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

Statins, also known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are widely prescribed long term for lowering serum cholesterol levels and for the prevention of cardiovascular events.^1-3 Simvastatin and atorvastatin are extensively metabolised by the cytochrome CYP3A4 enzyme and excreted in bile, and their amount excreted unchanged in urine is comparatively less.^4-6, Conversely, rosuvastatin does not undergo extensive metabolism and is primarily excreted unchanged in faeces (90%) and urine.^4,7

In Malaysia, there are currently 60 products containing atorvastatin, 47 containing rosuvastatin, and 39 containing simvastatin registered with the Drug Control Authority (DCA), available both as single-ingredient products and combination products with other drugs.⁸

While generally well tolerated, statins have been linked to muscle symptoms, constituting one of the most common adverse drug reaction (ADR).³ Among these, statin-induced rhabdomyolysis is a widely known adverse event but rarely occur, with its prevalence varying among different statins. ^1-3,9-10 The risk of rhabdomyolysis increases when statins are used concurrently with drugs that elevate their concentrations in the body.^1,9 Notably, about 60% of statin-related rhabdomyolysis cases were attributed to drug-drug interactions in randomised clinical trials.³

Despite the clear benefits of the combined use of statins and ticagrelor, an oral direct-acting antiplatelet agent, for secondary prevention of cardiovascular events, there is a growing concern about the potential drug interaction leading to rhabdomyolysis.^2-3

Rhabdomyolysis is a severe form of muscle damage characterised by the release of sarcoplasmic proteins, such as aspartate aminotransferase, alanine aminotransferase, creatine kinase (CK) and electrolytes, into the blood circulation.^1,9-10 Patients typically present with myalgia, muscle weakness, marked elevations of CK, myoglobinaemia, and/or myoglobinuria. This condition can lead to life-threatening complications, such as acute renal failure and cardiac arrhythmias.

 

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from European Medicines Agency (EMA) about the risk of rhabdomyolysis associated with the drug interaction between rosuvastatin and ticagrelor.¹¹ After reviewing the available data from the literature, including positive dechallenge in all cases and in view of a plausible mechanism of action, the Pharmacovigilance Risk Assessment Committee (PRAC) considered that this drug interaction resulting in rhabdomyolysis is established. Consequently, the PRAC concluded that the product information (PI) of products containing rosuvastatin should be amended accordingly.

Additionally, the NPRA has received safety notifications from a local product registration holder concerning updates from the Australian Therapeutic Goods Administration (TGA). Prompted by the PRAC assessment report, the TGA conducted an evaluation of all statin products for the similar risk. The TGA’s assessment of the available evidence concluded that there are sufficient grounds to update the PI for all products containing rosuvastatin, simvastatin, and atorvastatin to inform healthcare professionals about the potential interactions between specific statins and ticagrelor.

Ticagrelor is known to inhibit CYP3A4 enzymes and several transporters like organic anion transporting polypeptides (OATPs) and P-glycoprotein (P-gp), which has led to several proposed mechanisms for statin-ticagrelor interactions.^2,3,9,12-13 Potential mechanisms, varying among different statins, encompass the competitive inhibition of CYP3A4 enzymes (reducing metabolism of simvastatin and atorvastatin) and transporters (reducing biliary and renal clearance of statins) leading to statin accumulation. Genetic polymorphism affecting the functions of metabolic enzymes and transporters may also play a role in these interactions.^2,3,7

Additionally, a recent study reported that ticagrelor may inhibit intestinal breast cancer resistance protein (BCRP), potentially doubling rosuvastatin systemic exposure and increasing the risk of rhabdomyolysis.¹⁴ Ticagrelor-induced renal insufficiency could also result in statin retention, potentiating the risk of stain-induced myopathy and further worsening renal injury.^2,3,7,14

A published analysis of VigiBase, the World Health Organisation (WHO) Pharmacovigilance Database, reveals statin and ticagrelor combination accounts for over a quarter of statin-related rhabdomyolysis cases received globally.³ Most cases involving this combination occurred in the first six (6) months regardless of the drug administered, while some emerged after 48 months. Among all reported cases, 97.4% declared seriousness, and 5.4% reported death.

Based on the multivariate analysis, the risk of rhabdomyolysis reporting was higher when ticagrelor was co-administered with atorvastatin (reporting odds ratios (ROR): 1.3 [1.02–1.65]) or rosuvastatin (ROR: 1.9 [1.42–2.54]), which represent the most prescribed statins worldwide.³ Conversely, such increased risk was not observed with other antiplatelets like aspirin, clopidogrel, or prasugrel. The analysis also identified a dose–dependent risk of rhabdomyolysis reporting, with cases with higher doses of statins more likely to report rhabdomyolysis than medium and low doses.

 

Adverse Drug Reaction Reports

To date, the NPRA has received 6,200 reports with 9,807 adverse events suspected to be related to products containing simvastatin, atorvastatin, and rosuvastatin.¹⁵ Of these, there have been local reports of rhabdomyolysis associated with simvastatin (46 reports), atorvastatin (13) and rosuvastatin (3), but none were linked to drug interactions with ticagrelor.

