The Only One-Injection Treatment for up to 6 months of Osteoarthritis Knee Pain Relief

Transcription

1 The Only One-Injection Teatment fo up to 6 months of Osteoathitis Knee Pain Relief What is Synvisc-One? Synvisc-One is fo patients who have tied diet, execise and ove-thecounte pain medicines and still have knee pain due to osteoathitis 1 Synvisc-One supplements knee fluid to elieve pain and impove the knee joint s natual shock absobing capabilities Synvisc-One was appoved by the FDA on Febuay 26, 2009 Synvisc-One is the only single-injection viscosupplement appoved in the U.S. Synvisc-One is given by a physician in office and only takes a few minutes Why Synvisc-One? With just one teatment, Synvisc-One can delive up to 6 months of poven pain elief 1-3 Synvisc-One can be safely epeated 1 Is Synvisc-One Safe? The most common side effects ae tempoay pain o swelling in o aound the injected knee, these eactions ae usually mild to modeate Synvisc-One does not have the seious side effects associated with many pain pills Patients at isk fo side effects due to long-tem NSAID/Celebex theapy may benefit fom the poven pain elief of Synvisc-One What is Viscosupplementation? Viscosupplementation is a pocedue in which hyaluonic acid o a deivative is injected into the knee joint to supplement synovial fluid that typically becomes diluted o degaded in osteoathitis patients Peviously, 3-5 injections wee equied. But now with Synvisc-One, patients can have up to 6 months of pain elief with just one injection 1 In the epeat teatment phase of the pivotal clinical study involving 160 patients, 77 eceived a second injection of Synvisc-One. Celebex is a egisteed tademak of Pfize Inc.

2 Indication Synvisc-One (hylan G-F 20) is indicated fo the teatment of pain in osteoathitis (OA) of the knee in patients who have failed to espond adequately to consevative non-phamacologic theapy and simple analgesics, e.g., acetaminophen. Impotant Safety Infomation Synvisc-One is containdicated in patients with known hypesensitivity to hyaluonan poducts o patients with infections in o aound the taget knee. Do not inject Synvisc-One exta-aticulaly, into the synovial tissues, into the fat pad o joint capsule, o intavasculaly. The safety and efficacy of Synvisc-One in locations othe than the knee, o fo conditions othe than osteoathitis, o in combination with othe intaaticula injectables have not been established. Use caution when injecting Synvisc-One in patients allegic to avian poteins, feathes, o egg poducts; who have evidence of lymphatic o venous stasis in the leg to be injected; o who have sevee inflammation in the knee to be teated. Remove any synovial fluid o effusion befoe injecting Synvisc-One. Stict adheence to aseptic technique must be followed. The safety and effectiveness of Synvisc-One have not been established in childen o in pegnant o lactating women. Patients should be advised to avoid stenuous o polonged weightbeaing activities fo appoximately 48 hous afte teatment. The most commonly epoted elated local advese events (<2% each) wee tansient, mild-to-modeate athalgia, athitis, athopathy, injection site pain and joint effusion. No seious advese events in knees injected with Synvisc-One wee epoted in clinical tials. Seious local advese events have been epoted only aely in post-maketing use. Repeat teatment did not affect the safety pofile. In the pivotal tial, thee was one elated systemic event of syncope. The most common systemic side effects iespective of elationship to Synvisc-One ( 5%) wee headache, back pain, nasophayngitis and influenza. Systemic advese event pofiles wee simila between patients in the Synvisc-One and Saline Contol goups. Allegic eactions such as ash have been epoted aely in association with SYNVISC. Please see the full pescibing infomation fo Synvisc-One on the following page. Refeences: 1. Synvisc-One Pescibing Infomation. Cambidge, MA: Genzyme Cop; Bzusek D, Peton D. Teating knee osteoathitiswith inta-aticula hyaluonans. Cu Med Res Opin. 2008;24(12): Bellamy N, Campbell J, Robinson V, Gee T, Boune R, Wells G. Intaaticula coticosteoid fo teatment of osteoathitis of the knee. Cochane Database Syst Rev. 2006;(2):CD doi: / cd pub2

