Clinical Therapeutics/Volume 32, Number 5, 2010

May 2010 909

Accepted for publication April 5, 2010.doi: 10.1016/j.clinthera.2010.04.0170149-2918/$ - see front matter

© 2010 Excerpta Medica Inc. All rights reserved.

AbsTrACTBackground: Simvastatin, a 3-hydroxy-3-methylglutaryl-

coenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemia and plays an impor-tant role in both the primary and secondary prevention of cardiovascular disease. Danazol is a steroid analogue approved for the treatment of endometriosis, fibrocystic breast disease, and hereditary angioedema. Despite not being licensed, danazol has been used for other off-label indications, such as idiopathic thrombocytopenic pur-pura (ITP), paroxysmal nocturnal hemoglobinuria, and aplastic anemia.

Objective: We report a case of fatal rhabdomyolysis that occurred after concomitant administration of simvastatin and danazol in a patient with ITP.

Case summary: An 80-year-old white male (height, 182 cm; weight, 90 kg) presented to the emergency department of the Clinical Hospital Centre Zemun, Belgrade, Serbia, with head injuries after an accidental fall caused by generalized weakness. He denied other complaints, except fatigue, mild pretibial edema, and progressive bilateral leg pain and cramping that began 7 days before. At the time of presentation, he was re-ceiving aspirin 100 mg/d, clopidogrel 75 mg/d, ramipril 2.5 mg/d, pantoprazole 40 mg/d, danazol 600 mg/d, prednisone 60 mg/d, simvastatin 40 mg/d, and long-acting insulin 24 IU/d. After the injuries were treated, he was diagnosed with collapse and nasal contusion, and discharged without any changes in his therapy. Two days after initial presentation, the patient was readmit-ted to the hospital due to nausea, dark urine, and oligu-ria. All clinical signs (oliguria, dark urine, muscle pain, and tenderness) and laboratory markers (creatine kinase levels ~100 times the upper limit of normal, along with hyperkalemia, hyperphosphatemia, and hypoalbumin-emia) were consistent with severe rhabdomyolysis.

Despite intravenous hydration, forced diuresis, and he-modialysis, oliguria persisted and the patient died 6 days after admission. A score of 5 on the Naranjo adverse drug reaction probability scale was consistent with a probable association of rhabdomyolysis and concomitant treatment with simvastatin and danazol in this patient.

Conclusions: Statin-induced rhabdomyolysis must be considered whenever muscle or motor symptoms occur, especially when concomitant treatment with known inhibitors of statin metabolism is administered. Patients must be strictly monitored and the statin should be promptly discontinued with the onset of first signs and symptoms of myopathy. Clinicians should be aware of the potentially fatal consequences of both approved and unapproved treatments and be alert for the early detection of toxicity. (Clin Ther. 2010;32:909–914) © 2010 Excerpta Medica Inc.

Key words: simvastatin, danazol, rhabdomyolysis.

INTroduCTIoNDue to their beneficial effect in primary and secondary prevention of cardiac events, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become one of the most frequently prescribed medications in cardiovascular pathology.1 Although myopathy and a mild increase in liver aminotransferase level may occur as a consequence of statin therapy, drug discontinuation is rarely required.

Rhabdomyolysis is an uncommon adverse effect that occurs in <0.1% of patients treated with statins.2 It is

Case Report

Concomitant Administration of Simvastatin and Danazol Associated With Fatal Rhabdomyolysis

Ivan Stankovic, MD1; Alja Vlahovic-Stipac, MD1; Biljana Putnikovic, MD, PhD1; Zorica Cvetkovic, MD, PhD2; and Aleksandar N. Neskovic, MD, PhD, FESC, FACC1

1Department of Cardiology, Clinical Hospital Centre Zemun, Belgrade, Serbia; and 2Department of Hematology, Clinical Hospital Centre Zemun, Belgrade, Serbia

