ZALERG PAR 07-2011

Direction de l’Evaluation
des Médicaments et des Produits Biologiques
PUBLIC ASSESSMENT REPORT
Scientific Discussion
Zalerg – Zabak 0.25 mg/ml Eye Drops, Solution
Ketotifene Thea 0.25 mg/ml Eye Drops, Solution
(Ketotifen hydrogen fumarate)
FR/H/0411/001/DC
FR/H/0412/001/DC
Applicant: Laboratoires THEA
Date of the PAR: July 2011
ZALERG-ZABAK-KETOTIFENE 0.25mg/mleye drops solution,
FR/H/0411/01/DC, FR/H/0412/01/DC
Page 1 of 6
Information about the initial procedure:
Application/Legal Basis
Active substance
Pharmaceutical form
Strength
Applicant
EU-Procedure number
End of procedure
1.
Article 10 (1) / Article 10(3)
ketotifene hydrogen fumarate
eye drops, solution
0.25 mg/ml
Laboratoires THEA
FR/H/0411/001/DC
FR/H/0412/001/DC
Date of D210: 19 May 2010
INTRODUCTION
Based on review of the quality, safety and efficacy data, the Afssaps has granted a marketing
authorisation (MA) for ZALERG-ZABAK-KETOTIFENE 0.25 mg/ml eye drops solution, from
Laboratoires THEA on July 15th 2010.
ZALERG-ZABAK-KETOTIFENE is a ketotifen hydrogen fumarate eye drop solution, packed in an
ABAK system multidosis bottle of 5 ml which ensures anti-microbial protection of the solution by the
presence of a sterilising filter membrane with a pore size of 0.2 µm and therefore allow the absence of
preservative.
Ketotifen is a known histamine H1 receptor antagonist which is indicated for the “symptomatic
treatment of seasonal allergic conjunctivitis” in adults, elderly and children (age 3 and older) with a
recommended posology of one drop into the conjunctival sac twice a day.
This medicinal product was claimed to be essentially similar to ZADITEN 0.25mg/ml, eye drops,
solution in single dose container marketed in France by Novartis Pharma S.A.S (French MA granted
on 16- 02 -2001). Therefore, these applications were submitted according to Article 10 (1) or Article
10 (3) depending on the status of these products compared to the reference product in the Member
States.
No new non-clinical or clinical data have been provided in support of these generic/hybrid
applications, which is acceptable for these types of procedures.
During the procedure, no potential serious risk to public health concerns was raised.
About the disease & treatments:
Ocular allergy is a chronic disease that refers to several conditions that usually affects the conjunctiva
of the eye and is, therefore, often referred to as allergic conjunctivitis.
Ocular allergy is common in the general population, considering that allergy affects 15 - 20% of
people worldwide, and that ocular symptoms are present in a subset of around 50%. Seasonal allergic
conjunctivitis (SAC) and Perennial Allergic Conjunctivitis (PAC) are the most prevalent forms (≈
90%) and they are respectively defined by the duration of irritation of the offending allergens
(seasonal allergic conditions or year-round symptoms).
SAC is a hypersensitivity reaction to specific airborne allergens, mainly pollens. Histamine is the
cardinal mediator responsible for the signs and symptoms of SAC. Common ocular signs and
symptoms associated with SAC are itching (always present) located under the superior eyelid or inner
ZALERG-ZABAK-KETOTIFENE 0.25mg/mleye drops solution,
FR/H/0411/01/DC, FR/H/0412/01/DC
Page 2 of 6
cantus, injection (redness, hyperaemia) of conjunctiva, chemosis, discharge, tearing and photophobia.
Intermittent episodes may evolve into constant symptoms and an associated rhinitis may occur.