3 Infomation fo Pescibes Package contents povided steile. Genzyme Biosugey, a division of Genzyme Copoation 1125 Pleasant View Teace Ridgefield, New Jesey Telephone: SYNVISC ( ) Caution: Fedeal law esticts this device to sale by o on the ode of a physician (o popely licensed pactitione). DESCRIPTION Synvisc-One (hylan G-F 20) is an elastoviscous high molecula weight fluid containing hylan A and hylan B polymes poduced fom chicken combs. Hylans ae deivatives of hyaluonan (sodium hyaluonate). Hylan G-F 20 is unique in that the hyaluonan is chemically cosslinked. Hyaluonan is a long-chain polyme containing epeating disacchaide units of Na-glucuonate-N-acetylglucosamine. INDICATIONS FOR USE Synvisc-One is indicated fo the teatment of pain in osteoathitis (OA) of the knee in patients who have failed to espond adequately to consevative nonphamacologic theapy and simple analgesics, e.g., acetaminophen. CONTRAINDICATIONS Do not administe to patients with known hypesensitivity (allegy) to hyaluonan (sodium hyaluonate) pepaations. Do not inject Synvisc-One in the knees of patients having knee joint infections o skin diseases o infections in the aea of the injection site. WARNINGS Do not concomitantly use disinfectants containing quatenay ammonium salts fo skin pepaation because hyaluonan can pecipitate in thei pesence. Do not inject Synvisc-One exta-aticulaly o into the synovial tissues and capsule. Intavascula injections of Synvisc-One may cause systemic advese events. PRECAUTIONS Geneal The safety and efficacy of Synvisc-One in locations othe than the knee and fo conditions othe than osteoathitis have not been established. The safety and effectiveness of the use of Synvisc-One concomitantly with othe inta-aticula injectables have not been established. Use caution when injecting Synvisc-One into patients who ae allegic to avian poteins, feathes o egg poducts. The safety and efficacy of Synvisc-One in seveely inflamed knee joints have not been established. Stict aseptic administation technique must be followed. STERILE CONTENTS. The syinge is intended fo single use. The contents of the syinge must be used immediately afte its packaging is opened. Discad any unused Synvisc-One. Do not use Synvisc-One if package is opened o damaged. Stoe in oiginal packaging (potected fom light) at oom tempeatue below 86 F (30 C). DO NOT FREEZE. Remove any synovial fluid o effusion befoe injecting Synvisc-One. Synvisc-One should be used with caution when thee is evidence of lymphatic o venous stasis in the leg to be injected. Infomation fo Patients Povide patients with a copy of the Patient Labeling pio to use. Mild to modeate pain, swelling and/o effusion of the injected knee have been epoted in clinical tials that wee elated to inta-aticula injection of Synvisc-One. These events wee typically tansient and usually esolved on thei own o with consevative teatment. As with any invasive joint pocedue, it is ecommended that the patient avoid stenuous activities (fo example, high-impact spots such as socce, tennis o jogging) o polonged weightbeaing activities fo appoximately 48 hous following the intaaticula injection. The patient should consult his o he physician egading the appopiate time to esume such activities. Use in Specific Populations Pegnancy: The safety and effectiveness of Synvisc-One have not been established in pegnant women. Nusing mothes: It is not known if Synvisc-One is exceted in human milk. The safety and effectiveness of Synvisc-One have not been established in lactating women. Pediatics: The safety and effectiveness of Synvisc-One have not been established in pediatic patients. Pediatic patients ae defined as patients 21 yeas of age. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Repoted Device-Related Advese Events The most commonly epoted advese events associated with Synvisc-One ae the following: Athalgia Athitis Athopathy Injection site pain Joint effusion A complete list of the fequency and ate of advese events identified in the clinical study ae povided in the Safety section (Table 3). Potential Advese Events The following advese events ae among those that may occu in association with inta-aticula injections, including Synvisc-One: Athalgia Joint stiffness Joint effusion Joint swelling Joint wamth Injection site pain Athitis Athopathy Gait distubance A complete list of the fequency and ate of advese events identified in the clinical study ae povided in the Safety section (Table 