Hyalgan fidia solution for intra-articular administration 20 mg/2ml N1 syringe

Description:

Hyalgan Fidia is a product for intra-articular administration containing a solution of sodium hyaluronate.
The solution is injected by the doctor directly into the diseased joint and ensures the restoration of intra-articular fluid, thereby helping to cope with pain and impaired joint mobility due to osteoarthritis or after injury. In our pharmacy, the drug Gialgan Fidia is sold in an easy-to-use form - a filled syringe. The needle for administering the drug is selected by the doctor individually depending on the size of the joint and the patient’s build.

Pharmachologic effect:

Hyaluronic acid is an essential component of the extracellular matrix and is present in high concentrations in articular cartilage and synovial fluid. Endogenous hyaluronic acid provides viscosity and elasticity to synovial fluid, and is also necessary for the formation of proteoglycans in articular cartilage.

With osteoarthritis, there is a deficiency and qualitative changes in hyaluronic acid in the composition of synovial fluid and cartilage. Intra-articular administration of hyaluronic acid against the background of degenerative changes in the surface of synovial cartilage and pathology of synovial fluid leads to an improvement in the functional state of the joint.

When using Gialgan Fidia, there is an improvement in the clinical course of osteoarthritis within 6 months from the date of treatment, and an anti-inflammatory and analgesic effect is observed.

Hyalgan 20 mg/2 ml No. 1 solution for intra-articular administration in a syringe

Instructions for medical use of the drug Gialgan® Trade name Gialgan® International nonproprietary name No Dosage form Solution for intra-articular administration, 20 mg/2 ml 2.0 ml Composition active substance - sodium hyaluronate 20.00 mg, excipients: sodium chloride, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate , water for injections. Description Colorless, transparent viscous solution. Pharmacotherapeutic group Drugs for the treatment of diseases of the musculoskeletal system. Other drugs for the treatment of diseases of the musculoskeletal system. Hyaluronic acid. ATC code M09AX01 Pharmacological properties Pharmacokinetics The sodium salt of hyaluronic acid, when administered intra-articularly, is eliminated from the synovial fluid within 2-3 days. Pharmacokinetic studies have shown rapid distribution of the substance in the synovial membrane. The highest concentrations of labeled hyaluronic acid were found in the synovial fluid and joint capsule, lower concentrations in the synovial membrane, ligaments and adjacent muscles. Hyaluronic acid in synovial fluid does not undergo significant metabolic changes. Experimental models have established that metabolism occurs mainly in the periarticular tissues and liver, excretion is mainly carried out by the kidneys. Pharmacodynamics Hyalgan® is a sterile, pyrogen-free, viscous buffered aqueous solution of a highly purified sodium salt fraction of hyaluronic acid with a molecular weight of 500 to 730 kDa. Hyaluronic acid is an essential component of the extracellular matrix and is present in high concentrations in articular cartilage and synovial fluid. Endogenous hyaluronic acid provides viscosity and elasticity to synovial fluid, and is also necessary for the formation of proteoglycans in articular cartilage. With osteoarthritis, there is a deficiency and qualitative changes in hyaluronic acid in the composition of synovial fluid and cartilage. Intra-articular administration of hyaluronic acid against the background of degenerative changes in the surface of synovial cartilage and pathology of synovial fluid leads to an improvement in the functional state of the joint. When using Gialgan®, there is an improvement in the clinical course of osteoarthritis within six months from the date of treatment, and an anti-inflammatory and analgesic effect is observed. Indications for use - osteoarthritis and post-traumatic changes in joints - pain relief and improvement of joint mobility - as an adjuvant in orthopedic surgery. Method of administration and dosage: Intra-articular. The contents of one filled syringe (20 mg/2 ml) should be injected into the knee and hip joints once a week, in a course of 5 injections according to the standard method. Method of administration Before administering Gialgan®, the effusion from the joint capsule should be removed. The drug should be administered precisely into the joint cavity using standard methods, taking into account the anatomical features. The same needle can be used to remove the effusion and administer the drug, inserted once before aspiration. In this case, the syringe with the drug is attached to the needle freed from the syringe with aspirated liquid. To confirm that the needle is in the joint cavity, an available amount of synovial fluid should be aspirated before slowly injecting the drug. The rules of asepsis and antisepsis should be observed when performing the procedure. Administration of the drug into the joint cavity should be stopped if pain occurs during injection. Avoid getting air into the syringe with the drug. The drug, which has not been completely used, cannot be stored. Side effects Rarely - moderate pain, joint swelling, increased exudate in the joint cavity, increased temperature and redness in the injection area. The above symptoms are transient and usually disappear after 24 hours. If these symptoms occur, it is recommended to unload the affected joint and apply ice. In isolated cases - allergic (itching, skin rash, urticaria) and anaphylactic reactions Contraindications - hypersensitivity to the components of the drug or bird proteins - severe liver pathology - infection or damage to the skin in the injection area Drug interactions Gialgan® should not be prescribed simultaneously with other intra-articular injections, due to the lack of significant experience. Disinfectants containing quaternary ammonium salts should not be used, since hyaluronic acid precipitates in the presence of these substances. Special instructions During the first 2 days after the procedure, it is recommended not to overload the joint, especially prolonged loading should be avoided. When obtaining aspiration fluid, appropriate studies should be carried out before administering the drug to exclude a bacterial etiology of arthritis. Do not use Hyalgan® with damaged or opened packaging. Pregnancy and lactation should not be used during pregnancy or breastfeeding. Pediatric Use: Should not be used in children due to lack of clinical data. Peculiarities of influence on the ability to drive a vehicle or potentially dangerous mechanisms Gialgan® does not affect a person’s ability to engage in potentially hazardous activities that require increased concentration and speed of psychomotor reactions. However, given the effect of the drug on the functions of the joints of the lower extremities, you should refrain from driving for the first 2 days after the injection. Overdose There have been no cases of overdose. RELEASE FORM AND PACKAGING SOLUTION FOR INTRA-ARTICULAR ADMINISTRATION. 2.0 ML IN CLEAR GLASS SYRINGES TYPE I, SEALED WITH A RUBBER CAP. 1 SYRINGE TOGETHER WITH INSTRUCTIONS FOR USE IN THE STATE AND RUSSIAN LANGUAGES IS PLACED IN A PACK OF CARDBOARD. STORAGE CONDITIONS AT TEMPERATURES NOT HIGHER THAN 25 °C. DO NOT FREEZE. KEEP OUT OF THE REACH OF CHILDREN! SHELF LIFE IS 3 YEARS IN ORIGINAL PACKAGING DO NOT USE AFTER THE EXPIRATION DATE STATED ON THE PACKAGING. CONDITIONS FOR DISCHARGING FROM PHARMACIES ACCORDING TO A PRESCRIPTION MANUFACTURER/PACKAGER FIDIA PHARMACEUTIS S.P.A. 35031, ABANO TERME, VIA PONTE DELLA FABBRICA, Z/A, ITALY REGISTRATION AUTHORITY HOLDER FIDIA PHARMACEUTISI S.P.A. 35031, ABANO TERME, VIA PONTE DELLA FABBRICCA, Z/A, ITALY ADDRESS OF THE ORGANIZATION RECEIVING CLAIMS FROM CONSUMERS ON THE QUALITY OF PRODUCTS (GOOD) LLP IN THE TERRITORY OF THE REPUBLIC OF KAZAKHSTAN FIDIA PHARMA KAZAKHSTAN REPUBLIC KAZAKHSTAN, ALMATY, Ave. AL-FARABI 7, NURLY-TAU ADMINISTRATIVE RESIDENTIAL COMPLEX, BLOCK 4A, OFF. 6 TEL/FAX, 311 02 53 EMAIL ADDRESS

