Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, November 2016

Scheduling medicines and poisons

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2 February 2017

3.12 Follitropin delta

Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)

3. Advisory Committee on Medicines Scheduling (ACMS #19)

3.12 Follitropin delta

Referred scheduling proposal

A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance follitropin delta, proposing that the substance be listed in Appendix D, Item 1 - Poisons available only from or on the prescription or order of an authorised medical practitioner.

Current scheduling status and relevant scheduling history

Follitropin delta is not currently scheduled in Australia; however, the analogues follitropin alpha and follitropin beta are currently in the Poisons Standard as follows:

Schedule 4

# FOLLITROPIN ALPHA.

# FOLLITROPIN BETA.

Appendix D, Item 1 - Poisons available only from or on the prescription or order of an authorised medical practitioner.

FOLLITROPIN ALPHA (recombinant human follicle-stimulating hormone) for human use.

FOLLITROPIN BETA (recombinant human follicle-stimulating hormone) for human use.

Index

FOLLITROPIN ALPHA
cross reference: FOLLICLE-STIMULATING HORMONE, RECOMBINANT HUMAN

Schedule 4
Appendix D, Item 1

FOLLITROPIN BETA
cross reference: FOLLICLE-STIMULATING HORMONE, RECOMBINANT HUMAN

Schedule 4
Appendix D, Item 1

Australian regulatory information

No products containing follitropin delta are on the Australian Register of Therapeutic Goods (ARTG). Currently registered products containing follitropin alpha or follitropin beta on the ARTG are tabulated below.

Table 3.12A: ARTG entries for follitropin alpha and follitropin beta
Active ingredient/s Drug name Additional actives Relevant ARTG IDs Formulation Sponsor
Follitropin alpha AFOLIA N/A 262649, 262648, 262647, 262646, 262645. 5.5, 11, 16.5, 22 and 33 mg; solution for injection cartridge in a pre-filled pen. Finox Biotech Australia Pty Ltd
BEMFOLA N/A 231053, 231052, 231051, 231046, 231039. 5.5, 11, 16.5, 22 and 33 mg; solution for injection cartridge in a pre-filled pen
GONAL-F N/A 96237, 96236, 96230, 96114, 93043, 91564, 91563, 91562, 81623. 37.5 IU (2.73 mg), 75 IU (5.46 mg), 150 IU (10.92 mg), 300IU /0.5mL (21.84 mg), 450IU /0.75mL (32.76 mg), 900IU /1.5mL (65.52 mg); and 45 and 1050 IU (retrievable dose); solution for injection cartridge, pre-assembled in a pen; powder for injection vial with diluent vial/syringe; and/or multidose powder for injection vial with diluent pre-filled syringe. Merck Serono Australia Pty Ltd
PERGOVERIS Lutropin alpha 152797. 150 IU / 75 IU; powder for injection vial with diluent vial.
Follitropin beta PUREGON N/A 76437, 76436, 70858, 70857, 70856, 116843, 116842. 50 IU/0.5mL, 100 IU/0.5mL, 150 IU/0.5mL, 300 IU, 600 IU, 900 IU; solution for injection cartridge, solution for injection vial. Merck Sharp & Dohme Australia Pty Ltd
International regulatory information

Follitropin delta is not classified in New Zealand and does not appear to be an approved drug product in the USA or Canada. However, follitropin alpha and follitropin beta are approved as follows:

The US FDA:

USA FDA follitropin alpha and follitropin beta approvals

Canada:

Canada follitropin alpha and follitropin beta approvals
Canada follitropin alpha and follitropin beta approvals

Scheduling application

The proposed amendment to the Poisons Standard is as follows:

Schedule 4 - Proposed New Entry

FOLLITROPIN DELTA.

Appendix D - Proposed New Entry

FOLLITROPIN DELTA for human use.

Item 1 – Poisons available only from or on the prescription or order of an authorised medical practitioner.

The reason provided by the clinical delegate is that follitropin delta should only be prescribed by specialist medical practitioners (e.g., FRANZCOG, FRCOG) in respect of particular patients, following endocrine function tests carried out at an endocrine laboratory - as for other follitropins (alpha and beta).

Substance summary

Follitropin delta is a novel human recombinant follicle-stimulating hormone indicated for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technology (ART) therapy such as in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI). The most important effect resulting from parenteral administration of FSH is the development of multiple mature follicles.

Follitropin delta is a recombinant human follicle-stimulating hormone (FSH) produced in a human cell line (PER.C6®) by recombinant DNA technology. Follitropin delta is a heterodimer composed of one α and one β subunit (Table 3.12B).

