1.3. Interim decision in relation to calcifediol

1. Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #28, November 2019)

1.3. Interim decision in relation to calcifediol

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to amend the current Poisons Standard in relation to calcifediol as follows:

Proposed date of effect of the proposed amendment

1 June 2020

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Summary of pre-meeting public submissions | Summary of ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to create a new Schedule 4 entry for calcifediol was considered.

The Applicant's proposed amendments to the Poisons Standard were:

The Applicant's main points provided in support of the proposed amendment are as follows:

• Vitamin D (in both the colecalciferol and ergocalciferol forms) has a well-established profile and history of use. Calcifediol is the immediate metabolite of colecalciferol and is the circulating form of Vitamin D in the human body.
• The TGA has identified that calcifediol provides the same health benefits as colecalciferol, however the potency appears to be approximately three times greater. The safe daily dosage recommended by the TGA after evaluation is <10 micrograms/day in comparison to the Vitamin D scheduling limit of <25 micrograms/day.
• Calcifediol, as a direct metabolite of colecalciferol, would fall within the current scheduling entry for Vitamin D; i.e. it would be unscheduled at a daily dose of less than 25 micrograms per day. However, a safety evaluation performed by the TGA showed that the safe dosage for calcifediol is less than 10 micrograms per day. As such, it is proposed that a separate schedule entry be created for calcifediol to restrict the daily dosage to less than 10 micrograms per day unless medically prescribed.

Current scheduling status

Calcifediol monohydrate is not specifically scheduled in the current Poisons Standard. However, it is considered a derivative of vitamin D and is therefore covered by the existing schedule entries for Vitamin D.

Vitamin D is currently listed in Schedules 3 and 4 and Appendix H of the Poisons Standard as follows:

Calcifediol monohydrate is also a metabolite of the scheduled substance colecalciferol. Colecalciferol is currently listed in Schedule 7 and Appendix J of the Poisons Standard as follows:

Scheduling history

While calcifediol monohydrate is not specifically scheduled in the Poisons Standard, it is covered by the existing scheduled entry for vitamin D.

In March 1972, the National Drugs and Poisons Schedule Sub-committee (PSSC) first consider the scheduling of vitamin D. The PSSC considered a recommendation from the Nutrition Committee to set a concentration limit of vitamin A and D. A new Schedule 4 entry for vitamin D was created as follows: 'VITAMIN D when the recommended daily dosage on the label exceeds 10 micrograms'.

In July 1972, the PSSC gave consideration to Canadian restrictions (1972) on vitamin A and D products containing more than 1000 units (25 micrograms) of vitamin D in a recommended daily dose (RDD) being classified as prescription only medicines. The Sub-Committee agreed that high dosage requirements should be under medical supervision and a new Schedule 4 entry was recommended for vitamin D when the RDD exceeded 25 micrograms.

In November 1986, the Drugs and Poisons Schedule Committee (DPSC) revised the vitamin D Schedule 4 entry to clarify that the entry applied not just to preparations containing vitamin D, but also to the substance itself. The vitamin D Schedule 4 entry was amended to read, 'VITAMIN D for human therapeutic use except in preparations containing 25 micrograms or less of vitamin D per recommended daily dose'.

In November 1994, the National Drugs and Poisons Schedule Committee (NDPSC) noted that the vitamin D entry was originally intended to apply to preparations for internal use and that vitamin D was used in ointments and creams in the form of fish liver oils. Therefore, the Committee amended the Schedule 4 entry to 'VITAMIN D for human internal therapeutic use except in preparations containing 25 micrograms or less of vitamin D per recommended daily dose'.

In October 2009, the NDPSC considered an application from XXXXXXXXXXX to:

1. Implement a concentration cut-off from Schedule 4 to Schedule 3 for preparations within a RDD of 125 micrograms or less (retaining the current exemption for preparations with an RDD of 25 micrograms or less); and
2. Include vitamin D in Appendix H.

The NDPSC Evaluation report, while noting that the Applicant had presented a convincing case for both the prevalence of vitamin D deficiency and the need to treat such a deficiency, had not adequately justified why a high dose vitamin D should be listed as a Schedule 3 item rather than Schedule 4. The Committee generally agreed that while it was desirable to have a high potency vitamin D oral preparation available in Australia, professional medical diagnosis and management was required to treat moderate to severe vitamin D deficiency with such preparations. The Committee therefore decided that the scheduling of vitamin D remained appropriate.

