HYLAFORM - INSTRUCTIONS FOR USE - USA
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`Page 1 of 8
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`Hylaform®
`(hylan B gel)
`
`Federal (USA) law restricts this device to sale by or on the order of a licensed physician, or properly
`licensed practitioner.
`BEFORE USING PRODUCT, READ THE FOLLOWING
`INFORMATION THOROUGHLY.
`
`1. DEVICE DESCRIPTION
`
`Hylaform (hylan B gel) is a sterile, nonpyrogenic, viscoelastic, clear, colorless gel implant composed of cross(cid:173)
`linked molecules of hyaluronan. Hyaluronan is a naturally occurring polysaccharide of the extra-cellular matrix in
`human tissues, including skin.
`
`2. INTENDED USE/ INDICATIONS
`
`Hylaform gel is indicated for injection into the mid to deep dermls for correction of moderate to severe facial
`wrinkles and folds (such as nasolabial folds).
`
`3. CONTRAINDICATIONS
`
`• Hylaform gel is contraindicated for use in breast augmentation, or for implantation into bone, tendon, ligament,
`or muscle.
`
`• Hylaform gel is contraindicated for patients with a history of known hypersensitivity to avian proteins.
`
`• Hylaform gel must not be injected into blood vessels. Introduction of Hylaform gel into the vasculature may
`occlude the vessels and could cause infarction or embolization.
`
`4. WARNINGS
`
`• Use of Hylaform gel at specific sites in which an active inflammatory process (skin eruptions such as cysts,
`pimples, rashes, or hives) or infection is present, should be deferred until the underlying process has been
`controlled.
`
`•
`
`•
`
`The safety and efficacy of Hylaform gel for use in lip augmentation has not been established.
`
`Injection procedure reaction to Hylaform gel has been observed as consisting mainly of short-term
`inflammatory symptoms starting early after treatment and with less than 7 days duration. Refer to the
`CLINICAL STUDIES section for details.
`
`5. PRECAUTIONS
`
`• Hylaform gel is packaged for single patient use ready for use. Do not resterilize. Do not use if package is
`opened or damaged.
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`Genzyme Biosurgery
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`Exhibit 1080
`Prollenium v. Allergan
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`• Based on preclinical studies, patients should be limited to 20 ml of Hylaform gel per 60 kg (130 lbs} body
`mass per year. The safety of injecting greater amounts has not been established.
`
`•
`
`•
`
`The safety or effectiveness of Hylaform gel for the treatment of anatomic regions other than nasolabial folds
`has not been established in controlled clinical studies.
`
`Long-term safety and effectiveness of Hy1aform gel beyond one year have not been investigated in clinical
`trials.
`
`• As with all transcutaneous procedures, Hylaform gel implantation carries a risk of infection. Standard
`precautions associated with injectable materials should be followed.
`
`•
`
`•
`
`The safety of Hylaform gel for use during pregnancy, in breastfeeding females or in patients under 18 years
`has not been established.
`
`The safety of Hylaform gel in patients with increased susceptibility to keloid formation, hypertrophic scarring
`and pigmentation disorders has not been studied. Hylaform gel should not be used in patients with known
`susceptibility to keloid formation, hypertrophic scarring or pigmentation disorders. Genzyme is conducting a
`post approval study to determine the likelihood of keloid formation and pigmentation disorders in patients with
`Fitzpatrick Scale Skin types IV - VI receiving Hylaform injections
`
`• Hylaform gel shoulcj be used with caution in patients on immunosuppressive therapy.
`
`• Patients who are using substances that can prolong bleeding, such as aspirin, non-steroidal anti-inflammatory
`drugs and warfarin may, as with any injection, experience increased bruising or bleeding at injection sites.
`
`• After use, treatment syringes and needles may be potential biohazards. Handle accordingly and dispose of in
`accordance with accepted medical practice and applicable local, state and federal requirements.
`
`• Hylaform gel is a clear, colorless gel without particulates. In the event that the content of a syringe shows
`signs of separation and/or appears cloudy, do not use the syringe and notify I NAMED Corporation at (800)
`624-4261.
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`•
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`•
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`The patient should be informed that he or she should minimize exposure of the treated area to excessive sun
`and UV lamp exposure and extreme cold weather until any initial swelling and redness has resolved.
`
`If laser treatment, chemical peeling or any other procedure based on active dermal response is considered
`after treatment with Hylaform gel there is a possible risk of eliciting an inflammatory reaction at the implant site.
