«Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 MHRA: PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL ...»
Public Assessment Report
Alrex 0.2% Eye Drop Suspension
MHRA: PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 1
ALREX 0.2% EYE DROP SUSPENSION
TABLE OF CONTENTS
Lay Summary 3 Scientific discussion 4 Steps taken for assessment 38 Steps taken after authorisation – summary 39 Summary of Product Characteristics 40 Patient Information Leaflet 48 Labelling 51 MHRA: PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 2 ALREX 0.2% EYE DROP SUSPENSION
(LOTEPREDNOL ETABONATE)PL 00033/0160
LAY SUMMARYThe Medicines and Healthcare products Regulatory Agency (MHRA) has granted Chauvin Pharmaceuticals Limited a Marketing Authorisation (licence) for the medicinal product Alrex 0.2% Eye Drop Suspension (PL 00033/0160). This is a prescription only medicine [POM] for treating seasonal allergic (“hay fever”) conjunctivitis.
Seasonal allergic conjunctivitis affects between 5% and 22% of the general population and it is a response of the eye to specific irritants in the air. The active ingredient in this product, loteprednol etabonate, suppresses the response to these irritants, although there is no general agreement on how this suppression is achieved.
The clinical data presented to the MHRA, before licensing, demonstrated that Alrex 0.2% Eye Drop Suspension is effective in the treatment of seasonal allergic conjunctivitis. There were no significant safety concerns and it was decided that the benefits of using Alrex outweigh the risks, hence a Marketing Authorisation has been granted.
MHRA: PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 3 ALREX 0.2% EYE DROP SUSPENSION
(LOTEPREDNOL ETABONATE)PL 00033/0160
MHRA: PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 4
INTRODUCTIONBased on the review of the data on quality, safety and efficacy the UK granted a marketing authorisation for the medicinal product Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) (PL 00033/0160) to Chauvin Pharmaceuticals Limited on 17 July 2006. The product is a prescription only medicine.
The application was submitted as a full application according to Article 8.3(i) of Directive 2001/83/EC.
Alrex 0.2% Eye Drop Suspension contains the active ingredient loteprednol etabonate, with the chemical name chloromethyl 17α[(ethoxy-carbonyl)oxy]-11ß-hydroxy-3-oxoandrosta-1,4-dieneß-carboxylate.
Alrex 0.2% Eye Drop Suspension is indicated for the symptomatic treatment of seasonal allergic conjunctivitis.
Loteprednol etabonate belongs to a new class of corticosteroids. Corticosteroids suppress the inflammatory response to inciting agents of a mechanical, chemical or immunological nature. No generally accepted explanation of this steroid property has been advanced.
The active ingredient loteprednol etabonate was first authorised in the United States in 1998. It has also been licensed as a 0.5% eye drop suspension in the UK.
INTRODUCTIONThis is an application for a new drug, loteprednol etabonate, which is formulated as an eye drop suspension to be used for the symptomatic treatment of seasonal allergic conjunctivitis. It is preserved with benzalkonium chloride. It is stated that the drug belongs to a new class of corticosteroids with potent anti-inflammatory activity. In vivo transformation of hydrocortisone and its analogues produces cortienic acid as an inactive metabolite. This drug is an ester of ∆1 cortienic acid etabonate [PJ-91].
METHOD OF PREPARATIONA satisfactory description of the method of manufacture is provided.
The process validation studies are acceptable.
DRUG SUBSTANCEDrug substance specification A satisfactory drug substance specification is provided.
OTHER INGREDIENTSSuitable sources of all the excipients have been identified.
CONTAINER AND CLOSURE SYSTEMThe product is packed in either 7.5ml or 10ml size low density polyethylene containers containing either 5ml or 10ml of the suspension. The closure is a pink polypropylene cap.
CONTROL TESTS ON THE FINISHED MEDICINAL PRODUCTFinished product specification A satisfactory finished product specification is provided.
STABILITY Stability tests on the finished medicinal product The stability data were generated at 25ºC/40%RH and 40ºC/20%RH which is generally in line with the CPMP guidance for products in semi-permeable containers.
