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 olaparib, proposing that it be listed in Appendix L with warning statement 62 – Do not use if pregnant.
The proposed amendments to the Poisons Standard are as follows:
Schedule 4 - Proposed New Entry
Appendix L - Proposed New Entry
62 - Do not use if pregnant.
The reasons provided by the clinical delegate are based on its mechanism of action (PARP inhibition), LYNPARZA (olaparib) could cause foetal harm when administered to pregnant woman. Studies in rats have shown that olaparib causes embryofoetal lethality and induces major foetal malformations (major eye and vertebral/rib malformations) at exposures below those expected at the recommended human dose of 400 mg twice daily.
While this is currently approved for women who have had ovarian cancer (and will have had hysterectomy, salpingo-oophorectomy), there are proposed extensions of indications and the scheduling may not be reviewed again. This is a sensitive issue, as obviously such women cannot become pregnant.
Figure 3.7: Structure of olaparib
Chemical information for olaparib is shown in Table 3.7. Several polymorphs of olaparib are reported. Olaparib is a non-hygroscopic crystalline powder, stable in the A form (non-solvated polymorph). There are no potential olaparib isomers except for tautomers of the phthalazinone which are likely to strongly favouring one form in solution. The pKa has been calculated to be -1.16 (basic) and 12.07 (acidic) on the phthalazinone moiety. Given this, olaparib would be unionised across the physiological pH range. Solubility is independent of pH.
The structure is not closely related to registered kinase inhibitors, nor to veliparib (an experimental PARP inhibitor). There are no official monographs for olaparib.
|Molecular Weight||434.5 g/mol|
|BCS*||Class IV (low solubility, low permeability)|
* Biopharmaceutical Classification System
Pre-meeting public submissions
One public submission was received and supported the proposal. No additional reasons for the support were provided.
Summary of ACMS advice to the delegate
The committee advised that a new Schedule 4 entry for olaparib without an Appendix L entry is appropriate.
The recommended wording for the entry is as follows:
Schedule 4 - New Entry
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 risks of olaparib use include high potential for foetal death and/or malformations as has been shown in animal studies.
- The approved purposes for use of olaparib would exclude pregnancy, but there is potential for other approved and off-label uses in the future. Furthermore, the approved purpose for use of olaparib may cause distress if exclusion of pregnancy is included on the label. Olaparib should only be prescribed by oncology specialists who will appropriately counsel women about risks in pregnancy (if clinically relevant). Currently olaparib is very unlikely to be used in women with childbearing potential, as olaparib is only being used in patients with ovarian cancer.
- Anti-neoplastic agents are not routinely included in Appendix L or Appendix D with pregnancy warning, despite teratogenicity and other foetal abnormalities being a common concern with this class of drugs.
- There is some labelling inconsistency amongst oncology agents. Labelling with warning statements may be revisited with additional use approval.
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 olaparib without an Appendix L entry is appropriate.
The proposed Schedule entry is as follows:
Schedule 4 - 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 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.
- Olaparib should only be prescribed by oncology specialists who will appropriately counsel women about risks in pregnancy.
- Earliest possible implementation date.