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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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1.5 Stiripentol

Referred scheduling proposal

A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the proposal to create a new Appendix K entry for stiripentol.

Scheduling application

The delegate's proposed amendments to the Poisons Standard are:

Appendix K – New Entry

STIRIPENTOL

The reason for the request is that stiripentol is an antiepileptic medicine capable of causing sedation.

Scheduling status and relevant scheduling history

  • The NCE delegate has determined that a new entry in Schedule 4 will be created for STIRIPENTOL, with an implementation date of 1 February 2018.

There is no scheduling history available for stiripentol. This is the first committee presentation for this medicine.

Australian regulatory information

Stiripentol not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017.

According to the TGA Ingredient Database, stiripentol is available for use as an:

  • Active ingredient in export only and prescription medicines.

A search on the Australian Register of Therapeutic Goods (ARTG) confirmed no results for products containing stiripentol as this is an NCE.

In the last 20 years there have been no adverse event reports listed on the Database of Adverse Event Notifications - Medicines for stiripentol.

International regulations

Health Canada regulates stiripentol as a prescription medicine. Registered products include a 250 mg and 500 mg capsule, and 250 mg and 500 mg powders for oral suspension.

Medsafe New Zealand classifies stiripentol as a prescription medicine.

The European Commission granted a conditional marketing authorisation for stiripentol valid throughout the European Union in January 2007. This was updated to a full marketing authorisation in January 2014.

Substance summary

Stiripentol was designated as an orphan drug by the TGA in June 2016 for the treatment of severe myoclonic epilepsy in infancy.

Stiripentol is an antiepileptic intended for the treatment of severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome.

Stiripentol is a pentenol derivative with anticonvulsant activity in animals and antiepileptic efficacy in patients with Dravet syndrome. As with most anticonvulsants, the precise mechanism of action is unknown. However, it has been demonstrated that Stiripentol may increase γ-aminobutyric acid (GABA) levels in brain tissue by interfering with its reuptake and metabolism. Stiripentol has also been shown to improve the effectiveness of many other anticonvulsants (such as clobazam and valproate), possibly due to its inhibition of certain enzymes, slowing the drug's metabolism and increasing blood plasma concentrations. Stiripentol is an antiepileptic medicine capable of causing sedation.

It is chemically unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.

Table 1.5.1: Chemical properties of stiripentol
Property Stiripentol
CAS number 49763-96-4
Chemical structure Chemical structure of stiripentol
Molecular formula C14H18O3
Molecular weight 234.3 g/mol
IUPAC and/or common and/or other names (RS)-(E)-4,4-dimethyl-1-[3,4(methylenedioxy)-phenyl]-1-penten-3-ol (IUPAC);
Stiripentol (ANN and INN).

Pre-meeting public submissions

Two (2) submissions were received and both supported the proposal.

Main points in support:
  • One submission outlined stiripentol's use in the management of epilepsy, with its main effect being exerted on the central nervous system, resulting in sedation.
  • Stiripentol also enhances the central depressant effects of other substances, e.g. antipsychotics.

The public submissions will be made available on the TGA website.

Summary of ACMS advice to the delegate

The committee recommended that an Appendix K entry is not required for stiripentol.

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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice were:

  • Stiripentol is an anticonvulsant medicine used as an adjunct therapy in severe myoclonic epilepsy in infancy.
  • There is not enough clinical evidence to suggest that stiripentol causes drowsiness when administered, even when added to clobazam.
  • Stiripentol is not currently available in Australia as an active ingredient in a registered product.
  • Stiripentol is a prescription medicine in overseas countries (NZ, UK, Europe, Canada, and Japan).

Delegate's considerations

The delegate considered the following regarding 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 an Appendix K entry is required for stiripentol. The proposed Schedule entry is:

Appendix K – New Entry

STIRIPENTOL

The proposed implementation date is 1 February 2018, as this is the earliest possible implementation date.

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 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:

  1. the risks and benefits of the use of a substance:
    • Stiripentol is an anticonvulsant medicine used as an adjunct therapy in severe myoclonic epilepsy in infancy.
    • The Canadian Product Monograph in its Warning and Precautions section states:

      In 2 double-blind, placebo-controlled studies, drowsiness/sleepiness was reported in up to 71% of patients receiving stiripentol. Patients and their caregivers should be warned about the potential for somnolence, dizziness, confusion, and difficulty concentrating. Patients and their caregivers should be advised that patients treated with DIACOMIT should not operate machinery or drive until they have gained sufficient experience on DIACOMIT to assess whether it affects their mental and/or motor performance.

  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • As above (indicated only for treatment of severe myoclonic epilepsy in infancy). No use in Australia at all.
    • No current registered products containing stiripentol in Australia.
    • Stiripentol is a prescription medicine in overseas countries (NZ, UK, Europe, Canada, and Japan).
  3. the toxicity of a substance:
    • The risk of drowsiness/sleepiness as identified in clinical trials.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Currently not available in Australia as an active ingredient of any registered products.
    • The scheduling delegate notes the NCE delegate's decision to create a new entry in Schedule 4 for stiripentol.

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