Simvastatin Cyclosporine

Concomitant cyclosporine - In patients taking cyclosporine concomitantly with simvastatin, begin therapy with 5 mg/day do not exceed 10 mg/day. 

Renal function impairment For patients with severe renal insufficiency, do not start ezetimibe/simvastatin unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Exercise caution when ezetimibe/simvastatin is administered to these patients, and monitor them closely. Concomitant bile acid sequestrants Give ezetimibe/simvastatin either 2 hours or more before or 4 hours or more after administration of a bile acid sequestrant. Concomitant cyclosporine Exercise caution when initiating ezetimibe/simvastatin in the setting of cyclosporine. In patients taking cyclosporine, do not start ezetimibe/simvastatin unless the patient has already tolerated treatment with simvastatin at a dose of 5 mg or higher. Do not exceed 10 mg ezetimibe/10 mg simvastatin daily. 

Ezetimibe/Simvastatin (Vytorin) [Antilipemic/HMG CoA Reductose Inhibitor] Uses H rp cholest olemia Action X Absorption of cholesterol phytost ol w/ HMG-CoA reductase inhibitor Dose 10/10-10/80 mg/d PO w/ cyclosporine or danazol 10/10 mg/d max w/ amio-darone or verapamil 10/20 mg/d max -1- w/ sev e renal insuff Caution [X, -] w/ CYP3A4 inhibitors (Table VI-8), gemfibrozil, niacin >lg/d, danazol, amiodarone, verapamil Contra PRG/lactation livCT Dz, t LFTs Disp Tabs SE HA, GI upset, myalgia, myopathy (muscle pain, weakness, or tendOTiess w/ CK 10 x ULN, rhab-domyolysis), Hep, Infxn Interactions t Risk of myopathy W7 clarithromycin, erythromycin, itraconazole, ketoconazole EMS None OD Sxs unknown symptomatic and supportive... 

St. John s wort Alprazolam, cyclosporine, digoxin, indinavir, oral contraceptives, ritonavir, simvastatin, tacrolimus, warfarin... 

Itraconazole Alfentanil, alprazolam, astemizole, atorvastatin, buspirone, cisapride, cyclosporine, delavirdine, diazepam, digoxin, felodipine, indinavir, loratadine, lovastatin, midazolam, nisoldipine, phenytoin, quinidine, ritonavir, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, triazolam, verapamil, warfarin... 

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. 

Simvastatin [NE] Myopathy and rhabdomyolysis noted in patients taking sim-vastatin and cyclosporine. 

Simvastatin (Zocor) [Anrilipemic/HMG-CoA Reductase Inhibitor] Uses X Cholesterol Action HMG-CoA reductase inhibitor Dose Adults. 5-80 mg PO w/ meals X in renal insuff Peds. 10-17 y 10 mg, 40 mg/daily max Caution [X, —] Avoid concurrent use of gemfibrozil Contra PRG, liver Dz Disp Tabs 5,10, 20, 40, 80 mg SE HA, GI upset, myalgia, myopathy (muscle pain, tenderness or weakness w/ creatine kinase 10 x ULN), Hep Interactions T Effects OF digoxin, warfarin T risk of myopathy/iiiabdomyolysis W/ amiodarone, cyclosporine, CYP3A4 inhibitors, fibrates, HIV protease inhibitors, macrolides, niacin, verapamil, grapefruit juice X effects W/ cholestyramine, colestipol, fluvas-tatin, isradipine, propranolol EMS T Effects of warfarin use amiodarone and... 

Ogawa D, Maruyama K, Miyatake N, Kashihara N, Makino H. Concomitant use of simvastatin and cyclosporin A increases LDH in nephrotic syndrome. Nephron 1998 80(3) 351-2. 

Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA. Itraconazole-induced rhabdomyolysis and acute renal failure in a heart transplant recipient treated with simvastatin and cyclosporine. Transplantation 2002 73(12) 1962-4. 

Maxa JL, Melton LB, Ogu CC, Sills MN, Limanni A. Rhabdomyolysis after concomitant use of cyclosporine, simvastatin, gemfibrozil, and itraconazole. Ann Pharmacother 2002 36(5) 820-3. 

CYP3A4 Inhibition Amiodarone, clarithromycin, erythromycin, cimetidine, cyclosporine, fluoxetine fluvoxamine, itraconazole, ketoconazole, nefazodone, verapamil, diltiazem HIV antivirals delaviridine, indanavire, nelfmavire, ritonavire, sequinavire Atorvastatin Lovastatin Simvastatin ... 

A4 Midazolam, Testosterone (strongly recommended to use at least two structurally unrelated substrates) Nifedipine, Felodipine, Cyclosporine, Terfenadine, Erythromycin, Simvastatin Ketoconazole (recent evidence that it is also a potent inhibitor of 2C8), Troleandomycin Cyclosporine... 

CYP3A4 activity, significantly decreasing plasma concentrations and the pharmacologic effect of a number of agents, including alprazolam, amitriptyline, cyclosporine, indinavir, methadone, nevirapine, simvastatin, tacrolimus, and oral contraceptives (69-77). 

St. John s wort Cyclosporine Digoxin Indinavir, neverapine MAO inhibitors Oral contraceptives Simvastatin SSRIs Warfarin Decreased levels and decreased effect Decreased levels and decreased effect Decreased levels and decreased effect Increased risk of MAO toxicity Decreased levels and decreased effect Decreased levels and decreased effect Increased risk of serotonin syndrome Decreased levels and decreased effect... 

Ichimaru N, Takahara S, Kokado Y, Wang JD, Hatori M, Kameoka H, Inoue T, Okuyama A. Changes in hpid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus. Atherosclerosis 2001 158(2) 417-23. 

Johnson DW, Saunders FIJ, Field MJ, Pollock CA. In vitro effects of simvastatin on tubulointerstitial cells in a human model of cyclosporin nephrotoxicity. Am J Physiol 1999 276 F467-F475. 

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