Rhadbomyolysis associated with co‐administration of danazol and lovastatin

We report a probable, drug–drug interaction between danazol and lovastatin that led to an episode of severe rhabdomyolysis. A 91-year-old White male (weight 73 kg, height 172 cm) with a past medical history of coronary artery disease, hypertension, hyperlipidaemia, diabetes mellitus, hypothyroidism and idiopathic thrombocytopenic purpura (ITP) presented with a 2-week history of progressively increasing bilateral leg weakness involving both the distal and proximal muscle groups. He denied fever, skin rashes, back or joint pain. There was no bladder or bowel incontinence or other neurological symptoms. Active medications included aspirin (81 mg day−1), clopidogrel (75 mg day−1), metoprolol (200 mg day−1), lisinopril (10 mg day−1), isosorbide dinitrate (10 mg day−1), lovastatin (40 mg day−1), levothyroxine (50 µg day−1), glipizide (5 mg day−1) and danazol (400 mg day−1). About 2 months previously, he was changed from atorvastatin (10 mg day−1) to lovastatin, because his insurance declined to provide payment coverage for atorvastatin. Physical examination was notable for diffuse lower extremity weakness and skin ecchymosis but no rash, and no other significant cardiovascular, respiratory, abdominal or neurological findings or signs suggestive of dermatomyositis. Laboratory investigations were notable for an elevated white blood cell count of 14 200 (normal 3500–10 500 U l−1), elevated creatine kinase of 22 504 (normal 52–336 U l−1), aspartate aminotransferase of 368 (normal 15–46 U l−1), alanine aminotransferase of 415 (normal 12–63 U l−1) and a serum creatinine of 2.5 (normal <1.2 mg dl−1). He was managed with intravenous hydration, discontinuation of lovastatin and danazol and physical therapy. His symptoms improved, his creatine kinase and liver enzymes trended back to normal and renal function normalized within 4 days. Danazol, 17-alpha-ethinyl testosterone, is used clinically to treat of endometriosis, fibrocystic breast disease, hereditary angioedema and ITP. This patient had been on a stable dose of danazol for ITP (400 mg once daily) for over 25 years and concomitantly receiving several statins in the last 10 years including fluvastatin (dose range 20–40 mg daily), simvastatin (dose range 10–40 mg daily) and, most recently, atorvastatin 10 mg daily. He had never previously developed symptoms consistent with statin-induced myopathy. HMG-CoA reductase inhibitors are metabolized in the liver by the CYP450 enzymes [1] (see Table 1). Both atorvastatin and lovastatin are metabolized by CYP3A4 and danazol is reported to be a CYP3A4 inhibitor [2]. The combination of high-dose lovastatin and danazol was the likely offender in this patient. The inhibition of CYP3A4 likely led to increased accumulation of the high-dose of lovastatin. In this case, the adverse drug reaction Naranjo probability score was 8, suggestive of a probable causal relationship [3]. This putative danazol precipitated drug–drug interaction causing rhabdomyolysis with statins has been reported previously with lovastatin [4, 5] and simvastatin [6, 7]. In these reports, the adverse event was dose-related and the time course of onset of rhabdomyolysis was about 8–10 weeks. Table 1 Cytochrome metabolism of statins [1] Statin-related myopathy is an important side effect that can be precipitated by a number of drug–drug interactions. Physicians should be cautious of these drug interactions particularly when switching statin drugs, especially in the elderly who are on multiple concomitant medications.