`This also applies if Hylaform gel is administered before the skin has healed completely after such a procedure.
`
`6. ADVERSE EVENTS
`
`A. Clinical Evaluation of Hylaform Gel
`
`In a randomized, controlled clinical trial to evaluate the safety and effectiveness of Hylaform gel as a dermal filler
`for nasolabial folds, 261 patients 30 to 55 years of age were randomized between the treatment (Hylaform} and the
`control (Zyplast) implant. During the initial phase of the study, each patient was injected with the respective dermal
`filler in the nasolabial folds for wrinkle correction. Patients were followed for 12 weeks. Following completion of the
`initial phase, each of the patients who initially received Hylaforin gel treatment was offered repeat treatment with
`Hylaform products in both nasolabial folds and evaluated for safety for an additional 4 weeks.
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`Initial Treatment Phase
`
`Adverse events reported during the 12 weeks following treatment were categorized according to the reported
`severity (see Table 1 ).
`
`Table 1 - Injection Procedure Related Adverse Events by Maximum Severity Occurring in >5% of Patients
`[Number (%) of Patients]
`
`Primary System
`Organ Class/Preferred Term
`~t least 1 adverse event
`
`General disorders and
`administration site conditions
`
`Injection site erythema
`
`Injection site bruising
`
`Injection site swelling
`
`'
`
`Injection site pain
`
`Injection site pruritus
`
`Injection site desquamation
`
`Mod;;: Moderate
`
`Hylaform j Zyplast
`Total
`Total
`111
`109
`(85)
`(84)
`
`111
`(84)
`84
`(63)
`54
`(41)
`47
`{35)
`42
`(32)
`10
`{8)
`3
`(2)
`
`109
`(85)
`86
`(67)
`39
`(30)
`53
`(41)
`29
`(23)
`11
`{9)
`7
`(6)
`
`Hvlaform N = 133
`.
`Mod
`6
`(5)
`
`I
`
`Mild
`105
`(79)
`
`Severe
`0
`(0)
`
`105
`(79)
`83
`(62)
`52
`(39)
`45
`(34)
`40
`(30)
`10
`(8)
`3
`(2)
`
`6
`(5)
`1
`(1)
`2
`(2)
`2
`(2)
`2
`(2)
`0
`(0)
`0
`(0)
`
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`0
`(0)
`
`Zyplast N = 128
`
`Mild
`105
`(82)
`
`105
`(82)
`85
`(66)
`37
`(29)
`52
`(41)
`26
`(20)
`11
`(9)
`7
`(6)
`
`Mod°
`2
`(2)
`
`Severe
`2
`(2)
`
`2
`(2)
`1
`(1)
`2
`(2)
`1
`(1)
`1
`(1)
`0
`(0)
`0
`(0)
`
`2
`(2)
`0
`(0)
`0
`(0)
`0
`(0)
`2
`(2)
`0
`(0)
`0
`(0)
`
`i
`
`I
`
`I
`I
`
`Table 2: Duration of Procedure or Device Related Events Occurring in Greater than 5% of Patients
`
`Primary System
`Organ Class/Preferred
`Term
`Duration*
`
`Injection site erythema
`
`Injection site bruising
`
`Injection site swelling
`
`Injection site pain
`
`Injection site pruritus
`
`4-7
`da s
`16
`12
`3
`17
`2.
`9
`
`2
`
`~3
`da s
`53
`40
`9
`14
`1
`23
`9
`29
`
`6
`
`0
`0
`0
`0
`2
`2
`0
`Injection site
`des uamation
`2
`1
`1
`0
`*Duration refers to number of days irrespective of onset of Adverse Event to the date of the study device implantation
`
`Hylaform gel
`n = 133
`n %
`8-14 > 14
`s
`da
`13
`
`2
`
`Total
`
`84
`63
`
`~3
`da s
`59
`
`4-7
`da
`11
`
`Zyplast
`n = 128
`n %
`8-14 > 14
`s
`da s
`11
`
`5
`
`Total
`
`86
`
`41
`7
`35
`2
`32
`1
`8
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`Genzyme Biosurgery
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`0
`0
`0
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`7
`(6)
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`Device related adverse events occurred infrequently in both groups and were primarily of mild intensity; 2 patients
`(2%) experienced 3 events in the Hylaform group, and 9 patients (7%) experienced 14 events in the Zyplast group.
`The Hylaform device related adverse events were erythema, induration and pruritus.
`
`Clinical trial adverse events unrelated to the injection procedure reported in the Hylaform treatment group
`occurring in greater than 1 % of patients (n=133) were nasopharyngitis (5.3%), headache (4.5%), influenza (3.8%),
`rash (3%), conjunctivitis (1.5%), and sinusitis (1.5%).
`
`Repeat Treatment Phase
`
`During the initial and repeat treatment phases of the study, hylan B lgG antibody titers were measured at baseline
`and throughout treatment. Only one patient exhibited a positive antibody response after treatment with hylan B.
`This patient experienced adverse events of injection site bruising and headache lasting 11 days and 2 days after
`initial treatment, respectively. These adverse events were not reported as device-related and were not considered
`to be associated with the increased antibody titer level. None of the other study patients developed similar
`increases in antibody titer levels during the initial or repeat study phases.
`
`Of the 133 patients treated with Hylaform gel during the initial phase, 96 underwent repeat treatment with Hylaform
`products and were followed for up to 4 weeks for safety. The types of adverse events seen after repeat treatment
`with Hylaform products were similar to those seen during the initial clinical evaluation. The most frequently
`reported adverse event;; included injection site erythema, bruising, swelling, pain, nodules, pruritus and
`tenderness. Device-related adverse events were reported in 3 patients during repeat treatment with Hylaform gel
`and included involuntary muscle contraction described as eye fasciculations in one patient and dizziness in
`another. A third patient experienced bilateral aseptic abscess formation at the site of injection, but did not develop
`increased hylan B antibody titers throughout either the initial or repeat phase of the study.
`
`B. Surveillance outside the US
`Hylaform post market safety surveillance in countries outside of the United States indicates that
`the most frequently reported adverse events include: injection site erythema, nodule, swelling,
`and induration. These adverse events are similar in frequency and duration to what has been noted during clinical
`trials.
`
`7. CLINICAL STUDIES
`
`A. Study Design
`
`A prospective, double blind, randomized, multi-center clinical study was conducted to evaluate the safety and
`effectiveness of Hylaform gel when used as a dermal filler in the nasolabial folds. Patients were randomized
`between Hylaform gel and a commercially available control material, Zyplast implant (derived from bovine
`collagen) and were injected with enough material to achieve desired correction of each nasolabial fold. (Patients
`enrolled into the study underwent double bovine collagen skin testing.) At 2 weeks touch-up treatment with
`additional material was allowed, only if patients showed less than a 1-point improvement on the 6-point grading
`scale (see description below).
`
`The primary efficacy endpoint for the study was the ability to correct nasolabial folds at 12 weeks in comparison to
`the control material. Correction of nasolabial folds was determined by an independent panel of blinded
`dermatologists through photographic assessment. Photographs of nasolabial folds were taken prior to treatment
`and at 3 days, 2, 4, 8, and 12 weeks following treatment. A 6-point grading scale was used to rank wrinkle severity
`for each photograph in a random, blinded fashion. Additional analyses included the investigator's visual
`assessment of each patient's nasolabial folds using the 6-point grading scale, and a qualitative assessment of the
`level of correction by the investigator and by the patient.
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`Table 2 Demographics and Pretreatment Characteristics of Total Patient Population, N=261
`[Number (%) of Patients]
`Tobacco use
`Non-smoking
`Smokers
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`Page 5 of 8
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`216 (82.7)
`45 (17.2)
`
`....
`
`Gender
`
`Male
`Female
`
`16 (6.1)
`245 (93.9)
`
`Ethnicity
`
`Caucasian
`African American
`
`Asian
`Hispanic
`Other
`
`208 (79.7)
`5 (1.9)
`
`9 (3.4)
`34 {13.0)
`5 (1.9)
`
`B. Treatment Material Delivered
`
`Sun Exposure (mean)
`
`1.6 hrs/day
`
`Patients With Prior
`Dermal Treatments
`
`157 (60.1)
`
`The mean total volume injected per nasolabial fold was 0.8 ml for patients in the treatment group (Hylaform gel)
`and 1. 1 ml for patients in the control group (Zyplast implant). The mean volume injected was the same for left and
`right nasolabial folds and was approximately equivalent to the total volume supplied in one syringe of Hylaform gel
`(0.75 ml) and of Zyplast implant (1.0 ml) for the clinical study.