Directions for use and dosage:

The drug is intended for intra-articular administration.

The drug is administered to the knee and hip joints in a dose of 20 mg once a week (contents of 1 filled syringe). The course consists of 3-5 injections.

Rules for administering the drug

The rules of asepsis and antisepsis should be observed when performing the procedure.

Before administering Gialgan Fidia, effusion from the joint capsule should be removed. The drug should be administered precisely into the joint cavity using standard methods, taking into account the anatomical features. To remove the effusion and administer the drug, you can use the same needle, inserted once before aspiration. In this case, the syringe with the drug should be attached to the needle, freed from the syringe with the aspirated liquid. To confirm that the needle is in the joint cavity, an available amount of synovial fluid should be aspirated before slowly injecting the drug. Injection of the drug into the joint cavity should be stopped if pain occurs during injection.

Avoid getting air into the syringe with the drug.

The drug remaining in the syringe cannot be stored.

Use of the drug Gialgan Fidia for osteoarthritis of the knee joints

The review presents clinical studies of hyaluronic acid preparations in the treatment of osteoarthritis of the knee joints in comparison with traditional treatment using non-steroidal anti-inflammatory drugs. Results from studies, including our own open-label 12-month trial, indicate that Gialgan Fidia improves clinical outcomes and has long-lasting benefits in patients with knee osteoarthritis.

Table 1. Controlled studies of Hyalgan compared with placebo

Table 2. Dynamics of Gialgan’s effectiveness indicators in patients with gonarthrosis

Rice. Dynamics of the WOMAC functional index

Diseases of the musculoskeletal system are widespread in a wide variety of populations. Osteoarthritis (OA) occupies a leading position among this group of diseases as the most common cause of temporary disability and disability in patients.

