sinclair pharma plc - perfectha® hyaluronic acid dermal ......hyaluronic acid (ha) ... hyaluronic...

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2016

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SINCLAIR PHARMA PLC1st Floor, Whitfield Court

30-32 Whitfield StreetLondon, W1T 2RQUnited Kingdom

Marie-Odile Christen Paris, August [email protected]

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PERFECTHA® SAFETY A CROSS-LINKED HYALURONIC ACID

Safety Data Report by Marie-Odile Christen

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CONTENTS

1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2 PERFECTHA SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.1 PERFECTHA Product Component Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Hyaluronic acid (HA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1,4-butanediol diglycidyl ether (BDDE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.2 PERFECTHA FINISHED PRODUCT SAFETY . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Quality and specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 PERFECTHA experimental safety studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 PERFECTHA clinical study on durability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 PERFECTHA clinical studies: focus on safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 PERFECTHA Post Marketing Surveillance (PMS) . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.3 PERFECTHA Recommendations: IFUs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Precautions for use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Warnings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

3 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

4 CONCLUSION RELATED TO PERFECTHA SAFETY . . . . . . . . . . . . . . . 30

5 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

PERFECTHA SAFETY REPORT

1 INTRODUCTION

4

SAFETY REPORT

PERFECTHA® belongs to the widely expanding and well known hyaluronic acid family of dermal fillers . Their place in aesthetics has continued to grow dramatically since their development back to the 1990’s .

They emerged following the decline in the use in aesthetics of collagen products targeting the collagen loss, one of the main features of aging . This decline occurred due to the need to perform pre-testing, the appearance of some safety issues such as allergic reactions but also due to the arrival of this new class, the hyaluronic acids .

Hyaluronic acids (HAs), the most used filler substances currently on the market worldwide, have a number of advantages over their predecessors, especially regarding safety and duration of action . Over the past 15 years cross-linked HA fillers have been reported to have a favourable safety profile and to be generally well tolerated .

PERFECTHA is a range of cross-linked resorbable hyaluronic acid (HA) gel intended for reconstructive purposes in the treatment, for instance, of facial lipoatrophy, or morphological asymmetry associated with the aging process or other underlying conditions . The PERFECTHA product range is for intradermal and subcutaneous application and is implanted in the areas of the face and hands (PERFECTHA SUBSKIN) to fill skin depressions and also for the augmentation of tissue volume .

Five different PERFECTHA dermal fillers are available and used for specific indications: PERFECTHA FINELINES, PERFECTHA COMPLEMENT, PERFECTHA DERM, PERFECTHA DEEP and PERFECTHA SUBSKIN .

PERFECTHA is manufactured in FRANCE at the ObvieLine Laboratory located in Dardilly, nearby Lyon . Created in 2005 and acquired by Sinclair Pharma in 2014, ObvieLine Laboratory designs, develops and manufactures all the PERFECTHA range products .

PERFECTHA has obtained the CE Mark and the approvals by Health Authorities in around 70 countries, on the basis of the submitted and reviewed efficacy and safety data, including Korea, Australia, Brazil, Mexico, Colombia, Russia etc .

The ISO Certification and the CE Mark were obtained in 2007 for PERFECTHA FINELINES, PERFECTHA DERM and PERFECTHA DEEP; in 2010 for PERFECTHA SUBSKIN (1x3ml); in 2013 for PERFECTHA COMPLEMENT and PERFECTHA SUBSKIN (3x1ml)

Marie-Odile Christen

Introduction

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1

This report is aimed at providing available data, documenting the safety and defining the safety profile of PERFECTHA in its approved indication and common use in clinical practice . The available literature on hyaluronic acids, its main component, is huge; more than one thousand publications have been issued with hundreds dedicated to HA dermal fillers in aesthetics .

This report is not intended to be an exhaustive review, but a summary of various important aspects to provide evidence of PERFECTHA safety . It will cover the safety from its components to the finished product, on the basis of the data from experimental and clinical studies, as well as from the pharmacovigilance surveys .

When discussing product safety, it is important to consider the treatment modalities including: inappropriate selection of patients, injection errors such as incorrect technique, wrong area, wrong injection depth, excessive volume etc . The knowledge of the potential adverse events, their prevention and avoidance as well as the best treatment in case of complications is crucial, even if severe adverse events are rare .

Safety is essential for any drug or medical device; it is mandatory in the case of a product which is administered in healthy subjects .

The safety of PERFECTHA dermal filler will be discussed in this global context .

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1 INTRODUCTIONSAFETY REPORT

PERFECTHA, a biphasic BDDE cross-linked hyaluronic acid is represented by a range of five different products: PERFECTHA FINELINES, PERFECTHA COMPLEMENT, PERFECTHA DERM, PERFECTHA DEEP and PERFECTHA SUBSKIN with different approved indications, as defined in the Instructions For Use (IFUs) .

PERFECTHA is a Class III medical device, in accordance with the EU Medical Device Directive 93/42/ EEC .

PERFECTHA has obtained the CE Mark and the approvals by Health Authorities in around 70 countries .

PERFECTHA safety is based both on many experimental and clinical investigations reviewed and approved by the Health Authorities worldwide and on the outcome of its clinical use by experienced and trained physicians since its introduction 6 to 10 years ago, depending on the Stock Keeping Units (SKUs) . Indeed, its worldwide use in daily medical practice since then largely contributes to the knowledge of its safety .

This summary will consider PERFECTHA safety in relation to the following:

– from its main component, the hyaluronic acid, considering its key characteristics, main properties, its long term medical uses in numerous applications, its safety, and from the other component present at residual amount 1,4-butanediol diglycidyl ether (BDDE) . – to the finished product based on quality and safety data gathered from experimental and clinical studies, its clinical use in daily practice and the pharmacovigilance follow-up and surveys according to the current regulations .The report aims to provide data to support the safety of PERFECTHA and to encourage physicians to optimally and safely use this product in their practice with high satisfaction for themselves and their patients .

PERFECTHA Product Component Safety

l Hyaluronic acid (HA)

PERFECTHA is made of hyaluronic acid, a heteropolysaccharide macromolecule that has well-established and documented safety and performance characteristics . Hyaluronic acid has been included in the composition of many drugs and medical devices used for years in numerous applications . It is in particular the main component of the injectable dermal fillers; PERFECTHA belongs to this product family .

Hyaluronic acid:history

In 1934, Karl Meyer and John Palmer described in the Journal of Biological Chemistry an unusual polysaccharide with a very high molecular weight isolated from the vitreous of bovine eyes and they coined the name “hyaluronic acid“; before, the French scientist Portes isolated from the vitreous a mucin, the “hyalomucin“, a precursor of hyaluronic acid . During the second half of the twentieth century, hyaluronic acid (HA) was discovered in different tissues and liquids of vertebrae animals as well as humans and isolated from human umbilical cords, and shortly thereafter from rooster combs in a highly purified and high molecular weight form, as well as from synovial fluid .The chemical structure of hyaluronan was essentially solved by Karl Meyer in the 1950s .The development of HA as a product to be used in clinical applications is entirely due to Endre Balazs . He derived the new concepts and was the first to prepare HAs with sufficient purity to be tolerated . Balazs started to experiment with vitreous substitutes in surgery and introduced the “viscosurgery“; HA use in orthopaedic surgery developed in parallel .The introduction of HA-based Hylaform® from avian origin was the start of a continuous expansion in the use of HA dermal fillers, with the approval of Restylane®, the NASHA-Non Animal Stabilized Hyaluronic Acid of

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SAFETY REPORT

2.1

7

SILHOUETTE SOFT 2

bacterial origin in Europe in 1996 and in 2003 in the United States .

Hyaluronic acid: a major natural substance

Hyaluronic acid is a natural product present in all vertebrates; it is a vital component of the human body, an essential constituent of the Extra Cellular Matrix (ECM), found in particular within the skin; it is an ubiquitous substance identical across species and all tissues . It is found in a native homeostatic form within hydrated tissues such as the vitreous of the eye, articular cartilage, synovial fluid, lymphatics, and skin .Hyaluronic acid, also known as hyaluronan, is a glycosaminoglycan, a linear polysaccharide composed of a repeating disaccharide unit of 𝛽 (1,4)-glucuronic acid (GlcUA)-𝛽 (1,3)-N-acetylglucosamine (GlcNAc) .Hyaluronan is the only glycosaminoglycan member that is not sulphated and is not covalently bound to a proteoglycan core protein . Its structure is shown in figure 1.

Hyaluronic acid: an abundant substance

The importance of HA is related to its high content within the human body, but also to its essential functional properties .The incredible abundance of HA, estimated to be around 15 g in a 70 kg man in different tissues, and the fact that nearly one-third of it is removed and replaced each day (Fraser et al,1997), suggests a highly regulated molecule with functional importance (Maytin, 2016) . The largest quantity of hyaluronan (7-8 g per average adult human) resides in the human skin, the target organ for PERFECTHA, containing over 50% of the total of the

body’s hyaluronan (Boeriu et al, 2013) . It is present both in the epidermis, around 0 .1mg/g and in the dermis, around 0 .5 mg/g .

Hyaluronic acid: numerous applications

Many different hyaluronic acid-based products have been developed since the discovery and the characterization of this polysaccharide and are available for numerous medical conditions:In ophthalmology: the first hyaluronic acid-based biomedical product, was developed as an ophthalmic-surgical aid for use in various anterior segment procedures, as a vitreous replacement after vitrectomy and in retinal detachment surgery . It is the principle of viscosurgery . Developed by Balazs this purified product, the NIF-NaHA (Non Inflammatory Fraction of sodium hyaluronate) became a major product in ophthalmology surgery under the name Healon .In rheumatology and orthopaedics: the related indications were developed in parallel to those in ophthalmology . HAs are used in particular to treat knee pain caused by osteoarthritis (OA) characterized by a loss of cartilage, as a joint fluid supplement, typically administered by injection into the knee joint . Indeed, HA is contained in the synovial liquid, a substance that is present naturally in the joints . It works by acting like a lubricant and shock absorber, helping the joints to work properly .Viscosupplementation came into clinical use thanks to Balazs as early as 1987 in Japan and Italy . Hyalgan® and Synvisc® (Hylan G-F20) are the two pioneer products in this therapeutic domain . HAs are also used in orthopaedic surgery .

