Overview

Pemetrexed is a chemotherapy agent approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) and mesothelioma. Currently there are six (6) products containing pemetrexed registered with the Drug Control Authority (DCA).

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the Pharmacovigilance Risk Assessment Committee (PRAC), European Medicines Agency (EMA) on the potential risk of nephrogenic diabetes insipidus and renal tubular necrosis with the use of pemetrexed. The product registration holders were requested to amend the package inserts to include this new information.

This action was taken based on the available evidence in the European adverse drug reactions database (Eudravigilance) and the literature. There were reported cases of nephrogenic diabetes insipidus and renal tubular necrosis in the post marketing setting with the use of pemetrexed alone or with other chemotherapeutic agents. Most of these events resolved after pemetrexed withdrawal. The frequency, however, cannot be estimated from the available data.

Healthcare professionals are advised to regularly monitor the patients for acute tubular necrosis, decreased renal function, as well as signs and symptoms of nephrogenic diabetes insipidus, such as hypernatraemia¹.

Adverse Drug Reaction Reports

NPRA has received 18 reports with 36 adverse events suspected to be related to pemetrexed. To date, no reports have been received regarding nephrogenic diabetes insipidus or renal tubular necrosis².

Globally, there are a total of 14,597 reports suspected to be related to pemetrexed use. There were eight (8) cases reported as nephrogenic diabetes insipidus and 18 cases of renal tubular necrosis³.

Action taken by NPRA

NPRA is currently in discussion with the product registration holder of the innovator product containing pemetrexed to update the package insert with this new information regarding nephrogenic diabetes insipidus and renal tubular necrosis.

Advice for Healthcare Professionals

• Patients on pemetrexed should be regularly monitored for acute tubular necrosis, decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g. hypernatraemia).
• Advise patients to seek immediate medical attention if they have symptoms such as increased urine output, thirst and increased consumption of water.
• Please report all adverse events suspected to be related to the use of pemetrexed-containing products to NPRA.

A directive [Ruj. Kami: (29) dlm. BPFK/PPP/07/25 Jld. 2] has been issued by NPRA for updates to the local product packaging insert related to this safety issue. Please refer to the directive for more information.

References:

1. European Medicine Agency (2018). PRAC recommendations on signals: Adopted at the 8-11 January 2018 PRAC meeting. EMA/PRAC/8429/2018.
2. The Malaysian Adverse Drug Reaction database, NPRA [Accessed: 20 February 2018].
3. The WHO Vigilyze database, Uppsala Monitoring Centre [Accessed: 20 February 2018].

DISCLAIMER

This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.