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Scheduling delegate's final decisions, March 2017

Scheduling medicines and poisons

23 March 2017

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1.1 Pegbovigrastim

Part A - Final decisions on matters referred to an expert advisory committee

Advisory Committee on Chemicals Scheduling (ACCS#18)

1.1 Pegbovigrastim

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to consider whether pegbovigrastim requires scheduling.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Appendix B - New Entry

PEGBOVIGRASTIM.

The applicant's reasons for the request are:

  • Pegbovigrastim is a modified form of the naturally-occurring bovine immunoregulatory cytokine, bG-CSF. The naturally-occurring protein is produced by mononuclear leukocytes, endothelial cells and fibroblasts. Pegbovigrastim is identical in primary sequence to the endogenously-produced protein with the exception of the addition of a terminal methionine and a single amino acid substitution whereby a novel amino acid, p-acetylphenylalanine, is incorporated into the protein to enable site-specific covalent attachment of a 20 kDa polyethylene glycol (PEG) polymer chain to the protein;
  • No distribution, metabolism or excretion studies were submitted, however, these would be expected to be comparable to that of the endogenous protein. [Secretariat note: pegylation of CSFs, as well as other proteins, prolongs serum half-life (e.g. the pegylated form of human G-CSF has a half-life about 5 times longer than the non-pegylated form).] Distribution would be expected to be largely limited to the central compartment and the compound would be expected to be degraded to PEG and small peptides and amino acids which are excreted largely in urine;
  • Pegbovigrastim was not a skin or eye irritant in rabbits. No skin sensitisation studies were submitted;
  • No other toxicity studies were submitted for pegbovigrastim, but carcinogenicity and genotoxicity studies are generally not required for biological products. Pegbovigrastim might be expected to be of low toxicity as indicated by studies on the corresponding human colony stimulating factor;
  • The safety profiles of the equivalent human product (PEG hG-CSF [pegfilgrastim, Neulasta®]), and the non-PEGylated product (filgrastim, Neupogen®), are well established in humans. These medicines are used for a number of purposes where patients are suffering neutropenia. The most common adverse reaction is bone pain. Severe adverse reactions to these products are rare, and have generally been observed upon repeated administration. Filgrastim showed low toxicity after both single and repeated doses in laboratory animal species; and
  • The toxicity of polyethylene glycols is well understood and documented. Polyethylene glycols have low acute toxicity.
Current scheduling status and relevant scheduling history

Pegbovigrastim is not currently scheduled and has not been previously considered for scheduling; therefore a scheduling history is not available.

Three related substances (filgrastim, pegfilgrastim and lenograstim) have been considered for scheduling, and are currently in Schedule 4 for human therapeutic use.

International regulations

Products containing pegbovigrastim are registered in New Zealand, USA, Canada, the European Union (EU), Mexico and Brazil. Pegbovigrastim is subject to the following labelling requirements internationally:

  • New Zealand - The following signal heading on labels are required, 'Restricted veterinary medicine', 'Keep out of reach of children' and 'For animal treatment only'.
  • USA - Product Information leaflet include the following warning: 'Caution: federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.'
Substance summary

The pegylated bovine granulocyte colony stimulating factor (bG-CSF) (Figure 1) is almost identical to the endogenously produced bovine protein. The points of differences are:

  • the addition of an amino terminal methionine
  • a single amino acid substitution at position 133 whereby threonine in the endogenously produced bG-CSF is replaced with a novel amino acid, p-acetylphenylalanine glycol (F*) (Figure 1); this enables a site-specific covalent attachment of a 20 kDa polyethylene glycol (PEG) polymer chain to the protein through an oxime linkage
  • pegylation of CSFs, as well as other proteins, prolongs serum half-life (e.g. the pegylated form of human G-CSF has a half-life about 5 times longer than the non-pegylated form

The proposed product will contain 15 mg pegbovigrastim/syringe for subcutaneous injection as an aid in the prevention of mastitis in dairy cows, through restoration of immune function in the periparturient period.

