What is Restylane?1

Restylane is a FDA-approved dermal filler made of a biodegradable, non-animal stabilized hyaluronic acid (NASHA). Hyaluronic acid is a natural substance found in all living organisms and provides volume and fullness to the skin.

Restylane is a gel of hyaluronic acid generated by Streptococcus species of bacteria. It is produced biotechnologically by natural fermentation in a sterile laboratory environment. This significantly diminishes the risk of transmitting diseases between species or of eliciting allergic reactions in patients who are sensitive to common foods, such as beef, chicken and eggs. Restylane does not require any allergy or skin test prior to injection.

Restylane is indicated for mid-to-deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. Restylane is also indicated for submucosal implantation for lip augmentation in patients over the age of 21.

Restylane is formulated as a clear gel and uses a dual mechanism of action to correct moderate to severe wrinkles and folds. Upon being injected beneath the skin's surface, Restylane gel integrates into dermal tissue then attracts and binds to water molecules to help maintain volume. Restylane is gradually degraded by the body's own mechanism and disappears without any residue. Results can be seen immediately following Restylane treatment and for up to six months. Some patients may achieve results that last longer than six months, depending upon injection site.

Restylane is a gel of hyaluronic acid generated by a Streptococcus species of bacteria. As opposed to other hyaluronic acid products, NASHA is not derived from animal sources. It is produced biotechnologically by natural fermentation in a sterile laboratory environment. This significantly diminishes the risk of transmitting diseases between species or of eliciting allergic reactions in patients who are sensitive to common foods, such as beef, chicken and eggs. Restylane does not require any allergy or skin test prior to injection.

Restylane is also marketed and sold in more than 65 countries outside the United States where it has been used in more than ten million procedures.

Restylane Clinical Trials1

Six U.S. clinical trials were completed in support of the indications for Restylane. Four trials in over 500 patients evaluate safety and efficacy in mid-to-deep dermal implantation for correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. Two studies in roughly 200 patients were conducted in support of the indication of submucosal implantation for lip augmentation.

Restylane was shown to be effective when compared to cross-linked collagen and cross-linked hyaluronic acid dermal fillers with respect to the correction of moderate to severe facial folds and wrinkles, such as nasolabial folds and in lip augmentation.

Restylane is contraindicated:

• in patients with severe allergies, including allergies to gram positive bacterial proteins

• in patients with bleeding disorders
• for implantation in anatomical spaces other than the dermis or submucosal implantation for lip augmentation

• Delay use of Restylane at sites in which an active inflammatory process (skin eruptions such as cysts, pimples, rashes, or hives) or infection is present
• Short-term minor or moderate (7-14 days) injection site reactions to Restylane have been observed. Injections of greater than 1.5 mL per lip (upper or lower) per treatment session significantly 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.
• Restylane must not be implanted into 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

• Based on U.S. clinical studies, patients should be limited to 6 mL per patient per treatment in wrinkles and folds such as the nasolabial folds and to 1.5 mL per lip per treatment. The safety of injecting greater amounts has not been established.
• Safety in anatomic regions other than nasolabial folds or lips have not been established.
• Restylane implantation carries a risk of infection; follow standard infectious disease precautions.
• Safety of Restylane in pregnancy, breastfeeding, or patients under 18 years is not established. Safety and efficacy for lip augmentation in patients under 21 years is not established.
• Formations of keloids may occur after dermal filler injections, but keloids were not observed in Restylane clinical trials in 430 patients.
• Restylane injection may cause hyperpigmentation of the skin at the injection site. In African-American subjects, the incidence of post-inflammatory hyperpigmentation was nine percent, and in 50 percent the events lasted up to six weeks after initial implantation. Swelling may occur more frequently in subjects of color receiving lip augmentation.
• Restylane should be used with caution in patients on immunosuppressive therapy.
• Bruising or bleeding may occur at the injection site. Use with caution in patients who have undergone therapy with thrombolytics, anticoagulants, or platelet inhibitors in the previous 3 weeks.
• Dispose of syringes/needles in accordance with standard biohazard guidelines.
• Safety in combination with other dermal therapies, such as epilation, UV irradiation, or peeling procedures has not been evaluated. A possibility of an inflammatory reaction may exist prior to or after Restylane injections if combined with dermal procedures.
• Minimize sun, UV lamp, and extreme cold exposure until swelling/redness is resolved.
• Restylane injection may reactivate herpes in patients with a history of a previous herpetic eruption.
• Do not use syringe if content appears cloudy or if particulate matter is present. Use care with glass syringe to prevent breakage.
• Do not mix Restylane with other products prior to injection.

Restylane Adverse Events¹

Six U.S. studies reported adverse events with Restylane; four studies were completed in the facial wrinkle indication and two studies were completed in the lip augmentation indication. In three studies, adverse events were collected via patient diaries for 14 days after injection. Physician and investigator adverse events were identified at 72 hours, or 14 days or more after injection. In clinical studies, the following adverse events had a duration  of 7 to 14 days. At day 14, no patients reported the below adverse events, except one patient reported swelling.

Two subjects had adverse events that were severe, one subject with bilateral facial bruising and one subject with infection at the injection site. These events were considered probably or possibly related and both subjects had their events resolve in approximately 3 weeks.

In a meta-analysis of all Restylane Premarket Approval Studies the incidence of swelling was higher in younger patients (28%) compared to older patients (18%) and incidence of contusion was higher in older patients (28%) compared to younger patients (14%). The majority of these events were mild in severity.

Adverse event summary from studies conducted in moderate to severe facial wrinkles and folds, such as nasolabial folds (n=505 subjects)

• Bruising
• Redness
• Swelling
• Pain/Soreness
• Tenderness
• Itching
• Hyperpigmentation
• Injection site scabbing
• Infection
• Hardness/Nodule

One U.S. pilot study and one pivotal study were conducted to determine the safety for Restylane use in lip augmentation. Over 80 percent of subjects reported an adverse event at first injection, and over 60 percent of subjects reported adverse events after the second injection at 6 months. Over 95% of subjects reported at least one event of short-term swelling, redness, tenderness or pain. A majority of events (85-99 percent) were ranked as mild in intensity, and were transient, resolving in 15 days or less. One subject reported a mass formation (mucocele) that was drained and resolved

Injections of greater than 1.5 mL per treatment per lip increased the incidence of moderate and severe reaction site reactions. For subjects receiving more than 3 mL of Restylane the incidence was 43 percent; if 1.5 to 3 mL was used the incidence was 21 percent.

Adverse event summary from studies conducted for submucosal implantation for lip augmentation (n=200 subjects)

• Redness
• Swelling
• Pain/Soreness
• Tenderness
• Bruising
• Itching
• Headache
• Skin Exfoliation

Rare Post-Marketing Serious Adverse Events

• Delayed hypersensitivity reactions
• Immediate-onset allergic reactions and anaphylactic shock
• Vascular accidents and necrosis

For complete administration, dosing and safety information refer to the manufacturers package labeling for Restylane.