"The U.S. Food and Drug Administration today approved the VenaSeal closure system (VenaSeal system) to permanently treat varicose veins of the legs by sealing the affected superficial veins using an adhesive agent.
There are two types of vei"...
There were seven U.S. studies that reported adverse experiences. Five of the seven studies were conducted in support of the indication of mid-to-deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds, and two of the seven studies were conducted in support of the indication of submucosal implantation for lip augmentation.
Studies conducted in moderate to severe facial wrinkles and folds, such as nasolabial folds
Three U.S. studies (i.e., Study 31GE0003, MA-1400-01, and Study MA-1400-02) involved 430 patients at 33 centers. In study 31GE0003, 138 patients at 6 centers received Restylane injections in 1 side of the face and a bovine collagen dermal filler (ZyplastR) in the other side of the face. In Study MA-1400-01, 150 patients were injected with Restylane on one side of the face and PerlaneR on the other side of the face. In study MA-1400-02, 283 patients were randomized to receive either Restylane or Perlane injection on both sides of the face. The adverse outcomes reported in patient diaries during 14 days after treatment in these studies are presented in Tables 1–6. The physician diagnosed adverse events identified in studies MA-1400-01 and MA-1400-02 at 72 hours after injection are presented in Table 7. Table 8 presents all investigator-identified adverse experiences recorded at study visits 2 weeks or more after injection in studies MA-1400-01, MA-1400-02, and 31GE0003.
In the fourth U.S. study (MA-004-03) involving 75 patients at 3 centers, adverse events reported by Restylane patients are presented in Table 11. Patients in the study received Restylane injections in both nasolabial folds at baseline, a second treatment in one nasolabial fold at 4.5 months and in the contralateral nasolabial fold at 9 months.
In a fifth U.S. study (MA-1100-001) 60 patients at three centers randomly received Restylane-L injections on one side of the face and Restylane injections on the other side of the face. The adverse events reported in patient diaries during 14 days after treatment are presented in Tables 7 and 8. The physician recorded adverse events identified in study MA-1100-001 at 14 days after injection are presented in Table 12.
Table 9 shows the number of adverse experiences identified by investigators at 72 hours after injection for Studies MA-1400-01 and MA-1400-02. Some patients had multiple adverse experiences or had the same adverse experience at multiple injection sites. No adverse experiences were of severe intensity.
Table 10 presents the number of patients and per patient incidence of all adverse experiences identified by investigators at visits occurring two or more weeks after injection.
In a clinical study (31GE0003) in which safety was followed for 12 months with repeat administration of Restylane at six to nine months following the initial correction, the incidence and severity of adverse events were similar in nature and duration to those recorded during the initial treatment sessions.
In all three studies, investigators reported the following local and systemic events that were judged unrelated to treatment and occurred at an overall incidence of less than 2%, i.e., acne; arthralgia; tooth disorders (e.g., pain, infection, abscess, fracture); dermatitis (e.g., rosacea, unspecified, contact, impetigo, herpetic); unrelated injection site reactions (e.g., desquamation, rash, anesthesia); facial palsy with co-administration of botulinum toxin; headache/migraine; nausea (with or without vomiting); syncope; gastroenteritis; upper respiratory or influenza-like illness; bronchitis; sinusitis; pharyngitis; otitis; viral infection; cystitis; diverticulitis; injuries; lacerations; back pain; rheumatoid arthritis; and various medical conditions such as chest pain, depression, pneumonia, renal stones, urinary incontinence, and uterine fibroids.
Table 11 presents the number of patients and per patient incidence and severity of injection site adverse events identified by the investigator.
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.
Table 12 shows the number of adverse events identified by investigators during Day 1 through Day 14 after injection in Study MA-1100-001.
Some patients had multiple adverse events or had the same adverse events at bilateral injection sites. No adverse events were of severe intensity. Patients were queried on adverse events on the day of injection and at the Day 14 visit.
Study MA-1100-001, included 52 subjects who had no prior cosmetic treatment and 8 subjects who had prior dermal filler treatment. There were no statistical differences in the proportion of subjects with adverse events who had prior treatment and those with no prior treatment.
