Caution: Federal Law restricts this device to sale by or on the order of a physician or licensed practitioner.

Transcription

1 Restylae Lyft with Lidocaie Ijectable Gel with.% Lidocaie Cautio: Federal Law restricts this device to sale by or o the order of a physicia or licesed practitioer. Descriptio Restylae Lyft with Lidocaie is a sterile gel of hyaluroic acid geerated by Streptococcus species of bacteria, chemically cross-liked with BDDE, stabilized ad suspeded i phosphate buffered salie at ph=7 ad cocetratio of mg/ml with.% lidocaie. Idicatio Restylae Lyft with Lidocaie is idicated for implatatio ito the deep dermis to superficial subcutis for the correctio of moderate to severe facial folds ad wrikles, such as asolabial folds. Restylae Lyft with Lidocaie is idicated for subcutaeous to supraperiosteal implatatio for cheek augmetatio ad correctio of age-related midface cotour deficiecies i patiets over the age of. Cotraidicatios Restylae Lyft with Lidocaie is cotraidicated for patiets with severe allergies maifested by a history of aaphylaxis or history or presece of multiple severe allergies. Restylae Lyft with Lidocaie cotais trace amouts of gram positive bacterial proteis, ad is cotraidicated for patiets with a history of allergies to such material. Restylae Lyft with Lidocaie is cotraidicated for patiets with bleedig disorders. Warigs Restylae Lyft with Lidocaie should ot be used i patiets with previous hypersesitivity to local aesthetics of the amide type, such as lidocaie. Defer use of Restylae Lyft with Lidocaie at specific sites i which a active iflammatory process (ski eruptios such as cysts, pimples, rashes, or hives) or ifectio is preset util the process has bee cotrolled. Ijectio site reactios (e.g., swellig, redess, tederess, or pai) to Restylae Lyft with Lidocaie have bee observed as cosistig maily of short-term mior or moderate iflammatory symptoms startig early after treatmet ad with less tha weeks duratio. Refer to the adverse reactios sectio for details. Itroductio of Restylae Lyft with Lidocaie ito the vasculature may lead to embolizatio, occlusio of the vessels, ischemia, or ifarctio. Take extra care whe ijectig soft tissue fillers, for example iject the product slowly ad apply the least amout of pressure ecessary. Rare but serious adverse evets associated with the itravascular (4)

2 ijectio of soft tissue fillers i the face have bee reported ad iclude temporary or permaet visio impairmet, blidess, cerebral ischemia or cerebral hemorrhage, leadig to stroke, ski ecrosis, ad damage to uderlyig facial structures. Immediately stop the ijectio if a patiet exhibits ay of the followig symptoms, icludig chages i visio, sigs of a stroke, blachig of the ski or uusual pai durig or shortly after the procedure. Patiets should receive prompt medical attetio ad possibly evaluatio by a appropriate health care practitioer specialist should a itravascular ijectio occur. As with all dermal filler procedures, Restylae Lyft with Lidocaie should ot be used i vascular rich areas. Use i these highly vascularized areas, such as glabella ad ose, has resulted i cases of vascular embolizatio ad symptoms cosistet with ocular vessel occlusio, such as blidess, ad with brai vessel occlusio resultig i cerebral ifarctio. Delayed oset iflammatory papules have bee reported followig the use of dermal fillers. Iflammatory papules that may occur rarely should be cosidered ad treated as a soft tissue ifectio. Precautios Restylae Lyft with Lidocaie is packaged for sigle patiet use. Do ot resterilize. Do ot use if package is opeed or damaged. For the treatmet of moderate to severe facial wrikles ad folds, the maximum recommeded dose per treatmet is 6. ml based o U.S. cliical studies. For cheek augmetatio implatatio ad the treatmet of age-related midface volume deficit i patiets over the age of the maximum recommeded dose is also 6. ml per treatmet. The safety of ijectio greater amouts has ot bee established. The safety or effectiveess of Restylae Lyft with Lidocaie for the treatmet of aatomic regios other tha asolabial folds ad midface area has ot bee established i cotrolled cliical studies. Log term safety ad effectiveess of Restylae Lyft with Lidocaie beyod oe year have ot bee ivestigated i cliical trials. As with all trascutaeous procedures, Restylae Lyft with Lidocaie implatatio carries a risk of ifectio. Stadard precautios associated with ijectable materials should be followed. The safety ad efficacy of Restylae Lyft with Lidocaie for lip augmetatio has ot bee established. The safety of Restylae Lyft with Lidocaie for use durig pregacy, i breastfeedig females or i patiets uder 8 years has ot bee established. Formatio of keloids may occur after dermal filler ijectios icludig Restylae Lyft with Lidocaie. Keloid formatio was ot observed i studies ivolvig 79 patiets (icludig 6 Africa-Americas ad 76 other patiets of Fitzpatrick Ski Types IV, V ad VI). For additioal iformatio please refer to Studies MA-4-, MA-4-, GE, GE, ad MA-4-5 i the Cliical Trials Sectio. I study MA-4- with (4)

3 Restylae Lyft with Lidocaie ad Perlae, there were 5.7% (/6) of patiets with Fitzpatrick Ski Types IV, V, ad VI ad o reports of keloid formatio. Restylae Lyft with Lidocaie ijectio may cause hyperpigmetatio at the ijectio site. I a cliical study of 5 patiets with pigmeted ski (of Africa-America heritage ad Fitzpatrick Ski Types IV, V, ad VI), the icidece of post-iflammatory hyperpigmetatio was 6% (9/5). 5% of these evets lasted up to six weeks after iitial implatatio. I study MA-4- with Perlae ad Restylae Lyft with Lidocaie, there were 5.7% (/6) of patiets with Fitzpatrick Ski Types IV, V, ad VI ad o reports of hyperpigmetatio. I study MA-4-5 with Restylae Lyft with Lidocaie, there were.5% (6/) of patiets with Fitzpatrick Ski Types IV, V, ad VI ad o reports of hyperpigmetatio. Restylae Lyft with Lidocaie should be used with cautio i patiets o immuosuppressive therapy. Bruisig or bleedig may occur at Restylae Lyft with Lidocaie ijectio sites. Restylae Lyft with Lidocaie should be used with cautio i patiets who have udergoe therapy with thrombolytics, aticoagulats, or ihibitors of platelet aggregatio i the precedig weeks. After use, syriges ad eedles should be hadled as potetial biohazards. Disposal should be i accordace with accepted medical practice ad applicable local, state, ad federal requiremets. The safety of Restylae Lyft with Lidocaie with cocomitat dermal therapies such as epilatio, UV irradiatio, or laser, mechaical or chemical peelig procedures has ot bee evaluated i cotrolled cliical trials. Patiets should miimize exposure of the treated area to excessive su, UV lamp exposure ad extreme cold weather at least util ay iitial swellig ad redess has resolved. If laser treatmet, chemical peelig or ay other procedure based o active dermal respose is cosidered after treatmet with Restylae Lyft with Lidocaie, there is a possible risk of elicitig a iflammatory reactio at the implat site. This also applies if Restylae Lyft with Lidocaie is admiistered before the ski has healed completely after such a procedure. Ijectio of Restylae Lyft with Lidocaie ito patiets with a history of previous herpetic eruptio may be associated with reactivatio of the herpes. Restylae Lyft with Lidocaie is a clear, colorless gel without particulates. I the evet that the cotet of a syrige shows sigs of separatio ad/or appears cloudy, do ot use the syrige ad otify Galderma Laboratories, L.P. at Glass is also subject to breakage uder a variety of uavoidable coditios. Care should be take with the hadlig of the glass syrige ad with disposig of broke glass to avoid laceratio or other ijury. Restylae Lyft with Lidocaie should ot be mixed with other products before implatatio of the device. Cheek augmetatio or correctio of age-related midface cotour deficiecies i patiets over the age of,with Restylae Lyft with Lidocaie should oly be performed by physicias who have appropriate experiece ad who are kowledgeable about the aatomy ad the product for use i deep (subcutaeous ad/or supraperiosteal) ijectio for cheek augmetatio. (4)

