Medicines and Healthcare products Regulatory Agency (MHRA) announces that serious liver injury has been reported on treatment with tocilizumab from 2 weeks to more than 5 years after initiation.
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. 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. One 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 letter has been sent to healthcare professionals to advise them of this information.
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 the upper limit of normal (ULN). Tocilizumab treatment is not recommended in patients with elevated ALT or AST levels higher than 5-times the 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).
Healthcare professionals are advised:
- 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 ALT and 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 ULN; initiation of treatment is not recommended in patients with ALT or AST higher than 5-times the ULN.
- If liver enzyme abnormalities are identified, consult the dose modifications recommended, which have not changed.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/tocilizumab-roactemra-rare-risk-of-serious-liver-injury-including-cases-requiring-transplantation
In Hong Kong, there are 4 registered pharmaceutical products containing tocilizumab, namely Actemra Conc For Soln For Infusion 400mg/20ml (HK-59200), Actemra Conc For Solution For Inf 200mg/10ml (HK-59201), Actemra Conc For Soln For Infusion 80mg/4ml (HK-59202) and Actemra Solution For Injection in Pre-filled Syringe 162mg/0.9ml (HK-63771). All products are registered by Roche Hong Kong Limited, and are prescription-only medicines. So far, the Department of Health (DH) has received 8 cases of adverse drug reaction related to tocilizumab, but these cases are not related to hepatotoxicity. Related news was previously issued by Singapore Health Sciences Authority, Health Canada and Australia Therapeutic Goods Administration, and was posted on the Drug Office website on 12 Apr 2019, 22 May 2019 and 12 Jul 2019 respectively. Letters to inform local healthcare professionals were issued by the DH on 12 Apr 2019. As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Thursday, Jul 18, 2019
Issued at HKT 17:00
|
