Nefazodone May Inhibit Metabolism of HMG-CoA Reductase Inhibitors
Abstract & commentary
Source: Alderman CP. Possible interaction between nefazodone and pravastatin. Ann Pharmacother 1999;33:871.
We and others have previously described the important relationship between depression and cardiovascular disease (CVD). Many patients with CVD, therefore may be receiving multiple medications concomitantly, including antidepressants and cholesterol-lowering agents. This article discusses a possible drug interaction between nefazodone, an antidepressant, and pravastatin, an antilipemic agent.
The article describes a case involving a 74-year-old white man with a history of hypertension, ischemic heart disease, and hyperlipidemia who was admitted to a hospital for an episode of major depression. The patient was initially treated with citalopram 30 mg/d, atenolol 100 mg/d, enteric-coated aspirin 100 mg/d, and pravastatin 20 mg/d. All admission laboratory values were within normal limits. The antidepressant regimen was subsequently changed to nefazodone 50 mg twice daily, which was initiated after a 36-hour washout period. Approximately 36 hours after the introduction of nefazodone, plasma creatine kinase (CK) was 877 U/L (normal range 0-190). Lactate dehydrogenase was also elevated at 307 U/L (normal range 115-200), as were aspartate aminotransferase (AST) at 58 U/L (normal range 0-30) and alanine aminotransferase (ALT) at 64 (normal range 0-30). The CK was sent for fractionation, which determined that CK-MB constituted only 1% of the total CK concentration. This ruled out cardiac causes, thereby suggesting rhabdomyolysis.
Nefazodone was discontinued, but CK remained elevated (275 U/L) for 14 days at which time pravastatin was discontinued. CK returned to normal (169 U/L) within three days after pravastatin was discontinued. All laboratory values remained normal for approximately one month after pravastatin was reintroduced. Subsequent treatment with the antidepressant venlafaxine did not precipitate any clinical problems.
Comment by Michael F. Barber, pharmD
Nefazodone is an antidepressant that has a different mechanism of action than the SSRIs. Nefazodone is a relatively mild inhibitor of serotonin reuptake, but it seems to exert its antidepressive effect via 5-HT2 receptor antagonism. Nefazodone differs from the SSRIs not only in terms of adverse effects (with favorable rather than disruptive effects on sleep and lack of sexual dysfunction), but also in terms of pharmacokinetic drug interactions. Specifically, nefazodone is a relatively potent inhibitor of CYP3A4, a hepatic enzyme that is responsible for the metabolism of many drugs, such as terfenadine, astemizole, cisapride, and pimozide. While the above combinations of nefazodone and these agents can be fatal and must be avoided, drug interactions between nefazodone and other CYP3A4 substrates such as calcium channel blockers, macrolide antibiotics, anticonvulsants, and HMG-CoA reductase inhibitors are usually hypothetical since clinical data involving these combinations are often not available. Thus, the clinical significance of such hypothetical drug interactions is usually undetermined, leaving some question as to whether or not such combinations are relevant. The current report illustrates that the combination of nefazodone and the HMG-CoA reductase inhibitor pravastatin does in fact appear to result in a clinically important drug interaction. The impairment of the hepatic clearance of pravastatin by nefazodone presumably resulted in increased levels of pravastatin, causing rhabdomyolysis as evidenced by the large increase in CK levels. In this case, the offending agent was removed quickly after the CK increased; thus, the patient did not suffer any pain from skeletal muscle damage. It should also be noted that the dose of nefazodone used in this patient was relatively low, whereas higher doses may have resulted in an even more dramatic increase in CK. This finding was consistent with a report by Jacobsen et al, who reported myositis and rhabdomyolysis associated with the use of nefazodone and simvastatin.
In summary, clinicians should be aware of the drug interactions between CYP3A4-inhibiting antidepressants and HMG-CoA reductase inhibitors. Among antidepressants, nefazodone is the most potent inhibitor of CYP3A4; whereas fluvoxamine, and to a lesser extent fluoxetine, can inhibit this enzyme as well. Neither venlafaxine nor citalopram have not been shown to inhibit CYP3A4 to any appreciable effect. If such a combination is decided upon, patients should be monitored for toxic effects in order to allow for an early intervention before the problem can become severe.
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