June 2014 Australian Public Assessment Report for Bimatoprost Proprietary Product Name: Latisse Sponsor: Allergan Australia Pty Ltd About the Therapeutic Goods Administration (tga)



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List of commonly used abbreviations


Abbreviation

Meaning

AE

Adverse Event

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

AOI

Area of interest: the specific region that includes all eyelashes for a given eye

BAK

Benzalkonium chloride

Bim

Bimatoprost

CER

Clinical evaluation report

CRF

Case report form

CSR

Clinical study report

DIA

Digital Image Analyses

ECOG

Eastern Cooperative Oncology Group

ESQ

Eyelash Satisfaction Questionnaire

FDA

Food and Drug Administration

GCP

Good clinical practice

GEA

Global eyelash assessment

GGT

Gamma glutamyl transpeptidase

hct

haematocrit

ICH

International Conference on Harmonisation

IEC

Institutional ethics committee

IOP

Intraocular pressure

IRB

Institutional Review Board

ITT

Intention to treat

IVRS

Interactive voice response system

IWRS

Interactive web response system

LDH

Lactate dehydrogenase

LOCF

Last observation carried forward

MedDRA

Medical Dictionary for Regulatory Activities

mm

millimetres

mmHg

millimetres of mercury

NOS

Not otherwise specified

OH

Ocular hypertension

OTC

Over the counter

OU

Each eye

Pbo

Placebo

PI

Product information

Pixel

the smallest discrete component of a digital image

PK

Pharmacokinetic

PP

Per protocol

PRO

Patient reported outcomes

PSUR

Periodic safety update report

QD

Daily

SAE

Serious Adverse Event

SD

Standard deviation

SOC

System organ class

SOP

Standard operating procedure

spline

a narrow area approximately 5 pixels wide, bisecting the AOI (area of interest)

TP1

Treatment period 1 (0-6 months)

TP2

Treatment period 2 (6-12 months)

US

United States

VA

Visual acuity

Veh

Vehicle


I. Introduction to product submission

Submission details


Type of submission:

Extension of indications; New trade name and new dosage form

Decision:

Rejected

Date of initial TGA decision:

18 November 2013

Date of final TGA decision

9 April 2014

1AAT

Currently under review

Active ingredient:

Bimatoprost

Product name:

Latisse

Sponsor’s name and address:

Allergan Australia Pty Ltd.
Locked Bag 1514
Pymble NSW 2073

Dose form:

Solution 3 mL

Strength:

300 µg/mL (0.03% weight/volume (w/v))

Containers:

Low Density Polyethylene (LDPE) 3 mL bottle and Sterile Single use Disposable Applicators.

Pack size:

1 x 3 mL bottle plus 60 sterile single use applicators (packaged as 6 blister trays, each containing 10 sterile applicators)

Approved therapeutic use:

Not applicable

Route of administration:

Topical

Dosage:

The recommended use of Latisse is once nightly. Carefully apply one drop of Latisse (bimatoprost topical solution) to the disposable sterile applicator supplied with the package and apply evenly along the skin of the upper eyelid margin at the base of the eyelashes.

ARTG number:

Not applicable

Product background


This AusPAR describes the application by Allergan Pty Ltd to register Latisse (bimatoprost 0.3 mg/mL topical solution) for the following therapeutic indication:

For treatment of hypotrichosis of the eyelashes by increasing their growth, including length, thickness and darkness.

Bimatoprost is a synthetic prostamide (prostaglandin ethanolamide), structurally related to prostaglandin F2 (PGF2).

When treating with Latisse, one drop of solution is to be applied to the upper eyelid margin at the base of the eyelashes per day using an applicator. A new sterile applicator is to be used for each eye. The lower eyelash line is not to be treated.

This application for registration of Latisse involves:



  • A new route of administration and dosage form: 3 mL fill in 5 mL dropper bottle plus 60 sterile, single use, applicators. The package is classified as a medicinal kit (Section 7B Therapeutic Goods Act 1989).

  • New indication.

  • A new tradename (Latisse)

This is a re-submission the original application which was withdrawn by the sponsor prior to presentation to the TGA’s Advisory Committee on Prescription Medicines (ACPM).