4 I order to miimize the risks of potetial complicatios, this product should oly be used by health care practitioers who have appropriate traiig, experiece, ad who are kowledgeable about the aatomy at ad aroud the site of ijectio. Health care practitioers are ecouraged to discuss all potetial risks of soft tissue ijectio with their patiets prior to treatmet ad esure that patiets are aware of sigs ad symptoms of potetial complicatios. Adverse Experieces Restylae Lyft with Lidocaie is idicated for implatatio ito the deep dermis to superficial subcutis for the correctio of moderate to severe facial folds ad wrikles, such as asolabial folds ad for subcutaeous to supraperiosteal implatatio for cheek augmetatio ad correctio of agerelated midface cotour deficiecies i patiets over the age of. Adverse evet iformatio for Restylae Lyft with Lidocaie use i the correctio of moderate to severe facial folds ad wrikles, such as asolabial folds is preseted i Tables - ad for cheek augmetatio ad correctio of age-related midface cotour deficiecies is preseted i Tables -. Restylae Lyft with Lidocaie for the correctio of moderate to severe facial folds ad wrikles, such as asolabial folds. There were five US studies that reported adverse evets i support of the idicatio for treatmet of moderate to severe facial folds ad wrikles, such as asolabial folds. I two U.S. studies (i.e., Study MA-4- ad Study MA-4-) ivolvig 4 patiets at 5 ceters, the adverse outcomes reported i patiet diaries durig 4 days after treatmet are preseted i Tables 4. The physicia diagosed adverse evets idetified i these studies at 7 hours after ijectio are preseted i Table 7. I Study MA-4-, 5 patiets were ijected with Perlae o oe side of the face ad Restylae o the other side of the face. I study MA- 4-, 8 patiets were radomized to receive either Perlae or Restylae ijectio o both sides of the face. Table 8 presets all ivestigator-idetified adverse evets recorded at study visits weeks or more after ijectio i studies MA-4-, MA-4-, GE ad GE. I Study GE, 5 Caadia patiets were ijected with both Perlae ad Hylaform. I Study GE, 68 Scadiavia patiets uderwet both Perlae ad Zyplast ijectios. I a fifth U.S. study (Study MA-4-) 6 patiets at three ceters radomly received Restylae Lyft with Lidocaie ijectios o oe side of the face ad Perlae ijectios o the other side of the face. The adverse evets reported i patiet diaries durig 4 days after treatmet are preseted i Tables 5 ad 6. The physicia-recorded adverse evets idetified i study MA-4- at 4 days after ijectio are preseted i Table 9. 4 (4)

5 Table. Maximum Itesity of Symptoms after Iitial Treatmet, Patiet Diary (Study MA-4-) Perlae Restylae Perlae Patiets Restylae Patiets Total patiets reportig symptoms Total patiets reportig symptoms Noe Tolerable Affected Daily Activity Disablig Noe Tolerable Affected Daily Activity Disablig Bruisig (86.5%) (78.%) 7 (.%) 97 (69.8%) 4 (7.%) (.7%) 8 (.%) 8 (59%) 8 (.%) (.7%) Redess 8 (8.7%) 4 (8.%) (5.%) 5 (75.5%) (8.6%) (.7%) 5 (8%) 96 (69.%) 7 (.%) (.7%) Swellig Pai Tederess Itchig 8 (9.8%) 4 (8.9%) (9.%) 45 (.9%) 7 (89.4%) 8 (76.%) (86.6%) 67 (47.%) (7.9%) 5 (8%) 9 (6.5%) 94 (67.6%) 7 (77%) 96 (69.%) (8.6%) 4 (8.8%) 9 (.7%) 8 (.9%) 8 (.9%) (.%) (.4%) (.4%) (8.6%) (.%) 6 (.5%) 7 (5.8%) (7.4%) 9 (66.9%) 9 (78.4%) 66 (47.5%) (6.5%) 4 (.%) (8.6%) (.7%) (.4%) (.7%) (.4%) Other (.7%) (.%) NA NA NA NA NA NA NA NA Missig values are ot reported. Prospective defiitios for: tolerable, affected daily activity ad disablig were ot provided i the diary or protocol. Two patiets reported pimples (oe Perlae/oe Restylae); oe Restylae patiet reported a sore throat; oe Restylae patiet reported a ruy ose; degree of disability was ot reported for ay of the four evets. Bruisig Redess Swellig Pai Tederess Itchig Table. Duratio of Adverse Evets after Iitial Treatmet, Patiet Diary (Study MA-4-) Perlae Restylae Perlae Patiets Restylae Patiets Total patiets reportig symptoms (86.5%) 8 (8.7%) 8 (9.8%) 4 (8.9%) (9.%) 45 (.9%) Total patiets reportig symptoms (78.%) 4 (8.%) 7 (89.4%) 8 (76.%) (86.6%) 67 (47.%) 6 (4.9%) 9 (6.%) 6 (4.7%) 46 (4.4%) 4 (8.5%) 9 (4.%) Number of days Number of days -7 8 (66.4%) 87 (7.7%) (78.%) 66 (57.9%) 89 (68.5%) (5.%) 8-8 (%) 8 (6.8%) 7 (.%) (.8%) 6 (.%) (6.7%) 4 7 (5.7%) 4 (.4%) 5 (.9%) (.8%) 9 (8.%) (7.%) (9.4%) 7 (4.%) (7.%) (.8%) (6.%) 7 (6.%) 9 (7.%) 69 (6.9%) 9 (74.8%) 8 (56.7%) 8- (7%) 9 (7.9%) 9 (5.%) (.9%) 9 (7.%) 6 (9.%) 4 (.7%) (.6%) (.4%) (.8%) (.5%) Other (.7%) (.%) Missig values are ot reported. Data are cumulated from up to four ijectio sites per patiet with earliest ad latest time poit for ay reactio provided. Two patiets reported pimples (oe Perlae/oe Restylae); oe Restylae patiet reported a sore throat; oe Restylae patiet reported a ruy ose; degree of disability was ot reported for ay of the four evets. 5 (4)

6 Table. Maximum Itesity of Symptoms after Iitial Treatmet, Patiet Diary (Study MA-4-), Perlae Restylae Perlae Patiets Restylae Patiets Total patiets reportig symptoms Total patiets reportig symptoms Noe Tolerable Affected Daily Activity Disablig Noe Tolerable Affected Daily Activity Disablig Bruisig Redess Swellig Pai Tederess Itchig 74 (49.%) 9 (6.%) (8.7%) (68.7%) (86.7%) 58 (8.7%) 7 (46.7%) 87 (58%) 5 (8.%) 96 (64%) (8.%) 5 (5.%) 75 (5.%) 57 (8.%) 8 (8.8%) 46 (.9%) 9 (.8%) 9 (6.%) 67 (45%) 85 (57%) 8 (7.5%) 9 (6.4%) 6 (77.9%) 54 (6.%) 7 (4.7%) 7 (4.7%) (7.4%) (8.%) (8.7%) 4 (.7%) (.%) (.7%) (.7%) 79 (5%) 6 (4.6%) 4 (6.%) 5 (5.6%) 7 (8.%) 96 (64.4%) 66 (44.%) 8 (54.4%) 9 (7.%) 84 (56.4%) (7.8%) 49 (.9%) 4 (.7%) 6 (4%) 4 (9.4%) (7.4%) (7.4%) 4 (.7%) (.%) (.7%) (.7%) Other 4 NA NA (%) (%) Missig values are ot reported. Evets are reported as local evets; because of the desig (split-face) of the study, causality of the systemic adverse evets caot be assiged. Prospective defiitios for: tolerable, affected daily activity ad disablig were ot provided i the diary or protocol. 4 Two patiets reported mild trasiet headache ad oe patiet reported mild twitchig ; either could be associated with a particular product. Table 4. Duratio of Adverse Evets after Iitial Treatmet, Patiet Diary (Study MA-4-), Bruisig Redess Swellig Pai Tederess Itchig Perlae Restylae Perlae Patiets Restylae Patiets Total patiets reportig symptoms 74 (49.%) 9 (6.%) (8.7%) (68.7%) (86.7%) 58 (8.7%) Total patiets reportig symptoms 7 (46.7%) 87 (58%) 5 (8.%) 96 (64%) (8.%) 5 (5.%) Number of days Number of days (.%) (59.5%) 8 5 (4.%) (56.5%) 85 (8.%) (7.%) (.%) 6 (%) 9 (5%) 67 (65%) 94 (7.%) 6 (44.8%) 8-6 (8.%) (.%) (9.%) (.9%) 6 (4.6%) (.4%) 4 (.4%) (.5%) (.9%) 4 (.%) (.7%) (8.6%) (7.9%) (8.4%) 7 (8.%) 8 (%) (4.5%) -7 5 (7.9%) 5 (59.8%) 89 (7.%) 67 (69.8%) 87 (7.%) 7 (5.9%) 8-6 (8.6%) (.%) (9.6%) (.%) 7 (5.7%) 4 (7.5%) 4 (.8%) Other 4 (%) (%) Missig values are ot reported. Evets are reported as local evets; because of the desig (split-face) of the study, causality of the systemic adverse evets caot be assiged. Data are cumulated from up to two ijectio sites per patiet with earliest ad latest time poit for ay reactio provided. 4 Two patiets reported mild trasiet headache ad oe patiet reported mild twitchig ; either could be associated with a particular product. 6 (4)

