FDA Approves Terlipressin for Adults with Hepatorenal Syndrome

The US Food and Drug Administration (FDA) has approved terlipressin injection (Terlivaz) to improve kidney function in adults with hepatorenal syndrome (HRS), marking it as the first FDA-approved medication for the condition.

Its approval was granted to Mallinckrodt Pharmaceuticals.

"Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, Executive Vice President and Chief Scientific Officer, Mallinckrodt in a statement. “Terlivaz gives U.S. physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis."

As HRS involves progressive deterioration in kidney function in people with advanced liver disease, the prognosis can be poor if not treated with liver transplantation. High levels of serum creatinine in individuals with HRS also can indicate worsening kidney function.

The safety and efficacy of terlipressin was assessed in the double-blind, phase 3 CONFIRM trial, which provided the basis of the FDA approval.

Adults in the US and Canada with HRS type 1 were randomly assigned to receive 0.85 mg terlipressin (n = 199) or a placebo every 6 hours (n = 101) for a maximum of 14 days. Adjustments in dose were based on changes in kidney function.

CONFIRM’s primary efficacy outcome was the percentage of individuals who had improvement in kidney function, defined by two consecutive days of serum creatinine levels of 1.5 mg/dL or less at least two hours apart by day 14 or hospital discharge.

The trial met the primary endpoint of Verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012). Data show 29 percent of participants in the terlipressin group had kidney function improvement compared to 16 percent of participants in the placebo group.

The release noted that people with serum creatinine levels of ≥5 mg/dL should not take terlipressin, as they are unlikely to benefit from treatment.

The most common adverse events reported with terlipressin treatment, compared with placebo, were abdominal pain (19.5% vs 6.1%), nausea (16% vs 10.1%), respiratory failure (15.5% vs 7.1%), diarrhea (13% vs 7.1%), and dyspnea (12.5% vs 5.1%).

Both the American Association for the Study of Liver DIseases (AASLD) guidance and the American College of Gastroenterology (ACG) guidelines recommend the use of terlipressin.

The application for terlipressin received priority review and fast track status from the FDA. The agent additionally received orphan drug designation as a treatment for a rare disease.

“The FDA approval of Terlivaz is a significant milestone for Mallinckrodt as it brings an important treatment option to these critically ill patients requiring hospitalization and to U.S. physicians who historically have had limited treatment interventions,” added Siggi Olafsson, President and Chief Executive Officer, Mallinckrodt Pharmaceuticals. “We're excited to bring Terlivaz to U.S. patients and physicians and plan to launch the product in the coming weeks.”