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Restylane® Silk
(Lidocaine 0.3%) Injectable Gel

DESCRIPTION

Restylane Silk is a gel of hyaluronic acid generated by Streptococcus species of bacteria, chemically crosslinked with BDDE, stabilized and suspended in phosphate buffered saline at pH=7 and concentration of 20 mg/mL with 0.3% lidocaine.

INDICATIONS

Restylane Silk is indicated for submucosal implantation for lip augmentation and dermal implantation for correction of perioral rhytids in patients over the age of 21.

DOSAGE AND ADMINISTRATION

Directions for Assembly

For safe use of Restylane Silk, it is important that the needle is properly assembled.

Assembly Of 30 G Needle To Syringe

Use the thumb and forefinger to hold firmly around both the glass syringe barrel and the Luer-Lok adapter. Grasp the needle shield with the other hand. To facilitate proper assembly, both push and rotate firmly.

Pre-treatment Guidelines

Prior to treatment, the patient should avoid taking aspirin, nonsteroidal anti-inflammatory medications, St. John's Wort, or high doses of Vitamin E supplements. These agents may increase bruising and bleeding at the injection site.

Treatment Procedure

1. It is necessary to counsel the patient and discuss the appropriate indication, risks, benefits and expected responses to the Restylane Silk treatment. Advise the patient of the necessary precautions before commencing the procedure.

2. Assess the patient's need for appropriate anesthetic treatment for managing comfort, i.e., topical anesthetic, local or nerve block.

3. The patient's face should be washed with soap and water and dried with a clean towel. Cleanse the area to be treated with alcohol or another suitable antiseptic solution.

4. Sterile gloves are recommended while injecting Restylane Silk.

5. Before injecting, press rod carefully until a small droplet is visible at the tip of the needle.

6. Restylane Silk is administered using a thin gauge needle (30 G x ½”). The needle is inserted at an approximate angle of 30° parallel to the length of the wrinkle, fold, or lip. For rhytids, Restylane Silk should be injected into the mid-to-deep dermis. Restylane Silk should be injected into the submucosal layer for lip augmentation, care should be taken to avoid intramuscular injection. If Restylane Silk is injected too superficially this may result in visible lumps and/or bluish discoloration.

7. Inject Restylane Silk applying even pressure on the plunger rod. It is important that the injection is stopped just before the needle is pulled out of the skin to prevent material from leaking out or ending up too superficially in the skin.

8. Only correct to 100% of the desired volume effect. Do not overcorrect. With cutaneous deformities the best results are obtained if the defect can be manually stretched to the point where it is eliminated. The degree and duration of the correction depend on the character of the defect treated, the tissue stress at the implant site, the depth of the implant in the tissue and the injection technique.

9. Typical usage for each treatment session is specific to the site as well amount of augmentation or rhytids correction desired. Based on U.S. clinical studies, the maximum recommended dose per treatment is 1.5 mL per lip per treatment or 1.0 mL for perioral rhytid correction.

Injection Techniques

1. Restylane Silk can be injected by a number of different techniques that depend on the treating physician's experience and preference, and patient characteristics.

2. Serial puncture (F) involves multiple, closely spaced injections along wrinkles or folds. Although serial puncture allows precise placement of the filler, it produces multiple puncture wounds that may be undesirable to some patients.

3. Linear threading (includes retrograde and antegrade) (G) is accomplished by fully inserting the needle into the middle of the wrinkle or fold and injecting the filler along the track as a “thread.” Although threading is most commonly practiced after the needle has been fully inserted and is being withdrawn, it can also be performed while advancing the needle (“push-ahead” technique). To enhance the vermillion of the lip, the retrograde linear threading technique is the most advisable.

4. Serial threading is a technique that utilizes elements of both approaches.

Note! The correct injection technique is crucial for the final result of the treatment.

F. Serial Puncture

G. Linear Threading (includes retrograde and antegrade)

5. Dissection of the sub-epidermal plane with lateral movement of the needle, rapid flows ( > 0.3 mL/min), rapid injection or high volumes may result in an increase in short-term episodes of bruising, swelling, redness, pain, or tenderness at the injection site.

6. When the injection is completed, the treated site should be gently massaged so that it conforms to the contour of the surrounding tissues. If an overcorrection has occurred, massage the area firmly between your fingers or against an underlying area to obtain optimal results.

