LAVIVTM is an autologous cellular product indicated for improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults.

The safety and efficacy of LAVIV for areas other than the nasolabial folds have not been established.

The efficacy of LAVIV beyond six months has not been established.

For autologous intradermal injection only

Only healthcare providers who have completed a Fibrocell-approved training program should administer LAVIV.

A single vial of LAVIV contains approximately 18 million autologous fibroblasts in a 1.2 milliliters suspension, sufficient to administer 1 milliliter of product.

• Allogeneic use

If LAVIV is administered to a patient who is not the individual whose skin was used to produce the LAVIV, serious immunological reactions can occur. Each vial of LAVIV has a unique patient identifier to assist in ensuring that there is no mismatch.

• Severe Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, can occur in patients with known hypersensitivity to the ingredients in LAVIV. Do not use LAVIV in patients allergic to gentamicin, amphotericin, dimethyl sulfoxide (DMSO), or material of bovine origin.

• Active Infection

Injecting LAVIV into areas with skin infections can lead to local or systemic infection.

The most common adverse reactions, occurring in ≥1% of subjects in clinical trials, were injection-site reactions, including redness, bruising, swelling, pain, hemorrhage, edema, nodules, papules, irritation, dermatitis, and pruritus.

Adverse reactions occurring in less than 1% of trial subjects were acne, facial or eyelid edema, hypersensitivity or decreased skin sensation at the injection site, post-procedural discomfort (headache, toothache, and jaw pain), herpes labialis, hyperpigmentation at the injection site, injection-site ischemia, basal cell cancer, and leukocytoclastic vasculitis.

No drug interaction studies have been performed with LAVIV.

Patients taking aspirin, NSAIDS or anticoagulants may experience increased bruising or bleeding at biopsy and/or injection sites. Concomitant use of aspirin, NSAIDs or anticoagulants is not recommended. Decisions regarding continued use or cessation of anticoagulants should be made in consultation with the health care provider.

LAVIV is an autologous cellular product composed of fibroblasts suspended in Dulbecco's Modified Eagle's Medium (DMEM) without phenol red. Dermal fibroblasts from post-auricular skin biopsy tissue are aseptically expanded using standard tissue-culture procedures until sufficient cells for three doses are obtained. Cells are then cryopreserved in a protein-free solution containing DMSO. When the patient administration is scheduled, cells are thawed, washed, and shipped to the clinic. A final sterility test is initiated prior to shipping, but the result will not be available for up to 14 days. A passing sterility culture result from the test performed on the cryopreserved bulk material (Drug Substance) and a negative Gram stain test result on the final LAVIV drug product are required for release of a product for shipping.

The effectiveness of LAVIV was demonstrated in two identically-designed, multi-center, randomized, double-blind, vehicle-controlled studies. The study population consisted of subjects with moderate to severe bilateral nasolabial fold wrinkles. A total of 421 subjects, aged 23 to 81 years, were randomized to receive LAVIV (n=210) or vehicle-control (n=211). In both studies, the major demographic features were similar between LAVIV and vehicle-control groups. Subjects in Study One (n=203) were predominantly female (90%), White (95%), and had an overall mean age of 56.7 years. Subjects in Study Two (n=218) were predominantly female (91%), White (89%), and had an overall mean age of 54.6 years.

Each subject underwent three post-auricular skin punch biopsies to obtain skin tissue to generate LAVIV. Subjects whose biopsy samples met acceptance criteria were randomized in a 1:1 ratio to receive either LAVIV or vehicle-control (DMEM without phenol red). Biopsy samples for subjects assigned to receive LAVIV were provided to the manufacturer for culture and processing. The process for production of LAVIV takes approximately 11 to 22 weeks. Study agent (either LAVIV or vehicle-control) was then administered intradermally to nasolabial fold wrinkles on both sides of the face at a dose of 0.1 milliliter per linear centimeter, up to 2 milliliters (1-2 x107 cells/milliliter) per each treatment session. A total of three separate treatment sessions occurred at intervals of 5±1 weeks.

Since LAVIV must be grown from subjects' own skin biopsies, the manufacturing process may not yield sufficient quantities of fibroblasts. Due to product manufacturing failure, 6.2% of subjects randomized to receive LAVIV in the two trials did not receive any LAVIV. In addition, 5.7% of subjects randomized to receive LAVIV had insufficient quantities of LAVIV to complete the planned three treatment sessions. A repeat biopsy was required in 1.5% of subjects as a result of shipping errors.