2). Post-maketing Expeience SYNVISC (3 injection egimen) post-maketing expeience has identified the following systemic events to occu aely with administation: ash, hives, itching, feve, nausea, headache, dizziness, chills, muscle camps, paesthesia, peipheal edema, malaise, espiatoy difficulties, flushing and facial swelling. Thee have been ae epots of thombocytopenia coincident with SYNVISC (3 injection egimen) injection. PIVOTAL CLINICAL TRIAL Study Design: To detemine the safety and effectiveness of a single injection egimen of Synvisc-One in the eduction of the pain scoe in osteoathitis of the knee, a pospective, andomized, double-blind, 2-am (paallel goup) clinical tial in 21 centes in six Euopean counties was conducted. A total of 253 patients wee andomly assigned to study teatment; 123 eceived 6 ml of Synvisc-One and 130 eceived 6 ml of Phosphate-Buffeed Saline. Neithe the patients no the clinical obseves knew the patients teatment allocations. The outcome measues collected included the Westen Ontaio and McMaste Univesities Osteoathitis Index (WOMAC; Liket 3.1 A vesion); patient global assessment (PTGA); clinical obseve global assessment Fax Vesion 1

4 (COGA); and use of escue analgesic (see Teatment and Evaluation Schedule). The intent-to-teat (ITT) population (all patients andomized) was used fo the pimay analysis. The pimay efficacy analysis was a compaison ove 26 weeks between the two teatment goups of change fom baseline in the WOMAC A (Pain) Subscale (see Patient Population and Demogaphics), pefomed by analysis of covaiance (ANCOVA). Patient Population and Demogaphics Study patients had pimay osteoathitis of the knee pe Ameican College of Rheumatology citeia and wee at least 40 yeas old. The diagnosis was confimed via ecent adiogaph showing at least one osteophyte in the taget knee. Study patients had continued taget knee pain despite use of consevative teatment and analgesics/non-steoidal anti-inflammatoy dugs (NSAIDs). Patients with sevee disease (Gade IV) pe Kellgen- Lawence citeia, o who had pio athoplasty in the taget knee, wee excluded. At the beginning of the study, subjects had modeate o sevee taget knee pain when walking on a flat suface (on a 5-point Liket scale whee 0 = none, 1 = mild, 2 = modeate, 3 = sevee, 4 = exteme), and an aveage scoe of 1.5 to 3.5 on the five questions of the WOMAC A (Pain) Subscale. The WOMAC A Subscale asks study subjects to ate thei degee of pain when: 1. Walking on a flat suface 2. Going up and down stais 3. Resting duing the night 4. Sitting o lying 5. Standing upight Table 1 summaizes the demogaphics and baseline chaacteistics. Thee wee no clinically meaningful diffeences between teatment goups in any baseline paamete. Teatment and Evaluation Schedule Initial Teatment Phase Patients wee followed fo 26 weeks. Study visits wee scheduled fo sceening, baseline, and weeks 1, 4, 8, 12, 18 and 26. Injections wee pefomed aseptically at the baseline visit afte athocentesis to withdaw any effusion o synovial fluid pesent. Patients wee not pemitted to take long-acting NSAIDs (including cyclo-oxygenase II inhibitos), opioid analgesics o coticosteoids (by any oute) duing the study, but wee pemitted to take up to 4 g pe day of acetaminophen as needed fo escue of injected knee pain. Rescue medication was not pemitted within 48 hous of any study visit. Injected knee assessment, patient and clinician global assessments (PTGA & COGA), WOMAC and safety evaluations wee pefomed at each study visit. Repeat Teatment Phase If patients in eithe blinded teatment goup had at least mild pain in the injected knee at the week 26 visit (and did not expeience any significant clinical concens afte the fist teatment administation), they wee offeed an injection of (open-label) Synvisc- One. Those who chose to eceive the second injection wee followed fo 4 weeks fo safety only. Advese Event Summay: The fequency and type of advese events (AEs) wee simila between the goup of patients that eceived Synvisc-One and the goup that eceived saline contol. Initial Teatment Phase: The oveall popotions of patients with Teatment-Emegent AEs egadless of device elatedness (Synvisc-One: n=70, 56.9%; Saline Contol: n=79, 60.8%) and with injected knee AEs egadless of device elatedness (Synvisc-One: n=44, 35.8%; Saline Contol: n=44, 33.8%) wee compaable