Caution: Federal law restricts this device to sale by or on the order of a physician (or properly licensed practitioner).
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 glycosamino-glycan family. Hyaluronan is a long-chain polymer containing repeating disaccharide units of Na-glucuronate-N-acetylglucosamine.
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.
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 a patient receives. Reactions generally abate within a few days. Clinical benefit from the treatment may still occur after such reactions.
Intra-articular infections did not occur in any of the clinical trials and have been reported only rarely during clinical use of Synvisc.
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 the patients received additional Synvisc injections. The remaining generalized adverse events reported were calf cramps, hemorrhoid problems, ankle edema, muscle pain, tonsillitis with nausea, tachyarrhythmia, 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. )
The safety and effectiveness of Synvisc was studied in patients >/=40 years old in the three concurrently controlled clinical trials referred to in the "Adverse Events" section. 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 were 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).
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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).
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A second study conducted at a single-center in Germany 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).
A third study was a prospective, concurrently controlled, randomized, double-blinded 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- 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).
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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, and pain and X-ray inclusion criteria. Thus, 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.
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.
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 18-27 year old humans measured with a comparable method at 2.5 Hz: G' = 117 ± 13 Pa; G[Prime ] = 45 ± 8 Pa.)
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Synvisc® is supplied in a 2.25 mL glass syringe containing 2 mL Synvisc.
Product Number:-9149-023 disposable syringes
The contents of the syringe are sterile and nonpyrogenic.
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, if present, before injecting Synvisc.
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.
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.
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 Laboratories Inc.
A Wyeth-Ayerst Company
Philadelphia, Pennsylvania 19101
Telephone: 1-800-99-WYETH
Fax: (610) 964-5999
DEVELOPED AND MANUFACTERED BY:
Biomatrix, Inc.
65 Railroad Avenue
Ridgefield, New Jersey 07657
Telephone: (201) 945-9550
Fax: (201) 945-0363
Scale D, Wobig M, and Wolpert W: Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Curr Ther Res; 55:220-232, 1994.
CI 5014-3 Revised August 31, 1998