Download PUBLIC ASSESSMENT REPORT of the Medicines Evaluation Board

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PUBLIC ASSESSMENT REPORT
of the Medicines Evaluation Board
in the Netherlands
XTLuis, cutaneous solution 4% w/w
Novum Pharma BV, the Netherlands
dimeticone (100,000 cSt.)
This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report
comments on the registration dossier that was submitted to the MEB.
It reflects the scientific conclusion reached by the MEB at the end of the evaluation process and provides a summary
of the grounds for approval of a marketing authorisation.
This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare
professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the
latter category as the language in this report may be difficult for laymen to understand.
This assessment report shall be updated by a following addendum whenever new information becomes available.
General information on the Public Assessment Reports can be found on the website of the MEB.
To the best of the MEB’s knowledge, this report does not contain any information that should not have been made
available to the public. The MAH has checked this report for the absence of any confidential information.
Registration number in the Netherlands: RVG 101389
16 December 2010
Pharmacotherapeutic group:
ATC code:
Route of administration:
Therapeutic indication:
Prescription status:
Date of authorisation in NL:
Application type/legal basis:
other ectoparasiticides, incl. scabicides, insecticides
and repellents
P03AX
cuteanous
headlice infestations
OTC
24 November 2009
Directive 2001/83/EC, Article 8(3)
For product information for healthcare professionals and users, including information on pack sizes
andpresentations, see Summary of Product Characteristics (SmPC), package leaflet and labelling.
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INTRODUCTION
This is a national full application for XTLuis, cutaneous solution 4% w/w, submitted under E.C. Directive
2001/83/EC Article 8.3(i), for an existing active substance dimeticone.
Dimeticone has been licensed for at least 33 years and it is widely used as an ingredient in a number of
topical barrier cosmetic preparations. It is also used in pharmaceutical products indicated for the treatment
of flatulence. However, this is the first time that an application in the Netherlands is filed claiming the use
dimeticone as a pediculicidal agent. In the United Kingdom the same is registered as Hedrin®, it was
already acknowledged as a medicinal product. This product has a physiological mode of action (see
section on clinical pharmacology), however any pharmacological action cannot be ruled out. It was
therefore decided that XTLuis should be assessed as a medicinal product.
XTLuis solution acts on the lice by a physical process to cover the lice and disrupt the ability of the lice to
manage its water balance so that treated insects fail to excrete surplus water. Hedrin activity is not
diminished in insecticide resistant head lice. It is less effective in its ovicidal activity and therefore two
applications 7 days apart are required.
Based on the review of the quality, safety and efficacy data, the Netherlands has granted a marketing
authorisation for XTLuis cutenaous solution 4% w/w, from Novum Pharma BV, the Netherlands. The date
of authorisation was on 24 November 2009. The product is indicated for the eradication of headlice
infestations (voor de bestrijding van besmettingen met hoofdluis).
A comprehensive description of the indications and posology is given in the SmPC.
II
II.1
SCIENTIFIC OVERVIEW AND DISCUSSION
Quality aspects
Compliance with Good Manufacturing Practice
The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for
this product type at all sites responsible for the manufacturing of the active substance as well as for the
manufacturing and assembly of this product prior to granting its national authorisation.
Active substance
The active substance is dimeticone 100,000 cSt, an established substance, described in the Ph.Eur.* The
drug substance is practically insoluble in water and very slightly soluble to practically insoluble in glycerol,
ethylene glycol, stearyl alcohol, methanol and ethanol. It is miscible in non-polar solvents such as hexane,
heptane, toluene, xylene, ethyl acetate and methyl-ethyl-ketone. There are no chiral centres in the
molecule. Full documentation on the active substance has been included.
Manufacturing process
Dimeticone 100,000 cSt fluid is manufactured at elevated temperatures by hydrolysis →
polycondensation.The active substance has been adequately characterized and acceptable specifications
have been adopted for the starting materials.