Studies conducted for submucosal implantation for lip augmentation
In the U.S. pivotal study (MA-1300-15) involving 180 subjects at 12 centers, the adverse outcomes reported in subject diaries are presented in Tables 14 and 15. Physician reported treatment emergent adverse events are presented in Table 16. At baseline, subjects were randomized to receive Restylane injections in the lips or no treatment (control group). At 6 months, all subjects were eligible to receive treatment or re-treatment in the lips with Restylane.
Of the 180 subjects enrolled in the study, 172 subjects received their first treatment with Restylane at either baseline/Day 0 or at 6 months, and 93 subjects received a second treatment at 6 months. There were 8 subjects enrolled in the study that were never treated. The number of events and subjects reporting TEAEs decreased between the first and second treatments. 87% of subjects receiving their first treatment reported a total of 795 TEAEs while 65% of subjects that received a second treatment reported a total of 267 TEAEs. Furthermore, an overwhelming majority of these TEAEs were mild in intensity (672/795, 85%; and 264/267, 99%; first and second treatment respectively), and were transient in nature, resolving in approximately 15 days or less.
The study results showed injection of greater than 1.5 mL per lip (upper or lower), per treatment session increased the occurrence of the total of moderate and severe injection site reactions. The incidence was 43% (33/76) for subjects receiving more than 3.0 mL of Restylane and 21% (20/96) for subjects receiving less than 3.0 mL of Restylane in a single treatment session. When optimal correction requires greater than 1.5 mL per upper or lower lip, subsequent treatment using additional product is recommended.
97% of the subjects reported at least one event of swelling, redness, tenderness, or pain in their diaries. These were mainly short-term events, which occurred immediately after treatment and resolved within 14 days. 15% of the subjects reported adverse events (typically swelling and tenderness) that lasted longer than 15 days in their diary. 46% of subjects reported at least one event as “affecting their daily activity” or “disabling.”
Additional safety assessments in the study included lip texture, firmness, symmetry, movement, function, sensation, mass formation, and product palpability, which were evaluated as appropriate at the screening visits and at follow-up visits.
The majority of texture and firmness assessments showed mild abnormalities and lasted for less than 4 weeks. Sixteen subjects reported severe asymmetry (difference > 2 mm) post-treatment, which all resolved within 4 weeks. GAIS assessments by these 16 subjects were rated as at least improved during those visits.
Assessments made by the trained health care provider showed 92% of subjects had product palpability at week 8, and 61% at week 24. The majority of palpations were rated as “expected feel.” 3% of the subjects reported “unexpected feel” during the study, all of which were resolved with massaging.
One subject reported one mass formation (mucocele) during the study. The mucocele was drained and resolved by the next visit.
All other lip safety assessments showed no remarkable findings.
In the pilot study MA-1300-13K, 20 subjects were enrolled at 1 center and received Restylane for lip augmentation. Subjects were followed up through 24 weeks. Seven adverse events were reported. Two of the seven events, which were mild bruising, were related to injection procedure. The adverse outcomes reported in subject diaries are presented in Table 17.
Table 16 presents commonly reported ( ≥ 5%) treatment emergent adverse events (TEAEs) by treatment group.
For study MA-1300-13K, seven treatment emergent adverse events were experienced by four subjects. Two of these events, mild bruising, were considered related to treatment.
The following adverse events were received from post-marketing surveillance for Restylane and Perlane in the U.S. and other countries: presumptive bacterial infections, inflammatory adverse events, necrosis, injection site numbness/tingling, and vasovagal reactions. Reported treatments have included systemic steroids, systemic antibiotics, and intravenous administrations of medications. Additionally, delayed inflammatory reaction to Restylane has been observed with swelling, redness, tenderness, induration and rarely acneform papules at the injection site with onset as long as several weeks after the initial treatment. Average duration of these effects is two weeks.
