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Drugs and Health Products

Monograph: Fish Oil

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient. There are many N-3 polyunsaturated fatty acids, popularly known as omega-3 acids/omega-3 fatty acids (Ph.Eur. 2012). This monograph is specific to eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n-3, DHA). Notes: (i) Text in parentheses is additional optional information which can be included on the Product Licence Application and product labels at the applicants' discretion. (ii) The solidus (/) indicates that the terms are synonyms or that the statements are synonymous. Either term or statement may be selected by the applicant.

Date: 2013-07-10

NHPID Name

Fish Oil

Proper Name(s)

Fish oil ( BP 2012 , Ph.Eur. 2012 )

Common Name(s)

Fish oil ( BP 2012 , Ph.Eur. 2012 )

Source Material


The above corresponds to oil from the body of one or more of the following species in its natural triglyceride/triacylglycerol form and/or its concentrated esterified form (BP 2012; Ph.Eur. 2012; Froese and Pauly 2011; Martindale 2011): (i) Anchovy (any species of Engraulidae), (ii) Jack or pompano (any species of Carangidae), (iii) Herring, shad, sardine, or menhaden (any species of Clupeidae), (iv) Smelt (any species of Osmeridae), (v) Mackerel, tuna, or bonito (any species of Scombridae), (vi) Sand lance (any species of Ammodytidae), (vii) Salmonids (any species of Salmonidae)

Route Of Administration

Oral

Dosage Form(s)

  • The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.
  • This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Use(s) or Purpose(s)

Statement(s) to the effect of:

For products providing 100-5000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid, per day:

For products providing 200-5000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid and containing a ratio of Eicosapentaenoic acid:Docosahexaenoic acid between 0.5:1 and 2:1 , per day:
Helps maintain/support cardiovascular health  (EFSA 2012, Oh 2005, Wang et al. 2004, Leaf et al. 2003, Kris-Etherton et al. 2002)

For products providing 1000-5000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid and containing a ratio of Eicosapentaenoic acid:Docosahexaenoic acid between 0.5:1 and 2:1 , per day:
Helps to reduce serum triglycerides/triacylglycerols  (EFSA 2012, Oh 2005, Balk et al. 2004, Hooper et al. 2004, Nilsen et al. 2001, Sirtori et al. 1998)

For products providing 2800-5000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid and containing a ratio of Eicosapentaenoic acid:Docosahexaenoic acid between 0.5:1 and 2:1 , per day:
In conjunction with conventional therapy, helps to reduce the pain of rheumatoid arthritis in adults  (EFSA 2012, Volker et al. 2000, Skoldstam et al. 1992)

For products providing 100-5000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid, including at least 100 Milligrams Docosahexaenoic acid, per day:
Helps support cognitive health and/or brain function  (EFSA 2012, van de Rest et al. 2008, Freund-Levi et al. 2006, Fontani et al. 2005b, Haag 2003, Morris et al. 2003, IOM 2002)

For products providing 150-2000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid, including at least 150 Milligrams Docosahexaenoic acid, per day:
Helps support the development of the brain, eyes and nerves in children up to 12 years of age  (Marszalek and Lodish 2005, Haag 2003, IOM 2002, Giedd et al. 1999, Mills 1999)

For products providing 1500-5000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid and containing a ratio of Eicosapentaenoic acid:Docosahexaenoic acid between 1.75:1 and 2:1 , including at least 1000 Milligrams Eicosapentaenoic acid, per day:
Helps to promote healthy mood balance  (EFSA 2012, Nemets et al. 2006, Sontrop and Campbell 2006, Fontani et al. 2005b, Zanarini and Frankenburg 2003, Peet and Horrobin 2002, Stoll et al. 1999)

Dose(s)

Children 1 - 8 years:

Preparation: Oil fixed standardised

Dose(s): 100-1500 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid per day

Adolescents 9 - 13 years:

Preparation: Oil fixed standardised

Dose(s): 100-2000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid per day

Adolescents 14 - 18 years:

Preparation: Oil fixed standardised

Dose(s): 100-2500 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid per day

Adults:

Preparation: Oil fixed standardised

Dose(s): 100-5000 Milligrams Eicosapentaenoic acid + Docosahexaenoic acid per day

  • Adult maximum dose supported by US FDA 1997. Children and adolescent maximum doses, calculated as a fraction of the adult dose, are relative to body weight and caloric intake.
  • Adults includes pregnant and breastfeeding women.
  • Potency must be expressed as the quantity (mg) and/or percent (%) EPA and DHA (% w/w) relative to the total quantity of fish oil.
  • Restrictions to minimum dose may apply according to Use(s) or Purpose(s) section

Duration of use

No statement is required

Risk Information

Statement(s) to the effect of:

Caution(s) and Warning(s):
No statement is required

Contraindication(s):
No statement is required

Known Adverse Reaction(s):
No statement is required

Non-medicinal ingredients

Must be chosen from the current Natural Health Products Ingredients Database and must meet the limitations outlined in the database.

Storage Conditions

  • For all products, except those encapsulated: Refrigerate after opening (Wille and Gonus 1989).
  • For all products: Store in airtight container, protected from light (Ph.Eur. 2012, USP 34).