Quality control of drug substance
The drug substance specification is in line with the Ph.Eur. monograph for Silicone oil used as a lubricant.
This is acceptable since the drug product lubricates the hairs. Batch analytical data demonstrating
compliance with the Ph.Eur. monograph have been provided for three primary batches. The batches also
comply with the proposed specification.
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Stability of drug substance
Stability data on the active substance have been provided for three primary batches stored at 25°C/60%
RH (18 months) and 40°C/75% RH (6 months). The batches were stored in epoxy lined drums.
The drug substance remained stable under accelerated and long term conditions for all parameters
tested. No specific trends were observed. The proposed re-test period of 24 months is acceptable.
* Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for
substances are laid down by the authorities of the EU.
Drug Product
Composition
The drug product is a clear and colourless cutaneous solution containing dimeticone 100,000 cSt (4.0%
w/w). The drug product consists of 4.0% w/w Dimeticone 100,000 cSt and 96.0% w/w Cyclomethicone 5.
The drug product is supplied in HDPE and glass bottles of varying configurations.
Pharmaceutical development
The development of the product has been adequately described. The key physicochemical characteristic
for the drug substance is its high viscosity which is required for its pediculicidal activity in the drug product.
Formulation studies focussed on the development of a lotion that was prepared from the drug substance
in a suitable vehicle. A vehicle was required that could dissolve the required amount of dimeticone and
could be readily volatile. Cyclomethicone 5 is a volatile silicone that is widely used in the cosmetic industry
as a carrier for other silicones. Upon application, cyclomethicone evaporates, thus allowing a fine layer of
dimeticone to be deposited on the hair, ensuring even distribution.
Additionally, the vehicle should be simple, non-toxic and non-flammable. Cyclomethicones fulfils these
requirements. The pharmaceutical development of the product has been adequately performed.
Manufacturing process
A description of the manufacturing process and a flow chart are included. During manufacturing
Dimeticone 100,000 cSt and Cylomethicone 5 are mixed. Two sets of three batches were included in the
manufacturing process validation.
The results of the validation study indicated that the manufacturing process was able to consistently
produce a product that met the product specification requirements and the method of mixing did not
require further development. The manufacturing process can be regarded as sufficiently validated.
Excipients
Cyclomethicone 5 is described in the USP NF** and complies with the requirements in the monograph.
Quality control of drug product
The product specification includes tests for description, identity of product, identity of non-volatile drug
substance, weight per ml at 20° C, refractive index at 20° C, Dimeticone content, viscosity, total viable
aerobic count. The release and shelf-life requirements are identical and acceptable.
The analytical methods have been adequately validated. Batch analysis data are included for six
production scale batches. All batches comply with the proposed specification.
Stability of drug product
The MAH has started the stability studies with three batches packed into 100 ml white HDPE and Type III
glass containers for the purpose of generating stability data. These data are presented as supportive data
following the decision to change from a white to a neutral, translucent HDPE container. The batches were
stored at 25°C/60% RH (40 months) and 40°C/75% RH (40 months). The batches were tested for
appearance, identity by IR, Dimeticone content and viscosity. For none of these batches tested a
significant change is observed at both long term and accelerated storage condition.
An additional stability study was initiated and six further batches were packed into either natural,
translucent HDPE or Type III glass bottles to generate primary stability data. The batches were stored at
25°C/60% RH (24 months), 30°C/65% RH (18 months) and 40°C/75% RH (24 months). These batches
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were tested for appearance, Dimeticone content, viscosity, weight per ml and refractive index. For none of
these batches tested a significant change is observed at long term, intermediate and accelerated storage
condition.
On the basis of the currently available data the proposed shelf-life of 36 months is acceptable.
Other information
There are no substances of ruminant animal origin present in the product nor have any been used in the
manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.
** United States Pharmacopoeia National Formulary
II.2
Non clinical aspects
Good Laboratory Practice
All studies performed by the MAH for the current application are conform GLP regulations. It is presumed
that all other studies referred to in this dossier are not conform GLP regulations. Additional studies that
are required need to be conducted conform GLP regulations.
