Hylan G-F 20

Caution: Federal law restricts this device to sale by or on the order of a physician (or properly licensed practitioner).

Description

Synvisc (hylan G-F 20) is an elastoviscous fluid containing hylan polymers produced from chicken combs. Hylans are derivatives of hyaluronan (sodium hyaluronate), a natural complex sugar of the glycosaminoglycan family. Hyaluronan is a long-chain polymer containing repeating disaccharide units of Na-glucuronate-N-acetylglucosamine.

INDICATIONS

Synvisc is indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy and simple analgesics, e.g., acetaminophen.

Contraindications

• Do not administer to patients with known hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) preparations.
• Do not inject Synvisc in the knees of patients having knee joint infections or skin diseases or infections in the area of the injection site.

Warnings

• Do not concomitantly use disinfectants containing quaternary ammonium salts for skin preparation because hyaluronan can precipitate in their presence.
• Do not inject Synvisc extra-articularly or into the synovial tissues and capsule. Local and systemic adverse events, generally in the area of the injection, have occurred following extra-articular injection of Synvisc.
• Intravascular injections of Synvisc may cause systemic adverse events.

Precautions

General

• The effectiveness of a single treatment cycle of less than three injections of Synvisc has not been established.
• The safety and effectiveness of Synvisc in locations other than the knee and for conditions other than osteoarthritis have not been established.
• Do not inject anesthetics or other medications into the knee joint during Synvisc therapy. Such medications may dilute Synvisc and affect its safety and effectiveness.
• Use caution when injecting Synvisc into patients who are allergic to avian proteins, feathers and egg products.
• The safety and effectiveness of Synvisc in severely inflamed knee joints have not been established.
• Strict aseptic administration technique must be followed.
• STERILE CONTENTS. The syringe is intended for single use. The contents of the syringe must be used immediately after its packaging is opened. Discard any unused Synvisc.
• Do not use Synvisc if package is opened or damaged. Store in original packaging (protected from light) at room temperature below 86°F (30°C). DO NOT FREEZE.
• Remove synovial fluid or effusion before each Synvisc injection.
• Synvisc should be used with caution when there is evidence of lymphatic or venous stasis in that leg.

Information for Patients

• Provide patients with a copy of the Patient Labeling prior to use.
• Transient pain, swelling and/or effusion of the injected joint may occur after intra-articular injection of Synvisc. In some cases the effusion may be considerable and can cause pronounced pain; cases where swelling is extensive should be discussed with the physician.
• As with any invasive joint procedure, it is recommended that the patient avoid any strenuous activities or prolonged weight-bearing activities such as jogging or tennis following the intra-articular injection.
• The packaging of this product contains dry natural rubber latex.

Use in Specific Populations

• Pregnancy:   The safety and effectiveness of Synvisc have not been established in pregnant women.
• Nursing mothers:   It is not known if Synvisc is excreted in human milk. The safety and effectiveness of Synvisc have not been established in lactating women.
• The safety and effectiveness of Synvisc have not been established in children.

ADVERSE EVENTS

Adverse Events Involving the Injected Joint

Clinical Trials:   A total of 511 patients (559 knees) received 1771 injections in seven clinical trials of Synvisc. There were 39 reports in 37 patients (2.2% of injections, 7.2% of patients) of knee pain and/or swelling after these injections. Ten patients (10 knees) were treated with arthrocentesis and removal of joint effusion. Two additional patients (two knees) received treatment with intra-articular steroids. Two patients (two knees) received NSAIDs. One of these patients also received arthrocentesis. One patient was treated with arthroscopy. The remaining patients with adverse events localized to the knee received no treatment or only analgesics.

Postmarket Experience:   The most common adverse events reported have been pain, swelling and/or effusion in the injected knee. In some cases the effusion was considerable and caused pronounced pain. In some instances, patients have presented with knees that were tender, warm and red. It is important to rule out infection or crystalline arthropathies in such cases. Synovial fluid aspirates of varying volumes have revealed a range of cell counts, from very few to over 50,000 cells/mm ³ . Reported treatments included symptomatic therapy (e.g., rest, ice, heat, elevation, simple analgesics and NSAIDs) and/or arthrocentesis. Intra-articular corticosteroids have been used when infection was excluded. Rarely, arthroscopy has been performed. The occurrence of post-injection effusion may be associated with patient history of effusion, advanced stage of disease and/or the number of injections or treatment courses a patient receives. Reactions generally abate within a few days. Clinical benefit from the treatment may still occur after such reactions.

The clinical trials described above included 38 patients who received a second course of Synvisc injections (132 injections). There were twelve reports in nine patients (9.1% of injections, 23.7% of patients) of knee pain and/or swelling after these injections. Reports of two additional clinical trials in which patients received repeated courses of Synvisc treatment have appeared during the post-marketing period. One of these trials included 48 patients who received 210 injections during a second course of Synvisc treatment ¹ ; the other contained 71 patients who received 211 injections during a second course of Synvisc treatment.