The incidence of OA among the adult population is up to 14%, with the most common localization of the pathology being OA of the knee joints [1]. According to KM Jordan et al., the frequency of arthroplasty operations among patients over 65 years of age suffering from gonarthrosis averages 0.5–0.7 per 1000 people per year [2]. Unfortunately, statistics of recent decades indicate a constant increase in the number of patients with OA, which is explained, along with improved diagnosis of the disease, an increase in the life expectancy of the population and the accumulation of risk factors for the disease, especially obesity.

Currently, OA is considered as an organ pathology, since all tissues of the joint are involved in the pathological process: cartilage, subchondral bone, synovial membrane, capsule, ligaments and periarticular muscles. One of the mechanisms for the development of OA is an imbalance between the processes of matrix degradation and its formation: there is a disruption in the synthesis of the main components of the matrix by chondrocytes - proteoglycans and type II collagen - and/or their increased catabolism. An important role in the pathogenesis of OA is played by the increased production of pro-inflammatory cytokines by chondrocytes - interleukins (IL-1, IL-6), tumor necrosis factor alpha (TNF-α), nitric oxide, cyclooxygenase-2, which are involved in the degradation of cartilage [3] .

Cartilage degradation products enter the synovial fluid and, having antigenic properties, provoke inflammation of the synovial membrane. This leads to disruption of metabolic processes in synoviocytes, as a result of which the formation of synovial fluid and hyaluronic acid (HA) suffers. In addition, synovial cells produce inflammatory mediators that contribute to increased vascular permeability and increased plasma transfusion into synovial fluid. All these processes lead to a decrease in the concentration of HA and a decrease in the viscoelastic and lubricant properties of the synovial fluid [4, 5].

The role of hyaluronic acid in cartilage trophism and regulation of the environment in the joint cavity

HA is an organic compound that is present in the intercellular matrix of almost any tissue of the human body and is one of the main components of connective tissue. According to the chemical structure, HA is a heteropolysaccharide (glucosaminoglycan), the monomer of which is a disaccharide consisting of D-glucuronyl and DN-acetylglucosamine, interconnected by glycosidic bridges. A HA molecule can contain up to 25,000 disaccharide units. This long, unbranched chain of disaccharides forms the axis of a giant proteoglycan molecule, which, along with collagen, is the main biopolymer of connective tissue, including articular cartilage.

HA in linear form is secreted by synoviocytes into the joint cavity, where its macromolecules provide the unique viscoelastic properties of normal synovial fluid, which without HA is a simple plasma dialysate.

HA plays a key role in cartilage trophism and regulation of the environment in the joint cavity. At the level of macrohomeostasis, HA, which is constantly present on the surface of the articular cartilage and synovial membrane, prevents friction of the contacting surfaces. Due to its viscoelastic properties, HA is able to reduce mechanical stress on articular surfaces. At the level of mini-homeostasis, HA ensures the diffusion of nutrients and metabolic products between synovial fluid and articular cartilage, chondrocytes and cartilage matrix, proteoglycans and cartilage collagen, and regulates lymph circulation. In addition, HA molecules help neutralize and remove free radicals, and, accordingly, stabilize cell membranes, protect chondrocytes and synoviocytes from the effects of catabolic enzymes, desensitize sensory receptors (including pain ones), and create an optimal environment for synthetic processes [6].

Maintaining the homeostasis of synovial fluid and hyaline cartilage largely depends on the presence in the synovial fluid of the required concentration of HA (normally it ranges from 2.5 to 3.5 mg/ml) with an optimal molecular weight (from 500 to 3000 kDa). In OA, the concentration of HA in the synovial fluid decreases by 2–3 times compared to the normal level, which leads to a decrease in the viscoelastic and shock-absorbing properties of the synovial fluid. It was found that during acute and chronic inflammatory processes in the joint, the size of HA molecules decreases. Thus, according to C. Belcher et al. (1997), in the synovial fluid of patients with gonarthrosis, the concentration of GC, glycosaminoglycans and keratan sulfate is lower than in healthy people. In addition, animal experiments have demonstrated that proinflammatory cytokines, in particular IL-1 and TNF-α, stimulate the expression of hyaluronan synthetase, which causes HA fragmentation and progression of cartilage destruction. These changes lead to an increase in static and dynamic load on the articular surfaces. The joint becomes more vulnerable to traumatic influences, which, in turn, accelerates degenerative changes and is clinically manifested by pain and limitation of movements in the joint. These data served as the basis for the creation of exogenous HA preparations with structure-modifying properties that are injected into the OA-affected joint.

The mechanism of action of exogenous GC in the joint is not clear enough. There is no doubt that the viscoelastic properties of the synovial fluid are improved, but the presence of other mechanisms cannot be ruled out. Thus, the lifetime of the injected drug in the joint cavity ranges from several hours to several days, and the clinical effect lasts for several months. It is assumed that the mechanisms of “replenishment of elasticity” are associated with anti-inflammatory and antinociceptive effects, as well as stimulation of the synthesis of endogenous GC by externally administered drugs [7].