Pharmacology
Pharmacokinetics
No absorption studies have been performed with dimeticon 100,000 cSt. Although dimeticons in general
have been in use for many years in a wide range of products, including topical and oral applications, it is
not clear if any of these products contain dimeticon 100,000 cSt, or a lower viscosity dimeticon. The
absorption studies that have been performed with lower viscosity dimeticons show little absorption, and it
is therefore unlikely that higher polymer sizes would be absorbed at a relevant level.
Toxicology
Single dose toxicity
A dermal toxicity study was conducted in rats, in which low body weight gain or body weight loss was
observed in treated female rats. This indicates that there may be some systemic toxicity due to absorption
through the skin. However, an untreated control group is lacking, therefore body weights cannot be
compared. Moreover, the systemic exposure due to dermal absorption is not determined, but it can be
accepted that these exposures are clinically not relevant.
Repeated dose toxicity
No repeat dose toxicity studies have been conducted by the MAH.
Genotoxicity
No studies have been performed to assess the genotoxic potential of dimeticon 100,000 cSt. Instead, the
slightly less viscous dimeticon 60,000 cSt has been evaluated in the Ames test. As dimeticon 100,000 cSt
is a higher degree polymer, no difference in genotoxic potential is anticipated, and the results for
dimeticon 60,000 can be used as evidence of lack of genotoxicity in the Ames test. No further studies
have been reported concerning the genotoxic potential of dimenticon 100,000 cSt.
Carcinogenicity
No carcinogenicity studies have been performed with dimeticon 100,000 cSt. As this product is unlikely to
be used more than two times, carcinogenicity studies are not required.
Reproductive and developmental toxicity
Three studies in rats using subcutaneous administration are described. Since this route of administration
is likely to result in much higher systemic exposure than the dermal route, these studies are not relevant
for this application. In rabbits, there seems to be some dermal absorption of the lower viscosity
dimeticons, as reproduction toxicity is observed in two studies using dimeticon 10 and 350 cSt. It can be
accepted that dimeticon 100,000 cSt is not absorbed in significant amounts through human skin.
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Local tolerance
Two skin irritation studies and two eye irritation studies were performed in rabbits using dimeticon 60,000
and 100,000 cSt. The slight eye irritation observed after treatment, was most pronounced with treatment
of dimeticon 60,000 cSt. Since the results with dimeticon 100,000 cSt are more relevant, and showed
insignificant irritation, it is concluded that the dimeticon 100,000 cSt is not an eye or skin irritant, after
single administration. Dimeticon 100,000 cSt showed no potential for skin sensitisation, after single
administration.
Other toxicity studies
No other toxicity studies were performed.
Environmental risk assessment
As dimeticons are widely used in a large number of cosmetic and pharmaceutical products, this product is
not likely to add to the overall burden to the environment. Therefore, no environmental risk assessment is
deemed necessary.
II.3
Clinical aspects
Quality of clinical studies, compliance with GCP
The MEB has been assured that GCP standards were followed in an appropriate manner in the studies
conducted.
Clinical Pharmacology
The mechanism of action of dimeticone has not been fully elucidated. The available evidence suggests
that the activity of Hedrin is physical and due to coating of the lice by dimeticone. Dimeticone enters the
trachae of the lice and prevents excretion of water resulting in disruption of gut and other organ functions.
This product has a physiological mode of action, however any pharmacological action cannot be ruled out.