A total of 157 patients have received 553 injections in the three clinical trials of repeated courses of Synvisc treatment. The reports in these trials describe a total of 48 reports of adverse events localized to the injected knee in 35 patients that occurred after injections that patients had received during their second course of treatment. These adverse events accounted for 6.3% of injections in 22.3% of patients as compared to 2.2% of injections in 7.2% of patients in a single course of Synvisc injections. In addition, reports of two retrospective studies during the post-marketing period have described adverse events localized to the injected knee that have occurred after 4.4% and 8.5% of injections that patients had received during one or more repeated courses of Synvisc treatment. ^2,3

Intra-articular infections did not occur in any of the clinical trials and have been reported only rarely during clinical use of Synvisc.

Other Adverse Events

Clinical Trials:   In three concurrently controlled clinical trials with a total of 112 patients who received Synvisc and 110 patients who received either saline or arthrocentesis, there were no statistically significant differences in the numbers or types of adverse events between the group of patients that received Synvisc and the group that received control treatments.

Systemic adverse events each occurred in 10 (2.0%) of the Synvisc-treated patients. There was one case each of rash (thorax and back) and itching of the skin following Synvisc injections in these studies. These symptoms did not recur when these patients received additional Synvisc injections. The remaining generalized adverse events reported were calf cramps, hemorrhoid problems, ankle edema, muscle pain, tonsillitis with nausea, tachyarrythmia, phlebitis with varicosities and low back sprain.

Postmarket Experience:   Other adverse events reported include: rash, hives , itching, fever , nausea, headache , dizziness , chills , muscle cramps, paresthesia , peripheral edema, malaise , respiratory difficulties , flushing and facial swelling . There have been rare reports of thrombocytopenia coincident with Synvisc injection. These medical events occurred under circumstances where causal relationship to Synvisc is uncertain. (Adverse events reported only in worldwide postmarketing experience, not seen in clinical trials, are considered more rare and are italicized .)

Clinical Studies

The safety and effectiveness of Synvisc were studied in patients >/=40 years old in the three concurrently controlled clinical trials. The three studies investigated a total of 136 women and 81 men. The demographics of trial participants were comparable across treatment groups with regard to age, gender and duration of osteoarthritis, except that there was a significantly greater (p = 0.04) number of men in the Synvisc group and women in the control group in one study (see Table 1).

One study was a multicenter study conducted at four sites in Germany. This was a randomized, double-blind prospective clinical trial with two treatment groups. The study compared the safety and effectiveness of three weekly intra-articular injections of Synvisc and of physiological saline in 103 subjects (109 knees) with osteoarthritis of the knee over a 26-week period.

A significantly greater number of saline-treated patients took concurrent osteoarthritis medications than did patients treated with Synvisc (see Table 2). While both the Synvisc and the saline-treated groups improved significantly as compared to baseline in all effectiveness measures, the Synvisc group showed a significantly greater improvement in all outcome measures than did the saline-treated patients over a 26-week period (see Tables 3A and 3B).

A second study conducted at a single center in Germany ⁴ was a concurrently controlled, randomized, double-blind prospective clinical trial with two treatment groups. This study compared the safety and effectiveness over a 26-week period of three weekly intra-articular injections of Synvisc and of physiological saline in 29 subjects (29 knees) with osteoarthritis of the knee. The results of the study were similar to those in the German multicenter study, except that the significance levels in most comparisons were smaller (see Tables 3A and 3B). In both of these studies the most pain relief and the greatest amount of treatment success occurred 8 to 12 weeks after Synvisc treatment began.

Investigators obtained data at 26 weeks by telephone interviews. A validation study suggested that the results obtained in telephone interviews are equivalent to those obtained in office visits. Since investigators did not follow patients beyond week 26, the duration of pain relief beyond 26 weeks is not known.

A third study was a prospective, concurrently controlled, randomized, double-blind multicenter study conducted in 90 subjects (103 knees) at five U.S. sites. The study compared the safety and effectiveness of three weekly intra-articular injections of Synvisc and of three weekly arthrocenteses in subjects with osteoarthritis of the knee over a four-week period after the first injection or arthrocentesis.

Both the Synvisc-treated and the arthrocentesis-treated groups improved significantly as compared to baseline in all effectiveness measures. However, there were no significant differences between the Synvisc-treated and arthrocentesis-treated patients at any time during the four-week evaluation period (see Tables 3A and 3B).

Covariate analyses with the covariates of center, presence or absence of previous treatments, baseline levels of outcome measures, age, gender, body mass, effusion, baseline X-ray score, duration of osteoarthritis, treatment of contralateral knee, and presence or absence of concurrent therapies, did not reveal any factors that significantly affected the results of any of the three studies.

