Increased risk of marked hepatic enzyme elevations in patients taking SOMAVERT (pegvisomant) in combination with a somatostatin analogue - For Health Professionals

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Contact: Marketed Health Products Directorate (MHPD) Enquiries

Health Canada Endorsed Important Safety Information on SOMAVERT (pegvisomant)

2008-06-02

Subject: Increased risk of marked hepatic enzyme elevations in patients taking SOMAVERT^® (pegvisomant) in combination with a somatostatin analogue

Dear Health Care Professional,

Pfizer, in consultation with Health Canada, wishes to inform you of an increased risk of marked hepatic enzyme elevations in patients taking SOMAVERT (pegvisomant) in combination with a somatostatin analogue (octreotide acetate).

SOMAVERT, a growth hormone receptor antagonist, is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery, and/or radiation therapy, and other medical therapies, or for whom these therapies are not appropriate.

In a global post-marketing combination study with a somatostatin analogue, one out of 25 patients in the pegvisomant group and 1 out of 27 in the octreotide acetate group had transaminases greater than three or more times the upper limit of normal (ULN). Three patients out of 26 treated with the combination were found to have serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ranging from 13 to 45 times the ULN within 3 months of starting this treatment. Two of these patients received supratherapeutic doses of octreotide acetate (30 mg every 2 weeks) combined with a normal dose of SOMAVERT (10 mg daily). All three patients completely recovered after discontinuation of treatment.

Neggers et al¹ reported that elevated liver enzyme tests were observed in 11 out of 32 patients receiving pegvisomant in combination with a somatostatin analogue, at normal doses. Marked hepatic transaminases elevations >10 times the ULN were reported in 2 of these patients, at least one of which is known to have been on octreotide acetate.

During pre-marketing clinical studies, marked elevations of hepatic enzymes greater than 10 times the ULN were reported in 0.8% of patients treated with SOMAVERT².

For all patients using SOMAVERT, baseline serum ALT, AST, serum total bilirubin (TBIL), and alkaline phosphatase (ALP) levels should be obtained prior to initiating therapy with SOMAVERT and monitored routinely during the course of treatment.

If a patient develops liver test (LT) elevations, or any other signs or symptoms of liver dysfunction while receiving SOMAVERT the following patient management is recommended:

Continuation of Treatment with SOMAVERT Based on Results of Liver Tests

LT Levels and Clinical Signs/Symptoms	Recommendations
Greater than or equal to 3 but less than 5 times ULN (without signs/ symptoms of hepatitis or other liver injury, or increase in serum TBIL)	May continue therapy with SOMAVERT. However, monitor LTs weekly to determine if further increases occur (see below). In addition, perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present.
At least 5 times ULN, or transaminase elevations at least 3 times ULN associated with any increase in serum TBIL (with or without signs/symptoms of hepatitis or other liver injury)	Discontinue SOMAVERT immediately. Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal. If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious reinitiation of therapy with SOMAVERT, with frequent LT monitoring.
Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, right upper quadrant pain, ascites, unexplained edema, easy bruisability)	Discontinue SOMAVERT immediately. Immediately perform a comprehensive hepatic workup. If liver injury is confirmed, the drug should be discontinued permanently.

The Canadian Product Monograph will be revised to include this new information.

As part of Pfizer post-marketing safety activities, reports of abnormal hepatic function will continue to be closely monitored.

Healthcare professionals and patients who have additional questions may contact Pfizer Canada's medical information line at 1-800-463-6001.

Managing marketed health product-related adverse reactions depends on health care professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious hepatic dysfunction or other serious or unexpected adverse reactions in patients receiving SOMAVERT should be reported to Pfizer Canada Inc. or Health Canada at the following addresses:

Sincerely,

original signed by

Bernard Prigent, MD, MBA
Vice-President and Medical Director
Pfizer Canada Inc.

References:

1. Neggers SJCMM, van Aken MO, et al. 2007 Long-Term Efficacy and Safety of Combined Treatment of Somatostatin Analogs and Pegvisomant in Acromegaly. J Clin Endocrinol Metab 92: 4598-4601.
2. Pfizer Canada Inc. SOMAVERT Product Monograph, 28 February 2007.