Ostenil Plus

Clear, colourless, viscoelastic, sterile solution.
Each pre-filled syringe contains 40 mg/2 mL of sodium hyaluronate obtained by biofermentation. Sodium hyaluronate in OSTENIL PLUS has a molecular weight of 1-2 million Daltons (average molecular weight is 1.7 million Daltons).
Excipients/Inactive Ingredients: Mannitol, Sodium chloride, Disodium phosphate dodecahydrate, Sodium dihydrogen phosphate dihydrate, Water for injections.

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system. ATC code: M09AX01.
Pharmacology: Pharmacodynamics: Mechanism of action: Hyaluronic acid is an important component of the synovial fluid and of the articular cartilage. It provides lubricant and shock absorbing properties to the synovial fluid owing to its viscoelasticity. Moreover, it coats and protects the surface of the articular cartilage forming the backbone of the proteoglycan aggregates essential for structural and functional integrity.
In osteoarthritic joints, the concentration and the quality of hyaluronic acid is markedly reduced. As a consequence, the affected joint is exposed to mechanical damage, which may lead to synovial inflammation and cartilage destruction, and may result in pain and restricted mobility. Intraarticular administration of exogenous hyaluronic acid into osteoarthritic joints enhances the mechanical properties of the synovial fluid and has been shown to display viscoinduction, chondroprotectant, anti-inflammatory, and analgesic effects. Through these effects, its action in the joint may persist over longer periods, beyond its residency time in the synovial fluid.
Clinical efficacy and safety: A total of 1059 patients with degenerative and traumatic changes of the knee and other synovial joints were recruited into 9 clinical studies. Of these, 506 patients were treated with OSTENIL PLUS.
Three randomised controlled studies including a total of 191 patients treated with OSTENIL PLUS demonstrated that OSTENIL PLUS was efficacious in relieving pain and improving joint function in patients with knee osteoarthritis. A double-blind, randomised controlled trial conducted in France showed that a single injection of OSTENIL PLUS administered to 142 patients significantly relieved pain (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A score) and improved function (Lequesne index) for up to 6 months after treatment, with a responder rate of 83.0% according to the Outcome Measures in Rheumatology-Osteoathritis Research Society International (OMERACT-OARSI) response criteria. Similar findings were obtained in two other randomised clinical trials. The open randomised study by Lertwanich and Lamsam (2016) showed that 10 patients who received a single intraarticular injection of OSTENIL PLUS experienced a significant improvement in pain, stiffness and physical function (WOMAC scores) over the 6-month follow-up period and required lower amounts of diclofenac. The 12-month open randomised trial by Duymus et al. (2017) demonstrated that 1 injection of OSTENIL PLUS (39 treated patients) significantly improved pain, stiffness and physical function (visual analogue scale and WOMAC scores) for up to 6 months after treatment in patients with mild-moderate and moderate knee osteoarthritis.
Two open uncontrolled studies performed on a total of 105 patients also supported the efficacy of OSTENIL PLUS in the treatment of osteoarthritis. In the 3-month study by Frobenius (2009), 25 patients with hip or knee osteoarthritis received 1 or 3 (2-week interval) intraarticular injections of OSTENIL PLUS, respectively. At 3 months, pain, stiffness and function (WOMAC scores) significantly improved compared with baseline. Similarly, Borras-Verdera et al. (2012) demonstrated that a single OSTENIL PLUS injection (80 patients) relieved pain and improved joint function (visual analogue scale and WOMAC scores) over a period of 6 months in patients with knee osteoarthritis. Moreover, the patients significantly reduced their consumption of rescue medication at 3 months compared with baseline. Additionally, in the comparative study by Stoilov et al. (2011), a single injection of OSTENIL PLUS (95 treated patients) significantly relieved pain and improved function (WOMAC A score and Lequesne index, respectively) over 18 months in patients with knee osteoarthritis.
Three retrospective studies (115 injected patients) demonstrated the effectiveness of OSTENIL PLUS in the management of degenerative and traumatic changes of the knee joint. Dernek et al. (2016) reported that a single injection of OSTENIL PLUS significantly improved pain, stiffness and function (visual analogue scale and WOMAC scores) at 1 month post-injection in 28 patients with early-stage knee osteoarthritis, and that these benefits still persisted after 3 and 6 months. Guler et al. (2015) also observed a significant pain and function improvement (Knee Society's Knee Scoring System and visual analogue scales) in early-stage knee osteoarthritis patients (63 patients treated with 3 injections of OSTENIL PLUS at weekly interval) at 2 and 6 months after treatment. Finally, Dernek et al. (2017) showed the effectiveness of OSTENIL PLUS on pain and function (visual analogue scale and WOMAC scores) in 24 patients with early-stage meniscal injuries at 1, 3 and 6 months.
No significant safety concerns were identified.
In summary, all the previously-mentioned studies demonstrated the efficacy, effectiveness and safety of OSTENIL PLUS in the treatment of pain and restricted mobility in degenerative and traumatic changes of the knee joint and other synovial joints.
Pharmacokinetics: Hyaluronic acid has a local mode of action (see Pharmacodynamics as previously mentioned), which involves both the synovial fluid and the joint tissues. While the majority of exogenous hyaluronic acid remains in the joint for a few days, its half-life in the synovial fluid may vary from 1.5 hours to 4 weeks, depending on its molecular weight and structure.
The formulation of OSTENIL PLUS contains 2% high molecular weight sodium hyaluronate and 0.5% mannitol as antioxidant agent. These properties may prolong the presence of hyaluronic acid in the affected joint and allow the treatment of patients with fewer injections.
Toxicology: Preclinical safety data: No special hazard for humans is expected based on biocompatibility studies, namely implantation, cytotoxicity, intracutaneous reactivity, sensitisation, acute systemic toxicity, subacute/subchronic toxicity, and genotoxicity testing.

