The product is colorless and transparent, viscoelasticity gel-type injection contained in a glass tube clogged with rubber stoppers both top and bottom.
Each 1 syringe (2.0 mL) contains 4:1 w/w mixed hydrogel of sodium hyaluronate gel crosslinked by divinyl sulfone and sodium hyaluronate fluid 2.04 g (as Sodium Hyaluronate 40 mg).
Component: a sterile needle.
Excipients/Inactive Ingredients: Divinyl sulfone and phosphate buffered saline.
Pharmacology: Pharmacodynamics: When this product is injected into the joint cavity of a surgically induced rabbit osteoarthritis model, it increases the articular thickness of the knee joint and inhibits inflammatory edema around the joint, reduces the area of cartilage damage, inhibits the increase in the elongation angle of the knee joint, and inhibits the increase in the Makin score of the femur and tibia articular cartilage. In addition, it also inhibits the increase in joint thickness through reduction and inhibition of the thickness of articular cartilage and the number of chondrocytes, and has an anti-inflammatory effect by inhibiting IL-1β and TNF-α activity, which are inflammatory cytokines.
Pharmacokinetics: Absorption: The maximum plasma concentration (Cmax) of this product after intra-articular injection in non-fasting rats was reached at an hour after injection, and the median of the maximum plasma concentration reached at 9.88 hours. The maximum plasma concentration (Cmax) after subcutaneous injection in non-fasting rats was reached at an hour after injection, and the median of the maximum plasma concentration reached at 452 hours.
Distribution: After 2,400 hours of intra-articular injection, it was confirmed that 73.98% of the dose remained in most joint cavities. It was distributed in all tissues, and the concentration in all tissues, except for the injection site, decreased over time. It was also distributed in all tissues after subcutaneous injection and the concentration in all tissues decreased over time, but it was confirmed that it was removed more slowly than intra-articular injection.
Metabolism: After subcutaneous injection of this product, it was confirmed that various metabolites with a molecular weight of 21,100 Da or less were present in plasma, and it was also confirmed that metabolites with a molecular weight of 6,100 Da or less were mainly excreted in urine, which is the main excretion route.
Excretion: After intra-articular injection, 26.9% and 5.1% of this product was observed in urine and feces, respectively, and 68.8% of the injected dose was observed at the injection site. After subcutaneous injection, 19.9% and 3.7% were observed in urine and feces, and 74.6% of the injected dose was observed in all tissues.
Toxicology: Preclinical Safety data: Clinical Trial Information: Double-blind, Placebo-controlled Clinical Trial (YY_YYD302_001/2a): A multicenter, randomized, placebo-controlled, double-blind trial was conducted to compare and evaluate the safety and efficacy of the three groups in patients with osteoarthritis of the knee joint after receiving a single dose of this product and placebo. As a result of comparing the changes in pain score (WBP-100 mm VAS: pain assessment during weight bearing) at 12 weeks after injection of this product (2 mL: 12 subjects, 3 mL: 12 subjects) and placebo (3 mL: 6 subjects), the group receiving this product (2 mL), the group receiving this product (3 mL), and the group receiving the placebo (3 mL) showed a statistically significant decrease of -34.20±24.10 mm, -23.10±21.79 mm, and -29.00±33.15 mm, respectively.
Double-blind, Active-controlled Clinical Trial (YY_YYD302_003): A multicenter, randomized, active-controlled, double-blind trial was conducted to compare and evaluate the safety and efficacy in patients with osteoarthritis of the knee joint between the two groups after receiving a single injection of this product and the active comparator (Synovian). As a result of comparing (PP group) the pain score (WBP-100 mm VAS: pain assessment during weight bearing) at 12 weeks after injection of this product (95 subjects) and the active comparator (88 subjects), the WBP-100 mm VAS was decreased by an average of 31.76±18.93 mm for this product and an average of 29.74±20.54 mm for the active comparator compared to the baseline, statistically demonstrating non-inferiority between the two groups.
Re-injection Clinical Trial (YY_YYD302_003): A multicenter, randomized, active-controlled, double-blind trial was included in the clinical trial and conducted to confirm the safety and efficacy of this product for up to 6 months after a single injection in patients with osteoarthritis of the knee and to further evaluate the safety and efficacy of re-injection. WBP-100 mm VAS decreased by an average of 39.06±13.15 mm compared to the baseline at 12 weeks after a single dose (80 subjects, PP group), and decreased by 37.72±16.83 mm at 24 weeks.WBP-100 mm VAS at 36 weeks for subjects who were re-injected at 24 weeks (47 subjects) decreased by an average of 5.45±13.14 mm compared to the baseline (24 weeks). Safety and efficacy for long-term use other than the period revealed through clinical studies have not been confirmed.
Toxicity Test: Single Toxicity: When a single dose was injected intraperitoneally and intra-articularly to rats and beagle dogs up to the maximum feasible dose (MFD), the lethal dose exceeded the MFD in both genders, and no deaths were found.