The German studies and the U.S. study differed in several respects, including inclusion of patients with effusions, length of no treatment period prior to Synvisc injection, nature of control treatment, final evaluation time, mean duration of disease, mean weight, prior treatments for OA, pain and X-ray inclusion criteria. Thus, the German and the U.S. studies, which gave different results, investigated different patient populations and compared Synvisc with different control treatments.

Although success criteria for safety were not specified in any of the three studies, adverse events were enumerated in each study. These events are included in the "Adverse Events" section.

DETAILED DEVICE DESCRIPTION

Synvisc contains hylan A (average molecular weight 6,000,000) and hylan B hydrated gel in a buffered physiological sodium chloride solution, pH 7.2. Synvisc has an elasticity (storage modulus G') at 2.5 Hz of 111 ± 13 Pascals (Pa) and a viscosity (loss modulus G[Prime ]) of 25 ± 2 Pa (elasticity and viscosity of knee synovial fluid of 18 to 27-year-old humans measured with a comparable method at 2.5 Hz: G' = 117 ± 13 Pa; G[Prime ] = 45 ± 8 Pa.)

How Supplied

Synvisc is supplied in a 2.25 mL glass syringe containing 2 mL Synvisc.

Product Number: 0008-9149-02 3 disposable syringes

The contents of the syringe are sterile and nonpyrogenic.

DIRECTIONS FOR USE

Synvisc is administered by intra-articular injection once a week (one week apart) for a total of three injections.

Precaution:   Do not use Synvisc if the package has been opened or damaged. Store in original packaging (protected from light) at room temperature below 86°F (30°C). DO NOT FREEZE.

Precaution:   Strict aseptic administration technique must be followed.

Precaution:   Do not concomitantly use disinfectants containing quaternary ammonium salts for skin preparation because hyaluronan can precipitate in their presence.

Precaution:   Remove synovial fluid or effusion before each Synvisc injection.

Do not use the same syringe for removing synovial fluid and for injecting Synvisc, but the same needle should be used.

Take particular care to remove the tip cap of the syringe and needle aseptically.

Twist the gray tip cap before pulling it off, as this will minimize product leakage.

Inject Synvisc into the knee joint through an 18 to 22 gauge needle.

To ensure a tight seal and prevent leakage during administration, secure the needle tightly while firmly holding the luer hub.

Precaution: Do not over tighten or apply excessive leverage when attaching the needle or removing the needle guard, as this may break the tip of the syringe.

Do not inject anesthetics or any other medications intra-articularly into the knee while administering Synvisc therapy. This may dilute Synvisc and affect its safety and effectiveness.

Precaution:   The syringe containing Synvisc is intended for single use. The contents of the syringe must be used immediately after the syringe has been removed from its packaging. Inject the full 2 mL in one knee only. If treatment is bilateral, a separate syringe must be used for each knee. Discard any unused Synvisc.

DISTRIBUTED BY:

Wyeth-Ayerst Pharmaceuticals

Philadelphia, Pennsylvania 19101

Telephone: 1-800-99-WYETH

DEVELOPED AND
MANUFACTURED BY:

Genzyme Biosurgery

a division of Genzyme Corporation

1125 Pleasant View Terrace

Ridgefield, New Jersey 07657

Covered by U.S. patents #4,636,524, #4,713,448, #5,099,013, #5,143,724.

SYNVISC and GENZYME are registered trademarks of Genzyme Corporation.

References

1. Raynauld, J.P., Bellamy, N., Goldsmith, C.H., Tugwell, P., Torrance, G.W., Pericak, D., et al. (2002). An evaluation of the safety and effectiveness of repeat courses of hylan G-F 20 for treating patients with knee osteoarthritis. Osteoarthritis Research Society International, 2002 OARSI World Congress on Osteoarthritis, Sydney, Australia [Paper reference # PS128]. Presentation on File.
2. Leopold, S.S., Warme, W.J., Pettis, P.D. and Shott, S. (2002). Increased frequency of acute local reaction to intra-articular Hylan GF-20 (Synvisc) in patients receiving more than one course of treatment. J. Bone Joint Surg. 84-A (9): 1619-1623.
3. Waddell, D.D., Estey, D.J. and Bricker, D. (2001). Retrospective tolerance of Hylan G-F 20 using fluoroscopically- confirmed injection and effectiveness of retreatment in knee osteoarthritis. Proceedings of the American College of Rheumatology Annual Meeting 2001. Presentation on File.
4. Scale, D., Wobig, and Wolpert, W. (1994). Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Curr. Ther. Res. 55: 220-232.

CI 6082-5                                                               Revised October 7, 2003

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.