Because allergen avoidance is generally unachievable in SAC and that symptoms of SAC may cause
extreme discomfort and may highly affect the quality of life of patients, there is a need for
symptomatic eye drops treatments. Nowadays, the pharmacotherapy of allergic conjunctivitis consists
of five major classes of drugs (Antihistamines; Mast cell stabilizers; Dual-acting agents
(antihistamine/mast cell stabilizer combined action); Corticosteroids and Nonsteroidal antiinflammatory drugs.
2.
QUALITY ASPECTS
2.1 Introduction
The medicinal product is a clear, colourless to slightly brown-yellow solution containing 0.25 mg of
ketotifen base per millilitre of solution. It is presented in a preservative-free multidoses eye drop
packaging (ABAK® bottle), which consists in a white opaque polyethylene bottle (5 ml) with a white
polyethylene insert equipped with a 0.2 µm filtering membrane The white cap is in high density
polyethylene.
The formulation comprises the following excipients: Glycerol, Sodium hydroxide and Water for
injections.
2.2 Drug substance
Drug substance, Ketotifen hydrogen fumarate, is a white to brownish-yellow, fine, crystalline powder,
sparingly soluble in water.
The manufacturer of the active ingredient has been granted a Certificate of Suitability of Monographs
of the European Pharmacopoeia for Ketotifen Hydrogen Fumarate.
.
The active ingredient is analysed by the finished product manufacturer as per the CEP requirements.
Stability data from the drug substance manufacturer are provided. A retest period of 24 months below
25°C is accepted for the drug substance packed in HD-polyethylene bottles or double polyethylene
bags, in a fibre drum..
2.3 Medicinal product
In the course of development, reference was made to the innovator product ZADITEN eye drops
(Novartis) presented in a 5 mL multidoses bottle (preserved with benzalkonium chloride) or in single
dose containers (without preservative). To avoid the use of preservative, Laboratoires THEA propose
the ABAK bottle, which ensures anti-microbial protection of the solution by the presence of a
sterilising filter membrane with a pore size of 0.2 µm. The medicinal product Ketotifen Thea has the
same qualitative composition as ZADITEN eye drops solution in single dose container. Comparison of
the critical parameters between Ketotifen Thea and reference product ZADITEN demonstrated
similarity of both drug products.
The pharmaceutical development of the formulation, the manufacturing process and the container
closure system is satisfactorily documented.
.
The description of the manufacturing process, which includes sterilising filtration of bulk solution and
aseptic filling, is provided with manufacturing flow-chart. Operating parameters and in-process
controls are specified.
Process validation has been conducted at the declared manufacturing site. Laboratoires Thea have
committed to perform process validation on the first three commercial.
ZALERG-ZABAK-KETOTIFENE 0.25mg/mleye drops solution,
FR/H/0411/01/DC, FR/H/0412/01/DC
Page 3 of 6
The excipients (glycerol, sodium hydroxide, nitrogen and water for injections) are controlled
according to the corresponding EP monographs. A certificate of analysis is provided for each
excipient. There are no excipients of human or animal origin
The proposed drug product specifications are those expected for an eye-drop solution and include
opalescence, colour, pH, osmolality, deliverable volume, assay, impurities determination and sterility.
Limits for impurities are in line with the ICH Q3 B identification and qualification threshold for the
maximal daily dose given in the SPC.
Analytical procedures are adequately described and validated.
Satisfactory quality specifications and development data are provided for the packaging components.
The cap is sterilized by Gamma irradiation. The bottle and the insert are sterilized by Ethylene oxide.
Complete validation of the sterilisation methods of the packaging components is provided, including
validation of residual ethylene oxide of inserts and bottles.
Stability studies run on three industrial batches support a shelf-life of 24 months with no storage
precautions.
Photostability studies show that the product is sensitive to light, but that the opaque ABAK® bottle
ensures a sufficient protection towards light.
A negligible level of extractables from the packaging components has been demonstrated.
A shelf-life of 8 weeks after opening is proposed as already registered for other products from Thea
with an ABAK system. It is supported by the in-use stability study.
3.