7. If so called “blanching” is observed, i.e., the overlying skin turns a whitish color, the injection should be stopped immediately and the area massaged until it returns to a normal color.

8. If the wrinkles or lips need further treatment, the same procedure should be repeated until a satisfactory result is obtained. Additional treatment with Restylane Silk may be necessary to achieve the desired correction.

9. If the treated area is swollen directly after the injection, an ice pack can be applied on the site for a short period. Ice should be used with caution if the area is still numb from anesthetic to avoid thermal injury.

10. Patients may have mild to moderate injection site reactions, which typically resolve in less than 18 days in the lip.

HOW SUPPLIED

Restylane Silk is supplied in a disposable glass syringe with a Luer-Lok® fitting.

Restylane Silk is co-packed with sterilized needle(s) 30 G x ½” as indicated on the carton.

A patient record label is a part of the syringe label. Remove it by pulling the flap marked with three small arrows. This label is to be attached to patient records to ensure traceability of the product.

The contents of the syringe are sterile.

The volume in each syringe and needle gauge is as stated on the syringe label and on the carton.

Shelf Life And Storage

Restylane Silk must be used prior to the expiration date printed on the package.

Store at a temperature of up to 25° C (77° F). Do not freeze. Protect from sunlight. Refrigeration is not required.

Do not resterilize Restylane Silk as this may damage or alter the product.

Do not use if the package is damaged. Immediately return the damaged product to Galderma Laboratories, L.P.

Ordering Information

Galderma Laboratories, L.P. and its distributor, McKesson Specialty, are your only credits for FDA-approved Restylane Silk. Purchasing from any other agent is illegal. To order call 1-855-425-8722

Manufactured for: Galderma Laboratories, L.P., 14501 N. Freeway, Fort Worth, TX 76177 USA, Phone: 1-855-425-8722. Manufactured by: Q-Med AB, Seminariegatan 21, SE-752 28 Uppsala, Sweden. Revised: Sep 2014.

SIDE EFFECTS

Adverse Experiences

The U.S. pivotal study (MA-1700-04) involved 221 subjects at 14 centers. At baseline, subjects were randomized to receive Restylane Silk injections in the lips and perioral rhytids (as needed) or no treatment (control group). At 6 months, all subjects were eligible to receive treatment or re-treatment in the lips and perioral rhytids with Restylane Silk.

Of the 221 subjects enrolled in the study, 218 subjects received their first treatment with Restylane Silk at either baseline/Day 0 or at 6 months, and 133 subjects received a second treatment at 6 months. Safety was also evaluated for subjects with Fitzpatrick skin types IV and V (n=52) and for the subgroup of subjects ≤ 35 years of age (n=60).

An adverse event (AE) was defined as any untoward medical occurrence or an unintended sign, symptom, or disease temporally associated with the use of the device, whether or not considered related to the device. An AE was further defined as:

• any diagnosis, sign, symptom, or abnormal laboratory value not present, detected or complained of at the baseline assessment.
• any diagnosis, sign, symptom, or abnormal laboratory value noted at baseline that worsened in severity or intensity or increased in frequency during the study.

An AE that occurred during the study was considered a treatment emergent adverse event (TEAE) if:

• it was not present prior to receiving treatment (as determined by onset date of event and date treatment was received), or
• it was present prior to receiving treatment but the severity increased after treatment (as determined by onset date of the severity increase of the event and date treatment was received).

The investigator was to classify the severity of an adverse event according to the following definitions:

• Mild: did not interfere with routine activities, could perform daily functions
• Moderate: interfered with routine activities, could perform daily functions, but with concerted effort
• Severe: unable to perform routine activities

A Serious Adverse Device Event (SADE) was defined as an AE that:

• results in death;
• is life-threatening;
• results in permanent impairment of a body function;
• results in permanent damage to a body structure; or,
• necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.

Subjects were asked to grade symptoms of bruising, redness, swelling, pain, tenderness and itching. Subject's scores for the severity of these events are presented in Table 2 and durations are provided in Table 3. The majority of events ( > 85%) were mild in intensity and resolved in 2 – 7 days. Eight patients reported diary symptoms of “Affects Daily Activities” and “Disabling” that lasted longer than 7 days. These events were: Swelling (n=6), pain (n=2), tenderness (n=3), bruising (n=3), itching (n=2), and redness (n=1).

