DISCLAIMER: This publication is intended for healthcare professionals. The information provided aims to update on medication safety issues and should not substitute clinical judgment. 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 arising from the use of or reliance on this publication.

  

Overview of Products

Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor used in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor or fulvestrant.¹ To date, 12 products containing palbociclib are registered with the Drug Control Authority (DCA), all in oral dosage form.² Other CDK4/6 inhibitors registered in Malaysia include abemaciclib and ribociclib.

 

Overview of Safety Concern

Venous thromboembolism (VTE) is a condition that includes deep vein thrombosis (DVT) and pulmonary embolism (PE).³ The signs and symptoms of DVT and PE are often non-specific, making diagnosis particularly challenging. DVT most commonly occurs in the leg veins, presenting as leg pain, swelling, or localised tenderness upon palpation, but it can also develop in the splanchnic, cerebral, or arm veins. PE typically presents with breathlessness, pleuritic chest pain, tachycardia, and hypoxaemia.

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) has received information from Health Canada on the probable link between VTE and palbociclib use.⁴ Health Canada’s safety review was initiated following a 2020 publication by Thein et al., which reported an increased risk of VTE with the use of CDK4/6 inhibitors.⁵ Health Canada evaluated seven (7) randomised controlled trials (RCTs) of the innovator product, Ibrance (palbociclib), which included 8,793 patients, most (>95%) of whom had early or metastatic breast cancer.⁴ The analysis showed a higher risk of VTE with palbociclib treatment. In particular, among metastatic breast cancer patients, VTE was reported in 3.4% of those treated with palbociclib plus endocrine therapy, compared with 1.9% in patients receiving endocrine therapy alone. 

 

Background of Safety Issue

Recent clinical trials and real-world observational studies have reported an increased risk of venous and arterial thromboembolism associated with the use of CDK4/6 inhibitors, including palbociclib.^5-7 In one analysis on the data reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS), the time to onset of thromboembolic events ranged from approximately 46 to 123 days upon treatment initiation of CDK4/6 inhibitors.⁷

 

Local Adverse Drug Reaction Reports⁸

To date, the NPRA has received a total of 233 adverse drug reactions reports with a total of 365 adverse events associated with palbociclib use in Malaysia. Of these, there was one (1) report of pulmonary embolism received following palbociclib use.

 

Regulatory Action

NPRA completed a review of this safety issue and a directive [Ruj. Kami: NPRA.600-1/9/13(73) Jld.1] had been issued for all registration holders of products containing palbociclib to update the local package inserts and consumer medication information leaflets (Risalah Maklumat Ubat untuk Pengguna) to reflect this safety information.

 

Advice for Healthcare Professionals

• Be aware that VTE has been reported with palbociclib. Similar events have also been reported with other CDK4/6 inhibitors.
• Educate patients to seek medical advice promptly if they experience any of the following symptoms: breathlessness, chest pain, leg pain, redness, swelling or localised tenderness.
• Report all suspected adverse events related to palbociclib use to the NPRA.

 

References

1. National Pharmaceutical Regulatory Agency (NPRA). IBRANCE (palbociclib) [Package Insert]. QUEST3+ Product Search. 2025 November [cited 2025 November 19]. Available from: https://www.npra.gov.my
2. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 November 19). Available from https://www.npra.gov.my
3. Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet. 2021;398(10294):64-77. Available from: https://doi.org/10.1016/S0140-6736(20)32658-1
4. Health Canada. Summary Safety Review - Ibrance (palbociclib) - Assessing the Potential Risk of Venous Thromboembolism [Internet] 2024 {cited 2025 Sep 3]. Available from: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR1707157428464
5. Thein Z, Htut TW, Ball S, Swarup S, Sultan A, Oo TH. Venous thromboembolism risk in patients with hormone receptor‑positive HER2‑negative metastatic breast cancer treated with combined CDK 4/6 inhibitors plus endocrine therapy versus endocrine therapy alone: a systematic review and meta‑analysis of randomized controlled trials. Breast Cancer Res Treat. 2020 Sep;183(2):479-487. Available from: https://doi.org/10.1007/s10549-020-05783-3
6. Chiang H, Lin S, Chang Y-C, et al. Comparative Venous and Arterial Thromboembolism Profiles Associated with Different Cyclin-Dependent Kinase 4/6 Inhibitors: A Real-World Study. Blood. 2024;144(Suppl 1):5084-5085. Available from: https://doi.org/10.1182/blood-2024-209023.
7. Raschi E, Poluzzi E, De Ponti F, Ardizzoni A, Fusaroli M. Thromboembolic Risks of CDK 4/6 Inhibitors in Breast Cancer: A Pharmacovigilance Study. Cancers (Basel). 2021;13(8):1758. Available from: https://doi.org/10.3390/cancers13081758
8. National Pharmaceutical Regulatory Agency. The Malaysian National ADR Database [Internet]. 2024 [cited 2025 Dec 19]. Available from: https://www.npra.gov.my

 

Written by: Noor'ain Shamsuddin

Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Norleen Mohamed Ali