7 Bruisig Redess Swellig Pai Tederess Itchig Table 5. Maximum Itesity of Symptoms after Iitial Treatmet, Patiet Diary (Study MA-4-) Restylae Lyft with Lidocaie Total patiets reportig symptoms 6 (6.%) 4 (56.7%) 4 (7.%) 8 (46.7%) 5 (8.%) 6 (6.7%) Perlae Restylae Lyft with Lidocaie Patiets Perlae Patiets Total patiets reportig symptoms (55.%) (5.7%) 9 (65.%) 6 (4.%) 49 (8.7%) (.%) Noe Tolerable 4 (4.%) 6 (4.%) 8 (.%) (5.%) (6.7%) 44 (7.%) (5.%) (5.7%) 4 (56.7%) 5 (4.7%) 45 (75.%) 5 (5.%) Affected Daily Activity 4 (6.7%) (5.%) 8 (.%) (5.%) 5 (8.%) (.7%) Disablig Noe Tolerable Affected Daily Activity (.%) (.%) (.%) (.%) (.%) (.%) 7 (45.%) 9 (48.%) (5.%) 4 (56.7%) (8.%) 48 (8.%) 9 (48.%) 9 (48.%) 4 (56.7%) 4 (4.%) 47 (78.%) (.%) 4 (6.7%) (.%) 5 (8.%) (.%) (.%) (.%) Disablig (.%) (.%) (.%) (.%) (.%) (.%) Other (5.%) (.7%) NA NA NA NA NA NA NA NA Missig values are ot reported. Prospective defiitios for: tolerable, affected daily activity ad disablig were ot provided i the diary or protocol. Other icluded symptoms of ace, lumpiess, ad red/purple mark. Diary etries of hurts to swallow, lack of eergy, feelig of sickess, achy, headache, ad broke capillaries could ot be associated with a particular product. Bruisig Redess Swellig Pai Tederess Itchig Table 6. Duratio of Adverse Evets after Iitial Treatmet, Patiet Diary (Study MA-4-) Restylae Lyft with Lidocaie Total patiets reportig symptoms 6 (6.%) 4 (56.7%) 4 (7.%) 8 (46.7%) 5 (8.%) 6 (6.7%) Perlae Restylae Lyft with Lidocaie Patiets Perlae Patiets Total patiets reportig symptoms (55.%) (5.7%) 9 (65.%) 6 (4.%) 49 (8.7%) (.%) 6 (6.7%) 9 (6.5%) 4 (9.5%) 7 (6.7%) 6 (.%) 5 (.%) Number of days Number of days -7 7 (75.%) 4 (7.6%) (78.6%) (9.%) 4 (8.%) (6.5%) 8- (8.%) (.%) 4 (9.5%) (.%) 4 (8.%) (6.%) 4 (.%) (.9%) (.4%) (.%) (.%) (.%) 5 (5.%) 9 (9.%) 6 (5.4%) 5 (57.7%) 8 (6.%) 5 (4.7%) -7 (69.7%) 8 (58.%) 9 (74.4%) (4.%) 5 (7.4%) 7 (58.%) 8-4 (.%) (9.7%) (7.7%) (.%) 6 (.%) (.%) 4 (.%) (.%) (.6%) (.%) (.%) (.%) Other,4 (5.%) (.7%) (.%) (.%) (.%) (.%) (.%) (.%) (.%) (.%) Missig values are ot reported. Evets are reported as local evets; because of the desig (split-face) of the study, causality of the systemic adverse evets caot be assiged. Data are cumulated from up to two ijectio sites per patiet with earliest ad latest time poit for ay reactio provided. 4 Other icluded symptoms of ace, lumpiess, ad red/purple mark. Diary etries of hurts to swallow, lack of eergy, feelig of sickess, achy, headache, ad broke capillaries could ot be associated with a particular product. 7 (4)

8 Table 7 shows the umber of adverse evets idetified by ivestigators at 7 hours after ijectio for Studies MA-4- ad MA-4-. Some patiets had multiple adverse evets or had the same adverse evet at multiple ijectio sites. No adverse evets were of severe itesity. Table 7. All Ivestigator-Idetified Adverse Evets (7 Hours) Number of Evets per Patiet per Study Study Term MA-4- MA-4- Number of Evets Perlae (=5) Number of Evets Restylae (=5) Number of Evets Perlae (=4) Number of Evets Restylae (=4) Ecchymosis Edema Erythema 5 Tederess Pai Hyperpigmetatio Pruritus Papule Burig Hypopigmetatio Ijectio site scab Table 8 presets the umber of patiets ad per patiet icidece of all adverse evets idetified by ivestigators at visits occurrig two or more weeks after ijectio. Study Term Ecchymosis Edema Erythema Tederess Pai Papule Pruritus Rash Hyperpigmetatio Ijectio site scab Ski exfoliatio Table 8. Ivestigator-Idetified Adverse Evets ( Weeks or More After Implatatio) (Number of Patiets) (Perlae v. Specified Active Cotrols All Studies) MA-4- Perlae (=5) 7 (4.6%) (.%) (.7%) 7 (4.7%) MA-4- Restylae (=5) 4 (.7%) (.%) (.7%) (.7%) 8 (5.%) (.7%) MA-4- Perlae (=4) 5 (.6%) (.%) (.4%) (.7%) (.7%) MA-4- Restylae (=4) 4 (9.9%) (.4%) (.7%) (.7%) (.4%) (.7%) GE Perlae (=5) 6 (4.%) 4 (9.%) (8.7%) (.%) (8.7%) (7.%) (.%) (.7%) GE Hylaform (=5) (.%) 6 (4.%) 8 (5.%) (.%) (.7%) (.%) (.7%) GE Perlae (=68) 4 (5.9%) 6 (8.8%) (.5%) (4.4%) GE Zyplast (=68) 9 (.%) 8 (.8%) (.9%) 6 (8.8%) 5 (7.4%) 8 (4)

9 I two studies (i.e., GE ad GE) with repeat admiistratio of Perlae at 6 9 moths followig the iitial correctio, the icidece ad severity of adverse evets were similar i ature ad duratio to those recorded durig the iitial treatmet sessios. I all four studies, ivestigators reported the followig local ad systemic evets that were judged urelated to treatmet ad occurred at a icidece of less tha %, i.e., ace; tooth disorders (e.g., pai, ifectio, abscess, fracture); dermatitis (e.g., rosacea, uspecified, cotact, impetigo, herpetic); urelated ijectio site reactios (e.g., desquamatio, rash, aesthesia); facial palsy with coadmiistratio of botulium toxi; headache/migraie; ausea (with or without vomitig); sycope; gastroeteritis; upper respiratory or iflueza-like illess; brochitis; siusitis; pharygitis; otitis; viral ifectio; cystitis; diverticulitis; ijuries; laceratios; back pai; rheumatoid arthritis; ad various medical coditios such as chest pai, depressio, real stoes, ad uterie fibroids. Table 9 shows the umber of adverse evets idetified by ivestigators durig Day through Day 4 after ijectio i Study MA-4-. Table 9. All Ivestigator-Idetified Adverse Evets (4 Days) Number of Evets per Patiet per Study Study Term Number of Evets Restylae Lyft with Lidocaie (=4) MA-4- Number of Evets Perlae (=4) Ecchymosis 9 Edema 4 4 Erythema 5 5 Pai 4 4 Papule Pruritus 9 5 Tederess Some patiets had multiple adverse evets or had the same adverse evets at bilateral ijectio sites. No adverse evets were of severe itesity. Patiets were queried o adverse evets o the day of ijectio ad at the Day 4 visit. Study MA-4-, icluded 47 subjects who had o prior cosmetic treatmet ad subjects who had prior dermal filler treatmet. There were o statistical differeces i the proportio of subjects with adverse evets who had prior treatmet ad those with o prior treatmet. Table. MA-4- Related AE by prior procedure. By Subjects Related AE Prior procedure p-value* Yes No Yes 9 (69.%) 4 No (66.%) 6 * Fisher s exact test. 9 (4)