For both clinical trials, the co-primary efficacy outcomes were the proportion of subjects with a two-point improvement from baseline in the appearance of the nasolabial fold wrinkles at six months after the third treatment session. The outcomes were assessed with live evaluations performed independently by subjects and by evaluating physicians. Both subjects and evaluators were blinded to treatment assignment. To maintain the blinding, the injector and evaluator for any given subject were different investigators. Subjects assessed their nasolabial fold wrinkles on a five-point Subject Wrinkle Assessment scale that ranged from -2 to +2. The evaluating physicians used a six-point Evaluator Wrinkle Severity Assessment scale that ranged from 0 to 5 (Lemperle scale). Evaluation with the Lemperle scale was aided by a photoguide, which correlated wrinkle appearance with a specific numerical score.

Table 2 shows the efficacy results based on the intent-to-treat population, which included all randomized subjects. When subjects assessed themselves, 57% (Study One) and 45% (Study Two) of subjects receiving LAVIV achieved a 2-point improvement in the appearance of their nasolabial fold wrinkles compared with 30% (Study One) and 18% (Study Two) of subjects receiving vehicle-control. When assessed by evaluating physicians, 33% (Study One) and 19% (Study Two) of subjects receiving LAVIV achieved a 2-point improvement in their nasolabial fold wrinkles, compared with 7% of subjects receiving vehicle-control in both trials.

Efficacy beyond six months after the third administration has not been established. No clinical studies have been conducted to evaluate the efficacy of repeating treatment(s) beyond six months.

LAVIV is intended solely for autologous use.

LAVIV is supplied in two vials, each containing approximately 18 million cells in 1.2 milliliters. The vials are packaged together in a tamper-evident biohazard bag and shipped at 2-8°C (36-46°F) inside a temperature-controlled shipping container.

The manufacturing process for LAVIV takes approximately 11-22 weeks after receipt of the patient's biopsy samples by the manufacturer. Fibrocell will notify the clinic when each patient's treatment may be scheduled.

See FDA-approved patient labeling (Patient Information).

Prior to initiating treatment with LAVIV, the healthcare provider should

• Ask the patient about any history of skin cancer, keloids, scarring, or immune problems.
• Discuss the biopsy process and ask the patient to report any persistent symptoms related to the biopsy procedure.
• Manage expectations by telling the patient that
  • The effects of LAVIV are not immediate, but may appear over the course of the three-treatment regimen.
  • Sometimes the biopsies will not produce enough viable cells to manufacture enough LAVIV for injection. In such cases, the patient will be notified and may be offered the opportunity to repeat the procedure.

Following treatment with LAVIV, provide post-injection instructions including the following

• Do not apply ice to the face. A cold compress may be applied for 2-3 minutes at a time, if needed to ease swelling or discomfort.
• Do not wash the site of injections for at least 24 hours.
• Do not scrub, rub or manipulate the treatment area for at least 72 hours.
• Do not apply any products (e.g., make-up, facial creams, sunscreen) to the treatment area for 72 hours.
• Expect mild to moderate redness, swelling, puffiness, or bruising following injections.
• Call the doctor or emergency department for any persistent or unexpected side effects.

Manufactured and Distributed by
Fibrocell Technologies, Inc.
405 Eagleview Blvd.
Exton, PA 19341
T: 484-713-6000
F: 484-713-6001
www.fibrocellscience.com

U.S. License No. 1818

LAVIVTM is a registered trademark of Fibrocell Science, Inc., Exton, PA

LAVIVTM, autologous human fibroblast cells in suspension for injection, is covered by the following U.S. patent: U.S. Pat. No. 5591444.

FDA-Approved Patient Labeling

LAVIVTM (azficel-T)
(pronounced lah-VEEV)

This leaflet is designed to help you understand LAVIVTM. This leaflet does not take the place of talking with your healthcare provider about LAVIV. If you have questions about LAVIV, talk to your healthcare provider.

What is the most important information I should know about LAVIV?

LAVIV is made especially for you from your own skin cells. Your healthcare provider will check to see that the cells that come back from the manufacturer are yours. Using someone else's cells can cause a serious reaction. Do not let anyone else use your LAVIV.

The process for making LAVIV uses antibiotics (amphotericin and gentamicin), bovine serum (from cattle), and dimethyl sulfoxide (DMSO). If you are allergic to any of these, tell your healthcare provider.

Do not use LAVIV if you have a skin infection on your face because LAVIV treatment can make the infection worse. Talk to your healthcare provider if you have any other infection.

What is LAVIV?

LAVIV is made from your own skin cells, which are used to improve the appearance of wrinkles that go from the sides of your nose to the corners of your mouth (called nasolabial folds). LAVIV is injected into your face using a small needle.

Who should not get LAVIV?