Clinical Efficacy
One pivotal observer blind clinical efficacy study was conducted by the MAH to support the proposed
indication. This study involved an active controlled comparison of the efficacy of Hedrin (=XT Luis® 4%
w/w) and 0.5% phenothrin in patients with current active head louse infection. In addition to the pivotal
efficacy study, the clinical development programme comprised of a dose-finding Phase II pilot study to
evaluate optimum treatment-interval and follow-up regimen. In the two clinical studies conducted to
evaluate Hedrin® 87.5% (35/40) and 84.6% (220/260) were children aged 4-18 years; in total 57.7% of
these were aged less than 10 years in the pivotal study. The dose-finding pilot Phase II study was
performed in total 35 children and 5 adults, (conducted during the winter season). It compared a 20minute application versus 8-hours/overnight application in a once-a-week application regimen of Hedrin
for two weeks. The study indicated that 8 hours or overnight was the appropriate treatment exposure time
to achieve the intended maximum (at least 90%) eradication of head lice infections, although the study
was underpowered.
The pivotal Phase III study therefore included application of the product for 8 hrs or overnight. In this study
130 and 125 individuals with a median age of 9 years with head louse infection were treated with Hedrin
(=XT Luis® 4% w/w) and 0.5% phenothrin respectively according to the recommended regimen (two
applications on day 0 and 7 respectively (conducted during the summer season). The primary endpoints
of the study were not finding lice after the second treatment application (day 9 & day 14). The results
showed that 78/121 (64.46%) on Hedrin were cured versus 83/116 (71.55%) on with 0.5% phenothrin
liquid in the PP analysis. A further 6 (4.96%) with Hedrin and 7 (6.03%) with phenothrin were considered
to have been cured by the two treatments but subsequently re-infected. The difference in cure rates is
estimated as 8.16% with a 95% confidence interval (CI) of –3.02% to +19.34%. Thus, the two treatments
were regarded as equivalent to within 20%. Ovicidal failure was reported in 5 cases (4.13%) on Hedrin
and 2 cases (1.72%) on phenothrin.
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Of note the cure rate was significantly lower than the expected 90% for Hedrin on the basis of the dosefinding studywhereas high cure rates >90% are documented in the literature for pediculicides such as
permethrin containing products; see recent Cochrane publication (2007)1. High cure rates (>90%) are also
described for Phenothrin containing products, however, only abstracts could be retrieved from a
preliminary literature search. The presently observed low cure rate also for the used comparator has been
adequately explained by the MAH.
MAH offsets the lower cure rate on Hedrin with claimed advantage of Hedrin® over other products
currently marketed for this application that in ex vivo tests Hedrin® was effective against insecticide
resistant head lice (KER/LLE/D5D11.02). MAH’s explained that a high proportion of patients in the Phase
III study had used insecticide products without success prior to entry to the trial and that this is evidence
that the product is effective against head lice resistant to currently used products cannot be assessed
appropriately in the light of better results with the comparator product and the used exclusion criteria.
Finally, the comparator product 0.5% Phenothrin is not registered in the Netherlands, although it is
registered in some other EU countries.
In conclusion, the pivotal clinical trial has not demonstrated unequivocally that Hedrin (=XT Luis® 4% w/w)
has a high efficacy in killing head lice in comparison with an established comparator.
Clinical Safety
For the intent to treat (ITT) population adverse events were reported by 13.1% (17) of the patients in the
Hedrin group (in the phenothrin group: 20.2% (26) of the patients). Of the treatment-related adverse
events a total of 3.8% (5) were reported by patients in the Hedrin group compared to a total of 8.5% (11)
by patients in the phenothrin group. The adverse events related to Hedrin were 3 cases of scalp pruritis, 2
cases of transient mild eye irritation following accidental exposure. Eye irritation was also observed in
non-clinical studies in rabbits.
In the additional safety study carried out to determine skin irritation capacity of dimeticone (in 60 healthy
volunteers treated with a combination of two silicone-based materials: dimethiconol - a similar compound
to dimeticone-, and cyclometicone) no irritancy was observed after 16 hours of application.
In conclusion, the Hedrin (XTLuis) treatment related adverse events were mild/moderate and transient
and the incidence is lower than that of the comparator 0.5% phenothrin. Dimeticone (and cyclometicone)
have been in use for many years in dermal cosmetic products.