MHRA: PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 6 The results were within the specifications.
EXPERT REPORTA satisfactory statement has been provided.
PRODUCT NAME & APPEARANCE.
The product name is acceptable and the appearance is satisfactory.
SUMMARY OF PRODUCT CHARACTERISTICS
PATIENT INFORMATION LEAFLETLABELLING These are generally acceptable, from a pharmaceutical perspective.
CONCLUSIONSMarketing authorisation should be granted.
Note regarding consideration by Chemistry, Pharmacy and Standards Sub-committee:
This application was presented to the Chemistry, Pharmacy and Standards Sub-committee on 19 March 2003. The Sub-committee advised the grant of a Marketing Authorisation once the applicant had complied with certain conditions.
INTRODUCTIONThis is a stand-alone application for Alrex 0.2% Eye Drop Suspension submitted in accordance with Article 8.3(i) of Directive 2001/83/EC.
The product is a sterile multidose eye drop containing a new active ingredient, loteprednol etabonate (LE), at 0.2%w/v which is equivalent to 0.08mg loteprednol per eye drop.
Loteprednol etabonate or chloromethyl 17α[(ethoxy-carbonyl)oxy]-11ß-hydroxy-3oxoandrosta-1,4-diene-17ß-carboxylate is a new corticosteroid with anti-inflammatory activity. It is stated to undergo local transformation into inactive metabolites, thereby reducing the local and systemic side effects experienced with conventional corticosteroid therapy.
Alrex is indicated for the treatment of seasonal allergic conjunctivitis. The proposed dosage schedule is to apply one drop into the conjunctival sac of the affected eye(s) four times daily.
During the initial treatment within the first week, the dosing may be increased, up to one drop every hour, if necessary.
Assuming that one drop is 32µL, the maximum daily dose would be 32µL x 2 eyes x 16 treatment hours, or 1.024mL/day. The maximum dose of loteprednol, assuming that the specific gravity of the formulated product is approximately 1.0, would be 1.024mL x 0.08/100 – about 0.82µg/day or about 0.013µg/kg/day assuming 60kg bodyweight.
The single dose and repeated dose toxicity studies, as well as the mutagenicity and reproductive toxicity studies were conducted in compliance with GLP. The pharmacodynamic studies are not required and were not conducted in compliance with GLP. Many of the pharmacokinetic studies were not conducted in compliance with GLP, even though this is required as they form part of the safety studies.
The Expert has stated that although the reported detail and standard of presentation of some of these reports are variable, in general the conclusions reached appeared to be supported by the data presented.
PHARMACODYNAMICSPharmacodynamics for the proposed indication LE is an analogue of prednisolone but it is an ester rather than a ketone. It is rapidly metabolised by tissue esterases to the carboxylic acid PJ-91 which can be metabolised to the inactive PJ-90. PJ-91 does not bind to glucocorticoid receptors and does not have the typical MHRA: PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 8 activity of a corticosteroid. It is stated that the absence of a keto group at position 20 eliminates the adduction with lysine which would form in the crystalline lens, reducing the formation of corticosteroid-induced cataracts.
LE was evaluated in a number of anti-inflammatory screening tests in comparison with hydrocortisone-17-butyrate (HCB), hydrocortisone-17-butyrate propionate (HCBP), clobetasol-17-propionate (CBP), betamethasone-17-valerate (BMV) and dexamethasone sodium phosphate (DMS).
Four comparative studies of the potency of LE, HCB and BMV in the croton oil oedema model were conducted, two studies in mice and two in rats, with varying treatment schedules.
The relative potencies of the three corticosteroids varied in the different models; LE was active in this model. In two other models involving local action, histamine-induced vascular permeability and dinitrofluorobenzene-induced dermatitis, LE was slightly more active than DMS in the former and appeared to be marginally more active than HCBP in the latter, although in this case the difference in activity did not attain statistical significance. LE demonstrated a similar potency to both DMS and HCB in a model of homologous passive cutaneous anaphylaxis.
