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| The United Kingdom: Terlipressin: new recommendations to reduce risks of respiratory failure and septic shock in patients with type 1 hepatorenal syndrome (English only) |
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Medicines and Healthcare products Regulatory Agency (MHRA) announces new recommendations following a recent clinical trial which found that in patients with type 1 hepatorenal syndrome terlipressin may cause serious or fatal respiratory failure at a frequency higher than previously known, and that terlipressin increases the risk of sepsis and septic shock.
A recent European review into the benefits and risks of terlipressin treatment, which was triggered by the CONFIRM trial findings, concluded that new measures were required to reduce the risk of respiratory failure and sepsis when terlipressin is used in patients with type 1 hepatorenal syndrome. The Pharmacovigilance Expert Advisory Group of the UK’s Commission on Human Medicines agreed with the recommendations, while also highlighting the benefits of terlipressin treatment when an appropriate assessment of the benefits and risks has been made.
Changes will therefore be made to the product information for terlipressin medicines authorised for type 1 hepatorenal syndrome to note the new risk minimisation measures and information on risks. A letter has also been sent to UK healthcare professionals.
The review confirmed that terlipressin remains a highly effective treatment for type 1 hepatorenal syndrome but identified some risk factors that should be considered by prescribers when treatment decisions are made.
The review identified patients with severe renal impairment (in this review, defined as patients with baseline serum creatinine above 5 mg/dl) as being at reduced likelihood of response to terlipressin as well as at increased risk of death. A post-hoc subgroup analysis of the CONFIRM trial identified patients with severe renal impairment (in this review, defined as patients with baseline serum creatinine above 5 mg/dl) and severe reduction in liver function (in particular patients with ACLF grade 3 or a MELD score ≥ 39) as having a reduced likelihood of response to terlipressin as well as an increased risk of developing respiratory failure and fluid-overload-related serious adverse events and of death.
An assessment of benefits and risks for the individual patient should be made when deciding on appropriate treatment in patients with these risk factors.
It was acknowledged that the doses of albumin given in the CONFIRM trial were higher than would usually be advised in European guidelines and this may have contributed to fluid overload and the respiratory events seen. The dose of albumin should therefore be considered if signs of respiratory failure or fluid overload arise.
Continuous infusion has been added to the product information as an alternative method of administration to bolus injection.
Continuous infusion has been recommended within the European Association for the Study of the Liver (EASL) guidelines for some time and a small amount of literature suggests that this method is associated with a better safety profile and has a more stable lowering effect on portal pressure than bolus administration by avoiding high peak plasma concentrations of terlipressin. While the literature is insufficient to suggest that continuous infusion would lower the rate of respiratory events specifically, the evidence is sufficient to recommend this as an alternative method of administration.
Advice for healthcare professionals:
- Findings of the CONFIRM trial showed terlipressin to be effective at reversing type 1 hepatorenal syndrome, but also showed that patients who received terlipressin were more likely to die by day 90 (largely due to respiratory disorders) than those who received placebo
- There were also more serious respiratory events and cases of sepsis or septic shock in patients who received terlipressin than in those who received placebo
- Since both advanced renal impairment and advanced liver impairment were risk factors for poorer outcomes in patients with type 1 hepatorenal syndrome:
o Avoid terlipressin in those with advanced renal dysfunction (baseline serum creatinine at or above 442 µmol/L (5.0 mg/dL)), unless the benefit is judged to outweigh the risks
o Avoid terlipressin in those with severe liver disease (defined as Acute-on-Chronic Liver Failure (ACLF) grade 3, a Model for End-stage Liver Disease (MELD) score ≥ 39, or both), unless the benefit is judged to outweigh the risks
- Stabilise patients with new-onset breathing difficulties or worsening of existing respiratory disease before administering terlipressin and monitor closely during treatment
- Consider a reduction in albumin dose in patients with signs or symptoms of respiratory failure or fluid overload; discontinue terlipressin if symptoms are severe or do not resolve
- Monitor patients daily for signs and symptoms of infection
- Monitor blood pressure, heart rate, oxygen saturation, serum sodium and potassium levels, and fluid balance; terlipressin may induce myocardial ischaemia and pulmonary vascular congestion, especially in those with pre-existing cardiopulmonary disease
- Terlipressin can be administered as a continuous intravenous infusion as an alternative to bolus injection as infusion may be associated with lower rates of severe adverse events than bolus injection
- Patients with type 1 hepatorenal syndrome receiving terlipressin should be counselled on the benefits and risks, even if circumstance necessitates that counselling occurs after treatment with terlipressin is given
- This advice is not relevant to use of terlipressin for bleeding oesophageal varices
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/terlipressin-new-recommendations-to-reduce-risks-of-respiratory-failure-and-septic-shock-in-patients-with-type-1-hepatorenal-syndrome
In Hong Kong, there are 4 registered pharmaceutical products containing terlipressin. All products are prescription-only medicines. So far, the Department of Health (DH) has not received any case of adverse drug reaction related to terlipressin. Related news was previously issued by EMA, and was posted on the Drug Office website since 15 Jan 2022, with the latest update posted on 12 Nov 2022. Letters to inform local healthcare professionals were issued by the DH on 3 Oct 2022. As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Saturday, March 25, 2023
Issued at HKT 12:00
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