Published: 5 December 2024

Publications

Medicine-induced interstitial lung disease

Prescriber Update 45(4): 76–79
December 2024

At their September 2024 meeting, the Medicines Adverse Reactions Committee discussed a case report of non-specified lung injury with methotrexate (report ID NZ-Medsafe-157198). The Committee recommended that Medsafe reminds prescribers that medicines can cause interstitial lung disease.

Many medicines can cause ILD

ILD is an umbrella term encompassing a broad spectrum of disorders that cause inflammation or fibrosis (scarring) of the pulmonary interstitium (lung tissue). This damage impairs gas exchange in the lungs and can lead to respiratory failure and death.¹

ILD is the most common type of pulmonary toxicity associated with medicines.² Examples of medicines associated with ILD include nitrofurantoin, methotrexate, amiodarone, leflunomide, cytotoxic medicines and some biological agents (Table 1). However, hundreds of medicines have been reported to cause ILD.

Table 1: Examples of medicines associated with ILD (list not exhaustive)

Medicine	Comments
Nitrofurantoin	Irreversible interstitial pneumonitis and/or pulmonary fibrosis can occur with long-term therapy. Treatment should not be prescribed beyond six months unless the benefits outweigh the risks. Acute or subacute pulmonary reactions can also occur with short courses.
Methotrexate	Acute or chronic interstitial pneumonitis and pulmonary fibrosis may occur and progress rapidly.
Amiodarone	Pulmonary fibrosis and/or pneumonitis have been reported. This is usually reversible following early withdrawal of amiodarone therapy.
Leflunomide	ILD has been reported.
Cytotoxic medicines	Many cytotoxic medicines are associated with ILD, including bleomycin, mitomycin, gemcitabine, oxaliplatin, melphalan, busulfan, carmustine, bortezomib, docetaxel and cyclophosphamide.
Biological medicines	ILD has been reported with biological medicines, including immune checkpoint inhibitors, TNF-alpha inhibitors and monoclonal antibodies.
Other antineoplastic medicines	Pneumonitis and/or ILD has been reported with protein and tyrosine kinase inhibitors (eg, alectinib, dasatinib, everolimus) and poly (ADP-ribose) polymerase inhibitors (eg, niraparib, olaparib).

Sources:
Schwaiblmair M, Behr W, Haeckel T, et al. 2012. Drug induced interstitial lung disease. Open Respiratory Medical Journal 6: 63-74. DOI: 10.2174/1874306401206010063 (accessed 11 October 2024).
Medicine data sheets, available at: medsafe.govt.nz/Medicines/infoSearch.asp (accessed 14 October 2024).
New Zealand Formulary (NZF). 2024. NZF v148: Cytotoxic drugs 1 October 2024. URL: nzf.org.nz/nzf_4381 (accessed 14 October 2024).

Monitor for medicine-induced ILD

The presenting symptoms of ILD are non-specific and include cough, dyspnoea and fatigue. ILD diagnosis is based on clinical features and radiological and histological findings. Where appropriate, consider medicines as part of differential diagnosis of new or worsening respiratory symptoms.¹

Risk factors for medicine-induced ILD include:¹

• age (children and elderly patients are at an increased risk of drug toxicity)
• underlying lung disease
• co-administration with other medicines associated with ILD (drug interactions).

When treating patients with medicines known to cause ILD, monitor respiratory function and symptoms throughout treatment. Delayed recognition of ILD increases the risk of irreversible lung damage and death. Refer to medicine data sheets and local guidelines for specific monitoring requirements.

Treatment of medicine-induced ILD often involves prompt withdrawal of the medicine and treatment with corticosteroids. Early recognition and treatment may improve the prognosis.¹

Inform patients about the risk of ILD

Patients who are taking medicines associated with ILD should be aware of this risk. Advise them to seek prompt medical attention if they develop cough, chest pain, shortness of breath, fever or chills. Inform patients that early treatment of ILD is important to reduce the chance of irreversible lung damage.

New Zealand case reports

There were 173 cases of ILD reported with a medicine between 1 January 2014 and 30 September 2024, of which 30 had a fatal outcome. Nitrofurantoin, methotrexate and amiodarone were the most frequently reported medicines (Figure 1).

Figure 1: Number of interstital lung disease reports^a,b by medicine, 1 January 2014 to 30 September 2024

Notes:

1. Medicines (excluding vaccines) in the New Zealand Pharmacovigilance Database as suspected of causing interstitial lung disease (as indicated by Preferred Terms within the Standardised MedDRA Query ‘interstitial lung disease’) from 1 January 2014 to 30 September 2024.
2. The sum of the ILD reports by medicine (199) is greater than the number of reports (173) because a single case report can have more than one suspect medicine.

Source: Reports of suspected adverse reactions to the New Zealand Pharmacovigilance database (accessed 7 October 2024)

More information

For more information on individual medicines and ILD, refer to the data sheet.

• Search for a data sheet

See also previous Prescriber Update articles about medicine-induced ILD.

• Medicine-induced lung disease (June 2016)
• Nitrofurantoin – do the benefits outweigh the risks long-term? (June 2012)
• Amiodarone pulmonary toxicity – early recognition is vital (December 2013)

References

1. Wijsenbeek M, Suzuki A and Maher TM. 2022. Interstitial lung diseases. The Lancet 400(10354): 769-86. DOI: 10.1016/S0140-6736(22)01052-2 (accessed 11 October 2024).
2. Schwaiblmair M, Behr W, Haeckel T, et al. 2012. Drug induced interstitial lung disease. Open Respiratory Medical Journal 6: 63-74. DOI: 10.2174/1874306401206010063 (accessed 11 October 2024).