Table 1: MA-1700-04 Maximum Intensity of Symptoms after Initial Treatment from Subject Diary (N=218)

	None n (%)	Tolerable n (%)	Affected Daily Activities n (%)	Disabling n (%)
Upper and Lower Lip Combined (N=215)
Bruising	39 (18%)	142 (66%)	25 (12%)	9 (4%)
Redness	63 (29%)	129 (60%)	19 (9%)	4 (2%)
Swelling	2 ( < 1%)	111 (52%)	84 (39%)	18 (8%)
Pain	48 (22%)	123 (57%)	38 (18%)	6 (3%)
Tenderness	16 (7%)	146 (68%)	48 (22%)	5 (2%)
Itching	151 (70%)	59 (27%)	5 (2%)	0

Table 2: MA-1700-04 Duration of Symptoms from Patient Diary

	No Treatment at Baseline (N=44) Number of Days
	Any N (%)	1 n (%)	2 - 7 n (%)	8 - 13 n (%)	14 n (%)
Upper and Lower Lip Combined
Bruising	0	0	0	0	0
Redness	0	0	0	0	0
Swelling	1 (2%)	0	1 (100%)	0	0
Pain (includes Burning)	1 (2%)	1 (100%)	0	0	0
Tenderness	1 (2%)	1 (100%)	0	0	0
Itching	0	0	0	0	0
	First Treatment with Restylane Silk (N =218) Number of Days
	Any N (%)	1 n (%)	2 - 7 n (%)	8 - 13 n (%)	14 n (%)
Upper and Lower Lip Combined
Bruising	176 (81%)	10 (6%)	130 (74%)	34 (19%)	2 (1%)
Redness	152 (70%)	40 (26%)	97 (64%)	15 (10%)	0
Swelling	213 (98%)	9 (4%)	149 (70%)	40 (19%)	15 (7%)
Pain (includes Burning)	167 (77%)	43 (26%)	110 (66%)	13 (8%)	1 ( < 1%)
Tenderness	199 (91%)	17 (9%)	132 (66%)	41 (21%)	9 (5%)
Itching	64 (29%)	21 (33%)	34 (53%)	7 (11%)	2 (3%)
	Second Treatment with Restylane Silk (N=133) Number of Days
	Any N (%)	1 n (%)	2 - 7 n (%)	8 - 13 n (%)	14 n (%)
Upper and Lower Lip Combined
Bruising	89 (67%)	6 (7%)	65 (73%)	17 (19%)	1 (1%)
Redness	89 (67%)	18 (20%)	64 (72%)	7 (8%)	0
Swelling	124 (93%)	2 (2%)	96 (77%)	20 (16%)	6 (5%)
Pain (includes Burning)	100 (75%)	26 (26%)	70 (70%)	4 (4%)	0
Tenderness	118 (89%)	8 (7%)	88 (75%)	19 (16%)	3 (3%)
Itching	37 (28%)	8 (22%)	21 (57%)	8 (22%)	0

The treatment-emergent adverse events (TEAEs) reported during the study are presented in Table 1. The number of events and subjects reporting TEAEs decreased between the first and second treatments. Seventy-eight percent (169/281) of subjects receiving their first treatment reported a total of 632 TEAEs while 63% (84/133) of subjects that received a second treatment reported a total of 196 TEAEs. Furthermore, an overwhelming majority of these TEAEs were mild in intensity (540/632; 85%, and 178/196; 91%; first and second treatment respectively), and were transient in nature, resolving in a mean of 17.4 days (median 10 days).

The most common TEAEs occurring after initial treatment with Restylane Silk were lip swelling (43%), contusion (44%), and lip pain (10%). There was no increased risk with additional treatment with Restylane Silk. After the second treatment, the reported incidence decreased to 35%, 31%, and 7%, respectively.

In the overall population of subjects receiving their initial treatment with Restylane Silk, 12 severe events occurred in 6 subjects. Ten of the severe events were Lip Swelling which occurred in 5 subjects. There were 80 moderate events which occurred in 34 subjects (16%). There were 5 serious adverse events in three patients during the study. In the No Treatment group there were incidences of Clostridial Infection (n=1), and Urinary Tract Obstruction (n=1). In the Restylane Silk group there were Cystitis (n=1), Intervertebral Disc Protrusion (n=1), and Nephrolithiasis (n=1). None of the serious events were reported as related to treatment with Restylane Silk.