Australian regulations

• According to the TGA Ingredient Database, calcifediol monohydrate is:
  • Available for use as an active ingredient in: Export Only, Listed Medicines;
  • Not available as a Homoeopathic Ingredient in Listed Medicines;
  • Not available as an Excipient Ingredient in any application; and
  • Not available as an Equivalent Ingredient in any application.
• According to the TGA Ingredient Database, calcifediol is:
  • Not available as an Active Ingredient in any application;
  • Not available as an Excipient Ingredient in any application; and
  • Available for use as an Equivalent Ingredient in: Export Only, Listed Medicines.
• According to the TGA Ingredient Database, colecalciferol is:
  • Available for use as an Active Ingredient in: Biologicals, Export Only, Listed Medicines, Over the Counter, Prescription Medicines;
  • Not available as a Homoeopathic Ingredient in Listed Medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Export Only, Listed Medicines, Over the Counter, Prescription Medicines;
  • Available for use as an Equivalent Ingredient in: Listed Medicines, Prescription Medicines.
• According to the TGA Ingredient Database, ergocalciferol is available:
  • Available for use as an Active Ingredient in: Biologicals, Export Only, Listed Medicines, Over the Counter, Prescription Medicines;
  • Not available as a Homoeopathic Ingredient in Listed Medicines;
  • Available for use as an Excipient Ingredient in: Biologicals, Devices, Listed Medicines, Prescription Medicines;
  • Not available as an Equivalent Ingredient in any application.
• As of 5 July 2019, there are no products active on the Australian Register of Therapeutic Goods (ARTG)^[41] that contain calcifediol monohydrate as an active ingredient. There are also 45 products containing ergocalciferol and there are 1224 products that contain colecalciferol.
• An entry for calcifediol monohydrate is included in the current Therapeutic Goods (Permissible Ingredients) Determination (No. 4) of 2019^[42].
• Calcifediol is not included in the Prescribing medicines in pregnancy database.^[43]
• The Medicines Advisory Statement Specification 2019 (RASML No. 5 - Schedule 1)^[44] does not specifically list calcifediol monohydrate.
• The Database of Adverse Event Notifications (DAEN)^[45] does not contain any reports for calcifediol. However, the DAEN does contain 661 reports of adverse events for products containing colecalciferol (vitamin D3) as an active ingredient, with 569 reports where colecalciferol was the single suspected medicine. There were three reports of deaths associated with colecalciferol use.
• There are twenty-seven (27) entries for Vitamin D listed on the Public Chemical Registration Information System Search (PUBCRIS)^[46]. Five entries are for Vitamin D3 active constituent approvals (XXXX, XXXXX, XXXXX, XXXXX and XXXXX) and twenty-two are for product registrations. Of these product entries, one is a pesticide product (vertebrate poison) that contains Vitamin D as the sole active constituent (XXXXX) and twenty-one (21) are veterinary products (nutrition and metabolism) that contain Vitamin D in combination with other active constituents (XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX, XXXXX and XXXXX). There are no entries for calcifediol.

International regulations

• The European Chemicals Agency (ECHA) hazard classification and labelling for calcifediol monohydrate is 'Danger! According to the classification provided by companies to ECHA in CLP notifications this substance is fatal if swallowed, is fatal in contact with skin, is fatal if inhaled, causes damage to organs through prolonged or repeated exposure, is suspected of damaging fertility or the unborn child and may cause long lasting harmful effects to aquatic life'.
• Calcifediol is not available for use in New Zealand. However, The New Zealand Medicines and Medical Devices Safety Authority (MEDSAFE)^[47]: Vitamin D for internal use in medicines containing more than 25 micrograms per recommended daily dose except in parenteral nutrition replacement preparations is a prescription medicine. Vitamin D for external use or for internal use in medicines containing 25 micrograms or less per recommended daily dose; or in parenteral nutrition replacement preparations is available under general sale.
• Calcifediol is available as a prescription medicine in Canada as XXXXXXXX (calcifediol modified-release capsules, 30 mcg). It is a vitamin D3 analogue indicated for the treatment of secondary hyperparathyroidism (SHPT) in adults with Stage 3 or 4 chronic kidney disease (CKD) and low serum 25-hydroxyvitamin D levels (less than 75 nmol/L (30 ng/mL) at initiation). Calcifediol is also included in Health Canada's Prescription Drug List (PDL)^[48] and is available for use in human^[49] and veterinary^[50] products. In May 2019, Health Canada published a Notice of Consultation on the Prescription Drug List Vitamin D^[51]. Proposal is to allow non-prescription status to products containing up to 62.5 micrograms or 2500 internal units (IU)/day for oral use:

  	Current Listing	Proposed Listing
  Drugs containing any of the following	Vitamin D	Vitamin D
  Qualifier	In oral dosage form containing more than 1,000 International Units of Vitamin D per dosage form or, where the largest recommended daily dosage shown on the label would, if consumed by a person, result in the daily intake by that person of more than 1,000 International Units of Vitamin D	In oral dosage form containing more than 62.5 µg or 2,500 International Units of Vitamin D per dosage form or, where the largest recommended daily dosage shown on the label would result in the daily intake by that person of more than 62.5 µg or 2,500 International Units of Vitamin D
  Effective date	2013-12-19	To be determined

• XXXXXXXX is also available as a prescription medicine in the United States of America.

