Watch

RIFAXIMIN RECEIVES NEW INDICATION England Journal of Medicine) LABELING CHANGES FOR SIMVASTATIN that randomly assigned patients • Rifaximin (Xifaxan), a nonsys- in ­remission from hepatic enceph­ • The lipid-lowering drug simva­ temic antibiotic usually used to alopathy to receive rifaximin statin can cause severe myopathy treat traveler’s diarrhea, has (550 mg twice daily) or ­placebo and rhabdomyolysis, especially been approved for the preven­ at the highest approved dosage tion of recurrent hepatic en­ for six months. Most patients (80 mg per day). cephalopathy in patients with were also taking the standard • Rhabdomyolysis can lead to chronic liver disease. treatment of lactulose (a synthetic acute tubular necrosis or acute • The most common adverse effects sugar that prevents absorption of renal failure, which can be fatal. of rifaximin are peripheral edema, ammonia from the gastrointesti­ • The risk of rhabdomyolysis is nausea, gas, and headache. nal [GI] tract). Over the treatment ­further increased when simva­ period, rifaximin significantly re­ statin is taken in combination he Food and Drug Admin­ duced the risk of hepatic enceph­ with niacin by patients of Chi­ nese descent. Tistration has approved ri­ alopathy episodes compared with faximin (Xifaxan), a nonsystemic placebo (22.1% of patients in the antibiotic, for the prevention of rifaximin group ex­perienced a he Food and Drug Admin­ recurrent hepatic encephalopathy breakthrough episode compared Tistration (FDA) has recently in patients 18 years of age or with 45.9% in the placebo group). modified label warnings for older with liver disease. Struc­ Treatment also reduced the risk simvastatin (Zocor) as a result turally similar to the antituber­ of hospitalization for hepatic en­ of findings from clinical tri­ culosis drug rifampin (Rifadin), cephalopathy. als, according to a recent FDA rifaximin binds to a β-subunit of Because rifaximin alone hasn’t Drug Safety Communication bacterial DNA–dependent­ RNA been tested in a sufficient number (http://bit.ly/bBfLLY). Prelimi­ polymerase, thereby preventing of patients to determine its thera­ nary results from the Study of peutic effectiveness as monother­ the Effectiveness of Additional apy, it shouldn’t be administered Reductions in Cholesterol and alone. It also hasn’t been tested Homocysteine (SEARCH) has Rifaximin significantly in patients with severe disease found that the highest approved (scores higher than 25 out of 40 dosage of simvas­tatin (80 mg reduced the risk of hepatic on the Model for End-Stage Liver per day) in­creases the risk of Disease [MELD] scale) or in pa­ rhabdomyolysis, a serious and tients under the age of 18. possibly ­life-threatening muscular encephalopathy. Rifaximin is administered disorder. This high dosage con­ orally. The dose for preventing fers a higher risk of rhabdomy­ hepatic encephalopathy is higher, olysis than lower dosages and bacterial RNA synthesis. It’s been but the number of daily doses possi­bly a higher risk than other found to be effective against Es­ is less, than that prescribed for statins. cherichia coli in infectious diar­ traveler’s diarrhea (550 mg twice Rhabdomyolysis is the most rhea and was therefore already a day, compared with 200 mg serious form of myopathy (mus­ approved for use in treating three times a day for three days, cle damage evidenced by muscle ­traveler’s diarrhea. Because rifax­ respectively). The most common aches and pains), a more com­ imin also lowers levels of ammo­ adverse effects associated with ri­ mon adverse effect of all statins. nia in the blood, it’s believed to faximin use are peripheral edema, In rhabdomyolysis the protein be effective in decreasing the risk nausea, gas, and headache. Nurses myoglobin is released into the of recurrent hepatic encephalopa­ should monitor patients with he­ bloodstream as muscle fibers thy in patients with advanced patic impairment who are started break down. As the protein en­ liver disease. on rifaximin very closely because ters the kidneys it can damage The efficacy of rifaximin for they may be more likely to expe­ renal tubules, leading to acute this indication was evaluated in rience systemic adverse ­effects ­tubular necrosis or acute renal a placebo-controlled, double- from the drug in addition to the failure, which can be fatal. Rhab­ blind, multicenter trial (published expected ­localized effects within domyolysis is characterized by in the March 25 issue of the New the GI tract. red or dark urine, severe muscle