A large number of studies conducted in vitro and in vivo have shown that HA is able to induce aggregation and synthesis of proteoglycans, modulate the inflammatory response, reduce chemotaxis and the effect of superoxide anion radicals [8–13]. The presence of chondroprotective effect of GC was proven in an in vitro study by K. Fukuda et al. (1997), which showed that fluorescein-labeled HA is able to penetrate cartilage tissue and stimulate the synthesis of endogenous proteoglycans.

Experience in the use of hyaluronic acid preparations in medical practice

The first hyaluronic acid preparation used in medical experimental practice was hyaluronan, which appeared in the 1960s. The next generation of drugs in this group were hylans, developed in the 1980s, and later other drugs with different molecular weights appeared.

In the 80–90s. XX century A significant number of papers have been published in which the authors presented their experience of using a particular drug. Critical comparisons between them are difficult due to the fact that the studies used drugs with different molecular weights, different modes of their administration, a small number of subjects participated, there was no placebo control, in addition, there may be other factors that can significantly affect the results of the studies .

If we do not take into account some of the difficulties that arise when studying the effectiveness of intra-articular administration of GC drugs, the results of a large number of studies indicate a decrease in pain and restoration of joint function during therapy with GC drugs.

The effectiveness of GC drugs has been shown in many placebo-controlled studies. E. George in 1998 published the results of a meta-analysis of 43 studies of GC (6000 patients) [20], according to which the drug showed statistically significant effectiveness compared with placebo (p

A 2006 Cochrane systematic review, which included 76 clinical studies, found a significantly significant improvement with the introduction of GC compared to placebo in the main indicators: pain at rest and during exercise (VAS), WOMAC and Lequesne indices [14]. GC has been shown to have a longer lasting effect compared to corticosteroids when administered intra-articularly. Thus, the duration of the effect in most patients after completing the course of administration of GC drugs ranged from 4 months to 1 year, while the effect from intra-articular administration of corticosteroids was no more than 4 weeks.

The comparative effectiveness of GC and intra-articular corticosteroids has been studied in several studies. G. Leardini et al. were one of the first to conduct such a study (three injections of the drug Hyalgan every 1 week), the results of which a week after the end of treatment showed that the analgesic effect of GC was similar to the effect of 40 mg of methylprednisolone; at the end of the observation period (45 days after the end of treatment), there was a significant decrease in all pain parameters in patients who received GC. Both treatment options were well tolerated, as no local or systemic side effects were observed [17].

Similar results were obtained by V. Pietrogrande et al. [18]. Later, AC Jones et al. (1995) and L. Frizziero et al. (2001) compared the effect of intra-articular GC and triamcinolone hexacetonide in OA of the knee joint in a double-blind manner. At the treatment stage for 5 weeks, there were no significant differences in pain, functional joint mobility, or the need for NSAIDs in the groups, however, at a subsequent 6-month follow-up, the severity of pain was lower in patients receiving GC. A similar trend was observed for other criteria, which allowed the researchers to conclude that the administration of GCs may be a therapeutic alternative to corticosteroids for gonarthrosis [19].

Summarizing the data from experimental and clinical studies of the use of various GC drugs, VM Goldberg and JA Buckwalter in their review in 2005 concluded that the drugs have a structure-modifying effect and are capable of influencing the course of the disease, but the mechanisms of action have not yet been fully elucidated [22 ]. In 2000, the American College of Rheumatology included GC drugs in the recommendations for the treatment of gonarthrosis.

Further, in the review by D. Brzusek and D. Petron, analyzing a number of randomized placebo-controlled studies, the effectiveness and safety of therapy with GC drugs was confirmed, including when compared with various NSAIDs. The authors concluded that GC can be considered as a worthy alternative to NSAIDs; it was emphasized that, compared with NSAIDs, GC preparations do not have the risk of developing cardiovascular, gastrointestinal and renal complications [15].

The clinical effectiveness of GCs was demonstrated in a meta-analysis by CT Wang et al., which included 20 randomized clinical trials (RCTs) in patients with knee OA [23]. Data from these RCTs demonstrated that administration of high- and low-molecular-weight HA significantly reduced pain and improved function of the knee joints, but high-molecular-weight HA had a better therapeutic effect compared with low-molecular-weight HA.