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tion in platelet count, and the patient was discharged 2 weeks later with a platelet count of 99 × 109/L. Prior to danazol initiation, both patient and family members were informed about the cost and effectiveness of avail-able treatments. At that point, the patient had a moderate decrease in renal function (estimated glomerular filtra-tion rate of 47.7 mL/min/1.73 m2, calculated using the Modification of Diet in Renal Disease formula).10

One month later, the patient’s platelet count increased to 138 × 109/L and the danazol dose was reduced to 200 mg/d. However, 5 weeks before the index presenta-tion in the ED, the patient was readmitted to the hospital due to deterioration in platelet count (15 × 109/L), without signs of bleeding. Prednisone therapy was re-started at a high dose (2 mg/kg) while glucose control was achieved by insulin initiation (short-acting insulin in 4 doses, adjusted to blood glucose levels). Despite an increased dose of corticosteroids, the platelet count further decreased to 5 × 109/L on the second day of hospitalization. As other therapies for ITP (eg, intrave-nous immunoglobulin, splenectomy) were not available, the danazol dose was increased to 600 mg/d. This re-sulted in platelet elevation, with 19 × 109/L on the third hospital day, when the patient experienced anginal chest pain with transient ST-segment elevation. The patient was initially treated with intravenous nitroglycerin and metoprolol added to his therapy, with no antiaggrega-tion and anticoagulation drugs at that time. On the fifth day of hospitalization, the patient underwent primary percutaneous coronary intervention (PCI), after another episode of chest pain, associated with prominent ST-segment elevations and acute heart fail-ure.11 Despite the diagnosis of ITP, antiaggregation (clopidogrel 300 mg and aspirin 300 mg) and antico-agulation (fondaparinux 2.5 mg and unfractioned heparin 3500 IU) treatments were administered. After the procedure, the simvastatin dose was increased to 40 mg/d, fondaparinux was continued for 2 more days, while clopidogrel (75 mg) and aspirin (300 mg) were continued throughout the hospitalization. Concomitant treatment with methylprednisolone and danazol led to a sustained increase in platelet count that was fre-quently monitored (once or twice daily), with a maxi-mum in-hospital value of 10 × 109/L. The patient was discharged 7 days after PCI with the following regimen: aspirin 300 mg/d, clopidogrel 75 mg/d, ramipril 2.5 mg/d, pantoprazole 40 mg/d, prednisone 60 mg/d, long-acting insulin 24 IU/d, simvastatin 40 mg/d, and danazol 600 mg/d. The platelet count at discharge was 98 × 109/L.

a life-threatening clinical syndrome characterized by rapid destruction of skeletal muscle with marked creatine-kinase (CK) elevation as the main laboratory feature of the disease.

Simvastatin is an HMG-CoA reductase inhibitor that is metabolized by cytochrome P450 (CYP) 3A4 isozymes.3

Danazol is a steroid analogue with anabolic and androgenic effects, approved for the treatment of en-dometriosis, fibrocystic breast disease, and hereditary angioedema. Despite not being licensed, it has been used for other off-label indications, such as idiopathic thrombocytopenic purpura (ITP), paroxysmal nocturnal hemoglobinuria, and aplastic anemia.4–6 Both American and British ITP guidelines recognize danazol as second-line therapy for the patients in whom further conven-tional treatment with a standard dose of corticosteroids is inappropriate.7,8 There are also few randomized trials that deal with danazol use in ITP, and many of the recom-mendations are based on expert opinion.8 Of note, danazol is also an inhibitor of the CYP3A4 isozyme.9

We report a case of fatal rhabdomyolysis that oc-curred after concomitant administration of simvastatin and danazol in a patient with ITP.

CAsE suMMArYAn 80-year-old white male (height, 182 cm; weight, 90 kg) presented to the emergency department (ED) of the Clinical Hospital Centre Zemun, Belgrade, Serbia, with minor head injuries after a fall caused by generalized weakness.

The patient had a history of stable angina pectoris for which he was receiving aspirin 100 mg/d, isosorbide mononitrate 40 mg/d, and simvastatin 20 mg/d, which were well tolerated for 2 years. Besides coronary artery disease, he had mild aortic stenosis, hypertension, and type 2 diabetes mellitus managed with diet.

Importantly, 4 months before the onset of present symptoms, the patient had been admitted to the Depart-ment of Hematology because of easy bruising and low platelet count (10 × 109/L) (Figure). Clinical features, blood count, blood film, and bone marrow examination (normoblastic erythropoiesis, normal granulopoiesis, and lymphopoiesis with numerous megakaryocytes) were consistent with a diagnosis of ITP. The patient was initially treated with oral corticosteroids for 10 days (prednisone 1 mg/kg), but due to an inadequate response and worsened glucoregulation, danazol 400 mg/d was started instead of prednisone. It led to sustained eleva-

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suspected to be the cause of paraparesis. Both head and spine CT scans were unremarkable, and after the injuries were properly treated, the patient was sent home for bed rest. A urine test was not performed. He was discharged without any change in his treatment and a diagnoses of collapse and nasal contusion. Two days after his initial presentation, the patient was readmitted to the hospital due to nausea, dark urine, and oliguria. Because of muscle pain and weakness, the patient could not stand, walk, or lift his upper limbs. At physical examination, he ap-peared to be in no distress and his vital signs were within normal limits (body temperature, 36.2°C; heart rate, 75 beats/min; respiratory rate, 18 breaths/min; and blood pressure, 140/70 mm Hg). Except for diffuse muscle tenderness, pretibial edema, and nasal skin lacerations, other physical findings were unremarkable.

Fifteen days later, during an outpatient visit, the platelet count was 55 × 109/L and the patient was continued on the discharge therapy.

Six days after that outpatient visit, the patient pre-sented to the ED. Due to progressive bilateral leg pain and cramping that had started 1 week prior, he had difficulty standing and walking longer than a couple of minutes. He did not report any other symptoms, except fatigue and mild pretibial edema. Complete blood count revealed a mild increase in leukocyte count (12.8 [normal range, 4–10] × 109/L), mild anemia (hemoglobin, 10.7 [12–18] g/dL), and thrombocytopenia (platelet count, 59 [150–400] × 109/L). The emergency physician consulted a neurologist, who ordered a com-puted tomography (CT) scan of the head and lum-bosacral spine. At that time, medullary ischemia was

40

80

0

Plat

elet

Cou

nt (

×109 /

L)

−8−35−38−59−125 0−2−700 6Time (d)

Death

400

20

60

100

InitialED visitOutpatient

visit

PCI

Diagnosis of ITP

Myocardial infarction

ITP worsening

Hospitaladmission

Rhabdomyolysis

Outpatientvisit

Simvastatin 20 mg/d Simvastatin 40 mg/d

Danazol 400 mg/d 200 mg/d Danazol 600 mg/d

Figure. Major clinical events, treatments, and platelet counts from a diagnosis of idiopathic thrombocytopenic purpura (ITP) to death from rhabdomyolysis in an 80-year-old white male. PCI = percutaneous coronary intervention; ED = emergency department.

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propriate workup had been done at initial presentation and an adverse drug reaction had been considered in the differential diagnosis. The adverse drug reaction might have been prevented by proper choice of drugs and their doses for the existing underlying diseases.

We conducted a search of the MEDLINE database from 1966 through February 2010 (all languages) to identify all reports on rhabdomyolysis induced by a statin–danazol interaction using the terms rhabdomy-olysis, statin, simvastatin, and danazol. We identified one case report on rhabdomyolysis associated with simvastatin/danazol treatment in a patient with autoim-mune hemolytic anemia.16 Furthermore, 2 cases of rhabdomyolysis probably caused by lovastatin–danazol interaction were identified in patients administering danazol for ITP.17,18 As both lovastatin and simvastatin are a substrate of CYP3A4 isozymes, it might be as-sumed that concomitant danazol use led to the toxicity and muscle damage in all 4 cases (Table).

