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Scheduling delegate's final decisions, March 2017

Scheduling medicines and poisons

23 March 2017

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3.11 Guanfacine hydrochloride

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

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

3.11 Guanfacine hydrochloride

Referred scheduling proposal

The New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance guanfacine hydrochloride, proposing that the substance be listed in Appendix K.

Scheduling application

The proposed amendment to the Poisons Standard is as follows:

Schedule 4 – Proposed New Entry

GUANFACINE HYDROCHLORIDE.

Appendix K – Proposed New Entry

GUANFACINE HYDROCHLORIDE

The reason provided by the clinical delegate is on the basis that guanfacine hydrochloride causes sedation.

Current scheduling status and relevant scheduling history

Guanfacine hydrochloride is not currently scheduled in Australia and has not been previously considered for scheduling; a scheduling history is therefore not available.

International regulatory information

Guanfacine hydrochloride is not classified in New Zealand. In the USA and Canada, Guanfacine hydrochloride is classified as a Prescription Only medicine.

Substance summary

Guanfacine hydrochloride is a central alpha2A-adrenergic receptor agonist and is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in paediatric patients (children and adolescents 6-17 years old inclusive).

Guanfacine hydrochloride is not a central nervous system (CNS) stimulant, a monoamine transporter inhibitor or releaser of presynaptic dopamine or norepinephrine. The mode of action of guanfacine hydrochloride in ADHD is not fully established. Preclinical research suggests guanfacine hydrochloride modulates signalling in the prefrontal cortex and basal ganglia through direct modification of synaptic norepinephrine transmission at the alpha 2-adrenergic receptors. The INN is guanfacine31.

There is a USP 36 monograph for guanfacine hydrochloride, but no BP 2016 monograph.

Table 3.11: Chemical information
Property Guanfacine hydrochloride
CAS No. 29110-48-3
Chemical structure Chemical structure of Guanfacine hydrochloride
Chemical name N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride
Australian Approved Name (AAN) guanfacine hydrochloride (reference USP, USAN)
Molecular formula C9H9Cl2N3O.HCl
Molecular weight 282.6 g/mol (for the hydrochloride salt)
Form White to off-white powder (single polymorphic form)
Solubility sparingly soluble in water and alcohol and slightly soluble in acetone
partition coefficient (logP) 2-octanol/water: 0.10
Dissociation constant 7.69
pH ~4 when dissolved in water
Pre-meeting public submissions

No pre-meeting submissions were received for guanfacine.

Summary of ACMS advice to the delegate

The Committee advised that guanfacine should be entered in Schedule 4 with an Appendix K listing.

The recommended wording for the guanfacine entry is as follows:

Schedule 4 –New Entry

GUANFACINE.

Appendix K –New Entry

GUANFACINE.

The Committee also 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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the advice comprised the following:

  • Guanfacine is a central alpha2A-adrenergic receptor agonist used in the treatment of ADHD in children and adolescents.
  • Guanfacine hydrochloride carries a significant risk of causing sedation and somnolence in humans exhibited by a medicine in normal use. Data demonstrates impairment of critical motor reflexes and cognitive skills applicable to driving or the operation of machinery with guanfacine hydrochloride use and therefore there is a need to warn users of any potential danger of the medication.
  • There are no products containing guanfacine hydrochloride currently registered in the ARTG. This is a prescription-only medicine and Appendix K sedation warning is appropriate.
  • Guanfacine hydrochloride has no known potential for abuse or dependence. The current sedation warning statements are more appropriate for a medication used in adults rather than children and adolescents.
Delegate’s considerations

The delegate considered the following in regards to this application:

  • Scheduling proposal
  • ACMS advice
  • 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 guanfacine with an Appendix K listing is appropriate.

The proposed wording for the schedule and appendix entries is as follows:

Schedule 4 – New Entry

GUANFACINE.

Appendix K – New Entry

GUANFACINE

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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; (f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee’s advice.
  • Guanfacine hydrochloride has a significant risk of causing sedation.
Public submissions on the interim decision

No public submissions were received in response to the interim decision for guanfacine hydrochloride.

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 new Schedule 4 and Appendix K entries for guanfacine with an implementation date of 1 June 2017.

31 http://www.who.int/substance_abuse/publications/opioid_dependence_guidelines.pdf?ua=1 and http://apps.who.int/iris/bitstream/10665/68742/1/WHO_EDM_QSM_2004.5.pdf?ua=1

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