REFERENCE) is ≤ 0, non inferiority can be
concluded.
The analysis of the subject’s subjective score supports the conclusion that no statistically significant
difference between the formulations can be identified with respect to the subjects’ opinions on safety
and tolerability of the two patch formulations.
The test and reference products were well tolerated. No deaths or serious adverse events occurred during
the study period. 23 systemic adverse events were reported by 15 subjects. They were mild (7) or
moderate (15) in nature. The intensity of one event could not be verified. All known adverse events were
recovered at the end of study. No other clinically relevant adverse events or laboratory changes
occurred. No subject’s vital signs and ECGs were abnormal at the end of the study period.
Conclusion
No significant difference in the pharmacokinetic parameters was detected between the formulations.
Statistical analysis of the pharmacokinetic data proved that Buprenorphine 20 microgram/h transdermal
patch and Norspan® 20 microgram/h transdermal patch are bioequivalent at steady state.
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Satisfactory justification is provided for a biowaiver of the applicant’s 5 and 10 microgram/h
transdermal patches. As Panitaz 5, 10 and 20 micrograms/h Transdermal Patches meet the criteria
specified in the “for Guidance on modified release oral and transdermal dosage forms, section II
(pharmacokinetic and clinical evaluation) (CPMP/EWP/280/96, 28 July 1999) for a Transdermal
Delivery System (TDS), the results and conclusions of the bioequivalence studies for 20 microgram/h
transdermal patch formulation can be extrapolated to the other strengths, i.e. 5 and 10 microgram/h
transdermal patches.
Adhesion study of 5 microgram/h transdermal patch
This is an open, one-period, two-treatment, parallel administration, single dose pivotal study to
assess adhesion performance of Buprenorphine 5 microgram/h transdermal patches versus
Norspan® 5 microgram/h transdermal patch reference products in healthy adult volunteers.
In this adhesion performance study, 32 healthy subjects received the test and reference patch at about the
same time (one left, one right side) for 168 hours. The assignment of the application site was random. A
visual estimation (including photography) of patch detachment was performed immediately after
application and up to and including 167 hours 56 minutes, following application for both patches. All
subjects completed the study and were included in the statistical analysis.
The patch detachment was depicted on a transparent grid pattern by visual identification of areas where
lift-off occurred. According to the Draft Guideline on Quality of Transdermal Patches
(EMA/CHMP/QWP/911254/2011) detachment percentages calculated for each time point were
converted in to adhesion scores (0-10) at 5% steps. Cumulative adhesion scores (CAS) for statistical
analyses were performed over the last 24 hours before patch removal. In order to demonstrate non-
inferiority of the test versus reference, for the mean CAS, 90% confidence interval for the difference
between the CAS of test and CAS of reference was calculated. Statistical analysis demonstrated non-
inferiority of the test product compared with the reference product (table 6).
Table 6: Mean cumulative adhesion score (CAS) analysis
Non-inferiority is proven if the lower limit of the 95% CI for the test (mean CASTEST-0.8 x mean CASREFERENCE) is ≥ 0
Mean patch adhesion was higher than 90% for both study products (90.79% for reference and 91.84%
for test product).
Skin irritation during the study course (0 to 168 hours) was evaluated by visual assessment by the
physician using an 8-point scoring system and photographical documentation. Subjective tolerance was
estimated by the subject using a 4-point scale.
The test and reference products caused equal skin irritation during the dosing interval. Mean scores for
test and reference at the end of treatment were 10.66 and 10.25, respectively. There were no significant
differences between the products with respect to total objective skin irritation scores or in the subjective
irritation scores. The results of the tolerance estimation are given in table 7.
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Table 7: Total objective irritation score analysis
As the upper limit of the 90% CI of the test (mean TEST – 1.25 x mean REFERENCE) is ≤ 0, non-inferiority can be
concluded.
The analysis of the subject’s subjective score supported the conclusion that no statistically significant
difference between the formulations can be identified with respect to the subjects’ opinions on safety or
tolerability of the two patch formulations.
Systemic Tolerance:
No serious adverse events were reported during the study course. 12 systemic adverse events of mild
intensity and 13 of moderate intensity occurred in 13 subjects during the study course. All subjects
recovered before the end of the study. No clinically relevant changes in vital signs or laboratory
parameters were observed.
Conclusion
It can be concluded that both study products showed adhesion performance that is superior to minimum
requirement of the Draft Guideline on Quality of Transdermal Patches
(EMA/CHMP/QWP/911254/2011), which states that a mean adhesion of greater than 90% is
satisfactory. With respect to area under the adhesion percentage curve and mean patch adhesion,
equivalence of test and reference was confirmed. A statistical analysis of the study data revealed non-
inferiority of the test patches as compared with the reference patch.
Both products were generally well tolerated. Statistical analysis of objective and subjective irritation
scores proved that the test formulation is non-inferior to the reference formulation.
IV.3 Pharmacodynamics
No new pharmacodynamic data were submitted and none were required for applications of this type.
IV.4 Clinical efficacy
No new efficacy data were submitted and none were required for applications of this type.
IV.5 Clinical safety
No new safety data were submitted and none were required for applications of this type.
IV.6 Risk Management Plan (RMP)
The Marketing Authorisation Holder (MAH) has submitted a risk management plan (RMP), in
accordance with the requirements of Directive 2001/83/EC as amended, describing the
pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise
risks relating to Panitaz 5, 10 and 20 micrograms/h Transdermal Patches.
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A summary of safety concerns and planned risk minimisation activities, as approved in the RMP,
is listed below:
Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.
IV.7 Discussion on the clinical aspects
There are no objections to the approval of these applications from a clinical viewpoint.
The grant of Marketing Authorisations is recommended for these applications.
V User consultation A user consultation with target patient groups on the patient information leaflet (PIL) has been
performed on the basis of a bridging report making reference to BuTrans®
M 5, 10 and 20
micrograms/hour transdermal patches (DK/H/718/001-003/MR). The bridging report submitted by the
applicant is acceptable.
VI Overall conclusion, benefit/risk assessment and recommendation The quality of the products is acceptable, and no new non-clinical or clinical concerns have been
identified. Extensive clinical experience with buprenorphine is considered to have demonstrated the
therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.
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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels
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.
The approved labelling for Panitaz 5, 10 and 20 micrograms/h Transdermal Patches is presented below:
PAR Panitaz 5, 10 and 20 micrograms/h Transdermal Patches PL 08553/0564-0566
17
PAR Panitaz 5, 10 and 20 micrograms/h Transdermal Patches PL 08553/0564-0566
18
PAR Panitaz 5, 10 and 20 micrograms/h Transdermal Patches PL 08553/0564-0566
19
PAR Panitaz 5, 10 and 20 micrograms/h Transdermal Patches PL 08553/0564-0566
20
PAR Panitaz 5, 10 and 20 micrograms/h Transdermal Patches PL 08553/0564-0566
21
PAR Panitaz 5, 10 and 20 micrograms/h Transdermal Patches PL 08553/0564-0566
22
Table of content of the PAR update
Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II
variations, PSURs, commitments)
Date
submitted
Application
type
Scope Outcome