- Medicines and Healthcare products Regulatory Agency
- 20 July 2017
- Therapeutic area:
While an urgent EU-wide review of new information on liver safety is under way, promptly review patients on treatment. Only initiate daclizumab in restricted groups of patients with limited treatment options and keep all patients under close liver function monitoring.
Review of patients
Healthcare professionals should review promptly any patients who are currently taking daclizumab to assess whether this medicine continues to be appropriate for them. This should include a discussion with the patient of the risks.
Consider discontinuing therapy if the patient is not within the restricted indication (see below) or if an adequate response has not been achieved.
Doctors should monitor liver function (serum transaminase levels and bilirubin levels) as often as clinically indicated, at least monthly, both during treatment and for up to 4 months after the last dose of patients receiving daclizumab.
Closely watch patients for signs and symptoms of hepatic injury.
If there is evidence of hepatic injury (either clinically or laboratory), treatment should be stopped and the patient should be promptly referred to a hepatologist.
Restrictions on use
Treatment with daclizumab (Zinbryta▼) should now only be initiated in patients in the following restricted groups:
- highly active relapsing multiple sclerosis that has failed to respond to at least one disease-modifying therapy
- severe relapsing multiple sclerosis unsuitable for treatment with other disease-modifying therapies
Treatment with daclizumab is now contraindicated in patients with pre-existing hepatic disease or hepatic impairment. Treatment initiation is not recommended in patients with alanine transaminase or aspartate aminotransferase 2 or more times the upper limit of normal.
Treatment initiation is not recommended in patients with a history of concurrent autoimmune conditions (except for multiple sclerosis). Caution should be used when concomitantly administering medicinal products of known hepatotoxic potential, including non-prescription products and herbal supplements.
Daclizumab (Zinbryta▼) 150 mg solution for injection was authorised in the EU in July 2016 for adults with relapsing forms of multiple sclerosis. In the UK to date, daclizumab use has been mainly in clinical trials.
The National Institute for Health and Care Excellence (NICE) and The Scottish Medical Consortium issued treatment recommendations for daclizumab in April 2017.
Urgent Europe-wide review of new information on risk of liver injury with daclizumab
An urgent EU-wide review of daclizumab started after the death from liver injury (fulminant liver failure) of a patient involved in an ongoing observational study, as well as 4 cases of serious liver injury.
The risk of liver damage with daclizumab was already known at time of its approval in the EU. Several measures are already in place to manage this risk, including the requirement to monitor liver function regularly, and educational materials for healthcare professionals and patients on the risk of liver damage. However, the fatal case occurred despite compliance with the recommended liver monitoring and with test results that were within the normal range prior to and during treatment.
Reminder of existing advice about risk of liver injury
Discuss the risk of hepatic injury with patients and provide them with a Patient Card.
Advise patients to contact their doctor immediately if they develop any symptoms of liver problems, such as unexplained nausea (feeling sick), vomiting, abdominal pain, tiredness, loss of appetite, yellowing of the skin and eyes, and dark urine.
In case of elevations of transaminases or total bilirubin, treatment interruption or discontinuation may be required; see table below from the summary of product characteristics for daclizumab (Zinbryta).
Table: Summary of action required as a result of liver function test results1
|Test result||Summary of action required|
|Confirmed ALT or AST >5 x ULN OR Confirmed ALT or AST >3 x ULN and bilirubin >2 x ULN||Treatment discontinuation*|
|ALT or AST >3 x ULN||Treatment interruption and close monitoring. Resume when ALT or AST have reached <2 x ULN|
*Re-initiation of therapy may be considered if other aetiologies are found, values have returned to normal, and benefits to the patient of resuming therapy outweigh the risks. ALT: alanine aminotransferase. AST: aspartate aminotransferase. ULN: upper limit of normal.
Relevant healthcare professionals are being informed by letter about the need to promptly review patients currently on treatment, and to initiate daclizumab only in a restricted group of multiple sclerosis patients with limited treatment options who should be kept under close liver function monitoring.
We will provide further information as soon as this review is completed. For more about the review timetable see the European Medicines Agency website.
Article citation: Drug Safety Update volume 10 issue 12, July 2017: 1.
Published: 20 July 2017
Therapeutic area: Neurology