Omega-3-acid ethyl esters (K85EE)

Transcription

1 Technical Information May 2015 Supersedes issue dated September 2014 mega-3-s (K85EE) 03_081400e-01/Page 1 of 6 Last change WM-No = Registered trademark of BASF Ph. Eur., USP

2 03_081400e-01 May 2015 Page 2 of 6 mega-3-s (K85EE) 1. Medical indication mega-3-s (K85EE) is ethyl ester oil containing not less than 90% mega-3 and not less than 80% Eicosapentanoic acid (EPA) and Docosahexaenoic acid (DHA) combined, with a minimum of 40% EPA and 34% DHA ethyl esters. mega-3s in general are naturally occurring nutrients that are critical for human health. They cannot be synthesized by the human body but are vital for normal metabolism. EPA and DHA have been studied the most and have many vital, life-sustaining roles. Post Myocardial Infarction Adjuvant treatment in secondary prevention after myocardial infarction, in addition to other standard therapy (e.g. statins, antiplatelet medicinal products, betablockers, ACE inhibitors). Hypertriglyceridaemia Endogenous hypertriglyceridaemia as a supplement to diet when dietary measures alone are insufficient to produce an adequate response: type IV in monotherapy, type IIb/III in combination with statins, when control of triglycerides is insufficient. Pharmacokinetics During and after absorption, there are three main pathways for the metabolism of the omega-3 fatty acids: the fatty acids are first transported to the liver where they are incorporated into various categories of lipoproteins and then channelled to the peripheral lipid stores; the cell membrane phospholipids are replaced by lipoprotein phospholipids and the fatty acids can then act as precursors for various eicosanoids; the majority is oxidised to meet energy requirements. The concentration of omega-3 fatty acids, EPA and DHA, in the plasma phos pholipids corresponds to the EPA and DHA incorporated into the cell membranes. Animal pharmacokinetic studies have shown that there is a complete hydrolysis of the ethyl ester accompanied by satisfactory absorption and incorporation of EPA and DHA into the plasma phospholipids and cholesterol esters. Pharmacodynamics The omega-3 series polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential fatty acids. In mega-3-s (K85EE) we have the ethyl esters (EE) of theses 2 fatty acids. EPA/DHA EE are active on the plasma lipids by lowering triglyceride levels as a result of a fall in VLDL (very low density lipoprotein), and the substance is also active on haemostasis and blood pressure. EPA/DHA EE reduce the synthesis of triglycerides in the liver because EPA and DHA are poor substrates for the enzymes responsible for triglyceride synthesis and they inhibit esterification of other fatty acids. The increase in peroxisomes of b-oxidation of fatty acids in the liver also contributes to the fall in triglycerides, by reducing the quantity of free fatty acids available for their synthesis. The inhibition of this synthesis lowers VLDL. EPA/DHA EE increase LDL-cholesterol in some patients with hypertriglyceridaemia. A rise in HDL-cholesterol is only small, significantly smaller than seen after adminis tration of fibrates, and not consistent. The long-term lipid-lowering effect (after more than one year) is not known. therwise there is no strong evidence that lowering triglycerides reduces the risk of ischaemic heart disease. During treatment with EPA/DHA EE, there is a fall in thromboxane A2 production and a slight increase in bleeding time.

3 03_081400e-01 May 2015 Page 3 of 6 mega-3-s (K85EE) Precautionary measures Because of the moderate increase in bleeding time, patients receiving anticoagulant therapy must be monitored and the dosage of anticoagulant adjusted if necessary. Use of this medication does not eliminate the need for the surveillance usually required for patients of this type. Make allowance for the increased bleeding time in patients at high risk of haemorrhage (because of severe trauma, surgery, etc). In the absence of efficacy and safety data, use of this medication in children is not recommended. There is no experience regarding hypertriglyceridaemia in combination with fibrates. 2. Chemical information Name mega-3-s (K85EE) Nomenclature for the drug substance K85EE Nomenclature/Drug Substance K85EE USP current ed. mega-3-acid Ethyl Esters USAN mega-3-s Ph. Eur. (1250) current ed. mega-3-s 90 Nomenclature for the two primary components of K85EE Nomenclature/Primary Component EPA Ethyl Ester DHA Ethyl Ester International non-proprietary name (INN) Icosapent ethyl ester Doconexent ethyl ester Chemical name Ethyl (all-z)-5,8,11,14,17- eicosapentaenoate Ethyl (all-z)-4,7,10,13,16,19- docosahexenoate Trivial name Timnodonic Cervonic Synonyms All-cis 5,8,11,14,17- eicosapentaenoic All-cis 4,7,10,13,16,19- docosahexaenoic C20:5v3 ethyl ester C20:5n-3 ethyl ester C22:6v3 ethyl ester C22:6n-3 ethyl ester