between the two teatment goups (See Table 2). Table 3 lists the incidences of AEs in the injected knee that wee assessed by the investigato to be device-elated, defined as elated to eithe the study injection o the study teatment. Device-elated AEs involving the injected knee wee mild o modeate in natue and wee teated symptomatically. Thee wee no seious AEs in the injected knee in eithe the Synvisc-One o the saline contol goup. Repeat Teatment Phase: The epeat teatment phase evaluated the safety pofile of the initial phase of patients eceiving a second injection of Synvisc-One. One hunded and sixty patients wee teated duing this phase of the study, of which 77 patients eceived a second injection of Synvisc-One. Of these 77 patients, 4 (5.2%) expeienced five device elated AEs in the injected knee. All such events wee mild to modeate and wee teated symptomatically. These events wee athalgia (n=2), athitis (n=1), injection site hematoma (n=1) and injection site pain (n=1). Patients who developed injected knee AEs duing the initial phase of the study, and who subsequently eceived epeat teatment, did not expeience injected knee AEs upon epeat exposue to Synvisc-One. Oveall Injected Knee Safety Summay: The safety pofile of Synvisc-One is simila to the Clinical and Post-maketing expeience seen with SYNVISC (3 injection egiment) whee pain, swelling and effusion wee the most fequently occuing AEs in the injected knee. Thee have been post-maketing epots fo SYNVISC indicating that in some cases the joint effusion may be lage and can cause ponounced pain; it is impotant to emove and to analyze the fluid to ule out infection o cystalline athopathies. These types of sevee AEs wee not obseved in eithe the initial o epeat teatment phase of the Synvisc-One tial. Joint infections did not occu in any of the clinical tials of SYNVISC o Synvisc-One and have been epoted only aely duing clinical use of SYNVISC. Advese Events Outside of the Injected Knee Oveall 101 patients (Synvisc-One: n=47, 38.2%; Saline Contol: n=54, 41.5%) expeienced at least one AE outside the injected knee egadless of device elatedness. The most commonly occuing (5% o geate in eithe goup) AEs outside the injected knee wee headache, back pain, nasophayngitis and influenza. In the Synvisc-One goup thee was one AE of syncope consideed device-elated. No new systemic AEs wee identified duing this study as compaed to SYNVISC. Pimay Efficacy Endpoint: The pimay endpoint fo the study, the diffeence between the teatment goups in change fom baseline ove 26 Weeks in the WOMAC A Pain Scoe (Table 4) was met. Synvisc-One also demonstated supeioity to saline contol in multiple pe-defined seconday outcome measues, which included PTGA ove and at 26 weeks, COGA ove and at 26 weeks, and pain while walking on a flat suface (WOMAC A1) ove and at 26 weeks (see Figue 1 and Table 5). The WOMAC A1 esponde ate (whee esponse was defined as a 1-o-moe categoy impovement fom baseline and the patient did not withdaw fom the study) was significantly highe in the Synvisc-One goup than in the saline contol goup. Seventyone pecent (71%) of the patients wee espondes at week 18 in the Synvisc-One goup (vesus 54% in the saline contol goup). At week 26, 64% of patients in the Synvisc-One goup wee espondes, while only 50% of patients in the saline contol goup wee espondes. DETAILED DEVICE DESCRIPTION Synvisc-One combines the thee doses of SYNVISC (hylan G-F 20) which consists of hylan A (aveage molecula weight 6,000,000 daltons) and hylan B hydated gel in a buffeed physiological sodium chloide solution, ph 7.2. Synvisc-One has an elasticity (stoage modulus G') at 2.5 Hz of 111 ± 13 Pascals (Pa) and a viscosity (loss modulus G") of 25 ± 2 Pa (elasticity and viscosity of knee synovial fluid of 18- to 27-yea-old humans measued with a compaable method at 2.5 Hz: G' = 117 ± 13 Pa; G" = 45 ± 8 Pa.) Each 10-mL syinge of Synvisc-One combines the thee 2-mL doses (16 mg each) of a complete SYNVISC teatment egimen (48 mg). Each Synvisc-One 10-mL syinge contains: Hylan polymes (hylan A + hylan B) 48 mg Sodium chloide 51 mg Disodium hydogen phosphate 0.96 mg Fax Vesion 2