Regulatory status


Latisse topical solution for treatment of hypotrichosis has been registered in the USA (2008) and Canada (2009). An application to the EU was withdrawn.

II. Quality findings

Introduction


The proposed product and the applicators are supplied together in one package, as a “medicinal kit”.

There are no British Pharmacopeia (BP)/European Pharmacopeia (Ph. Eur.)/or US Pharmacopeia (USP) monographs for bimatoprost or products containing it.


Drug substance (active ingredient)


The details of the drug substance have been evaluated by the TGA in a previous submission, including the manufacture sites of bimatoprost, apart from editorial updating of test method numbers (but not the methods themselves), which are the same independent of manufacturing site. These changes are acceptable.

Drug product


The differences in this application compared to the previous submission relate to the additional sites for manufacturing of filled bottles and additional sites for sterilisation of empty bottles, bottle caps and tips. These are acceptable, as additional evidence for Good Manufacturing Practice (GMP) pre-clearance for additional sites have been provided.

The differences between this submission and the previously approved submission have been accepted with respect to finished product specifications including justifications for impurities levels at release and expiry.

The stability data support the proposed shelf-life of 2 years stored below 25°C for the unopened product and 4 weeks in-use shelf-life for opened product.

The chemistry and quality control aspects of the draft PI have been finalised to the satisfactory of the quality evaluator; as well as the carton and bottle labels and the Provisional ARTG Records.


Biopharmaceutics


No bioavailability data are required as the proposed product is intended to act locally, without systemic absorption. The quality evaluator has not reviewed the pharmacokinetic section of the PI.

Quality summary and conclusions


All issues raised with regards to sterility aspects have been adequately addressed during Second Round evaluation.

Overall,


  • There are no outstanding issues from quality or sterility perspective; hence approval can be recommended from chemistry, quality control and biopharmaceutics perspective.

  • Given that this is a “new route of administration and dosage form” and an “extension of indication” no new issues were identified which required details of the product to be presented for consideration by the Pharmaceutical Subcommittee of ACPM (PSC).

III. Nonclinical findings

Introduction


Nonclinical data submitted in support of the extension of indication and new route of administration comprised pharmacology studies investigating the effect of bimatoprost on hair growth and pharmacokinetic studies on dermal absorption.

Pharmacology


Bimatoprost is a synthetic prostamide (prostaglandin ethanolamide), structurally related to prostaglandin F2 (PGF2).

Topical ocular administration of the commercial / Latisse formulation (0.03% bimatoprost) once daily for two weeks significantly increased eyelash length, thickness and number in female C57BL/6 mice. The increase in eyelash number appeared related to an increased number of eyelash follicles containing two hairs, not an increase in the number of hair follicles. No signs of inflammation, hyperproliferation or other unwanted side effects were noted. While there is no validated animal model for eyelash hypotrichosis, the C57BL/6 mouse is a useful model for studying the biology of hair growth. Although the human hair cycle (a mosaic pattern) is different to that in mice (a synchronous pattern), it is noted that the structure of the hair follicles in the two species is almost the same.2

Bimatoprost (≥10 nM) was shown to increase hair synthesis in vitro in cultured human scalp hair follicles in the growing (anagen) phase, acting via a prostamide receptor dependent mechanism.

Effects on hair growth are reported for other members of the class, as well as PGF2. Application of 100 µL of PGF2, latanoprost (Xalatan; 0.005%) or isopropyl unoprostone (Rescula; 0.12%) to the dorsal skin of C57BL/6 mice once daily for three weeks showed stimulatory effects on hair growth.2 All three agents were shown to stimulate murine hair follicles and the follicular melanocytes in both the telogen and anagen phases. Similarly, latanoprost (0.5 mL) applied to the scalp of 5 to15 year old stump-tailed macaques with moderate to advanced degree of baldness for 5 out of 7 days/week for 4 months at 50 µg/mL with and without an additional 3 months dosing at 500 µg/mL, was associated with minimal and moderate to marked hair regrowth, respectively.3