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PERFECTHA Safety 2

O--

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OHO

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Glucuronic Acid N-Acetyl-glucosamine

nFigure 1. Hyaluronic acid structure.

Other medical and surgical applications: HA is used in otolaryngology (for the treatment of vocal folds), for periodontal diseases (Aziz et al, 2016), for wound healing and regenerative engineering, oncological and infectious diseases . HA may offer the ability to reduce bacterial adhesion and biofilm formation; these properties are discussed by Romano et al, 2017 . The development of drug release systems based on HA has been applied to several drugs (Arpicco et al, 2014) .

In aesthetic medicine: the use of hyaluronic acid based products as dermal fillers has been the object of an exceptional development in recent years, reaching first place in the injectable dermal filler group . HA is a key molecule in skin aging that has the unique capacity of retaining water (Papakonstantinou et al, 2012) . The rationale is based on the fact that HA is a major component of the Extra Cellular Matrix of the skin and that the process of aging is characterized by volume loss and redistribution, linked amongst other aging changes, to atrophy of underlying adipose tissue and wrinkle appearance . A progressive decrease in the hyaluronic acid content in aging skin has also been described by some authors (Ghersetich,1994), leading to the suggestion that variations of hyaluronic acid levels in the dermis may account for some of the changes seen in aged skin . Since the introduction of Hylaform® (Hylan G-F20) from avian source in the US, approved by the FDA in 2004, and Restylane®, the first NASHA (Non-Animal Stabilized HA) from bacterial origin, in 1996 in Europe and in 2003 in the US, the number of HA dermal fillers has continued to increase, with around one hundred HA dermal fillers available today (Gold, 2007; Brandt et al, 2008; Wollina and Goldman, 2011; Mansouri and Goldberg, 2015), (table 1) .

These HA-based dermal fillers are the object of this safety evaluation report .

Hyaluronic acid: mechanism of action

THA mechanism of action has been extensively studied . The hydrophilic characteristics related to its original structure are the basis of the skin hydration effect; HAs form gels, that through the viscous consistency, allow viscosupplementation in particular in osteoarthritis, and filling for depressions, volume loss and wrinkles correction in aesthetic medicine . HAs provide structural support via cell-interactions . Several receptors that bind HA have been identified: CD44 is the main receptor for hyaluronan, present at the cell membrane of almost all human cells . Others are RHAMM, TLR-4, HARE .There is some evidence suggesting that HA fillers may stimulate de novo collagen synthesis in the skin, enhancing its properties as a filler . In a study by Wang, eleven patients received intradermal injections of Restylane into photodamaged forearm on one side and saline into the other forearm .There was significantly more type I pro-collagen formation at the HA injection site measured on punch biopsies, taken at 4 and 13 weeks . The authors postulated that collagen production by HAs could be due to mechanical stretching of fibroblasts (Wang et al, 2007) . Since this work, the effect of HAs on collagen production has been regularly evoked and accepted as a mechanism participating in HA biological action (Turlier et al, 2013) .

Hyaluronic acid: safetyThe safety of hyaluronic acid benefits from its long-term use and the knowledge of its characteristics and properties acquired on numerous HA-based products in various applications . HA-based products can differ in terms of HA concentration, particle size, cross-linking degree, reticulation agent, duration, stiffness, hydration, production process technology leading to monophasic or biphasic HA products, and the presence of lidocaine (Greene and Sidle, 2015) .Rheological properties corresponding to the physical response to applied forces, allow us to predict how a filler will perform clinically: viscoelasticity and cohesivity also play an important role . A filler with a high elasticity, high G’ value, characterizing a firm product to be injected deep, will provide better

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Area Application Example

Biomedical Othopedic surgery Arthritis Rheumatology Osteoarthritis Opthalmology Eye surgery Otolaryngology Treatment of the vocal fold Dermatology and plastic surgery Dermal filler Wound healing and dressing Diabetic ulcer, skin burns Tissue engineeringPharmacology Drug delivery

Table 1: Hyaluronic Acid medical applications

Table 1: Hyaluronic acid medical applications

PERFECTHA Safety

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SAFETY REPORT

lift . Many publications are devoted to HA rheology and the clinical implications (Kablik et al, 2009; Sundaram et al, 2010; Stocks et al, 2011; Sundaram and Cassuto, 2013) . The HA physicochemical characteristics are an integral part of the safety/efficacy evaluation as they will influence the choice of the physician following his patient assessment, regarding the area to be injected, the depth and the indications . So the number of experimental and efficiency safety clinical study data on HA dermal fillers that were reviewed and approved by Health Authorities worldwide, have accumulated over time . Core information, both on safety based experimental and clinical studies, are provided in this report, with a focus on safety .

l Experimental safety studies

The toxicity data of hyaluronic acid have been described in detail in a safety assessment report by a panel of experts of the Cosmetic Ingredient Review committee (CIR panel) . Voluntary industry reports to the US Food and Drug Administration (FDA) include use in 223 products (Becker et al, 2009) . The experts’ panel concluded that:– ”Hyaluronic acid was not toxic in a wide range of acute animal toxicity studies, over several species and with different exposure routes .– Hyaluronic acid was not immunogenic, nor was it a sensitizer in animal studies .– Hyaluronic acid was not a reproductive or developmental toxicant .– Hyaluronic acid was not genotoxic . – Hyaluronic acid does not likely play a causal role in cancer metastasis; rather, increased expression of hyaluronic acid genes may be a consequence of metastatic growth . – Widespread clinical use of hyaluronic acid, primarily by injection, has been free of significant adverse reactions .– Hyaluronic acid and its sodium and potassium salts are considered safe for use in cosmetics as described in the safety assessment” (Becker et al, 2009).

This safety report was preceded by a review on hyaluronic acid (Hyaluronan) from Necas presenting data on cytotoxicity, neurotoxicity, ototoxicity, carcinogenicity, mutagenicity and reproductive toxicity, all providing similar conclusions (Necas et al, 2008) .

Additionally, a recent study (Guo et al, 2015) has assessed HA cytotoxicity on L929 mouse fibroblasts and their repairing ability to thermal-injured HaCaT keratinocytes . A scratch test was used to observe the effects on cell migration .Hyaluronans with different molecular weights were nontoxic, even at the concentration of 0 .5% . Cell viability and cell density of the thermal-injured keratinocytes treated with HA (600, 1070, and 1500 kDa) were increased significantly compared with that of model control (P<0 .05) . Hyaluronans promoted cell migration significantly with higher cell density in the scratch area, compared with the control after culture for 48 hours .The authors concluded that “Hyaluronans can repair cell injury and promote cell migration and proliferation. They also have good biocompatibility” (Guo et al, 2015).Moreover, it is important to recall that, in the process of obtaining the CE Mark and the registration approvals worldwide, HA dermal fillers as for any medical device, have to pass a number of tests according to ISO 10993 standards, described in international guidelines to evaluate their biocompatibility, cytotoxicity, acute and sub-chronic toxicity, and sensitization capacity .The fact that all the HA dermal fillers available, accounting for around 100 products, had been tested successfully for these officially requested tests, confirms their safety according to the standards of today and has to be integrated as important evidence in the safety evaluation .The accumulated information is impressive and contributes to support the product safety .

l Clinical safety studies

Clinical studies are essential in the contribution to the safety of HA dermal fillers . The knowledge on safety is based on all data gathered on up to one hundred available HA dermal fillers in around 100 clinical studies including thousands of subjects; in addition, their use worldwide in daily practice further supports their safety .This review will not consider the individual studies conducted on each product due to their number and the variety of designs . It will be focused on systematic reviews and meta analyses as well as on review publications specifically dedicated to HA-induced adverse events .

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2PERFECTHA Safety

Hyaluronans can repair cell injury and

promote cell migration

and proliferation. They also have good

biocompatibility »(Guo et al, 2015).

l Sytematic reviews and meta-analyses

Systematic reviews and data meta-analyses on large populations allow definition of the HA safety profile; moreover, references will be made to a number of published reviews devoted to dermal filler adverse events or complications, their prevention and management, as well as consensus papers from experts’ panels .Given that Restylane was the first HA dermal filler approved (in 1996 in Europe and in 2003 in the US), to evaluate its safety on the basis of its use in a very large patient population, is of great value for profiling HA dermal filler safety . This is particularly relevant as PERFECTHA is a biphasic HA dermal filler like Restylane and possesses similar properties . In addition, this report also includes other HA dermal fillers made of BDDE reticulated HA .

Friedman et al, 2002: a NASHA retrospective review

Friedman made a retrospective review of the worldwide data on reported adverse events using Restylane®, a non-animal stabilized hyaluronic acid gel, in a very large population . Adverse reactions were defined as all reported signs and symptoms that were felt to be related to the HA injection . The database included data from physicians in Europe, Canada, Australia, South America and Asia from 1999 to 2000 .

The review included 406,000 patients (n= 144,000 in 1999 and n= 262,000 in 2000) . 222 adverse events (AEs) were reported from 144,000 patients treated in 1999 corresponding to 1 AE for every 650 patients treated .

“The major react ion was local ized hypersensitivity reaction in 1 of every 1,400 patients treated, consisting of swelling, erythema and induration at the implant site, sometimes with edema in the surrounding tissues with a median duration of 15 days . They were no reports of systemic symptoms or anaphylaxis .”“68 cases of injection site inflammation were reported, corresponding to 1 of every 2,100 patients treated, including redness, oedema, and tenderness shortly after injection, as mild to moderate and self-timing, with an average duration of 4 days . This reaction started either shortly after injection, or after a delay of 2 days . There were also rare reports of granulo-matous reactions, bacterial infection, as well as acneiform and cystic lesions .“144 AEs were reported from 262,000 patients treated in 2000, corresponding to 1 AE in every 1,800 patients treated .

Based on the data presented, the overall proportion of patients experiencing an AE is 0.15% in 1999 and 0.06% in 2000 (Friedman et al, 2002), (table 2).

