Verzenios ® (abemaciklib)

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Verzenios® ▼ (abemaciclib): Pneumonit

Pneumonit/ILD har lagts till som en varning till produktresumén för abemaciclib.

Detailed Information

Pneumonitis is a general term that refers to inflammation of the lungs. The term ILD is an imprecise clinical term that refers to a group of more than 200 chronic lung disorders characterized by inflammation of the lung tissue, which often leads to scarring.1,2 In clinical practice, the terms ILD and pneumonitis are often used interchangeably.

Interstitial lung disease can be caused by autoimmune diseases, genetic abnormalities (eg, Hermansky–Pudlak syndrome) and long-term exposures to hazardous materials (eg, medications such as bleomycin, occupational exposures such as asbestos, tobacco smoke, or agents in the environment that cause an immune reaction called hypersensitivity pneumonitis). However, the cause of ILD is mostly unknown and the lung manifestations are described as idiopathic interstitial pneumonia.1

Drug-induced interstitial lung disease occurs when exposure to a drug causes inflammation and eventually fibrosis of the lung interstitium. Drug-induced interstitial lung disease has been associated with chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. Cancer drugs account for approximately 23% to 51% of DIILD cases.3 It becomes challenging to identify potentially causative agents in oncology when drugs are combined with other agents, or given in association with radiotherapy; the risk of developing DIILD may be increased when causative agents are combined.3

Monitoring and Dose Modification

Interstitial lung disease and/or pneumonitis was reported in patients receiving abemaciclib. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and treat as medically appropriate. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.4 Based on the severity of ILD/pneumonitis, abemaciclib may require dose modification.5

Dose modification and management is summarized in Table 1.

Table 1. Management recommendations for interstitial lung disease (ILD)/pneumonitis5

Toxicitya

Management recommendations

Grade 1 or 2

No dose adjustment required.

Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1

Suspend dose until toxicity resolves to baseline or Grade 1.

Resume at next lower dose.

Grade 3 or 4

Discontinue abemaciclib.

a NCI CTCAE

Mechanism of Action and Etiology of ILD

The reasons patients develop ILD/pneumonitis when they are taking anticancer medications are not fully understood. There can also be multiple confounding factors, especially in cancer treatment, where multiple drugs are often administered at the same time. Based on the mechanism of action of abemaciclib, a CDK 4/6 inhibitor and the etiology of ILD, there is no known mechanistic explanation for an association of abemaciclib and ILD.4

Incidence of Pneumonitis in the MONARCH Trials

Across the MONARCH clinical trials, the incidence of ILD/pneumonitis was

  • 2.3% in MONARCH 1,

  • 2.0% in MONARCH 2, and

  • 5.2% in MONARCH 3.4

Deaths in MONARCH trials

Death due to ILD/pneumonitis in abemaciclib-treated patients in the United States was reported in

  • 1 patient in MONARCH 1

  • 2 patients (0.5%) in MONARCH 2, and

  • 1 patient (0.3%) in MONARCH 3.6

Incidence of Pneumonitis in Postmarketing Reports

Interstitial lung disease/pneumonitis was identified as a common (>1.0% to <10%) adverse drug reaction based on spontaneous data from postmarketing reports.4

Drug-Induced Interstitial Lung Disease in Japanese Population

A higher prevalence of pneumonitis reports are noted in Japanese populations, which may be a combination of genetic susceptibility and variation in reporting.3,7

Based on the data from EudraVigilance, the EMA’s database for adverse drug reactions, findings show

  • as of 31 December 2014, there were 26,551 case reports of ILD in EudraVigilance of which 17,526 (66%) originated in Japan

  • the reporting rate of ILD for Japan has been consistently higher over the period, and

  • the odds that a case report from Japan in EudraVigilance refers to ILD is 20.7 (95% CI: 20.2-21.3; p<.001), compared to OR=0.60 (95% CI: 0.54-0.67; p<.001) for pulmonary fibrosis.8

Geographic Variability of ILD/Pneumonitis

With respect to differences in DIILD/pneumonitis in Japan vs other East Asian countries, a recent meta-analysis for EGFR TKI-induced pneumonitis in more than 15,000 patients across the world was performed.9 The meta-analysis found