Pharmacokinetics


Limited skin penetration of bimatoprost was demonstrated in a study in mice. Skin and blood concentrations of bimatoprost increased in a dose-dependent manner following application of 0.1 mL of a 0.01 to 0.06% gel formulation to a 12 cm2 area on the back (clipped of hair), with systemic bimatoprost exposure representing <0.1% of that for skin (based on area under the concentration time curve (AUC)). Bimatoprost appeared to accumulate in skin, but not blood, following repeated dosing at 30 or 60 µg/day for 21 days. Based on pharmacokinetic modelling, following multiple daily dermal applications of bimatoprost, skin exposure at steady state is not anticipated to be more than 3 times the exposure achieved following a single dose, with steady-state achieved in less than one week.

The limited dermal penetration of bimatoprost seen in mice stands in contrast with the significant scleral penetration of the drug observed in vitro in experiments with human eyeballs (Study PK‑93‑078; evaluated in the original application . The predictive value of the mouse study is diminished, though, by anticipated differences in permeability between dorsal and eyelid skin.

Human eyelid skin penetration of <1.5% is reported for fluticasone propionate4, and comparable low penetration can be expected for bimatoprost given the similarity in molecular weight and lipophilicity (physicochemical properties that influence dermal absorption) between the two compounds (molecular weights of 415.58 for bimatoprost and 500.70 for fluticasone propionate; log P values of 3.41 and 3.70, respectively). Bioavailability of bimatoprost by the topical ocular route is considerably higher (56%). Lower systemic exposure with Latisse is further indicated by the smaller dose administered (that is, one drop applied to the applicator and then applied to the small area of skin compared to one drop direct to the eye).

Toxicology


No repeat-dose toxicity studies by the dermal route have been conducted. However, distribution studies in monkeys demonstrated considerable radioactivity in ocular tissues, including the eyelids, after both single and multiple topical ocular doses of radioactively labelled (3H)-bimatoprost (0.1%). The tissue concentrations were higher than those predicted by the sponsor’s skin absorption model in mice, and this is likely related to exposure of the mucosal surface of the eyelid after ocular instillation. Greater absorption into the eyelid is anticipated with topical ocular compared to topical dermal administration. Long-term studies involving topical ocular administration of bimatoprost to rabbits (up to 6 months duration) and monkeys (up to 12 months) produced adequate exposure of the eyelids without signs of histomorphological changes to skin. Skin hyperpigmentation, reported as an adverse event in Latisse trial participants in draft Product Information document, was not observed in previously evaluated nonclinical studies. Ocular effects seen in laboratory animal species (transient conjunctival hyperaemia, signs of ocular discomfort, increased iridial pigmentation and an increase in the prominence of the periocular sulci) are less likely in patients treated with Latisse given the different route and lower dose/exposure.

Systemic safety has been adequately established in previously evaluated repeat-dose toxicity studies conducted by the ocular, oral (PO) and/or intravenous (IV) routes in mice, rats and/or monkeys. Animal:human exposure margins at the No Observable Effect Levels (NOELs) were very large with respect to topical ocular administration, and will be larger still with respect to dermal administration.



Pregnancy classification


The sponsor proposes Pregnancy Category B35. This is considered appropriate.

Nonclinical summary and conclusions


  • Nonclinical studies on pharmacology and pharmacokinetics were submitted in support of the application.

  • An eyelash enhancing effect of bimatoprost was demonstrated in mice after topical ocular administration of the clinical formulation. Bimatoprost was also shown to increase the growth of human scalp hair follicles in vitro.

  • Limited dermal penetration of bimatoprost was evident in mice following topical application to dorsal skin (systemic exposure, <0.1% of that in skin).

  • With the different route of administration and the different means of application (dermal application of a drop applied to an applicator compared to direct administration of a drop to the eye), systemic exposure to bimatoprost with this product is expected to be lower.

  • No repeat-dose dermal toxicity studies were conducted, but existing toxicity studies conducted by the topical ocular, PO and IV routes, are sufficient to support the local (dermal) and systemic safety of the product. No histomorphological changes to eyelid skin were observed in rabbits or monkeys, with the drug shown to be absorbed into the eyelid after topical ocular dosing. Ocular effects seen in laboratory animal species (transient conjunctival hyperaemia, signs of ocular discomfort, increased iridial pigmentation and an increase in the prominence of the periocular sulci) are less likely in patients treated with Latisse given the different route and lower dose/exposure.