On the other hands, reports of myopathy were noted for simvastatin (35), atorvastatin (10) and rosuvastatin (1), with none involving drug interactions with ticagrelor.¹⁴ No spontaneous reports involving rhabdomyolysis, myopathy, or myositis have been received, either locally and globally, in relation to the combined use of ticagrelor and other locally registered statins, including pitavastatin, pravastatin, or lovastatin.^15-16

 

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware that there have been reports of rhabdomyolysis involving the co-administration of ticagrelor with the most prescribed statins worldwide.
• Although statin-induced rhabdomyolysis is dose-dependent, co-administration of ticagrelor and statin is generally safe at routinely prescribed doses.
• Exercise caution and consider regular monitoring of CK and renal function in patients with risk factors for rhabdomyolysis, including:
  • older age, male gender, prior elevated CK levels, diabetes, renal impairment, cardiovascular disease, use of high-dose statins, or co-administration with certain interacting drugs
• Educate patients to consult doctors if they encounter any signs and symptoms of muscle pain, tenderness, or weakness that persist or worsen, particularly during the initiation of combination therapy or any periods of upward dosage titration of either drug.
• In cases of rhabdomyolysis under statin therapy, consider its association with ticagrelor. In such cases, consider temporarily suspending the statin, depending on clinical and laboratory improvement. Subsequent managements may include titrating the statin therapy to the optimal tolerated dose or switching to an alternative lipid-lowering agent or antiplatelet agent.
• Report all adverse events suspected to be related to the use of statins and ticagrelor to NPRA.

 

References:

1. Banakh I, Haji K, Kung R, Gupta S, Tiruvoipati R. Severe Rhabdomyolysis due to Presumed Drug Interactions between Atorvastatin with Amlodipine and Ticagrelor. Case Rep Crit Care. 2017;2017:3801819. Available from: https://doi.org/10.1155/2017/3801819 
2. Danielak D, Karaźniewicz-Łada M, Główka F. Assessment of the Risk of Rhabdomyolysis and Myopathy During Concomitant Treatment with Ticagrelor and Statins. Drugs. 2018 Jul;78(11):1105-1112. Available from: https://doi.org/10.1007/s40265-018-0947-x
3. Roule V, Alexandre J, Lemaitre A, Chrétien B, Sassier M, Fedrizzi S, Beygui F, Dolladille C. Rhabdomyolysis with Co-Administration of Statins and Antiplatelet Therapies-Analysis of the WHO Pharmacovigilance Database. Cardiovasc Drugs Ther. 2023 Apr 28. Available from: https://doi.org/10.1007/s10557-023-07459-8
4. Sizar O, Khare S, Jamil RT, et al. Statin Medications. [Updated 2023 Feb 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan [cited 2023 Oct 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430940/ 
5. National Pharmaceutical Regulatory Agency (NPRA). ZOCOR (simvastatin) [Package Insert]. QUEST3+ Product Search. 2023 Jun 02 [cited 2023 Oct 18]. Available from: http://www.npra.gov.my.
6. National Pharmaceutical Regulatory Agency (NPRA). LIPITOR (atorvastatin) [Package Insert]. QUEST3+ Product Search. 2022 Feb 09 [cited 2023 Oct 18]. Available from: http://www.npra.gov.my.
7. National Pharmaceutical Regulatory Agency (NPRA). CRESTOR (rosuvastatin) [Package Insert]. QUEST3+ Product Search. 2021 Jul [cited 2023 Oct 18]. Available from: http://www.npra.gov.my.
8. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2023 [cited 2023 Dec 13]. Available from: https://www.npra.gov.my
9. Kariyanna PT, Haseeb S, Chowdhury YS, Jayarangaiah A, Maryniak A, Mo G, Hegde S, Marmur JD, McFarlane IM. Ticagrelor and statin interaction induces rhabdomyolysis and acute renal failure: case reports and scoping review. American journal of medical case reports. 2019;7(12):337. Available from: http://pubs.sciepub.com/ajmcr/7/12/9/index.html
10. Nguyen KA, Li L, Lu D, Yazdanparast A, Wang L, Kreutz RP, Whipple EC, Schleyer TK. A comprehensive review and meta-analysis of risk factors for statin-induced myopathy. Eur J Clin Pharmacol. 2018 Sep;74(9):1099-1109. doi: 10.1007/s00228-018-2482-9. Available from: https://doi.org/10.1007/s00228-018-2482-9
11. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s): Ezetimibe/ Rosuvastatin [Internet]. 2021 March [cited 2023 Oct 18]. Available from: https://www.ema.europa.eu/en/documents/psusa/ezetimibe/rosuvastatin-cmdh-scientific-conclusions-grounds-variation-amendments-product-information-timetable/00010271/202007_en.pdf 
12. Sibley RA, Katz A, Papadopoulos J. The Interaction Between Rosuvastatin and Ticagrelor Leading to Rhabdomyolysis: A Case Report and Narrative Review. Hosp Pharm. 2021 Oct;56(5):537-542. Available from: https://doi.org/10.1177/0018578720928262 
13. National Pharmaceutical Regulatory Agency (NPRA). BRILINTA (ticagrelor) [Package Insert]. QUEST3+ Product Search. 2022 Jul [cited 2023 Oct 18]. Available from: http://www.npra.gov.my.
14. Lehtisalo M, Kiander W, Filppula AM, Deng F, Kidron H, Korhonen M, Sinkko J, Koivula K, Niemi M. Rhabdomyolysis during concomitant ticagrelor and rosuvastatin: A breast cancer resistance protein-mediated drug interaction? Br J Clin Pharmacol. 2023 Jul;89(7):2309-2315. Available from: https://doi.org/10.1111/bcp.15684
15. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2023 [cited 2023 Sep 22]. Available from: https://www.npra.gov.my (access restricted)
16. Uppsala Monitoring Centre (UMC). The WHO Global ICSR Database (VigiLyze) [Internet]. 2023 [cited 2023 Dec 12]. Available from: https://www.vigilyze.who-umc.org (access restricted)

 

Written by: Wo Wee Kee
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali