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.

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“) 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 syringe of Synvisc contains:

Last updated on RxList: 3/30/2009

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.

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

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.

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.

Synvisc is supplied in a 2.25 mL glass syringe containing 2 mL Synvisc. The contents of the syringe are sterile and nonpyrogenic.

Manufactured and Distributed by: Genzyme Biosurgery, A division of Genzyme Corporation, 1125 Pleasant View Terrace, Ridgefield, New Jersey 07657. Telephone: 1-888-3-SYNVISC (1-888-379-6847). Revised December 15, 2006.

Last updated on RxList: 3/30/2009

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/mm³ . 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 treatment¹; 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 Synvisctreated 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.)

No information provided.

REFERENCE

¹Raynauld JP, Bellamy N, Goldsmith CH, Tugwell P, Torrance GW, Pericak D. et al. 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.

²Leopold SS, Warme WJ, Pettis PD and Shott S. 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, 2002.

³Waddell DD, Estey DJ and Bricker D. 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.

Last updated on RxList: 3/30/2009

• 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.

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.

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.

Last updated on RxList: 3/30/2009

No information provided.

• 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.

Last updated on RxList: 3/30/2009

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.

TABLE 1 - DEMOGRAPHIC DATA¹

TABLE 2 - CONCURRENT OSTEOARTHRITIS THERAPIES¹

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 Germany⁴ 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 evaIuation period (see Tables 3A and 3B).

TABLE 3A - EFFECTIVENESS OF WEIGHT-BEARING PAIN¹ EVALUATED BY PATIENTS

TABLE 3B - EFFECTIVENESS OF NIGHT PAIN1 EVALUATED BY PATIENTS

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.

REFERENCE

⁴Scale, D., Wobig, M. and Wolpert, W. (1994). Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Curr Ther Res; 55:220-232.

Last updated on RxList: 3/30/2009

Be sure to read the following important information carefully. This information does not take the place of your doctor's advice. If you do not understand this information or want to know more, ask your doctor.

WHAT IS SYNVISC?

Synvisc is a gel-like mixture that is made up of hylan A fluid, hylan B gel, and salt water. Hylan A and hylan B are made from a substance called hyaluronan (pronounced hye-a-loo-ROE-nan), also known as sodium hyaluronate that comes from chicken combs. This is a natural substance found in the body and is present in very high amounts in joints. The body's own hyaluronan acts like a lubricant and a shock absorber in the joint and is needed for the joint to work properly. Osteoarthritis (pronounced os-TE-o-ar-THRI-tis) (OA) is a type of arthritis that involves the wearing down of cartilage (the protective covering on the ends of your bones). In OA, there may not be enough hyaluronan, and there may be a decrease in the quality of the hyaluronan in the joint. Synvisc comes in syringes containing 2 mL (half a teaspoon) of product. Synvisc is injected directly into your knee.

WHAT IS SYNVISC USED FOR?

Synvisc is used to relieve knee pain due to OA. It is used for patients who do not get enough relief from simple painkillers, such as acetaminophen, or from exercise and physical therapy.

WHAT ARE THE BENEFITS OF SYNVISC?

Two medical studies involving a total of 132 patients were done in Germany. The patients in these studies were at least 40 years old and had knee pain due to OA. The patients were placed in one of two groups. One group was given an injection of Synvisc into one or both knees once a week for three weeks. The second group was given an injection of salt water once a week for three weeks. As part of the study, knee joint pain was measured for 26 weeks. Also, patients and doctors were asked to judge the success of the treatment for 26 weeks. Patients with OA knee pain, who did not get pain relief with other medicines, got pain relief with Synvisc. The patients given Synvisc had more pain relief than the patients given salt water. Some patients started to feel pain relief after the first week of Synvisc treatment. The most pain relief and the greatest amount of treatment success was seen 8 to 12 weeks after Synvisc treatment started.

A medical study done in the United States involved 90 patients. The patients were at least 40 years old and had knee pain due to OA. Patients were placed into one of two groups. One group was given Synvisc once a week for three weeks. The second group had a needle inserted into the knee to have any fluid removed (this procedure is called arthrocentesis [pronounced AR-thro-sen-TE-sis]) once a week for three weeks.

Patients improved after Synvisc treatment, but not more than patients who had arthrocentesis. This study was different from the German studies because the last time the two groups were compared was only two weeks after the last Synvisc injection. The study was also different in other ways, including length of time that patients had to stop taking medicines before they could start treatment. The length of time patients had to stop taking medicines was two weeks in the German studies and four weeks in the U.S. study.

WHAT OTHER TREATMENTS ARE AVAILABLE FOR OA?

If you have OA, there are other things you can do besides getting Synvisc. These include:

Non-drug treatments

• avoiding activities that cause knee pain
• exercise
• physical therapy
• removal of excess fluid from your knee

Drug therapy

• pain relievers such as acetaminophen and narcotics
• drugs that reduce inflammation (signs of inflammation are swelling, pain or redness), such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen
• steroids that are injected directly into your knee

ARE THERE ANY REASONS WHYYOU SHOULD NOT RECEIVE SYNVISC?