Brandt and Cazzaniga, 2008: HAs general review

In a general paper on hyaluronic acid gel fillers for the management of facial aging, Brandt commented on the HA adverse events, referring to some published studies:“The most common local ized s ide effects encountered after treatments with HA dermal fillers are temporary pain, induration, bruising, tenderness, itching, oedema, and erythema at the injection site (Lowe et al, 2005) . These side effects usually resolve after a few days and they can be ameliorated by experience, slow injection

2 PERFECTHA Safety

1999 2000

Adverse effect type Number of Incidencea of Number of Incidencea of adverse events adverse events adverse events adverse events (per 100 treated) (per 100 treated)

Hypersensitivity 104 0.07 52 0.02

Injection site inflammation 68 0.05 49 0.02

Other 50 0.04 43 0.02

Total 222 0.15 144 0.06


Lorem ipsum

Table 2: Reported Restylane® adverse events in 1999 and 2000.aAssuming 144,000 patients treated in 1999 and 262,000 in 2000 (based on the number of syringes sold) From Friedman et al., Safety data of nonanimal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 2002; 28 :491-494

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SAFETY REPORT

techniques, changing the needles often, and by instructing the patient to avoid aspirin several days prior to treatment . There have been reports of hypersensitivity reactions ranging from 0 .0005% to 0 .42% (Brown and Frank 2003; Hönig et al 2003) and, in rare cases, necrosis or embolization might occur (Schanz et al 2002; Hirsch et al 2007) .“

Hanke et al, 2011: a systematic review of soft tissue fillers

A systematic review of literature on the safety and efficacy of soft-tissue fillers made in the frame of the science conference organized by the American Academy of Dermatology and the American Society of Plastic Surgeons was published by Hanke 2011 . The analys is was made based on 198 studies, including 33 randomised controlled trials (RCT’s) on soft-tissue fillers . Interestingly hyaluronic acids were most often investigated with 83 studies including among others 25 RCTs, 4 cohorts, 13 uncontrolled studies, 1 cross sectional study and 1 systematic review that describe adverse events of HA fillers . Restylane® appeared the most often in the relevant studies followed by Juvéderm®, and the most treated area was the nasolabial folds . The authors stated that overall, the evidence is that soft-tissue fillers were effective and well-tolerated for correcting nasolabial folds, other moderate to severe wrinkles and folds, and volume loss in cheeks from subjects seeking aesthetic facial rejuvenation and from Human Immunodeficiency Virus (HIV) associated facial lipoatrophy patients .

Regarding safety, the adverse events were mild and transient, such as erythema and ecchymosis, and typically resolved within several days without treatment.

Cohen et al, 2013: a review on large-and small-gel particle HAs

A systematic review by Cohen, 2013 focused on large-gel particle (Restylane) and small-gel particle (Perlane®) hyaluronic acid soft fillers; the products were tested on nasolabial folds (NLFs) in 17 RCT’s and 4 studies showing good results . Most randomized controlled HA clinical studies have been limited to injections of the NLFs, at least in part because there are several validated scales for this area and the protocol designs are quite standardized . Few studies have been reported for the lips, oral commissures, cheeks, and other areas . The level of evidence for efficacy and safety data in these areas is often low, based mostly on practical experience and extrapolations from studies of NLF correction .

Regarding safety, common adverse events (AEs) across anatomic areas were pain, bruising, swelling, and redness. Serious AEs were uncommon (8 events in 8 patients of 4,605 total patients) and were considered to be unrelated (7 events) or probably unrelated (1 event) to treatment (Cohen et al, 2013).

Daines et al, 2013: a soft filler retrospective review

Daines made a 5-year retrospective medical record review on 2,089 injectable soft tissue filler treatments including 1,047 with HAs . The number of adverse events was very low; they are summarized in table 3.

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2PERFECTHA Safety


Filler Type (Total No. No. (%) of Complications

of Treatments) Cellulitis Nodule Necrosis Other Total or Granuloma Formation

Hyaluronic acid (n = 1047) 0 1 (0.1) 0 1 (0.1) 2 (0.2)

Poly-L-lactic acid (n = 811) 0 5 (0.6) 0 1 (0.1) 6 (0.7)

Calcium hydroxylapatite (n = 231) 4 (1.7) 1 (0.4) 1 (0.4) 0 6 (2.6)

All fillers (N = 2089) 4 (0.2) 7 (0.3) 1 (0.05) 2 (0.1) 14 (0.7)

Table 3: Breakdown of injectable soft-tissue filler types and their associated complications.From Daines et al., Complications Associated With Injectable Soft-Tissue Fillers A 5-Year Retrospective Review JAMA Facial Plast Surg.2013;15(3):226-231

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”Injectable soft-tissue fillers offer patients noticeable and immediate results, without the downtime associated with traditional facial rejuvenation surgery .”

• Regarding safety

”Whereas mild pain, swelling, and bruising at the injection site are common and expected consequences of these treatments, true complications arise less commonly” (Daines et al, 2013) .

Huang et al, 2013: a HAs meta-analysis

A systematic review and meta-analysis on HAs efficacy and safety was recently published; in this review, focus will be mainly on safety, as described hereafter .Indeed, Huang made a systematic review and meta-analysis of various hyaluronic acids based on studies selected on inclusion criteria such as a duration of 0 .5 to 24 months, HA use in the treatment of nasolabial folds, and adverse event incidence reports; a total of 25 studies comprising 18 RCTs (Randomized Clinical Trials) involving 2,521 patients and 7 CTs (Clinical Trials) involving 346 patients were eligible . It is interesting to note that the study on PERFECTHA from Pinzon et al 2010 is part of the RCT studies included in this meta-analysis .

Regarding safety, “The most common short term AE (diminished in 1 or 2 weeks after injection, with no intervention required) was swelling, 37.3% and the second most common AE was redness, 28.7%. The most common long term AE (occurring 2 weeks after injection) was skin induration, 11.5%”.In the HA subgroup, including various HA products such as monophasic and biphasic HAs, the subgroup analysis indicated that the AE incidences of Juvéderm® were significantly higher than for other products (such as pain, bruising, injection site nodules, pruritus, skin induration and skin discoloration, p<0 .01 . “Monophasic fillers demonstrated a significant higher AE incidence rate than biphasic, p<0.0001%.”The main risk factors related to the HA characteristics, patient population, or the modalities of treatment, were considered by the authors, showing that: – AE occurrence is possibly higher in patients with lighter skin colour, Fitzpatrick

type I-III than in patients with skin type IV to VI .– Immediate AEs are generally technique-dependent and nodule formation related to overcorrection or too superficial injection .

Taken together, “the safe and effective track record of HA dermal fillers makes them currently the most popular filling material. The utilization of these fillers by trained professionals provides an effective and safe therapy for the management of the aging face” (Brandt et al, 2008).

Reviews on HA adverse events and management

To complete this HA safety evaluation, reference is made to several papers dealing specifically with some particular dermal fillers adverse events, their prevention, avoidance and management and to a recent experts’ consensus recommendation report .Indeed, several experts have focused straight to the point, recognizing that even if HAs are associated with a very low rate of adverse reactions when used appropriately, some risks exist, as they do for any procedure, even the less invasive ones . They have to be known and avoided and properly managed in case they occur . The increasing number of products, their increased use worldwide and in larger indications, also contribute to some increase in risk occurrence .

Adverse event avoidancePhysicians have to be aware of patient, product, procedure-related factors that can impact the occurrence of AEs; some areas can also be at risk of vascular complications such as glabella, alar base, nose, and the temples that have to be cautiously executed .Patient medical history, current medical t reatment and prev ious aesthet ic treatments have to be recorded and the patient carefully assessed and informed of the procedure and the risks involved prior to treatment .Strict precaution of asepsis has to be taken into consideration to avoid the risk of infection .De Boul le and Heydenrych, 2015, members of a consensus group, analysed patient factors influencing dermal filler complications and considered prevention, assessment and treatment .

SAFETY REPORT 2 PERFECTHA Safety

The utilization of these fillers by

trained professionals provides an effective

and safe therapy for the management

of the aging face » (Brandt et al, 2008).

“The majority of complications are related to accepting patients inappropriate for treatment or issues of sterility, placement, volume, and injection technique . It is clear that aesthetic practitioners need an in-depth knowledge of all aspects of treatment with dermal fillers to achieve optimal outcomes for their patients” .Strategies to minimize the risk with HA have been proposed (Signorini et al, 2016) . It is necessary to: – know anatomy -be aware of ”danger” areas; – slowly inject with the least amount of pressure possible;– incrementally inject 0 .1 to 0 .2 ml of product;– use small syringe, small needle;– stop injecting if there is some resistance and if the patient has pain and /or discomfort . (Signorini et al, 2016) .

Types of AEToday the possible adverse events that can occur related to HAs are well characterized and there is a general agreement among experts of the potential risks . Adverse events are classified as early and late reactions to the dermal fillers .Vanaman recently made a review of the common complications appearing after treatment with different procedures, including the use of HAs (Vanaman et al, 2016) .Interestingly one of the most recent publications (Signorini et al, 2016) presents the consensus recommendations of an experts’ panel and identifies the possible AEs that can occur with soft-tissue fillers and reflects the general opinion of physicians, based on their experience (table 4).In 2017, recommendations of a panel of experts addressed the different phases of the treatment, from the preparation (patient interview, medical history, informed consent, clinical assessment), to the procedure (patient and theatre preparation, preparation of the treatment area, injection techniques) and the post-procedural care . The consensus allows to standardize the process and to establish how to prevent complications by strictly following all procedure steps (Urdiales-Galvez et al, 2017) .

