Overview

Methotrexate is a disease-modifying anti-rheumatic drug (DMARD) and also an anti-neoplastic agent. The current registered indications of methotrexate include oncologic indications such as acute leukaemia and osteosarcoma, as well as non-oncologic indications such as rheumatoid arthritis¹.

Alveolar haemorrhage is characterised by bleeding into the alveolar spaces from the pulmonary microcirculation due to microvascular damage. It is a rare and potentially life-threatening condition. Clinical findings usually include haemoptysis, anaemia, and diffuse alveolar opacities seen in imaging².

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) on the risk of pulmonary alveolar haemorrhage associated with methotrexate use.

Having considered the available evidence in the European adverse drug reactions database (Eudravigilance) and in the literature, EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has agreed on the need to amend the product information of methotrexate accordingly to include the risk of pulmonary alveolar haemorrhage. Pulmonary alveolar haemorrhage has been reported with methotrexate use in rheumatologic and related indications which may be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected, in order to confirm the diagnosis³.

Adverse Drug Reaction Reports

NPRA has received a total of 282 reports with 558 adverse events suspected to be related to methotrexate. Majority of the adverse events (97 events, 17.4%) involved skin and subcutaneous tissue disorders, such as rash and pruritus.

There were also a number of reports involving respiratory, thoracic and mediastinal disorders (22 events, 3.9%) such as coughing, breath shortness, pleural effusion and pulmonary fibrosis. However, no pulmonary alveolar haemorrhage cases following the use of methotrexate have been reported to NPRA up to present⁴.

Globally, there are a total of 26 reports of pulmonary alveolar haemorrhage suspected to be related to methotrexate⁵.

Advice for Healthcare Professionals

• Monitor patients on methotrexate for signs of pulmonary alveolar haemorrhage.
• Advise patients to contact their doctor immediately if they start spitting or coughing up blood.
• Please report all adverse events suspected to be related to the use of methotrexate-containing products to NPRA.

References:

1. The Quest 3+ Database, NPRA [Accessed Mac 2018].
2. Lazor, R (2011). Alveolar Haemorrhage Syndromes. Eur Respir Mon. 54: 15-31.
3. European Medicines Agency (2018). PRAC recommendations on signals adopted at the 8-11 January 2018 PRAC meeting. EMA/PRAC/8429/2018.
4. The Malaysian National ADR Database, NPRA [Accessed Mac 2018].
5. The WHO Vigilyze database, Uppsala Monitoring Centre [Accessed: 24 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.