Rhabdomyolysis associated with simvastatin-nefazodone therapy.

Abstract: Simvastatin is a hydroxymethyl glutaryl coenzyme A reductase inhibitor commonly used to treat patients with hyperlipidemia. It is a safe and effective medication in most patients when used appropriately. A serious side effect known as rhabdomyolysis may rarely occur in patients who take simvastatin, especially at higher doses and with agents that interact and increase the level of simvastatin in the blood. We describe the case of a patient with rhabdomyolysis that occurred after the patient's simvastatin was titrated to 80 mg at approximately the same time that his antidepressant medication was switched to nefazodone. We found only two other similar cases in the literature, both of which were presented as letters to the editor in two different journals. We present this case to add to the literature and to assist practitioners by raising their awareness of this interaction so that it can be monitored.

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Discussion

Simvastatin is a potent medication that is used commonly at increasingly higher doses to try to achieve aggressive cholesterol goals and control in patients with hyperlipidemia. It has long been known that medications that inhibit the cytochrome P-4503A4 enzyme system have the potential of inhibiting the metabolism of agents such as simvastatin and therefore of causing increased levels, which increases the risk of myopathy and rhabdomyolysis. (2,3,6) In a search of the literature, we found only two previously reported cases that described the possibility of the simvastatin-nefazodone interaction. (7,8) These cases were reported as letters to the editor, without much detailed discussion or support.

The first case was a 44-year-old white man who had been taking simvastatin 40 mg/d for 19 weeks with good control of his low-density lipoprotein cholesterol and with normal CPK levels and LFTs. (7) The patient was then started on 100 mg nefazodone administered twice daily for depression. The patient then returned 1 month later complaining of "tea-colored" urine and severe myalgias in his legs. His condition was initially diagnosed as a urinary tract infection, so the patient was placed on amoxicillin-clavulanic acid and was told to follow up in 1 month as scheduled. After another month had passed, the patient still complained of tea-colored urine and severe myalgias. Laboratory tests revealed elevated AST, ALT, CPK, and myoglobin levels. His creatinine and blood urea nitrogen were normal. The patient was diagnosed with rhabdomyolysis, and his nefazodone and simvastatin were discontinued. All of his laboratory tests were within normal limits, and he was asymptomatic when he returned for follow-up 3 weeks later.

The other case involved a 72-year-old Hispanic man with diabetes, depression, anxiety, hypertension, and hyperlipidemia. (8) He was taking paroxetine, lorazepam, mirtazapine, risperidone, zolpidem, insulin, metformin, and simvastatin when he was referred to a psychiatrist. The psychiatrist discontinued the patient's paroxetine, mirtazapine, lorazepam, and risperidone and initiated 100 mg nefazodone twice daily, clonazepam, and trazodone. Four weeks later, his nefazodone was titrated to 200 mg twice daily.

Two weeks after the increase in his dose of nefazodone, the patient was admitted to the hospital for generalized weakness, cough, and fever that were initially diagnosed as a viral syndrome. His laboratory tests at admission included a CPK level of 10,555 U/L and elevated LFTs. Also, his urine contained blood. The patient's nefazodone was discontinued, and he was administered IV hydration and then discharged a couple of days later when his CPK level was decreasing. One week later, his weakness had resolved and his CPK level was normal at 261 U/L. He was taking simvastatin and venlafaxine without any further problems.

Both of these case reports discuss the potential interaction of the highly suspect nefazodone as the probable cause of the rhabdomyolysis. In both of the cases, the patient was not having any problems with simvastatin as monotherapy but started showing symptoms and laboratory abnormalities approximately 1 month after starting nefazodone therapy. Our case should be added to these documented cases to support the potential for this serious interaction and the warning that the possibility of side effects does exist with this combination.

Conclusions

As cholesterol guidelines continue to become more aggressive and agents such as simvastatin are used more frequently and at higher doses, their concurrent use with agents such as nefazodone will continue to increase. We think that this case further supports and documents this important interaction. We hope that by increasing awareness of this likely interaction, other cases can be prevented.

From the Department of Pharmacy Practice, School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, NE.

Reprint requests to Maryann Z. Skrabal, PharmD. Department of Pharmacy Practice, School of Pharmacy and Health Professions, Creighton University Medical Center, 2500 California Plaza, Omaha, NE 68178. Email: [e-mail]

Accepted February 27, 2003.