It is worrisome that danazol appears to have been prescribed for an unapproved (hematologic) indication in all cases, although it is noted as a therapeutic option in current ITP guidelines.7,8 Unfortunately, the treatment recommendations for ITP are largely derived from expert opinion, as studies regarding treatment for this condi-tion have come from uncontrolled case series.19 There-fore, those treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than evidence from high-quality clini-cal trials.20 The present case report emphasizes the danger of unproven treatments whose implementation can turn into unregulated human experimentation with adverse outcomes.

There are 2 possible modes of simvastatin–danazol interaction: the altered clearance of the statin mediated by the CYP family of enzymes and changes in the trans-port proteins, notably of the P glycoprotein (P-gp), a transport protein located in the gastrointestinal tract, liver, placenta, kidneys, and brain.21

With the exception of pravastatin and rosuvastatin, the remaining statins are substrates of intestinal and hepatic CYP. Simvastatin, atorvastatin and lovastatin are metabolized by the CYP3A4 isozymes, whereas fluvastatin is metabolized by the CYP2C9 isozyme.22

Danazol is a potent inhibitor of the CYP3A4 isozyme and its concomitant use with simvastatin, atorvastatin, and lovastatin may result in increased plasma levels of the used statin drug. Direct muscle toxic effects of danazol have also been reported.23

The patient denied any other drug or herbal/home remedy use, alcohol consumption, or intake of any compound known to increase simvastatin plasma levels (eg, grapefruit juice). Initial laboratory tests revealed a CK value of 22,700 U/L, which was ~100 times the upper limit of normal (normal range, 40–226 U/L). Blood urea nitrogen was 42 mmol/L (1.7–8.3 mmol/L); serum creatinine, 720 µmol/L (44–133 µmol/L); lactate dehydrogenase, 2600 U/L (200–400 U/L); aspartate aminotransferase 442 U/L (<37 U/L); and alanine ami-notransferase, 314 U/L (<43 U/L). Leukocytosis (19 [normal, 4–10] × 109/L) with neutrophilia (neutrophils, 17.7 [1.6–7.5] × 109/L), hyperkalemia (potassium, 7.2 [3.5–5.5] mmol/L), hyperphosphatemia (phosphorus, 1.81 [0.80–1.45] mmol/L), and hypoalbuminemia (albumin, 25 [35–45] g/L) were also present. Urinalysis revealed the presence of hematuria and proteinuria. Serum tests for hepatitis B and C virus and HIV were negative.

Apart from aspirin 300 mg/d and clopidogrel 75 mg/d, all other medications were ceased after admission: simvastatin 40 mg/d, danazol 600 mg/d, ramipril 2.5 mg/d, pantoprazole 40 mg/d, and prednisone 60 mg/d. Despite intravenous hydration, sodium bicarbonate adminis-tration, and forced diuresis, oliguria persisted, while the patient’s CK level rose to 35,000 U/L. Consequently, hemodialysis was started 2 days after admission. Despite all of those treatment measures, the patient died of acute renal failure 6 days after admission.

dIsCussIoNPatients with coronary heart disease often take several drugs, thus increasing the probability of drug interac-tions.12 Some of these are well documented, and con-comitant administration of such medications is avoided in clinical practice.13 However, there are some uncom-mon drug combinations that may lead to serious com-plications. A score of 5 on the Naranjo adverse drug reaction probability scale14 suggests a probable associa-tion of concomitant treatment with simvastatin and danazol and the rhabdomyolysis in our patient.

