Identification
- Summary
Tranexamic acid is an antifibrinolytic used to reduce or prevent hemorrhagic episodes, especially in the context of hyperfibrinolytic disorders.
- Brand Names
- Cyklokapron, Lysteda
- Generic Name
- Tranexamic acid
- DrugBank Accession Number
- DB00302
- Background
Tranexamic acid is a synthetic derivative of lysine used as an antifibrinolytic in the treatment and prevention of major bleeding. It possesses a similar mechanism of action to aminocaproic acid but is approximately 10-fold more potent.6
It was first patented in 19572 and received its initial US approval in 1986.5
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Tranexamic acid (DB00302)
- Weight
- Average: 157.2102
Monoisotopic: 157.110278729 - Chemical Formula
- C8H15NO2
- Synonyms
- Acide tranéxamique
- ácido tranexámico
- Acidum tranexamicum
- Tranexamic acid
- Tranexamsaeure
- Tranexmic acid
- Tranhexamic acid
- Trans AMCHA
- trans-4-(Aminomethyl)cyclohexanecarboxylic acid
- trans-4-aminomethylcyclohexane-1-carboxylic acid
- trans-Amcha
- trans-Tranexamic acid
- External IDs
- CL 65336
- CL-65336
- RP-18429
Pharmacology
- Indication
Taken orally, tranexamic acid is indicated for the treatment of hereditary angioedema,6 cyclic heavy menstrual bleeding in premenopausal females,5 and other instances of significant bleeding in the context of hyperfibrinolysis.6 Given intravenously, tranexamic acid is indicated for short-term use (2-8 days) in patients with hemophilia to prevent or reduce bleeding following tooth extraction.4
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
Tranexamic acid is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin.5 At much higher concentrations it behaves as a noncompetitive inhibitor of plasmin similar to aminocaproic acid, a similar antifibrinolytic which is 10-fold less potent.6 Tranexamic acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. In patients with hereditary angioedema, inhibition of the formation and activity of plasmin by tranexamic acid may prevent attacks of angioedema by decreasing plasmin-induced activation of the first complement protein (C1).3
Off-target antagonism of GABA(A) receptors may be associated with the development of convulsions and hyperexcitability following tranexamic acid administration1 - the risk appears higher with improper administration or administration during cardiovascular surgery.6 Consider EEG monitoring of patients with a history of seizure.
- Mechanism of action
Tranexamic acid competitively and reversibly inhibits the activation of plasminogen via binding at several distinct sites, including four or five low-affinity sites and one high-affinity site, the latter of which is involved in its binding to fibrin. The binding of plasminogen to fibrin induces fibrinolysis - by occupying the necessary binding sites tranexamic acid prevents this dissolution of fibrin, thereby stabilizing the clot and preventing hemorrhage.5
Target Actions Organism APlasminogen inhibitorHumans - Absorption
The bioavailability of tranexamic acid after oral administration in humans is approximately 30 to 50% of the ingested dose and is not affected by food intake.5 The Cmax and Tmax following multiple oral doses (1300 mg three times daily x 5 days) were 16.41 mcg/mL and 2.5 h, respectively.5
- Volume of distribution
The initial volume of distribution of tranexamic acid is 0.18 L/kg and its steady-state volume of distribution is 0.39 L/kg.5 Tranexamic acid distributes into cerebrospinal fluid and the aqueous humor of the eye at concentrations approximately 1/10th of typical plasma concentrations. Tranexamic acid is also able to cross the placenta, found in cord blood at concentrations equivalent to maternal plasma concentrations.5
- Protein binding