5 Sodium dihydogen phosphate monohydate 0.24 mg Wate fo injection q.s. to 6.0 ml HOW SUPPLIED Synvisc-One is supplied in a 10-mL glass syinge containing 3 doses (48 mg) of hylan G-F 20. The contents of the syinge ae steile and non-pyogenic. DIRECTIONS FOR USE Pecaution: Do not use Synvisc-One if the package has been opened o damaged. Stoe in the oiginal packaging (potected fom light) at oom tempeatue below 86 F (30 C). DO NOT FREEZE. Pecaution: The syinge containing Synvisc-One is intended fo single use. The contents of the syinge must be used immediately afte the syinge has been emoved fom its packaging. Pecaution: Do not concomitantly use disinfectants containing quatenay ammonium salts fo skin pepaation because hyaluonan can pecipitate in thei pesence. Synvisc-One is administeed as a single inta-aticula injection. Stict aseptic administation technique must be followed. Using an 18- to 20-gauge needle, emove synovial fluid o effusion befoe injecting Synvisc-One. Do not use the same syinge fo emoving synovial fluid and fo injecting Synvisc-One; howeve, the same 18- to 20-gauge needle should be used. Twist the tip cap befoe pulling it off, as this will minimize poduct leakage. To ensue a tight seal and pevent leakage duing administa tion, secue the needle tightly while fimly holding the lue hub. Pecaution: Do not ove tighten o apply excessive leveage when attaching the needle o emoving the needle guad, as this may beak the syinge tip. Inject the full 6 ml in one knee only. MANUFACTURED AND DISTRIBUTED BY: Genzyme Biosugey, a division of Genzyme Copoation 1125 Pleasant View Teace Ridgefield, New Jesey Telephone: SYNVISC ( ) SYNVISC-ONE, SYNVISC and GENZYME ae egisteed tademaks of Genzyme Copoation. Table 1. Summay of Demogaphic and Baseline Chaacteistics Paamete/Categoy Synvisc-One Saline Contol Total (N=124) (N=129) (N=253) Age, n Mean (SD) 63.6 ( 9.6) 62.5 ( 9.2) 63.0 ( 9.4) Range 42, 83 43, 84 42, 84 Sex, n Female, n (%) 92 (74%) 88 (68%) 180 (71%) Race, n Caucasian, n (%) 118 ( 95%) 125 (97%) 243 (96%) Non-Caucasian, n (%) 6 (5%) 4 (3%) 10 (4%) Body Mass Index (kg/m 2 ),n Mean (SD) 29.1 (4.8) 29.8 (5.7) 29.4 (5.3) Range 20.7, , , 52.4 Pio Coticosteoids In Taget Knee, n Yes n (%) 40 (32%) 31 (24%) 71 (28%) Pio Athoscopy In Taget Knee, n Yes n (%) 26 (21%) 28 (22%) 54 (21%) Tibio-Femoal Joint Modified Kellgen-Lawence Numeical Gading System Gade II 63 (51%) 51 (39%) 114 (45%) Gade III 60 (49%) 78 (60%) 138 (55%) Ga de IV 0 1 (1%) 1 (0%) Total WOMAC Scoe (0-96); Mean (SD) 55.1 (10.5) 54.8 (9.4) WOMAC A Scoe (0-4); Mean (SD) 2.30 (0.43) 2.25 (0.41) PTGA -- Mean (SD) (0-4) 2.57 (0.67) 2.50 (0.64) COGA -- Mean (SD) (0-4) 2.44 (0.76) 2.49 (0.75) ITT Population Safety Population Fax Vesion 3

6 Table 2: Patients with Advese Events in the Injected Knee Regadless of Relatedness Synvisc-One Saline Contol MedDRA Pefeed Tem N=123 N=130 n (%) n (%) Any Teatment- Emegent Advese Event 44 (35.8%) 44 (33.8%) Athalgia 31 (25.2%) 28 (21.5%) Joint stiffness 10 (8.1%) 13 (10.0%) Joint effusion 7 (5.7%) 7 (5.4%) Joint swelling 5 (4.1%) 7 (5.4%) Joint wamth 2 (1.6%) 5 (3.8%) Post-taumatic pain 0 3 (2.3%) Injection site pain 1 (0.8%) 1 (0.8%) Synovial cyst 0 2 (1.5%) Athitis 1 (0.8%) 0 Athopathy 1 (0.8%) 0 Gait distubance 1 (0.8%) 0 Joint ange of motion deceased 0 1 (0.8%) Osteoathitis 0 1 (0.8%) Note: Patients ae counted once fo each unique AE egadless of device elatedness, and may have had moe than one unique AE. Table 3: Patients with Device-Related Advese Events in the Injected Knee Synvisc-One Saline Contol MedDRA Pefeed Tem N=123 N=130 n (%) n (%) Any Device- Related Advese Event 7 (5.7%) 4 (3.1%) Athalgia 2 (1.6%) 3 (2.3%) Athitis 1 (0.8%) 0 Athopathy 1 (0.8%) 0 Injection site pain 1 (0.8%) 1 (0.8%) Joint effusion 2 (1.6%) 0 Note: Patients ae counted once fo each unique AE, and may have had moe than one unique AE. Table 4. Pimay Efficacy Results: WOMAC A (Pain) Scoe Oveall Change fom Baseline Ove 26 Weeks ITT Population Baseline Mean Post- Estimated Estimated p-value Mean (SE) teatment (SE) Change (SE) Diffeence fom (ANCOVA) (0-4 Scale) (0-4 Scale) Saline Contol (95% CI) Synvisc-One (n=124) 2.30 (0.04) 1.43 (0.06) (0.06) Saline Contol (n=129) 2.25 (0.04) 1.59 (0.06) (0.06) 0.15 (-0.302, ) WOMAC A scale using 5 point Liket scale, whee 0 = no pain and 4 = exteme pain Repeated measues Analysis of Covaiance was used fo the WOMAC A pain scoe change fom the baseline Fax Vesion 4

