Data Sheet
HYALGAN
Sodium hyaluronate 20 mg/2 ml
Presentation
Vial:
Colourless, Type I borosilicate glass vial with rubber stopper and aluminium flip-off seal. It contains 2 ml of solution.
Prefilled syringe:
Sterile, colourless Type I borosilicate glass syringe with polypropylene plunger rod and rubber stopper. It contains 2 ml of solution.
Uses
Actions
Solution for Injection (2 ml vials or 2 ml pre-filled syringes) contains sodium hyaluronate 20 mg/2 ml. It is a viscous solution of highly purified hyaluronic acid (which has a molecular weight of 500-730 kDaltons). Sodium hyaluronate, the sodium salt of hyaluronic acid, extracted from biological material (rooster combs), is the only active ingredient in Hyalgan.
Hyaluronic acid, a natural polymer of the glycosaminoglycan family (acid mucopolysaccharides), is an important component of the extracellular matrix and is present in a particularly high concentration in cartilage and synovial fluid. Hyaluronic acid is composed of alternating sequences of sodium-D-glucuronate and N-acetyl-D-glucosamine, which are linked by beta-glycoside bonds. Linear repeating chains of high molecular weight (up to 8,000,000) are formed this way. The unique physico-chemical properties of hyaluronic acid enable it to interact with other molecules such as proteins, water and electrolytes.
Endogenous hyaluronic acid provides viscosity and elasticity to synovial fluid, which is fundamental for its lubricating and shock absorbing properties, and it is essential for the correct structure of proteoglycans in articular cartilage. In osteoarthritis there is an insufficient amount of, and a change in the quality of, hyaluronic acid in synovial fluid and cartilage.
In humans and in different experimental models, Hyalgan has been shown to improve many degenerative arthropathies. The intra-articular administration of Hyalgan into arthritic joints leads to a normalisation of synovial fluid quality and to an activation of tissue repair processes in articular cartilage.
There is evidence that the prolonged benefits of Hyalgan therapy are related to a number of different effects. It has been documented that Hyalgan stimulates endogenous production of hyaluronic acid by synoviocytes and this may account for the prolonged effect achieved: in addition, Hyalgan can intervene with the metabolism of proteoglycan aggregates. It has been shown that hyaluronic acid interacts with chondrocytes, synoviocytes and many other cell types through specific receptors.
In human joint fluid Hyalgan decreases inflammatory and pain mediators thus indicating an anti-inflammatory and analgesic activity. Furthermore, a protection from oxidative damage has been documented.
Clinical use:
There are four pivotal randomised clinical studies: one controlled versus reference oral therapy and placebo (495 patients), one controlled versus intra-articular reference therapy (63 patients) and two controlled versus placebo (210 patients). Altman (1995) compared the effect of Hyalgan (20 mg/2 ml, administered as 5 intra-articular injections at weekly intervals) and naproxen (500 mg twice daily for 26 weeks) and placebo during a 26 week trial in 495 patients with idiopathic osteoarthritis of the knee joint. At week 26, a statistically significant higher proportion of patients in the Hyalgan group reported none or slight pain when compared to the placebo group. Relief from pain during walking was statistically significantly greater for the Hyalgan compared to placebo at 4,5,12,21 and 26 weeks. At week 26, Hyalgan-treated patients had the lowest mean visual analogue scores when compared to the naproxen or placebo treated groups. The results showed clear evidence of the clinical efficacy of Hyalgan in everyday activities of osteoarthritis patients.
Doherty (1992) compared the effect of Hyalgan (20 mg/2 ml, given as 5 intra-articular injections at weekly intervals) and triamcinolone (20 mg /ml i.a. injection followed by 4 placebo injections) in 63 patients with painful osteoarthritis of both knees and joint effusion of both knee joints. The results showed that despite comparable pain relief for the two treatment groups in the first 5 weeks of the study. Long-term results showed statistically significant superiority for Hyalgan for pain on activity and at night. Patients treated with Hyalgan remained stable or continued to improve with time, compared to the triamcinolone group who showed progressive deterioration. The Hyalgan group also showed a statistically significant improvement in an anxiety depression scale.
