Synvisc-One

SIDE EFFECTS

Potential Adverse Effects Of The Device On Health

Reported Device-Related Adverse Events

The most commonly reported adverse events associated with Synvisc-One (hylan g-f 20 single intra-articular injection) are the following:

A complete list of the frequency and rate of adverse events identified in the clinical study are provided in the Safety section (Table 3).

Potential Adverse Events

The following adverse events are among those that may occur in association with intra-articular injections, including Synvisc-One (hylan g-f 20 single intra-articular injection) :

  • Arthralgia
  • Joint stiffness
  • Joint effusion
  • Joint swelling
  • Joint warmth
  • Injection site pain
  • Arthritis
  • Arthropathy
  • Gait disturbance

A complete list of the frequency and rate of adverse events identified in the clinical study are provided in the Safety section (Table 2).

Post-marketing Experience

SYNVISC® (3 injection regimen) post-marketing experience has identified the following systemic events to occur rarely with administration: 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 (3 injection regimen) injection.

Pivotal Clinical Trial

Study Design: To determine the safety and effectiveness of a single injection regimen of Synvisc-One (hylan g-f 20 single intra-articular injection) in the reduction of the pain score in osteoarthritis of the knee, a prospective, randomized, double-blind, 2-arm (parallel group) clinical trial in 21 centers in six European countries was conducted. A total of 253 patients were randomly assigned to study treatment; 123 received 6 mL of Synvisc-One (hylan g-f 20 single intra-articular injection) and 130 received 6 mL of Phosphate-Buffered Saline. Neither the patients nor the clinical observers knew the patients' treatment allocations. The outcome measures collected included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; Likert 3.1 A version); patient global assessment (PTGA); clinical observer global assessment (COGA); and use of rescue analgesic (see Treatment and Evaluation Schedule). The intent-to-treat (ITT) population (all patients randomized) was used for the primary analysis. The primary efficacy analysis was a comparison over 26 weeks between the two treatment groups of change from baseline in the WOMAC A (Pain) Subscale (see Patient Population and Demographics), performed by analysis of covariance (ANCOVA).

Patient Population and Demographics

Study patients had primary osteoarthritis of the knee per American College of Rheumatology criteria and were at least 40 years old. The diagnosis was confirmed via recent radiograph showing at least one osteophyte in the target knee. Study patients had continued target knee pain despite use of conservative treatment and analgesics/non-steroidal anti-inflammatory drugs (NSAIDs). Patients with severe disease (Grade IV) per Kellgren- Lawrence criteria, or who had prior arthroplasty in the target knee, were excluded. At the beginning of the study, subjects had moderate or severe target knee pain when walking on a flat surface (on a 5-point Likert scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme), and an average score of 1.5 to 3.5 on the five questions of theWOMACA (Pain) Subscale. The WOMAC A Subscale asks study subjects to rate their degree of pain when:

  1. Walking on a flat surface
  2. Going up and down stairs
  3. Resting during the night
  4. Sitting or lying
  5. Standing upright

Table 1 summarizes the demographics and baseline characteristics. There were no clinically meaningful differences between treatment groups in any baseline parameter.

Treatment and Evaluation Schedule

Initial Treatment Phase

Patientswere followed for 26weeks. Study visitswere scheduled for screening, baseline, andweeks 1, 4, 8, 12, 18 and 26. Injectionswere performed aseptically at the baseline visit after arthrocentesis towithdraw any effusion or synovial fluid present. Patients were not permitted to take long-acting NSAIDs (including cyclo-oxygenase II inhibitors), opioid analgesics or corticosteroids (by any route) during the study, but were permitted to take up to 4 g per day of acetaminophen as needed for “rescue” of injected knee pain. “Rescue”medication was not permitted within 48 hours of any study visit. Injected knee assessment, patient and clinician global assessments (PTGA & COGA),WOMAC and safety evaluations were performed at each study visit.

Repeat Treatment Phase

If patients in either blinded treatment group had at least mild pain in the injected knee at the week 26 visit (and did not experience any significant clinical concerns after the first treatment administration), they were offered an injection of (open-label) Synvisc-One (hylan g-f 20 single intra-articular injection) . Those who chose to receive the second injection were followed for 4 weeks for safety only.

