Folate and folic acid for use in listed medicines

This factsheet has been created for sponsors who wish to list folate products on the ARTG. It is intended to provide general information on the most commonly used folates and answer the most frequently asked questions.

Folate, or vitamin B9, is an essential vitamin required by the human body for normal growth and development as it plays a critical role in the synthesis of DNA and RNA, and in the metabolism of certain amino acids.

The term "folate" is actually a generic name for a group of related compounds with similar nutritional properties. The three most commonly used forms are folic acid, calcium folinate and levomefolate salts. All three forms can be incorporated into the body's metabolic pathways and may provide sources of the same biologically active form of folate – a compound known as 5-methyltetrahydrofolate (5-MTHF) or levomefolic acid.

Folic acid

Folic acid is the most common form of Vitamin B9 and is a synthetic compound that must be metabolised by the body before it can be used. It is converted by the body first to dihydrofolate (DHF), then tetrahydrofolate (THF) and finally to the biologically active form, levomefolic acid.

Folinic acid

Folinic acid, also known as 5-formyltetrahydrofolate or leucovorin, is a formyl derivative of THF. It exists in two isomeric forms, and only the 6S-isomer is converted to THF and then levomefolic acid/ 5-MTHF. As a result, unless provided as purified 6S-isomer it does not provide a 1:1 molar equivalent source of folate relative to folic acid.

Levomefolic acid

Levomefolic acid, also known as 5-methyltetrahydrofolate (5-MTHF) is the biologically active form of folate and the form found in circulation. It does not require enzymatic conversion and can be utilised directly by the body.

Metabolic Pathway

The relationship between these forms of folate is summarised in the diagram below. Specifically, it demonstrates the point at which these ingredients enter the metabolic pathway.

Folates in Listed Medicines

There are four folate sources currently permitted for use in listed medicines via the Permissible Ingredients Determination (the Determination). These are folic acid, calcium folinate, levomefolate glucosamine, and levomefolate calcium.

These ingredients are most commonly used in preparations indicated for reducing the risk of having a child with spina bifida and/or neural tube defects. These indications are restricted representations and a sponsor must have an advertising exemption for the claim, or have a product that meets the requirements of the folic acid advertising exemption (see FAQs below). When a sponsor wishes to make these indications, products must contain a dose equivalent to 400-500 micrograms of folic acid and include the following statements on the label:

• (NEUR) 'Warning: Do not exceed the stated dose except on medical advice. If you have had a baby with a neural tube defect/spina bifida - seek specific medical advice (or words to that effect)'; and
• (VIT) 'Vitamins can only be of assistance if the dietary vitamin intake is inadequate.' or 'Vitamin supplements should not replace a balanced diet'.

Frequently asked questions

If the ingredient in my product is calcium folinate or a levomefolate salt, can I use the Coded (Standard) Indications NEUR1, NEUR2, FOLIC1, FOLIC2 and VIT2 for my product?

No. Standard indications for folic acid are not currently available for folinate or levomefolate. However, sponsors are able to enter their own indications for their medicine, for which they hold evidence at the time of listing. It should be noted that calcium folinate may be provided as a racemic mixture of enantiomers and, as only the 6S-isomer has similar activity (as folic acid) in the body, folinic acid is not a molar equivalent substitute for folic acid when provided as this mixture.

If the ingredient in my product is calcium folinate or a levomefolate salt, does the Advertising Exemption of 15 May 2015: 'Folic acid (minimum recommended daily dosage of 400 micrograms)' apply to my product?

No. This advertising exemption does not apply to folinate or levomefolate. As levomefolates are considered distinct from folic acid in certain aspects, this advertising exemption cannot be extended to levomefolic acid as it has not been assessed in accordance to the advertising provisions under Chapter 5 of the Therapeutic Goods Act 1989 (the Act). However, you may submit an application under section 42DF of the Act to facilitate such an assessment.

If the ingredient in my tablet or capsule is calcium folinate or a levomefolate salt, do I need to comply with the requirements of section 9 of the Therapeutic Goods Order No. 78 – Standard for Tablets and Capsules (TGO 78)?

No. Calcium folinate and levomefolate salts are considered distinct from folic acid for the purposes of TGO 78 and as such, section 9 ('Tablet or capsules containing folic acid') does not apply to tablets or capsules containing only calcium folinate and levomefolate salts.

However, sponsors may still choose to include these tests as part of the testing protocol for tablets or capsules containing calcium folinate and levomefolate salts. This will ensure the tablets or capsules are compliant should the TGO 78 requirements for folic acid be broadened in the future to include salts of folinate and levomefolate.