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, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Overview of Product(s)

Cyclin-Dependent Kinase Inhibitors (CDKIs) are anticancer drugs used with endocrine therapy to treat hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER-2) negative breast cancer.¹ Statins, on the other hand, are first-line therapy for lowering low-density lipoprotein cholesterol (LDL-C) and are integral to the management of cardiovascular disease.^1,2 In Malaysia, there are 19 products containing CDKIs and 190 products containing statin registered with the Drug Control Authority (DCA).³ There are three (3) types of CDKIs namely palbociclib, abemaciclib and ribociclib registered for use, while the statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, and pitavastatin.

Overview of Safety Concern

Rhabdomyolysis is one of the known complications of statins.¹ It occurs when severe muscle damage causes a significant increase in creatinine kinase (CK), often accompanied by renal dysfunction, and in some cases, renal failure or death. While the interaction between CDKIs and statins has been linked to CK elevations of varying severity, reports of rhabdomyolysis remain rare. Analysis of the WHO database revealed 44 cases of rhabdomyolysis have been reported in association with possible interactions between CDKIs and certain statins, with no cases reported for lovastatin, pravastatin or pitavastatin.⁴

Source of Safety Concern

The National Pharmaceutical Regulatory Agency (NPRA) received information from Health Canada on the potential risk of rhabdomyolysis associated with drug interaction between CDKIs (abemaciclib, palbociclib and ribociclib) and registered statins in Canada (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin).⁵ The safety review was initiated following the European Medicines Agency (EMA)’s investigation into the interaction between palbociclib and statins, which concluded with a requirement to update the product information (PI) for palbociclib accordingly.^5,6

Following this, Health Canada reviewed data from drug manufacturers, the Canada Vigilance adverse event database, and relevant scientific literature on CDKI-statin interactions.⁵ The evaluation found a possible link between rhabdomyolysis and this drug interaction. Although reported cases involved palbociclib or ribociclib in combination with rosuvastatin or simvastatin, the overall evidence supports a precautionary conclusion that rhabdomyolysis is a potential risk due to a drug interaction between these drug classes. Consequently, Health Canada has mandated the update of CDKI-containing products with information on the risk of rhabdomyolysis when co-administered with statins.

Background of Safety Issue

There are multiple possible mechanisms of CDKI-statin interaction discussed in the literature.^1,7-13 Simvastatin, atorvastatin and lovastatin are substrates of cytochrome CYP3A4, ^{1,7,9,10,13,14} whereas palbociclib and ribociclib are weak and strong CYP3A4 inhibitors, respectively.^1,7,8,10 Concomitant administration of these drugs from both classes may lead to increased serum concentration of the CYP3A4 substrates, thereby potentiating the risk of rhabdomyolysis.^1,8-10,13

Other mechanisms include inhibition of certain transporters- such as organic anion-transporting polypeptide (OATP), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP)- by the three CDKIs, each affecting one or more of these transporters.^10,12,15 In this context, OATP mediates hepatic uptake of statins, while P-gp and BCRP are efflux pumps that transport statins into the intestinal lumen or bile for excretion.^8,9,16 Inhibition of these transporters can increase systemic statin concentration, and thereby enhance toxicity risk.¹²

Several literatures reported that the onset of muscle-related symptoms leading to rhabdomyolysis following concomitant usage of either ribociclib or palbociclib with simvastatin or atorvastatin occurred as early as 3 days and up to 16 months.^1,8-10,13 It is also noteworthy that these patients have been on statins for many years, suggesting no adverse effects experienced until the commencement of CDKIs. The outcome for most of these patients who suffered from rhabdomyolysis was reported as recovered or recovering, except for one fatal case involving necrotising rhabdomyolysis from drug interaction between atorvastatin and palbociclib.

Local Adverse Drug Reaction Reports¹⁷

To date, the NPRA has received 771 reports with 1,556 adverse events suspected to be related to products containing CDKIs, and 8,960 reports with 14,141 adverse events for products containing statins. There have been no events related to rhabdomyolysis reported for all CDKIs. Although there have been cases of rhabdomyolysis reported across all the statins, these reports were not associated with drug interaction with any of the CDKIs. Other related events such as myopathy or myositis were also reported for the statins, but none of the reports involved drug interaction with CDKIs.

Advice for Health Care Professionals

• While NPRA is still reviewing this safety issue, be aware of the risk of rhabdomyolysis involving the co-administration of CDKIs and statins.
• Although WHO reports of rhabdomyolysis are limited to interactions between CDKIs and certain statins, caution should be exercised across all statin drugs.
• If rhabdomyolysis is suspected in patients with high cardiovascular risk where statin discontinuation is not feasible, consider temporary dose reduction and initiate routine monitoring of creatine kinase (CK) levels to detect early signs of toxicity.
• Educate patients to seek medical advice if they have symptoms such as muscle pain, general weakness and brown-coloured urine.
• Report all adverse events suspected to be related to the use of CDKIs and statins to the NPRA.

