Toxic interaction between atorvastatin and clarithromycin causing myositis and rhabdomyolysis

Case

A 79-year-old male presented to his cardiologist for routine review. He had longstanding hypercholesterolaemia with significant coronary artery disease, atrial fibrillation, hypertension and hypertrophic cardiomyopathy, requiring tight lipid control. His current medications included atorvastatin 80 mg once daily, rivaroxaban 20 mg once daily, furosemide 40 mg in the morning, digoxin 125 micrograms once daily, colecalciferol 2000 international units once daily, coenzyme Q10 one tablet once daily, and potassium chloride 600 mg once daily. Clarithromycin 250 mg twice daily had been prescribed for sinusitis 1 month prior, and the patient had remained on it since.

He reported progressive aches, malaise and difficulty rising from a chair. Investigations showed an erythrocyte sedimentation rate of 91 mm/hour (reference range 2 to 25 mm/hour) and C-reactive protein of 80 mg/L (0.0 to 4.9 mg/L). Full blood count and electrolytes, urea and creatinine were normal. Liver function tests showed elevated transaminases: aspartate aminotransferase (AST) 161 U/L (0 to 35 U/L), alanine aminotransferase 105 U/L (0 to 40 U/L), and elevated gamma-glutamyl transferase 104 U/L (0 to 50 U/L). The cardiologist started prednisolone for a provisional diagnosis of polymyalgia rheumatica and admitted the patient for further evaluation.

On day 3 of admission, the patient complained of increasing pain and weakness of the muscle in the lower limbs. A rheumatology consultation was requested. The rheumatologist saw the patient on day 4, where the patient mentioned a slight improvement since starting prednisolone but then started to worsen. On further history-taking, the rheumatologist suspected a drug interaction between atorvastatin and clarithromycin that led to the myositis, and stopped both drugs. On examination, the patient had proximal muscle weakness, with no associated features of systemic disease. The creatine kinase (CK) was elevated to 1640 U/L (20 to 200 U/L).

Despite stopping atorvastatin and clarithromycin, the patient deteriorated. There was further weakness of both upper and lower limbs, with failure of the sit-to-stand test and he developed dark urine positive for myoglobin. There was ongoing elevation of the CK peaking at 39,800 U/L 12 days after admission, with AST peaking at 1690 U/L. Magnetic resonance imaging of the thighs revealed prominent abnormal symmetrical swelling and oedema-like changes involving the thigh musculature. Comprehensive autoimmune serology, including myositis antibodies, was negative. A diagnosis of rhabdomyolysis was likely. The prednisolone was weaned and intravenous fluids with aggressive diuresis were started as per Therapeutic Guidelines: Toxicology and Toxinology.¹

During the third week of admission, the patient gradually improved with a CK down to 313 U/L. On day 21 of admission, he was cleared for discharge and was referred for outpatient rehabilitation. This adverse drug reaction has since been reported to the Therapeutic Goods Administration (TGA).

 

Comment

Statins (HMG-CoA reductase inhibitors) are widely prescribed for dyslipidaemia. Although generally well tolerated, they can cause toxic myositis, autoimmune myositis, and rhabdomyolysis. Statins are taken up into hepatocytes via organic anion transporters (OATs) and are primarily metabolised through the cytochrome P450 (CYP) system. From a statin toxicological perspective, CYP activity plays a more critical role than OATs in determining systemic drug exposure.² When CYP metabolism is inhibited, systemic drug exposure increases and adverse effects are more likely. Our patient was prescribed clarithromycin, which is a potent inhibitor of CYP3A4.^2,3 We concluded that the patient developed myositis and rhabdomyolysis from increased systemic exposure to atorvastatin after clarithromycin was prescribed.

Lipophilic statins undergo hepatic metabolism predominately by membrane-bound CYP3A4 enzymes, whereas hydrophilic statins are largely excreted unchanged.⁴ This distinction is clinically significant as lipophilic statins can readily cross cellular membranes and accumulate in non-hepatic tissues such as skeletal muscle, increasing the risk of myositis and rhabdomyolysis. In contrast, hydrophilic statins have limited muscle penetration and therefore a lower risk of toxic injury to off-target tissues.⁴ Table 1 summarises the solubility profiles and primary CYP metabolic pathways of commonly used statins.

Table 1 Solubility and metabolism of common statins^2,5,6

Statin	Solubility	CYP metabolism
atorvastatin	lipophilic	CYP2C9, CYP3A4
pravastatin	hydrophilic	minimal
rosuvastatin	hydrophilic	CYP2C9, CYP2C19
simvastatin	lipophilic	CYP3A4, CYP2C8
CYP = cytochrome P450

The pathophysiological mechanism of statin-induced muscle injury is thought to involve depletion of intramuscular cholesterol and reduced production of ubiquinone, leading to muscle damage, though this remains under investigation.⁵ Consequently, the combination of a lipophilic statin and elevated drug exposure due to CYP inhibition substantially increases the risk of myositis and rhabdomyolysis.

Co-administration of clarithromycin with lipophilic statins markedly increases statin exposure as measured by the area under the curve (AUC), peak plasma concentration (C_max) and half-life.⁷ In pharmacokinetic studies, atorvastatin had a 4-fold increase in AUC and 5-fold increase in C_max. Simvastatin had the greatest change in exposure, with a 10-fold increase in AUC, 7-fold increase in C_max, and 2-fold prolongation in half-life.⁷ In 2011, the TGA published a statement advising prescribers to limit the prescription of high-dose (80 mg) simvastatin to certain patients due to the increased risk of myositis and rhabdomyolysis and to be aware of co-administration with other drugs that may interact.⁸

 

Conclusion and recommendations

Statins and clarithromycin are commonly prescribed medications. However, as this case demonstrates, their potential for clinically significant drug–drug interactions should not be underestimated. It is reasonable for clinicians to consider temporarily withholding statin therapy during antimicrobial therapy that inhibits CYP metabolism. Alternatively, dose reduction or substitution with a hydrophilic statin may serve as effective risk mitigation strategies. These approaches should be accompanied by close clinical monitoring, particularly in patients at increased risk of statin-associated adverse effects.

Given the prevalence of polypharmacy, it is imperative that prescribers actively check for interactions when starting new therapies, regardless of treatment duration. Clinicians should be familiar with common drug interactions with statins, and several resources are available to support prescribers. Day et al. published a comprehensive list of drug interactions and associated harms.⁹ Additional resources include the Australian Medicines Handbook, and an Australian Prescriber article that compares specific drug interaction tools, including their limitations.

This article was finalised on 27 February 2026.

Patient consent for publication of this case study was obtained by the authors.

Acknowledgements: The authors would like to acknowledge Professor Richard Day and Professor Jonathan Brett for their expert commentary on the case.

Conflicts of interest: Mitchel Hurlbert is a Clinical Pharmacology Trainee participant on the Australian Prescriber Editorial Advisory Committee. He was excluded from editorial decision-making related to the acceptance and publication of this case study.

Tien Tay, Cameron Holloway and Laila Girgis have no conflicts of interest to declare.

This article is peer reviewed.

 

References

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