Nineteen subjects reported AEs associated with treatment of the lip whose onset was more than 3 weeks after a Restylane Silk injection. There were a total of 35 events in the lip reported in these 19 subjects. Most of the events were Lip Swelling (26/35; 745) and also included Lip Disorder (6/35; 17%), Lip Pain/Pain 2/35; 6%), and Contusion (1/35; 3%). None of the events were reported as serious and all of the events were reported as either mild (24/35; 69%) or moderate (11/35; 31%).

Table 3: MA-1700-04 Summary of Treatment Emergent Adverse Events

System Organ Class/ Preferred Term	Severity	No Treatment at Baseline (N=44)		First Treatment with Restylane Silk (N=218)		Second Treatment with Restylane Silk (N=133)
Any TEAE		Events	Subjects	Events	Subjects	Events	Subjects
	Total	20	12 (27%)	632	169 (78%)	196	84 (63%)
	Mild	16	10 (23%)	540	129 (59%)	178	73 (55%)
	Moderate	2	1 (2%)	80	34 (16%)	18	11 (8%)
	Severe	2	1 (2%)	12	6 (3%)	0	0
Gastrointestinal Disorders
Lip Disorder	Total	0	0	17	11 (5%)	1	1 ( < 1%)
	Mild	0	0	17	11 (5%)	1	1 ( < 1%)
	Moderate	0	0	0	0	0	0
	Severe	0	0	0	0	0	0
Lip Pain	Total	0	0	34	21 (10%)	12	9 (7%)
	Mild	0	0	30	19 (9%)	12	9 (7%)
	Moderate	0	0	4	2 ( < 1%)	0	0
	Severe	0	0	0	0	0	0
Lip Swelling	Total	0	0	186	94 (43%)	74	46 (35%)
	Mild	0	0	154	77 (35%)	65	41 (31%)
	Moderate	0	0	22	12 (6%)	9	5 (4%)
	Severe	0	0	10	5 (2%)	0	0
General Disorders and Administrative Site Conditions
Pain	Total	0	0	32	18 (8%)	6	4 (3%)
	Mild	0	0	24	13 (6%)	4	3 (2%)
	Moderate	0	0	8	5 (2%)	2	1 ( < 1%)
	Severe	0	0	0	0	0	0
Injury, Poisoning, and Procedural Complication
Contusion	Total	0	0	145	96 (44%)	55	41 (31%)
	Mild	0	0	134	87 (40%)	53	39 (29%)
	Moderate	0	0	11	9 (4%)	2	2 (2%)
	Severe	0	0	0	0	0	0
Nervous System Disorders
Headache	Total	7	4 (9%)	11	10 (5%)	3	2 (2%)
	Mild	7	4 (9%)	10	9 (4%)	2	1 ( < 1%)
	Moderate	0	0	1	1 ( < 1%)	1	1 ( < 1%)
	Severe	0	0	0	0	0	0

The vast majority of all symptoms reported in subject diaries resolved within 2-7 days of treatment. Furthermore, the duration profiles are similar between first treatment and second treatments with Restylane Silk.

Table 4: Duration of Commonly Occurring Treatment Emergent Adverse Events

System Organ Class/ Preferred Term	No Treatment at Baseline (N=44)	First Treatment with Restylane Silk (N=218)	Second Treatment with Restylane Silk (N=133)
All TEAEs
n	11	168	83
Mean (S.D.)	15.2 (28.8)	17.7 (29.0)	9.7 (8.3)
Median (min, max)	6.0 (1, 101)	10.0 (1, 174)	7.0 (1, 38)
Gastrointestinal Disorders
Lip Disorder
n	0	10	1
Mean (S.D.)	- (-)	49.1 (44.4)	27.0 (-)
Median (min, max)	-	38.5 (1, 124)	27.0
Lip Pain
n	0	21	9
Mean (S.D.)	- (-)	10.6 (14.5)	5.2 (2.3)
Median (min, max)	-	7.0 (3, 71)	6.0 (2, 8)
Lip Swelling
n	0	94	46
Mean (S.D.)	- (-)	7.3 (4.1)	7.4 (8.1)
Median (min, max)	-	6.0 (2, 21)	5.0 (1, 38)
General Disorders and Administrative Site Conditions
Pain
n	0	18	4
Mean (S.D.)	- (-)	3.6 (2.3)	3.5 (1.9)
Median (min, max)	-	3.0 (1, 9)	3.0 (2, 6)
Injury, Poisoning, and Procedural Complication
Contusion
n	0	96	41
Mean (S.D.)	- (-)	8.4 (3.9)	8.6 (5.9)
Median (min, max)	-	8.0 (2, 20)	7.0 (3, 32)
Nervous System Disorders
Headache
n	4	10	2
Mean (S.D.)	2.8 (2.9)	1.6 (1.1)	1.0 (0.0)
Median (min, max)	1.5 (1, 7)	1.0 (1, 4)	1.0 (1, 1)

In addition, subjects with Fitzpatrick skin types IV and V and subjects ≤ 35 years of age had safety results similar to the general study population.

Concomitant treatment of perioral rhytids with lip augmentation does not increase the risk for adverse events. TEAEs for subjects receiving treatment for perioral rhytids were similar in type and frequency to those in the overall population for the common events of lip disorder (bumps), lip pain, lip swelling and contusion. No important differences were noted between those subjects receiving treatment for perioral rhytids and those not receiving treatment for perioral rhytids for first and second injections of Restylane Silk.

Post-Marketing Surveillance

The adverse events received from post-marketing surveillance for the use of Restylane Silk when used outside the US for lip augmentation were infrequent and included mostly reports of swelling of the lip. Treatments for the events of swelling in the lip included corticosteroids, antibiotics, antihistamines, NSAIDs and hyaluronidase.  Post-marketing reports for the use of Restylane Silk for all indications, including lip augmentation, occurring at the implant site in more than one patient included (in order of decreasing frequency reported) swelling, pain/tenderness, inflammation, mass/induration, erythema, and papules/nodules, infection/abscess, bruising/bleeding, non-dermatological events, and discoloration.

The following adverse events were received from post-marketing surveillance for Restylane and Perlane in the U.S. and other countries when used for indications other than lip augmentation: presumptive bacterial infections, inflammatory adverse events, necrosis, injection site numbness/tingling, hypoesthesia, delayed inflammatory reactions, vasovagal reactions, telangiectasias and capillary disorder, ischemic events, symptoms associated with herpetic eruptions, and rarely acneiform papules at the injection site. Reported treatments have included systemic steroids, systemic antibiotics, and intravenous administrations of medications. Serious adverse events have been rarely reported. The most commonly reported serious adverse events (by MedDRA Preferred Term) were hypersensitivity, and implant and/ or injection site swelling, ischemia and discoloration. Serious abscess formations have also been reported.

Vision abnormalities including blindness have been reported following injection of hyaluronic acid, with and without lidocaine, into the nose, glabella, periorbital areas, and/or cheek, with a time to onset ranging from immediate to a few days following injection. Reported treatments include anticoagulant, epinephrine, aspirin, hyaluronidase, steroid treatment and hyperbaric oxygen. Outcomes ranged from resolved to ongoing at the time of last contact. Events requiring medical intervention, and events where resolution information is not available were reported after injection of hyaluronic acid with or without lidocaine. In these cases, the product was injected into the highly vascularized areas of the glabella, nose, and periorbital area, which are outside the device indications for use (See WARNINGS section).

Adverse reactions should be reported to Galderma Laboratories, L.P. at 1-855-425-8722.

DRUG INTERACTIONS

No information provided.

WARNINGS

• Defer use of Restylane Silk at specific sites in which an active inflammatory process (skin eruptions such as cysts, pimples, rashes, or hives) or infection is present until the process has been controlled.
• Injection site reactions (e.g., lip swelling, lip pain, and contusion) to Restylane Silk have been observed as consisting mainly of short-term minor or moderate inflammatory symptoms starting shortly after treatment, with an average of less than 18 days duration in the lips. In some cases delayed onset of these events has been observed with a range of 21 to 142 days after treatment. Most events with delayed onset resolved within 18 days. Injection site swelling appears to occur more frequently with the linear antegrade method of injection. Rare post-market Restylane reports of immediate post-injection reactions included extreme swelling of lips, the whole face and symptoms of hypersensitivity such as anaphylactic shock.
• Restylane Silk must not be implanted into blood vessels. Localized superficial necrosis and scarring may occur after injection in or near vessels, such as in the lips, nose, or glabellar area. It is thought to result from the injury, obstruction, or compromise of blood vessels.
• Delayed onset inflammatory papules have been reported following the use of dermal fillers. Inflammatory papules that may occur rarely should be considered and treated as a soft tissue infection.
• Injections of 3.0 mL or greater (upper and lower lip combined) per treatment session increases the occurrence of injection site reactions. If a volume of more than 3 mL is needed to achieve optimal correction, a follow-up treatment session is recommended.
• As with all dermal filler procedures, Restylane Silk should not be used in vascular rich areas. Use of similar products in these areas, such as glabella and nose, has resulted in cases of vascular embolization and symptoms consistent with ocular vessel occlusion, such as blindness. For additional information please see the Post- Marketing Surveillance in Adverse Events.

PRECAUTIONS

• Restylane Silk is packaged for single patient use. Do not resterilize. Do not use if package is opened or damaged.
• The safety or effectiveness of Restylane Silk for the treatment of anatomic regions other than lips or perioral rhytids has not been established in controlled clinical studies. Refer to the clinical studies section for more information on implantation sites that have been studied.
• The safety and efficacy of Restylane Silk for lip augmentation has not been established in patients under the age of 22 years. There is limited information on the safety of Restylane Silk in patients less than 36 years of age. In a premarket study of Restylane Silk, the incidence of injection site reactions in 60 patients less than 36 years was similar to the 157 patients between the ages of 36 and 65 years. The majority of these injection site reactions were mild in severity.
• As with all transcutaneous procedures, Restylane Silk implantation carries a risk of infection. Standard precautions associated with injectable materials should be followed.
• The safety of Restylane Silk for use during pregnancy, in breastfeeding females or in patients under 18 years has not been established.
• The safety in patients with known susceptibility to keloid formation has not been studied. Formation of keloids may occur after dermal filler injections including Restylane Silk. In a premarket study of Restylane Silk, the incidence and severity of adverse events in 52 subjects with Fitzpatrick Skin Types IV (n=48) and V (n=3) was similar to that reported in the general population and no unique adverse events associated with these patient subgroups was observed.
• Hyperpigmentation may occur after dermal filler injections including Restylane Silk. Hyperpigmentation was not observed in the Restylane Silk study of 221 subjects including subjects with Fitzpatrick Skin Types IV (n=50) and V (n=2). Hyperpigmentation in patients with Fitzpatrick Skin Type VI has not been evaluated.
• The safety profile for Restylane Silk lip augmentation in persons of color is based upon information from 52 subjects with Fitzpatrick Skin Types IV and V. Within this population, the incidence of adverse events was similar to the overall study population. The safety of Restylane Silk in patients with Fitzpatrick Skin Type VI has not been established.
• Restylane Silk should be used with caution in patients on immunosuppressive therapy.
• Bruising or bleeding may occur at Restylane Silk injection sites. Patients who have undergone therapy with thrombolytics, anticoagulants, or inhibitors of platelet aggregation in the 3 weeks preceding treatment with Restylane Silk have not been studied.
• After use, syringes and needles should be handled as potential biohazards. Disposal should be in accordance with accepted medical practice and applicable local, state and federal requirements.
• The safety of Restylane Silk with concomitant dermal therapies such as epilation, UV irradiation, or laser, mechanical or chemical peeling procedures has not been evaluated in controlled clinical trials.
• Patients should minimize exposure of the treated area to excessive sun, UV lamp exposure and extreme cold weather at least until any initial swelling and redness has resolved.
• If laser treatment, chemical peeling or any other procedure based on active dermal response is considered after treatment with Restylane Silk, there is a possible risk of eliciting an inflammatory reaction at the implant site. This also applies if Restylane Silk is administered before the skin has healed completely after such a procedure.
• Injection of Restylane Silk into patients with a history of previous herpetic eruption may be associated with reactivation of the herpes.
• Restylane Silk is a clear, colorless gel without particulates. In the event that the content of a syringe shows signs of separation and/or appears cloudy, do not use the syringe and notify Galderma Laboratories, L.P. at 1-855-425-8722. Glass is subject to breakage under a variety of unavoidable conditions. Care should be taken with the handling of the glass syringe and with disposing of broken glass to avoid laceration or other injury.
• Restylane Silk should not be mixed with other products before implantation of the device.

OVERDOSE

No information provided.

CONTRAINDICATIONS

• Restylane Silk is contraindicated for patients with severe allergies manifested by a history of anaphylaxis or history or presence of multiple severe allergies.
• Restylane Silk contains trace amounts of gram positive bacterial proteins, and is contraindicated for patients with a history of allergies to such material.
• Restylane Silk is contraindicated for patients with bleeding disorders.
• Restylane Silk is contraindicated for implantation in anatomical spaces other than the dermis or submucosal implantation for lip augmentation.
• Restylane Silk should not be used in patients with previous hypersensitivity to local anesthetics of the amide type, such as lidocaine.

CLINICAL PHARMACOLOGY

U.S. Clinical Study

The safety and effectiveness of Restylane Silk for lip fullness augmentation and treatment of perioral rhytids was evaluated in a randomized, evaluator blinded, no treatment controlled study.

MA-1700-04: Randomized Clinical Study

Design

This was a randomized, evaluator-blinded, no treatment as a control study of 221 subjects who were seeking lip fullness augmentation at 14 U.S. investigational centers. At entry to the study, subjects were randomized 3:1 to (1) Restylane Silk or (2) no treatment. The study recruited a minimum of 30 subjects with Fitzpatrick skin types IV, V, or VI. An additional 40 subjects seeking lip fullness augmentation who were ≤ 35 years of age at study entry and met all except the Medicis Lip Fullness Scales (MLFS) thin/very thin lip criterion were to be enrolled; these subjects were not randomized. Subjects may have returned at 2 weeks after the initial injection for touch-up treatment (if necessary). Subjects were also given the opportunity to have their perioral rhytids treated along with the lip augmentation. Each lip that was treated for augmentation was analyzed for effectiveness and all lips were analyzed for safety. Subjects randomized to treatment at baseline were re-treated at 6 months and subjects randomized to no treatment at baseline received their first treatment at 6 months. The safety of all subjects was then monitored for one month after the 6 month treatment.

There were a total of 177 subjects that received treatment with SPHAL at the Baseline Visit. Of these subjects, 44 subjects did not receive treatment at the Month 6 treatment visit (Visit 10). Of these 44 subjects, 11 subjects were lost to follow-up (LTFU) and six subjects withdrew consent (see response to Question 8) prior to Visit 10

Endpoints - Effectiveness

Primary

The Primary effectiveness objective was to identify whether Restylane Silk was more effective in lip augmentation than no treatment. This was determined by the change from baseline in blinded evaluator assessments of lip fullness at 8 weeks after the first treatment, separately in the upper and lower lips (co-primary effectiveness endpoints) in the randomized subjects using separate five grade MLFS with photoguides for each lip. Treatment success was defined as at least a one grade increase from baseline in the MLFS for the blinded evaluator assessment at Week 8 (compared to the baseline assessment).

The primary safety objective was to determine the incidence of reported treatment emergent adverse events at 72 hours, 2, 4, 8, 12, 16, 20 and 24 weeks after the initial injection(s) and 72 hours, 2 weeks and 4 weeks after the 6 month treatment. Subjects maintained diaries for 14 days after the initial and 6 month treatments to record the severity and duration of bruising, redness, swelling, pain, tenderness and itching.

Secondary

Secondary effectiveness objectives included

Assessment of lip fullness augmentation after treatment with Restylane Silk compared to no treatment as assessed by the blinded evaluator, treating investigator, and independent photographic reviewer (IPR) at post-baseline time points as compared to the baseline assessment. Response was defined as at least one grade improvement from baseline in the upper and lower lips using MLFS.

Identification of lip improvement at each time point after treatment with Restylane Silk as compared to no treatment using the Global Aesthetic Improvement Scale (GAIS) by the treating investigator and the subjects. Response was defined as a GAIS rating of “improved” or better in the upper and lower lips.

