Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, November 2016
Scheduling medicines and poisons
Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)
3. Advisory Committee on Medicines Scheduling (ACMS #19)
Referred scheduling proposal
A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance brivaracetam, proposing that the substance be listed in Appendix K.
Current scheduling status and relevant scheduling history
Brivaracetam is not currently scheduled in Australia and has not been previously considered for scheduling; a scheduling history is therefore not available.
Australian regulatory information
Brivaracetam is registered (product name Briviact) on the ARTG (as of 4 August 2016) for use as add-on therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients from 16 years of age with epilepsy. Briviact (UCB Australia Pty Ltd T/A UCB Pharma Division of UCB Australia) is available as:
- 10 mg, 25 mg, 50 mg, 75 mg and 100 mg film-coated tablets (AUST R. 243794, 243796, 243797, 243798 and 243792 respectively);
- 50 mg/5 mL injection vial (AUST R. 243795); and
- 10 mg/mL oral solution bottle (AUST R. 243793)
International regulatory information
Brivaracetam is not classified in New Zealand. In the USA and Canada, brivaracetam is classified as a Prescription Only medicine.
The proposed amendment to the Poisons Standard is as follows:
Schedule 4 - Proposed New Entry
Appendix K - Proposed New Entry
The reason provided by the clinical delegate is that brivaracetam is an antiepileptic medicine causing sedation.
Brivaracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients from 16 years of age with epilepsy. As a 4-n-propyl analogue of levetiracetam, brivaracetam is also a Synaptic Vesicle Glycoprotein 2A (SV2A) anti-seizure/anti-epileptic drug, displaying a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain. Binding to SV2A is considered to be the primary mechanism for brivaracetam anticonvulsant activity, however, the precise mechanism by which brivaracetam exerts is anticonvulsant activity has not been fully elucidated. Brivaracetam did not act via Na+ channels in normal adult neurons and may act, in part, by inhibiting N-methyl-D-aspartate (NMDA) excitatory pathways and disinhibiting gamma-amino butyric acid (GABA) and glycine inhibitory pathways.
Figure 3.10: Structure of Brivaracetam
Brivaracetam (Figure 3.10) has 2 chiral centres associated with C2 of the butanamide group and C4 of the 2-oxo-4-(1-propyl)pyrrolidine ring. Two polymorphs of brivaracetam are reported. Brivaracetam is highly soluble and is Class I according to the Biopharmaceutical Classification System (BCS) (Table 3.10).
The pharmacokinetic proﬁle of brivaracetam is favourable and linear, and it undergoes extensive metabolism into inactive compounds, mainly through the hydrolysis of its acetamide group. Furthermore, it does not signiﬁcantly interact with other antiepileptic drugs and more than 95% is excreted through the urine, with an unchanged fraction of 8 - 11%.
|Molecular Weight||212.3 g/mol|
|BCS status||Class 1|
|pKa||Brivaracetam has no ionisable centres, so pKa cannot be measured.|
|Form||White to off-white crystalline powder|
|Solubility||It is very soluble in water, buffer (pH 1.2, 4.5 and 7.4), ethanol, methanol, and glacial acetic acid. Brivaracetam is freely soluble in acetonitrile and acetone and soluble in toluene. It is very slightly soluble in n-hexane.|
Pre-meeting public submissions
One (1) public submission was received and supported the proposal. No reasons were given.
Summary of ACMS advice to the delegate
The committee advised that brivaracetam should be entered in Schedule 4 with an Appendix K entry.
The recommended wording for brivaracetam is as follows:
Schedule 4 - New Entry
Appendix K - New Entry
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; e) the potential for abuse of a substance.
The reasons for the advice comprised the following:
- The benefit for brivaracetam is that, as a newly-registered drug, it is an add-on therapy in the treatment of partial onset seizures with or without secondary generalisation in patients with epilepsy, from 16 years of age. The purpose is appropriate; clinical efficacy seems adequate.
- The risks and toxicity of brivaracetam are listed in the Clinical Evaluation Report (CER). However, somnolence, dizziness and fatigue are important risks to consider in relation to including brivaracetam in Appendix K. Inclusion in Appendix K would permit pharmacists to apply statements that are appropriate. Clinical safety at the doses suggested is adequately documented.
- The benefits outweigh the risks for this indication. Documentation provided by the applicant is considered adequate.
- Brivaracetam is available as tablets with 10 mg, 25 mg, 50 mg, 75 mg, 100 mg; 10 mg/mL oral solution and 50 mg/5 mL solution for injection, sponsored by XXXXX. This is a prescription medicine. The Appendix K entry would require pharmacists to include sedation warning statements on dispensed medicines. CMI will be made available as per TGA requirements. The dosage, formulation, labelling and packaging is appropriate and similar to overseas applications.
- The CER states that there were no reports of abuse, misuse, dependence or withdrawal with brivaracetam in the clinical studies.
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 brivaracetam with an Appendix K entry is appropriate.
The proposed Schedule entry is as follows:
Schedule 4 - New Entry
Appendix K - New Entry
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; d) the dosage, formulation, labelling, packaging and presentation of a substance; and e) the potential for abuse of a substance.
The reasons for the recommendation comprised the following:
- The delegate acknowledges the committee's advice.
- Brivaracetam is an additional therapy for epilepsy in patients from 16 years of age.
- The benefits outweigh the risks for this indication.
- Somnolence, dizziness and fatigue are important risks to consider. Brivaracetam is a prescription medicine available as tablets, as an oral solution and for injection. The Appendix K entry would require pharmacists to include sedation warning statements on dispensed medicines.
- Earliest possible implementation date.