Adverse Event Summary

The frequency and type of adverse events (AEs) were similar between the group of patients that received Synvisc-One (hylan g-f 20 single intra-articular injection) and the group that received saline control.

Initial Treatment Phase: The overall proportions of patients with Treatment-Emergent AEs regardless of device relatedness (Synvisc-One (hylan g-f 20 single intra-articular injection) : n=70, 56.9%; Saline Control: n=79, 60.8%) and with injected knee AEs regardless of device relatedness (Synvisc-One (hylan g-f 20 single intra-articular injection) : n=44, 35.8%; Saline Control: n=44, 33.8%) were comparable between the two treatment groups (See Table 2).

Table 3 lists the incidences of AEs in the injected knee that were assessed by the investigator to be device-related, defined as related to either the study injection or the study treatment.

Device-related AEs involving the injected knee were mild or moderate in nature and were treated symptomatically. There were no serious AEs in the injected knee in either the Synvisc-One (hylan g-f 20 single intra-articular injection) or the saline control group.

Repeat Treatment Phase: The repeat treatment phase evaluated the safety profile of the initial phase of patients receiving a second injection of Synvisc-One (hylan g-f 20 single intra-articular injection) . One hundred and sixty patients were treated during this phase of the study, of which 77 patients received a second injection of Synvisc-One (hylan g-f 20 single intra-articular injection) . Of these 77 patients, 4 (5.2%) experienced five device related AEs in the injected knee. All such events were mild to moderate and were treated symptomatically. These events were arthralgia (n=2), arthritis (n=1), injection site hematoma (n=1) and injection site pain (n=1). Patients who developed injected knee AEs during the initial phase of the study, and who subsequently received repeat treatment, did not experience injected knee AEs upon repeat exposure to Synvisc-One (hylan g-f 20 single intra-articular injection) .

Overall Injected Knee Safety Summary: The safety profile of Synvisc-One (hylan g-f 20 single intra-articular injection) is similar to the Clinical and Post-marketing experience seen with SYNVISC (3 injection regiment) where pain, swelling and effusion were the most frequently occurring AEs in the injected knee. There have been post-marketing reports for SYNVISC indicating that in some cases the joint effusion may be large and can cause pronounced pain; it is important to remove and to analyze the fluid to rule out infection or crystalline arthropathies. These types of severe AEs were not observed in either the initial or repeat treatment phase of the Synvisc-One (hylan g-f 20 single intra-articular injection) trial. Joint infections did not occur in any of the clinical trials of SYNVISC or Synvisc-One (hylan g-f 20 single intra-articular injection) and have been reported only rarely during clinical use of SYNVISC.

Adverse Events Outside of the Injected Knee

Overall 101 patients (Synvisc-One (hylan g-f 20 single intra-articular injection) : n=47, 38.2%; Saline Control: n=54, 41.5%) experienced at least one AE outside the injected knee regardless of device relatedness. The most commonly occurring (5% or greater in either group) AEs outside the injected knee were headache, back pain, nasopharyngitis and influenza. In the Synvisc-One (hylan g-f 20 single intra-articular injection) group there was one AE of syncope considered device-related.

No new systemic AEs were identified during this study as compared to SYNVISC.

Primary Efficacy Endpoint

The primary endpoint for the study, the difference between the treatment groups in change from baseline over 26 Weeks in the WOMAC A Pain Score (Table 4) was met.

Synvisc-One (hylan g-f 20 single intra-articular injection) also demonstrated superiority to saline control in multiple pre-defined secondary outcome measures, which included PTGA over and at 26 weeks, COGA over and at 26 weeks, and pain while walking on a flat surface (WOMAC A1) over and at 26 weeks (see Figure 1 and Table 5).

TheWOMACA1 responder rate (where response was defined as a 1-or-more category improvement from baseline and the patient did not withdraw from the study) was significantly higher in the Synvisc-One (hylan g-f 20 single intra-articular injection) group than in the saline control group. Seventyone percent (71%) of the patients were responders at week 18 in the Synvisc-One (hylan g-f 20 single intra-articular injection) group (versus 54% in the saline control group). At week 26, 64% of patients in the Synvisc-One (hylan g-f 20 single intra-articular injection) group were responders, while only 50% of patients in the saline control group were responders.