• You should not get this product if you have had any allergic reaction before to Synvisc or hyaluronan products. Signs of an allergic reaction may include swelling of your face, tongue, or throat; difficulty breathing or swallowing; shortness of breath; wheezing; chest pain; a tightness in your throat; sleepiness; rash; itching; hives; flushing; and/or fever. You should call your doctor immediately if you develop any of these signs of an allergic reaction.
• You should not be given Synvisc if you have a knee joint infection or skin diseases or infections around the area where the injection will be given. Talk to your doctor if you have any questions about this information.

THINGS YOU SHOULD KNOWABOUT SYNVISC:

• Synvisc is only for injection into the knee, performed by a doctor or other qualified health care professional.
• Tell your doctor if you are allergic to products from birds such as feathers, eggs, and poultry.
• After you receive the injection, you may need to avoid activities such as jogging, tennis, heavy lifting, or standing for a long time.
• Synvisc has not been tested in pregnant women, or women who are nursing. You should tell your doctor if you think you are pregnant, or if you are nursing a child.
• The safety and effectiveness of Synvisc have not been tested in children.

POSSIBLE SIDE EFFECTS

• The side effects (also called reactions) sometimes seen when Synvisc is injected into the knee as a first or repeat set of injections were pain, swelling, heat, redness, and/or fluid build-up around the knee. These reactions were generally mild and did not last long, but sometimes fluid accumulation was considerable and painful; cases where the swelling is extensive and painful should be discussed with your doctor. The reactions seemed to occur more often when Synvisc was injected into the knee as a repeat set of injections than when Synvisc was injected as a first set of injections.
• These reactions were generally treated by giving pain relievers by mouth such as acetaminophen or by giving NSAIDs by mouth or injections of steroids, or by removing fluid from the knee joint. Patients have rarely undergone arthroscopy (a surgical inspection of the knee joint) and other medical procedures.
• Rare cases of knee joint infection have been reported after Synvisc injections.
• Rashes, hives and itching have been seen in patients after Synvisc treatment. Before you are given Synvisc, tell your doctor if something like this has ever happened to you after receiving an injection of Synvisc or other hyaluronan products.
• Other less common side effects have been: muscle pain/cramps, flushing and/or swelling of your face, fast heartbeat, nausea (or feeling sick to your stomach), dizziness, fever, chills, headache, difficulty breathing, swelling in your arms and/or legs, prickly feeling of your skin, and in rare cases a low number of platelets in the blood (platelets are a type of blood cell that are needed to help clot your blood when you are cut or injured).
• If any of the above symptoms or signs appear after you are given Synvisc, or if you have any other problems, you should call your doctor.

HOWIS SYNVISC GIVEN?

Your doctor will give you your injection of Synvisc (2mL) into your knee once a week, for a total of three injections.

Manufactured and Distributed by: Genzyme Biosurgery a division of Genzyme Corporation, 1125 Pleasant View Terrace, Ridgefield, New Jersey 07657

HOW DO I GET MORE INFORMATION ABOUT SYNVISC?

If you have any questions or would like to find out more about Synvisc, you may call Genzyme Biosurgery at 1-888-3-SYNVISC (1-888-379-6847).

Last updated on RxList: 3/30/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

HYALURONATE - INJECTION

(hi-uh-LYOU-ron-ate SO-dee-um)

COMMON BRAND NAME(S): Hyalgan, Synvisc

USES: This medication is used to treat knee pain in patients with joint inflammation (osteoarthritis). It is usually used in patients who have not responded to other treatments such as acetaminophen, exercise, or physical therapy. Hyaluronate is similar to a substance that occurs naturally in the joints. It may work by improving the joint fluid that helps the knee to move smoothly, thereby lessening pain.

HOW TO USE: Read the Patient Information Leaflet provided by your health care professional before you start using hyaluronate and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Your doctor will give this medication by injection into the affected joint, usually once a week. Skin disinfectants that contain ammonium salts (e.g., benzalkonium chloride) should not be used to prepare the injection site. Your doctor may need to remove extra fluid from the joint before injecting the medicine. Dosage is based on your medical condition and response to treatment.

After receiving an injection of hyaluronate, you should avoid any activities that put stress on your knee (e.g., jogging, tennis, heavy lifting, standing on your feet for more than an hour) for 48 hours.

Tell your doctor if your condition persists or worsens.

SIDE EFFECTS: Pain, swelling, redness/warmth/bruising at the injection site, or headache may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: back pain, severe headache, fast/pounding heartbeat, fever, tingling skin feelings.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using hyaluronate, tell your doctor or pharmacist if you are allergic to it; or to bird proteins, feathers, or egg products; or to latex; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: knee joint infections, skin infections/problems in the area around the injection site.

Hyaluronate should not be injected into a vein or artery because increased side effects may occur.

Tell your doctor if you are pregnant before using this medication.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Before using this product, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Non-drug treatments for osteoarthritis include exercising, doing physical therapy, having extra fluid removed from the knee, and avoiding activities that cause pain in your knee.

MISSED DOSE: If you miss a dose, consult your doctor as soon as possible to establish a new dosing schedule.

STORAGE: Store below 77 degrees F (25 degrees C) away from light and moisture. Do not freeze. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.