4 03_081400e-01 May 2015 Page 4 of 6 mega-3-s (K85EE) Nomenclature for the primary and secondary mega-3 components of K85EE Primary components Eicosapentaenoic acid (EPA) EE Docosahexaenoic acid (DHA) EE Secondary components ctadecatrienoic acid EE ctadecatetraenoic acid EE Eicosatetraenoic acid EE Heneicosapentaenoic acid EE Docosapentaenoic acid EE USP IUPAC Numeric Notation Eicosapentaenoic Docosahexaenoic Alpha-linolenic acid ethyl ester Moroctic acid ethyl ester Eicosatetraenoic acid ethyl ester Heneicosapentaenoic Docosapentaenoic (Clupanodonic acid ethyl ester) Ethyl (all-z)-5,8,11,14,17- eicosapentaenoate Ethyl (all-z)-4,7,10,13,16,19- docosahexaenoate Ethyl (all-z)-9,12,15- octadecatrienoate Ethyl (all-z)-6,9,12,15- octadecatetraenoate Ethyl (all-z)-8,11,14,17- eicosatetraenoate Ethyl (all-z)-6,9,12,15,18- heneicosapentaenoate Ethyl (all-z)-7,10,13,16,19- docosapentaenoate CAS Registry Number C20:5 n C22:6 n C18:3 n C18:4 n C20:4 n C21:5 n C22:5 n Structural formula EPA EE DHA EE Molecular formula EPA EE C 22 H 34 2 DHA EE C 24 H 36 2 Relative Molecular Mass EPA EE DHA EE Antioxidant Vitamin E preparation (Mixture of d-alpha Tocopherol 1000 IU/ g and soy bean oil) d-alpha Tocopherol CAS-No

5 03_081400e-01 May 2015 Page 5 of 6 mega-3-s (K85EE) 3. PRD-No. PRD-Nos.* Description (PRD) Item number Sales Region K85EE Europe, and countries accepting CEP 1) mega 3 fatty nly for Italy K85EE mega-3-acid ethylesters Global, excepting Europe 1) CEP; Certification of Suitability of monographs of the European Pharmacopeia * BASF s commercial product numbers. 4. Retest period See separate documentation: Q&R PI (not for regulatory purposes) When stored below 25 C in original containers blanketed with nitrogen a re-test period of 24 months is justified. 5. Storage The results from the long term stability studies comply with the specification at all time points up to 24 months storage below 25 C in original containers blanketed with nitrogen. Do not freeze. 6. Container size The container closure system used for K85EE is steel drums with a net volume of 217 litres. The plugs and flanges are of plated steel and the washers are of polyethylene. 7. Physical and chemical properties Appearance Light yellow liquid Solubility Practically insoluble in water, very soluble in acetone, ethanol (96 per cent), in heptane and in methanol. Freezing point < -20 ºC Boiling point > 400 ºC Flash point > 95 ºC Ignition temperature 260 ºC Vapor pressure Density Negligible 0.9 g/ml (20 C)

6 03_081400e-01 May 2015 Page 6 of 6 mega-3-s (K85EE) 8. Regulatory Status mega-3-s (K85EE) meet Ph. Eur. (1250), USP monograph and FDA Draft Guidance on mega-3-s, appendix Specification See separate documents: Standard Specifications (not for regulatory purposes) Note This document, or any answers or information provided herein by BASF, does not constitute a legally binding obligation of BASF. While the descriptions, designs, data and information contained herein are presented in good faith and believed to be accurate, it is provided for your guidance only. Because many factors may affect processing or application/use, we recommend that you make tests to determine the suitability of a product for your particular purpose prior to use. It does not relieve our customers from the obligation to perform a full inspection of the products upon delivery or any other obligation. N WARRANTIES F ANY KIND, EITHER EXPRESS R IMPLIED, INCLUDING WARRANTIES F MERCHANTABILITY R FITNESS FR A PARTICULAR PURPSE, ARE MADE REGARDING PRDUCTS DESCRIBED R DESIGNS, DATA R INFRMATIN SET FRTH, R THAT THE PRDUCTS, DESIGNS, DATA R INFRMATIN MAY BE USED WITHUT INFRINGING THE INTELLECTUAL PRPERTY RIGHTS F THERS. IN N CASE SHALL THE DESCRIPTINS, INFRMATIN, DATA R DESIGNS PRVIDED BE CNSIDERED A PART F UR TERMS AND CNDITINS F SALE. May 2015 BASF Nutrition & Health