10 Restylae Lyft with Lidocaie for cheek augmetatio ad correctio of midface cotour deficiecies i patiets over the age of. Oe U.S. study reported adverse evets i support of Restylae Lyft with Lidocaie for the idicatio of cheek augmetatio ad correctio of midface cotour deficiecies. I the U.S. pivotal study (MA-4-5) ivolvig patiets at ceters, patiets received Restylae Lyft with Lidocaie i both the right ad left midface at baselie or i the cotrol group at Moth. Subjects were asked to record symptoms of bruisig, redess, swellig, pai, tederess ad itchig i a 4-Day patiet diary. Subject s scores for the severity of these evets are preseted i Table ad duratios are provided i Table. The majority of evets were mild cosidered tolerable ad resolved i 7 days. Bruisig teded to have a loger duratio with the majority of subjects resolvig betwee 8 ad 4 days. (4)

11 Table. MA-4-5 Overall Summary of Selected Adverse Evets* as Reported i Subject s Diary by Maximum Severity Safety Populatio No Treatmet at Baselie (N=49) Treatmet Group First Treatmet Secod Treatmet with with Restylae Restylae Lyft with Lyft with Lidocaie Lidocaie (N=99) (N=8) Right ad Left Midface Combied (N=98) Maximum Severity Reported for ay Diary Symptom Noe 47 (96%) (%) (<%) Tolerable (4%) 46 (74%) 94 (74%) Affects Daily Activities 45 (%) 6 (%) Disablig 4 (%) 6 (5%) Pai (Icludig Burig) Noe 48 (98%) 4 (%) 8 (%) Tolerable (%) 4 (68%) 84 (66%) Affects Daily Activities Disablig (<%) (%) Tederess Noe 49 9 (5%) (8%) Tolerable 7 (86%) 4 (8%) Affects Daily Activities 7 (9%) (9%) Disablig (<%) (<%) Redess Noe 49 4 (%) 7 (%) Tolerable 9 (7%) 88 (69%) Affects Daily Activities 6 (8%) (8%) Disablig (%) Bruisig Noe 49 5 (8%) 8 (%) Tolerable (66%) 79 (6%) Affects Daily Activities (6%) 6 (%) Disablig (<%) 4 (%) Swellig Noe (4%) Tolerable 45 (7%) 94 (74%) Affects Daily Activities (5%) (9%) Disablig 4 (%) 4 (%) Itchig Noe 48 (98%) (66%) 9 (7%) Tolerable (%) 6 (%) (6%) Affects Daily Activities (%) (<%) Disablig (<%) (<%) Note: Percetages are based o the umber of Subjects i the Safety Populatio with ay o-missig assessmet for locatio ad parameter (if applicable). Note: For right ad left combied, the overall maximum severity is take as the maximum of overall right severity ad overall left severity. The combied maximum severity withi symptom category is take as the maximum of right severity ad left severity withi the symptom category. *Selected Adverse Evets are those that were pre-listed i the diary (bruisig, redess, swellig, pai, tederess, itchig) ad required a recordig of oe or the presece ad extet. These diary recordigs were hadled separately from adverse evets that were elicited from a iterview about ay medical occurrece that meets the defiitio of Adverse Evet. (4)

12 Table : Duratio of Selected Adverse Evets* as Reported i the Subject s Diary Safety Populatio No Treatmet at Baselie (N = 49) Number of Days -7 Locatio/ Adverse Evet Ay 8- Right ad Left Midface Combied Pai (Icludig Burig) (%) Tederess Redess Bruisig Swellig Itchig (%) First Treatmet with Restylae Lyft with Lidocaie (N = 99) Number of Days 4 Locatio/ Adverse Evet Ay Pai (Icludig 57(79%) 4 (%) 9 (69%) (8%) Burig) Tederess 89(95%) 7 (9%) (59%) 47 (5%) (7%) Redess 55(78%) 9 (5%) 96 (6%) 8 (%) Bruisig 6(8%) (6%) 66 (4%) 7 (4%) 7 Swellig 79(9%) 4 (8%) (74%) 6 (5%) 7 (4%) Itchig 67(4%) 6 (4%) 4 (6%) 9 (%) Secod Treatmet with Restylae Lyft with Lidocaie (N=8) Number of Days Locatio/ Adverse Evet Ay Pai (Icludig 99 (77%) 7 (7%) 7 (7%) (%) Burig) Tederess 7 (9%) 9 (8%) 7 (6%) 9 (5%) 8 (7%) Redess (78%) 9 (9%) 67 (67%) (%) Bruisig 99 (77%) 5 (5%) 46 (46%) 5 (5%) (%) Swellig 9 (85%) 5 (4%) 7 (66%) (8%) (%) Itchig 5 (7%) 9 (6%) 9 (54%) 5 (4%) (6%) ¹ Percetages are based o the umber of subjects i the Safety populatio. Note: Note: Percetages for duratio categories are based o the umber of subjects reportig the symptom ( Ay ) for the specified locatio, uless otherwise oted. Secod Treatmet with Restylae Lyft with Lidocaie colum oly icludes diary summaries from subjects who actually received a secod treatmet at Moth. *Selected Adverse Evets are those that were pre-listed i the diary (bruisig, redess, swellig, pai, tederess, itchig) ad required a recordig of oe or the presece ad extet. These diary recordigs were hadled separately from adverse evets that were elicited from a iterview about ay medical occurrece that meets the defiitio of Adverse Evet. Midface safety assessmets, such as firmess, symmetry, fuctio (movemet), mass formatio ad sesatio were evaluated at the screeig visit, optioal touch up visit, week follow up visit, 4 week follow up visit,,4,6,8 ad moth follow up visits, ad the moth follow up visit. I additio, midface safety assessmets, such as firmess, symmetry, fuctio, mass formatio ad sesatio were evaluated at the followig moth post treatmet visits: optioal touch up visit, week post-treatmet visit, 4 week post-treatmet visit, ad the week post-treatmet visit. Device palpability was assessed at each scheduled visit listed above with the exceptio of the screeig visit. Oe subject reported greater tha mild for the midface safety assessmets of firmess, symmetry, fuctio, mass formatio ad abormal device palpability. This subject reported a mild hematoma i the right cheek startig five days after the iitial treatmet that progressed to a moderate hematoma startig 6 days later ad lastig 6 days. Reported treatmet icluded atibiotics. The ivestigator believed that the hematoma was exacerbated by self-maipulatio. (4)