Implant and injection site reactions, mostly non-serious events, have also been reported. These include: discoloration, bruising, swelling, mass formation, erythema, pain, scarring and ischemia. Most instances of discoloration including hyperpigmentation, sometimes described as a blue or brown color and ranging from mild to severe, have occurred within the same day as treatment but have also occurred up to 6 months posttreatment. These events typically resolve within a few days but with some infrequent instances lasting up to 18 months. Implant and/or injection site bruising, swelling, erythema and pain generally occurred on the same day as treatment usually resolving within 1 to 4 weeks. Some occurrences have persisted for up to 6 months. Severity for these events is generally mild to moderate although some cases have been severe. Mild to moderate mass formations (typically described as lumps or bumps) have also been seen ranging in onset from 1 day to 6 months post-implantation. Rarely, events of this type have been observed for up to 13 months. These events usually resolved within 1 to 5 months. Mild to moderate scarring was rarely observed. Onset of symptoms ranged from immediate post-treatment to up to 1 year following implantation. Symptom resolution was approximately 3 weeks with 1 instance lasting up to 3 years. Most ischemic events have occurred immediately following implantation and ranged in severity from moderate to severe. Events were resolving as early as 2 days and up to 9 weeks post-treatment.
Symptoms associated with herpetic eruptions which included swelling, pain, whiteheads, vesicles and erythema have been reported and commonly occurred within 2 days to 1 month following implantation. Severity ranged from mild to moderate and resolution of symptoms ranged from 1 to 15 weeks.
Telangiectasias and capillary disorders, commonly characterized as broken capillaries, have been reported and occurred with an onset of 1 day to 7 weeks. Most events ranged in severity from mild to moderate with a few severe instances. Duration of events ranged from 2 weeks up to 13 months.
Events of mild to moderate hypoaesthesia have occurred ranging in onset from 1 day to 1 week. Duration and resolution occurred between 1 day and 10 weeks.
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. Of these infrequently reported serious events, only the following occurred in a frequency of 5 or greater:
- Hypersensitivity reactions ranging from moderate to severe mostly occurred within 1 to 2 days of implantation and up to 3 weeks. Reported symptoms included swelling; itching on chest and back; puffy, burning, watery, and itchy eyes; and shortness of breath. Treatments included steroids, diphenhydramine, unspecified intravenous medication, oxygen and various creams. An evaluation of patients who reported potential hypersensitivity reactions did not demonstrate any evidence of IgE or cell mediated immunologic reactions specifically directed at hyaluronic acid. Most hypersensitivity events resolved within 1 to 14 days with or without treatment.
- Allergic reaction and anaphylactic shock: Eight patients experienced immediate post-injection reactions which included extreme swelling of lips and the whole face. Two of these patients had symptoms of hypersensitivity and one patient experienced anaphylactic shock and presented with shortness of breath, headache, nausea and vomiting. These patients had to be admitted to the emergency room or were hospitalized for immediate medical interventions. Delayed hypersensitivity: Two patients developed symptoms of hypersensitivity 7–10 days after injection. One patient experienced severe erythema and swelling in the lips and all over her face to the point that her eyes were shut and the other had swelling of the lips accompanied by dyspnea, lymphadenopathy, peripheral and laryngeal edema.
- Vascular accidents and necrosis: In 5 patients, skin discoloration, bruising, and blanching was seen immediately post-injection due to vascular accidents. The lesions later turned into necrosis and in some cases remained as scarring or dark spots. One example was a patient who had a “mustache-like” mark above her lips, even after receiving treatments. Later, one patient in this group developed hard bumps in her upper lips that looked like “granulomas.”
- Infection/Abscess: Serious abscess formations ranging from moderate to severe occurred in eleven patients. Onset ranged from 3 days to one week with an average duration of approximately one month to resolution. Symptoms included swelling, redness, pain and hard nodules. Five patients required hospitalization for incision and drainage (I&D) and intravenous (IV) antibiotic therapy. Cultures for all patients ranged from gram positive staphylococcal, gram negative cellulitis, apathogen streptococci, gram positive cocci infection, polymorphonuclear neutrophils (PMN) with no bacteria and positive proprionibacterium malassezia. The remaining cultures were either negative or not reported. Treatment included various antibiotics and steroids in some cases.
The following non-serious events, extrusion of device, ischemia/necrosis, and device dislocation, were also reported in a frequency of 5 or more. These events were considered non-serious as they did not meet seriousness criteria.
Adverse reactions should be reported to Medicis Aesthetics Inc. at 1-800-900-6389.
Read the Restylane-L (hyaluronic acid dermal filler injectable gel with 0.3% lidocaine) Side Effects Center for a complete guide to possible side effects
No information provided.
Last reviewed on RxList: 7/8/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Restylane-L Information
Report Problems to the Food and Drug Administration
Find out what women really need.