Monograph - Multi-Vitamin/Mineral Supplements

October 22, 2007

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Table Of Contents

1.0 Proper name(s), Common name(s) and Source material(s)

1.1 Vitamin proper name(s), common name(s) and source material(s)

1.2 Mineral proper name(s), common name(s) and source material(s)

1.3 Other medicinal ingredient proper name(s), common name(s) and source material(s)

2.0 Route(s) of administration

3.0 Dosage form(s)

4.0 Use(s) or Purpose(s)

4.1 General use or purpose statement(s)

4.1.1 Medicinal ingredients for which only general use or purpose statement(s) are permitted

4.2 Specific use or purpose statements(s)

4.2.1 Specific use or purpose statement(s) for vitamins

4.2.2 Specific use or purpose statement(s) for minerals

4.2.3 Specific use or purpose statement(s) for other medicinal ingredients

5.0 Dose(s)

5.1 Background on dose

5.2 Dose information for vitamins

5.3 Dose information for minerals

5.4 Dose information for other medicinal ingredients

5.5 Directions for use

6.0 Duration of use

7.0 Risk information

7.1 Caution(s) and warning(s)

7.2 Contraindication(s)

7.3 Known adverse reaction(s)

8.0 Non-medicinal ingredients

9.0 Specifications

10.0 References

11.0 Appendices

Appendix I: Guidelines for use or purpose statements

Appendix II: Dosage value definitions and derivations

Appendix III: Recommended Dietary Allowance (RDA) and Adequate Intake (AI) values

Appendix IV: Conversion factors

Multi-Vitamin/Mineral Supplement Monograph

• This monograph is intended for multi-vitamin, multi-mineral or multi-vitamin/mineral supplements that contain any two or more of the medicinal ingredients listed in Tables 1, 2 or 3 with the exception of combinations containing only the following medicinal ingredients: boron, choline, inositol, L-methionine, lutein, lycopene, nickel, silicon, tin and vanadium.
• For products containing a single vitamin or mineral as their sole medicinal ingredient, please refer to the appropriate single ingredient monograph.
• Products that are manufactured, sold or represented for use as a food or beverage are excluded.
• Sodium is not permitted as a medicinal ingredient on this monograph due to health concerns associated with chronic supplemental use, namely hypertension, which remains the most common and most important risk factor for cardiovascular disease. However, the use of sodium as a counter-ion in medicinal or non-medicinal ingredients (e.g. sodium salts of minerals) is acceptable where warranted.
• Chlorine, fluorine and sulfur are not permitted as medicinal ingredients on this monograph.

1.0 Proper name(s), Common name(s) and Source material(s)

1.1 Vitamin proper name(s), common name(s) and source material(s)

Table 1: Vitamin proper name(s), common name(s) and source material(s)

^1,2 At least one of the following references was consulted per name: NIH 2007; Sweetman 2007; USP 30; IOM 2003; O'Neil et al. 2001.
³ At least one of the following references was consulted per source material: HC 2007a; NIH 2007; Sweetman 2007; USP 30; IOM 2003; Van Der Kuy et al. 2002; O誰eil et al. 2001; Chalmers et al. 2000; EC 2000; Zeitlin et al. 1985; Yamagata et al. 1966.
Additional note: The slash (/) indicates that the terms are synonyms. Either term may be selected by the applicant.

1.2 Mineral proper name(s), common name(s) and source material(s)

Table 2: Mineral proper name(s), common name(s) and source material(s)

