Herbs used as Non-medicinal Ingredients in Nonprescription Drugs for Human Use

Contact: BGIVD Enquiries

Drugs Directorate
Tunney's Pasture
Postal Locator # 0702A
OTTAWA, Ontario K1A 0L2

September 22, 1995

Sent to Various Associations

Please find attached the Drugs Directorate Policy on Herbals used as Non-medicinal Ingredients in Nonprescription Drugs in Human Use.

This policy provides written clarification of the currently applied policy for non-medicinal ingredients of botanical origin and provides expanded direction and detail. The increased understanding of and compliance with this policy by industry is expected to result in efficiencies that, in turn, will assist the Directorate in achieving its performance standards.

Please note that this policy is effective immediately. All Drug Identification Number (DIN) submissions which contain herbals as non-medicinal ingredients (NMIs) received in the Drugs Directorate after publication of the policy, and those that have been received but not yet accepted for review, will be screened for compliance with this policy in accordance with the Drugs Directorate Policy on Management of Drug Submissions.

For those DIN submissions that have already been screened and accepted for review prior to publication of this revised policy, but for which the review has not yet started, sponsors are encouraged to voluntarily update their submissions to comply with this policy only, without penalty to the status of those submissions. The update should consist of a completed Appendix III form and a covering letter/fax which identifies the name of the drug and the Submission Control Number, and should be sent to the Bureau of Nonprescription Drugs, Fax (613) 954-6511.

For those DIN submissions that have not been updated before being picked up for review, sponsors will be sent a Clarifax, and incomplete or late responses will be treated as stated in the Drugs Directorate Policy on Management of Drug Submissions.

If, upon subsequent review of the response to the Clarifax, noncompliance with provisions of the policy is noted, a Notice of Noncompliance will be issued. If compliance with this policy is verified upon review but other submission deficiencies are noted, a separate Clarifax relating to these deficiencies will be issued.

Note that the following Category IV monographs have been revised to be consistent with this policy on herbals used as nonmedicinal ingredients:

• Acne Therapy
• Antidandruff Products
• Antiperspirants
• Antiseptic Skin Cleansers
• Athlete's Foot Treatments
• Medicated Skin Care Products
• Sunburn Protectants

In addition, the Category IV Submission Certification Form has been revised to provide for attestation of compliance with this policy and other guidance documents. Copies of the revised monographs and Category IV Certification Form are posted on the Electronic Bulletin Board.

(originally signed by:)

Dann M. Michols
Executive Director

Attachment

Policy Issues
From the Drugs Directorate

September 11, 1995
950911.EXT

Bureau of Nonprescription Drugs: Herbs used as Non-medicinal Ingredients in Nonprescription Drugs for Human Use

Purpose:

This policy is intended to describe the conditions under which non-medicinal ingredients of botanical origin (herbs,), having therapeutic properties, may be accepted in nonprescription drug products for human use and to define the information that must be submitted by drug manufacturers to confirm compliance with those conditions.

Scope:

This policy will be applied to oral and topical nonprescription drug products for human use identified below that are not homeopathics and are not otherwise restricted with respct to content of non-medicinal ingredients of botanical origin (eg.,as a Category IV monograph requirement).

Policy:

Part A - For topical nonprescription products to be applied to unbroken skin:

1. Ingredients of botanical origin may be included as non-medicinals provided:
   1. they are listed in the Cosmetics, Toiletry and Fragrance Dictionary^{Footnote 1} and,
   2. they are not listed in Schedule F or C.01.038 of the Regulations to the Food and Drugs Act (Appendix 1) and,
   3. they are within the limits described in Appendix 1 and,
   4. they do not have the same pharmacological action(s) as the medicinal ingredient(s).
2. Information contained in the Drug Identification Number (DIN) application and Submission Certification forms will be considered sufficient to confirm compliance with Part A of this policy.

