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Poly-L-lactic acid
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Brand Name: Sculptra  Audio
Drug Class: Opportunistic Infection and Other Drugs

Drug Description
Poly-L-lactic acid (PLLA) is a biocompatible, biodegradable, and immunologically inert synthetic polymer from the alpha-hydroxy-acid family. Microparticles of PLLA are the active ingredient in Sculptra, the injectable implant used for treatment of facial atrophy.[1][2]

HIV/AIDS-Related Uses
PLLA was approved by the FDA on August 3, 2004, for the restoration and correction of the signs of facial fat loss in people with HIV.[3] Facial wasting is a common and disfiguring side effect of highly active antiretroviral therapy (HAART). Both nucleoside analogues and protease inhibitors are associated with the development of lipoatrophy.[4]

PLLA was approved in 1999 in Europe under the brand name New-Fill for the cosmetic treatment of wrinkles and has been used by an estimated 100,000 people. Dermik Laboratories, a Pennsylvania-based division of Sanofi-Aventis, filed with the FDA for premarket approval of PLLA in the United States under the brand name Sculptra.[5] On March 25, 2004, the FDA's General and Plastic Surgery Devices Advisory Panel recommended conditional approval for Sculptra for the treatment of HIV-associated lipoatrophy. Requirements for approval in the United States included a physician training program, a postmarket study enrolling women and people of color, clear labeling with warnings against off-label use, and a description of the product as having a reconstructive rather than a cosmetic purpose. Such strong labeling conditions are intended to greatly reduce the likelihood of adverse events reported in three previous U.S. trials and to discourage off-label use in HIV uninfected people.[6]

Non HIV/AIDS-Related Uses
PLLA was approved in Europe in 1999 for the cosmetic correction of scars and wrinkles. PLLA is currently used in a variety of orthopedic and maxillofacial applications.[7]

Dosing Information

Mode of Delivery
Deep dermis or subcutaneous (SQ) injection.[8]

Dosage Form
Clear glass vials containing freeze-dried preparation for injection sealed with a penetrable stopper and covered by an aluminum seal with a flip-off cap.[9] Sterile lyophilisate must be reconstituted with three ml of sterile water and should be injected using a 26-gauge needle.[10]

In clinical studies, patients have received three to five injection sessions at 2-week intervals. The dosage (quantitiy of injections and of sessions) depends upon the severity of facial depression.[11]

Storage
Store PLLA injection at room temperature, up to 30 C (86 F). Do not freeze.[12]

Pharmacology
PLLA is the only treatment approved to correct sunken cheeks, hollow eyes, indentations, and other signs of facial fat loss, a common side effect of antiretroviral therapy for HIV. PLLA is injected into and around the deep dermis. The injections provide a gradual and significant increase in skin thickness, improving the appearance of folds and sunken areas.[13]

In a study of fifty HIV infected patients with severe facial atrophy, mean increases in facial total cutaneous thickness (TCT) of 6.8 mm were reported at Week 96, and 43% of patients had a facial TCT greater than 10 mm at Week 96. Patients in the study received three, four, or five sets of PLLA injections at 2-week intervals. One vial of reconstituted PLLA was injected into multiple points of each cheek per session. The number of sessions and the quantity of injected PLLA were dependent upon the severity of facial depression.[14]

A single-center study of PLLA was conducted in thirty HIV infected patients with facial lipoatrophy, and patients were followed for 12 or 24 weeks. All patients received three injection sessions conducted at 2-week intervals. All patients experienced statistically-significant increases in mean skin thickness compared with baseline. A mean increase in skin thickness of approximately 4 to 6 mm was observed in all patients at Week 12. In the fourteen patients observed for 24 weeks, mean increase in skin thickness was approximately 5 mm at Week 24.[15]

The progressive increase in dermal thickness may result from a local reaction followed by a progressive increase in collagen deposition. The bioactive material is degraded and safely undergoes resorption. Although PLLA injections are associated with an increase in TCT, there is no increase in subcutaneous fat.[16] For most people who participated in PLLA clinical studies, the treatment results lasted for up to 2 years after the first treatment session.[17]