13 There were o sigs of iflammatio i subjects reportig mild or moderate abormality i the safety assessmets of midface. The physicia diagosed adverse evets idetified i this study are preseted i Table. Of the subjects erolled i the study, 99 subjects received their first treatmet with Restylae Lyft with Lidocaie at either baselie/day or at Moth, ad 8 subjects received a secod treatmet at Moth. Forty-ie percet (49%) of subjects receivig their first treatmet reported a total of 69 TEAEs while 9% of subjects that received a secod treatmet reported a total of 77 TEAEs. The majority of these TEAEs were mild i itesity (/69; 79%, ad 7/77; 9%; first ad secod treatmet respectively), ad were trasiet i ature. The most commo TEAEs occurrig after iitial treatmet with Restylae Lyft with Lidocaie were implat site haematoma (8%), implat site haemorrhage (5%), implat site pai (9%), implat site swellig (8%), ad headache (7%). There was o icreased risk with additioal treatmet with Restylae Lyft with Lidocaie. Subjects with Fitzpatrick Ski Types IV, V ad VI (=6) ad had safety results similar to the geeral study populatio. Table. MA-4-5 Summary of Treatmet Emerget Adverse Evets Occurrig i % of Treated Subjects Safety Populatio No Treatmet at Baselie (N=5) Treatmet Group First Treatmet with Restylae Lyft with Lidocaie (N=99) Secod Treatmet with Restylae Lyft with Lidocaie (N=8) Evets Subjects Evets Subjects Evets Subjects Ay TEAE 8 5 (%) (48.7%) 77 7 (8.9%) Geeral Disorders ad Admiistratio Site Coditios Implat Site Haematoma 5 6 (8%) 8 (8%) Implat Site Haemorrhage 8 (5%) 9 (7%) Implat Site Mass 6 5 (.5%) (.8%) Implat Site Pai 6 7 (9%) 6 (5%) Implat Site Swellig 6 5 (8%) 6 4 (%) Ifectios ad Ifestatios Nasopharygitis (%) 4 4 (%) Upper Respiratory Tract 4 4 (%) Ifectio Nervous System Disorders Headache (6%) 4 (7%) (<%) Hypoaesthesia 5 4 (%) ¹ A subject with more tha oe treatmet emerget adverse evet withi a system orga class ad/or preferred term is oly couted oce. Note: For the No Treatmet at Baselie group a adverse evet is cosidered treatmet emerget if the start date is o or after the Visit (Day ) date. For the First Treatmet with Restylae Lyft with Lidocaie group a adverse evet is cosidered treatmet emerget if the start date is o or after the date of iitial treatmet ijectio ad before the date of Moth ijectio. For the Secod Treatmet with Restylae Lyft with Lidocaie group a adverse evet is cosidered treatmet emerget if the start date is o or after the date of the Moth ijectio. Two subjects (%, /99) reported four serious adverse evets (SAEs) that were cosidered to be related to the device ad/or the procedure. Oe subject reported implat site iflammatio (late oset iflammatory reactios) i both cheeks at separate times. The secod subject experieced implat site hematomas i the right cheek ad implat site ifectio/abscess. Treatmet of the SAEs icluded NSAIDs, atibiotics, icisio ad draiage ad, hyaluroidase. All evets resolved. (4)

14 Approximately % of subjects had a delayed oset (> days after treatmet) of implat site erythema, implat site hematoma, implat site iflammatio, implat site mass, implat site pai, implat site swellig, implat site warmth, iduratio, twitchig or rosacea that occurred up to 8 days after treatmet. Adverse evets associated with the use of the device ad occurrig i < % of subjects whether related or ot related were suke eyes, ausea, implat site ifectio/abscess, implat site iflammatio, implat site mass, implat site warmth, implat site irritatio, iduratio, muscle tightess, muscle twitchig, pai i jaw, presycope, 7th erve paralysis, ace, eedle track marks, rosacea, cojuctivitis, eyelid cyst, colitis ischemic, detal carries, gigival swellig, tooth ache, cyst, discomfort, ijectio site pai, geeral swellig, ulcer, acarodermatitis, brochitis, eye ifectio, implat site cellulitis, iflueza, oral herpes, peumoia, soft tissue ifectio, arthropod stig, icisio site pai, exposure to toxic aget, facial ijury, ligamet sprai, meiscus lesio, thermal bur, tooth fracture, type diabetes, arthralgia, back pai, bursitis, myalgia, eck pai, pai i extremity, basal cell carcioma, pacreatic carcioma, metastatic carcioma, carpal tuel sydrome, abortio spotaeous, depressio, prostatitis, pulmoary vascular disorder, dermatitis cotact, rash, urticaria, eurectomy, ad hypertesio. Post-Marketig Surveillace: The adverse evets received from post-marketig surveillace for the use of Restylae Lyft with Lidocaie whe used outside the US for cheek augmetatio were ifrequet ad icluded mostly reports of swellig ad mass/iduratio. Serious adverse evets which occurred 5 times were the followig, i descedig order of frequecy: implat site swellig, implat site abscess, implat site ifectio, implat site erythema, implat site mass purulet discharge, implat site odule, medical device implatatio (i.e. evets reported as overcorrectio, overfill, ski depressio, or irregular ski). The icidece of post market evets potetially related to treatmet with Restylae Lyft with Lidocaie for all idicatios ad that occurred i greater tha 5 subjects icluded the followig, i descedig order of frequecy: swellig, device ieffective, accidetal exposure, mass/iduratio, odermatological evets, erythema, pai/tederess, ifectio/abscess, bruisig/abscess, bruisig/bleedig, papules/odules, iflammatio, eurological symptoms, medical device implatatio (i.e. evets reported as overcorrectio, overfill, ski depressio, or irregular ski), ijectio site reactios, hypersesitivity, pruritus, discoloratio, eye disorders, ischemia/ecrosis, scar/scab/ski atrophy, procedural complicatios, herpes, device dislocatio, device misuse, ad rash. Reported treatmets have icluded systemic steroids or systemic atibiotics admiistered itraveously, orally or by ijectio.. Serious adverse evets have bee rarely reported. The most commoly reported serious adverse evets (by MedDRA Preferred Term) were hypersesitivity, ad implat ad/ or ijectio site swellig, ischemia ad discoloratio. Serious abscess formatios have also bee reported. Visio abormalities icludig blidess have bee reported followig ijectio of hyaluroic acid, with ad without lidocaie, ito the ose, glabella, periorbital areas, ad/or cheek, with a time to oset ragig from immediate to week followig ijectio. Reported treatmets iclude aticoagulat, epiephrie, aspiri, hyaluroidase, corticosteroid treatmet, hyperbaric oxyge ad surgery. Outcomes raged from resolved to ogoig at the time of last cotact. Evets requirig 4 (4)

15 medical itervetio, ad evets where resolutio iformatio is ot available were reported after ijectio of hyaluroic acid with or without lidocaie. I these cases, the product was ijected ito the highly vascularized areas of the glabella, ose, ad periorbital area, which are outside the device idicatios for use (See Warigs sectio). Implat ad ijectio site reactios, mostly o-serious evets, have also bee reported. These iclude: discoloratio, bruisig, swellig, mass formatio, erythema, pai, scarrig ad ischemia. Most istaces of discoloratio icludig hyperpigmetatio, sometimes described as a blue or brow color ad ragig from mild to severe, have occurred withi the same day as treatmet but have also occurred up to 6 moths post treatmet. These evets typically resolve withi a few days but with some ifrequet istaces lastig up to 8 moths. Implat ad/or ijectio site bruisig, swellig, erythema ad pai geerally occurred o the same day as treatmet usually resolvig withi to 4 weeks. Some occurreces have persisted for up to 6 moths. Severity for these evets is geerally mild to moderate although some cases have bee severe. Adverse reactios should be reported to Galderma Laboratories, L.P. at Cliical Trials Restylae Lyft with Lidocaie is idicated for implatatio ito the deep dermis to superficial subcutis for the correctio of moderate to severe facial folds ad wrikles, such as asolabial folds ad for subcutaeous to supraperiosteal implatatio for cheek augmetatio ad correctio of agerelated midface cotour deficiecies i patiets over the age of. Cliical trial iformatio for Restylae Lyft with Lidocaie use i the correctio of moderate to severe facial folds ad wrikles, such as asolabial folds is preseted i the sectio titled "U.S. Cliical Studies to support Perlae /Restylae Lyft with Lidocaie i the treatmet of facial folds ad wrikles (asolabial folds ad oral commissures)" ad for cheek augmetatio ad correctio of age-related midface cotour deficiecies is preseted i the sectio titled "U.S. Cliical Study to support the use of Restylae Lyft with Lidocaie i cheek augmetatio ad correctio of midface cotour deficiecies". The safety ad effectiveess of Perlae i the treatmet of facial folds ad wrikles (asolabial folds ad oral commissures) were evaluated i four prospective radomized cotrolled cliical studies ivolvig 59 Perlae-treated patiets. Perlae was show to be effective whe compared to cross-liked collage ad cross-liked hyaluroic acid dermal fillers with respect to the correctio of moderate to severe facial folds ad wrikles, such as asolabial folds. The safety ad pai reductio effect of Restylae Lyft with Lidocaie i the treatmet of facial folds ad wrikles (asolabial folds) was evaluated i a prospective radomized cotrolled cliical study ivolvig 6 patiets. The additio of lidocaie to Perlae resulted i a statistically sigificat reductio i the pai experieced by the patiets. The study also showed that the safety profile of Restylae Lyft with Lidocaie was cosistet with Perlae. 5 (4)