^1,2 At least one of the following references was consulted per name: NIH 2007; Sweetman 2007; USP 30; IOM 2003; O誰eil et al. 2001.
³ At least one of the following references was consulted per source material: Guiry and Guiry 2007; HC 2007a; NIH 2007; Sweetman 2007; USP 30; Albion 2004a; Albion 2004b; Commonwealth of Australia 2004; Gruenwald et al. 2004; Albion 2003a; Albion 2003b; IOM 2003, Allen 2002; Commonwealth of Australia 2002; Van Der Kuy et al. 2002; Anderson et al. 2001; Firoz and Graber 2001; Hendler and Rorvik 2001; O誰eil et al. 2001; Albion 2000; Chalmers et al. 2000; EC 2000; Patrick 1999; Albion 1997a; Albion 1997b; Grant et al. 1997; Albion 1996a; Albion 1996b; Murray 1996; Albion 1995; Albion 1993a; Albion 1993b; Albion 1993c; Albion 1993d; Albion 1993e; Evans and Pouchnik 1993; Albion 1992; Zeitlin et al. 1985; Abbott and Hollenberg 1976; Yamagata et al. 1966.
⁴ When bone meal is used as a source material for calcium or phosphorus, it must be sourced from a non-human animal that is not susceptible to Transmissible Spongiform Encephalopathy (TSE) diseases, including Bovine Spongiform Encephalopathy (BSE) (HC 2006).
⁵ Data (or certification) must be submitted to show that thiaminase has been inactivated.
⁶ There is no evidence to support tin as a factor in the maintenance of good health (FSA 2003; FSA 2002).

Additional note: the slash (/) indicates that the terms are synonyms. Either term may be selected by the applicant.

1.3 Other medicinal ingredient proper name(s), common name(s) and source material(s)

Table 3: Other medicinal ingredient proper name(s), common name(s) and source material(s)

^1,2 At least one of the following references was consulted per name: NIH 2007; Sweetman 2007; USP 30; IOM 2003; O誰eil et al. 2001.
³ At least one of the following references was consulted per source material: HC 2007a; NIH 2007; Sweetman 2007; USP 30; IOM 2003; O誰eil et al. 2001.
⁴ Ingredient must be pharmacopoeial grade (for a list of acceptable pharmacopoeial grades, see the Compendium of Monographs) or cited in an approved NHP Master File, authorized by a letter of access issued to the applicant by the NHP Master File's registered owner.
Additional note: The slash (/) indicates that the terms are synonyms. Either term may be selected by the applicant.

2.0 Route(s) of administration

Oral

3.0 Dosage form(s)

Those pharmaceutical dosage forms suited to oral administration, including but not limited to chewable tablets, caplets, capsules, strips, lozenges, powders or liquids where the dose is measured in drops, teaspoons or tablespoons, are acceptable. This monograph is not intended to include food-like dosage forms such as bars, gums or beverages.

4.0 Use(s) or Purpose(s)

Refer to Appendix I for guidelines on using the use(s) or purpose(s) outlined in this section.

4.1 General use or purpose statement(s)

The following use or purpose statement(s) can be used in reference to any combination of vitamins or minerals, as appropriate.

Statement(s) to the effect of:

• Vitamin supplement, mineral supplement, vitamin/mineral supplement, multi-vitamin, multi-mineral or multi-vitamin/mineral
• A factor in the maintenance of good health.

4.1.1 Medicinal ingredients for which only general use or purpose statement(s) are permitted

Table 4: Medicinal ingredients for which only general use or purpose statement(s) are permitted

¹ The term "lipotropic factor" is not permitted to describe choline, inositol or L-methionine. This term may mislead consumers to perceive the product as fat-burning or for the purpose of weight loss.
² There is no evidence to support tin as a factor in the maintenance of good health (FSA 2003; FSA 2002). ).

4.2 Specific use or purpose statement(s)

Statements(s) to the effect of:

4.2.1 Specific use or purpose statement(s) for vitamins

Table 5: Specific use or purpose statement(s) for vitamins

¹ At least two of the following references were consulted per use or purpose statement: IOM 2006; Shils et al. 2006; MacKay and Miller 2003; IOM 2001; Groff and Gropper 2000; IOM 2000; NIH 2000; IOM 1998; IOM 1997.
² A specific use or purpose statement must be made for products providing > 35 mg niacin or niacinamide per day
^* This use or purpose statement is acceptable only if the vitamin is present at dosages at or above the Recommended Dietary Allowance (RDA) or Adequate Intake (AI). See Appendix II for RDA and AI definitions and Appendix III for detailed values according to life stage group. Note that most vitamin deficiencies are rare in North America.