The placebo-controlled study of Huskisson (1995) assessed the efficacy, tolerability and patient satisfaction of five weekly intra-articular injections of Hyalgan 20 mg/ 2ml or placebo administered to 100 patients with osteoarthritis of one or both knees. Statistically significant differences in favour of Hyalgan treatment were revealed for the primary efficacy criteria, pain on walking (starting at week 5 to 6 months, end of trial) and the Lequesne index (improvement in functional impairment) from week 5 to 4 months. At month 6, there were significant differences in favour of Hyalgan for patient satisfaction with treatment on the basis of efficacy, acceptability and anti-inflammatory effect.
Amor (1989, 1991) investigated the effects of four i.a injections of Hyalgan 20 mg/2 ml versus placebo once weekly over 3 weeks in 110 patients with painful unilateral or bilateral osteoarthritis of the knee with joint effusion. Four weeks after the last injection Hyalgan treated patients showed a statistically significant reduction in pain (p=0.003) and an amelioration of function (p=0.003) as compared to placebo. At the end of one year follow-up the improvement in functional impairment (Lequesne index) was significantly greater for Hyalgan compared to placebo (p=0.046) and globally more Hyalgan patients improved (77%) compared to placebo (54%) (p=0.011).
Given that Hyalgan has been marketed in Europe since 1987, an estimated 1,600,000 patients have been treated with Hyalgan worldwide
Pharmacokinetics
Absorption:
Sodium hyaluronate administered intra-articularly is eliminated from the synovial fluid within 2 to 3 days. Pharmacokinetic studies have shown that it is quickly distributed to the synovial membrane. The highest concentrations of labelled hyaluronic acid have been detected in the synovial fluid and the articular capsule, followed by, in decreasing order, the synovial membrane, the ligaments and the adjacent muscle.
Metabolism:
Hyaluronic acid in synovial fluid is not significantly metabolised.
Elimination:
Animal studies have shown that some degradation occurs in the tissue surrounding the joints, but the major site for metabolism is the liver and excretion is mainly through the kidneys.
The results of studies carried out in dogs and rabbits after single and repeated intra-articular administration have shown that hyaluronic acid is rapidly distributed in articular tissues and persists for a long period of time: the labelled product was found in the synovial membrane within 2 hours and persisted for 7 days; the maximum concentration of labelled product was seen mainly in the synovial fluid and then declining, in joint capsule, ligaments and adjacent muscle.
With regard to organ distribution, radioactivity was found in liver, kidneys, bone marrow and lymph nodes; the product was excreted mainly through the kidneys. A study carried out in pregnant rats, through i.v. administration, showed radioactivity in the placenta and in various organs of the foetus.
Indications
Sustained relief of pain and joint dysfunction in osteoarthritis of the knee
Dosage And Administration
The usual dosage is 2 ml of Hyalgan (20 mg) administered intra-articularly once a week for 3-5 weeks. Treatment may be repeated, usually, at 6 up to 12-month intervals. More than one joint may be treated at the same time.
Method of Administration: Hyalgan is for intra-articular injection and is supplied as a single use, ready to use, sterile solution in a 2 ml vial or in a 2 ml pre-filled syringe, and must not be diluted. The contents of the vial and syringe are sterile and must be used immediately once the container has been opened. A 20-gauge needle may be used on the syringe.
Intra-articular injection of Hyalgan should be made using precise, anatomical localisation into the joint cavity of the knee to be treated. The injection site in the knee is determined by that location which is easier to reach. Usually a lateral approach can be followed, but in some cases a medial approach is preferable. Strict aseptic precautions should be observed during the administration. The solution in the vial requires a suitable sterile disposable syringe and needle while the solution in the pre-filled syringe is ready for use and requires only a sterile disposable needle. To ensure sterility, the injection site must be carefully cleansed with antiseptic. Care should be taken to expel any trapped air bubbles from the syringe containing Hyalgan prior to administration.
Joint effusion, if present, should be aspirated by arthrocentesis prior to injection of Hyalgan. The arthrocentesis should be made using, for example, a 20gauge needle and the joint should be aspirated to almost dryness, but not to a degree that would compromise the accuracy of the subsequent Hyalgan injection. An appropriate examination of the joint fluid present should be carried out to exclude bacterial infection, prior to injection. The intra-articular injection of Hyalgan can be given using the same needle as used for the arthrocentesis by simply detaching the aspirating syringe and attaching the syringe containing Hyalgan.
To make sure the needle is correctly positioned, some synovial fluid should be aspirated prior to the slow injection of Hyalgan. If the patient experiences pain during injection, the procedure may need to be stopped.
For the first 48 hours after the injection, the patient should be advised to rest the treated knee, with as a little exercise as possible, avoiding any strenuous activities or prolonged weight-bearing activities such as jogging or tennis. Subsequently, they may gradually return to their normal level of activity.
Discard any unused portions of Hyalgan.
Contraindications
Individual hypersensitivity to any of the components of Hyalgan or to avian proteins. In addition, intra-articular injections are contra-indicated in cases of infections or skin diseases in the area of the injection site.
Warning and Precautions
It is necessary to follow the correct technique of intra-articular injection in accurately aseptic conditions. (See Method of Administration).
Particular attention must be paid in case of patients with an infection close to the injection path, in order to avoid the possibility of developing bacterial arthritis.
Remove joint effusion, if present, before injecting Hyalgan.
Patients should be carefully examined prior to administration to determine signs of acute inflammation and the physician should evaluate whether Hyalgan treatment should be initiated when objective signs of inflammation are present.
As with any invasive joint procedure, it is recommended that care be taken not to overburden the joint immediately following the intra-articular injection.
Use only if the solution is clear.
Use in children:
The safety and effectiveness of Hyalgan in children have not been demonstrated
Use in elderly:
No particular precautions are recommended in this patient group.
Impaired renal or hepatic function:
No information is available on the use of Hyalgan in this population.
Carcinogenesis, mutagenesis and impairment of fertility:
Sodium hyaluronate was tested in a standard range of toxicological tests, including mutagenicity and reproductive toxicity studies, and produced negative results throughout.
Use in pregnancy - (Category B3):
No embryotoxicity or teratogenicity has been observed in animal studies. However, there is no experience of the use of Hyalgan in pregnant women and therefore the expected benefit to the mother should be weighed against any potential risk to the foetus.
If Hyalgan is prescribed to a woman of child bearing potential, she should be advised to contact her physician regarding discontinuance of the product if she intends to become, or suspects that she is, pregnant.
Use in lactation
No information is available regarding the excretion of Hyalgan in breast milk. Caution should be exercised when Hyalgan is administered to a nursing mother and the expected benefit to the mother should be weighed against any potential risk to the neonate.
Effects on ability to drive and use machines:
Hyalgan is not expected to affect the ability of the patient to operate machinery or drive a motor vehicle. However, it is recommended to watch for any signs of discomfort following the intra-articular administration.
Adverse Effects
Analysis of the adverse events that have been reported with the use of Hyalgan reveals that most of the events are related to local symptoms such as pain, swelling/effusion and warmth or redness at the injection site.
Local or systemic allergic reactions due to individual hypersensitivity have been rarely recorded. Isolated cases of an anaphylactic-like reaction have been reported (0.0002% of the total population treated) in post-marketing experience and they had favourable outcomes. No case of anaphylactic-like reactions has been reported during clinical trials.
In a 495-patient US multicentre placebo- and naproxen- controlled clinical study, the following adverse events occurred with a frequency greater than 5% in the Hyalgan group (versus placebo): headache 18% (17%), rash 7% (9%), ecchymosis 7% (6%) and pruritus 7% (4%). As these events occurred with equal frequency in the placebo group, there is no proven causality in respect of Hyalgan.
Interactions
There are currently insufficient data to support the compatibility of Hyalgan with other drugs administered intra-articularly. Since there is limited experience available, Hyalgan should not be intra-articularly administered simultaneously or mixed with other products.
Do not use concomitantly with disinfectants containing quaternary ammonium salts because hyaluronic acid can precipitate in their presence.
Overdosage
Overdosage is unlikely given the route of administration and the single use pack of the drug. No case of overdosage has been reported to date.
Pharmaceutical Precautions
Storage The shelf life of the packaged product is 3 years. Do not use Hyalgan if package is opened or damaged. Store in original packaging (protected from light) below 25°C. Do not freeze. Discard any unused portion of Hyalgan.
Medicines Classification
General sale Medicine
Package Quantities
1 vial,
1 pre-filled syringe
Further Information
The inactive ingredients are sodium chloride, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate and water for injection. Hyaluronic acid CAS number: 9004-61-9.
Name and Address
Douglas Pharmaceuticals Ltd
PO Box 45-027
Auckland 0651
New Zealand
Ph: (09) 835-0660
Fax: (09) 835-0665
Date of Preparation
06 September 2005