Detailed Device Description

Synvisc-One (hylan g-f 20 single intra-articular injection) combines the three doses of SYNVISC (hylanG-F 20) which consists of hylanA(average molecular weight 6,000,000 daltons) and hylan B hydrated gel in a buffered physiological sodium chloride solution, pH7.2. Synvisc-One (hylan g-f 20 single intra-articular injection) has an elasticity (storagemodulusG') at 2.5Hz of 111 ± 13 Pascals (Pa) and a viscosity (lossmodulusG”) 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” = 45 ± 8 Pa.)

Each 10-mL syringe of Synvisc-One (hylan g-f 20 single intra-articular injection) combines the three 2-mL doses (16 mg each) of a complete SYNVISC treatment regimen (48 mg). Each Synvisc-One (hylan g-f 20 single intra-articular injection) 10-mL syringe contains:

  • Hylan polymers (hylan A + hylan B) 48 mg
  • Sodium chloride 51 mg
  • Disodium hydrogen phosphate 0.96 mg
  • Sodium dihydrogen phosphate monohydrate 0.24 mg
  • Water for injection q.s. to 6.0 mL

Table 1: Summary of Demographic and Baseline Characteristics

Parameter/Category Synvisc-One®
(N=124)*
Saline Control
(N=129)*
Total
(N=253)
Age, n * 124 129 253
  Mean (SD) 63.6 (9.6) 62.5 ( 9.2) 63.0 ( 9.4)
  Range 42,83 43,84 42,84
Sex, n * 124 129 253
  Female, n (%) 92 (74%) 88 (68%) 180(71%)
Race, n * 124 129 253
  Caucasian, n (%) 118 (95%) 125 (97%) 243 (96%)
  Non-Caucasian, n (%) 6 (5%) 4 (3%) 10 (4%)
Body Mass Index (kg/m²), n* 123 129 252
  Mean (SD) 29.1 (4.8) 29.8 (5.7) 29.4 (5.3)
  Range 20.7, 46.0 19.5, 52.4 19.5, 52.4
Prior Corticosteroids In Target Knee, n** 123 130 253
  Yes - n (%) 40 (32%) 31 (24%) 71 (28%)
Prior Arthroscopy In Target Knee, n ** 123 130 253
  Yes - n (%) 26 (21%) 28 (22%) 54 (21%)
Tibio-Femoral Joint Modified Kellgren-Lawrence Numerical Grading System**
  Grade II 63 (51%) 51 (39%) 114 (45%)
  Grade III 60 (49%) 78 (60%) 138(55%)
  Grade IV 0 1 (1%) 1 (0%)
Total WOMAC Score (0-96); Mean (SD) * 55.1 (10.5) 54.8 (9.4)  
WOMAC A Score (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

Table 2: Patients with Adverse Events in the Injected Knee Regardless of Relatedness

MedDRA Preferred Term Synvisc-One® (hylan g-f 20 single intra-articular injection)
N=123
n (%)
Saline Control
N=130
n (%)
Any Treatment-Emergent Adverse Event 44 (35.8%) 44 (33.8%)
  Arthralgia 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 warmth 2 (1.6%) 5 (3.8%)
  Post-traumatic pain 0 3 (2.3%)
  Injection site pain 1 (0.8%) 1 (0.8%)
  Synovial cyst 0 2 (1.5%)
  Arthritis 1 (0.8%) 0
  Arthropathy 1 (0.8%) 0
  Gait disturbance 1 (0.8%) 0
  Joint range of motion decreased 0 1 (0.8%)
  Osteoarthritis 0 1 (0.8%)
Note: Patients are counted once for each unique AE regardless of device relatedness, and may have had more than one unique AE.

Table 3: Patients with Device-Related Adverse Events in the Injected Knee

MedDRA Preferred Term Synvisc-One® (hylan g-f 20 single intra-articular injection)
N=123
n (%)
Saline Control
N=130
n (%)
Any Device-Related Adverse Event 7 (5.7%) 4 (3.1%)
  Arthralgia 2 (1.6%) 3 (2.3%)
  Arthritis 1 (0.8%) 0
  Arthropathy 1 (0.8%) 0
  Injection site pain 1 (0.8%) 1 (0.8%)
  Joint effusion 2 (1.6%) 0
Note: Patients are counted once for each unique AE, and may have had more than one unique AE.

