Tocilizumab (RoActemra): rare risk of serious liver injury including cases requiring transplantation
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be measured before starting treatment with tocilizumab and monitored every 4–8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. Serious liver injury has been reported on treatment with tocilizumab from 2 weeks to more than 5 years after initiation.
Advice for healthcare professionals:
- rare but serious cases of drug-induced liver injury, including acute liver failure and hepatitis, have been reported in patients treated with tocilizumab; some cases required liver transplantation
- advise patients to seek medical help immediately if they experience signs and symptoms of liver injury, such as tiredness, abdominal pain, and jaundice
- monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at initiation, every 4–8 weeks during the first 6 months of treatment, and every 12 weeks thereafter in patients with rheumatological indications
- exercise caution when considering treatment initiation in patients with ALT or AST higher than 1.5-times the upper limit of normal (ULN); initiation of treatment is not recommended in patients with ALT or AST higher than 5-times the ULN (see table below)
- if liver enzyme abnormalities are identified, consult the dose modifications recommended, which have not changed (see below)
- report any suspected adverse reactions associated with tocilizumab to the Yellow Card Scheme
Review of reports of serious liver injury
Tocilizumab is known to cause transient or intermittent mild to moderate elevation of hepatic transaminases, with increased frequency when used in combination with potentially hepatotoxic drugs (for example, methotrexate). A recent EU cumulative review found that, in rare cases, treatment was associated with severe liver injury.
The review of data from clinical trials, non-interventional studies, spontaneous reports, and the published literature identified 8 cases of tocilizumab-related drug-induced liver injury worldwide, including acute liver failure, hepatitis, and jaundice.
At the time of publication, worldwide exposure for tocilizumab is estimated to be more than 1 million patient-years.
Details of reports
These events occurred on treatment with tocilizumab at between 2 weeks and more than 5 years after initiation, with a median latency of 98 days. 2 cases of acute liver failure required liver transplantation.
In 1 case, increased liver function test enzymes were seen after 2 weeks of tocilizumab treatment, with drug-induced liver injury diagnosed approximately 6 weeks after treatment initiation. It is noted that this patient had previously experienced increased liver function test enzymes with certolizumab pegol.
Of the remaining cases, 4 reports had an onset time of roughly 3–4 months. In another case, the patient began tocilizumab treatment and had normal liver function test results for approximately 18 months before the onset of symptoms of liver dysfunction. 1 patient was noted to have normal liver function before starting tocilizumab and then elevated liver function test enzymes at routine testing 5 years later. In the final case, the time to onset was not reported.
These reports of serious liver injury are considered to be rare and the benefit-risk profile of tocilizumab in the approved indications remains favourable. A to advise them of this information.
Recommended liver monitoring
In patients with rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis receiving tocilizumab, monitor alanine aminotransferase (ALT) or aspartate aminotransferase (AST) every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter.
As per the current prescribing information, continue to exercise caution when considering initiation of tocilizumab treatment in patients with ALT or AST higher than 1.5-times ULN. Tocilizumab treatment is not recommended in patients with elevated ALT or AST levels higher than 5 times the upper limit of normal (ULN).
Advise patients to immediately seek medical help if they experience signs and symptoms of hepatic injury, such as tiredness, abdominal pain, or jaundice.
Please note, these updates do not apply to the indication for treatment of cytokine release syndrome (CRS).
Dose adjustments due to liver enzyme abnormalities
The dose adjustments due to liver enzyme abnormalities remain the same as those advised in the current product information. For ease of reference, these are recorded in the table below.
| Laboratory value of ALT or AST | Action in patients with rheumatoid arthritis and giant cell arteritis treated with pre-filled pens or syringes | Action in patients with rheumatoid arthritis and giant cell arteritis treated with infused solution | Action in patients with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis |
|---|---|---|---|
| 1–3-times ULN | Modify the dose of concomitant disease-modifying anti-rheumatic drugs (for rheumatoid arthritis) or immunomodulatory agents (giant cell arteritis) if appropriate. For persistent increases in this range, reduce tocilizumab dose frequency to every other week injection or interrupt tocilizumab until ALT or AST have normalised. Restart with weekly or every other week injection, as clinically appropriate | Modify the dose of the concomitant methotrexate if appropriate. For persistent increases in this range, reduce tocilizumab dose to 4 mg/kg or interrupt tocilizumab until ALT or AST have normalised. Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate | Modify the dose of the concomitant methotrexate if appropriate. For persistent increases in this range, interrupt tocilizumab until ALT or AST have normalised |
| 3–5-times ULN | Interrupt tocilizumab dosing until lower than 3-times ULN and follow recommendations for ALT/AST 1–3-times ULN. For persistent increases higher than 3 times the ULN (confirmed by repeat testing), discontinue tocilizumab | Interrupt tocilizumab dosing until lower than 3-times ULN and follow recommendations above for 1–3-times ULN. For persistent increases higher than 3-times ULN, discontinue tocilizumab | Modify the dose of the concomitant methotrexate if appropriate. Interrupt tocilizumab dosing until lower than 3-times the ULN and follow recommendations for 1–3-times ULN |
| Higher than 5-times ULN | Discontinue tocilizumab | Discontinue tocilizumab | Discontinue tocilizumab. The decision to discontinue tocilizumab in polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis for a laboratory abnormality should be based on the medical assessment of the individual patient |
Background
Tocilizumab (brand name RoActemra) is an interleukin inhibitor indicated for the treatment, in combination with methotrexate, of rheumatoid arthritis, giant cell arteritis in adult patients [subcutaneous formulation only], polyarticular juvenile idiopathic arthritis (in patients 2 years of age and older), and systemic juvenile idiopathic arthritis.
RoActemra can be given as monotherapy in case of intolerance to methotrexate or where continued treatment with methotrexate is inappropriate.
RoActemra is also indicated for the treatment of chimeric antigen receptor (CAR) T-cell-induced severe or life-threatening cytokine release syndrome (CRS) in patients 2 years of age and older [intravenous formulation only].
Report any suspected adverse drug reactions
Please continue to report suspected adverse drug reactions (ADRs) to the Yellow Card Scheme. Reporting suspected ADRs, even those known to occur, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.
Article citation: Drug Safety Update volume 12, issue 12: July 2019: 2.