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9610-1034

References

1. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;55:1096-1105.

2. Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 1995;52:1639-1645.

3. Elick K. Sprague JE. Renal and muscle damage induced by the statins. Pharmacy Times 2001;67:22-25.

4. Bottorff M. Hansten P. Long-term safety of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors. Arch Intern Med 2000;160:2273-2280.

5. Davidson MH. Safety profiles for the HMG-CoA reductase inhibitors: Treatment and trust, Drugs 2001;61:197-206.

6. White CM. An evaluation of CYP3A4 drug interactions with HMG-CoA reductase inhibitors. Formulary 2000;35:343-352.

7. Jacobsen RH. Wang P. Glueek CJ. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA 1997;277:296-297 (letter).

8. Thompson M. Samuels S. Rhabdomyolysis with simvastatin and nefazodone. Am J Psychiatry 2002;159:1607 (letter).

RELATED ARTICLE: Case Report

A 56-year-old white man with a history of hyperlipidemia, coronary artery disease, erectile dysfunction, allergic rhinitis, and sinusitis presented to his primary care provider complaining that he was having problems with impotence and depression. He currently was taking simvastatin, atenolol, terazosin, and fluoxetine. His provider stopped the atenolol, terazosin, and fluoxetine and started him on buspirone, nefazodone, lisinopril, and aspirin.

The patient then presented to the hypertension clinic 4 days later for routine follow-up. His blood pressure was in good control, but on examining his other risk factors, it was discovered that his low-density lipoprotein cholesterol was high, measuring 188 mg/dl, with a goal of less than 100 mg/dl because of his coronary artery disease history. His simvastatin was titrated from 40 to 80 mg/dl at this visit to adjust for this and to try to reach the aggressive goal.

The patient returned to his primary care provider 3 weeks later for follow-up of these changes and stated that he felt great except for some congestion in his nose, plugging of his ears, and severe headaches. He was placed on fexofenadine and azithromycin at this visit for treatment of an upper respiratory or suspected sinus infection. His low-density lipoprotein cholesterol was found to be much improved at 112 mg/dl, and all of his other laboratory values were within normal ranges, except for elevated liver function tests (LFTs) as follows: aspartate aminotransferase (AST), 171 1U/L (normal range, 1-45 1U/L), and alanine aminotransferase (ALT), 99 1U/L (normal range, 1-55 1U/L).

Five days after his last appointment, the patient called the care nurse to report leg and back aches and pains that had been occurring for the past 2 to 3 days. He mentioned that he thought it was due to a change in activity but that it was not getting any better. He mentioned that his urine was "cola" colored, which concerned him. He was told to report to the emergency room immediately.

The patient was admitted to the hospital, and a renal consultation was obtained immediately. The patient's creatine phosphokinase (CPK) level was elevated at 10,738 U/L (normal range, 1-250 U/L) at admission, and it increased to 79,868 U/L before slowly decreasing to normal levels by the time of discharge and follow-up 2 weeks later. His AST and ALT levels also were elevated at admission (2,324 and 700 1U/L) and reached levels of 2,665 and 1,139 1U/L before decreasing to normal. His blood urea nitrogen (15-22 mg/dl) and creatinine (0.9-1 mg/dl) remained normal during his hospitalization. He was diagnosed with rhabdomyolysis and was administered IV hydration, bicarbonate, mannitol, and albumin. His simvastatin, fexofenadine, temazepam, and nefazodone were stopped at admission.

At the time of discharge, the patient's medications included buspirone, docusate sodium, morphine, acetaminophen with codeine, and felodipine. The patient was weak at that time and required physical therapy to overcome extensive muscle weakness during the next few weeks. His provider is currently trying to get his cholesterol levels in control, but without much success to date.

RELATED ARTICLE: Key Points

* Rhabdomyolysis occured in a patient whose dose of simvastatin recently had been titrated to the maximum and whose antidepressant had just been changed.

* Only two other cases of a simvastatin-nefazodone interaction have been described previously in the literature.

* Awareness of this interaction is important so that practitioners can avoid this combination and choose alternative therapies when appropriate.

Maryann Z. Skrabal, PHARMD, CDE, Julie A. Stading, PHARMD, and Michael S. Monaghan, PHARMD