Hyruan One

Butanediol diglycidyl ether-crosslinked sodium hyaluronate gel.

1 mL contains 1.0g of BDDE-crosslinked sodium hyaluronate gel (20mg of BDDE-crosslinked sodium hyaluronate).
Each prefilled syringe contains BDDE-crosslinked sodium hyaluronate gel.
3 mL of Hyruan ONE contains 3.0g of BDDE-crosslinked sodium hyaluronate gel (60mg of BDDE-crosslinked sodium hyaluronate).
Excipients/Inactive Ingredients: No excipient is used.

Pharmacology: Pharmacodynamics: Mechanism of Action: Hyaluronic acid improves pain in osteoarthritis as intra-articular lubrication and intra-articular viscosity and elasticity are gradually recovered by intra-articular injection of hyaluronic acid, which is the major ingredient constituting synovia and surface of cartilage. This is a treatment method based on the concept of viscosupplementation and the synovia of the patients with arthritis with lower viscoelasticity and elasticity compared to normal people.
Pharmacodynamics of Hyruan One: For the pharmacodynamic study, it is considered that it can be replaced with the clinical study data of Hyruan ONE and other pre-licensed products containing sodium hyaluronate as the active ingredient (such as Hyruan Plus, LG Life Sciences, Ltd.). In addition, neither the general pharmacology nor safety pharmacology study was conducted separately, as there was no special concern in the toxicological study and in the pharmacological study for the intra-articular administration of ¹⁴C-Hyruan ONE in rats, there was insignificant amount of the drug transferred to the systemic circulation or other tissue/organ. The relevant details are described in Pharmacokinetics and Toxicology as follows.
Pharmacokinetics: For the pharmacokinetics of Hyruan ONE, the radiolabelled (¹⁴C)-BDDE, the crosslinking agents of Hyaluronic acid was used to investigate the information on the exposure level in blood, distribution in the tissue/organ, metabolism/degradation products, and excretion etc. of the radioactivity.
Absorption: The pharmacokinetics of ¹⁴C-radiolabelled Hyruan ONE after intra-articular injection was studied in rat. Peak radioactivity concentration in plasma was observed at the first sampling time (1 hr post-dose). Then, plasma radioactivity declined quickly and decreased below the limit of quantification at 72 hr post-dose.
Distribution: Most of administered radioactivity remained at the administration site until 70 days post-dose after intra-articular injection of ¹⁴C-radiolabelled Hyruan ONE to rat. Except for the administration site, relatively higher organ/tissue distribution was observed at liver, spleen, kidney, and mesenteric lymph node, etc. In cerebrum, thyroid gland, adrenal gland, skeletal muscle, and stomach, radioactivity was not detected at any sampling time.
Metabolism: Metabolite profile of ¹⁴C-radiolabelled Hyruan ONE was assessed with plasma and urine samples following intra-articular injection of ¹⁴C-radiolabelled Hyruan ONE to rat. Molecular weight of metabolites was confirmed by comparing HPLC retention time of samples with that of reference marker. In plasma, metabolites below 200,000 Da were detected at 8 hr post-dose. In urine, metabolites below 5,900 Da were detected at 0~24 hr, 144~168 hr, and 240~336 hr post-dose. At the last sampling time (70 days post-dose), 12.9% of administered dose remained at the administration site.
Elimination: Total 82.5% of administered radioactivity was excreted into the urine, feces, and exhaled air while 12.9% of administered radioactivity still remained at the administration site until 70 days post-dose. 72.2% of administered radioactivity was recovered in the urine, indicating that urinary excretion is the major excretion pathway.
Toxicology: Preclinical safety data: The safety of Hyruan ONE was tested by single dose toxicity study in rats and dogs, repeated dose toxicity study in rats and dogs, genotoxicity battery tests, and antigenicity study in guinea pigs.
Based on conventional studies, no special hazard for humans was observed.

Treatment of pain in osteoarthritis in knee in patients who have failed nonpharmacologic treatment and simple analgesics or nonsteroidal anti-inflammatory drugs (NSAIDS).

Method of administration: Intra-articular.
Dose and administration: Hyruan ONE is a single injection, single dose preparation and should only be injected once per treatment course. The recommended dose is 3 mL for knee joint. Hyruan ONE should be administered by a medical professional.
Geriatrics: Since physiological function of geriatrics has a declining tendency, administration should be made carefully. Although the number of geriatrics over the age of 65 treat with Hyruan ONE is not sufficient as 18.5% (53/287), difference in the reaction incidence rate after administration of Hyruan ONE between geriatrics and non-geriatric group was not observed in the clinical trial.