NON-CLINICAL ASPECTS
3.1 Discussion on the non-clinical aspects
ZALERG-ZABAK-KETOTIFENE is a new presentation of ketotifen 0.25 mg/ml eye drops, without
change in the qualitative and quantitative composition of the currently marketed reference product
Zaditen eye drops unpreserved single dose unit (Novartis Pharma). In accordance to directive 83/2001
as amended, adequate scientific literature has been provided: thirty-three bibliographical references
related to non-clinical tests have been submitted, dated from 1978 to 2008.
4.
CLINICAL ASPECTS
4.1 Introduction
Ketotifen has been shown to be a potent histamine H1 receptor antagonist and this is well validated.
Ketotifen is currently used to relieve the signs and symptoms of seasonal allergic conjunctivitis.
In accordance to directive 83/2001 as amended, since this product is submitted as a biowaiver, no new
non-clinical or clinical data have been submitted in support of these applications.
The equivalence of the ABAK product with the originator has been appropriately established through
in vitro data as per the Note for Guidance on the Clinical Requirements for Locally Applied, Locally
Acting Products Containing Known Constituents CPMP/EWP/239/95 Final. The comparison of the
critical parameters between originator and generic products confirmed the maintenance of the
specified physicochemical characteristics for the bottle content and the expelled drops, as well as the
efficacy of the antimicrobial barrier membrane (Please refer to Quality part).
4.2 Discussion on the clinical aspects
The originator ZADITEN was registered in France either since 1979 (hard cap 1 mg) or 2001
(unpreserved eye drops) and therefore, with more than 10 years or 6 years of experience, respectively.
ZALERG-ZABAK-KETOTIFENE 0.25mg/mleye drops solution,
FR/H/0411/01/DC, FR/H/0412/01/DC
Page 4 of 6
The pharmacodynamics, pharmacokinetics and toxicology as well as the benefit risk balance of
ketotifen are well established through the thirty-three and sixty-one non-clinical and clinical
bibliographical references submitted by Thea that cover the period from 1978 to 2008. These data
have been appropriately discussed through the non clinical and clinical overviews. These data remind
the main pharmacodynamic, pharmacokinetic, toxicology, efficacy and safety experiments or studies
carried out with the originator (ZADITEN). In addition, the safety contribution of the unpreserved
ABAK system to avoid the potential deleterious effects of preservatives is discussed.
Efficacy:
According to the bibliographic review submitted, the efficacy superiority of ketotifen eye drops was
appropriately demonstrated versus placebo through either CAC standardised and reproducible study
conditions (using a model, that mimics the signs and symptoms of allergic conjunctivitis by topically
challenging individuals with histories of allergic conjunctivitis with an antigen to which they are
sensitized) or environmental studies. Although rhinoconjunctivitis is a validated indication for oral
ketotifen formulations, the potential for relieving the nasal signs and symptoms of allergic
rhinoconjunctivitis was considered insufficiently tested for the eye drops to grant an indication or a
property since it was based on a one and only CAC test.
Superiority to mast cell stabilizers was also demonstrated.
When compared with other histamine H1 receptor antagonist (levocabastine, emedastine) no clear
differences between treatments were observed.
Results versus olopatadine frequently classified as a dual agent, are contradictory as they show either
no significant differences between products or superiority or inferiority of ketotifen vs olopatadine.
Some of these studies were part of the registration file of ketotifen but negative studies carried out
with ketotifen were not found in the references submitted by the MAH (e.g. the second environmental
study provided for Zaditen registration).
In all these studies “Itching” was assessed as “primary variable”.
Safety:
Globally, the safety profile can be considered as well-established and no product-specific
pharmacovigilance issues were identified which are not adequately covered by the current SPC.
Additional risk minimisation activities have not been identified for the reference medicinal product. A
detailed Risk management Plan is not necessary for this product.
The SmPC of ZALERG-ZABAK-KETOTIFENE ® is exactly the same as the reference products.
Paediatrics:
In Paediatrics an acceptable safety benefit risk balance was also confirmed.
