Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: ADYNOVATE is distributed in New Zealand by: Takeda New Zealand Limited, Level 10, 21 Queen Street, Auckland 1010, New Zealand, Phone 0508 169 077, www.takeda.com/en-au
Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule ADVATE, mouse or hamster protein, or other constituents of ADYNOVATE (see excipients listed in section 6.1).
Hypersensitivity reactions can occur following administration of ADYNOVATE. Allergic-type hypersensitivity reactions including anaphylaxis have been reported with FVIII concentrates. Immediately discontinue administration and initiate treatment as clinically appropriate if hypersensitivity reactions occur.
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor all patients carefully for inhibitor occurrence following any product switch.
In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.
In patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the cardiovascular risk.
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
After reconstitution this medicinal product contains 0.45 mmol sodium (10 mg) per vial. To be taken into consideration by patients on a controlled sodium diet.
It is strongly recommended that every time ADYNOVATE is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product.
The listed precautions apply both to adults and children.
Clinical studies of ADYNOVATE did not include subjects aged 65 and over.
No interactions of human coagulation factor VIII (rDNA) products with other medicinal products have been reported.
The effects of ADYNOVATE on fertility have not been established.
Pregnancy Category B2. The safety of ADYNOVATE for use in pregnant women has not been established. Animal reproduction studies with recombinant factor VIII, including ADYNOVATE, have not been conducted. Healthcare professionals should balance the potential risks and only prescribe ADYNOVATE if clearly needed.
The safety of ADYNOVATE for use in lactating women has not been established. It is not known if ADYNOVATE or its metabolites are excreted in human milk. Healthcare professionals should balance the potential risks and only prescribe ADYNOVATE to a breast feeding woman if clearly needed.
ADYNOVATE has no influence on the ability to drive and use machines.
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely after treatment with Factor VIII and may in some cases progress to severe anaphylaxis (including shock).
Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.
The safety of ADYNOVATE has been evaluated in 6 completed multi-centre, prospective, open label clinical trials and 1 ongoing studies in 365 previously treated and untreated patients with severe haemophilia A (FVIII <1% of normal), who received at least one dose of ADYNOVATE. Table 2 lists the adverse reactions reported during clinical studies.
Table 2. Adverse drug reactions (assessed by Sponsor) following treatment:
| MedDRA System Organ Class | Preferred MedDRA term | Number & rate by subjecta (N=365) n(%) | Frequency categoryc | Number & rate by infusionb (N=74,487) n(%) | Frequency categoryc |
|---|---|---|---|---|---|
| BLOOD AND LYMPHATIC DISORDERS | Factor VIII inhibition | 1 (0.274) | Uncommon | 1 (0.001) | Very Rare |
| GASTROINTESTINAL DISORDERS | Diarrhoea | 25 (6.849) | Common | 31 (0.042) | Rare |
| Nausea | 8 (2.192) | Common | 11 (0.015) | Rare | |
| EYE DISORDERS | Ocular hyperamia | 3 (0.822) | Uncommon | 3 (0.004) | Very Rare |
| IMMUNE SYSTEM DISORDERS | Hypersensitivity | 2 (0.548) | Uncommon | 2 (0.003) | Very Rare |
| NERVOUS SYSTEM DISORDERS | Headache | 41 (11.233) | Very Common | 67 (0.090) | Rare |
| Dizziness | 7 (1.918) | Common | 7 (0.009) | Very Rare | |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | Rash | 10 (2.740) | Common | 11 (0.015) | Rare |
| Urticaria | 7 (1.918) | Common | 7 (0.009) | Very Rare | |
| Drug eruption | 1 (2.740) | Uncommon | 1 (<0.01) | Very Rare | |
| VASCULAR DISORDERS | Flushing | 1 (0.274) | Uncommon | 1 (0.01) | Very Rare |
| INVESTIGATIONS | Eosinophil count increased | 2 (0.548) | Uncommon | 4 (0.005) | Very Rare |
| INVESTIATIONS INJURY, POISONING AND PROCEDURAL COMPLICATIONS | Infusion related reaction | 2 (0.548) | Uncommon | 2 (0.003) | Very Rare |
a Rate by subject = total number of subjects experiencing the AE (related and unrelated) divided by total number of subjects (N) and multiplied by 100.
b Rate by infusions = total number of adverse events (related and unrelated) divided by total number of infusions (N) and multiplied by 100. Frequencies presented were calculated using all adverse events, related and unrelated.
c Frequencies has been evaluated using the following criteria: Very common (≥1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000).
Clinical trial subjects were monitored for neutralising (inhibitory) antibodies to FVIII. None of the subjects who participated in one or more of 6 completed clinical trials in previously treated patients (PTPs) developed persistent neutralising (inhibitory) antibodies against FVIII of ≥ 0.6 BU/mL (based on the Nijmegen modification of the Bethesda assay). One patient developed a transient FVIII inhibitor at the lowest limit of positivity (0.6 BU) during personalised prophylaxis targeting a FVIII level of 8-12%.
Immunogenicity was also evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII, PEGylated (PEG)-factor VIII, PEG and Chinese hamster ovary (CHO) protein using validated ELISA assays. No subject developed persistent treatment-emergent binding antibodies against FVIII, PEG-FVIII or PEG. Binding antibodies that were detected prior to exposure to ADYNOVATE, that transiently developed during the trials or were still detectable at study completion or data cut-off could not be correlated to any impaired treatment efficacy. There was no causal relationship between observed adverse events and binding antibodies except in one subject, a PUP where a causal relationship can neither be confirmed nor ruled out based on available data. No subject had pre-existing or treatment-emergent antibodies to CHO protein.
From an ongoing study in previously untreated patients <6 years with severe haemophilia A, preliminary reports on 9 cases of FVIII inhibitor development associated with treatment with ADYNOVATE were received.
The detection of antibodies that are reactive to factor FVIII is highly dependent on many factors, including: the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to rurioctocog alfa pegol with the incidence of antibodies to other products may be misleading.
Hypersensitivity reactions are possible with ADYNOVATE (see Table 2). Allergictype hypersensitivity reactions, including anaphylaxis, are rare complications of treatment with recombinant factor VIII, including the parent molecule, ADVATE.
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
Adverse reactions include: Anaphylactic reaction, Hypersensitivity, Factor VIII inhibition.
No additional adverse reactions, other than those from clinical trials, have been reported from postmarketing sources.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
Not stated.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