Adverse Events/Toxicity
PLLA injection has been associated with some adverse effects. In five clinical studies of HIV infected patients, no major adverse events were reported. Mild to moderate adverse events included bruising and hematoma related to injection.[18] The most common device-related adverse event was delayed occurrence of subcutaneous papules, which were confined to the injection site and were typically palpable, asymptomatic, and nonvisible.[19] Side effects reported at the March 25, 2004, meeting of the FDA General and Plastic Surgery Devices Advisory Panel included discomfort, bruising, edema, hematoma, inflammation, and erythema at the injection site. [20]

All patients had some degree of postinjection edema. A large proportion of patients (77%) experienced pain during the injection procedure, and about 28% of these patients required pain medication. About 13% of patients had postinjection noninflammatory nodules or papules. Severe side effects observed in limited clinical trials of PLLA included vagal hypertonia and lightheadedness (7.5%), inflammatory nodule development (1%), facial palsy upon hitting the facial nerve during treatment (1%), and anaphylaxis (1%).[21]

Drug And Food Interactions
No studies of interactions with PLLA with drugs or other substances or implants have been done.[22]

Contraindications
PLLA should not be used in any person who has hypersensitivity to any of the components of the product.[23]

Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Poly-L-lactic acid.

Chemistry

CAS Name
Propanoic acid, 2-hydroxy-, (S)-, homopolymer[24]

CAS Number
26811-96-1[25]

Molecular Formula
(C3-H6-O3)x-[26]

Molecular Weight
40 to 50 kDa[27]

Stability
Each vial of PLLA for injection is packaged for single-use only; do not resterilize.[28]

PLLA is physically, chemically, and microbiologically stable for up to 72 hours after reconstitution, and for up to 2 years as a lyophilisate.[29][30]

Further Reading
Sculptra Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site.

PMID/16820069 Barton SE, Engelhard P, Conant M. Poly-L-lactic acid for treating HIV-associated facial lipoatrophy: a review of the clinical studies. Int J STD AIDS. 2006 Jul;17(7):429-35.

PMID/16549708 Cattelan AM, Bauer U, Trevenzoli M, Sasset L, Campostrini S, Facchin C, Pagiaro E, Gerzeli S, Cadrobbi P, Chiarelli A. Use of polylactic acid implants to correct facial lipoatrophy in human immunodeficiency virus 1-positive individuals receiving combination antiretroviral therapy. Arch Dermatol. 2006 Mar;142(3):329-34.

PMID/16912248 El-Beyrouty C, Huang V, Darnold CJ, Clay PG. Poly-L-lactic acid for facial lipoatrophy in HIV. Ann Pharmacother. 2006 Sep;40(9):1602-6. Epub 2006 Aug 15. Review.

PMID/17083585 Mest DR, Humble G. Safety and efficacy of poly-L-lactic acid injections in persons with HIV-associated lipoatrophy: the US experience. Dermatol Surg. 2006 Nov;32(11):1336-45.

PMID/16494632 Moyle GJ, Brown S, Lysakova L, Barton SE. Long-term safety and efficacy of poly-L-lactic acid in the treatment of HIV-related facial lipoatrophy. HIV Med. 2006 Apr;7(3):181-5.

Manufacturer Information
Poly-L-lactic acid
  Dermik Laboratories, Inc.
  1050 Westlakes Dr.
  Berwyn,  PA  19312
  (484) 595-2700
    

Sculptra
  Dermik Laboratories, Inc.
  1050 Westlakes Dr.
  Berwyn,  PA  19312
  (484) 595-2700
    