Management of complications

Numerous reviews discussed all possible complications, early reactions and/or late reactions on the basis of the experts’ own

experience and through literature; several authors provided management options (among the most recent: Vanaman et al, 2016; Abduljabbar and Basendwh, 2016; Rzany et al, 2015; Funt and Pavicic, 2013, 2015; Luebberding and Armenakas, 2013; Gladstone and Cohen, 2007) .Treatment algorithms have been also published by several authors:In his review, based on his experience and published articles, Kim et al, 2014 discussed the early and late HA-induced AEs and suggests a treatment algorithm to help wound healing and tissue regeneration and to generate good aesthetic results with early treatment in response to the side effects of fillers . Familiarity with the treatment of these rare complications is essential for achieving the best possible outcome (Kim et al, 2014) .Funt and Pavicic published, in 2013 and 2015, two overviews of AEs mediated by dermal fillers in aesthetics and the treatment approach including algorithms for: – the management of antibody-mediated or non-antibody mediated edema;

13

Table 4: Classification of soft-tissue filler complications by onset of adverse event

Early reactions

Vascular infarction/soft-tissue necrosisInflammatory reactions (acute/chronic)

InfectionAllergic reactions/ hypersensitivity

Injection-related eventsPainEcchymosisErythemaBruisingBleeding

Inappropriate/superficial placementDistant spread

Late reactions

Inflammatory reactions (acute/chronic)InfectionGranuloma (typically chronic)Differential diagnosis

NodulesDyspigmentationDisplacement of hyaluronic acid filler material

Table 4: Classification of soft-tissue filler complications by onset of adverse event .From Signorini et al., Global Aesthetics Consensus: Avoidance and Man-agement of Complications from Hyaluronic Acid Fillers—Evidence-and Opinion-Based Review and Consensus Recommendations Plast Reconstr Surg 2016; 137: 961e-971e, with permission

2PERFECTHA Safety

14

– the management of malar edema– the management of nodular masses – the management of vascular compromise . The author outlined that ”The majority of adverse reactions are mild and transient, such as bruising and trauma-related oedema . Serious adverse events are rare, and most are avoidable with proper planning and technique . For optimum outcomes, aesthetic physicians should have a detailed understanding of facial anatomy; the individual characteristics of available fillers; their indications, contraindications, benefits, and drawbacks and be aware of ways to prevent and avoid potential complications .” Algorithms for management of antibody-mediated

and nonantibody-mediated edema and algorithm for management of malar edema are provided . (Funt and Pavicic, 2013, 2015) . Signorini presented algorithms for treatment of early and late mild to moderate complications of dermal filler injection and for the treatment of suspected intravascular injection with dermal fillers (Signorini et al, 2016) .A panel of experts from Germany (G), Austria (A) and Switzerland (CH), very recently developed the “DACH recommendations”, intended to complement other published guidance, to inform clinicians how to best recognize and prevent potential risks, and provide recommendations on how to


Early complications

BruisingBleedingEdema

Small gaugeSlow Injection

Avoid exercice (24 hr) Cold compresses

Lumping Superficial placement

Tyndall effect

Early acuteinfection

Fluctuant abscess

I&D or aspirationEmpiric

antibiotics†

Empiric antibiotics†

No improvement No improvement

Possible biofilm

Culture antibiotics

Culture antibiotics

Possible biofilmfibrosis

Recovery

Recovery

Non fluctuant

Consider antibiotics‡

Hyaluronidase (for HA)ExcisionSteroïd

Culture antibiotics

Consider excision(granuloma)

HA, hyaluronic acid; I&D, incision and drainage

Empiric antibiotics‡

Hyaluronidase (for HA)I&D (fluctuant nodule)Steroïd (granuloma)

Non-inflammatorynodule

Inflammatory nodule or granuloma

Late complications

DisplacementHyaluronidase*

Massage

Hyaluronidase*

No improvement

Figure 2. Algorithm for treatment of early and late mild to moderate complications following dermal filler injections.From Signorini et al., Global Aesthetics Consensus: Avoidance and Management of Complications from Hyaluronic Acid Fillers—Evidence-and Opinion-Based Review and Consensus Recommendations Plast Reconstr Surg 2016; 137: 961e-971e, with permission

*Recommended hyaluronidase schema:• <2 .5 mm area: 10 to 20 U single injection; repeat injection if required• 2 .5 mm to 1 cm: 2 to 4 injection points with 10 to 20 U per injection point; repeat injection if required

†Recommended empiric antibiotic therapy :• Amoxicillin + clavulanate or• Cephalexin or• Ciprofloxacin 750 mg twice daily for 1 week (if penicillin allergy)Both antibiotic and antiviral therapy are reasonable options when etiology is uncertain

‡Recommended empiric antibiotic therapy :• Clarithromycin 500 mg + moxifloxacin 400 mg twice daily for 10 days or• Ciprofloxacin 500 to 750 mg twice daily for 24 weeks or• Minocycline 100 mg once daily for 6 months

manage AEs, if they occur . Contraindications to hyaluronic acid are detailed and ways to prevent AEs are discussed (Philipp-Dormston et al, 2017) .

Some physicians have addressed one particular adverse event in a dedicated publication .Funt discussed how to avoid malar oedema during midface/cheek augmentation with dermal fillers . The author concluded that “although malar edema is a severe adverse event, its incidence can be reduced by proper patient selection, proper filler selection, limiting filler volume, and by placing filler material deep into the malar septum at the immediate preperiosteal level .” (Funt, 2011) .Artzi, focused on resistant and recurrent late reactions to hyaluronic acid-based gel . Late reactions have a recorded rate of 0 .02% which is now the accepted threshold for HA-based products but in this retrospective study involving 400 patients, one filler (Juvéderm® Volbella) injected in the tear trough area and the lips showed higher rate of reactions with a tendency to persistency and recurrences . Indeed 4 .25% of the patients developed prolonged (up to 11 months) and recurrent (average: 3 .17 episodes) late (average onset: 8 .41 weeks after the injection) inflammatory cutaneous reactions . This finding evidenced the role of the product characteristics and of the treated area in the occurrence of AEs . In the authors’ experience, broad-spectrum antibiotics in conjunction with repeated high-dose hyaluronidase injections into the inflammatory nodules were effective treatments (Artzi et al, 2016) .Kim considered the vascular complications related to HA fillers and the management with hyaluronidase . According to the authors “hyaluronidase can reduce the vascular complication of HA fillers if used early, but there is no benefit in injecting hyaluronidase the day after the HA filler injection” (Kim et al, 2011) .

Hyaluronidase: HA-complication management

One advantage of hyaluronic acids over other dermal fillers is the possibility of being effectively removed if necessary by enzymatic cleavage . Indeed, hyaluronidase is a specific tool for hyaluronic acid

complication management, particularly in case of overcorrection, or superficial HA placement or of appearance of serious adverse events such as nodule formation, vascular embolism and tissue necrosis . Hyaluronidases (Hyals: HYAL-1, -2, -3, -4 in particular) are naturally occurring enzymes that have been long used in medicine to facilitate the diffusion of anaesthesia prior to ophthalmic procedures, and have the ability to degrade hyaluronic acid by cleavage of the 𝛽 (1,4) bond (Buhren et al, 2016) . There are currently no widely accepted standardized guidelines for its use . Several authors provided their view and recommendations .Landau devoted a paper specifically to hyaluronidase in an attempt to answer several of the practical questions related to its use in aesthetics in case of treatment with HAs .For nodule treatment, the dose and the need for repetitive treatment with Hyals are dependent upon several factors:– The type of complication and its location;– The importance (size and nature) of the damaged area;– The HAs responsible for the complication;– The quantity of HA that was injected .Indeed, there are differences of sensitivity to Hyals between the various HAs available for treatment, leading consequently to the need to use higher doses of Hyals for adverse event management in case of resistant HAs; this affects also the speed at which the HA will “dissolve” in the presence of Hyals (Rao et al, 2014) .Repetition of treatment is often necessary in case the initial treatment is not sufficient; it can happen in case of inflammatory nodules or long lasting fillers . If a great amount of HA has been used, an initial incision should be necessary .It is also the case when Hyal is used for vascular embolism treatment; the injection has to be made extremely rapidly at a much higher dose than for other adverse events, and in case the reaction is insufficient, another injection has to be done rapidly in 1 hour with sometimes even higher doses of Hyals .A consensus recommendation by a panel of experts has provided protocols of treatment with hyaluronidase in a large review of HA-induced complications and management (Signorini et al, 2016), (figure 2) .

15

2PERFECTHA Safety

16

Another consensus recommendation paper was published at the end of 2015 and was dedicated to the treatment of HA-induced necrosis by hyaluronidase (Cohen et al, 2015) .So it appears obvious and mandatory to make a very early accurate diagnosis of the complication for an optimal management taking into consideration all those listed factors above, before implementing the corrective treatment . In case of vascular embolism and necrosis, the treatment has to be started very soon after the complication has appeared to have chance to improve the severe condition .


Although rare (0 .05%), the hyaluronidase main adverse event reported is allergy, noted in ophthalmology, but not reported up to now in aesthetics; nevertheless, a pre-testing could be important in some patients . On the other hand, it is wise to recall that in case of infection or infectious nodules, Hyals have to be administered after antibiotic treatment to avoid spreading of the infection . Regarding the possible negative effect on the native HA, Hyals “can theoretically induce tissue toxicity by breaking out the native HA, but no documentation of toxicity is available“; no report on this kind of potential risk exists today in aesthetics .

• In conclusion

Hyaluronidases are at the disposal of most of the physicians even if their use is off-label and not authorized in France for example . A number of conditions that have been mentioned more frequently have to be followed carefully for Hyal efficacy and safety in complication treatment . There is no strict standard universal protocol of Hyal use; that needs to be adapted to the condition and the response to treatment .In fact, the benefit / risk has to be weighted for each specific case encountered on the basis of a rapid and accurate diagnosis and an excellent experience based on training, that should limit the use of hyaluronidase which remains a very reassuring and beneficial tool .In a recent overview on filler complications, Rzany 2015, who also published a report on hyaluronidase in 2009, concluded in

this recent paper that “so far hyaluronidase is the only available antidote for HA injection”; “Prevention is the best medicine and experience and education are our best tools“ (Razny et al, 2009, Rzany and Delorenzi, 2015) .

l 1,4-butanediol diglycidyl ether (BDDE)

Another component besides hyaluronic acid should be considered in the safety evaluation: 1,4-butanediol diglycidyl ether (BDDE), even if present at residual amount in the finished product .

BDDE: most used reticulating agent

BDDE is an agent involved in the production process of a majority of HAs and it has the potential to be present at residual levels in the finished product; so it is important to document its safety .Natura l f ree hya luron ic ac ids a re characterized by a very short duration of action; the half-life in the skin is 24 to 48 hours; so research has focused on finding ways to allow the increase in their longevity by introducing chemical and structural modifications .The vast majority of the injectable hyaluronic acid dermal fillers available today are cross-linked and the cross-linking conditions greatly influence the properties of the final product . Most of the leading hyaluronic acid fillers are cross-linked using the reticulating agent, 1,4-butanediol diglycidyl ether, or BDDE, converting them in hydrogels . Given that BDDE is involved in this main HA production step and that residual level is part of the product composition, it is wise to discuss its safety in this HA and PERFECTHA safety analysis, all the more so as its safety has been debated . A recent review provides detai led information on its metabolism (de Boulle et al, 2013) .The knowledge acquired on BDDE and on BDDE-reticulated HAs over 20 years can explain why it has become the standard, ahead from other cross linkers such as 2,7,8 – diepoxyoctane, divinyl sulfone .