Repeat Toxicity: This product was injected intra-articularly to rats at doses of 30, 60, and 120 μL/head/day, 8 times repeatedly at 4-week intervals, and to beagle dogs at doses of 2, 4, and 6 mL/head/day, 8 times repeatedly at 16-week and 40-week intervals. No toxicologically significant changes were observed at any dose.
Genotoxicity: Mutagenicity and chromosomal aberration were not found in the genotoxicity test of the reverse mutation test using bacteria, the chromosomal aberration test using CHL cells, and the micronucleus test using ICR mouse.
Antigenicity: It did not show antigenicity in the active systemic anaphylactic shock (ASA) response test and allogeneic passive cutaneous anaphylaxis (PCA) response test using Hartley guinea pigs.
The product is treatment of pain in Osteoarthritis (OA) of the knee.
Adult: One syringe at a time is administered into the knee joint cavity, but depending on the symptoms, it is administered appropriately considering the administration interval (6 months or more).
This product 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.
This product should be injected with caution: In patients with hypersensitivity to other substance.
In patients with liver disease or prior history of the liver disease.
General Precautions: Administration of this product to severely inflamed joints caused by deformative osteoarthritis can lead to exacerbation of the local inflammation symptoms. Thus, this product is desired to be given after the removal of existing inflammation symptoms.
Administration of this product may occasionally cause local pain, erythema, or swelling, therefore patients should be informed to avoid strenuous exercise or action leading to joint pain of knee up to 48 hours after administration, and actions such as local relaxation should be guided after injection.
Leakage of this product at an area other than articular cavity might cause pain; therefore this product should be accurately injected into articular cavity.
This product should be administered by a medical professional.
Precautions in Use: Since this product 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 this product, 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 with a disinfectant fourth-grade ammonium salt such as benzalkonium chloride and chlorohexidine.
This product 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 this product is injected into both knees, a separate product should be used for each administration.
Do not re-administer if symptoms do not improve.
Precautions in Handling: This product should be kept in original packaging; storing this product in a different packaging can cause misuse of product or decline the product quality.
Effects on ability to drive and use machine: Not applicable.
Use in Pregnancy & Lactation: See USE IN PREGNANCY & LACTATION section for further information.
Use in Children: The pediatric safety and efficacy of this product have not been established, therefore administration of this product to pediatrics is not recommended.
Use in the Elderly: Since physiological function of geriatrics has a declining tendency, administration should be made carefully. In two clinical trials, subjects aged 65 years or older who received this product were 55.4% (118/213 subjects) of the total subjects, and there was no difference in response to the drug between the elderly and non-elderly subjects.
Pregnancy and nursing mothers: Safety and efficacy of this product in pregnant woman and nursing mothers have not been established, therefore administration of this product to pregnant women or nursing mothers is not recommended.
There were no serious adverse events related to this product.
In a clinical trial (YY_YYD302_003) of this product in patients with osteoarthritis of the knee, using Synovian Injection as a control group, the occurrence rate of adverse events at injection site following injection into articular cavity was 48.42% (46/95 subjects) and 47.27% (26/55 subject) after the first injection and re-injection of this product, respectively. The reported adverse events at injection site are shown in the following Table 1. The severe adverse events were reported in the decreasing order of swelling (9.47% and 7.27% after the first injection and re-injection of this product, respectively), redness (erythema) (6.32% and 3.64% after the first injection and re-injection of this product, respectively), and pain (3.16% and 12.73% after the first injection and re-injection of this product, respectively). Adverse events at injection site lasting for 7 days or more after injection of this product were pain 5.26%, warmth 3.16%, and swelling 1.05%, yet all of them resolved within 14 days without any special treatment. After re-injection, adverse event at injection site lasting for 7 days or more were pain 10.91%, swelling 5.45%, warmth 3.64%, and redness (erythema) 1.82%, yet all of them resolved without any special treatment. (See Table 1.)
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In the clinical trial (YY_YYD302_003) of this product in patients with osteoarthritis of the knee, using Synovian as a control group, the occurrence rate of adverse events excluding ones occurred at the injection site was 9.47% (9/95 subjects, 19 cases) during 12 weeks after the first injection of this product, 29.09% (16/55 subjects, 35 cases) during 36 weeks after the first injection of this product, and 14.55% (8/55 subjects, 13 cases) during 12 weeks after re injection of this product. Most of them were mild to moderate. Table 2 indicates the adverse events reported to be occurred in 1% or more after injection of this product. (See Table 2.)
Click on icon to see table/diagram/image
Safety and efficacy of interactions between this product and with other drugs have not been established so that administration of this product with other drugs is not recommended.
Incompatibilities: Safety and efficacy of interactions between this product and with other drugs have not been established so that administration of this product with other drugs is not recommended.
Hermetic container, store at 1-30°C.
Shelf life: 3 years from the manufacturing date.
M09AX01 - hyaluronic acid ; Belongs to the class of other drugs for disorders of the musculo-skeletal system.
Atri ONE injectable gel 40 mg/2 mL
2 mL x 1's
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