Part B - For nonprescription drug products intended for oral use:

1. Only those ingredients of botanical origin that present negligible risk may be considered acceptable as non-medicinal ingredients in nonprescription drug products for oral use. Some herbs that are considered unacceptable in this regard are identified in Appendix II. Note that this list is intended as a guide only and is not necessarily all inclusive.
2. The amount of a non-medicinal ingredient of botanical origin contained in the daily dose must not exceed 10% of the lowest therapeutic daily dose documented in traditional herbal literature.
3. In the case of two or more like-acting herbs, the pharmacological effects are considered to be additive and their combined activity must not exceed 10% for the same pharmacological action, based on the lowest documented therapeutic daily dose for each ingredient concerned.
4. A drug submission for a product intended for oral use and containing herbal non-medicinal ingredient(s) may be accepted for review if compliance with the policy, and with other requirements, is confirmed. Information in the submission must support compliance as follows:
   
   
   1. herbal non-medicinal ingredients, that are identified as being unacceptable, are not included (Appendix II):
   2. a herbal evaluation form, completed according to the instructions given in Appendix III, is appended to the submission:
   3. photocopies of two herbal references (Appendix IV) are included with the title page (title, year, authorship, place of publication) and monograph indicating:
      1. the reputed pharmacological action(s)/ therapeutic uses for the part of the plant used, as identified in the submission, (eg., leaf, root), and
      2. the minimum dosage for:
         • the part of the plant in the product, as identified in the submission, (eg.,leaf, root, stem...)
         • the form used, as identified in the submission, (eg., powdered extract, liquid extract, powdered leaf, tincture...)
   4. where a herb is present in a concentrated form (extract, tincture), the specifications must be provided in the following manner:
      1. where the specifications are exactly the same as given in the references provided, in terms of the concentration (eg., 1:5) and content of alcohol (if applicable), they should be declared accordingly in the submission or,
      2. where different from those stated in the references provided, the specifications and the crude dried herb equivalent must be declared as follows:
         
         Rosemary (leaf) ................. X mg
         (Rosemarinus Officinalis)
         (liquid extract 1:5
         in 25% alcohol)
         
         Passiflora (aerial parts) ....... Ymg
         (Passiflora incarnata)
         (solid extract 1:5)
      This means that contained in each unit of finished product (eg., dosage unit, millilitre etc.) is the equivalent of X mg or Ymg of the crude dried herb, respectively, provided by the liquid or solid extracts (as the source).
      
      Regarding the composition of the extract itself:
      
      Solid extract: 1:5 means that 1g of extract was derived from 5g crude dried material
      
      Liquid extract: 1:5 means that 1g crude dried material was used to prepare 5ml liquid extract
      
      For liquid extracts, the concentration of alcohol in the extract should also be declared as in the example above.
   5. the non-medicinal herb is present in an amount that is no more than 10% of the minimum reference dose, calculated as shown in Appendix III
   6. the combined activity of two or more like-acting non-medicinal herbs results in the product being medicated to a level that is no more than 10% for the same pharmacologic action:
   7. non-medicinal herbs must not have the same pharmacological action as medicinal ingredients.

Part C - For nonprescription drug products not included in Parts A or B

This group includes, but may not be limited to, drugs administered via the rectal, vaginal, nasal otic, ocular and sublingual routes or topically to abraded skin. The acceptability of nonmedicinal herbs in these products will be assessed on a case by case basis since the Drugs Directorate must be satisfied that there is no additional risk imposed by their presence.

Implementation

Following publication of the policy, submissions received in the Drugs Directorate for all products that are subject to the policy will be screened for compliance with the policy upon receipt. This is consistent with the provisions of the Drugs Directorate Policy on Management of Drug Submissions.

For Category IV products, an attestation of compliance with published policies is included in the DIN Certification form.

September 11, 1995

Appendix I - Herbal Ingredients to be Excluded from or Limited in Products Intended for Topical Use that are Subject to Part A

The following ingredients are listed in the CTTA Dictionary but are subject to the following limitations as nonmedicinal ingredients in topical products to be applied to unbroken skin:

Rauwolfia extract
(Schedule F)
0 level

Centenella asiatica extract (Hydrocotyl extract)
(Schedule F)
0 level

Wintergreen oil
up to 1% methyl salicylate

NOTE: this list is intended as a guide and is not necessarily all inclusive

Appendix II - List of herbs unacceptable as nonmedicinal ingredients in oral use products subject to part B

Note: Botanical names in bold type

(F) French Synonyms

This list is intended as a guide only and is not necessarily all inclusive

Appendix III

Ex. 1: Compliance with the 10% limit for a product with herbal nonmedicinal ingredient(s) in non-concentrated form is ascertained as follows:

Calculate the % medication for each ingredient using the following formula:

minimum reference daily dose .... X mg
content in minimum daily dose.... Y mg

(see table below for example)

Identify and attach the two references used and note that all pharmacological actions given should be identified; dosages must be for the part of the plant and form used.