Diagram of pegbovigrastim amino acid structure

Figure 1.1: Amino acid sequence of pegbovigrastim

Note the two di-sulfide bridges at positions 36 to 42 and 64 to 74. At position 133 (F*), threonine in the endogenously produced bG-CSF has been replaced with a novel amino acid, p-acetylphenylalanine glycol.

Table 1.1A: General information
Property Pegbovigrastim
Amino acid sequence MTPLGPARSLP QSFLLKCLEQ VRKIQADGAE LQERLCAAHK LCHPEELMLLRHSLGIPQAP LSSCSSQSLQ LTSCLNQLHG GLFLYQGLLQ ALAGISPELAPTLDTLQLDV TDFATNIWLQ MEDLGAAPAV QPFQGAMPTF TSAFQRRAGGVLVASQLHRF LELAYRGLRY LAEP
Molecular weight 40 600 Da
Empirical formula C859H1370N236O248S9[C2H4O]n where n = 454
CAS number 1363409-60-2
IUPAC and/or common and/or other names Pegylated bovine Granulocyte Colony Stimulating Factor (PEG bG-CSF)
SUSMP name To be advised. 'Pegbovigrastim' or 'Pegylated bovine Granulocyte Colony Stimulating Factor' suggested.
Product name Elanco Imrestor

The following information was extracted from the APVMA Human Health Risk Assessment Technical Report for pegbovigrastim (product name: Elanco Imrestor).

Table 1.1B: Acute toxicity end-points for pegbovigrastim
Toxicity Species Pegbovigrastim SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) No data No data No data
Acute dermal toxicity LD50 (mg/kg bw) No data No data No data
Acute inhalational toxicity LC50 (mg/m3/4h) No data No data No data
Skin irritation Rabbit Non-irritant Non-irritant
Eye irritation Rabbit Non-irritant Non-irritant
Skin sensitisation No data No data No data
Pre-meeting public submissions

No pre-meeting submissions were received for pegbovigrastim.

Summary of ACCS advice to the delegate

The committee advised that a new Appendix B entry for pegbovigrastim be created in the Poisons Standard as follows:

Appendix B - New Entry

PEGBOVIGRASTIM

Part 1 - Reasons for entry
a (low toxicity)

Part 2 - Area of use
2.1 (For animal use)

The committee also advised an implementation date of 1 June 2017.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) 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; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice comprised the following:

  • Available and extrapolated evidence suggests pegbovigrastim is likely to have effects (though probably no serious effects) on humans if systemically absorbed/introduced.
  • At present pegbovigrastim is likely to be registered only for use in periparturient cows.
  • Pegbovigrastim has low toxicity.
  • The presentation of pegbovigrastim is pre-filled single dose syringes that would be suitable for use by trained non-veterinarians.
  • Pegbovigrastim is to be used under veterinary supervision.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACCS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
Delegate's interim decision

The delegate's interim decision is to create a new Appendix B entry for pegbovigrastim for use in animals due to its low toxicity.

The proposed wording for the schedule entry is as follows:

Appendix B - New Entry

PEGBOVIGRASTIM

Part 1 - Reasons for entry
a (low toxicity)

Part 2 - Area of use
2.1 (For animal use)

The proposed implementation date is 1 June 2017.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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 reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • Low toxicity of pegbovigrastim
  • At present pegbovigrastim is likely to be registered only for use in periparturient cows.
  • The presentation of pegbovigrastim is pre-filled single dose syringes that would be suitable for use by trained non-veterinarians.
  • Pegbovigrastim is to be used under veterinary supervision.
  • Earliest possible implementation date.
Public submissions on the interim decision

No submissions were received for pegbovigrastim.

Delegate's final decision

The delegate has confirmed the interim decision and reasons for the decision as no evidence has been received to alter the interim decision. The delegate's final decision is to create a new Appendix B entry for pegbovigrastim for use in animals due to its low toxicity to be implemented on 1 June 2017.

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