Tranexamic acid is approximately 3% protein-bound in plasma at therapeutic concentrations. As it does not bind to serum albumin, it is likely that this protein binding is accounted for by tranexamic acid's binding to serum plasminogen.5
- Metabolism
Tranexamic acid metabolism is poorly characterized but does not appear to be a significant means of drug elimination. According to prescribing information, approximately 1% and 0.5% of an orally administered dose are excreted as a dicarboxylic acid and acetylated metabolite, respectively.5
- Route of elimination
Urinary excretion is the primary means of tranexamic acid elimination, with >95% of an administered dose excreted in the urine as unchanged parent drug.5 The rate of excretion is dependent on the route of administration - approximately 90% of an intravenously administered dose is excreted within 24 hours whereas only 39% of an orally administered dose is excreted within the same time frame.6
- Half-life
Following intravenous administration, the apparent elimination half-life is approximately 2 hours and the mean terminal half-life is approximately 11 hours.5
- Clearance
The plasma clearance of tranexamic acid is 110-116 mL/min.5
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Reported symptoms of tranexamic acid overdose include severe gastrointestinal symptoms, hypotension, thromboembolism, visual impairment, convulsions, mental status changes, and rash.4,5
- Pathways
Pathway Category Tranexamic Acid Action Pathway Drug action - Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAlbutrepenonacog alfa Tranexamic acid may increase the thrombogenic activities of Albutrepenonacog alfa. Alpha-1-proteinase inhibitor Alpha-1-proteinase inhibitor may increase the thrombogenic activities of Tranexamic acid. Alteplase The therapeutic efficacy of Tranexamic acid can be decreased when used in combination with Alteplase. Aminocaproic acid Tranexamic acid may increase the thrombogenic activities of Aminocaproic acid. Andexanet alfa Tranexamic acid may increase the thrombogenic activities of Andexanet alfa. Anistreplase The therapeutic efficacy of Tranexamic acid can be decreased when used in combination with Anistreplase. Anti-inhibitor coagulant complex Tranexamic acid may increase the thrombogenic activities of Anti-inhibitor coagulant complex. Antihemophilic factor (recombinant), PEGylated Tranexamic acid may increase the thrombogenic activities of Antihemophilic factor (recombinant), PEGylated. Antihemophilic factor human Tranexamic acid may increase the thrombogenic activities of Antihemophilic factor human. Antihemophilic factor, human recombinant Tranexamic acid may increase the thrombogenic activities of Antihemophilic factor, human recombinant. 
Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- Take with or without food. The co-administration of food does not significantly affect tranexamic acid disposition.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Images
- International/Other Brands
- Cyclo-F / Espercil / Femstrual / Rikavarin / Transamin / Transcam / Traxyl
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Cyklokapron Injection, solution 100 mg/1mL Intravenous Pfizer Laboratories Div Pfizer Inc 1986-12-30 Not applicable US 
Cyklokapron Tablet 500 mg/1 Oral Pharmacia and Upjohn Company 2006-01-04 2006-01-04 US Cyklokapron 100 mg/ml Solution 100 mg / mL Intravenous Pfizer Canada Ulc 1995-12-31 Not applicable Canada 