16 U.S. Cliical Studies to support Perlae /Restylae Lyft with Lidocaie i the treatmet of facial folds ad wrikles (asolabial folds ad oral commissures) Desig Edpoits MA-4-: Prospective, Radomized, Blided, Cotrolled Cliical Study : radomized, prospective study at 7 U.S. ceters, which compared the safety ad effectiveess of Perlae ad Restylae followig treatmet to baselie coditio. Patiets were radomized to either Perlae or Restylae treatmet. A touch-up was allowed weeks after iitial treatmet. Patiets were partially masked; evaluatig physicias were idepedet ad masked; treatig physicias were umasked. Effectiveess was studied with 6 moths follow-up. Safety was studied with 6 moths follow-up. Effectiveess Primary: The differece i effect of Perlae at week versus baselie coditio o the visual severity of the asolabial folds, as assessed by the Blided Evaluator. The primary study edpoit was wrikle severity weeks after optimal correctio was achieved. Wrikle severity was evaluated o a five-step validated Wrikle Severity Ratig Scale (WSRS) (i.e., oe, mild, moderate, severe, extreme) by a live evaluator blided to treatmet. Patiet success was defied as maitaiig at least a oe poit improvemet o the WSRS at weeks after optimal correctio was achieved. The percet of patiet successes was calculated for each treatmet group. Each group was compared to its ow baselie, with o compariso of Perlae to Restylae. Secodary: Wrikle Severity Ratig Scale (WSRS) assessed at other follow-up poits (, 6, ad 4 weeks after optimal correctio) by the Blided Evaluator, the ivestigator ad the patiet ad compared to baselie score by the same evaluator. Duratio of effect defied as 6 moths or time poit, if earlier, at which less tha 5% of patiets had at least a -grade respose remaiig i both asolabial folds (NLFs). Safety assessmets icluded: collectio of patiet symptoms i a 4-day diary; ivestigator evaluatio of adverse evets at 7 hours, ad at, 6,, ad 4 weeks; developmet of humoral or cell-mediated immuity; ad the relatioship of adverse evets to ijectio techique. Outcomes Demographics: The study erolled 8 (i.e., 4 Perlae ad 4 Restylae ) patiets with moderate to severe NLF wrikles. The patiets were predomiatly healthy ethically diverse females. Bilateral NLFs ad oral commissures were corrected i most patiets with.9 ml to 4.6 ml of Perlae. The greatest 6 (4)

17 amout used i ay patiet was 9. ml. Geder Female: 66 (94%); Male: 7 (6%) Ethicity White: 6 (8%); Hispaic or Latio: ; Africa America: (8%); Asia: Efficacy: The results of the blided evaluator assessmet of NLF wrikle severity for Perlae ad cotrol (Restylae ) are preseted i Table 4. I the primary effectiveess assessmet at weeks, 87% of the Perlae ad 77% of the cotrol patiets had maitaied at least a poit improvemet over baselie. Table 4. Blided Evaluator Wrikle Severity Respose Scores No. of No. of Restylae Perlae Patiets Patiets Time poit No. of Perlae Pts. No. of Restylae maitaiig Pts. maitaiig Uit Uit Improvemet of Improvemet of NLF o WSRS NLF o WSRS 6 weeks 6 (89%) 6 (8%) weeks 4 (87%) 4 8 (77%) 4 weeks 8 87 (6%) 4 (74%) All p-values <. based o t-test compared to baselie coditio Atibody Testig: 5/4 (.6%) patiets displayed a pre-treatmet atibody respose agaist Perlae, (which was believed to be related to co-purifyig Streptococcus capsule atiges). Oe patiet also developed a measurable icrease i atibody titer after Perlae ijectio. 4/6 (7%) patiets with atibodies agaist Perlae had adverse evets at the ijectio site, which was similar to the local adverse evet rate observed i the etire Perlae populatio (i.e., 49/4 (5%)). With the exceptio of oe moderate bruisig evet, all the adverse evets i the patiets with a humoral respose agaist Perlae were mild i severity. No severe evets were oted ad the patiet who developed a atibody respose after Perlae ijectio did ot experiece ay adverse evet at the ijectio site. Immediate type ski testig demostrated that o patiet developed IgE to Perlae. Post-exposure histopathology of ski biopsies of a implat site o each patiet demostrated that o patiet developed cell-mediated immuity to Perlae. 7 (4)

18 Desig MA-4-: Prospective, Radomized, Blided, Cotrolled Cliical Study : radomized, prospective study at U.S. ceters, which compared the safety ad effectiveess of Perlae ad Restylae followig treatmet to baselie coditio i 5 patiets with pigmeted ski ad predomiatly Africa-America ethicity. Patiets were radomized to either Perlae or Restylae treatmet i a withi-patiet model of augmetatio correctio of bilateral asolabial folds (NLFs) ad oral commissures with oe treatmet assiged to oe side ad the other treatmet to the other side. A touch-up was allowed weeks after iitial treatmet. Patiets ad treatig physicias were partially masked. Evaluatios were performed by live ivestigator assessmet for the primary aalysis. Effectiveess was studied with 6 moths follow-up. Safety was studied with 6 moths follow-up. Edpoits Effectiveess Primary: The differece i effect of Perlae at week versus baselie coditio o the visual severity of the NLFs. The primary study edpoit was wrikle severity weeks after optimal correctio was achieved. Wrikle severity was evaluated with a five-step validated Wrikle Severity Ratig Scale (WSRS) (i.e., oe, mild, moderate, severe, extreme) by a o-site Blided Evaluator. Patiet success was defied as maitaiig at least a oe poit improvemet o the WSRS at weeks after optimal correctio was achieved. The percet of patiets success was calculated for each group. Each treatmet group was compared to its ow baselie, with o compariso of Perlae to Restylae. Secodary: Wrikle Severity Ratig Scale (WSRS) was assessed at other follow-up poits (, 6, ad 4 weeks after optimal correctio) by the ivestigator ad the patiet ad compared to baselie score by the same evaluator. A photographic assessmet of patiet outcomes was also performed. Duratio of effect defied as 6 moths or time poit, if earlier, at which less tha 5% of patiets had at least a -grade respose at both asolabial folds. Outcomes Safety assessmets icluded: collectio of patiet symptoms i a 4-day diary; ivestigator evaluatio of adverse evets at 7 hours, ad at, 6,, ad 4 weeks; the developmet of humoral or cell-mediated immuity; ad the relatioship of adverse evets to ijectio techique. Demographics: The study erolled 5 patiets with moderate to severe NLF wrikles. The patiets were predomiatly healthy Africa-America females. Geder Female: 4/5 (9%); Male /5 (7%) 8 (4)

19 Ethicity White: (.%); Hispaic or Latio: 9 (6%); Africa-America: 7 (9%); America Idia: (.%) Fitzpatrick Ski Type I to III: ; IV: 44 (9%); V: 68 (45%); VI: 8 (5%) Efficacy: The results of the live blided evaluator assessmet of wrikle severity for Perlae ad cotrol (Restylae ) are preseted i Table 5 ad are based o the Itet-to-Treat aalysis. I the primary effectiveess assessmet at weeks, 9% of the Perlae-treated ad 9% of the Restylae-treated NLF maitaied at least a poit improvemet over baselie. Time poit Table 5. Live Evaluator Wrikle Severity Respose Scores No. of patiets No. of Perlae Pts. maitaiig Uit Improvemet o WSRS 95% Perlae Cofidece Iterval No. of Restylae Pts. maitaiig Uit Improvemet o WSRS 95% Restylae Cofidece Iterval 6 weeks 48 4 (95%) 9-99 % 4 (96%) 9-99% weeks 49 7 (9%) 87-97% 9 (9%) 89-98% 4 weeks 47 4 (7%) 6-77% 8 (7%) 66-8% All p-values <. based o t-test compared to baselie coditio Atibody Testig: 6/5 (4%) patiets displayed a pre-treatmet atibody respose agaist Perlae (which was believed to be related to co-purifyig Streptococcus capsule atiges). No patiets developed a measurable icrease i atibody titer after Perlae ijectio. /6 patiets with atibodies agaist Perlae had adverse evets at the ijectio site as compared to the local adverse evet rate observed i the etire Perlae populatio (i.e., 4/5 (9%)). All the adverse evets i the patiets with a humoral respose agaist Perlae were mild i severity. Immediate type ski testig demostrated that o patiet developed IgE to Perlae. Post-exposure histopathology of ski biopsies of a implat site o each patiet demostrated that o patiet developed cell-mediated immuity to Perlae. 9 (4)