Not known.

Hyruan ONE should not be injected: To patients who are known to be sensitive to the product or ingredients of it.
To patients with an infection or severe inflammation at joint cavity.
To patients with a disease or infection of skin near the injection site.
Hyruan ONE should be injected with cautions: In patients with hypersensitivity to other substance.
In patients with liver disease or prior history of the liver disease.

General precautions: Administration of Hyruan ONE to severely inflamed joints caused by deformative osteoarthritis can lead to exacerbation of the local inflammation symptom. Thus, Hyruan ONE is desired to be given after the removal of existing inflammation symptoms.
Administration of Hyruan ONE may occasionally cause local pain or swelling, therefore patients should be informed to avoid strenuous exercise or action leading joint pain of knee up to 48 hours after administration, and actions such as local relaxation should be guided after injection.
Leakage of Hyruan ONE other than articular cavity might cause pain; therefore Hyruan ONE should be accurately injected into articular cavity.
Precautions in use: Since Hyruan ONE is injected directly into the joints, administration should be performed under intact sterilization status.
In case of retention of articular fluid, the fluid should be removed by puncturing prior to administration of Hyruan ONE, if necessary.
Intravascular injection, extra-articular injection or injection in the synovial tissues should be avoided.
It is desirable to administer the product using enclosed needles.
Care should be taken with a disinfectant fourth-grade ammonium salt such as benzalkonium chloride and chlorhexidine.
Hyruan ONE is intended for single use only. No re-sterilization or reuse is allowed. Do not use if packaging or syringe is opened or damaged.
The injection site must be sterilized either by alcohol or other disinfecting solution prior to administration.
Used syringe, needle and unused materials all need to be discarded after administration.
In case Hyruan One is injected into both sides of knee, a separate product should be applied for each administration.
Precautions in Handling: Hyruan ONE should be kept away from children.
Hyruan ONE should be kept in original packaging; storing Hyruan ONE in a different packaging can cause misuse of product or decline the product quality.
Effects on ability to drive and use machine: Not known.

Safety and efficacy of Hyruan ONE in pregnant woman and nursing mothers have not been established, therefore administration of Hyruan ONE to pregnant women or nursing mothers is not recommended.

Serious adverse events: Shock: Since symptoms of shock (frequency unknown) may occur, careful observation should be made. In case abnormalities are noticed, administration should be discontinued and proper measures should be taken.
In pivotal trial of Hyruan ONE in patients with the knee osteoarthritis (a total of 285 subjects), the occurrence rate of local reaction at injection site after injection into articular cavity was 48.9% (68/139 subjects) in the study group and 49.3% (72/146 subjects) in the control group. The reported adverse events are shown in Table 1. The serious adverse events were reported in the decreasing order of pain (7.2% of the study group, 6.2% of the control group), redness (erythema) (5.0% of the study group, 2.1% of the control group) and swelling (1.4% of the study group, 2.1% of the control group). Adverse events lasting over a week were pain 5.3%, redness 1.4%, swelling and warmth each accounting for 1.0%, yet all of them completely resolved in two weeks without any special treatment. (See Table 1.)

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Of the patients with the knee osteoarthritis (285 subjects), the occurrence rate of the adverse events excluding ones occurred at the injection site is 34.5% (48/139, 73 cases) for the study group and 28.8% (42/146, 63 cases) for the control group. Most of them were mild to moderate. Table 2 indicates the adverse events occurred in more than 1% of the study group. (See Table 2.)

Click on icon to see table/diagram/image

Safety and efficacy of interactions between Hyruan ONE and with other intra-articular injectables have not been established, therefore administration of Hyruan ONE with other intra-articular injectables is not recommended.

Incompatibilities: As hyaluronic acid may cause a precipitation with a disinfectant tertiary ammonium such as benzalkoniurm chloride or chlorhexidine, the product should not be taken with those substances even though the active substance of Hyruan ONE is BDDE-crosslinked hyaluronate gel.
Safety and efficacy of interactions between Hyruan ONE and with other intra-articular injectables have not been established, therefore administration of Hyruan ONE with other intra-articular injectables is not recommended.

Store below 25°C in a light-resistant, hermetic container. Do not freeze.
Shelf life: 24 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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