Table 4: Primary Efficacy Results: WOMAC A (Pain) Score Overall Change from Baseline Over 26 Weeks – ITT Population

  Baseline Mean (SE)
(0-4 Scale)
Mean Post- treatment (SE)
(0-4 Scale)
Estimated Change (SE) Estimated Difference from Saline Control
(95% CI)
p-value
(ANCOVA)
Synvisc-One® (n=124) 2.30 (0.04) 1.43 (0.06) -0.84 (0.06) 0.15 (-0.302, -0.002) 0.047
Saline Control (n=129) 2.25 (0.04) 1.59 (0.06) -0.69 (0.06)
WOMAC A scale using 5 point Likert scale, where 0 = no pain and 4 = extreme pain Repeated measures Analysis of Covariance was used for the WOMAC A pain score change from the baseline.

Table 5: Clinical Meaning of Secondary Efficacy Endpoints

  Odds Ratio1 Definition Explanation
Generalized Estimating Equation for catagorical data.    
WOMAC
A1
Over 26 weeks 0.64* The odds (probability [Worse] /Probability [Better]) for Synvisc-One for over 26 weeks and at 26 weeks is approximately 64%, and 56%, respectively, to the odds for control. Synvisc-One patients were 1.56 times more likely to self-report pain relief while walking on a flat surface compared to those patients treated with saline control over 26 weeks and 1.79 times more likely to self-report pain relief while walking on a flat surface compared to those patients treated with saline control at 26 weeks.
At week 26 0.56*
PTGA Over 26 weeks 0.69* The odds (probability [Worse] /Probability [Better]) for Synvisc- One for over 26 weeks and at 26 weeks is approximately 69%, and
51%, respectively, to the odds for control.
PTGA: Patient Global Assessment has 5 scales (Very well, Well, Fair, Poor, Very poor)
Synvisc-One patients were 1.45 times more likely to self-report improvement in overall health status compared to those patients treated with saline control over 26 weeks and 1.96 times more likely to self-report improvement in overall health status compared to those patients treated with saline control at 26 weeks.
At week 26 0.51*
COGA Over 26 weeks 0.71* The odds (probability [Worse] / Probability [Better]) for Synvisc- One for over 26 weeks and at 26 weeks is approximately 71%, and 56%, respectively, to the odds for control.
COGA: Clinical Observer Global Assessment has 5 scales (Very well, Well, Fair, Poor, Very poor)
Blinded clinical observers were 1.41 times more likely to assess patients treated with Synvisc-One as showing overall improvement in disease status compared to those patients treated with saline control over 26 weeks and 1.79 times more likely to assess patients treated with Synvisc-One as showing overall improvement in disease status compared to those patients treated with saline control at 26 weeks.
At week 26 0.56*
OMERACTOARSI
Responder
Over 26 weeks 0.66 This responder analysis did not reach statistical significance between the treatment groups.  
At week 26 0.69
Estimate of Treatment
Difference (Analysis of Covariance)
   
WOMAC C Over 26 weeks -0.18 The study did not show a statistically significant difference in functional improvement between the treatment groups.  
  At week 26 -0.11
*Statistically significant at the 5% significance level; not adjusted for multiplicity
1Odds ratio = Odds for Synvisc-One (hylan g-f 20 single intra-articular injection) /Odds for Control
Odds ratio = (Probability [Worse] / Probability [Better]) for Synvisc-One (hylan g-f 20 single intra-articular injection) / (Probability [Worse] /Probability [Better]) for Control
If odds ratio < 1, then in favor of Synvisc-One (hylan g-f 20 single intra-articular injection)

Figure 1: Plot for Categorical Secondary Endpoints – ITT Population

Plot for Categorical Secondary Endpoints – ITT Population - 1Illustration

Figure 2: Patient Responder Rate on WOMAC A1 (Walking Pain) -ITT Population

Patient Responder Rate on WOMAC A1 (Walking Pain) -ITT Population - Illustration

Read the Synvisc-One (hylan g-f 20 single intra-articular injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No information provided.

Last reviewed on RxList: 7/29/2010
This monograph has been modified to include the generic and brand name in many instances.

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