Example 2:

Compliance with the 10% limit for a herb in concentrated form (extract^*, tincture) is ascertained by calculating 10% of the daily dose as follows:

1. where the specifications of the dosage form is exactly the same as those in the references provided.
   
   eg. product contains:
   echinacea (E. augustifolia) tincture 1:5 (in 45% alcohol) as a nonmedicinal ingredient and
   
   reference dose:
   
   1 - 2 ml of echinacea tincture 1:5 (in 45% alcohol)
   
   maximum amount of this extract that can be provided by the daily dose of the product is:
   
   
   
2. where the specifications of the dosage form are different from those in the references provided:
   
   eg. product contains:
   
   Capsicum (C. minimum) (dried fruit extract 1:3)
   
   reference dosages:
   
   three times daily:
   dried fruit 30 - 120 mg or
   tincture 1:20 in 60% alcohol, 0.3-1ml or
   strong tincture 1:3 in 60% alcohol, 0.06-0.2 ml
   
   maximum amount:
   
   since specifications of the reference doses are not the same as that of the nonmedicinal concentrated capsicum in the product, the equivalent weight of dried herb (expressed as in 4 (d), Part B of the policy) must be used as the basis for calculating the 10% limit
   
   
   

* liquid extract, solid extract, powdered extract etc.

Appendix IV

The following list of reference texts is intended as a guide only and is not all inclusive. It is comprised of some references texts available to the Drugs Directorate. Although certain references are more frequently used than others, the Drugs Directorate does not specifically endorse any of those listed and it is recognized that references outside of this collection may also provide valuable information.

Note that more recent evidence of toxicity will take precedence over information contained in the following references on traditional use.

Herbals- general / Produits a base de plantes médicinales- général

• American Chemical Society, Folk Medicine, Washington, DC, Editor: Richard P. Steiner, 1986.
• Blackwell, William H. Poisonous and Medicinal Plants. Englewood Cliffs, New Jersey : Prentice Hall, 1990.
• Boca Raton, CRC Handbook of Medicinal Herbs, edited by James A. Duke, Florida : CRC Press, 1985.
• British Herbal Medicine Association, British Herbal Compendium, Vol. 1. Published by the , Great Britain, 1992.
• Canadian Pharmaceutical Journal, Herbal Plants Issues from 1985.
• Castleman, Michael. The Healing Herbs. Emmanus, Pennsylvannia : Rodale Press, 1991.
• Claus, Edward P., et al. Pharmacognosy, Philadelphia, Lea & Febiger, 1970.
• CRC Press, Herbal Drugs and Phytopharmaceuticals, Medpharm Scientific Publishers, Ed. Norman Grainger Bisset, London, 1994.
• De Smet et al, Adverse effects of Herbal Drugs, vol. 1 & 2. , 1992, Springer Verlag.
• Gaia Books, The Complete New Herbal, London, , 1988.
• Gaia Books Ltd., The New Age Herbalist, New York, 1988.
• Grieve, M. A Modern Herbal. New York : Dover Publications, Inc., 1971.
• Hamon N.W., and Blackburn J.L., Herbal Products. Winnipeg, Cantext Publications, 1985.
• Lawrence Review of Natural Products, edited by Lawrence Liberti. Copies from 1985.
• Lust, John. The Herb Book. Toronto : Bantam Books, 1983.
• Osol, A. and Farrar, G. The Dispensatory of the United States of America 25th edition. Philadelphia : J.B. Lippincott, 1955.
• Polunin Miriam and Christopher Robbins, The Natural Pharmacy. Great Britain, Ed. Helen Barnett, 1992.
• Spoerke, David G. Herbal Medications. Santa Barbara, California : Woodridge Press Pub. Co., 1980.
• Stodola, Jiri and Frantisek Severa, The Illustrated Book of Herbs, Artia Prague, Ed. Sarah Bunney, 1984.
• Talalaj, S. and Czechowicz, Herbal Remedies: Harmful and Beneficial Effects. Australia, Hill of Content Publishing Pty Ltd, 1989.
• The Pharmaceutical Press, Martindale : The Extra Pharmacopoeia, 29th edition, ed James Reynolds, London, 1989.
• Tyler, V.E., Herbs of Choice: The Therapeutic Use of Phytomedicinals. Haworth Press, 1994.
• Tyler, Varro E., The Honest Herbal, Philadelphia, George F. Stickley Company, 1982.
• Tyler, Varro E. The New Honest Herbal. Philadelphia : George F. Strickley Company, 1987.
• Tyler, V.E., Brady L. and Robbers J. Pharmacognosy. Philadelphia: Lae & Febiger, 1988.
• Van Nostrand Reinhold Company, Herbs and Herbalism, edited by Malcolm Stuart, New York, 1979.
• Weiner, Michael, Weiner's Herbal. Stein and Day Publishers, New York, 1980.
• Weiss, Rudolf Fritz. Herbal Medicine Beaconsfield, England : Beaconsfield Publishers Ltd, 1988.
• Willard, Terry. Textbook of Advanced Herbology. Calgary, Alberta. Wild Rose College of Natural Healing, 1992.
• Willard, Terry. Textbook of Modern Herbology. Calgary, Alberta. C.W. Progressive Publishing, 1988.
• Willard, Terry, The Wild Rose Scientific Herbal. Wild Rose College of Natural Healing, Canada, 1991.
• Witchl, Max, Herbal Drugs and Phytopharmaceuticals, Norman Grainger Bisset Ed., CRC Press, Medpharm Scientific Publishers Stuttgart 1994,.
• Wren, R.C. Potter's New Cyclopaedia of Botanical Drugs & Preparations. Saffron Waldon, England : C.W.Daniel Co. Ltd., 1989.