7 Table 5. Clinical Meaning of Seconday Efficacy Endpoints Odds Ratio 1 Definition Explanation Genealized Estimating Equation fo catagoical data. WOMAC A1 PTGA Ove weeks At 0.56 week 26 Ove weeks At 0.51 week 26 The odds (pobability [Wose] / Pobability [Bette]) fo Synvisc- One fo ove 26 weeks and at 26 weeks is appoximately 64%, and 56%, espectively, to the odds fo contol. The odds (pobability [Wose] / Pobability [Bette]) fo Synvisc- One fo ove 26 weeks and at 26 weeks is appoximately 69%, and 51%, espectively, to the odds fo contol. PTGA: Patient Global Assessment has 5 scales (Vey well, Well, Fai, Poo, Vey poo) Synvisc-One patients wee 1.56 times moe likely to self-epot pain elief while walking on a flat suface compaed to those patients teated with saline contol ove 26 weeks and 1.79 times moe likely to self-epot pain elief while walking on a flat suface compaed to those patients teated with saline contol at 26 weeks. Synvisc-One patients wee 1.45 times moe likely to self-epot impovement in oveall health status compaed to those patients teated with saline contol ove 26 weeks and 1.96 times moe likely to self-epot impovement in oveall health status compaed to those patients teated with saline contol at 26 weeks. COGA OMERACT- OARSI Responde Ove weeks At 0.56 week 26 Ove 26 weeks 0.66 At week Estimate of Teatment Diffeence (Analysis of Covaiance) The odds (pobability [Wose] / Pobability [Bette]) fo Synvisc- One fo ove 26 weeks and at 26 weeks is appoximately 71%, and 56%, espectively, to the odds fo contol. COGA: Clinical Obseve Global Assessment has 5 scales (Vey well, Well, Fai, Poo, Vey poo) This esponde analysis did not each statistical significance between the teatment goups. Blinded clinical obseves wee 1.41 times moe likely to assess patients teated with Synvisc-One as showing oveall impovement in disease status compaed to those patients teated with saline contol ove 26 weeks and 1.79 times moe likely to assess patients teated with Synvisc-One as showing oveall impovement in disease status compaed to those patients teated with saline contol at 26 weeks. WOMAC C Ove weeks At week 26 The study did not show a statistically significant diffeence in functional impovement between the teatment goups. Statistically significant at the 5% significance level; not adjusted fo multiplicity 1 Odds atio = Odds fo Synvisc-One/Odds fo Contol Odds atio = (Pobability [Wose] / Pobability [Bette]) fo Synvisc-One / (Pobability [Wose] / Pobability [Bette]) fo Contol If odds atio <1, then in favo of Synvisc-One Fax Vesion 5

8 Figue 1: Plot fo Categoical Seconday Endpoints ITT Population 2 Odds Ratio (+/- 95% Confidence Inteval) WOMAC A1 Ove 26 Weeks WOMAC A1 PTGA Ove at 26 Weeks 26 Weeks PTGA at 26 Weeks COGA Ove 26 Weeks COGA at 26 Weeks OMERACT- OMERACT- OARSI OARSI Responde Responde at Ove Weeks Weeks Response in favo of Saline Contol Odds Ratio = 1: Positive esponse is equally likely in both goups Response in favo of Synvisc-One Statistically significant at the 5% significance level; not adjusted fo multiplicity Figue 2: Patient Responde Rate on WOMAC A1 (Walking Pain) -ITT Population Responde Rate (%) Synvisc-One Saline Contol Weeks Teatment Note: Analyzed using genealized estimating equation (GEE) fo binay outcomes Statistically significant at the 5% significance level; not adjusted fo multiplicity Revised Januay 5, Fax Vesion 6

9 PATIENT INFORMATION Be sue to ead the following impotant infomation caefully. This infomation does not take the place of you docto s advice. If you do not undestand this infomation o want to know moe, ask you docto. Glossay of Tems Hyaluonan (ponounced hy-al-u-roe-nan): is a natual substance that is pesent in vey high amounts in joints. It acts like a lubicant and a shock absobe in the joint and is needed fo the joint to wok popely. Non-steoidal anti-inflammatoy dugs: also known as NSAIDs ; medication used to teat pain o swelling. Thee ae many examples of NSAIDs, including (but not limited to) aspiin and ibupofen. Some of these ae ove-the-counte dugs, and some can be obtained only by pesciption. Osteoathitis (ponounced OS-te-o-ath-RI-tis): (OA) is a type of athitis that involves the weaing down of catilage (the potective coveing on the ends of you bones) and loss of cushioning fluid in the joint. Table of Contents Glossay of Tems Table of Contents What is the Synvisc-One poduct? How is the Synvisc-One poduct