ADR that result in revision of patient information
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| Canada: VOTRIENT® (pazopanib hydrochloride) - Important Change to Frequency of Serum Liver Test Monitoring for Hepatotoxicity |
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GlaxoSmithKline Inc., in consultation with Health Canada, informed healthcare professionals and the public of important new safety information related to the change in frequency of serum liver test monitoring for hepatotoxicity during use of VOTRIENT®. VOTRIENT® is a tyrosine kinase inhibitor indicated for the treatment of patients with metastatic renal cell (clear cell) carcinoma as first-line systemic therapy or as second line systemic therapy after treatment with cytokines for metastatic disease. It is also indicated for the treatment of patients with selective subtypes of advanced soft tissue sarcoma who have received prior chemotherapy for metastatic disease, or who have progressed within 12 months after (neo) adjuvant therapy.
VOTRIENT® (pazopanib hydrochloride) is associated with hepatotoxicity including hepatic failure and fatalities. VOTRIENT® should not be used in patients who have baseline plasma bilirubin concentrations >1.5 X Upper Limit of Normal (ULN) with direct bilirubin >35% and ALT elevations of >2 X ULN, or who have moderate or severe hepatic impairment (Child Pugh B and C). These are not new recommendations, and remain unaltered from the previously approved Product Monograph.
Physicians are asked to monitor serum liver tests before initiation of treatment, during treatment with VOTRIENT® and interrupt, reduce or discontinue dosing as recommended in the Product Monograph (see below).
Testing of serum liver enzyme and bilirubin levels during treatment has increased in frequency to include monitoring during weeks 2, 4, 6, 8 and months 3 & 4, and as clinically indicated. Periodic monitoring should continue after Month 4.
Elevated Serum Liver Tests should be managed as described below and in the Canadian Product Monograph (see WARNINGS AND PRECAUTIONS, Hepatic Effects):
Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT® with weekly monitoring of liver function until ALT returns to Grade 1 (NCI CTCAE) or baseline.
Patients with ALT elevations of >8 X ULN should have VOTRIENT® interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT® is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT® at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Following reintroduction of VOTRIENT®, if ALT elevations >3 X ULN recur, then VOTRIENT® should be permanently discontinued.
If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT® should be permanently discontinued. Patients should be monitored until return to Grade 1 (NCI CTCAE) or baseline. VOTRIENT® is a uridine diphosphate glucuronyltransferase (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome. Patients with only a mild indirect hyperbilirubinemia, known or suspected Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations.
For isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other signs/symptoms of liver injury) treatment could continue and dose modification is not required. However, further evaluation for a possible underlying cause should be considered.
Concomitant use of VOTRIENT® and simvastatin increases the risk of ALT elevations. Concomitant use of VOTRIENT® and statins should be undertaken with caution and close monitoring.
Please refer to the following website in Health Canada for details:
http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/../34855a-eng.php
In Hong Kong, Votrient Tab 200mg (HK-60351) and Tab 400mg (HK-60352) are registered by GlaxoSmithKline (GSK) Limited. GSK had issued a Dear Healthcare Professional Letter on 2 April 2013 to draw the attention from healthcare providers concerning the need of frequent monitoring of serum liver test for hepatotoxicity. Related news had been released by the Health Sciences Authority (Singapore) and was posted on the website of Drug Office on 27 April 2013. The package insert of captioned registered products in Hong Kong had been updated to include the safety information regarding the need of frequent monitoring of serum liver test for hepatotoxicity. DH will keep vigilant on any safety updates of the drug and actions taken by overseas regulatory authorities for consideration of any further action deemed necessary.
Ends/ Saturday, August 10, 2013
Issued at HKT 13:15
isease. It is also indicated for the treatment of patients with selective subtypes of advanced soft tissue sarcoma who have received prior chemotherapy for metastatic disease, or who have progressed within 12 months after (neo) adjuvant therapy.
VOTRIENT® (pazopanib hydrochloride) is associated with hepatotoxicity including hepatic failure and fatalities. VOTRIENT® should not be used in patients who have baseline plasma bilirubin concentrations >1.5 X Upper Limit of Normal (ULN) with direct bilirubin >35% and ALT elevations of >2 X ULN, or who have moderate or severe hepatic impairment (Child Pugh B and C). These are not new recommendations, and remain unaltered from the previously approved Product Monograph.
Physicians are asked to monitor serum liver tests before initiation of treatment, during treatment with VOTRIENT® and interrupt, reduce or discontinue dosing as recommended in the Product Monograph (see below).
Testing of serum liver enzyme and bilirubin levels during treatment has increased in frequency to include monitoring during weeks 2, 4, 6, 8 and months 3 & 4, and as clinically indicated. Periodic monitoring should continue after Month 4.
Elevated Serum Liver Tests should be managed as described below and in the Canadian Product Monograph (see WARNINGS AND PRECAUTIONS, Hepatic Effects):
Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT® with weekly monitoring of liver function until ALT returns to Grade 1 (NCI CTCAE) or baseline.
Patients with ALT elevations of >8 X ULN should have VOTRIENT® interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT® is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT® at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Following reintroduction of VOTRIENT®, if ALT elevations >3 X ULN recur, then VOTRIENT® should be permanently discontinued.
If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT® should be permanently discontinued. Patients should be monitored until return to Grade 1 (NCI CTCAE) or baseline. VOTRIENT® is a uridine diphosphate glucuronyltransferase (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome. Patients with only a mild indirect hyperbilirubinemia, known or suspected Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations.
For isolated hyperbilirubinemia (i.e., in the absence of elevated ALT or other signs/symptoms of liver injury) treatment could continue and dose modification is not required. However, further evaluation for a possible underlying cause should be considered.
Concomitant use of VOTRIENT® and simvastatin increases the risk of ALT elevations. Concomitant use of VOTRIENT® and statins should be undertaken with caution and close monitoring.
Please refer to the following website in Health Canada for details:
http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/../34855a-eng.php
In Hong Kong, Votrient Tab 200mg (HK-60351) and Tab 400mg (HK-60352) are registered by GlaxoSmithKline (GSK) Limited. GSK had issued a Dear Healthcare Professional Letter on 2 April 2013 to draw the attention from healthcare providers concerning the need of frequent monitoring of serum liver test for hepatotoxicity. Related news had been released by the Health Sciences Authority (S |
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