Specifications

  • The finished product specifications must be established in accordance with the requirements described in the NHPD Quality of Natural Health Products Guide.
  • The medicinal ingredient must comply with the requirements outlined in the Natural Health Products Ingredient Database (NHPID).
  • Peroxide, anisidine, and totox values of fish oil or omega-3 fatty acids derived from fish oil must be in accordance with the methods set out by the Association of Analytical Community (AOAC) and/or Pharmacopoeial analytical methods. These specifications are necessary to ensure the oxidative stability of the fish oil and the omega-3 fatty acids from seal oil (HC 2007). The maximum peroxide value (PV) must be 5 mEq/kg, the maximum anisidine value (AV) must be 20 while the maximum Totox value must be 26 (calculated as 2 X PV + AV). (Refer to Appendix 1 Table 3)
  • The dioxins, polychlorinated dibenzo-para-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), and the polychlorinated biphenyls (PCBs), which include the dioxin-like polychlorinated biphenyls (DL PCBs), and the non dioxin-like polychlorinated biphenyls (NDL-PCBs) are contaminants in oils from marine sources. Testing for these contaminants are required, and must be performed using either the analytical method of the European Commission Regulation EU 252/2012 (EU 2012) or the U.S. Environmental Protection Agency's method 1613B for PCDDs and PCDFs and method 1668A for PCBs (USP 35, US EPA 2010, 2008,1994). Applicants are advised to consult the Council of the European Union document on these contaminants for further information (EU 2011). The maximum limits from EU1259/2011 are: for dioxins (sum of PCDDs and PCDFs) -- a maximum of 1.75 pg/g, for the sum of dioxins and DL-PCBs -- a maximum of 6 pg/g, and for PCBs -- a maximum of 200 ng/g. The maximum limits from USP 35 are for dioxins (sum of PCDDs and PCDFs) -- a maximum of 1.0 pg/g, and for PCBs -- a maximum of 0.5ppm (Refer to Appendix 1 Table 4) [(i)Maximums levels are expressed in World Health Organization (WHO 2005) toxic equivalents using WHO-toxic equivalent factors (TEFs). Analytical results relating to 17 individual dioxin congeners of toxicological concern are expressed in a single quantifiable unit: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxic equivalent concentration (TEQ) (USP 35~ EU 2011).(ii) Sum of dioxins: WHO-PCDD/F-TEQ (USP 35~ EU 2011) (iii) Sum of dioxins and dioxin-like PCBs: WHO-PCDD/F-PCB-TEQ (EU 2011) (iv) Sum of PCB congeners 28, 52, 101, 118, 138, 153 and 180 (USP 35~ EU 2011) (v) Equivalence: 0.5 ppm = 500 ng/g.
  • The medicinal ingredient must comply with the requirements outlined in the Natural Health Products Ingredients Database (NHPID). In addition, the medicinal ingredient may comply with the specifications outlined in the Fish Oil, Rich in Omega-3-Acids Monographs published in the European and British Pharmacopoeias or Fish oil containing Omega-3 Acids from the USP (Refer to Appendix 1 Table 2)

References cited

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Appendix 1

Table 1 Daily dose for eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in fish oil
Subpopulation EPA + DHA (mg/day)
Minimum Table 1 Footnote 1 Maximum Table 1 Footnote 2
Children 1-8 y 100 1,500
Adolescents 9-13 y
14-18 y
100
100
2,000
2,500
Adults Table 1 Footnote 3 ≥ 19 y 100 5,000

Table 1 Footnotes

Table 1 Footnote 1

Restrictions to minimum dose may apply according to Use(s) or Purpose(s) section above.

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Table 1 Footnote 2

Adult maximum dose supported by US FDA 1997. Children and adolescent maximum doses, calculated as a fraction of the adult dose, are relative to body weight and caloric intake.

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Table 1 Footnote 3

Includes pregnant and breastfeeding women.

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Table 2 Fish Oil Monographs published in the American (USP), British (BP) and European (Ph.Eur.) Pharmacopoeias
Pharmacopoeia Monograph
BP Fish Oil, Rich in Omega-3-Acids
Ph.Eur. Fish Oil, Rich in Omega-3-Acids
USP Fish Oil Containing Omega-3 Acids


Table 3 Maximum values of oxidative stability parameters for fish oil (HC 2007)
Oxidative stability parameter Maximum value
Peroxide value (PV) 5 mEq/kg
p-Anisidine value (AV) 20
Totox value 26 (calculated as (2 x PV) + AV)


Table 4 Maximum levels of dioxins, dioxin-like polychlorinated biphenyls (DL PCB) and polychlorinated biphenyls (PCBs) in oils from marine sources
Dioxin, DL PCB, and PCB contaminants Maximum level
EU 1259/2011 USP 35
Dioxins (sum of PCDDs + PCDFs) Table 4 Footnote 1 Table 4 Footnote 2 1.75 pg/g 1.0 pg/g
Sum of dioxins and DL-PCBs Table 4 Footnote 1 Table 4 Footnote 3 6.0 pg/g
PCBs Table 4 Footnote 4 200 ng/g 0.5 ppm Table 4 Footnote 5

Table 4 Footnotes

Table 4 Footnote 1

Expressed in World Health Organization (WHO 2005) toxic equivalents using WHO-toxic equivalent factors (TEFs). Analytical results relating to 17 individual dioxin congeners of toxicological concern are expressed in a single quantifiable unit: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxic equivalent concentration (TEQ) (USP 35; EU 2011)

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Table 4 Footnote 2

Sum of dioxins: WHO-PCDD/F-TEQ (USP 35; EU 2011)

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Table 4 Footnote 3

Sum of dioxins and dioxin-like PCBs: WHO-PCDD/F-PCB-TEQ (EU 2011)

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Table 4 Footnote 4

Sum of PCB congeners 28, 52, 101, 118, 138, 153 and 180 (USP 35; EU 2011).

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Table 4 Footnote 5

Equivalence: 0.5 ppm = 500 ng/g

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