Daclizumab (Zinbryta▼) and risk of severe liver injury: new restrictions to use and strengthened liver monitoring

The use of daclizumab (daclizumab beta) is now restricted to adults with relapsing multiple sclerosis who have had an inadequate response to at least 2 other disease-modifying therapies (DMTs) and for whom other DMTs are contraindicated or unsuitable. Do not use daclizumab in patients with pre-existing hepatic disease or hepatic impairment. Discuss with patients the risk of hepatic injury and the liver monitoring requirements before starting or continuing daclizumab and ask them to sign an acknowledgement form to confirm they understand the information.

Advice for healthcare professionals:

Restricted indication

  • daclizumab (daclizumab beta) should only be prescribed in adults with relapsing multiple sclerosis who have had an inadequate response to at least 2 other disease-modifying therapies (DMTs) and for whom other DMTs are contraindicated or unsuitable; do not use in patients with pre-existing hepatic disease or hepatic impairment
  • review any patient currently receiving daclizumab to check that treatment remains appropriate

New precautions for use

  • screen patients for hepatitis B and C viral infections before starting daclizumab and refer those with evidence of infection to a liver specialist for advice
  • initiation is not recommended in patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels equal to or greater than 2-times the upper limit of normal or in those with autoimmune conditions other than multiple sclerosis
  • exercise caution when prescribing daclizumab in patients receiving other medication that may be hepatotoxic, including over-the-counter products and herbal medicines

Revised liver monitoring requirements

  • monitor ALT, AST, and bilirubin levels closely before each dose (or more frequently if clinically indicated); and continue monitoring for up to 6 months after the last dose (see monitoring requirements below)

Updated hepatic risk management programme

  • discuss risk of hepatic injury and monitoring requirements with patients and ensure they read the patient card; both patient and physician should sign an acknowledgement form to confirm that the discussion has taken place and the patient understands the information that has been given to them
  • advise patients to seek urgent medical attention if they develop any symptoms or signs of potential hepatic injury

Restricted indication and new precautions for use

In July 2017, we highlighted restrictions on the use of daclizumab (Zinbryta▼) for relapsing multiple sclerosis during an urgent EU review into the risk of severe liver injury. The review found that unpredictable and potentially fatal immune-mediated liver injury can occur during treatment with daclizumab and for up to 6 months after discontinuation. Serious liver reactions, including autoimmune hepatitis, hepatitis, and jaundice, were observed in 1.7% of patients taking daclizumab in clinical trials.

Following the review’s conclusions, daclizumab should only be started in adult patients with relapsing forms of multiple sclerosis who have had an inadequate response to at least 2 other disease-modifying therapies (DMTs) and for whom treatment with any other DMT is contraindicated or unsuitable.

Review any patient receiving daclizumab and stop treatment if they are not within this revised indication or if treatment is contraindicated. Also, consider stopping treatment if an adequate response has not been achieved or if the patient does not comply with the necessary liver monitoring (below).

Revised liver monitoring requirements

Check liver function tests (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin levels) at least monthly as close as possible before each dose, or as often as clinically indicated during treatment, and for up to 6 months after the last dose of daclizumab. Treatment discontinuation is recommended if ALT or AST levels exceed 3 times the upper limit of normal; refer the patient to a liver specialist for advice promptly.

Monitor patients closely for signs and symptoms of hepatic injury. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, promptly measure serum transaminases, discontinue treatment with Zinbryta, as appropriate, and refer patients urgently to a liver specialist.

Updated hepatic risk management programme

The hepatic risk management guide for physicians and patient card will be updated with detailed information on the risk of severe liver injury and the revised monitoring requirements.

Provide patients with the patient card and discuss with them the risk of hepatic injury and necessary monitoring requirements before prescribing daclizumab. Both the patient and physician should sign the acknowledgement form to confirm that the discussion has taken place and that the patient understands the information that has been given to them.

Advise patients to seek medical attention immediately if they develop any signs and symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, tiredness, loss of appetite, yellowing of the skin and eyes, or dark urine.

Background

Daclizumab (Zinbryta▼) 150 mg solution for injection was authorised in the EU in July 2016 for the treatment of adults with relapsing forms of multiple sclerosis. Daclizumab has mainly been used in clinical trials in the UK and use outside trials has been small to date.

Call for reporting

Daclizumab (Zinbryta▼) is subject to additional monitoring to allow quick identification of new safety information. Report any suspected adverse reactions (ADRs) promptly to the Yellow Card Scheme.

Further information

EMA concludes review of Zinbryta and confirms further restrictions to reduce risk of liver damage. 10 November 2017.

Direct Healthcare Professional Communication. Zinbryta▼ (daclizumab): restrictions of use due to the risk of fulminant liver failure. 29 November 2017.

Article citation: Drug Safety Update volume 11 issue 6; January 2018: 1.

Published 9 January 2018