`
`Twenty-two (16.5%) of 133 Hylaform patients and 9 (7.1%) of the 128 Zyplast patients required a touch-up
`treatment. The mean volume injected for touch-up per nasolabial fold was 0.3 ml for Hylaform patients and
`0.5 ml for Zyplast patients.
`
`C. Hylaform Gel Efficacy
`
`Hylaform gel was found to be equivalent to the control material {Zyplast implant) in the correction of nasolabial
`folds after 12 weeks using the independent review of photographs.
`
`M ean s core ase on - om
`6 P . t G d" S
`le
`B
`d
`ra mg ca
`Blinded Photographic Assessment
`Pretreatment
`12 Weeks after Treatment
`2.3
`2.2
`Hylaform
`2.3
`2.2
`Zvolast
`Grading scale: O=No wrinkles, 1=Just perceptible wrinkle, 2=Shallow wrinkles, 3=Moderately deep wrinkle, 4=Deep wrinkle, well-defined
`edges, S=Very deep wrinkle, redundant fold
`
`Peak treatment effect with one injection of Hylaform gel was observed during the first 2 weeks after treatment.
`Photographic assessment showed that, on average, patients had returned to baseline in both groups at 12 weeks.
`However, the secondary endpoints of investigator's visual assessment and a qualitative assessment of correction
`by the investigator and by the masked patient during the controlled clinical study support the effectiveness of
`Hylaform and Zyplast at 12 weeks.
`
`Mean Score Based on 6-Point G
`S
`rading cal
`e
`Investigator Live Assessment
`Pretreatment 12 weeks after treatment
`2.4
`Hylaform
`3.5
`Zyplast
`3.5
`2.3
`Grading scale: O=No wrinkles, 1 =Just perceptible wrinkle, 2=Shallow wrinkles, 3=Moderately deep wrinkle, 4=Deep wrinkle. well-defined
`edges, 5=Very deep wrinkle, redundant fold
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`Page 6 of 8
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`Based on investigator live assessment, 15% of Hylaform patients and 10% of Zyplast patients returned to
`pretreatment levels at 12 weeks.
`
`8. INDIVIDUALIZATION OF TREATMENT
`
`Severely indurated, sharply marginated and very superficial wrinkles may be difficult to distend and, therefore, are
`difficult to correct. If a defect cannot be distended because of extensive scarring or non-elastic tissue, the course of
`correction will be prolonged, if correction is achievable.
`
`Touch-up implantations may be required in areas with greater motion or mechanical stress (e.g., nasolabial folds).
`All patients should be counseled to anticipate supplemental implantations to achieve and maintain optimal
`correction.
`
`9. HOW SUPPLIED
`
`Hylaform gel is supplied in individual treatment syringes with needles, and is packaged for single patient use,
`ready for injection (implantation). The contents of the syringe are sterile and non-pyrogenic. The volume markings
`on the syringe are for reference only.
`
`TO ATTACH NEEDLE TO SYRINGE
`'
`1. Peel sealed cover off the needle guard.
`
`2. Remove tip cap from syringe.
`3. Attach needle to syringe and twist to secure. To assure proper needle attachment, use the needles
`provided or 30-gauge needles with similar needle guards. Fully seat hub of needle in syringe. Do not over
`tighten, as this may break the needle and/or dislodge the syringe.
`
`4. Pull off the needle guard to expose needle.
`
`PROCEDURE TO CHANGE NEEDLE
`1. Peel sealed cover off new needle guard.
`
`2. Twist used needle to disconnect it from the syringe.
`
`3. Attach new needle to syringe and twist to secure.
`
`4. Pull off the needle guard to expose needle.
`
`To place an order, contact INAMED Corporation at (800) 624-4261.
`
`INSTRUCTIONS FOR USE
`
`1. Hylaform gel is indicated for injection into the mid to deep dermis for correction of moderate to severe
`facial wrinkles and folds (such as nasolabial folds). Prior to treatment with Hylaform gel, the patient should
`be fully apprised of the indications, contraindications, warnings, precautions, treatment responses, adverse
`reactions, and method of administration. Patients also should be advised that supplemental "touch-up"
`implantations may be required to achieve and maintain maximum correction.
`
`2. A complete medical history, including allergies, should be obtained to determine whether the patient is an
`appropriate candidate for Hylaform treatment.
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`Page 7 of 8
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`3. The patient's soft tissue deficiencies should be characterized with regard to etiology, distensibility, stress at
`the site, and depth of lesion. Depending on the type of skin, best results are obtained when the defect is
`readily distensible and correction can be visualized by manual manipulation (stretching) of the skin.