Further study of the physiological, pharmacological and clinical properties of GCs has led to the assumption that the original concept of “viscoelasticity” [24, 25] as a mechanism of action of GCs is insufficient to explain the long-term clinical effects of such therapy. The hypothesis that the molecular weight of GC is the main factor in its clinical effectiveness has been questioned [26]. AD Aviad and JB Houpt suggested that the concentration of HA is more important than its molecular weight. A systematic review of five meta-analyses by JG Divine et al found that administration of low- and high-molecular-weight GCs showed similar results. All drugs are effective in reducing symptoms of knee OA in terms of pain, swelling and stiffness. No advantages of one drug over another were noted, although it was emphasized that the analyzed works are difficult to compare [27]. However, in preclinical studies assessing structural changes in joint tissue, it was shown that it is low-molecular-weight GCs that have a more pronounced effect in relation to disease modification.

Many authors report a good effect of therapy in most patients with repeated administrations of the drug after an average of 4–8 months [28–34].

Currently, a number of HA preparations with different molecular weights are used, which are obtained by different methods: the bacterial fermentation method (HA of non-animal origin - Orthovisc, Fermatron, Ostenil), the NASHA™ method (Non-Animal Stabilized Hyaluronic Acid - Durolan) and the extraction method from biological material (cockscombs), which is used for the production of the drug Gialgan (Fidia Pharmaceutical S.p.A., Italy).

The drug Gialgan Fidia is a concentrated (2 mg/2 ml) viscous solution of HA with a high degree of purification (molecular weight 500–730 kDa). Sodium salt of HA is the only active ingredient of Gialgan Fidia. The drug is well absorbed and retained in the layer of synovial cells and cartilage, distributed in the reticuloendothelial system, metabolized in the liver and excreted in the urine and through sweating. There is no data on the biological accumulation of the drug in the body. Gialgan Fidia has been used in clinical practice since 1987 and is registered in 80 countries. In our country, it has been used since 2009. In Russia, it is the only HA drug registered as a medicine.

The effectiveness and safety of the drug Gialgan was studied in randomized placebo-controlled studies (Table 1) for OA of the knee and other joints. Two studies were blinded and seven were double-blind. HA injections were performed at 1-week intervals. In a dose-response study conducted by A. Bragantini et al., 2 ml and 4 ml of HA or placebo were administered [35]. No differences were observed between the two dosing regimens. Pain scores in both GC groups significantly decreased compared to the placebo group throughout the observation period.

In one study, EB Henderson et al. showed no differences between Gialgan and placebo [36]. After a washout period from NSAIDs for two weeks, patients received five weekly injections of GC or placebo. The study included 91 patients and assessed them at the end of the treatment period (5 weeks) and after 5 months. The outcome measure was pain assessment (VAS). There were no significant differences between groups at the 5-week and 5-month assessments. However, in patients in the GC group compared to the placebo group, the need for NSAIDs appeared much later after therapy. The results obtained are explained by the incorrect design of this study: the first assessment was performed at the end of the course of therapy, which is obviously early for the development of the effect of GC; the number of patients was insufficient to detect between-group differences in pain scores (VAS); At the 5-month pain assessment, 38% of patients were unavailable for follow-up, resulting in non-comparable groups.

M. Carrabba et al. [40] studied the optimal regimen for using Gialgan. The double-blind study of Gialgan compared one, three and five weekly injections of the drug with placebo and arthrocentesis, as it was shown that any intra-articular intervention can lead to clinical improvements in OA. Three and five injections of Gialgan were significantly more effective than one injection of the drug, placebo and arthrocentesis. Although no statistically significant differences were found between three and five injections, there was a trend indicating that five injections were more effective. These results allowed the authors to suggest that the optimal number of Gialgan injections is from three to five.

Other placebo-controlled studies showed a statistically significant reduction in pain, improvement in the Lequesne index, and a reduction in the need for NSAIDs and intra-articular corticosteroid injections in patients receiving GCs compared with placebo [21, 37–42].

A comparative study of three injections of Hyalgan and methylprednisolone 40 mg in 36 patients after 2 months and 12 months, conducted by G. Lenardini et al., showed their equal effectiveness in reducing pain intensity, pain during exercise and improving the functional state of the joints [43]. D. D. Guidolin et al. compared five weekly injections of Hyalgan with three weekly injections of methylprednisolone 40 mg/ml in 59 patients for clinical and morphological changes. Assessments included clinical parameters (VAS pain, joint function and joint effusion) and anatomical lesions assessed by arthroscopy and histological analysis of biopsy material. Anatomical assessments were performed under blinded conditions. The authors concluded that after 6 months, both drugs reduced cartilage damage and inflammation in the synovium, and the improvement in clinical parameters of therapy was almost the same in both groups [44].

In another double-blind study, AC Jones et al. compared five injections of GC with one injection of the longest-acting corticosteroid, triamcinolone hexacetonide (TH), and four injections of placebo in 63 patients with inflammatory knee effusion [45]. Assessments included VAS pain scores, duration of stiffness, joint functional status, and presence of joint effusion. After a week, TG had a more pronounced effect on pain, functional state of the joint and reduced the need for NSAIDs compared to GC. From the 5th week until the end of the observation period (6 months), GC was more effective in all clinical parameters. However, because a significant number of patients lost follow-up after 4 months, the between-group differences decreased by the end of the study.

In the ongoing open-label studies [46–48], where the observation period after therapy was short (4 weeks), the same trend was observed as in the blinded studies: a short but more pronounced anti-inflammatory effect of corticosteroids, followed by a significant and longer-lasting superiority of Hyalgan from the beginning. from the 21st and 28th day. Based on data from a preliminary study by G. Grecomoto et al., the addition of dexamethasone to the first of five HA injections resulted in better clinical results.

In a double-blind 6-month study, RD Altman et al. compared Hyalgan with placebo and naproxen at a dose of 1000 mg/day [42]. Patients in the naproxen group received a local subcutaneous injection of lidocaine. Aspiration of synovial fluid was performed only in cases of clear evidence of joint effusion. Analysis of the effectiveness of therapy in patients who completed the study showed that naproxen was more effective than GC at week 2. However, from weeks 4 to 26, HA was equally effective as naproxen in reducing pain.

From 1987 to 2010, 84 clinical studies of Hyalgan Fidia for various joints were conducted (46 placebo-controlled, 34 uncontrolled, 4 post-marketing), involving 13,000 patients. As most clinical studies show, the development of the effect begins 2–4 weeks after the administration of Gialgan and continues for 6–12 months.

Is Hyalgan a structure-modifying drug for OA? In vitro studies in OA suggest that HA, with a molecular weight of 500–730 kDa, may be a potential structure-modifying drug. Four studies were conducted that examined the structure-modifying effect of the drug Hyalgan in OA of the knee joints [44, 49–52].

A double-blind, controlled, randomized study lasting 1 year was conducted by V. Listrat et al. [49] in 39 patients with knee OA. After lavage of the joint cavity (2 ml of saline) during arthroscopy, patients were divided into two groups, one of which received 3 injections of HA at weekly intervals. Each course of HA injections was repeated once every 3 months (9 injections in total). Patients were assessed using the following criteria: pain VAS, Lequesne index and the French version of the Arthritis Impact Measurement Scale (0AIMS2). The structural-modifying effect was assessed by the degree of joint space narrowing during anteroposterior radiography of the knee joint during loading and during arthroscopic examination. Baseline and final assessments were recorded on various videotapes, which were reviewed by a physician blinded to patient information and the chronology of the tapes. The results showed the presence of significantly fewer pathological changes in structural parameters in the GC group compared to the control group.

In 1998, L. Frizziero et al. evaluated clinical and morphological changes in the condition of the knee joints after five weekly injections of the drug Hyalgan in 40 patients in an open study. Assessments were carried out using microarthroscopic and morphological analyzes of biopsy material obtained at baseline and after 6 months of follow-up. All histological samples were analyzed in a blinded manner. According to the data obtained, the majority of patients (60%) did not reveal any microscopic changes in the cartilage tissue, in 32.5% there was a decrease in the degree of cartilage damage: compared with the initial values, the condition of the surface amorphous layer of cartilage was restored (p = 0.0039), increased chondrocyte density (p = 0.0023) and their viability (p = 0.05). These changes were accompanied by a significant decrease in inflammation in the synovium (p = 0.001). These results were confirmed by morphological assessment. Clinically, patients noted a decrease in pain at rest and during exercise, an improvement in the functional state of the joints and a decrease in the amount of effusion starting from 35 days until the end of observation. Deterioration was noted in only 7.5% of patients [16].

To confirm the structure-modifying effect of the drug Gialgan, a double-blind, placebo-controlled study was conducted, which included 408 patients with OA of the knee joints [52]. Injections of Gialgan or placebo were carried out 3 times at weekly intervals. The assessment of the structural effect was carried out radiographically before the start of therapy and after 1 year. 319 people completed the study, and 273 patients underwent dynamic radiography. These studies showed that the mean reduction in joint space width was significantly less in the GC group than in the placebo group: -0.13 + 1.1 mm compared with -0.5 + 1.0 mm, respectively (p = 0.02 ) in patients with an initial joint space size greater than the median. As previously noted in the study by V. Listrat et al., these results confirm that intra-articular administration of HA with a molecular weight of 500–730 kDa in OA of the knee joints can have a structure-modifying effect [49].

Gialgan's tolerability is generally very good. Local reactions are relatively rare. Thus, AS Dixson et al. [38] noted reactions in the form of redness and moderate pain in the knee joint, which spontaneously resolved within 1–3 days in only 1–2% of patients. One case of hemarthrosis, accompanied by signs of inflammation, was described after one of the injections. M. Dougados et al. [39] reported an equal frequency (33%) of local reactions in the GC and placebo groups, EB Henderson et al. [36] observed more frequent local reactions in the GC group compared with placebo (47% and 22%, respectively). RD Altman et al. [42] reported that 23% of patients receiving GC complained of injection site pain compared with 13% of patients receiving placebo and 9% of patients receiving naproxen (sham injection). In another open-label study lasting 30 months (a course of 5 HA injections), adverse reactions in the form of local swelling and mild pain in the knee joint were noted in only five patients out of 75 (6%) [53].

The drug Gialgan has been used for intra-articular administration since 1987. According to estimates as of May 2010, the drug was received by more than 6,500,000 patients with primary and secondary OA of the knee joints and during orthopedic surgical interventions. During this period, there were 997 health professional-verified reports of adverse events (AEs) in 344 patients (0.01%) from commercial use of the drug (Fidia Pharmaceutici S.p.A., unpublished data). The most common AEs were local and minor. At the same time, 5.9% of patients had local swelling and 6.3% had pain at the injection site. In 9.4% of patients, AEs were associated with intra-articular effusion. Signs and symptoms of allergy, such as pruritus, rash, erythema and urticarial rash, were extremely rare. There are no reports of the development of inflammatory reactions after the use of Gialgan.

Results of an open study of the effectiveness and safety of the drug Gialgan Fidia

We conducted a multicenter, open-label, 12-month study of the efficacy and safety of Gialgan Fidia in patients with primary OA of the knee joints. The study involved 47 patients of both sexes (34 women and 13 men) aged 45–70 years (mean age 58.8 ± 11.6) with gonarthrosis of stages I, II, III according to Kellgren – Lawrence. All patients met the American College of Rheumatology diagnostic criteria for OA. The intensity of pain when walking corresponded to 40 mm or more (VAS); patients regularly took NSAIDs for 30 days in the last 3 months before the study. All patients signed informed consent to participate in the study. Exclusion criteria were the presence of synovitis, osteonecrosis of the articular surfaces, intra-articular administration of any drugs within the previous 6 weeks, varus/valgus alignment of the joint (more than 15 degrees), therapy with slow-acting drugs for OA (4 months before the start of therapy), history of surgery on the target joint . Hyalgan was administered 4 times (once a week). The duration of observation was 12 months, patients were examined 4, 12, 24 and 48 weeks after drug administration (Table 2).

The treatment effectiveness was assessed according to the currently generally accepted criteria for evaluating drugs for the treatment of OA: the WOMAC index, assessment of the effect of therapy by the doctor and the patient (improvement, significant improvement, no effect, worsening), daily requirement for NSAIDs. These parameters were analyzed before the start of treatment (Visit 1) and at each subsequent visit. AEs, assessment of the effectiveness of treatment and the daily requirement for NSAIDs were recorded at each follow-up visit. 35 patients had various concomitant diseases, the most common of which were: arterial hypertension - in 30 (63.8%) patients, coronary heart disease - in 7 (14.8%), type 2 diabetes mellitus - in 6 (12.8%), 6%), varicose veins of the lower extremities – in 4 (8.4%), duodenal ulcer – in 1 (2.1%). All 47 patients completed the study. Analysis of the results showed the presence of a significant analgesic effect already 1 month after administration of the drug, which persisted until the end of observation. A statistically significant reduction in stiffness was noted at the end of the course of Gialgan administration and at the last visit. A significant improvement in the functional state of the joints and a decrease in the total WOMAC index were observed after 1 month of therapy (Visit 2) and persisted for 12 months (see figure).

The drug was generally well tolerated. AEs were reported in 3 patients. 1 patient had pain in the knee joint after administration of the drug, 1 patient developed synovitis on the 4th day, and 1 patient had redness of the skin at the injection site. 94% of patients noted the tolerability of the drug as “good” and only 6% of patients as “satisfactory”.

Patient and physician assessments of treatment effectiveness were virtually identical. Improvement at the end of the observation period after 12 months was observed in 96% (45 patients), and no effect – in 4% (2 patients).

Reducing the severity of pain made it possible to gradually reduce the need for NSAIDs in 28 patients (58.8%), discontinue NSAIDs in 15 people (32%), and only in 4 patients the dose of NSAIDs remained the same.

Thus, Gialgan Fidia is an effective, safe and long-acting drug for OA of joints of various locations. The effectiveness of Gialgan has been confirmed by numerous clinical studies. The development of the effect begins 2–4 weeks after the administration of Gialgan and continues for 6–12 months. The optimal number of Gialgan injections is from three to five.

Special instructions:

During the first 2 days after the procedure, it is recommended not to overload the joint, especially prolonged activity should be avoided.

When obtaining aspiration fluid, appropriate studies should be carried out before administering the drug to exclude a bacterial etiology of arthritis.

Use in pediatrics: due to the lack of clinical data on use in pediatrics, the drug should not be prescribed to children.

Effect on the ability to drive vehicles and operate machinery: Gialgan Fidia does not affect the ability to drive vehicles and other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Gialgan Fidia, solution for intra-articular injection. 20mg fl 2ml (Fidia Pharmaceutical S.p.A., ITALY)

Composition and release form.

bottles: 2 ml in bottles of colorless borosilicate glass type I, sealed with rubber stoppers, varnished aluminum caps and removable plastic seals; 1 or 5 bottles with instructions for use are placed in a cardboard box.

syringes: 2 ml in sterile syringes of colorless borosilicate glass type I, with rubber stoppers on which polypropylene pistons are fixed; syringes are equipped with luer locks to protect the needle; 1 or 5 syringes, each of which is placed in a blister pack made of PVC and paper, placed in a cardboard box with instructions for use.

Description of the dosage form.

Colorless transparent viscous solution.
Pharmachologic effect. Analgesic, corrective metabolism of bone and cartilage tissue, anti-inflammatory.

Pharmacodynamics.

Hyalgan Fidia is a sterile, pyrogen-free, viscous buffered aqueous solution of a highly purified sodium salt fraction of hyaluronic acid with a molecular weight of 500 to 730 kDa. Hyaluronic acid is an essential component of the extracellular matrix and is present in high concentrations in articular cartilage and synovial fluid. Endogenous hyaluronic acid provides viscosity and elasticity to synovial fluid, and is also necessary for the formation of proteoglycans in articular cartilage. With osteoarthritis, there is a deficiency and qualitative changes in hyaluronic acid in the composition of synovial fluid and cartilage. Intra-articular administration of hyaluronic acid against the background of degenerative changes in the surface of synovial cartilage and pathology of synovial fluid leads to an improvement in the functional state of the joint. When using Gialgan Fidia, there is an improvement in the clinical course of osteoarthritis within six months from the date of treatment, and an anti-inflammatory and analgesic effect is observed.

Pharmacokinetics.

When administered intra-articularly, the sodium salt of hyaluronic acid is eliminated from the synovial fluid within 2–3 days. Pharmacokinetic studies have shown rapid distribution of the substance in the synovial membrane. The highest concentrations of labeled hyaluronic acid were found in the synovial fluid and joint capsule, lower concentrations in the synovial membrane, ligaments and adjacent muscles.

Hyaluronic acid in synovial fluid does not undergo significant metabolic changes. In experimental models, the main metabolism occurs in the periarticular tissues and liver, excretion is mainly carried out by the kidneys.

Indications.

● osteoarthritis and post-traumatic changes in joints;

● pain relief and improvement of joint mobility;

● as an aid in orthopedic surgery.

Contraindications.

● established hypersensitivity to the components of the drug or avian proteins;

● severe liver pathology;

● the presence of infection or damage to the skin in the injection area.

Use during pregnancy and breastfeeding.

Should not be used during pregnancy, breastfeeding or children due to the lack of clinical data.

Side effects.

Rarely, moderate transient pain, swelling, increased exudate in the joint cavity, increased temperature and redness in the injection area may occur. The above symptoms are transient and usually disappear after 24 hours. If these symptoms occur, it is recommended to unload the affected joint and apply ice.

There have been isolated cases of allergic reactions (itching, rash, urticaria) and anaphylactic reactions to the drug.

Interaction.

Gialgan Fidia should not be prescribed concomitantly with other intra-articular injections due to the lack of significant experience.

Disinfectants containing quaternary ammonium salts should not be used, since hyaluronic acid precipitates in the presence of these substances.

Method of administration and dose.

Intra-articular.

The contents of one bottle (20 mg/2 ml) or a filled syringe (20 mg/2 ml) should be administered into the knee and hip joints once a week, in a course of 5 injections according to the standard method.

Method of administration

Before administering Gialgan Fidia, effusion from the joint capsule should be removed. The drug should be administered precisely into the joint cavity using standard methods, taking into account the anatomical features. The same needle can be used to remove the effusion and administer the drug, inserted once before aspiration. In this case, the syringe with the drug is attached to the needle freed from the syringe with aspirated liquid. To confirm that the needle is in the joint cavity, an available amount of synovial fluid should be aspirated before slowly injecting the drug. The rules of asepsis and antisepsis should be observed when performing the procedure. Administration of the drug into the joint cavity should be stopped if pain occurs during injection. Avoid getting air into the syringe with the drug. The drug, which has not been completely used, cannot be stored.

Overdose.

There have been no cases of overdose.

Special instructions.

During the first 2 days after the procedure, it is recommended not to overload the joint, especially prolonged loading should be avoided. When obtaining aspiration fluid, appropriate studies should be carried out before administering the drug to exclude a bacterial etiology of arthritis.

Gialgan Fidia does not affect a person’s ability to drive vehicles or engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Do not use Gialgan Fidia with damaged or opened packaging.

Conditions for dispensing from pharmacies.

On prescription.