Pharmacopeias / Pharmacopées

• British Herbal Pharmacopoeia, Vols 1-3. Produced by the British Herbal Medicine Association Scientific Committee, 1980/81.
• British Herbal Pharmacopeia, Vol. 1. Published by the British Herbal Medicine Association (revised by the Scientific Committee), 1990.
• British Pharmaceutical Codex. London: The Pharmaceutical Press. Prepared by the Pharmaceutical Society of Great Britain, 1968.
• British Pharmacopeia. 1993, with subsequent Addenda up to 1995.
• European Pharmacopeia, 2nd Edition, Part I, 1980; Part II, First fascicule (1980) to tenth fascicule. Published by Maisonneuve S.A., 57160 Saint-Ruffine, France, under the direction of the Council of Europe.
• The International Pharmacopeia,
• Pharmacopée Internationale, Vol. 1-3, Organisation mondiale de la santé, 1980-1981.
• The United States Pharmacopeia, The National Formulary (USP XXIII-NF XVIII). U.S. Pharmacopeial Convention Inc., 1995.

Chinese herbal / Produits a base de plantes médicinales chinoises

• Chang, Hson-Mou and Paul Pui-Hay But, Pharmacology and applications of Chinese Materia Medica, Vol. 1 & 2, Philadelphia, World Scientific Publishing Co Pte Ltd, 1986.
• Chinese Herbal Medicine. Washington, Eastland Press Inc., 1993.
• Duke, J.A and Ayensu, E.S. Medicinal Plants of China (2 Vols). Algonac, Michigan: Reference Publications Inc., 1985.
• Huang, Kee Chang, The Pharmacology of Chinese Herbs, Kentucky, CRC Press, 1993.
• Keys, John D. Chinese Herbs. Tokyo:Charles E. Tuttle Company, 1981.
• Khory, Rustomjee Naserwanjee, et al, Materia medica of India and their therapeutics, New Delhi, Neeraj Publishing House, 1985.
• Kirtikar, K.R. et al, Indian Medicinal Plants, IndiaLalit Mohan Basu, Second Edition.
• Kurup, Dr. P.N.V. et al, Handbook of medicinal plants, New Dehli, Central Council for Research in Ayurveda and Siddha (CCRAS), 1979.
• Leung, Albert Y., Chinese Herbal Remedies, New York:Universe Books, 1984.
• National Academy of Sciences, Herbal Pharmacology in the People's Republic of China. Washington, D.C. : , 1975.
• Running Press, A Barefoot Doctor's Manual, A translation of the Official Chinese Paramedical Manual. Philadelphia, Pennsylvania:, 1990.