References:

1. Badran O, Abu Amna M, Turgeman I, Bar-Sela G. Rhabdomyolysis Induced by the Interaction Between Ribociclib and Statins- Case Report and Literature Review. Breast Cancer (Dove Med Press). 2023 Jan 24;15:47-50. Available from: https://doi.org/10.2147/bctt.s380485
2. Ministry of Health (MOH), Malaysia. Management of dyslipidemia [Internet]. Clinical Practice Guidelines. 2023 [cited 2025 Oct 7]. Available from: https://www.moh.gov.my/moh/resources/Penerbitan/CPG/CARDIOVASCULAR/e-CPG_on_Dyslipidaemia_2023_6th_Ed.pdf
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 July 23]. Available from: https://www.npra.gov.my
4. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2025 [cited 2025 June 18]. Available from: https://www.vigilyze.who-umc.org (access restricted)
5. Health Canada. Summary safety review- Cyclin-dependent kinase inhibitors (abemaciclib, palbociclib and ribociclib) and HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin) (statins) - assessing the potential risk of rhabdomyolysis due to drug interaction [Internet]. 2025 May 14 [cited 2025 May 15]. Available from: https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SSR1742565339867
6. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s): palbociclib [Internet]. 2024 March 21 [cited 2025 May 22]. Available from: https://www.ema.europa.eu/en/documents/scientific-conclusion/ibrance-h-c-psusa-00010544-202308-epar-scientific-conclusions-grounds-variation-terms-marketing-authorisation_en.pdf
7. Li S, Yu Y, Jin Z, Dai Y, Lin H, Jiao Z, Ma G, Cai W, Han B, Xiang X. Prediction of pharmacokinetic drug-drug interactions causing atorvastatin-induced rhabdomyolysis using physiologically based pharmacokinetic modelling. Biomed Pharmacother. 2019 Nov;119:109416. Available from: https://doi.org/10.1016/j.biopha.2019.109416
8. Nelson KL, Stenehjem D, Driscoll M, Gilcrease GW. Fatal Statin-Induced Rhabdomyolysis by Possible Interaction with Palbociclib. Front Oncol. 2017 Jul 17;7:150. Available from: https://doi.org/10.3389/fonc.2017.00150
9. Nersesjan V, Hansen K, Krag T, Duno M, Jeppesen TD. Palbociclib in combination with simvastatin induce severe rhabdomyolysis: a case report. BMC Neurol. 2019 Oct 22;19(1):247. Available from: https://doi.org/10.1186/s12883-019-1490-4
10. Streicher C, Daulange A, Madranges N, Vayre L. Severe rhabdomyolysis induced by possible drug-drug interaction between Ribociclib and Simvastatin. J Oncol Pharm Pract. 2021 Apr;27(3):722-726. Available from: https://doi.org/10.1177/1078155220945365
11. Teo SW, Hayes T, Gome J. Ribociclib may potentiate rosuvastatin effect in causing late onset rhabdomyolysis. BMJ Case Rep. 2023 Sep 11;16(9):e255632. Available from: https://doi.org/10.1136/bcr-2023-255632
12. Bellet M, Ahmad F, Villanueva R, Valdivia C, Palomino-Doza J, Ruiz A, Gonzàlez X, Adrover E, Azaro A, Valls-Margarit M, Parra JL, Aguilar J, Vidal M, Martín A, Gavilá J, Escrivá-de-Romaní S, Perelló A, Hernando C, Lahuerta A, Zamora P, Reyes V, Alcalde M, Masanas H, Céliz P, Ruíz I, Gil M, Seguí MÀ, de la Peña L. Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication. Ther Adv Med Oncol. 2019 May 10;11:1758835919833867. Available from: https://doi.org/10.1177/1758835919833867
13. François P, Anna F, Jérémie D, Quentin M, Olivier C, Emmanuelle UC, Céline M, Florence D, Pierre G, Anaïs R. Severe toxic rhabdomyolysis under combined palbociclib and simvastatin treatment: A case report. Front Oncol. 2022 Dec 14;12:1026434. doi: 10.3389/fonc.2022.1026434. Erratum in: Front Oncol. 2023 Feb 07;13:1149399. Available from: https://doi.org/10.3389/fonc.2022.1026434
14. Lovastatin [Internet]. Medscape Tools and References; 2025 [cited 2025 July 22]. Available from: https://reference.medscape.com/drug/mevacor-altoprev-lovastatin-342458#0
15. European Medicines Agency (EMA). VERZENIOS (abemaciclib) [Package Insert]. 2025 March 7 [cited 2025 July 23]. Available from: https://www.ema.europa.eu/en/documents/product-information/verzenios-epar-product-information_en.pdf
16. Murphy C, Deplazes E, Cranfield CG, Garcia A. The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins. Int J Mol Sci. 2020 Nov 19;21(22):8745. Available from: https://doi.org/10.3390/ijms21228745
17. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 June 9]. Available from: https://www.npra.gov.my (access restricted)

Written by: Wo Wee Kee
Reviewed/Edited by: Lim Sze Gee, Dr Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali