Restylane Silk

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)

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

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

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

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.

Read the entire FDA prescribing information for Restylane Silk (Lidocaine 0.3% Injectable Gel)