The Clinical Guide to Supportive and Palliative Care for HIV/AIDS

A Clinical Guide to Supportive and Palliative Care for HIV/AIDS • Chapter 27: Pharmacologic Interactions of Clinical SignificanceDrug Interactions of Clinical SignificanceInvolving HMG-CoA Reductase Inhibitors (Statins)Recent medical and lay literature has raised a number of concerns regarding adverse eventswith the HMG-CoA group of cholesterol-lowering agents, culminating in the removal of at leastone product, cerivastatin (Baycol), from the U.S. market following reports of rhabdomyolysis(destruction of skeletal muscle, leading to renal failure) and myopathy. Clinically significantdrug interactions occur with the statins when these agents, all of which are substrates to theCYP450 enzyme system and so are amenable to the action of these enzymes, are combined withother drugs that cause muscle damage or drugs that interact to give rise to increased statinplasma levels resulting from inhibition of statin metabolism.Numerous interactions between statins metabolized by CYP3A and several CYP3A inhibitors,including the protease inhibitors, the azole antifungals, grapefruit juice, and kaolin/pectin (especiallylovastatin) have been reported. 4 DHHS guidelines specifically suggest avoiding combinationsof protease inhibitors and simvastatin (Zocor) and lovastatin (Mevacor), with fluvastatin(Lescol) and atorvastatin (Lipitor) as alternatives that must be used with caution. 1 Fibratessuch as gemfibrizol may cause myopathy when used alone and also in combination with most ofthe statins, with the exception of fluvastatin (Lescol). An increased incidence of myopathy hasbeen reported when niacin is combined with lovastatin but not with fluvastatin, pravastatin orsimvastatin. 19Despite the increased risk of adverse events, providers are sometimes compelled to continuestatin therapy in order to ward off serious cardiovascular sequalae. In such circumstances, patientsshould be counseled to report immediately any signs or symptoms of myopathy such asmuscle pain, calf tenderness or muscle weakness.Significant Induction Interactions: Estrogens and CorticosteroidsEstrogens and corticosteroids are substrates to the cytochrome P450 enzyme system, henceremain susceptible to the action of these enzymes and can be changed or metabolized by themor by substances that act as inducers or inhibitors on CYP450 enzymes. Protease inhibitors suchas nelfinavir or ritonavir, which can act both as inducers and inhibitors of the CYP450 enzymesystem, have been shown to increase the degradation of ethinyl estradiol, a major component oforal contraceptive pills. 20 Women with HIV taking these PIs should receive additional or alternativecontraceptive methods in order to ensure full protection.As a result of the recent decreases in the estrogen and progestin concentrations of oral contraceptives,reports of unintended pregnancies and episodes of breakthrough bleeding seem to beon the rise. 16 Reports of clinically significant drug interactions secondary to enzyme inductionhave implicated phenobarbital, phenytoin, carbamazepine, ethosuximide, primidone andrifampin. 21,22,23,24 Such reports have not been made for gabapentin, lamotrigine, topiramate andvalproate. When such interactions are suspected, a higher dose oral contraceptive containing50 mg ethinyl estradiol, medroxyprogesterone or a non-hormonal alternative method of contraceptionis usually recommended.Corticosteroids, which often remain the mainstay of management of diseases that occur in palliativecare of advanced HIV infection, have their clearances increased in a similar fashion tothe estrogens by the same agents, when administered concomitantly. Patients receiving steroidsfor chronic diseases should be monitored for exacerbation of symptoms in these situationsand the necessary dosage adjustments made. 24568U.S. Department of Health and Human Services • Health Resources and Services Administration • HIV/AIDS Bureau