`Pretreatment photographs are recommended.
`
`4. Topical or injectable anesthesia may be used to manage pain during and after injection.
`
`5. After ensuring that the patient has thoroughly washed the treatment area with soap and water, the area
`should be swabbed with alcohol or other antiseptic. Prior to injecting Hylaform gel, depress the plunger
`rod until the product flows out of the needle.
`
`6. Hylaform gel is administered using a thin gauge needle (30G x ½"). The injection technique with regard to
`the angle and orientation of the bevel, the depth of injection, and the quantity administered may vary. A
`linear threading technique, serial puncture injections, or a combination of the two have been used to
`achieve optimal results. Subdermal application should be avoided because such application may not
`provide optimal correction. If Hylaform gel ls injected too deep, the duration of the effect will be shorter. If
`Hylaform gel is injected too superficially this may result in visible lumps and/or discoloration.
`
`7.
`
`Inject Hylaform gel applying even pressure on the plunger rod while slowly pulling the needle backwards.
`The wrinkle should be lifted and eliminated by the end of the injection. It is important that the injection is
`stopped just before the needle is pulled out of the skin to prevent material from leaking out or ending up
`too superficially in the skin.
`
`8. Only correct to 100% of the desired volume effect. Do not overcorrect. The degree and duration of the
`correction depend on the character of the defect treated, the tissue stress at the implant site, the depth of
`the implant in the tissue and the injection technique. Markedly indurated defects may be difficult to correct
`
`9.
`
`If immediate blanching occurs, the injection should be stopped and the area massaged until it returns to a
`normal color.
`
`10. When injection is completed, the treated site should be gently massaged so that it conforms to the contour
`of the surrounding tissues. If an over correction has occurred, massage the area between your fingers or
`against an underlying superficial bone to obtain optimal results.
`
`11. If the wrinkle needs further treatment, the same procedure should be repeated until a satisfactory result is
`obtained. With patients who have localized swelling the degree of correction is sometimes difficult to judge
`at the time of treatment. In these cases, it is better to invite the patient to a touch-up session after 1-2
`weeks.
`
`12. Patients may have mild to moderate injection site reactions, which typically resolve in a few days. If the
`treated area is swollen immediately after the injection, an ice pack can be applied to the site for a short
`period.
`
`13. After the initial treatment (from 1 to 2 weeks later), an additional treatment of Hylaform gel may be
`necessary to achieve the desired level of correction. The need for an additional treatment may vary from
`patient to patient and is dependent upon a variety of factors such as wrinkle severity, skin elasticity and
`dermal thickness at the treatment site.
`
`14. The physician should instruct the patient to promptly report to her/him any evidence of problems possibly
`associated with the use of Hylaform geL
`
`PATIENT INSTRUCTIONS
`
`It is recommended that the following information be shared with patients:
`
`Genzyme Biosurgery
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`z..1
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`Page 8 of 8
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`•
`
`To report an adverse reaction, phone the Product Support Department,
`INAMED Corporation, (800) 624-4261.
`
`• Within the first 24 hours, patients should avoid:
`o Strenuous exercise
`o Extensive sun or heat exposure
`o Alcoholic beverages
`Exposure to any of the above may cause temporary redness, swelling, and/or itching at the injection sites.
`
`• Make-up may be applied a few hours post-treatment if no complications are present (e.g. open wounds,
`bleeding and infection).
`
`STORAGE
`
`Hylaform gel should be stored at room temperature, 2°-30°C (36°-86°F). DO NOT FREEZE.
`
`Hylaform gel has a clear appearance. In the event that a syringe contains material that is not clear do not use the
`syringe and notify INAMED Corporation immediately at (800) 624-4261.
`
`STERILITY
`
`Hylaform gel is packag:d for single patient use. Do not resterilize. Do not use if package is opened or damaged.
`
`Manufactured by:
`
`Genzyme Biosurgery
`1125 Pleasant View Terrace
`Ridgefield, New Jersey 07657 USA
`
`Distributed by:
`
`INAMED Aesthetics
`5540 Ekwill Street
`Santa Barbara, CA 93111 USA
`{800) 624-4261
`
`Hylaform® and Genzyme® are registered trademarks of Genzyme Corporation.
`Zyplast® and INAMED® are registered trademarks of I NAMED Corporation.
`© (2004) Genzyme Corporation and I NAMED Corporation.
`
`Genzyme Biosurgery
`
`