4.2.2 Specific use or purpose statement(s) for minerals

Table 6: Specific use or purpose statement(s) for minerals

¹ At least two of the following references were consulted per use or purpose statement: IOM 2006; Shils et al. 2006; Meisel et al. 2005; Schwartz et al. 2005; IOM 2001; Groff and Gropper 2000; IOM 2000; NIH 2000; IOM 1997; Klimis-Tavantis 1994.
² A specific use or purpose statement must be made for products providing > 35 mg iron per day.
³ A specific use or purpose statement must be made for products providing > 350 mg magnesium per day.
⁴ A specific use or purpose statement must be made for products providing > 40 mg zinc per day.
^*This use or purpose statement is acceptable only if the mineral is present at dosages at or above the RDA or AI. See Appendix II for RDA and AI definitions and Appendix III for detailed values according to life stage group. Note that most mineral deficiencies are rare in North America.

4.2.3 Specific use or purpose statement(s) for other medicinal ingredients

Table 7: Specific use or purpose statement(s) for other medicinal ingredients

¹ At least two of the following references were consulted per use or purpose statement: IOM 2006; Shils et al. 2006; IOM 2001; Groff and Gropper 2000.
^* This use or purpose statement is only acceptable if beta-carotene is present at dosages at or above the RDA or AI for vitamin A. See Appendix II for RDA and AI definitions and Appendix III for detailed values according to life stage group. Note that most vitamin deficiencies are rare in North America.

5.0 Dose(s)

5.1 Background on dose

• The daily dose of each medicinal ingredient must be at or above the minimum dosage value and at or below the maximum dosage value. Refer to Appendix II for definitions and derivations of dosage values.
• Vitamin E is expressed as milligrams (mg) of RRR-α-tocopherol (AT) and vitamin A as micrograms (μg) of retinol activity equivalents (RAE).
• Refer to Appendix IV for conversion factors (pantothenic acid, vitamin A, beta-carotene, vitamin D, and vitamin E).

5.2 Dose information for vitamins

Table 8: Dose information for vitamins presented as dose per day

¹ Products providing folate at doses = 200 µg per day must supplement with vitamin B₁₂ at the RDA dosage (HC 2005a). See Appendix II for the RDA definition and Appendix III for a detailed list of RDA values.
² A specific use or purpose statement must be made for products providing > 35 mg niacin or niacinamide per day.
³ The maximum daily dose for beta-carotene in combination with other vitamin A source materials must not exceed the Tolerable Upper Intake Level (UL) for vitamin A. (The UL for vitamin A is equivalent to the maximum daily dose outlined in Table 8.)
⁴ The maximum dose for cobalt and vitamin B₁₂ combined must not exceed 1000 µg vitamin B₁₂ per day.

5.3 Dose information for minerals

Table 9: Dose information for minerals presented as dose per day

¹ The maximum dose for cobalt and vitamin B₁₂ combined must not exceed 1000 ｵg of vitamin B₁₂ per day.
² A specific use or purpose statement must be made for products providing > 35 mg iron per day.
³ A specific use or purpose statement must be made for products providing > 350 mg magnesium per day.
⁴ A specific use or purpose statement must be made for products providing > 40 mg zinc per day.
⁵ Products providing zinc without copper or with copper at doses less than those specified below must be labelled with the risk statement set out in 7.3.

5.4 Dose information for other medicinal ingredients

Table 10: Dose information for other medicinal ingredients presented as dose per day

¹ Beta-carotene must be expressed in both micrograms (ｵg) or milligrams (mg) of beta-carotene and micrograms (ｵg) or milligrams (mg) of RAE. For conversion factors for beta-carotene to RAE, see Appendix IV.
² The maximum daily dose for beta-carotene in combination with other vitamin A source materials must not exceed the Tolerable Upper Intake Level (UL) for vitamin A. (The UL for vitamin A is equivalent to the maximum daily dose outlined in Table 8.)