Cyklokapron 500 mg Tablet 500 mg Oral Pfizer Canada Ulc 1995-12-31 Not applicable Canada Erfa-tranexamic Solution 100 mg / mL Intravenous Erfa Canada 2012 Inc 2017-07-31 Not applicable Canada Lysteda Tablet 650 mg/1 Oral Ferring Pharmaceuticals 2010-05-17 2015-12-31 US Lysteda Tablet 650 mg/1 Oral Amring Pharmaceuticals Inc. 2010-05-17 Not applicable US Lysteda Tablet 650 mg/1 Oral Xanodyne Pharmaceuticals 2010-05-17 2010-05-17 US Lysteda Tablet 650 mg/1 Oral Ferring Pharmaceuticals Inc. 2010-05-17 2022-12-31 US Lysteda Tablet 650.0 mg Oral Ferring Pharmaceuticals Not applicable Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Gd-tranexamic Acid Solution 100 mg / mL Intravenous Genmed A Division Of Pfizer Canada Ulc Not applicable Not applicable Canada Gd-tranexamic Acid Tablet 500 mg Oral Genmed A Division Of Pfizer Canada Ulc 2014-03-07 Not applicable Canada Mar-tranexamic Acid Tablet 500 mg Oral Marcan Pharmaceuticals Inc 2020-06-04 Not applicable Canada Tranexamic Acid Tablet, film coated 650 mg/1 Oral American Health Packaging 2015-12-18 2020-05-31 US Tranexamic Acid Injection, solution 100 mg/1mL Intravenous Apotex Corp. 2020-08-05 Not applicable US Tranexamic Acid Injection, solution 100 mg/1mL Intravenous Athenex Pharmaceutical Division, Llc. 2017-03-27 Not applicable US Tranexamic Acid Injection, solution 100 mg/1mL Intravenous Provepharm Inc. 2021-09-30 Not applicable US Tranexamic Acid Tablet 650 mg/1 Oral Prasco Laboratories 2010-05-17 2019-04-30 US Tranexamic Acid Injection 100 mg/1mL Intravenous Armas Pharmaceuticals Inc. 2021-06-11 Not applicable US Tranexamic Acid Injection, solution 1 g/10mL Intravenous Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc. 2014-08-13 Not applicable US - Over the Counter Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Pure Whitenol Serum Cream 0.05 mg/50mL Topical Skin M.D. Korea 2015-02-01 Not applicable US Skinmd Laboratories Pure Whitenol Serum Cream 0.05 g/50mL Topical Reviresco Co., Ltd. 2017-12-01 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Skinmd Laboratories Pure Whitenol Intensive Tranexamic acid (0.02 g/10mL) + Adenosine (0.004 g/10mL) Cream Topical Reviresco Co., Ltd. 2017-12-01 Not applicable US SKINMD LABORATORIES ReviTox blue Tranexamic acid (0.001 g/10mL) + Adenosine (0.004 g/10mL) Liquid Topical Reviresco Co., Ltd. 2017-12-01 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Pure Whitenol Serum Tranexamic acid (0.05 mg/50mL) Cream Topical Skin M.D. Korea 2015-02-01 Not applicable US Skinmd Laboratories Pure Whitenol Intensive Tranexamic acid (0.02 g/10mL) + Adenosine (0.004 g/10mL) Cream Topical Reviresco Co., Ltd. 2017-12-01 Not applicable US Skinmd Laboratories Pure Whitenol Serum Tranexamic acid (0.05 g/50mL) Cream Topical Reviresco Co., Ltd. 2017-12-01 Not applicable US SKINMD LABORATORIES ReviTox blue Tranexamic acid (0.001 g/10mL) + Adenosine (0.004 g/10mL) Liquid Topical Reviresco Co., Ltd. 2017-12-01 Not applicable US
Categories
- ATC Codes
- B02AA02 — Tranexamic acid
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as amino acids. These are organic compounds that contain at least one carboxyl group and one amino group.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Amino acids
- Alternative Parents
- Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organic oxides / Monoalkylamines / Hydrocarbon derivatives / Carbonyl compounds
- Substituents
- Aliphatic homomonocyclic compound / Amine / Amino acid / Carbonyl group / Carboxylic acid / Hydrocarbon derivative / Monocarboxylic acid or derivatives / Organic nitrogen compound / Organic oxide / Organic oxygen compound
- Molecular Framework
- Aliphatic homomonocyclic compounds
- External Descriptors
- monocarboxylic acid (CHEBI:48669)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 6T84R30KC1
- CAS number
- 1197-18-8
- InChI Key
- GYDJEQRTZSCIOI-LJGSYFOKSA-N
- InChI
- InChI=1S/C8H15NO2/c9-5-6-1-3-7(4-2-6)8(10)11/h6-7H,1-5,9H2,(H,10,11)/t6-,7-
- IUPAC Name
- (1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylic acid
- SMILES
- NC[C@H]1CC[C@@H](CC1)C(O)=O
References
- Synthesis Reference
Noa Zerangue, Bernd Jandeleit, Yunxiao Li, "Acyloxyalkyl carbamate prodrugs of tranexamic acid, methods of synthesis and use." U.S. Patent US20070027210, issued February 01, 2007.
US20070027210- General References
- Furtmuller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, Redl H: Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect. J Pharmacol Exp Ther. 2002 Apr;301(1):168-73. doi: 10.1124/jpet.301.1.168. [Article]
- Ng W, Jerath A, Wasowicz M: Tranexamic acid: a clinical review. Anaesthesiol Intensive Ther. 2015;47(4):339-50. doi: 10.5603/AIT.a2015.0011. Epub 2015 Mar 23. [Article]
- Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, Fay AC, Longhurst HJ, Morrison L, Price A, Price M, Watters D: C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005 Mar;139(3):379-94. doi: 10.1111/j.1365-2249.2005.02726.x. [Article]
- FDA Approved Drug Products: Cyklokapron (tranexamic acid) for intravenous injection [Link]
- FDA Approved Drug Products: Lysteda (tranexamic acid) tablets for oral use [Link]
- Health Canada Product Monograph: Cyklokapron (tranexamic acid) tablets for oral use [Link]
- CaymanChem: Tranexamic acid MSDS [Link]
- External Links
- Human Metabolome Database
- HMDB0014447
- KEGG Drug
- D01136
- PubChem Compound
- 5526
- PubChem Substance
- 46508089
- ChemSpider
- 10482000
- BindingDB
- 50428067
- 10691
- ChEBI
- 48669
- ChEMBL
- CHEMBL877
- ZINC
- ZINC000100071256
- Therapeutic Targets Database
- DAP000199
- PharmGKB
- PA164750514
- PDBe Ligand
- AMH
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Tranexamic_acid
- PDB Entries
- 1b2i / 1ceb
- MSDS
- Download (63.5 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Anterior Cruciate Ligament Rupture 1 4 Active Not Recruiting Treatment Blood Loss During Surgery 1 4 Active Not Recruiting Treatment Burns / Surgery / Tranexamic Acid / Wounds and Injuries 1 4 Active Not Recruiting Treatment Fracture of Femur 1 4 Active Not Recruiting Treatment Rotator Cuff Injuries / Rotator Cuff Tears / Subacromial Impingement / Subacromial Impingement Syndrome 1 4 Active Not Recruiting Treatment Tibial Tubercle Osteotomy 1 4 Completed Not Available Hypermenorrhea 1 4 Completed Other Complication of Extracorporeal Circulation / Pediatric Cardiac Surgery 1 4 Completed Other Revision Total Hip Arthroplasty (RTHA) 1 4 Completed Prevention Adenoidectomy / Tonsillectomy / Tranexamic Acid 1
Pharmacoeconomics
- Manufacturers
- Pharmacia and upjohn co
- Ferring pharmaceuticals as
- Packagers
- Gallipot
- Pfizer Inc.
- Pharmacia Inc.
- Professional Compounding Centers America LLC
- Xanodyne Pharmaceuticals Inc.
- Dosage Forms
Form Route Strength Injection, solution Parenteral 100 MG/ML Injection, solution Injection, solution 100 MG/ML Injection, solution Oral Solution Intravenous 500 mg Solution Oral Tablet Oral 500 mg/1 Solution Intravenous 100 mg / mL Injection, solution Parenteral Tablet, film coated Oral Injection Intravenous 100 mg/ml Tablet Oral 0.5 g Capsule Oral Tablet Oral 650 mg/1 Tablet Oral 650.0 mg Injection, solution Intravenous 100 mg/ml Tablet Oral Tablet 500 MG Injection Intravenous Cream Topical 0.05 mg/50mL Cream Topical Cream Topical 0.05 g/50mL Liquid Topical Capsule Oral 250 mg Injection, solution Parenteral 500 MG/5ML Injection Intravenous 100 mg/1mL Injection, solution Intravenous 1 g/10mL Injection, solution Intravenous 100 mg/1mL Tablet Oral 650 1/1 Tablet, film coated Oral 650 mg/1 Injection, solution Intravenous 10 mg/1mL Solution Intravenous 1000 mg / 10 mL Solution Intravenous 500 mg / 5 mL Injection, solution Intravenous Solution 50 mg/1ml Injection, solution Intravenous 250 mg/5mL Injection, solution Oral 500 MG/5ML Solution Intravenous Solution Intravenous 100 mg Injection, solution 50 mg/1ml Tablet, coated Oral 500 mg Tablet, film coated Oral 500 mg Tablet Oral 250 mg Capsule Oral 500 mg Solution 100 mg/1ml Tablet Oral 500 mg - Prices