BDDE: main characteristics1,4-Butanediol diglycidyl ether (BDDE), molecular formula C10H18O4 and chemical


structure given in figure 3, is a viscous liquid, which is hygroscopic in nature, able to crosslink by the reaction of the epoxide groups with the hydroxyl groups of the HA backbone, forming stable ether bonds, thus explaining the longer clinical duration of action of cross-linked HAs reaching or exceeding 1 year (figure 3).

BDDE: safetyBDDE is biodegradable and its safety has been extensively studied via BDDE containing products and HAs in particular . BDDE can be present in different states in the final product: 1) fully reacted crosslinker, a BDDE molecule that has reacted with HA on both ends, 2) pendant crosslinker, a BDDE molecule that has reacted with HA on one end only,3) deactivated crosslinker, a BDDE molecule that has reacted with H2O (hydrolysed BDDE),4) residual crosslinker, a BDDE molecule that has not reacted with HA or H2O (de Boulle et al, 2013) .The BDDE carcinogenic potential has been questioned in previous years, so it is important to provide up-to-date information about this potential risk; this originates from a mutagenic effect of unreacted BDDE evidenced in the Drosophila test (Foureman, 1994) thought to be due to the reactive nature of the epoxide groups, but no carcinogenic effect was observed in mice in a dedicated study requested by the FDA (Ciba Geigy, 1987) . “Since negative results were obtained in the mutagenicity studies of Restylane, and since the estimated excess cancer risk is in the range determined to be acceptable for

compounds released from medical devices (based on ISO 10993- 17), it is unlikely that BDDE-associated carcinogenic effects would be observed in patients who receive this product” . Toxicity data are presented in different registries (National Toxicology Program, Toxnet) . Unreacted BDDE is degraded via hydrolysis of the ether bonds; the hydrolysed BDDE which was shown to be nontoxic, nongenotoxic, gives rise to two by-products butanediol and glycerol:• 1,4-butanediol is known to be non-mutagenic, nonsensitizing, and a slight irritant, no carcinogenic effect was noted, some neurotoxicity at dose of 100 mg/kg (WHO expert Committee 2012 ; Irwin, 1996; Ishikawa, 2000); • glycerol classified as Generally Recognized As Safe Substance (GRAS) by the FDA was shown to be non-mutagenic, non-teratogenic, non-sensitizing and non-irritant, with a NOAEL of 2,000 mg/kg per day and an LD50 of 4,090 mg/kg (Robertson, 2002; Robergs, 1998) . Both by-products, butanediol and glycerol, are metabolized in water and CO2 .Moreover, the numerous BDDE-cross-linked HA biocompatibity and experimental toxicity studies bring additional support for the safety of BDDE present at the low residual recommended dose < 2ppm reached through the production process, including dialysis . The safety data generated in the clinical studies on BDDE-containing HA dermal fillers especially, and from their clinical practice for years, evidenced the clinical safety of BDDE obtaining HAs .

2PERFECTHA Safety

epoxy group

epoxy group

Figure 3. BDDE chemical structure.

... given the strength of the empirical

evidence, physicians should be confident

in offering these products to their patients » (de Boulle, 2015).

17

18

PERFECTHA FINISHED PRODUCT SAFETY

PERFECTHA is a sterile BDDE cross-linked biphasic hyaluronic acid gel available in a single-use syringe . PERFECTHA contains HA that is produced by bacterial streptococcus equi fermentation . PERFECTHA is a line of resorbable hyaluronic ac id (HA) gel implants intended for reconstructive purposes in the treatment, for instance, of facial lipoatrophy, or morphological asymmetry associated with the aging process or other underlying conditions . PERFECTHA is for intradermal and subcutaneous application and is implanted in the areas of the face and hands to fill skin depressions and also for the augmentation of tissue volume .PERFECTHA comprises 5 different products: PERFECTHA FINELINES, PERFECTHA COMPLEMENT, PERFECTHA DERM, PERFECTHA DEEP and PERFECTHA SUBSKIN, that differ by their respective particle size, their specific injection modal i t ies and dif ferent approved indications, as defined in the Instructions

For Use (IFUs) and summarized in the table 5 below .Different studies and supporting analyses have highlighted the specific features of the PERFECTHA products which incorporate advantages of both monophasic and biphasic gels .Those specific features of PERFECTHA are due to the employment of the E-Brid™ Technology in a state of the art manufacturing process, in particular:– The use of high molecular weight and high quality NaHA to manufacture a high quality product;– An enhanced process of cross-linking to obtain a higher number of bonds in order to make a very elastic gel giving excellent support to the skin as well as an excellent duration;– A controlled mixing process to combine highly cross-linked HA with a small amount of free HA, to maintain a highly elastic gel whilst also achieving excellent flow properties and ease of injection .Thanks to the specific E-Brid™ Technology, PERFECTHA exhibits particular properties:– High elasticity expressed by the G’ value, providing a good lifting effect;


PERFECTHA® PERFECTHA® PERFECTHA® PERFECTHA® PERFECTHA®

FINELINES COMPLEMENT DERM DEEP SUBSKIN

INDICATIONS • Superficial facial lines • Superficial facial lines • Medium facial lines • Deep facial lines • Volume creation and skin depressions and skin depressions and skin depressions and skin depressions • Facial contours • Periorbital lines • Forehead finelines • Glabellar lines • Lip volume • Malar areas • Perioral lines • Lip contour • Nose • Chin and cheeks • Nasolabial folds • Nose bridge • Marionette lines • Hands • Oral commissures • Cheekbones and chin moderate augmentation

DEPTH OF SUPERFICIAL DERMIS SUPERFICIAL DERMIS MID-DERMIS DEEP DERMIS

SUBCUTANEOUS ORINJECTION SUPRAPERIOSTEAL

HA 20 mg/ml 20 mg/ml 20 mg/ml 20 mg/ml 20 mg/mlCONCENTRATION

VOLUMIZING + + ++ +++ ++++CAPACITY

VOLUME 0.5 ml 0.8 ml 1 ml 1 ml 1 x 3 ml 3 x 1 ml

NEEDLES 2 X 30G 2 X 30G 2 X 30G 2 X 27G

22G needle + 22G cannula& CANNULAS 21G needle + 21G cannula

Table 5: PERFECTHA product range characteristics

2.2

– Low extrusion force allowing a precise and easy injection .– Long lasting action by minimizing effects of hyaluronidase and oxidation due to a higher number of cross-linking bonds .– Biologically safe product with a very low impurity profile .

l Quality and specifications

PERFECTHA gels are manufactured in France at the Obvieline Laboratory (Dardilly), created in 2005 .All production steps leading to the release of the finished product, namely filling, sterilization, packaging and analytical testing are also performed in France and under controlled conditions according to ISO .PERFECTHA is a sterile product, an important characteristic for an injectable dermal filler . The cross-linked hyaluronic acid gel of non-animal or igin at a concentration of 20 mg/ml in phosphate-buffered saline is supplied in a pre-filled, ready-to-use, single-use syringe .PERFECTHA is subject to strict quality control, from the raw materials to the finished product, which is released in accordance with the product specifications; the control tests performed on all the batches produced evaluate the key physical properties, HA content, pH, BDDE residual level, microbiological quality with bioburden and endotoxin level, physical characteristics, viscosity and extrusion force . The specifications and results obtained with PERFECTHA for the residual BDDE, the endotoxin levels and protein concentration, are as follows and ensure that PERFECTHA is a high purity product:– Low residual BDDE: the l imit in PERFECTHA is < 2 ppm; routinely it is non detectable .It is in accordance with the European Medicines Evaluation Agency (EMEA) CHMP/QWP/251344/ 2006 guidelines of June 28th 2006, indicating the maximum level of BDDE to be comprised between 2 and 10 ppm.

– Low level of endotoxins: the limit in PERFECTHA is < 4 UI/ml; routinely it is < 0 .5 UI/ml according to the European Pharmacopeia requirements .– Low protein content: the protein concentration in PERFECTHA is < 6µg /ml .

The EU CE Mark, and other national regulatory Authorities’ approvals, confirm

the quality of the production of the PERFECTHA products . The approvals and launches in around 70 countries for many years support its safety in the approved indications in humans . The Quality Management System of Obvieline is ISO 13485:2003 and EN ISO 13485:2012 certified, covering design, development, manufacturing and sales .

Adherence to the European Medical Device Directive 93/42/EEC covers the legislative, regulatory and administrative framework for an authorisation in Europe; the essential requirements are in terms of safety, performance and protection of patients, to minimize or reduce device risks .Regular internal and external audits take place to guarantee compliance and quality of the production process and of the final product .

Unannounced inspections by the Notified Body and Health Authorities can also occur, which are conducted to verify the compliance with the described and approved process and the manufacturing conditions .

l PERFECTHA experimental safety studies

In the course of the CE Mark regulatory process, PERFECTHA was assessed according to ISO 10993 standards “Biological evaluation of Medical devices“ .

Biocompatibility and toxicity assessment

Safety was tested in vitro and in vivo for biocompatibility and toxicity evaluating:

• Cytoxicity: no cellular abnormality was observed after 24 hours of contact between cells NTC L929 and the Medical Device tested . The size of the particles of cross-linked hyaluronic acid does not lead to specific cytotoxicity . The PERFECTHA products do not have any cytotoxic effect.

• Sensitization: no abnormality (sensitization reaction or allergy) was observed 6 hours,

24 hours, 48 hours and 72 hours after injection . The PERFECTHA products do not have any sensitizing effect.

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2PERFECTHA Safety

20

• Intradermal irritation and intradermal toxicity: no abnormality was observed 24 hours, 48, and 72 hours after application .

• I m p l a n t a t i o n : n o m a c r o s c o p i c abnormality, no internal coagulation point were observed after implantation .

• Acute, subacute and subchronic systemic toxicity: no mortality, no clinical signs or abnormal behaviour, no weight loss was noted .

