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Mylotarg
Sponsor
Device/Product name
Mylotarg
Active Ingredient
Gemtuzumab ozogamicin
Date of decision
Published
Submission type
New biological entity
ATC codes
L01XC05
Decision
Approved
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Mylotarg was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application.
| Description | Date |
|---|---|
| Submission dossier accepted and first round evaluation commenced | 13 June 2019 |
| First round evaluation completed | 12 November 2019 |
| Sponsor provides responses on questions raised in first round evaluation | 24 December 2019 |
| Second round evaluation completed | 12 February 2020 |
| Delegate's overall benefit-risk assessment | 17 March 2020 |
| Sponsor's pre-Advisory Committee response | Not applicable |
| Advisory Committee meeting | Not applicable |
| Registration decision (Outcome) | 8 April 2020 |
| Completion of administrative activities and registration on ARTG | 9 April 2020 |
| Number of working days from submission dossier acceptance to registration decision* | 175 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes. This product will remain in the scheme for 5 years, starting on the date the product is first supplied in Australia
Dose forms
Powder for injection
Strength
5 mg
Other ingredients
Dextran 40, Dibasic sodium phosphate, Monobasic sodium phosphate monohydrate, Sodium chloride, Sucrose
Containers
Vial
Pack sizes
1
Routes of administration
Intravenous infusion
Dosage
Mylotarg should be administered under the supervision of a physician experienced in the use of anticancer medicinal products and in an environment where full resuscitation facilities are immediately available.
Premedication with a corticosteroid, antihistamine, and acetaminophen (or paracetamol) is recommended 1 hour prior to Mylotarg dosing to help ameliorate infusion-related symptoms (see Product Information (PI) Section 4.4 Special warnings and precautions for use).
Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia such as hydration, administration of antihyperuricaemic or other agents for treatment of hyperuricaemia must be taken (see PI Section 4.4 Special warnings and precautions for use).
Mylotarg must be reconstituted and diluted before administration (see PI Section 4.2 Dose and method of administration, Instructions for use and handling).
Traceability
In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.
Dosage
Induction
The recommended dose of Mylotarg is 3 mg/m2/dose (up to a maximum of one 5 mg vial) infused over a 2 hour period on Days 1, 4, and 7 of the induction chemotherapy cycle.
If a second induction is required, Mylotarg should not be administered during second induction therapy. Only standard anthracycline and cytarabine (AraC) should be administered during the second induction cycle.
Consolidation
For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 x 109 cells/L with a platelet count of 100 x 109/L or more in the peripheral blood in the absence of transfusion, the recommended dose of Mylotarg is 3 mg/m2/dose (up to a maximum dose of one 5 mg vial) infused over a 2 hour period on Day 1 of the consolidation chemotherapy cycle.
For further information refer to the Product Information.
Pregnancy category
DDrugs 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.
What was approved
Mylotarg (gemtuzumab ozogamicin) was approved for the following therapeutic use:
Mylotarg is indicated for combination therapy with standard anthracycline and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL) (see Section 4.4 Special warnings and precautions for use, and Section 5.1 Pharmacodynamic properties).
What is this medicine and how does it work
Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). Gemtuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognizes human CD33. The antibody portion (hP67.6) binds specifically to the CD33 antigen, a sialic acid dependent adhesion protein found on the surface of myeloid leukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoietic stem cells. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic semisynthetic natural product. N-acetyl gamma calicheamicin is covalently attached to the antibody via an AcBut (4- (4'-acetylphenoxy) butanoic acid) linker.Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumour cells, followed by internalization of the ADC CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
What post-market commitments will the sponsor undertake
- Mylotarg (gemtuzumab ozogamicin) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Mylotarg must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date that the sponsor notifies the TGA of supply of the product.
- The Mylotarg European Union-Risk Management Plan (EU-RMP) (version 1.2, dated 9 January 2018; data lock point (DLP) 23 May 2016), with Australian specific Annex (version 1.1, dated 11 December 2019), included with submission PM-2019-01426-1-6, 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 this 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.
- Batch release testing and compliance with Certified Product Details (CPD)
- It is a condition of registration that all batches of Mylotarg gemtuzumab ozogamicin imported into/manufactured in Australia must comply with the product details and specifications approved during evaluation and detailed in the Certified Product Details (CPD).
- It is a condition of registration that up to 5 initial batches of Mylotarg gemtuzumab imported into/manufactured in Australia is not released for sale until samples and/or the manufacturer's release data have been assessed and endorsed for release by the TGA Laboratories Branch. Outcomes of laboratory testing are published biannually in the TGA Database of Laboratory Testing Results.
- The sponsor should be prepared to provide product samples, reference materials and documentary evidence as defined by the TGA Laboratories branch. The sponsor must contact Biochemistry.Testing@health.gov.au for specific material requirements related to the batch release testing/assessment of the product. More information on TGA testing of biological medicines is available at Testing of biological medicines.
This batch release condition will be reviewed and may be modified on the basis of actual batch quality and consistency. This condition remains in place until the sponsor is notified in writing of any variation.
- Certified Product Details
The Certified Product Details (CPD), as described in Guidance 7: Certified Product Details of the Australian Regulatory Guidelines for Prescription Medicines (ARGPM), in PDF format, for the above products should be provided upon registration of these therapeutic goods. In addition, an updated CPD should be provided when changes to finished product specifications and test methods are approved in a Category 3 application or notified through a self-assessable change.
- For all injectable products the Product Information must be included with the product as a package insert.