Table 3.12B: General information for follitropin delta
Property Follitropin delta
CAS No. 14679-72-3
Form Clear and colourless in solution (pH 6.0-7.5)
Subunit FSH subunit α FSH subunit β
Amino acid sequence
N - indicates glycosylation sites of the mature α and β subunits)

1 APDVQDCPEC TLQENPFFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC

61 VAKSYNRVTV MGGFKVENHT ACHCSTCYYH KS

1 NSCELTNITI AIEKEECRFC ISINTTWCAG YCYTRDLVYK DPARPKIQKT CTFKELVYET

61 VRVPGCAHHA DSLYTYPVAT QCHCGKCDSD STDCTVRGLG PSYCSFGEMK

Molecular Weight (Da)
(Approximately 40% of the total molecular weight of the molecule is due to glycosylation)
15,200 18,500

The amino acid sequences of the two FSH subunits are identical to the endogenous human FSH sequences. The expressing cell line can influence the characteristics of the recombinant FSH. Differences in glycosylation profile, salic acid pattern and isoform profile have been documented between follitropin delta and recombinant FSH products, such as follitropin alpha and follitropin beta which are produced in Chinese hamster ovary (CHO) cell lines.

Compared to unglycosylated FSH, the glycosylated FSH contains:

  • both α2,3- and α2,6-linked sialic acid (2,6-linked sialic acid is absent in CHO-derived recombinant FSH) and higher overall sialic acid content than CHO-derived recombinant FSH;
  • different sugars such as N-acetylgalactosamine;
  • additional linkages between carbohydrates such as bisecting N-acetylglucosamine and antennary fucose; and
  • a higher proportion of tetra-antennary structures.
Pre-meeting public submissions

Two public submissions were received and both supported the proposal. The main points were that the entry in Appendix D for UROFOLLITROPIN (human follicle stimulating hormone) for human use covers its recombinant forms as well. However, for clarity it would be desirable to add follitropin delta to Appendix D.

Summary of ACMS advice to the delegate

The committee advised that follitropin delta should be entered in Schedule 4 with an Appendix D, Item 1 listing.

The recommended wording for the follitropin delta entry is as follows:

Schedule 4 - New Entry

#FOLLITROPIN DELTA.

Appendix D - New Entry

Item 1. Poisons available only from or on the prescription or order of an authorised medical practitioner.

FOLLITROPIN DELTA (recombinant human follicle-stimulating hormone) for human use.

The committee recommended an implementation date of 1 June 2017.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: 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; d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice comprised the following:

  • The benefit of follitropin delta is that an additional medicine can be used in assisted reproductive technology (ART).
  • The risks around follitropin delta should be mitigated, provided that it is prescribed by an appropriate specialist skilled in the area of ART risks, such as ovarian hyper-stimulation syndrome (OHSS).
  • Pharmacologically, follitropin delta appears to be similar to follitropin alpha and follitropin beta, with minor pharmacokinetic differences. The use and toxicity of follitropin delta are similar to follitropin alpha and follitropin beta. Toxicity is able to be managed by appropriate specialists.
  • Follitropin delta is only to be used in ART and only after endocrine function testing. Therefore, it should only be prescribed by medical specialists skilled in this area (i.e., O&G specialists). Dosage is clearly related to the required endocrine functioning, which is to be completed before use, and body weight of the patient. Product information will include the requirements for dosing according to endocrine testing.
  • Follitropin alpha and beta are already scheduled in Appendix D, item 1. It is appropriate for consistency that follitropin delta be scheduled in the same way.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACMS advice
  • Public submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is that a new Schedule 4 entry for follitropin delta with an Appendix D Item 1 listing is appropriate.

The proposed Schedule entry is as follows:

Schedule 4 - New Entry

#FOLLITROPIN DELTA.

Appendix D - New item 1 entry

FOLLITROPIN DELTA (recombinant human follicle-stimulating hormone) for human use.

Index

FOLLITROPIN DELTA
cross reference: FOLLICLE-STIMULATING HORMONE, RECOMBINANT HUMAN

Schedule 4
Appendix D, Item 1

The proposed implementation date is 1 June 2017.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; and d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • The delegate acknowledges the committee's advice.
  • Follitropin delta is an additional medicine for assisted reproductive technology (ART).
  • Follitropin delta appears to be similar to follitropin alpha and follitropin beta, with minor pharmacokinetic differences.
  • Follitropin alpha and beta are already listed in Appendix D, item 1. For consistency it is appropriate that follitropin delta be similarly scheduled.
  • Earliest possible implementation date.

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