• Chronic systemic toxicity: the effects of long-term administration of HA in the form of an implant (polyvinyl sponge) containing a central reservoir placed subcutaneously on the back of CD-1 adult male mice was investigated . The treatment was administered every 3 days for 2 weeks by intradermal injection . A histological evaluation was carried out . After 2 weeks, the cellular density and quantity of granular deposits in the tissue was lower in the HA-treated group . The organization of collagen fibre bundles was less dense in the HA-treated group .

No signs or symptoms of systemic toxicity were observed following long-term subcutaneous administration of HA .

• Genotoxicity: Tests were carried out on 5 mutant s t ra ins o f Sa lmonel la typhimurium . The mutagenic potential was defined by counting and comparing the colonies modified by PERFECTHA products and the control cultures .The PERFECTHA products do not cause genotoxicity .

• Reproduction and development: the level of the dose of Na hyaluronate 1% that had no effect in the study was estimated at 4mg/kg/day (40 mg Na hyaluronate/ kg/day) based on the general appearance and reproductive performance of the parent animals and their embryos and foetuses .

• Teratogenicity: a study was conducted in rats to determine the effect of Na hyaluronate on the parents and the 1st generation offspring . The level of the dose of NaHA that has no effect

on rats during pregnancy and on their 1st generation offspring was 50mg/kg .

• Pyrogenicity: the PERFECTHA products do not cause any pyrogenic reaction .

The PERFECTHA products were tested according to the ISO standards, as described above, and all comply . As the chemical composition and materials are identical for all products; the conclusions apply to the whole PERFECTHA product range .

The PERFECTHA products were shown to be non-cytotoxic, non-irritant, non-sensitizing, non-immunogenic and non-toxic.

Physicochemical characteristic evaluation

In addition, recently published studies investigating further into the physicochemical characteristics of PERFECTHA, provide additional information .

Park et al, 2014Park assessed some physicochemical characteristics of PERFECTHA DEEP and of another biphasic HA Perlane, (Galderma) compared to the monophasic HA, Juvéderm Ultra-XC, (Allergan), all produced with a BDDE cross-linking process .

– In vitro assay: Cell toxicity measured on fibroblast cell line, resistance to enzyme degradation using hyaluronidase, ‘syringeability’ assessing how much ‘injection force’ was required to extrude the filler from the syringe, and morphology of particles observed by scanning electron microscopy, SEM, were tested . There was no cell toxicity in any of the 3 HA fillers . Resistance to enzymatic degradation and ‘syringeability’ were better in PERFECTHA and Perlane, the 2 biphasic HA fillers than in the monophasic HA, Juvéderm Ultra-XC .Regarding the particle morphology, the monophasic product was also found to contain apparent particles although there was a slight difference compared to the biphasic products .– In vivo assay:The three fillers were also tested in vivo for efficacy and safety by injecting 0 .2 ml of all


The PERFECTHA products were

shown to be non-cytotoxic,

non-irritant, non-sensitizing,

non-immunogenic and non-toxic.

the fillers into the dorsal skin of hairless mice . Morphological pattern of filler was assessed by digital photography . For each group, after 6 weeks, the total remaining amount of filler was assessed in 5 mice, and histological evaluation of mice was assessed in 2 mice .In vivo testing showed about twice as much oedema in the monophasic filler compared with the 2 biphasic fillers immediately after injection . Volume assessment in animal skin was superior with the monophasic compared with the 2 biphasic HA fillers . After 6 weeks of filler injections in the mice, the total remaining amount of the monophasic HA filler was significantly greater compared with the biphasic fillers (no p value available) .

• Conclusion

The authors concluded that “PERFECTHA and Perlane, the biphasic HA fillers, have advantages in hyaluronidase resistance, syringeability and lower risk for over-correction, and may be better suited to wrinkle restoration .” (Park et al, 2014) .

Costa et al, 2013Confirmation of a better resistance to hyaluronidase was obtained in a study evaluating the properties before and after passage to the needle of PERFECTHA DERM and Restylane, two biphasic HAs, compared to monophasic HAs: Teosyal® Meso, Teosyal® UltraDEEPLine and Esthelis® Basic . The measurement was made with toluidine coloration put in the syringes through their tips, on photographs taken at various time intervals for macroscopic visualization . PERFECTHA DERM and Restylane appeared to be the ones having higher rheological stability when in contact with hyaluronidase after passing through the needle (Costa et al, 2013) .

Koenig, 2016 inflammatory potential

It is well established and it has been widely documented that hyaluronic acids (HAs) are generally considered as safe .However, some side effects such as swelling and oedema, generally considered as immediate AEs, but delayed in some cases, and inflammatory nodules have also been reported . Those AEs are related to an inflammatory process .

Acute / chronic inflammatory reactions are characterized by the release of specific mediators of inflammation from immune ef fector ce l l s . Polymorphonuclear neutrophils (PMN) and macrophages are the most important effector cells of acute inflammatory processes, and their mediators are significantly involved in the development of chronic inflammatory processes” .Those mediators include numerous interleukins belonging to the cytokines family, some are pro-inflammatory, others anti-inflammatory . The “chemokines” stemming from “chemotactic cytokines” and signifying their prototype function of “chemotaxis” of immune cells are represented in particular by the interleukins-8 (IL-8), pro-inflammatory chemokines that attract the neutrophils .

• Method

The effect of the PERFECTHA range on the interleukins-8 release from adherent macrophages, which can be taken as a reflection of its potential inflammatory effect and so related to the risk of appearance of side effects after injection (swelling and/or oedema), was evaluated in a recent in vitro study on human cells (Koenig, 2016) .All the products within the PERFECTHA range were tested both undiluted and at different dilutions; controls include a positive control using lipopolysaccharide, LPS and a negative control using peptidoglycan PG, both tested at different concentrations . LPS, a major outer membrane component of Gram-negative bacteria, causes tissue injury and shock by activation of monocytes and macrophages, and subsequent release of multiple proinflammatory cytokines . Peptidoglycan -PG is a major surface component of Gram-positive bacteria . It is embedded in a relatively thick cell wall and is usually covalently attached to other polymers, such as lipoproteins and lipoteichoic acids .THP-1 cells, derived from a human tumour cell line, differentiated in adherent macrophages by addit ion of PMA . PERFECTHA was added in the cell culture for 48h at 37° . Released interleukins levels were measured on the cell culture supernatant by enzyme immunosorbent assay, ELISA; experiments and ELISA measures were both performed in triplicate .

21

2PERFECTHA Safety

22

ResultsThe results showed that LPS induces a very high level of released IL-8 in a dose dependent manner (figure 4) . Peptidoglycan does not induce Il-8 release, as expected .PERFECTHA products induce a very low release of IL-8, around 50pg/ml evidencing that the products are devoid of inflammatory effect in the selected experimental conditions (figure 5) .

• Conclusion

The author indicated that the in vitro results can be transferred to in vivo conditions and concluded as follows; “according to our results the response in the skin due to the presence of phagocytes should be minimal to all PERFECTHA products“ (Koenig, 2016) .

l PERFECTHA clinical study on durability

Costa et al, 2017A recent clinical study was conducted to evaluate the durability in humans of PERFECTHA DERM in comparison to two other HA dermal fillers .The study was performed on 25 women between 45 and 60 years of age, with skin type I to VI (Fitzpatrick classification); 24 completed the study .PERFECTHA DERM, a 20 mg/ml biphasic HA, was compared to a monophasic monodensified HA, Teosyal Global Action 25 mg/ml, and a monophasic polydensified

HA, Esthelis Basic 22 .5 mg/ml . The products were injected by a bolus technique at a volume of 0 .2 ml and a depth of 0 .7mm in the lumbar area .On day 2, D 92 and D 182, biopsies were taken and prepared for histology with Alcian blue staining . The evaluation was based on a determination of the presence or absence of HA islets at the three selected times . At 6 months, the reduction of product amount was 62 .5% for Esthelis, 25% for Teosyal and only 12 .5 % for PERFECTHA . The authors conclude that PERFECTHA, a biphasic HA, has the highest durability . This is an essential element for the longevity and duration of action of the product .

l PERFECTHA clinical studies: focus on safety

Relevant information regarding PERFECTHA safety can be drawn also from the clinical studies evaluating both efficacy and safety; in this report, particular emphasis will be put on the safety data . The main studies are presented below:

de Arruda et al, 2008The study evaluated the satisfaction of 33 patients treated by PERFECTHA DEEP for the nasolabial folds and PERFECTHA DERM for the upper and lower l ip filling, combining brain mapping and a questionnaire technique on the well-being feeling, self-evaluation of the face, satisfaction with the results of the treatment, judgement of the family, friends and people at work, on the results of the treatment, decision to repeat the treatment and to recommend it to friends and family . Patients were very satisfied or satisfied with immediate results and those 3 months later . EEG mapping showed them to be satisfied with their appearance and with the treatment involving similar brain areas; electrophysiological data through the study of the brain activity while the person is involved in cognitive tasks, support the “subjective“opinion (de Arruda et al, 2008) .

Regazzini and Fares, 2008• Design

A prospective study by Regazzini assessed the efficacy and the safety of PERFECTHA SUBSKIN in enhancement of the chin


1.20000,00

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Figure 4. LPS induced IL-8 levels (Koenig, 2016)

(mental area) or cheeks (malar area) up to 18 months after treatment (n=126) in patients judged to have moderate to severe mid-face volume loss . Injections were made into the subcutaneous and/or supraperiosteal plane under anaesthesia in each cheek by fanning technique and each side of the mental area directly under the muscle; all patients were assessed at baseline and at 2, 4, 8, and 12 to 18 months post-injection . Subjects were evaluated using digital photography and clinical examinations, which included the use of subjective scales (Physician Evaluator Aesthetic Rating) to measure satisfaction with facial appearance, and the Global Aesthetic Improvement Scale (GAIS) . Photographs were taken prior to treatment and at each subsequent visits; the GAIS was used to assess the degree of patient and research doctor satisfaction with the procedure and scored . Patients all showed a persistence of benefit during the post treatment observation period up to 72 weeks . The patients and injectors observed augmentation of the areas injected .