used? (Indications) How is the Synvisc-One poduct given? Ae thee any easons why I should not eceive a Synvisc-One injection? (Containdications) What should my docto wan me about? What ae the isks of getting a Synvisc-One injection? What ae the benefits of getting a Synvisc-One injection? What do I need to do afte I get Synvisc-One injection? What othe teatments ae available fo OA? Non-dug teatments Dug theapy When should you call you docto? (Toubleshooting) What advese events wee obseved in the clinical study? How do I get moe infomation about the Synvisc-One poduct? (Use Assistance) What is the Synvisc-One poduct? Synvisc-One is a gel-like mixtue that comes in a syinge containing 6 ml (1 ½ teaspoon) and is injected into you knee. It is made up of hylan A fluid, hylan B gel, and salt wate. Hylan A and hylan B ae made fom a substance called hyaluonan (ponounced hy-al-u-roe-nan), also known as sodium hyaluonate that comes fom chicken combs. Hyaluonan is a natual substance found in the body and is pesent in vey high amounts in joints. The body s own hyaluonan acts like a lubicant and a shock absobe in the joint and is needed fo the joint to wok popely. How is the the Synvisc-One poduct used? (Indications) The FDA-appoved indication fo Synvisc-One is: Synvisc-One is indicated fo the teatment of pain in osteoathitis (OA) of the knee in patients who have failed to espond adequately to consevative non-phamacologic theapy and simple analgesics, e.g., acetaminophen. How is the Synvisc-One poduct given? You docto will inject Synvisc-One into you knee. Ae thee any easons why I should not eceive a Synvisc-One injection? (Containdications) You docto will detemine if thee is any eason why you ae not an appopiate candidate fo Synvisc-One. You should be awae that Synvisc-One: Should not be used in patients who have had any pio allegic eactions to SYNVISC, Synvisc-One o any hyaluonan-based poducts. Signs of an allegic eaction may include swelling of you face, tongue, o thoat; difficulty beathing o swallowing; shotness of beath; wheezing; chest pain; a tightness in you thoat; sleepiness; ash; itching; hives; flushing and/o feve. Should not be used in patients with a knee joint infection, skin disease o infection aound the aea whee the injection will be given, o ciculatoy poblems in the legs. What should my docto wan me about? The following ae impotant teatment consideations fo you to discuss with you docto and undestand in ode to help avoid unsatisfactoy esults and complications: Synvisc-One is only fo injection into the knee, pefomed by a docto o othe qualified health cae pofessional. Synvisc-One has not been tested to show pain elief in joints othe than the knee. Synvisc-One has not been tested to show bette pain elief when combined with othe injected medicines. Tell you docto if you ae allegic to poducts fom bids such as feathes, eggs, and poulty. Tell you docto if you have significant swelling o blood clots in the leg. Synvisc-One has not been tested in pegnant women, o women who ae nusing. You should tell you docto if you think you ae pegnant, o if you ae nusing a child. Synvisc-One has not been tested in childen ( 21 yeas of age). What ae the isks of getting a Synvisc-One injection? The side effects (also called eactions) sometimes seen afte any injection into the knee, including Synvisc-One, include: pain, swelling, heat, edness, and/o fluid buildup aound the knee. These eactions ae geneally mild and do not last long. Reactions ae geneally teated by esting and applying ice to the injected knee. Sometimes it is necessay to give pain elieves by mouth such as Revised Januay 5, Fax Vesion 1

10 acetaminophen o NSAIDs, o to give injections of steoids, o to emove fluid fom the knee joint. Patients aely undego athoscopy (a sugical inspection of the knee joint) o othe medical pocedues elated to these eactions. Othe side effects seen with SYNVISC o Synvisc-One ae: ashes, hives, itching, muscle pain/camps, flushing and/o swelling of you face, fast heatbeat, nausea (o feeling sick to you stomach), dizziness, feve, chills, headache, difficulty beathing, swelling in you ams and/o legs, pickly feeling of you skin, and in ae cases a low numbe of platelets in the blood (platelets ae a type of blood cell that ae needed to help you blood clot when you ae cut o injued). Rae cases of