20 Desig MA-4-: Radomized, Blided, Cotrolled Cliical Study : radomized, prospective study at U.S. ceters, which compared the safety, tolerability, ad pai reductio of Restylae Lyft with Lidocaie to Perlae i 6 patiets. Patiets were radomized to Restylae Lyft with Lidocaie or Perlae treatmet i a withi-patiet model of bilateral asolabial folds (NLFs) correctio, with oe treatmet assiged to oe side ad the other treatmet to the remaiig side. Patiets ad treatig physicias were blided; evaluatig physicias were idepedet ad blided. The study icluded 5.7% of patiets with darker ski types based o classificatio of Fitzpatrick Ski Types IV, V, or VI (6.7% Ski Type IV ad 5.% Ski Type V or VI). Pai was assessed by each patiet for each treatmet site idepedetly o the Visual Aalog Scale (VAS) at the ed of ijectio ad at 5-miute itervals for 6 miutes post-treatmet. Patiet assessmet of appearace usig the Global Aesthetic Improvemet Scale (GAIS) (Very much improved / much improved / improved / o chage / worse) was performed at the Day 4 visit. Safety was studied with 4-day follow-up. Edpoits Primary: The proportio of patiets that had a withi-patiet differece i the VAS (Perlae -Restylae Lyft with Lidocaie ) of at least mm at ijectio together with a 95% cofidece iterval. The objective was to show that the cofidece iterval lay above 5%. Secodary: The proportio of patiets that had a withi-patiet differece i VAS of at least mm at post-ijectio time poits (5,, 45 ad 6 miutes after ijectio) together with a 95% cofidece iterval, the mea VAS by treatmet ad withi-patiet differece i VAS at each time poit, the compariso of VAS betwee Restylae Lyft with Lidocaie ad Perlae, at each time poit, ad patiet assessmet o GAIS by treatmet. Safety assessmets icluded: collectio of patiet symptoms i a 4-day diary ad ivestigator evaluatio of adverse evets at 4 days. (4)

21 Outcomes Demographics: The study erolled 6 patiets with moderate to severe NLF wrikles. The patiets were predomiatly healthy ethically diverse females. Geder Female: 56 (9.%); Male: 4 (6.7%) Ethicity White: 9 (65.%); Hispaic or Latio: 6 (6.7%); Africa America: 5 (8.%) Fitzpatrick Ski Type- Type I-III; 9 (48. %); Type IV: (6.7%); Type V ad VI: 9 (5.%) Volume: The mea volume of Restylae Lyft with Lidocaie per wrikle was. ml. The mea volume of Perlae per wrikle was. ml. Volume Ijected per Wrikle (ml) (Study MA-4-) Treatmet Restylae Lyft with Lidocaie per NLF Volume (ml) Mea Std Mi Media Max Perlae per NLF Differece withi patiet* * Perlae volume - Restylae Lyft with Lidocaie volume Abbreviatios: = umber of patiets; std = stadard deviatio; Mi = miimum; Max = maximum Primary: The primary efficacy aalysis for pai reductio showed that 95.% of patiets had a withi-patiet differece i VAS (Perlae mius Restylae Lyft with Lidocaie ) of at least mm at the time of ijectio. The primary objective was met, sice statistically more tha 5% of patiets had at least mm lower VAS score o the side treated with Restylae Lyft with Lidocaie (cofidece iterval was 86. to 99.). At 5 miutes post ijectio, 56.7% still had a withi-patiet differece i VAS of at least mm. Treatmet Differece (Δ) i VAS (Perlae Side Restylae Lyft with Lidocaie Side) ITT Populatio (Study MA-4-) Time pot No. of patiets with assessmets** Number of patiets with Δ > mm % 95% LCL 95% UCL Treatmet* Miutes Miutes Miutes Miutes * Primary edpoit ** Deomiator (N), % = */N; UCL=upper cofidece limit; LCL=lower cofidece limit (4)

22 Secodary: Both pai scores decreased over time, but the mea withi-patiet differece o VAS (Perlae Restylae Lyft with Lidocaie ) was statistically sigificatly larger tha zero at all time poits (at ijectio ad at 5,, 45 ad 6 miutes post-ijectio). Patiets Mea VAS Assessmets of Pai by Time Poit (Study MA-4-) Time poit VAS pai by treatmet (mm) Restylae Lyft with Lidocaie Perlae VAS differece (mm) * p-value** Treatmet <. 5 Miutes <. Miutes <. 45 Miutes <. 6 Miutes * Withi-patiet differece (Perlae side Restylae Lyft with Lidocaie side), ** Oe-sample T-test At Day 4, patiets showed improvemet from baselie: 95% o the Restylae Lyft with Lidocaie side of the face ad 96.7% o the Perlae side of the face. Global Aesthetic Improvemet Scale (GAIS) Evaluatio at the Day 4 Visit (Study MA-4-) GAIS Category Restylae Lyft with Lidocaie Perlae % % Very Much Improved (4) Much Improved () Improved () No Chage () 5.. Worse ().. (4)

23 No-U.S. Cliical Studies Desig Edpoits GE: Prospective, Radomized, Blided, Cotrolled Cliical Study : radomized, prospective study at 6 Caadia ceters, which compared the safety ad effectiveess of Perlae ad Hylaform. Patiets were radomized to either Perlae or Hylaform i a withi-patiet model of augmetatio correctio of bilateral asolabial folds (NLFs) with oe treatmet assiged to oe side ad the other treatmet to the other side. A touch-up was allowed weeks after iitial treatmet. Patiets were partially masked; evaluatig physicias were idepedet ad masked; treatig physicias were partially masked. Effectiveess was studied with 6 moths follow-up. Safety was studied with 6 moths follow-up. Effectiveess Primary: The differece i effect of Perlae as compared to Hylaform o the visual severity of the NLFs, as assessed by a Blided Evaluator at 6 moths after baselie. The primary evaluatio parameter was a five-step validated Wrikle Severity Ratig Scale (WSRS) score (abset, mild, moderate, severe, extreme) by the Blided Evaluator at 6 moths. Success was defied as maitaiig at least a oe poit improvemet of the NLF o the WSRS at 6 moths after optimal correctio was achieved. The percet of successful NLFs after Perlae ad cotrol treatmets were compared, as well as a withi-patiet matched aalysis (McNemar s Test). Secodary: Wrikle Severity Ratig Scale (WSRS) was assessed at other follow-up poits ( weeks ad, 4.5, ad 6 moths after optimal correctio) by the Blided Evaluator ad the patiet. Global Aesthetic Improvemet (GAI): very much improved /much improved / improved / o chage / worse, assessed at same time poits by patiet. Outcomes Safety assessmets icluded: ivestigator evaluatio of adverse evets at all time poits. Demographics: The study erolled 5 patiets with moderate to severe asolabial fold wrikles. The patiets were predomiatly healthy white females. The study was completed by 4 of 5 patiets at six moths ad additioal safety data were available i of 5 patiets at 9 moths. Geder Female: 4 (9%); Male: (7%) Ethicity White: 4/5 (95%); No-caucasia: 8/5 (5%) (4)

24 Efficacy: The results of the blided evaluator assessmets are preseted i Table 6 ad are based o a Itet-to-Treat (ITT) aalysis. At 6 moths, /5 (75%) of the Perlae-treated NLFs maitaied at least a sigle poit improvemet o the WSRS compared to 57/5 (8%) of the cotrol-treated NLFs. Table 6. Blided Evaluator Wrikle Severity Respose Rates Time poit Number of NLFs No. of Perlae NLFs maitaiig Uit Improvemet o WSRS No. of Hylaform NLFs maitaiig Uit Improvemet o WSRS moths 5 (87%) 94 (6%) 4.5 moths 5 (7%) 69 (46%) 6 moths 5 (75%) 57 (8%) Table 7 shows the results for the withi-patiet ivestigator assessmet of NLF o the WSRS. Table 7. Evaluatig Ivestigator s Assessmet of NLF Severity; Score Chage Mos. after last treatmet From Pre-Treatmet Util, 4.5, ad 6 Moths After Last Treatmet Perlae superior to Perlae equal to Hylaform superior to p-value* Hylaform Hylaform Perlae 95 (6.%) 46 (.7%) 9 (6.%) p< (58.%) 54 (6.%) 9 (6.%) p< (64.%) 4 (8.%) (8.%) p<. * McNemar s test with %=/N, where N=umber of patiets i the ITT populatio Desig GE: Prospective, Radomized, Blided, Cotrolled Cliical Study : radomized, prospective study at Scadiavia ceters, which compared the safety ad effectiveess of Perlae ad Zyplast. Patiets were radomized to either Perlae or Zyplast i a withi-patiet model of augmetatio correctio of bilateral asolabial folds (NLFs) with oe treatmet assiged to oe side ad the other treatmet to the other side. Patiets were partially masked; evaluatig physicias were idepedet ad masked; treatig physicias were partially masked. A touch-up was allowed weeks after the iitial treatmet. Re-treatmet was allowed at 6 or 9 moths. Effectiveess was studied with 9 moths follow-up. Safety was studied with moths follow-up. Edpoits Effectiveess Primary: Superiority of correctio of the NLF by Perlae as compared to Zyplast based o the visual severity of the NLF, as assessed by a Blided Evaluator at 6 moths after optimal correctio was achieved. The primary evaluatio parameter was a five-step validated Wrikle Severity Ratig Scale (WSRS) score (abset, mild, moderate, severe, extreme) by the Blided Evaluator at 6 moths. NLF success was defied as maitaiig at least a oe poit improvemet o the WSRS at 6 moths after optimal correctio was achieved. The 4 (4)