Pain and restricted mobility in degenerative changes of the knee and hip joints.

Posology: Inject a single dose of OSTENIL PLUS into the affected joint. The treatment effect will persist for up to 6 months. Several joints may be treated at the same time: Based on clinical studies, up to 3 consecutive doses can be given at 1-2 week interval.
No adaptations of dose or posology are required in elderly patients or patients with renal or hepatic insufficiency.
Paediatric population: No data are available.
Method of administration: For intraarticular use.
The content and the outer surface of the OSTENIL PLUS pre-filled syringe are sterile as long as the sterile pack is intact.
Take the pre-filled syringe out of the sterile pack.
Unscrew the Luer-Lok tip cap from the syringe.
Attach a suitable needle (for example 18 to 25G) and secure it by turning slightly.
Remove any air bubble, if present, before injection.
OSTENIL PLUS should be injected accurately into the joint cavity, if necessary under imaging control such as ultrasound. Avoid injections into blood vessels or surrounding tissues. In case of prior joint effusion, it is advisable to reduce the effusion by aspiration, rest, application of an ice pack and/or intraarticular corticosteroid injection. Treatment with OSTENIL PLUS can be started when the effusion has clinically resolved, or at least one week later in case of intraarticular corticosteroid injection. This interval is intended to reduce the potential risk of infection associated with intraarticular corticosteroids.

No specific reactions are to be expected with an intraarticular overdose of the product.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Intraarticular injections are contraindicated in case of joint infections or skin diseases in the area of the injection site.

As with all invasive joint treatments, in very rare cases an infection may occur. Strict aseptic measures must be taken during the administration of OSTENIL PLUS.
OSTENIL PLUS must not be used to treat patients with inflammatory joint diseases as no evidence of clinical efficacy of the use of OSTENIL PLUS in these diseases is available.
Effects on ability to drive and use machines: OSTENIL PLUS has no or negligible influence on the ability to drive and use machines.
However, some of the effects mentioned under Interactions and Adverse Reactions may temporarily affect the ability to drive or use machines.

Pregnancy: There is no experience regarding the safety of OSTENIL PLUS in pregnant women.
Animal studies do not indicate harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). It is preferable to avoid the use of OSTENIL PLUS during pregnancy as a precautionary measure.
Breast-feeding: There is no experience regarding the safety of OSTENIL PLUS in human breast-feeding. It is preferable to avoid the use of OSTENIL PLUS during breast-feeding as a precautionary measure.

Summary of the safety profile: The most commonly reported undesirable effects reported with OSTENIL PLUS are injection site reactions, including pain, effusion, swelling, inflammation, redness and warmth. Application of an ice pack onto the joint for five to ten minutes reduces the incidence of these events.
List of adverse reactions: Adverse reactions associated with OSTENIL PLUS obtained from clinical studies and postmarketing surveillance are listed as follows by body system organ class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Common: Injection site pain, injection site effusion, injection site swelling, injection site inflammation, injection site redness, injection site warmth.
Description of selected adverse reactions: As with all injectables, adverse reactions may include the risk of infection (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

OSTENIL PLUS must not be administered simultaneously or mixed with other intraarticular injections. In particular, in vitro studies suggest that the properties of hyaluronic acid may be altered by different agents such as corticosteroids, lidocaine, or iodinated contrast agents.
In vivo studies have indicated that hyaluronic acid may extend the effect of certain local anesthetics.
Moreover, the product must not be used concomitantly with disinfectants containing quaternary ammonium salts, because hyaluronic acid can precipitate in their presence.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, refer to Interactions.

Store below 30°C. Do not freeze.
Store in the original package in order to protect from light.
Shelf life: 36 months.

Other Drugs Acting on Musculo-Skeletal System

M09AX01 - hyaluronic acid ; Belongs to the class of other drugs for disorders of the musculo-skeletal system.

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