Unit description Cost Unit Cyklokapron 100 mg/ml ampul 8.8USD ml Tranexamic acid powder 1.97USD g Cyklokapron 500 mg Tablet 1.3USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8022106 No 2011-09-20 2025-03-04 US US8273795 No 2012-09-25 2025-03-04 US US8487005 No 2013-07-16 2025-03-04 US US8791160 No 2014-07-29 2025-03-04 US US8809394 No 2014-08-19 2025-03-04 US US8957113 No 2015-02-17 2025-03-04 US US9060939 No 2015-06-23 2025-03-04 US US7947739 No 2011-05-24 2025-03-04 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) >300 °C https://www.caymanchem.com/msdss/19193m.pdf logP 0.3 Not Available - Predicted Properties
Property Value Source Water Solubility 18.2 mg/mL ALOGPS logP -1.4 ALOGPS logP -1.6 ChemAxon logS -0.94 ALOGPS pKa (Strongest Acidic) 4.56 ChemAxon pKa (Strongest Basic) 10.22 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 63.32 Å2 ChemAxon Rotatable Bond Count 2 ChemAxon Refractivity 41.9 m3·mol-1 ChemAxon Polarizability 17.28 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9538 Blood Brain Barrier + 0.8672 Caco-2 permeable - 0.8957 P-glycoprotein substrate Non-substrate 0.7572 P-glycoprotein inhibitor I Non-inhibitor 0.9915 P-glycoprotein inhibitor II Non-inhibitor 0.8475 Renal organic cation transporter Non-inhibitor 0.7446 CYP450 2C9 substrate Non-substrate 0.8862 CYP450 2D6 substrate Non-substrate 0.7898 CYP450 3A4 substrate Non-substrate 0.829 CYP450 1A2 substrate Non-inhibitor 0.9504 CYP450 2C9 inhibitor Non-inhibitor 0.907 CYP450 2D6 inhibitor Non-inhibitor 0.9577 CYP450 2C19 inhibitor Non-inhibitor 0.9452 CYP450 3A4 inhibitor Non-inhibitor 0.9313 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9698 Ames test Non AMES toxic 0.8916 Carcinogenicity Non-carcinogens 0.8495 Biodegradation Ready biodegradable 0.6921 Rat acute toxicity 1.0517 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.8797 hERG inhibition (predictor II) Non-inhibitor 0.9156
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Serine-type peptidase activity
- Specific Function
- Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In...
- Gene Name
- PLG
- Uniprot ID
- P00747
- Uniprot Name
- Plasminogen
- Molecular Weight
- 90568.415 Da
References
- Dunn CJ, Goa KL: Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999 Jun;57(6):1005-32. [Article]
- Marti DN, Schaller J, Llinas M: Solution structure and dynamics of the plasminogen kringle 2-AMCHA complex: 3(1)-helix in homologous domains. Biochemistry. 1999 Nov 30;38(48):15741-55. [Article]
- Jansen AJ, Andreica S, Claeys M, D'Haese J, Camu F, Jochmans K: Use of tranexamic acid for an effective blood conservation strategy after total knee arthroplasty. Br J Anaesth. 1999 Oct;83(4):596-601. [Article]
- Bangert K, Thorsen S: Assay of functional plasminogen in rat plasma applicable to experimental studies of thrombolysis. Thromb Haemost. 2000 Aug;84(2):299-306. [Article]
- Hanson AJ, Quinn MT: Effect of fibrin sealant composition on human neutrophil chemotaxis. J Biomed Mater Res. 2002 Sep 5;61(3):474-81. [Article]
- FDA Approved Drug Products: Lysteda (tranexamic acid) tablets for oral use [Link]
Drug created at June 13, 2005 13:24 / Updated at July 01, 2022 12:31