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The Australian Prescription Medicine Decision Summary provides a short overview of the TGA's evaluation process leading to the registration of a new prescription medicine on the Australian Register of Therapeutic Goods (ARTG).
More in-depth information about the evaluation will be available in the Australian Public Assessment Report (AusPAR) for a particular prescription medicine, which can be found on the AusPAR search page once published.
Australian prescription medicine decision summary
|Submission type|| |
New chemical entity
|Product name|| |
|Active ingredients|| |
|ATC codes|| |
Approved for provisional registration
|Date of decision|| |
15 January 2020
|Date of entry onto ARTG|| |
14 January 2020
|ARTG numbers|| |
|Black Triangle Scheme|| |
Yes. As a provisionally registered product, this medicine will remain in the Black Triangle Scheme for the duration of its provisional registration.
Celgene Pty Ltd
|Sponsor address|| |
Level 15, 60 City Road, Southbank, VIC 3006
|Dose forms|| |
Film coated tablet
50 mg and 100 mg
|Other ingredients|| |
Microcrystalline cellulose, Sodium starch glycollate, Hydroxypropyl cellulose, Colloidal silicon dioxide, Magnesium stearate, Hypromellose acetate succinate, Sodium lauryl sulphate (E487)
Tablet film coating
Polyvinyl alcohol, Titanium dioxide (E171), Polyethylene glycol 3350 (Macrogol 3350 / PEG 3350), Purified talc, Iron oxide yellow (E172)
|Pack sizes|| |
|Routes of administration|| |
Treatment with Idhifa must be initiated and monitored under the supervision of a registered Specialist Physician experienced in the management of haematological and oncological malignancies.
The recommended starting dose of Idhifa is 100 mg taken orally once daily. It is recommended to treat patients for a minimum of 6 months to allow time for clinical response and to continue treatment until disease progression or unacceptable toxicity.
For further information refer to the Product Information.
|Pregnancy category|| |
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
Idhifa (enasidenib) was provisionally approved for the following therapeutic use:
This medicine has Provisional Approval in Australia for the treatment of adult patients with relapsed or refractory acute myeloid leukaemia who are ineligible for haematopoietic stem cell transplant, and who have an isocitrate dehydrogenase-2 (IDH2) mutation confirmed by a validated diagnostic test.
The decision to approve this indication has been made on the basis of preliminary clinical data from a Phase 1/2 clinical trial with a primary endpoint of overall response rate. An improvement in OS or PFS has not been established. The sponsor is required to submit further clinical data to confirm the efficacy and safety of the medicine.
The provisional registration period for the above medicine(s) is two years starting on the day specified in the ARTG certificate of registration.
Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Mutant IDH2 variants R140Q, R172S and R172K are selectively targeted by enasidenib, with the drug’s potency against these approximately 40 times greater than against wildtype IDH2. Such IDH2 mutations confer a gain of function, whereby the aberrant enzyme catalyses the production of the oncogenic metabolite 2-hydroxyglutarate (2-HG). 2-HG induces a block of cell differentiation by inhibiting the activity of chromatin-modifying histone and DNA demethylases. Inhibition of the IDH2 mutant variants R140Q and R172S/K by enasidenib, led to decreased 2 HG levels and induction of myeloid differentiation in vitro and in vivo in human xenograft models of IDH2-mutated acute myeloid leukaemia (AML).
In patients with IDH2-mutated AML, enasidenib decreased 2-HG levels in blood, releasing the differentiation block of leukaemic cells and resulting in increased percentages of mature myeloid cells in bone marrow. Enasidenib reduced blast counts in a subset of patients and was not myelosuppressive.
The following table summarises the key steps and dates for this application.
30 April 2018, extension 8 October 2018
27 September 2018
|Submission dossier accepted and first round evaluation commenced||2 January 2019|
|First round evaluation completed||6 September 2019|
|Sponsor provides responses on questions raised in first round evaluation||30 October 2019|
|Second round evaluation completed||13 January 2020|
|Delegate's overall benefit-risk assessment||10 January 2020|
|Sponsor's pre-Advisory Committee response||Not applicable|
|Advisory Committee meeting||Not applicable|
|Registration decision (Outcome)||15 January 2020|
|Completion of administrative activities and registration on ARTG||17 January 2020|
|Number of working days from submission dossier acceptance to registration decision*||220|
*Statutory timeframe for standard applications is 255 working days
- Idhifa (enasidenib) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Idhifa must include the black triangle symbol and mandatory accompanying text for the products entire period of provisional registration.
- Confirmatory trial data (as identified in the sponsor’s plan to submit comprehensive clinical data on the safety and efficacy of the medicine before the end of the 6 years that would start on the day that registration would commence) must be provided.
Specifically the sponsor must conduct studies as described in the clinical study plan in version 0.2 (date 8 January 2019) of the Australia-specific Annex. The following study report(s) should be submitted to TGA.
- AG-221-AML-004 study as soon as it becomes available in 2020.
The sponsor will provide the full clinical study reports of the following post-market studies required by the Food and Drug Administration (FDA), as soon as available:
- Meta-analysis to characterise enasidenib related differentiation syndrome (PMR 3240-1).
- To characterise the long-term safety of enasidenib in R/R AML, submit the final study report with 3 years of follow-up data of the AG221-C-001 trial. Include data from approximately 280 patients with R/R AML (PMR 3240-2).
- A study sufficient to characterise the long-term safety of enasidenib compared to conventional care regimens in patients with AML (PMR 3240-3).
- Pharmacokinetic trials to evaluate the effect of multiple doses of enasidenib on the single dose pharmacokinetics of sensitive substrates of CYP3A4, CYP2D6, CYP2C19, CYP2C9, UGTs, P-pg and BCRP to address the potential for excessive drug toxicity (PMR3240-4).
- A clinical pharmacokinetic trial to determine the appropriate dose of enasidenib in patients with hepatic impairment.
Further guidance for sponsors is available on the TGA website.
- The Idhifa European Union-Risk Management Plan (EU-RMP) (version 0.2, dated 8 January 2019, data lock point 1 September 2017), with Australian Specific Annex (version 1.2, dated 8 January 2019), included with submission PM-2018-04819-1-6, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.
An obligatory component of risk management plans is routine pharmacovigilance. Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).
Reports are to be provided in line with the current published list of EU reference dates and frequency of submission of PSURs until the period covered by such reports is not less than three years from the date of the approval letter.
The reports are to at least meet the requirements for PSURs as described in the European Medicines Agency’s Guideline on Good Pharmacovigilance Practices (GVP) Module VII-periodic safety update report (Rev 1), Part VII.B Structures and processes. Note that submission of a PSUR does not constitute an application to vary the registration.