References
[1] AIDS - 2003 Nov 21;17(17):2471-7
[2] FDA - Sculptra Prescribing Information, June 2004, p. 1. Available at: http://www.fda.gov/cdrh/PDF3/p030050c.pdf Accessed 01/23/07.
[3] Dermik Laboratories - Press and Media: FDA Approves Sculptra [press release], August 3, 2004. Available at: http://www.dermik.com/press/2004/08/0301.aspx. Accessed 01/23/07.
[4] AIDS - 2003 Nov 21;17(17):2471-7
[5] FDA - Brief Summary From the General and Plastic Surgery Devices Panel Meeting. Available at: http://www.fda.gov/cdrh/panel/summary/gpsd-032504.html. Accessed 01/23/07.
[6] Clinical Care Options for HIV - New-Fill Recommended for Approval in U.S. as Sculptra [news report], April 2, 2004. Available at: http://clinicaloptions.com/hiv/news/news_NAM_259.asp. Accessed 01/23/07.
[7] AIDS - 2003 Nov 21;17(17):2471-7
[8] Sanofi-Aventis - Sculptra Prescribing Information, June 2006. Available at: http://products.sanofi-aventis.us/sculptra/sculptra.html. Accessed 01/23/07.
[9] FDA - Sculptra Prescribing Information, June 2004, p. 7. Available at: http://www.fda.gov/cdrh/PDF3/p030050c.pdf. Accessed 01/23/07.
[10] FDA - General and Plastic Surgery Devices Panel Meeting, 03/25/04. Available at: http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4031t1.htm. Accessed 01/23/07.
[11] Sanofi-Aventis - Sculptra Prescribing Information, June 2006. Available at: http://products.sanofi-aventis.us/sculptra/sculptra.html. Accessed 01/23/07.
[12] FDA - Sculptra Prescribing Information, June 2004, p. 11. Available at: http://www.fda.gov/cdrh/PDF3/p030050c.pdf. Accessed 01/23/07.
[13] Dermik Laboratories - Press and Media: FDA Approves Sculptra [press release], August 3, 2004. Available at: http://www.dermik.com/press/2004/08/0301.aspx. Accessed 01/23/07.
[14] Sanofi-Aventis - Sculptra Prescribing Information, June 2006. Available at: http://products.sanofi-aventis.us/sculptra/sculptra.html. Accessed 01/23/07.
[15] Sanofi-Aventis - Sculptra Prescribing Information, June 2006. Available at: http://products.sanofi-aventis.us/sculptra/sculptra.html. Accessed 01/23/07.
[16] AIDS - 2003 Nov 21;17(17):2471-7
[17] Dermik Laboratories - Press and Media: FDA Approves Sculptra [press release], August 3, 2004. Available at: http://www.dermik.com/press/2004/08/0301.aspx. Accessed 01/23/07.
[18] FDA - Brief Summary from the General and Plastic Surgery Devices Panel Meeting. Available at: http://www.fda.gov/cdrh/panel/summary/gpsd-032504.html. Accessed 01/23/07.
[19] Sanofi-Aventis - Sculptra Prescribing Information, June 2006. Available at: http://products.sanofi-aventis.us/sculptra/sculptra.html. Accessed 01/23/07.
[20] FDA - Sculptra Prescribing Information, June 2004, pp. 3-4. Available at: http://www.fda.gov/cdrh/PDF3/p030050c.pdf. Accessed 01/23/07.
[21] Natap.org - HIV Articles: Report 2 on Sculptra (New-Fill): FDA Study Review; Advocacy Issues. Available at: http://www.natap.org/2004/HIV/032904_02.htm. Accessed 01/23/07.
[22] FDA - Sculptra Prescribing Information, June 2004, p. 2. Available at: http://www.fda.gov/cdrh/PDF3/p030050c.pdf. Accessed 01/23/07.
[23] FDA - Sculptra Prescribing Information, June 2004, p. 1. Available at: http://www.fda.gov/cdrh/PDF3/p030050c.pdf. Accessed 01/23/07.
[24] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 01/23/07.
[25] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 01/23/07.
[26] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 01/23/07.
[27] Natap.org - HIV Articles: Report 2 on Sculptra (New-Fill): FDA Study Review; Advocacy Issues. Available at: http://www.natap.org/2004/HIV/032904_02.htm. Accessed 01/23/07.
[28] FDA - Sculptra Prescribing Information, June 2004, p. 11. Available at: http://www.fda.gov/cdrh/PDF3/p030050c.pdf. Accessed 01/23/07.
[29] Natap.org - HIV Articles: Report 2 on Sculptra (New-Fill): FDA Study Review; Advocacy Issues. Available at: http://www.natap.org/2004/HIV/032904_02.htm. Accessed 01/23/07.
[30] FDA - General and Plastic Surgery Devices Panel Meeting, 3/25/04. Available at: http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4031t1.htm. Accessed 01/23/07.
Updated January 23, 2007