28 AJN ▼ July 2010 ▼ Vol. 110, No. 7 ajnonline.com By Diane S. Aschenbrenner, MS, APRN-BC

Table 1. Simvastatin Coadministration with CYP3A4 Inhibitorsa

Avoid in most patients; if a listed Don’t use more than Don’t use more Don’t use more than antifungal or antibiotic must be used, 10 mg simvastatin than 20 mg sim- 40 mg simvastatin discontinue use of simvastatin during with these medications vastatin with these with this medication therapy medications

• Itraconazole (Sporanox), ketoconazole • Gemfibrozil (Lopid) • Amiodarone • Diltiazem (Cardizem (Nizoral and others), and other azole • Cyclosporine • Verapamil (Calan and others) antifungals • Danazol (Danocrine) and others) • Erythromycin and clarithromycin (Biaxin) • Telithromycin (Ketek) • Protease inhibitors • Nefazodone • Grapefruit juice in large amounts ­ (> 1 qt per day)

aCYP3A4 is an isoenzyme in the cytochrome P-450 enzyme system. Simvastatin is a substrate of CYP3A4 and is metabolized by it. Drugs that inhibit CYP3A4 therefore prevent simvastatin metabolism and increase the risk of adverse effects, including rhabdomyolysis. aches throughout the body, and in Table 1. FDA analysis has re­ how to look for its symptoms, fatigue. vealed that despite these warn­ and to notify their prescriber im­ Rhabdomyolysis is rare, occur­ ings, simvastatin is ­frequently mediately if these symptoms oc­cur. ring in fewer than 1% of ­patients prescribed with drugs that alter Nurses should remind patients receiving even large dosages of CYP3A4, placing patients at risk. that rhabdomyolysis is very rare simvastatin (0.9% in patients re­ Because rhabdomyolysis can be and that they shouldn’t stop sim­ ceiving 80 mg per day, compared fatal, it’s important that nurses vastatin therapy unless signs of with 0.02% in those receiving check for a risk of drug–drug in­ rhabdomyolysis are present. Pa­ 20 mg per day in the SEARCH teractions when prescribing sim­ tient education should also ­include trial). Rhabdomyolysis is more vastatin. the positive effects simva­statin can likely to occur if the patient is Findings from a separate, on­ have on cardiovascular health. older than 65, has hypothyroid­ going clinical trial, the Heart Pro­ Nurses should closely assess all ism or impaired kidney function, tection Study 2, have prom­pted a other drugs a patient is prescribed or takes other drugs that decrease label warning against using sim­ in addition to simva­statin and simva­statin metabolism (which in­ vastatin with niacin in patients contact the prescriber if simva­ creases circulating ­levels). of Chinese descent, in whom the statin is prescribed with CYP3A4 Drug interactions with simva­ study has found an increased inhibitors or if the recommended statin occur through the cyto­ risk of myopathy (0.43% versus dosage limit is exceeded. chrome P-450 (CYP) enzyme 0.03% in non-Chinese patients). Nurses should be aware that system. Simvastatin is a sub­strate The revised label states that pa­ simvastatin is also available in of the specific isoenzyme CYP3A4 tients of Chinese descent should­ combination products. When and is metabolized by that isoen­ n’t receive simvastatin 80 mg with combined with ezetimibe its zyme. Drugs that inhibit CYP3A4 cholesterol-modifying dosages trade name is Vytorin, and therefore prevent simvastatin (≥1 g per day) of niacin-­containing when combined with niacin metabolism and increase the risk products. Additionally, caution its trade name is Simcor. Oc­ of adverse effects, including rhab­ should be used if Chi­nese pa­ currences of rhabdomyolysis domyolysis. These drug inter­ tients are treated with simva­stat­in should be reported to the FDA actions have been listed in the 40 mg or less in combination MedWatch program at www.fda. prescribing information for some with cholesterol-modifying doses gov/Safety/MedWatch. t time; some of the drugs should of niacin-containing products. never be used with simvastatin Whether or not other Asian pop­ Diane S. Aschenbrenner is the course and some can be coadministered ulations are at increased risk for coordinator for undergraduate pharma­ cology at Johns Hopkins University as long as the simvastatin dose myopathy isn’t known. School of Nursing in Baltimore, MD. doesn’t exceed what’s recom­ Nurses should teach patients She also coordinates Drug Watch: mended. These drugs are shown about the risk of rhabdomyolysis, [email protected]. [email protected] AJN t July 2010 t Vol. 110, No. 7 29