Local adverse reactions are consistent with those expected of a filler material and appear to be related to the injection procedure/site rather than to the product itself . Adverse events were reported in only 6 of 119 patients (7%) . Two patients reported mild oedema and hematoma, which resolved in less than 2 weeks . Four reported mild ecchymosis and oedema following initial treatment, and mild oedema after receiving touch-up treatment . The effects resolved within 5 days .I n t h i s s t udy , m a l a r a nd m en ta l augmentation with injectable Hyaluronic Acid (PERFECTHA SubSKIN) Proved to be effective, easy to administer, and safe . Adverse events that did occur were minor in both nature and degree (e .g ., bruising and oedema), were limited to the injection site, and resolved spontaneously within several days; such effects are consistent with the use of fillers for soft tissue augmentation in general . Importantly, there were no cases of granuloma formation, development of nodules or product migration . The author concludes that “The product provided durable improvement for most

patients for at least 1 year . There were no serious adverse effects and no treatment interruptions because of side effects“ (Regazzini and Fares, 2008) .

Resende et al, 2008• Design

A long-term prospective study by Resende et al (2008) assessed the safety and efficacy of PERFECTHA DERM and Restylane for facial implants interestingly including a large patient population (n=1,366) . The treated areas were: nasolabial folds (n=658), lips (n=341), nasolabial folds and lips (n=260), ear lobes (n=16), cheeks (n=10), other (n=81) . Follow-up was at 1, 6, 8, and 12 months . Efficacy was determined by photographs taken before and after treatment (at 30 and 130 days) . All patients were satisfied with the filling . The practitioners’ estimate of the duration of the beneficial effect was between 8 months and 1 year .


Reverse effects occurred in 164 patients (12%): ecchymosis, asymmetry, palpable nodules, prolonged oedema > 5 days, recurrence of labial herpes recidive and haematoma . Complications occurred in 8 patients (0 .6%) including palpable fibrous cord (n=2), ectropion (n=2), frontal cellulitis (n=1), foreign body granuloma (n=1) and extrusion (n=2) . One patient developed nodules in the site of filling . Biopsy was taken and it was concluded to be a sterile abscess .

23

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1:2 1:4 1:8 1:16 1:32 1:64 1:128 1:256 1:512

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Figure 5. PERFECTHA induced IL-8 levels (Koenig, 2016)

2PERFECTHA Safety

24

In conclusion “the hyaluronic acid is safe and effective for use as a dermal filler with a low risk of complications and a high level of satisfaction“ (Resende et al, 2008) .

Ami, 2009• Design

A prospective study by Ami assessed the effectiveness and safety of PERFECTHA SUBSKIN in 36 patients, n=26 for malar and n=10 for chin aesthetic contours, following weight loss or ageing . Follow-ups were carried out after 1 day, 30 days, 3, 6, 12 and 18 months . No follow-up injections were given . Photographs were taken prior to treatment and at each subsequent check-up; the GAIS was used to assess the subjective degree of patient and research doctor satisfaction with the procedure . The doctor and subject analysed the photograph prior to treatment and at the different visits; the responses were graded from 1 to 5 (1=optimum, 5=worsening) .When assessed 3 months after treatment, 24 (92 .4%) subjects considered their results optimum, which was still the case at the 12-month assessment and 18 months after treatment, with around 90% of patients being satisfied with the chin correction and the cheek correction results . The authors concluded that it is important that the product be deposited in small quantities and at multiple sites (using the multiple tunnelling technique) in order to avoid pooling in the soft tissues .


The adverse reactions observed were related to the injection procedure and not to the product . At the chin site, these included local inflammation and redness (n=3), bruising (n=1) and moderate pain at the injection site (n=3) . These reactions did not appear to be related to the volume of injection and were temporary, generally subsiding within 4 to 8 days following treatment . There was no evidence of superficial nodularity, which would indicate product mobility or migration, in any of the patients . At the malar area, on the day following the treatment, some inflammation, induration and slight pain were reported, but subsided on the third day .

Pinzon et al, 2010• Design

A prospective study by Pinzon evaluated the efficacy, duration, and safety of PERFECTHA SUBSKIN for the correction of nasolabial folds in 30 subjects with darker skin types (Fitzpatrick types IV to VI) . This study is included in the meta-analysis on Hyaluronic acids of Huang et al, 2013 .Injection was applied using serial puncture, linear threading, layering and radial (fanning) techniques and completed in 1 or 2 sessions (2 weeks later) . Follow-up assessments were done at 2 weeks, 3, 6, and 9 months by using digital photographs and ratings on the GAIS satisfaction scale . The efficacy initially increased with time and was optimal at 3 months, where 80% of subjects with moderate folds and 100% of their physicians reported ‘very much improved’ . Grade 1 and 2 improvements on the GAIS was maintained at 9 months in moderate, severe, and extreme nasolabial folds with 90% of subjects satisfied with the procedure .


Transient post-injection effects, such as erythema at puncture sites and needle marks, were noted in twenty-four (80%) patients and bruising was seen in 10% of patients . No delayed hypersensitivity was seen in any patient . No hypertrophic scarring or keloidal formation was seen or reported at any point of clinical evaluation .PERFECTHA SUBSKIN was demonstrated as a safe and effective product to correct moderate to severe nasolabial folds . (Pinzon et al, 2010) .

Talarico et al, 2010• Design

PERFECTHA DERM safety and efficacy were evaluated in an open multicentric study including 87 subjects on nasolabial fold (n=58) and lip (n=29) correction . Efficacy was measured by the Global Aesthetic Improvement Scale (GAIS) and the Wrinkle Severity Rating Scale (WSRS), and safety through observation and the reporting of side effects . Improvement in NLFs and lips was observed in 86% and 89% of the women respectively at one week, and


PERFECTHA was effective and safe »

(Talarico, 2010).

the effect maintained at 3 and 6 months respectively .


Mild or moderate inflammatory reaction and ecchymosis occurred in 15% and 9% of the patients, mainly in nasolabial folds . The intensity of the inflammatory reaction varied from light to moderate, beginning soon after application and ending spontaneously up to seven days later . These reactions are comparable to similar studies in the literature, which report inflammation ranging from one to two days up to eight days (Micheels, 2001) . Two patients presented labial herpes simplex after treatment of the lips . No delayed reactions or unexpected adverse events were reported .The author concluded that “PERFECTHA was effective and safe in these indications“ (Talarico, 2010) .

Kalil et al, 2011• Design

Kalil assessed in an open prospective study, the efficacy and safety of PERFECTHA DERM in 20 patients with superficial wrinkles in the superior lip contour, and a prominent nasolabial fold . Significant clinical improvement was observed on the Wrinkle Severity Rating Scale (WSRS) after 15 days, which was sustained for 4 months . A minor worsening was observed after that period, although patients still presented favourable aesthetic results up to 12 months after the procedure . In some patients, biopsies were taken from the left retroauricular region 180 days after the procedure, showing the persistence of the product at least up to this amount of time, and no foreign body granuloma was observed in any case .


“Adverse effects associated with HA and the procedure itself included ecchymoses, oedema, erythema and local pain . These findings were of mild to moderate intensity, with a duration of a few days . Only one patient who received filling of the NLF presented the formation of a nodule around 30 days after the application of the product; the nodule disappeared after 15 days of massage with

medium potency corticoid; no foreign body granuloma was observed“ (Kalil, 2011) .Taken together, the authors consider the results of the studies show that PERFECTHA is safe and well tolerated.

l PERFECTHA Post Marketing Surveillance (PMS)

As discussed previously, HA dermal fillers are considered as safe but some risks can exist . Adverse events that can occur are well characterized; they have been reported during numerous clinical trials and during the use of the products in clinical practice . Several Health Agencies have listed and published those AEs that can occur following treatment . The French Agency, ANSM, differentiated AEs by:– Immediate side effects (1 day-15 days): haematoma, erythema, oedema-estimated duration 8 days;– Semi-delayed side effects (15 days-3 months): infection (relating to condition of asepsis), necrosis, nonspecific inflammation- estimated duration 1-6 months;– Delayed side effects (3-24 months): allergy, erythema, pigmentation- estimated duration 1-12 months;– Delayed (rare) side effects (> 3 Months-X years): granuloma X months, permanent .Based on available data up to 2012 ANSM estimated that side effects affect between 0 .1 to 1 % of injected persons . In line with this, the US FDA has also listed side effects related to dermal fillers and stated that “as in any procedure, there are risks involved with the use of soft tissue fillers . That is why it is important to understand their limits and possible risks” .The PERFECTHA Instruction For Use (IFU) includes undesirable post-operative effects “Typical absorption is spontaneous, 1 or 2 days after injection into the skin and 1 week after injection into the lips . However, secondary reactions may appear in the implanted area or the adjacent tissues, generally in the 4 weeks following injection .These reactions can be cutaneous erythema, swelling, oedema, nodosity, indurations, haematoma, pain, itching or increased sensitivity . In rare cases the formation of granulomas may be seen . Normally all these phenomena disappear 1 to 2 weeks after the injection . If the effects persist, the

25

2PERFECTHA Safety

26

treatment must be stopped and the patient must consult his/her doctor” .The following post market review on PERFECTHA fits with this description of potential side effects .

Adverse Events : Post Market Review of PERFECTHA

A recent analysis of the vigilance data relating to PERFECTHA made in June 2017, provides the current picture of PERFECTHA safety profile (Sheikh and Smith, 2017) . This analysis included a review of all adverse events received from July 2012 to May 2017, covering 4 years’ usage of PERFECTHA, presented by product presentation and by failure mode .

Adverse Events by product presentation

In summary, a total of 260 adverse events were reported from July 2012 to May 2017 . During the same period, in excess of 1,417,000 syringes were sold, resulting in an adverse event rate of 0.018% or one adverse event in 5450 syringes .The adverse event rate is known by product presentation (figure 6) .

Adverse Events by symptomThe majority of the cases reported were considered minor adverse events: swelling, inflammation or lumps . These cases were mostly not considered serious enough to meet vigilance reporting criteria i .e . no potential for serious injury or death and

equally no permanent damage to a bodily structure (figure 7) . Swelling (or oedema) is a normal reaction of the body to any trauma to help protective cells migrate to the area involved . It can be considered as a complication only if it persists over several days or is of major importance . The swelling can be caused by trauma of the injection (needle/cannula and the level of injection), dilution of the product itself, injecting large volumes, or individual insensitivity . Lumps or nodules seem to appear when large volumes are injected at any point, within scar tissues, close to the dermis or within the dermis . These factors lead us to believe that their formation comes from the attempt of the body to release an abnormal tension applied to the tissues . D e t a i l e d i n f o r m a t i o n o n t h e contraindications, warnings, precautions and directions for use are given in the Instructions for Use .