Summary of pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment, two (2) submissions were received. One (1) submission supported the amendment and one (1) submission opposed the amendment.

The main points in support of the proposed amendment were:

• Given the potency of calcifediol monohydrate has been identified to be approximately three times greater than colecalciferol, a lower limit of 10 micrograms (compared to the 25 micrograms for colecalciferol) to be applied to the Schedule 4 entry seems appropriate.

The main points in opposition of the proposed amendment were:

• Access to calcifediol monohydrate should not require a prescription. If there is a concern about the potency of this particular version of vitamin D, then a Schedule 3 listing would address these concerns by ensuring that pharmacists are involved in the sale and could reinforce the difference between this substance and other vitamin D preparations available on the market.
• Calcifediol monohydrate meets the Scheduling Factors for inclusion in Schedule 3:
  • it is a vitamin and is substantially safe with pharmacist intervention and counselling to ensure consumers are aware of the difference in potency compared to other products on the market;
  • it is not a drug of dependence, and there is no risk of abuse or illicit use. Inadvertent overdose can be managed with pharmacist involvement in its supply; and
  • the risk profile of vitamin D is well defined and can be managed by a pharmacist.

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that a new Schedule 4 entry for calcifediol be created in the Poisons Standard as follows:

The Committee also recommended an implementation date of 1 June 2020.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a)the risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Calcifediol has been shown to adequately raise serum 25-hydroxyvitamin D levels and has better oral bioavailability than other Vitamin D substances in current use. It is more potent than other Vitamin D substances in current use and may be more useful in patients with malabsorption diseases. Calcifediol is pharmacodynamically similar to other Vitamin D substances and therefore would be expected to have similar adverse effects and drug interactions, supporting scheduling consistent with other Vitamin D substances.
b - the purposes for which a substance is to be used and the extent of use of a substance	Current consensus recommendation that Vitamin D supplementation should only be used where Vitamin D deficiency is confirmed is consistent with the medical oversight required by Schedule 4.
c - the toxicity of a substance	The effectiveness and by extrapolation the toxicity of calcifediol is calculated to be approximately three times the same dose of other Vitamin D forms available (colecalciferol and ergocalciferol). Well known dose related toxicity which means medical monitoring and oversight is necessary, consistent with a Schedule 4 classification.
d - the dosage, formulation, labelling, packaging and presentation of a substance	Human studies confirm the safety of low daily dosing and support exemption from scheduling at a daily dose of 10 micrograms for adults.
e - the potential for abuse of a substance	Nil
f - any other matters that the Secretary considers necessary to protect public health	Nil

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to calcifediol;
• Advisory Committee on Medicines Scheduling's advice;
• The public submissions received by the first closing date;
• Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• Scheduling Handbook (V 1.1, July 2019).

Reasons for the interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the Scheduling Factors for Schedule 4.

I have made an interim decision to amend the Poisons Standard by creating a new Schedule 4 entry for calcifediol and I have set out my reasons below.

I have considered that as a direct metabolite of and the circulating form of colecalciferol in the body, calcifediol would fall within the current Schedule 4 entry for Vitamin D and would be unscheduled at a daily dose of 25 micrograms per day. However, I am of the view that while the toxicity and safety markers for calcifediol can be considered the same as for colecalciferol, a separate scheduling entry is warranted due to their differing potencies. I note that calcifediol has been assessed by the TGA as safe at a daily dose of 10 micrograms or less, and this is significantly lower than the 25 micrograms per day recommended for colecalciferol. On balance I find the proposed 10 microgram daily dose cut-off is consistent with combined consideration of the three-fold potency of calcifediol compared to colecalciferol.

I have considered that there is a potential for drug interactions between Vitamin D substances and other drugs. Cytochrome P450 inhibitors such as ketoconazole, clarithromycin and various antiretroviral drugs may inhibit enzymes involved in Vitamin D metabolism and hence alter serum levels of calcifediol. As Cytochrome P450 3A4 (CYP3A4) is involved in Vitamin D metabolism, other medicines metabolised by this enzyme, such as statin drugs, may compete for enzyme activity with Vitamin D substances. Due to these potential interactions and subsequent adverse effects (particularly dose dependent adverse effects) means there remains a need to have a primary entry for any Vitamin D substance in Schedule 4. In view of this, recommendation that supplementation only be undertaken where a person has confirmed Vitamin D deficiency also supports a primary Schedule 4 entry for all Vitamin D substances, including calcifediol.

I find that a Schedule 4 entry with a 10 microgram daily dose cut-off to exempt from scheduling for calcifediol would be consistent with the current Schedule 4 entry for Vitamin D. Further, I find that it is important to specify internal use in humans as no information was presented regarding topical use and there has been no consideration of animal use.

---