5.5 Directions for use

Statement(s) to the effect of:

For products containing calcium, iron or zinc, the following statement is required:

• Take a few hours before or after taking other medications (Sweetman 2007; ASHP 2005).

For products containing niacin at doses = 30 mg per day or containing iron or zinc, the following statement is required:

• Take with food (Sweetman 2007).

In all other cases, optional statement(s), as appropriate:

• Take with food, or
• Take on an empty stomach.

6.0 Duration of use

No statement required.

7.0 Risk information

Statement(s) to the effect of:

7.1 Caution(s) and warning(s)

Table 11: Caution(s) and warning(s) for all medicinal ingredients with associated daily doses

¹ There is no evidence to support tin as a factor in the maintenance of good health (FSA 2003; FSA 2002).

7.2 Contraindication(s)

For products providing niacin at doses of 500 mg per day, the following statement is required.

• Do not exceed the recommended dose except on the advice of a physician.

7.3 Known adverse reaction(s)

Table 12: Known adverse reaction(s) for all medicinal ingredients with associated daily doses

8.0 Non-medicinal ingredients

Ingredients must be chosen from the current NHPD List of Acceptable Non-medicinal Ingredientsand must meet the limitations outlined in the list.

9.0 Specifications

Products must comply with the minimum specifications outlined in the current NHPD Compendium of Monographs.

10.0 References

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Albion 1992: Zinc - the multifaceted trace mineral.  Albion Research Notes 1992;1(3) [Accessed 2007-03-21]. Available from:
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IOM 2006: Institute of Medicine. Otten JJ, Pitzi Hellwig J, Meyers LD, editors. Institute of Medicine.  Dietary Reference Intakes: The Essential Guide to Nutrient Requirements.  Washington (DC): National Academies Press; 2006.

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11.0 Appendices

Appendix I

Guidelines for use or purpose statements

It is mandatory for all natural health products to cite at least one use or purpose statement.

General use or purpose statements:

1) Permissible use or purpose statements for products containing one or more minerals and one or more vitamins:

• Vitamin/mineral supplement
• Multi-vitamin/mineral supplement
• A factor in the maintenance of good health.

2) Permissible use or purpose statements for products containing two or more minerals:

• Mineral supplement
• Multi-mineral supplement
• A factor in the maintenance of good health.

3) Permissible use or purpose statements for products containing two or more vitamins:

• Vitamin supplement
• Multi-vitamin supplement
• A factor in the maintenance of good health.

Specific use or purpose statements:
Ingredient specific use or purpose statements can be used for any or all of the medicinal ingredients contained in a multi-ingredient product as applicable (see Section 4.2 - Specific use or purpose statement(s)).

A specific use or purpose statement must be made for products providing magnesium (> 350 mg per day), niacin (> 35 mg per day), iron (> 35 mg per day), or zinc (> 40 mg per day).

Inclusion of medicinal ingredient names in a specific use or purpose statement is optional, for example, the specific use or purpose statement can be applied to the whole product. However, if medicinal ingredient names are specified in a use or purpose statement, the statement must be valid for all medicinal ingredients specified. See below for examples on the correct and incorrect use of specific ingredient use or purpose statements:

Correct use:
"Biotin and pantothenic acid to help the body metabolize carbohydrates, fats and proteins."
This is correct because both medicinal ingredients contribute to that use or purpose.

Incorrect use:
"Biotin and folate to help the body metabolize carbohydrates, fats and proteins."
This is incorrect because biotin has that purpose but folate does not.

Appendix II

Dosage value definitions and derivations

1) Definitions:

Adequate Intake (AI):The recommended average daily intake level based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is used when an RDA cannot be determined (IOM 2006).

Maximum dosage value:The highest medicinal ingredient quantity which a product can supply in a daily dose.

Minimum dosage value: The lowest medicinal ingredient quantity which a product can supply in a daily dose.

Recommended Dietary Allowance (RDA):The average daily dietary nutrient intake level sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in a particular life stage and gender group (IOM 2006).

Tolerable Upper Intake Level (UL):The highest average daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population. As intake increases above the UL, the potential risk of adverse effects may increase (IOM 2006).