25 withi patiet compariso of Perlae ad cotrol treatmets was evaluated i a matched aalysis (McNemar s Test). Secodary: Superiority of correctio of the NLF by Perlae or Zyplast based o the visual severity of the NLFs, as assessed by a Blided Evaluator at 9 moths after baselie. Safety assessmets icluded: ivestigator evaluatio of adverse evets at all time poits. Outcomes Demographics: The study erolled 68 patiets with correctable NLF wrikles. The patiets were predomiatly healthy white females. Geder Female: 65 (96%); Male: (4%) Ethicity White: 68/68 Efficacy: The results of the blided evaluator assessmets are preseted i Table 8. At the primary effectiveess time poit of 6 moths, the Perlae-treated NLF experieced more improvemet from baselie (judged by the WSRS) i 5% of the patiets; the cotrol-treated side experieced more improvemet i.% of the patiets. Table 8. Evaluatig Ivestigator s Assessmet; Differece i the Severity Ratig Scale From Pre-Treatmet Util, 4, 6, ad 9 Moths After Baselie Time poit Perlae NLF is Perlae NLF Cotrol NLF is superior to cotrol is equal to superior to p-value NLF cotrol NLF Perlae NLF moths (47.%) 8 (4.%) 8 (.8%). 4 moths 8 (55.9%) 5 (6.8%) 5 (7.4%). 6 moths 4 (5.%) 7 (9.7%) 7 (.%). 9 moths (48.8%) 6 (7.%) 6 (4.9%).9. McNemar s test. Percet = /Number of patiets i the ITT populatio at Moth 6. Percet = /Number of patiets i the ITT populatio at Moth 9; icludes oly patiets ot re-treated (=4) 5 (4)

26 U.S. Cliical Study to support the use of Restylae Lyft with Lidocaie i cheek augmetatio ad correctio of midface cotour deficiecies. Desig Edpoits MA-4-5: Prospective, Radomized, Blided, Cotrolled Cliical Study This was a : radomized, prospective study at U.S. ceters, which compared the safety ad effectiveess of Restylae Lyft with Lidocaie to a o treatmet cotrol i subjects seekig cheek augmetatio. A touch-up was allowed weeks after iitial treatmet. Patiets were re-treated at Moth ad patiets origially radomized to the o treatmet group received their iitial treatmet at Moth. Blided evaluatig physicias were idepedet ad masked; treatig physicias were umasked. Safety ad Effectiveess was studied mothly through Moth ad weeks after the Moth re-treatmet/treatmet. Ijectios were performed with the supplied 9 G TW x ½ eedle. Effectiveess Primary: The proportio of respoders with at least a oe grade icrease from the baselie assessmet of the Medicis Midface Volume Scale (MMVS) for BOTH the right ad left sides of the face at Moth as assessed by the blided evaluator. The MMVS was a four poit validated scale to assesses the fulless of the midface from Fairly Full () to Substatial Loss of Fulless (4). The proportio of respoders was calculated for each treatmet group ad compared usig Fisher s Exact Tests. Secodary: MMVS assessed at other follow-up poits (, 4, 6, 8,, ad moths after optimal correctio ad, 4, ad weeks after the Moth treatmet) by the blided evaluator ad the ivestigator. Satisfactio with treatmet as assessed by the subject ad the ivestigator usig the Global Aesthetic Improvemet Scale (GAIS). Additioal assessmet of patiet satisfactio was assessed with the FACE-Q scale. The GAIS ad FACE-Q scales were ot validated at the time of the study. Safety assessmets icluded: collectio of patiet symptoms i a 4-day diary; ivestigator evaluatio of adverse evets; ad midface safety assessmets (firmess, symmetry, movemet, fuctio, sesatio, mass formatio, ad device palpability). 6 (4)

27 Outcomes Demographics: The study erolled patiets (5 Restylae Lyft with Lidocaie ad 5 o treatmet) seekig cheek augmetatio. Overall, the mea age for study subjects was 5.9 ± 7.6 years. The study icluded 6 subjects (%) of Fitzpatrick ski types IV, V, or VI with subjects of Fitzpatrick Ski Types V (7 subjects) ad VI (4 subjects). Baselie MMVS were similar betwee the right ad left midface with a majority of subjects (6% ad 6%, respectively) havig a MMVS score of (moderate loss of fulless with slight hollowig below malar promiece). Geder Female: 8 (9%); Male: 7 (9%) Ethicity White: 78 (89%); Africa America: (5%), Asia: (%), America Idia/Alaska Native (<%), Other: 8 (4%) Ijectio volumes averaged 6.7 ml (iitial + touch-up at weeks; right ad left midface combied). Efficacy: The results of the blided evaluator assessmet of midface fulless (MMVS) for Restylae Lyft with Lidocaie ad o treatmet cotrol are preseted i Table 9. I the primary effectiveess assessmet at Moth, 88.7% of the Restylae Lyft with Lidocaie ad 6.% of the o treatmet cotrol patiets had at least a poit improvemet over baselie. Similar results were see for the treatig ivestigator s assessmet of MMVS. Table 9. Proportio of Respoders Measured by the Blided Evaluator s Assessmet of Midface Fulless (MMVS) at Moth Restylae Lyft Timepoit with Lidocaie No Treatmet P-Value Right ad Left Midface Combied Moth (88.7%) 8 (6.%) <. Primary edpoit N = Subjects with a missig blided evaluator assessmet at Moth for a midface are imputed usig the hot deck method. Fisher s Exact Test 7 (4)

28 Figure : Proportio of Respoders Measured by the Blided Evaluator s Assessmet of Midface Fulless (MMVS) - ITT Populatio The results of the subject s satisfactio with the aesthetic improvemet i midface fulless (GAIS) for Restylae Lyft with Lidocaie ad o treatmet cotrol are preseted i Figure. Subjects were satisfied with treatmet with 98% reportig improvemet at weeks after treatmet ad satisfactio see i 7% of subjects after moths.. 8 (4)

29 Figure : Right ad Left Midface Combied: Proportio of Respoders Measured by Subject s Assessmet of GAIS by Visit ITT Populatio With regard to the photographic assessmet of MMVS coducted by a Idepedet Photographic Reviewer (IPR), the betwee-group differece i the proportio of respoders from baselie for the right ad left midface combied was statistically sigificat (p<.5) i favor of Restylae Lyft with Lidocaie treatmet at all visits except the Moth visit. The proportio of respoders from baselie i the Restylae Lyft with Lidocaie group as assessed by the IPR was 8.8% at Moth, 8.% at Moth 4, 78.6% at Moth 6, 79.7% at Moth 8, 8.7% at Moth, ad 75.7% at Moth. I the o treatmet group the proportio of right ad left midface combied respoders was 69.6% at Moth, 6.% at Moth 4, 54.% at Moth 6, 6.% at Moth 8, 6.8% at Moth, ad 57.4% at Moth. HOW SUPPLIED Restylae Lyft with Lidocaie is supplied i a disposable glass syrige with a luer-lock fittig. Restylae Lyft with Lidocaie is co-packed with sterilized eedle(s) as idicated o the carto ( 9 G TW x ½ ). 9 (4)