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

3.8 Ceritinib

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

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

3.8 Ceritinib

Scheduling proposal

A New Chemical Entity (NCE) delegate from the Therapeutic Goods Administration has referred the substance ceritinib, proposing that the substance be listed in Appendix L with warning statement 62 - Do not use if pregnant.

Current scheduling status and relevant scheduling history

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

Australian regulatory information

One registered product containing ceritinib (150 mg) was entered onto the ARTG on 16 September 2016. It is available for use as an active ingredient in prescription medicines but not available as an excipient or equivalent ingredient in any application.

International regulatory information

Ceritinib lactate is not classified in New Zealand. In the USA and Canada, ceritinib is a Prescription Only Medicine.

Scheduling application

The proposed amendments to the Poisons Standard are as follows:

Schedule 4 - Proposed New Entry

CERITINIB.

Appendix L - Proposed New Entry

CERITINIB.

62 - Do not use if pregnant

The reason provided by the clinical delegate is on the basis that there are no human data, but in animals, embryofoetal toxicity occurred at very low exposures (as low as 0.2-fold exposure intended in humans).

Substance summary

Ceritinib (Figure 3.8, Table 3.8) is an inhibitor of anaplastic lymphoma kinase (ALK). The ALK inhibitor works against the ALK translocation involved in the development of certain cancers.

Structure of ceritinib

Figure 3.8: Structure of ceritinib

Ceritinib is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on or who are intolerant of crizotinib. This indication is approved based on tumour response rates and duration of response. An improvement in survival or disease-related symptoms has not been established.

Table 3.8: General information for ceritinib
Property Ceritinib
CAS No. 1032900-25-6
Chemical name 5-chloro-2-N-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-4-N-[2-(propane-2-sulfonyl) phenyl]pyrimidine-2,4-diamine
Molecular formula C28H36ClN5O3S
Molecular Weight 558.1 g/mol
Origin Synthetic
Form white to almost white or light yellow or light brown powder
Solubility Good solubility in very acidic aqueous medium. The solubility decreases significantly with increasing pH. Good solubility is achieved in methanol.
pH 6.86 (in 1% water)
Melting point 174°C
pKa 4.1 and 9.7
Biopharmaceutical Classification System (BCS) status Class IV (Low Permeability, Low Solubility)
Isomerism Ceritinib shows no isomerism with two known polymorphs.
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 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 ceritinib in Appendix L appears to not be applied to substances with a similar or greater risk profile.
  • The PI does not have a contraindication. The approved PI states "ZYKADIA should not be given to a pregnant women unless the potential benefits for her outweigh the potential risk to the fetus." "If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus."
  • 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: "Women of childbearing potential should be advised to use a highly effective method of contraception noting the potential for ceritinib to decrease the effectiveness of the oral contraceptive (see Interactions with Other Medicines) while receiving ZYKADIA and for up to 3 months after discontinuing treatment."
  • 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 ceritinib be entered in Schedule 4 without an Appendix L entry.

The recommended wording for the entry is as follows:

Schedule 4 - New Entry

CERITINIB.

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

The reasons for the advice comprised the following:

  • Although there is no human data, pregnant rats and rabbits given ceritinib had increased skeletal abnormalities during organogenesis as well as a low incidence of visceral anomalies.
  • The benefits of ceritinib use include its efficacy as a second line therapy for people who are intolerant or show disease progression with first-line therapy.
  • The risks of olaparib include embryofoetal toxicity at very low exposure in animals.
  • Generally Appendix L would not be applied to anti-neoplastics when patients are being counselled to avoid pregnancy in the treatment period and shortly thereafter.
  • The purpose for olaparib is treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) where the disease has progressed on or who are intolerant of crizotinib (which has similar mechanism of action). Only a small number of patients would require ceritinib as its use is narrow (as a chemotherapeutic agent for NSCLC). Use of ceritinib will be prescribed only by specialist oncologists to patients under ongoing specialist care.
  • Adverse events most common for ceritinib include gastrointestinal disorders (diarrhoea, nausea, vomiting, abdominal pain). Other very common adverse reactions include decreased appetite, fatigue, liver laboratory test abnormalities, abdominal pain and rash, as well as possible foetal toxicity.
  • 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. The dosage formulation is 150 mg oral capsules taken daily, and its use will be closely monitored by specialists. Therefore, the issue of pregnancy should be raised by treating clinicians.
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 ceritinib without an Appendix L entry is appropriate.

The proposed Schedule entry is as follows:

Schedule 4 - New Entry

CERITINIB.

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.
  • Ceritinib should only be prescribed by oncology specialists who will appropriately counsel women about risks in pregnancy.
  • Earliest possible implementation date.

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