Improvement in the appearance of upper perioral rhytids compared to no treatment at each time point using the Wrinkle Assessment for Upper Lip Lines (WASULL) by the assessment of the blinded evaluator and the treating investigator.

Proportion of responders for the co-primary and secondary endpoints for subjects with pre-treatment Fitzpatrick scores IV, V, and VI as well as for subjects ≤ 35 years old at baseline.

Secondary safety objectives included assessment of lip texture, firmness, symmetry, product palpability, mass formation, lip movement, lip function, and lip sensation.

Outcomes

Demographics

The study enrolled an adult population of predominately Caucasian healthy females.

Characteristics	Total (N=221)
Age (years)
n	221
Mean (S.D.)	45.5 (12.3)
Median	48.0
Minimum	18
Maximum	65
Gender
Male	6 (3%)
Female	215 (97%)
Race
American Indian/Alaskan Native	1 ( < 1%)
Black/African American	1 ( < 1%)
Native Hawaiian/Pacific Islander	0
Asian	3 (1%)
White	211 (95%)
Other	5 (2%)
Ethnicity
Not Hispanic or Latino	178 (81%)
Hispanic or Latino	43 (19%)
Fitzpatrick Skin Type
I, II, and III	169 (76%)
IV, V, and VI	52 (24%)

Volume of Restylane Silk Used

	Initial Treatment		6 Month Treatment
	No Treatment (N=43)	Restylane Silk (1st Treatment) (N=176)	No Treatment (1st Treatment) (N=43)	Restylane Silk (2nd Treatment) (N=176)
Volume of Injection (mL) for upper and lower lip(s) (includes treatment and touch up)
n	--	176	41	133
Mean	--	2.18 (1.07)	2.12 (0.74)	1.50 (0.81)
Median	--	1.00	2.00	1.25
Minimum	--	0.10	1.00	0.20
Maximum	--	6.80	4.00	4.40
Volume of Injection (mL) for perioral rhytids (includes treatment and touch up)
n	--	65	18	32
Mean	--	0.48 (0.44)	0.89 (0.70)	0.70 (0.53)
Median	--	0.30	0.90	0.60
Minimum	--	0.03	0.02	0.10
Maximum	--	1.70	1.90	2.00

It was recommended in the study protocol that the investigator treating the subject not exceed injections of 1.5 mL of Restylane Silk per lip per treatment session.

Effectiveness

The purpose of this study was to evaluate the safety and effectiveness of Restylane Silk for soft tissue augmentation of the lips and improvement of perioral rhytids. The results of assessments confirm that Restylane Silk is effective for adding fullness to both the upper and lower lips for at least 6 months.

Proportion (%) of MLFS Responders Measured by the Blinded Evaluator (Upper and Lower Lip Combined)

p < 0.001 for all time points

The study also showed that the appearance of upper perioral rhytids improved in patients whose perioral rhytids were treated with Restylane Silk as assessed by the blinded evaluator.

Proportion (%) of Responders Measured by the Blinded Evaluator for Upper Perioral Rhytids

p < 0.001 for all time points

Subjects assessed lip improvement at each time point after treatment with a 7-point GAIS. When upper and lower lip outcomes were combined, the study showed that subjects were pleased with the visual improvement in their lips. No patients in the No Treatment group assessed themselves as improved from baseline at any visit.

Subjects assessed lip improvement at each time point after treatment with a 7-point non-validated GAIS. When upper and lower lip outcomes were combined, the following percentage of Restylane Silk subjects assessed themselves as improved or better from Baseline: 97.7% (Week 2), 95.3% (Week 4), 90.1% (Week 8), 87.5% (Week 12), 79.4 % (Week 16), 76.5% (Week 20), and 76.5% (Week 24). No patients in the No Treatment group assessed themselves as improved from Baseline at any visit.

76% of the eligible subjects elected to receive re-treatment at Week 24 which suggests that subjects believed that the safety concerns associated with Restylane Silk lip and perioral injections were less than the aesthetic value provided by the device. Of the subjects that elected to not receive re-treatment at Week 24, six (3%) reported refusal due to adverse events experienced during their initial treatment.

Lip safety assessments, such as lip texture, firmness, symmetry, movement, function, sensation, mass formation, and device palpability were evaluated at the screening visit and throughout the study. None of the lip assessments were remarkable or presented any safety concerns.

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.