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

3.9 Panobinostat lactate

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

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

3.9 Panobinostat lactate

Referred scheduling proposal

A delegate from the Therapeutic Goods Administration has referred the substance panobinostat lactate, a new chemical entity (NCE), proposing that it be listed in Appendix L with warning statement 62 - Do not use if pregnant.

Current scheduling status and relevant scheduling history

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

Australian regulatory information

Panobinostat lactate is as an active ingredient in Farydak (Novartis Pharmaceuticals Australia Pty Ltd) as 10 mg, 15 mg and 20 mg capsules (AUST R. 229941, 230844 and 230845 respectively), registered on 31 March 2016.

International regulatory information

Panobinostat lactate is not classified in New Zealand or Canada. In the USA, panobinostat lactate is a Prescription Only medicine.

Scheduling application

The proposed amendment to the Poisons Standard is as follows:

Schedule 4 - Proposed New Entry

PANOBINOSTAT.

Appendix L - Proposed New Entry

PANOBINOSTAT.

62 - Do not use if pregnant.

The reason provided by the clinical delegate is on the basis that the effects of panobinostat are unknown in humans, but there is evidence of maternal toxicities, embryo-foetal lethality and malformations in two species, including at 0.5 times the proposed clinical exposure in rabbits in the nonclinical studies.

Other consideration: There is a boxed warning to alert prescribers and consumers to the potentially multiple and severe toxicities that may occur with this medicine. The indication was restricted to those with very limited remaining treatment options and includes the following statement: Treatment should be initiated and monitored by a specialist with experience in treating haematological malignancies.

Substance summary

Panobinostat lactate (Figure 3.9), in combination with bortezomib and dexamethasone, is indicated for the treatment of adult patients with relapsed and/or refractory multiple myeloma, who have received at least 2 prior regimens including bortezomib and an immunomodulatory agent. Treatment should be initiated and monitored by a specialist with experience in treating haematological malignancies.

Structure of panobinostat lactate

Figure 3.9: Structure of panobinostat lactate

Panobinostat lactate is a pan-inhibitor of Class I, II, and IV histone (and non-histone) deacetylases (HDACs/DACs).

While the free base of panobinostat has no chiral centres, the lactic acid is chiral and the racemate of lactic acid is used to prepare panobinostat lactate. The panobinostat double bond has controlled E (trans) stereochemistry. Panobinostat has a hydroxamic acid group ( CONHOH). See Table 3.9 for additional chemical information on panobinostat and panobinostat lactate.

Table 3.9: General information for panobinostat lactate
Property Panobinostat (free base) Panobinostat lactate
CAS No. 404950-80-7 960055-68-9
Molecular formula C21H23N3O2 C21H23N3O2.C3H6O3
Molecular Weight 349.4 g/mol 439.5 g/mol
Chemical name 3-[4-[2-(2-methyl-1H-indol-3-yl)ethylaminomethyl]phenyl]-2(E)-propenohydroxamic acid (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]-2-propenamide 2-hydroxypropanoate (1:1)
IUPAC name (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide;2-hydroxypropanoic acid
Origin and form Synthetic; yellow solid Synthetic; stable; crystalline (one known polymorph)
Melting point - 175°C
pKa 8.4 and 9.0 (alkaline) -
Solubility - The aqueous solubility of panobinostat lactate is pH dependent, with maximum solubility at pH 2 or 3 (~ 5 mg/mL) and low solubility at neutral pH (0.3 mg/mL at pH 6.8); low solubility at pH 7.6 (0.07 mg/mL)
Biopharmaceutics Classification System (BCS) - Class II (low solubility, high permeability).*

* The solubility classification is borderline high.

Pre-meeting public submissions

Two (2) public submissions were received. One (1) submission supported the Appendix L entry, with warning statement 62 - 'Do not use if pregnant'; and one (1) submission did not support the proposal.

The main points in opposition of the proposal were:

  • Recent oncology approvals for Category X medicines vismodegib and sonidegib and Category D medicine crizotinib are not in Appendix L. The proposal to include panobinostat in Appendix L appears to not be applied to substances with a similar or greater risk profile.
  • The approved PI does not have a contraindication. The approved PI states "The patient should be advised of the risk to a fetus, if FARYDAK is used during pregnancy or if the patient becomes pregnant while taking this drug".
  • The PI and CMI clearly state risk/benefits of taking the drug while pregnant. Both PI and CMI state highly effective contraception should be used. PI states: "Sexually-active females of reproductive potential should have a pregnancy test prior to the initiation of treatment with FARYDAK". "Women of child-bearing potential should be advised to use a highly effective method of contraception (methods that result in less than 1% pregnancy rates) during treatment with FARYDAK and for 3 months after the last dose of FARYDAK"; and
  • Patients must be under the care of a specialist in order to be prescribed this drug. It is the physician's role and responsibility to discuss with their patients the risks associated with these medicines even though the risk of pregnancy is low in both patient populations.
Summary of ACMS advice to the delegate

The committee advised that panobinostat should be entered in Schedule 4 without an Appendix L entry.

The recommended wording for the entry is as follows:

Schedule 4 - New Entry

PANOBINOSTAT.

The ACMS advised 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; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the advice comprised the following:

  • The risk of panobinostat to a human foetus is unknown. Data suggests high risk of foetal malformation or non-viability in animal trials at half the dose used in humans.
  • Panobinostat was registered as a Prescription-only Medicine by the TGA in March 2016 as an adjunctive therapy in adults with refractory multiple myelomas who have not responded to treatment with at least two prior regimens, including bortezomib and an immunomodulatory agent. Therefore the potential patient population is low.
  • The product contains a boxed warning to alert prescribers and consumers to the potentially multiple and severe toxicities that may occur with this medicine. The indication was restricted to those with very limited remaining treatment options and includes the following statement: Treatment should be initiated and monitored by a specialist with experience in treating haematological malignancies.
  • Generally, Appendix L would not be applied to anti-neoplastics when patients are already being counselled to avoid pregnancy in the treatment period and shortly afterwards. Antineoplastic agents are not routinely included in Appendix L or Appendix D with pregnancy warnings despite teratogenicity and other foetal abnormalities being a common concern with this class of drugs.
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 panabinostat without an Appendix L entry is appropriate.

The proposed Schedule entry is as follows:

Schedule 4 - New Entry

PANOBINOSTAT.

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 f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

  • The delegate acknowledges the committee's advice.
  • Anti-neoplastic agents are not routinely included in Appendix L or Appendix D with a pregnancy warning, despite teratogenicity and other foetal abnormalities being a common concern with this class of drugs.
  • Panabinostat should only be prescribed by oncology specialists who will appropriately counsel women about risks in pregnancy.
  • Earliest possible implementation date.

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