knee joint infection have been epoted. If any of the above side effects o symptoms appea afte you ae given Synvisc-One, o if you have any othe poblems, you should call you docto. What ae the benefits of getting a Synvisc-One injection? As shown in a medical study of 253 patients with osteoathitis (OA) of the knee, whee appoximately half eceived eithe a single injection of Synvisc-One o an injection of the same volume of salt wate (a Saline Contol injection), the majo benefits of Synvisc-One ae pain elief and impovement in othe symptoms elated to OA of the knee. What do I need to do afte I get a Synvisc-One injection? It is ecommended you avoid stenuous activities (fo example, high-impact spots such as tennis o jogging) o polonged weight-beaing activities fo appoximately 48 hous following the injection. You should consult you docto egading the appopiate time to esume such activities. What othe teatments ae available fo OA? If you have OA, thee ae othe things you can do besides getting Synvisc-One. These include: Non-dug teatments Avoiding activities that cause knee pain Execise o physical theapy Weight loss Removal of excess fluid fom you knee Dug theapy Pain elieves such as acetaminophen and nacotics Dugs that educe inflammation (signs of inflammation ae swelling, pain o edness), such as aspiin and othe non-steoidal anti-inflammatoy dugs (NSAIDs, fo example ibupofen and napoxen) Steoids that ae injected diectly into you knee When should I call my docto? (Toubleshooting) If any of the side effects o symptoms descibed above appea afte you ae given Synvisc-One, o if you have any othe poblems, you should call you docto. What did the clinical studies show? A study was conducted in 6 counties outside the United States with 21 physicians. The patients in the study had mild to modeate knee OA, modeate to sevee pain, and did not have sufficient elief of thei pain and symptoms with medications taken by mouth. A total of 253 patients in the study wee assigned by chance to eceive eithe a single injection of Synvisc- One (n=123 patients), o an injection of the same volume of salt wate (a Saline Contol injection) (n=130 patients). Neithe the patients no the doctos evaluating them knew which teatment they eceived. Any fluid that was pesent in the patient s knee was emoved befoe the injection. The patients wee seen by thei docto at standad times ove 6 months. Infomation was collected about how much pain they wee expeiencing doing vaious types of activities, how much they wee limited in thei daily activities by thei OA, and on thei oveall condition. Thei docto also povided an oveall ating of thei OA. The main measue of the study was how much pain the subjects had doing five common types of activities ove the 6 months duation of the study. Daily activity limitations and oveall evaluations wee also compaed between the goup of patients eceiving Synvisc-One injection and the goup eceiving salt wate injection. The study showed that patients eceiving Synvisc-One had significantly less pain ove 6 months, and felt significantly bette than the patients who eceived the salt wate injections. The diffeence in pain scoe eduction fom baseline to 6 months between the Synvisc-One and salt wate contol injection was 0.15 out of a 5 point scale fo the measuement of OA pain in the knee. What advese events wee obseved in the clinical study? The following ae the most common advese events that occued duing the clinical tial of Synvisc-One: Pain in the knee o at the injection site Stiffness, swelling o wamth in o aound the knee Changes in the way that you walk (e.g., limping) Sevee advese events wee not obseved in the Synvisc- One tial. Joint infections did not occu in the injected knee in the Synvisc-One clinical tial. The most commonly occuing advese events outside of the injected knee wee headache, back pain, soe thoat and the flu. One patient had a single episode of feeling faint. How do I get moe infomation about the Synvisc-One poduct? (Use Assistance) If you have any questions o would like to find out moe about Synvisc-One, you may call Genzyme Biosugey at SYNVISC ( ) o visit Manufactued and Distibuted by: Genzyme Biosugey A division of Genzyme Copoation 1125 Pleasant View Teace Ridgefield, New Jesey SYNVISC-ONE, SYNVISC and GENZYME ae egisteed tademaks of Genzyme Copoation Fax Vesion 2