Apart from the potential statin–danazol interaction, our patient had 3 additional risk factors for statin-induced adverse events: advanced age, renal dysfunction, and history of diabetes.15 Unfortunately, although clini-cal signs at initial presentation were suggestive of severe rhabdomyolysis, they went unrecognized by both the emergency physician and the neurologist. Therefore, the fatal outcome might have been avoided if an ap-

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the choice of statin drug to pravastatin or rosuvastatin, which are neither CYP450 nor P-gp substrates.28–31

CoNClusIoNsStatin-induced rhabdomyolysis must be considered whenever muscle or motor symptoms occur, especially when concomitant treatment with known inhibitors of statin metabolism is required. One example of a poten-tially lethal combination is the concomitant administra-tion of statin and danazol observed in this elderly patient. Therefore, if parallel treatment with known inhibitors of statin metabolism is initiated, the patient must be strictly monitored and the statin should be promptly discontinued at the first signs and symptoms of myopa-thy. Furthermore, physicians must be fully aware of the dangers of any drug, especially one used for an off-label treatment, while the patients must be warned of any known interactions that unproven treatment might have when administered with the indicated drug.

ACKNoWlEdGMENTsDrs. Stankovic and Putnikovic have received honoraria for educational lectures from Merck Sharp & Dohme and Boehringer Ingelheim. Dr. Neskovic has received honoraria for educational lectures from Pfizer, Merck Sharp & Dohme, Merck, sanofi-aventis, AstraZeneca, Boehringer-Ingelheim, PharmaSwiss SA, Abbott Vascular, and Cordis/Johnson & Johnson.

The authors have indicated that they have no other conflicts of interest regarding the content of this article.

More recently, there is evidence that some statin–drug interactions may involve mechanisms beyond CYP450 metabolism. Simvastatin, atorvastatin, and lovastatin are modulators of P-gp.21 Therefore, concomitant adminis-tration of simvastatin with other P-gp substrates or in-hibitors may promote statin–drug interactions. As the great overlap exits between agents that are CYP3A4 and P-gp substrates or inhibitors,24,25 potential inhibitory effect of danazol on P-gp transport systems could play a role in increasing the statin serum concentrations.

However, the tolerability profile of statins is sup-ported by numerous postmarketing clinical studies, with an overall adverse-event frequency of <0.5% and a myotoxicity event rate of <0.1%.26 Rhabdomyolysis is a rare but clinically important adverse event that can occur with all statins when used alone or particularly with a combination therapy.

As with other HMG-CoA reductase inhibitors, the risk of simvastatin-induced myopathy/rhabdomyolysis is dose related—the incidence of myopathy is approxi-mately 0.02%, 0.08%, and 0.53% at 20, 40, and 80 mg/d, respectively.27 According to the manufacturer’s recommendation, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant treatment with danazol. Importantly, in all 4 reported cases of rhabdomyolysis induced by statin and danazol, which includes the current report, the recommended statin dose was exceeded by 2 to 4 times.16–18 If concomitant administration of a statin and danazol (or other CYP450 inhibitors) is to be used, it seems reasonable to confine

Table. Published case reports, including the present study, on rhabdomyolysis potentially associated with concomitant administration of statin/danazol.

Case Report (Year of Publication)

Drugs and Daily Doses Use of Danazol

Peak CK, U/L Outcome

Stankovic et al (2010) Simvastatin 40 mg Danazol 600 mg

ITP 35,000 Death

Andreou and Ledger16 (2003) Simvastatin 40 mg Danazol 600 mg

Autoimmune hemolytic anemia

50,060 Recovery

Hsieh and Chen17 (2008) Lovastatin 40 mg Danazol 600 mg

ITP 68,193 Recovery

Dallaire and Chamberland18 (1994) Lovastatin 40 mg Danazol 600 mg Doxycycline 200 mg

ITP 31,770 Recovery

CK = creatine kinase; ITP = idiopathic thrombocytopenic purpura.

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sanofi-aventis Canada Inc; 2008. http://www.sanof iaventis.ca/ products/en/cyclomen.pdf. Ac-cessed April 15, 2010.

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25. Wacher VJ, Wu CY, Benet LZ. Over-lapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Impli-cations for drug delivery and activity in cancer chemotherapy. Mol Car-cinog. 1995;13:129–134.

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Address correspondence to: Ivan Stankovic, MD, Department of Cardiology, Clinical Hospital Centre Zemun, Vukova 9, 11080 Belgrade, Serbia. E-mail: future.ivan@gmail.com