Discussion on clinical aspects
In the Board meeting of 3 April 2008 it was
medicinal product. It was concluded that
acknowledged as a medicinal product. This
pharmacological action cannot be ruled out.
medicinal product.
discussed whether XT Luis should be acknowledged as a
in the United Kingdom XT Luis (Hedrin) was already
product has a physiological mode of action, however any
The Board decided that XT Luis should be assessed as a
In the Board meetings held 26 November 2008 and 25 February 2009 it was decided to request the UK
assessment reports, subsequently it was concluded that the submitted documentation for XT Luis was the
same as Hedrin. In the Board meeting of 29 October 2009 the Board decided to register the product,
based on the request of the MAH, the submitted data and fact that the product is on the market in the UK
already for 4 years. The Board also acknowledged that this medicinal product has the non prescription
status in the United Kingdom. There are no safety concerns, Therefore the Board decided that the legal
status of supply could be set as non-prescription (UAD) in the Netherlands.
1 Strong M, Johnstone PW. Interventions for treating scabies. Cochrane Database of Systematic Reviews, 2007.
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Product information
SmPC
The content of the SmPC approved during this national procedure in the Netherlands is in accordance
with the SmPC of Hedrin (registered in the United Kingdom).
Readability test
The 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 test consisted of a pilot test with 2 participants,
followed by two rounds with 10 participants each. The questions covered the following areas sufficiently:
traceability, comprehensibility and applicability. The readability test has been sufficiently performed.
III
OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
XT Luis has a proven chemical-pharmaceutical quality.
The MAH has provided written confirmation that systems and services are in place to ensure compliance
with their pharmacovigilance obligations.
In the Board meeting of 3 April 2008 it was
medicinal product. It was concluded that
acknowledged as a medicinal product. This
pharmacological action cannot be ruled out.
medicinal product.
discussed whether XT Luis should be acknowledged as a
in the United Kingdom XT Luis (Hedrin) was already
product has a physiological mode of action, however any
The Board decided that XT Luis should be assessed as a
In the Board meetings held 26 November 2008 and 25 February 2009 the application was discussed and
it was decided to request the UK assessment reports, subsequently it was concluded that the submitted
documentation for XT Luis was the same as Hedrin, the commercial name in the UK.
The MEB, on the basis of the data submitted, considered that XTLuis demonstrated evidence of efficacy
for the approved indication as well as a satisfactory risk/benefit profile acknowledging that XT Luis was a
licensed medicinal product in the United Kingdom, and therefore granted a marketing authorisation.
The board conluded that XT Luis can be approved with the legal status of supply non prescription (UAD in
the Netherlands).
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List of abbreviations
ASMF
ATC
AUC
BP
CEP
CHMP
CI
Cmax
CMD(h)
CV
EDMF
EDQM
EU
GCP
GLP
GMP
ICH
MAH
MEB
OTC
PAR
Ph.Eur.
PIL
PSUR
SD
SPC
t½
tmax
TSE
USP
Active Substance Master File
Anatomical Therapeutic Chemical classification
Area Under the Curve
British Pharmacopoeia
Certificate of Suitability to the monographs of the European Pharmacopoeia
Committee for Medicinal Products for Human Use
Confidence Interval
Maximum plasma concentration
Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
Coefficient of Variation
European Drug Master File
European Directorate for the Quality of Medicines
European Union
Good Clinical Practice
Good Laboratory Practice
Good Manufacturing Practice
International Conference of Harmonisation
Marketing Authorisation Holder
Medicines Evaluation Board in the Netherlands
Over The Counter (to be supplied without prescription)
Public Assessment Report
European Pharmacopoeia
Package Leaflet
Periodic Safety Update Report
Standard Deviation
Summary of Product Characteristics
Half-life
Time for maximum concentration
Transmissible Spongiform Encephalopathy
Pharmacopoeia in the United States
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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY
Scope
Change of
manufacturer
Type
of
modification
active
substance
II
Date of start
of
the
procedure
Feb 2010
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Date
of
end of the
procedure
April 2010
Approval/
non
approval
approved
Assessment
report
attached
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