2) Derivations:

AI, RDA and UL values:

These values were established by the Food and Nutrition Board of the Institute of Medicine in collaboration with Health Canada (IOM 2006).

Maximum dosage value:

The method used to set maximum dosage values varied for each medicinal ingredient depending on numerous factors. The method used to derive maximum dosage levels for vitamins and minerals with established physiological functions was different from the method used for those with unestablished physiological functions.

1. Maximum dosage values for vitamins and minerals with established physiological functions were developed based on the following criteria:
   1. Is there an established UL?
      • If there is an established UL, does it apply to supplements only or to food and supplements?
      • If there is an established UL, how was it derived (i.e., what was the critical adverse reaction on which it was based? was it serious or non-serious? if non-serious, could it be mitigated?)?
   2. What is the average dietary intake?
   3. What doses have previously been marketed in Canada?
   4. What do other regulatory agencies and expert groups recommend as their maximum daily dose?
   5. What doses have been used in clinical trials and have demonstrated evidence for safety and efficacy?
      
      
      The only vitamins which were excluded from the method outlined above were:
      • • Vitamin D (due to its listing on Schedule F of the Food and Drug Regulations at 25 µg/ day (HC 2007b))
      • Vitamin E (due to the potential health risks of high dose vitamin E in certain subpopulations)
      • Vitamin K₁ and K₂ (adult dose was set in Canada Gazette II (HC 2005b) and children痴 doses were set at the AI level (IOM 2006)).
2. Maximum dosage values for minerals with unestablished physiological functions (boron, nickel, silicon, tin and vanadium) were calculated from the No Observed Adverse Effect Level (NOAEL) divided by an uncertainty factor (UF). The UF chosen was based on the following: 10 for extrapolation of animal data to humans, 10 for intra-species variation, and 10 for chronic use in humans. If applicable, (i.e., NOAEL was based on animal data) the final value was multiplied by an average adult body weight of 70 kg.

With the exception of beta-carotene, the maximum dosage value for non-vitamin and non-mineral ingredients was set based on doses demonstrated to be safe in clinical trials. For beta-carotene the maximum dosage value was set as per the vitamin A UL.

Minimum dosage value:

For medicinal ingredients which did not have an RDA or AI, the minimum dose was set at zero. For the remaining medicinal ingredients (with the exception of potassium and choline), the minimum was set using the following method:

5% of the RDA and/or AI was calculated for each life stage group (This method was modelled after the Food and Drug Regulation vitamin and mineral minimum dose requirements as per Sections D.01.004 and D.02.002 (HC 2007b)).

1. The highest value derived for children (1-13 years) was applied to all children within this age category;
2. the highest value derived for adolescents (= 14 years) and adults (including pregnant and breastfeeding women) was applied;
3. The highest value derived for infants (0-12 months) was applied (if applicable).

For potassium and choline, the AIs were inappropriate for setting minimum dosage values and therefore, the minimums were set at zero.

Appendix III

Recommended Dietary Allowance (RDA) and Adequate Intake (AI) values

The AI (as indicated by an asterisk) and RDA values are provided below. For the purpose of this monograph, these values are intended to:

• provide targets for setting appropriate supplement dosage levels;
• provide the minimum dose for the use of the dose specific use or purpose statement: 滴elps to prevent (appropriate vitamin or mineral) deficiency?;
• facilitate the optional labelling of % RDA and AI values.

Notes:

• RDA and AI values have not been provided for those Life Stage Groups where the vitamin or mineral dosage is outside the scope of this Monograph.
• For certain minerals, an RDA or AI value has not been established.

Table 13: Recommended Dietary Allowance and Adequate Intake* values for vitamins (IOM 2006)

¹ The AI for vitamin K is based on median dietary intakes. Vitamin K1 is the predominant form of vitamin K in the diet (IOM 2006; IOM 2001).