• Vigilance Cases

In total, there were 35 cases that were serious enough to meet vigilance reporting criteria, where mostly the appearance of an abscess (17) and subsequent surgical evacuation of this was the indicator for reporting, and not necessarily a life-threatening situation .Root cause investigation of these cases confirmed that the product was released in compliance with specifications . Sinclair’s medical board indicated that the abscesses could be related to the injection technique (aseptic conditions or superficial placement of the filler) or to the use of PERFECTHA in combination with other products . The Instructions For Use for PERFECTHA advises against the use of PERFECTHA on an area where non HA injectable implants have previously been placed .

• Conclusion

Based on the above summary including the rates presented at this time, the PERFECTHA products would appear to have an excellent risk profile .

2 PERFECTHA Safety

0,035

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Figure 6. Adverse event rate per presentation.

SAFETY REPORT

From July 2012 toMay 2017, in excess

of 1,417,000 syringes were sold, resulting in an adverse event

rate of 0.018% »(PMS survey, 2017)

PERFECTHA Recommendations: IFUs

Precautions for use• This product may be administered only by a registered medical practitioner in accordance with local regulations .• All injections carry a risk of infection, aseptic techniques and standard practices should be employed to avoid contamination and infection .• Knowledge of the anatomy of the site to be treated and specific precautions are essential in order to avoid perforation or compression of vessels, nerves and other more fragile structures .• Use o f the supp l ied need le i s recommended . Their design, diameter and length have been validated for optimum use with the injection . However, it is possible to use the same gauge needle but with a different cannula length to suit your injection technique . Use of other injection equipment increases the risk of the needle and/or the Luer lock fitting becoming detached .• There is known incompatibility between hyaluronic acid and quaternary ammonium

salts such as benzalkonium chloride (precipitation of hyaluronic acid) . Therefore, PERFECTHA should never come into contact with such products or with medical or surgical equipment treated with this type of product . The physician should check the composition of the disinfectant used to clean the patient’s skin prior to the injection and exclude the use of products containing such substances .• The maximum recommended dose of PERFECTHA gel is no more than 30 ml per 60 kg bodyweight per full course of treatment without prior anaesthesia, and should not exceed 60 ml per 60 kg bodyweight per year .• The patient should be advised not to apply make-up for 24 hours following the injection and to avoid prolonged exposure to UV rays, temperatures below 0°C, saunas and Turkish baths for 2 to 3 weeks following the injection .

Contraindications• Do not mix with other products before injection . This can alter the functionality of the product and affect the sterility of the gel leading to an increased risk of infection .

2PERFECTHA SafetyAb

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Figure 7. Adverse events by failure mode.

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• Do not inject via the intramuscular or intravascular route . Risk of vascular compression events, which can manifest as discolouration, necrosis or ulceration at the implant site or in the area supplied by the affected blood vessels; risk of ischaemic events in other organs as a result of embolism . In the event of superficial discolouration or blanching of the skin, the injection must be stopped immediately and the area massaged until its normal colour is restored .• Do not over-correct .• Avoid injection in patients with clotting disorders or tak ing thrombolyt ics , anticoagulants, aspirin, non-steroidal anti- inf lammatory drugs or vitamin C . These can predispose to swelling reactions at the injection site and can increase bleeding and the risk of bruising after the injection . These substances should be temporarily discontinued at least 7 to 10 days before the injection, and only with medical clearance with prescr ibed ant icoagulants such as warfarin or clopidogrel bisulfate .• Avoid injections in patients with known hypersensitivities to avian proteins, feathers and egg products, as patients with known hypersensitivities to these items may also be sensitive to sodium hyaluronate .• Do NOT use in patients with:– epilepsy which is not controlled by treatment– tendency to develop hypertrophic scars– known hypersensitivity to hyaluronic acid– porphyria– active (or a history of) autoimmune disease– a history of streptococcal disease (recurrent throat infections, acute rheumatic fever with or without cardiac involvement)– areas affected by inflammatory and/or infectious skin problems (acne, herpes etc .) or tumours at or near the treatment site– undergoing laser or UV treatment, deep chemical peel, dermabrasion or prolonged sun exposure . Following a superficial

peel, injection is not recommended if the inflammatory reaction induced by the peel is significant and/or still visible– receiving medical treatment that reduces or inhibits liver metabolism (cimetidine, beta blockers)– pregnant or breastfeeding women, children• Do not use on areas previously treated with fillers of animal origin, permanent implants or implants containing a substance other than hyaluronic acid . Risk of incompatibility between products; risk of activation or reactivation of the immune system and/or latent infections (biofilm) .

Warnings• Do not freeze (<2°C) for risk of implant degradation .• Check the integrity of the packaging, product, needles and cannulas provided; also check the expiry dates stated on the labelling: do not use the device if the carton is damaged or open;• Check the expiry dates stated on the labelling: do not use the device if the expiry date has passed .• Do not re-sterilise as the product quality cannot be guaranteed following additional processing .• Do not reuse: PERFECTHA is for single use . The syringe, needle and any remaining product must be discarded in suitable containers after use . The reuse of disposable single-use syringes and needles exposes the public to serious risks of infection and viral transmission . Reuse of any residual product can result in an increase in known undesirable effects .• Never attempt to straighten a bent needle/cannula; they must be discarded in suitable containers and replaced .

The expiry date of the product is stated on the packaging .Store between 2°C and 30°C, protect from frost and sunlight .


PERFECTHA is a biphasic BDDE-cross-linked hyaluronic acid belonging to the large HA dermal filler family . Five PERFECTHA products are available covering different indications and patient needs .PERFECTHA has been sold in 70 countries reaching 2 .8 million syringes sold worldwide . The safety of PERFECTHA is closely linked to the safety of hyaluronic acid, a natural and ubiquitous product, a component found in many products that have been used worldwide for many years, in many applications . PERFECTHA has been extens ive ly investigated both in experimental and clinical studies and data have accumulated to support i ts safety . PERFECTHA tested according to the requirements of ISO 10993 was shown to be non-cytotoxic, non-irritant and non-sensitizing; its biocompatibility was evidenced . In the clinical trials PERFECTHA was shown to be effective and safe .The pharmacovigilance and quality systems in place ensure regular follow-up of the product safety and quality . The adverse events reported for PERFECTHA are in line with those listed by the French Health agency or the US FDA in

relation to dermal fillers . On the basis of the updated vigilance information covering the last 4 years, PERFECTHA appears to have an excellent risk profile; between July 2012 and June 2016, the adverse event rate was low (0 .018%) .Nevertheless, precautions for use have to be strictly respected as well as all the recommendations regarding patient history, aseptic environment and modalities of treatment in order to avoid side effects . Recent recommendations of a panel of experts addressed the different phases of the treatment, from the preparation (patient interview, medical history, informed consent, clinical assessment), to the procedure ( patient and theatre preparation, preparation of the treatment area, injection techniques) and the post-procedural care . The consensus allows to standardize the process and to establish how to prevent complications by strictly following all the procedure steps (Urdiales-Galvez et al, 2017) .Physicians’ knowledge of anatomy, product characteristics, indications, patient history and general practice conditions are key to successful outcomes; training is an important step for optimal practice .

29

DISCUSSION 3

RELATED TO PERFECTHA SAFETY

30

l PERFECTHA Product Component Safety PERFECTHA is a biphasic hyaluronic-based dermal filler of 20mg/ml produced by bacterial fermentation and cross-linked with BDDE; it is a class III Medical Device produced in France .It is a sterile product presented in a pre-filled, ready-to-use, single use syringe .PERFECTHA safety is documented through that of its main component, hyaluronic acid, its residual component, the reticulating agent 1,4- butanediol diglycidyl ether (BDDE), and of the finished product, through all the data accumulated that were reviewed and approved by Health Authorities worldwide, and through physicians’ experience .Hyaluronic acid (HA) is a natural product, of similar composition among species, in favour of its non-immunogenicity . It has been used in many products and in many applications worldwide for many years .Its safety has been extensively studied in experimental and clinical settings and in clinical practice in numerous medical indications .HA and HA-based products have passed all standard ISO 10993 tests and have been the object of many efficacy and safety clinical trials, showing a good safety profile .The HA adverse events are well described, defined as early and late reactions .BBDE, the most used reticulating agent in HA-dermal fillers, has been particularly studied regarding its carcinogenic potential and the no risk assessment allowed, fixing the recommended level between 2 and 10 ppm . “Since negative results were obtained in the mutagenicity studies of Restylane, and since the estimated excess cancer risk is in the range determined to be acceptable for compounds released

from medical devices (based on ISO 10993-17), it is unlikely that BDDE-associated carcinogenic effects would be observed in patients who receive this product” .

l PERFECTHA finished product safety

PERFECTHA is produced according to GMP and released following controls of all batches in accordance with the product specifications: BDDE<2ppm routinely non detectable- endotoxin level <4 UI/ml routinely <0 .5 UI/ml- protein concentration <6µg/ml .

PERFECTHA passed all ISO 10993 in vitro and in vivo standard tests: it is non non-cytotoxic, non-irritant, non-sensitizing, non-immunogenic, and non-toxic .PERFECTHA was further investigated in dedicated studies regarding cytotoxicity, enzymatic degradation, syringeability and inflammatory potential .A number of clinical studies evaluated the efficacy and safety of PERFECTHA which was judged to be safe and well tolerated .A recent pharmacovigilance survey, covering the period between July 2012 and May 2017, concluded a total of 260 adverse events were reported, and during the same period, in excess of 1,417,000 syringes were sold, resulting in an adverse event rate of 0 .018%, or one adverse event in 5450 syringes .Based on the above summary including the rates presented within this report, this product would appear to have an excellent risk profile .Fu r the r deve lopment and use o f PERFECTHA worldwide, and additional investigations of its efficacy and mechanism of action will contribute to further strengthen its good safety profile .

4 CONCLUSIONSAFETY REPORT

This product appears to have

an excellent risk profile. »

(PMS survey, 2016)

Marie-Odile Christen

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5 ReferencesSAFETY REPORT

Marie-Odile Christen Paris, September [email protected]

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