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Ultomiris

Sponsor
Alexion Pharmaceuticals Australasia Pty Ltd
ARTGs
Device/Product name
Ultomiris
Active Ingredient
Ravulizumab rch
Date of decision
Published
Submission type
New biological entity
ATC codes
L04AA43
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 Ultomiris 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 2 January 2019
First round evaluation completed 31 May 2019
Sponsor provides responses on questions raised in first round evaluation 27 June 2019
Second round evaluation completed 21 August 2019
Delegate's overall benefit-risk assessment and request for Advisory Committee advice 23 September 2019
Sponsor's pre-Advisory Committee response N/A
Advisory Committee meeting N/A
Registration decision (Outcome) 8 October 2019
Completion of administrative activities and registration on ARTG 17 October 2019
Number of working days from submission dossier acceptance to registration decision* 180

*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
Injection, intravenous solution
Strength
10 mg/mL
Other ingredients
Monobasic sodium phosphate, dibasic sodium phosphate, sodium chloride, polysorbate 80, water for injections
Containers
Vial
Pack sizes
1
Routes of administration
Intravenous infusion
Dosage

The recommended dosing regimen for adult patients (≥ 18 years of age) with paroxysmal nocturnal haemoglobinuria (PNH) consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. The doses to be administered are based on the patient's body weight. Maintenance doses should be administered at a once every 8 week interval, starting 2 weeks after loading dose administration.

For further information refer to the Product Information.

Pregnancy category
Category B2Drugs 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

Ultomiris (ravulizumab rch) was approved for the following therapeutic use:

Ultomiris is indicated for the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH).
What is this medicine and how does it work
Ravulizumab rch is a humanised monoclonal antibody (mAb) consisting of 2 identical 448 amino acid heavy chains and 2 identical 214 amino acid light chains and has a molecular weight of approximately 148kDa.Ravulizumab rch is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the pro-inflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9, also known as the membrane attack complex (MAC)]) and preventing the generation of the C5b-9 or MAC. By binding specifically to C5, ravulizumab rch antagonises terminal complement-mediated inflammation, cell activation, and cell lysis while preserving the early components of complement activation that are essential for opsonisation of microorganisms and clearance of immune complexes.This mechanism of action provides the therapeutic rationale for the use of Ultomiris in paroxysmal nocturnal haemoglobinuria (PNH), in which uncontrolled complement activation is involved. In patients with PNH, complement mediated intravascular haemolysis is blocked with Ultomiris treatment.Ravulizumab rch was specifically engineered to dissociate from C5 and associate with human neonatal Fc receptor (FcRn) at pH 6.0 (while minimising the impact in binding to C5 in intravascular space where the normal pH is 7.4). As a result, dissociation of antibody:C5 complexes in the acidified environment of the early endosome after pinocytosis is increased. Therefore, free antibody is recycled from the early endosome back into the vascular compartment by FcRn, resulting in an extended ravulizumab rch terminal elimination half-life.
What post-market commitments will the sponsor undertake
  1. Ultomiris (ravulizumab rch) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Ultomiris 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.
  2. The Ultomiris European Union (EU)-Risk Management Plan (RMP) (version 1.4, dated 8 March 2018; DLP 2 May 2019), with Australian Specific Annex (version 2.0, dated 21 June 2019), included with submission PM-2018-05023-1-6, to be revised to the satisfaction of 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.

  3. For all injectable products the Product Information must be included with the product as a package insert.

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