One study versus placebo using CAC model was described including paediatrics from 8 to 16 years of
age. Paediatrics of more than twelve years old were included in the Zaditen environmental study (Kidd
2003).
Also, another CAC study (Greiner, Minno 2003) included paediatrics of more than ten years old.
Finally, a 6-week placebo-controlled study evaluating the ocular tolerability and safety of ketotifen
fumarate 0.025% ophthalmic solution administered four times daily (at twice the recommended daily
dose) to volunteers, including a subgroup of 61 children from 3 to 11 years of age (ketotifen, 42;
placebo, 19), with normal ocular health which was published by Abelson et al in 2002 to brought
additional support to paediatric use.The pattern of results in this subgroup was similar to that in the
overall study population: no significant between- or within-group differences in all ocular signs and
symptoms and non significant between-group differences in pupillary size and reactivity, intraocular
pressure, and slit-lamp and direct ophthalmoscopy findings. The most frequently occurring treatmentemergent adverse events in children were fever, flu syndrome, headache, and rhinitis, reported by
57.1% of the ketotifen group compared with 68.5% of the placebo group (p = 0.572). In total, limited
data on children aged from 3 to 11 years did not reveal specificities in this population.
ZALERG-ZABAK-KETOTIFENE 0.25mg/mleye drops solution,
FR/H/0411/01/DC, FR/H/0412/01/DC
Page 5 of 6
5.
OVERALL DISCUSSION , BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The chemical-pharmaceutical quality of ZALERG-ZABAK-KETOTIFENE 0.25 mg/ml Eye Drops
Solution, from Laboratoires THEA is demonstrated as a generic form of ZADITEN 0.25mg/ml, eye
drops, solution in single dose container which is a well-known medicinal product with an established
favourable efficacy and safety profile.
The equivalence of the product with the originator has been appropriately established through in vitro
data as per the Note for Guidance on the Clinical Requirements for Locally Applied, Locally Acting
Products Containing Known Constituents CPMP/EWP/239/95 Final.
The acceptable risk benefit balance of ketotifene fumarate from Thea presented as a preservative free
eye drops solution in multidose container (ABAK system) is supported by a relevant updated
bibliographical review of efficacy and safety of clinical data available for the originator (Zaditen).
No major concerns were raised with regard to the non clinical and clinical part of the file.
No safety concern was raised from the data submitted or from the post marketing data of the
originator.
The SPC adequately reflects the safety profile of this drug and appropriately describes the ABAK
system and its specific use which avoids preservative in eye drop solution.
This allows a multidose presentation that might present some advantages particularly for these allergic
patients who are repeatedly treated by antiallergic eye drops therapies.
Overall, no major deficiencies with regard to the non clinical and clinical parts of the file were raised
during the Decentralized Procedure.
The SPC is consistent with that of the reference product.
The SPC, Package Leaflet (PL) and Labelling are in the agreed template.
The Member States mutually recognised the French evaluation of the marketing authorisation.
There was no discussion in the CMD(h).
Therefore, a favourable opinion was given on the clinical part of the dossier which was also supported
by in vitro data (please refer to quality part).
Nevertheless, the following post-approval quality commitments were made during the procedure:
- to analyse 3 consecutive production batches of drug substance already expired (batches manufactured
in 2002) with the Ph. Eur. monograph method and the in-house method in order to show that no
impurity is formed (other than synthesis impurities A and B), and to either demonstrate that the inhouse method is stability indicating or to use the Ph. Eur. monograph method for all on-going and
future stability studies.
- to perform process validation on the first three commercial batches in order to confirm hold times for
each manufacturing step from start of compounding to end of sterile filling.
- to add the sterility test in routine for each batch of primary packaging material sterilised by Ethylene
oxide.
ZALERG-ZABAK-KETOTIFENE 0.25mg/mleye drops solution,
FR/H/0411/01/DC, FR/H/0412/01/DC
Page 6 of 6