Table 14: Recommended Dietary Allowance and Adequate Intake* values for minerals (IOM 2006)

¹ Calculated from the vitamin B₁₂ RDA (IOM 2006)

Appendix IV

Conversion factors

1) Pantothenic Acid(USP 30):

Table 15: Conversion of pantothenic acid source material quantity into pantothenic acid quantity

2. Vitamin A(IOM 2006):

The quantity of vitamin A must always be provided in terms of retinol activity equivalents (RAE) (i.e. μg all-trans retinol), irrespective of the source material used.

International Units (IU) may be provided as optional additional information on the Product Licence Application (PLA) form in the "potency" field and on product labels.

1 IU Vitamin A = 2 IU beta-carotene

Table 16: Conversion of vitamin A source material quantity into vitamin A quantity in terms of retinol activity equivalents (RAE) and vitamin A activity in terms of International Units (IU)

Examples using the vitamin A conversion factors:

1. Converting vitamin A activity into quantity of RAE (µg)
   
   Convert 500 IU of vitamin A activity from all-trans retinol into μg RAE:
   = 500 IU x 1 μg RAE/3.33 IU vitamin A
   = 150 μg RAE
   
   Convert 3000 IU of vitamin A activity from all-trans retinyl acetate into μg RAE:
   = 3000 IU x 1 μg RAE/3.33 IU vitamin A
   = 900 μg RAE
   
   or
   
   = 3000 IU x 0.87 μg RAE/2.94 IU vitamin A
   = 900 μg RAE
   
   
2. Converting vitamin A source material quantity into quantity of RAE (µg)
   
   Convert 2000 µg of all-trans retinyl palmitate into µg RAE:
   = 2000 µg x 0.55 µg RAE/µg all-trans retinyl palmitate
   = 1100 µg RAE
   
   
3. Converting beta-carotene activity into quantity of RAE (µg)
   
   Convert 500 IU of beta-carotene activity into µg RAE:
   = 500 IU beta-carotene x 1 IU vitamin A/2 IU beta-carotene x 1 µg RAE/3.33 IU vitamin A
   = 75 µg RAE
   
   or
   
   = 500 IU beta-carotene x 1 IU vitamin A/2 IU beta-carotene x 0.5 µg RAE/1.67 IU vitamin A
   = 75 µg RAE
   
   or
   
   see beta-carotene conversion factors below.

3. Beta-carotene(IOM 2006):

1 IU beta-carotene = 0.15 μg RAE
1 μg beta-carotene = 0.50 μg RAE

Examples using the beta-carotene conversion factors:

1. Converting beta-carotene activity into quantity of RAE (µg)
   
   Convert 500 IU of beta-carotene activity into μg RAE:
   = 500 IU beta-carotene x 0.15 μg RAE/IU beta-carotene
   = 75 μg RAE
   
   
2. Converting beta-carotene quantity into quantity of RAE (µg)
   
   Convert 2000 μg of beta-carotene into μg RAE:
   = 2000 μg beta-carotene x 0.5 μg RAE/μg beta-carotene
   = 1000 μg RAE

4. Vitamin D:

5. Vitamin E (IOM 2006):

The quantity of vitamin E must always be provided in terms of α-tocopherol (AT) (i.e. mg RRR-α-tocopherol), irrespective of the source material used.

IUs may be provided as optional additional information on the PLA form in the "potency" field and on product labels.

Table 17: Conversion of vitamin E source material quantity into vitamin E quantity in terms of alpha-(a)-tocopherol (AT) and vitamin E activity in terms of International Units (IU)

Table 18: Conversion of vitamin E source material activity into vitamin E quantity in terms of alpha-(a)-tocopherol (AT)

Examples using the vitamin E conversion factors:

1. Converting vitamin E activity into quantity of AT (mg)
   
   Convert 400 IU of RRR-α-tocopheryl succinate activity into mg AT:
   = 400 IU x 0.67 mg AT/IU
   = 268 mg AT
   
   
2. Converting vitamin E source material quantity into quantity of AT (mg)
   
   Convert 200 mg of all rac-α-tocopheryl acetate into mg AT:
   = 200 mg x 0.46 mg AT/mg
   = 92 mg AT