You should NOT get LAVIV if you have any of the following problems or conditions:

• Allergy to the antibiotics gentamicin or amphotericin, DMSO, or to things made from cattle (bovine).
• Skin infections in the face.

What should I tell my healthcare provider before getting LAVIV?

Your health care provider will help you to decide whether you are a candidate for LAVIV and may help you avoid some of the adverse reactions from LAVIV. Before getting LAVIV, tell your healthcare provider if you have any of the following medical problems:

• Allergic reactions to any drugs or food
• Bleeding disorders or take blood-thinning medicines like aspirin, ibuprofen, or coumadin
• Keloids or excessive scarring
• Skin cancer or any malignancy
• Genetic disorders affecting your skin
• Immune problems or take medicines that affect your immune system
• Any other illness or medical problem

How will I get LAVIV?

Your healthcare provider will take three small skin samples (called biopsies) from behind your ears and send them to the manufacturer. Certain cells, called fibroblasts, are grown from the samples. This takes about three to six months.

The cells (LAVIV) are sent back to your healthcare provider, who will inject them into your nasolabial fold wrinkles using a small needle.

You usually get LAVIV in three treatment sessions about 3-6 weeks apart.

It is very important that you arrive on time for your treatment sessions. If you miss a treatment session, your LAVIV cells will expire and must be thrown out. Your healthcare provider will work with you to schedule a new treatment session.

There is a chance that your skin samples will not make enough cells to use. In this case, your doctor may ask you if you wish to try biopsy again.

What should I avoid while I am getting LAVIV treatments?

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription drugs (like aspirin, vitamins, and dietary supplements). Your healthcare provider will advise you about the use of these medicines during LAVIV treatment.

• People who have bleeding disorders or who take blood thinning medicines may have more bleeding with LAVIV treatment.
• People with immune problems or who take medicines that affect the immune system can get infection or have healing problems with LAVIV treatment.

Expect some redness, swelling, puffiness, pain or bruising following LAVIV treatments. You can help yourself by doing the following:

• Do not rub, scrub, or massage the injection site for at least 72 hours.
• Apply a cold compress for 2-3 minutes at a time. DO NOT apply ice to the face.
• Do not wash the site of injections for at least 24 hours.
• Do not use make-up, facial creams, sunscreen, or other skin products on the face for 72 hours.

What are the possible or reasonably likely side effects of LAVIV?

The most common side effects are at the injection-site, including

• Redness
• Bruising
• Swelling
• Pain
• Bleeding
• Lumps
• Irritation
• Itchiness

Tell your healthcare provider or call the emergency department right away if you have

• Difficulty breathing, trouble swallowing, rash, hives, or severe redness and swelling, because these may be signs of a serious allergic reaction.
• Fever over 100ºF, redness, warmth, or pain at the injection or biopsy sites lasting for more than three days, because these may be signs of serious infection.

These are not all the possible side effects of LAVIV. Tell your health provider about any side effects that concern you. You may report side effects to FDA at 1-800-FDA-1088.

What are the ingredients in LAVIV?

LAVIV is made from your own skin cells placed in a mixture of water and salts.

Antibiotics (amphotericin and gentamicin), bovine serum (from cattle) and dimethyl sulfoxide (DMSO) are used during processing. Trace amounts of these ingredients may be present in LAVIV.

Fibrocell Technologies, Inc.

405 Eagleview Blvd.
Exton, PA 19341
T: 484-713-6000
F: 484-713-6001
www.fibrocellscience.com

Principal Display Panel – 1mL Vial Label

azficel-T (LAVIVTM) 1mL

Fibrocell Technologies, Inc.

PIN #: 1234567

DOB: 01JAN1950

Initials: ABC

Expires: 01FEB2011 6:00PM EST

Lot #: 201010001 RMS-5213v01

Principal Display Panel – Carton Label

azficel-T

LAVIVTM

NDC# 75935-001-01 Rx Only

FOR AUTOLOGOUS USE ONLY

No preservatives. Do not freeze.

Mix gently prior to administration.

CONTENTS: Two vials each
containing approximately 18 million
human dermal fibroblasts suspended
in Dulbecco's Modified Eagle Medium
without Phenol Red.

One autologous dose for injection. See
package insert for full prescribing information
and instructions for administration.

Store Refrigerated 2-8°C

No U.S. standard of potency

NOT EVALUATED FOR INFECTIOUS SUBSTANCES

Manufactured by:

Fibrocell Technologies, Inc.

405 Eagleview Blvd., Exton, PA 19341

Telephone: (855) 365-2848

U.S. Lic. #1818 RMS-5211v01