CDK4/6 inhibitors (abemaciclib▼, palbociclib▼, ribociclib▼): reports of interstitial lung disease and pneumonitis, including severe cases

Cases of interstitial lung disease and pneumonitis have been reported in patients receiving CDK4/6 inhibitors indicated for some breast cancers. Ensure that patients taking these medicines are aware of the need to seek advice right away if they develop new or worsening respiratory symptoms.

From:
Medicines and Healthcare products Regulatory Agency
Published
17 June 2021
Therapeutic area:
Cancer

Advice for healthcare professionals:

  • abemaciclib, palbociclib, and ribociclib are indicated for some locally advanced or metastatic breast cancer (see product information for full indications)
  • there have been reports of interstitial lung disease and pneumonitis with these medicines, in some cases severe or fatal
  • during clinic appointments, ask patients about pulmonary symptoms indicative of interstitial lung disease and pneumonitis, such as cough or dyspnoea, and advise them to seek advice right away if they occur
  • evaluate patients with new or worsening respiratory symptoms, refer to the Summary of Product Characteristics (SmPC; linked above), particularly advice in sections 4.2 and 4.4, and consider dose interruption, modification, or discontinuation according to the severity of the event
  • ensure patients are provided with a copy of the Patient Information Leaflet (PIL), which provides information about the medicine and explains the symptoms that patients should be aware of
  • report all suspected adverse drug reactions associated with CDK4/6 inhibitors to the Yellow Card scheme

Advice for healthcare professionals to provide to patients:

  • if you are experiencing new or worsening respiratory symptoms such as a cough or shortness of breath when taking a CDK4/6 inhibitor, it is important to seek advice right away from your care team
  • cases of lung disease, including inflammation in the lungs, have been reported in patients taking these medicines; these lung conditions can be severe or life-threatening
  • always read the leaflet that accompanies your medicines and talk to your doctor, nurse, or pharmacist if you are concerned about any side effects

CDK4/6 inhibitors

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) abemaciclib (Verzenios▼), palbociclib (Ibrance▼), and ribociclib (Kisqali▼) are authorised for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant – see product information for full indication for each medicine. In premenopausal or perimenopausal women, the endocrine therapy should be combined with a luteinising-hormone-releasing hormone (LHRH) agonist (see product information for full details).

Review of cases of interstitial lung disease and pneumonitis

Cases of interstitial lung disease and pneumonitis have been reported with the use of CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib. There have also been reports of some fatal cases.

Following European reviews of safety data, the Summary of Product Characteristics (SmPC) and Patient Information Leaflets (PILs) for these products have been updated to include warnings about these risks. In patients who have new or worsening respiratory symptoms and who are suspected to have developed interstitial lung disease or pneumonitis, refer to the product information, particularly advice in sections 4.2 and 4.4 of the SmPC, and consider dose interruption, modification, or discontinuation according to the severity of the event.

Frequency of interstitial lung disease and pneumonitis

Clinical trials

For abemaciclib, the product information notes that 3.4% of participants treated in clinical trials (n=768) had interstitial lung disease or pneumonitis of any grades of severity. The frequency of grade 3 (severe) events was 0.4% and grade 4 (life-threatening) events was 0.1% of participants.[footnote 1]

For palbociclib, the product information notes that 1.4% of participants treated in clinical trials (n=872) had interstitial lung disease or pneumonitis of any grade. One grade 3 event was reported (0.1%) and no grade 4 events (although fatalities have been reported post-marketing).

For ribociclib, the product information notes that interstitial lung disease (any grade 0.3%, including 0.1% grade 3) was reported in the ribociclib-treated group in clinical studies, with no cases in the placebo-treated group. Pneumonitis was reported in both the ribociclib and the placebo-treated groups (any grade 0.4%; with no grade 3 or 4 events in either group).

Yellow Card reports in the UK

CDK4/6 inhibitors are relatively new medicines. Palbociclib, ribociclib, and abemaciclib were licensed in the EU in 2016, 2017, and 2018 respectively.

Since authorisation and up to 21 Jan 2021, the number of suspected adverse reports of interstitial lung disease, pneumonitis and related terms in the UK received by the Yellow Card scheme was 8 for abemaciclib (of which 4 were fatal), 18 for palbociclib (of which 7 were fatal), and one for ribociclib. In interpreting these data, caution should be exercised and comparisons not drawn between the medicines given different exposures[footnote 2] and other factors unrelated to the inherent safety of the medicines that may affect the number of reports. Reporters are asked to submit Yellow Card reports even if they only have a suspicion that the medicine may have caused the adverse drug reaction.

Report any suspected adverse drug reactions

Please continue to report suspected adverse drug reactions (ADRs) via the Yellow Card scheme. All ADRs associated with black triangle medicines should be reported – this will allow quick identification of new safety information.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 14, issue 11: June 2021: 1.

  1. Grading of events according to Common Terminology Criteria for Adverse Events (CTCAE). Consult SmPC for relevant information on version used. ↩

  2. Estimated usage for these medicines in the UK is 940 patient-years for abemaciclib, 7850 patient-years for palbociclib, and 780 patient-years for ribociclib (data derived from IQVIA MIDAS, quarter 4 2016, to quarter 3 2020, by the MHRA, February 2021). Data based on volume of drug dispensed in UK retail and hospital pharmacies. Patient-year estimates made using defined daily dose. ↩

Updates to this page

Published 17 June 2021
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