  • There are no nonclinical objections to registration of Latisse.

  • The nonclinical evaluator also recommended changes to the draft Product Information but these are beyond the scope of this AusPAR.

IV. Clinical findings


A summary of the clinical findings is presented in this section. Further details of these clinical findings can be found in Attachment 1.

Introduction

Clinical rationale


The sponsor stated that eyelashes protect the eye from particles getting into it and so help prevent pain and possible infection. This occurs because particles hitting the eyelashes produce a blink reflex. There was also a claim that eyelash prominence can have a positive psychological effect on patients which can then result in a positive effect on quality of life. Hypotrichosis of the eyelashes was defined as ‘inadequate or not enough eyelashes’. The causes of this were listed as idiopathic, post alopecia-inducing medication such as chemotherapy and secondary to systemic conditions such as hypothyroidism or alopecia areata. As there are currently no approved products for hyopotrichosis of the eyelashes, the sponsor claims this is an area of unmet need.

Contents of the clinical dossier


The submission contained the following clinical information:

  • two pivotal efficacy/safety studies (192024-0386 and 12 month reports and 192024-032).

  • one phase IV efficacy/safety study (192024-039).

  • one dose-finding phase II study (192024-051).

  • one non-treatment study evaluating the efficacy assessment scale (192024-033).

  • one study using human biomaterials (BIO-10-876).

  • one stability study in human blood (PK-01-024).

  • one efficacy/safety study in a different indication (192024-031) and a Patient Reported Outcome dossier (eyelash satisfaction questionnaire).

  • one Periodic Safety Update Report (PSUR) (March 2011 to Feb 2012).

  • Literature references and tables for the sponsor’s Integrated Summary of Efficacy and Integrated Summary of Safety.

Paediatric data


The submission did not include paediatric data.

Good clinical practice


All clinical trials included in the dossier contained a statement that they were conducted according to Good Clinical Practice guidelines and local ethical and regulatory requirements.

Pharmacokinetics

Studies providing pharmacokinetic data


No additional clinical pharmacology studies were conducted. A justification for not providing biopharmaceutic studies was included in in the sponsor’s submission. The sponsor’s justification was based on the following points:

  • Latisse is administered with an applicator used to apply bimatoprost to the eyelid margins and is designed to deliver a fraction of a 1 drop bimatoprost dose. With this application method administration, absorption of bimatoprost is limited by the protective skin barrier and the small surface area upon which the dose is applied.

  • After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time.”

Comment: this appears to the same justification as discussed in the Clinical Evaluation Report for the initial submission and the evaluator agrees with the two latter points. Data were not presented in the clinical dossier on the actual amount of one drop that is administered via the use of the applicator.

The sponsor included a stability study of bimatoprost (AGN 192024) and its metabolite AGN191522 in human blood after storage at -20°C for 12 months (PK-01-024). , The study found both compounds were stable, as measured by concentrations within the 80 to 120% stability criteria, during 12 months storage.


Evaluator’s conclusions on pharmacokinetics


The route of administration at the eyelid margin rather than to the ocular surface is expected to result in an even lower systemic exposure. This may be assisted by the use of the specific applicator which the sponsor states delivers a dose of under one drop, although details of this information were not provided.

Pharmacodynamics

Studies providing pharmacodynamic data


There was only one study submitted with the clinical data which provided pharmacodynamic data (BIO-10-876). This was a nonclinical study on the mechanism of action of bimatoprost for hair growth. No other data were submitted and in vivo drug-drug interaction studies have not been conducted due to the low systemic absorption.

Evaluator’s conclusions on pharmacodynamics


Bimatoprost is a synthetic prostamide analogue, structurally related to prostaglandin F2 (PGF2). The precise mechanism of action through which bimatoprost causes eyelash growth is currently unknown although it believed to be via a direct action on prostanoid receptors on the hair follicle.
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