  • the incidence in the trial cohorts from Japan was significantly higher compared to the cohorts of studies of non-Japan origin with odds ratios ranging from 5.01 to 5.54,

  • the incidence in Japanese cohorts was higher than the incidence in the cohorts from other East Asian countries including Korea, Taiwan, and China, and

  • it appears that the incidences of pneumonitis in Korea and Taiwan are between those of Japan and non-Asian countries.9

Geographic Variability in MONARCH 2 and MONARCH 3

In a pooled analysis for ILD/pneumonitis including patients treated with abemaciclib in MONARCH 2 and MONARCH 3, some geographic variability in terms of ILD/pneumonitis incidence was observed. Numerical higher incidence was observed in Japan compared to other countries.4

Japanese PMDA Action

In Japan, ILD/pneumonitis has been added as a warning to the abemaciclib label. Clinicians in Japan were notified of this update on May 17, 2019. Lilly worked closely with PMDA, the drug regulatory body in Japan, to update the appropriate language in the abemaciclib prescribing information.10

This update was a result of several postmarketing cases of ILD/pneumonitis in Japan. Interstitial lung disease is reported to be in general more frequently observed in Japanese patients.8 The reason for the higher incidence of ILD in Japan is not fully understood. However, differences in genetic sensitivity may have a role,11 as well as variation in reporting ILD as an adverse drug reaction.8

Interstitial lung disease was already listed as an adverse reaction for abemaciclib in the Japanese label when it was approved in September 2018.4

References

1. Anthimopoulos M, Christodoulidis S, Ebner L, et al. Lung pattern classification for interstitial lung diseases using a deep convolutional neural network. IEEE Trans Med Imaging. 2016;35(5):1207-1216. http://dx.doi.org/10.1109/tmi.2016.2535865

2. Bourke SJ. Interstitial lung disease: progress and problems. Postgrad Med J. 2006;82(970):494-499. http://dx.doi.org/10.1136/pgmj.2006.046417

3. Skeoch S, Weatherley N, Swift AJ, et al. Drug-induced interstitial lung disease: a systematic review. J Clin Med. 2018;7(10). http://dx.doi.org/10.3390/jcm7100356

4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5. Verzenios [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

6. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2019.

7. Schwaiblmair M, Behr W, Haeckel T, et al. Drug induced interstitial lung disease. Open Respir Med J. 2012;6:63-74. http://dx.doi.org/10.2174/1874306401206010063

8. Pinheiro L, Blake K, Januskiene J, et al. Geographical variation in reporting interstitial lung disease as an adverse drug reaction: findings from an European Medicines Agency analysis of reports in EudraVigilance. Pharmacoepidemiol Drug Saf. 2016;25(6):705-712. http://dx.doi.org/10.1002/pds.3998

9. Suh CH, Park HS, Kim KW, et al. Pneumonitis in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitor: Meta-analysis of 153 cohorts with 15,713 patients: Meta-analysis of incidence and risk factors of EGFR-TKI pneumonitis in NSCLC. Lung Cancer. 2018;123:60-69. http://dx.doi.org/10.1016/j.lungcan.2018.06.032

10. PMDA, 2019. Blue Letter. https://www.pmda.go.jp/files/000229624.pdf. Accessed May 28, 2019.

11. Furukawa H, Oka S, Shimada K, et al. Genetics of interstitial lung disease: Vol de Nuit (Night Flight). Clin Med Insights Circ Respir Pulm Med. 2015;9(suppl 1):1-7. http://dx.doi.org/10.4137/ccrpm.S23283

Glossary

AI = aromatase inhibitor

CDK = cyclin-dependent kinase

DIILD = drug-induced interstitial lung disease

EGFR = epidermal growth factor receptor

EMA = European Medicines Agency

ILD = interstitial lung disease

Lilly = Eli Lilly and Company

OR = odds ratio

PMDA = Pharmaceuticals and Medical Devices Agency

TKI = tyrosine kinase inhibitor

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2020 M01 13


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