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Andexxa

Sponsor
AstraZeneca Pty Ltd
ARTGs
Device/Product name
Andexxa
Active Ingredient
Andexanet alfa
Date of decision
Published
Submission type
New Biological Entity
ATC codes
V03AB38
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 Andexxa 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

30 June 2022

First round evaluation completed

30 November 2022

Sponsor provides responses on questions raised in first round evaluation

25 January 2023

Second round evaluation completed

6 April 2023

Delegate’s Overall benefit-risk assessment and request for Advisory Committee advice

1 May 2023

Sponsor’s pre-Advisory Committee response

15 May 2023

Advisory Committee meeting

1 and 2 June 2023

Registration decision (Outcome)

27 June 2023

Completion of administrative activities and registration on ARTG

3 July 2023

Number of working days from submission dossier acceptance to registration decision*

206

*Statutory timeframe for standard applications is 255 working days

Date of entry onto ARTG
Black triangle scheme
Yes
Dose forms
Powder for injection
Strength
200 mg
Other ingredients

Trometamol, trometamol hydrochloride, arginine hydrochloride, sucrose, mannitol, and polysorbate 80.

Containers
Vial
Pack sizes
4
Routes of administration
Intravenous
Dosage

Andexxa is administered as an intravenous (IV) bolus at a target rate of approximately 30 mg/min over 15 minutes (low dose) or 30 minutes (high dose), followed by administration of a continuous infusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 minutes. The continuous infusion is to be administered within two minutes following the bolus dose.

For further information refer to the Product Information.

Pregnancy category
B2
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.

Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

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

Andexxa (andexanet alfa) was provisionally approved for the following therapeutic use:

Andexxa (andexanet alfa) has provisional approval in Australia for adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

The decision to approve this indication has been made on the basis of haemostatic efficacy and reduction in anti-FXa activity. Continued approval of this indication depends on verification and description of benefit in a confirmatory trial.

What is this medicine and how does it work
Andexanet alfa is a recombinant form of human Factor Xa (FXa) protein that has been modified to lack FXa enzymatic activity. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin, and the gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the ability of the protein to assemble into the prothrombinase complex, thus removing any anti-coagulant effects.

Andexanet alfa is a specific reversal agent for FXa inhibitors. The predominant mechanism of action is the binding and sequestration of the FXa inhibitor. In addition, andexanet alfa has been observed to bind to, and inhibit tissue factor pathway inhibitor (TFPI). Inhibition of TFPI activity can increase tissue factor-initiated thrombin generation inducing a pro-coagulant effect.
What post-market commitments will the sponsor undertake
  • Andexxa (andexanet alfa) is to be included in the Black Triangle Scheme. The PI [Product Information] and CMI [Consumer Medicines Information] for Andexxa must include the black triangle symbol and mandatory accompanying text for five years, or the product’s entire period of provisional registration, whichever is longer.
  • The Andexxa EU [European Union]-risk management plan (RMP) (version 3.0 succession 2.0 (date 7 November 2022; DLP [data lock point] 30 June 2022), with Australian specific annex (version 1.0 succession 3, date 10 May 2023), included with Submission PM‑2022‑01981‑1‑3, 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).
    • Unless agreed separately between the supplier who is the recipient of the approval and the TGA, the first report must be submitted to TGA no later than 15 calendar months after the date of the approval letter. The subsequent reports must be submitted no less frequently than annually from the date of the first submitted report until the period covered by such reports is not less than three years from the date of the approval letter, or the entire period of provisional registration, whichever is longer.
    • 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. Each report must have been prepared within ninety calendar days of the data lock point for that report.
  • The sponsor must conduct Study 18-513 (ANNEXA-I) and submit the study report to the TGA, as described in the clinical study plan in version 1.0 succession 3 (date 10 May 2023) of the Australia-specific annex.
  • Laboratory testing & compliance with Certified Product Details (CPD)
  1. All batches of Andexxa supplied in Australia must comply with the product details and specifications approved during evaluation and detailed in the Certified Product Details (CPD).
  2. When requested by the TGA, the Sponsor should be prepared to provide product samples, specified reference materials and documentary evidence to enable the TGA to conduct laboratory testing on the Product. Outcomes of laboratory testing are published biannually in the TGA Database of Laboratory Testing Results http://www.tga.gov.au/ws-labs-index and periodically in testing reports on the TGA website.

Further information

The latest Product Information (PI) and Consumer Medicines Information (CMI) can be found at the Australian Register of Therapeutic Goods (ARTG) search page.

Australian Public Assessment Reports (AusPARs) can be found at the AusPAR search page.

The latest news and updates regarding therapeutic goods regulation can be found at the TGA news page.

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