LE was less active than both HCB and DMS in both the rat carragenin-induced skin and paw oedema models and was inactive in the adjuvant-induced arthritis model. In the cotton pellet granuloma assay, both BMV and HCB showed anti-inflammatory activity over a wide dose range. In this assay, treatment with both BMV and HCB resulted in between 20% and 80% thymic suppression over a dose range from 75-1000µg/pellet, whereas the thymic suppression resulting from treatment with LE over a dose range of 100-5000 µg/pellet was approximately 20%. This study indicates that LE exhibits anti-granuloma activity at doses below those that cause thymic suppression.
LE was compared with flurbiprofen sodium and DMS using a series of ocular inflammatory models (paracentesis, nitrogen mustard 1% and 4%, shigella endotoxin and immune uveitis) each with the common endpoint of determination of total protein infiltration into the anterior chamber. With the exception of the nitrogen mustard 4% model, animals pre-treated with LE showed less total protein migration into the anterior chamber, although the reductions were generally not statistically significant.
The anti-inflammatory efficacy of LE 1% and prednisolone acetate 1% were compared in an endotoxin-induced model of ocular inflammation in rabbits. LE was shown to be as effective as the comparator, both in lowering leukocyte infiltration in the aqueous humour and in reducing cellular accumulation in the iris-ciliary body as measured by myeloperoxidase activity. Animals treated with either compound exhibited a crossover effect in the untreated, contra-lateral eye.
LE, fluoromethalone (FML) and dexamethasone (Dexa) were compared using a similar model of endotoxin-induced (300ng E.coli lipopolysaccharide (LPS) in each eye) ocular inflammation compared with both FML and Dexa. However, LE reduced both the inflammatory response and protein infiltration into the aqueous humour in comparison with the saline-treated control group.
A further study was conducted in the rabbit to evaluate the effect of LE in a chronic model of uveitis. A higher concentration (1%) of LE was used. Leukocyte infiltration into the aqueous humour of animals treated with LE (1%) was reduced compared with saline-treated controls and was also lower than in animals treated with FML or Dexa. Similarly, protein infiltration MHRA; PAR – Alrex 0.2% Eye Drop Suspension (loteprednol etabonate) PL 00033/0160 9 into the aqueous humour in animals receiving LE (1%) was lower than in controls, but LE was less effective than FML or Dexa in reducing protein infiltration.
Another evaluation of the anti-inflammatory activity of LE was a study designed to compare the effectiveness of a range of concentrations of LE (0.05%, 0.1%, 0.5%, 1.0% and 2.0%) with two concentrations of prednisolone acetate (0.125% and 1.0%). Concentrations of LE 0.5% were not effective, 0.5% LE was equally as effective as 0.125% prednisolone acetate in reducing corneal inflammation and LE achieved its peak activity at 1.0%, at which concentration it was equally as effective as 1.0% prednisolone acetate. Further studies were conducted to evaluate the effect of commencing treatment prior to the induction of inflammation. This had no effect on the anti-inflammatory activity of either steroid.
A further element of this study was a comparison of inhibition of full thickness corneal wound healing of LE vehicle, LE (1%), prednisolone acetate 1% (Pred), and dexamethasone sodium phosphate 1% (DMS). LE (1%) and Pred (1%) produced a statistically significant decrease in the IOP required for wound rupture when compared with LE vehicle. The decrease produced by DMS was even greater.
LE is presumed to act at the glucocorticoid (Type II) receptors. In rat lung cytosol preparations, LE was shown to displace tritiated triamcinolone acetonide from glucocorticoid receptor binding sites ligand with a potency of 1.5 times that of dexamethasone. This was considered to possibly indicate either binding to transcortin or enzymatic inactivation of the compound. In the presence of cortienic acid which saturated the transcortin binding sites, LE demonstrated a potency of 4.3 times that of DMS.
A further study was conducted to determine the relative binding efficiencies of LE and its metabolites PJ-91 and PJ-90 using a similar rat lung cytosol preparation to that described above. These data indicate that LE binds competitively to transcortin, in common with other non-fluorinated corticosteroids. PJ-91 did not displace tritiated triamcinolone acetonide from the glucocorticoid (Type II) receptor, indicating that it lacks significant glucocorticoid activity.