Simvastatin Fibrates

Dosingof selected agents by class fibrate (gemfibrozil 600 mg twice a day) niacin (1.5-3 g/day of immediate-release product) statin (simvastatin 10-40 mg/day if glomerular filtration rate [GFR] <30 mL/min, 20-80 mg/day if GFR >30 mL/min) bile acid sequestrant (cholestyramine 4-16 g/day). 

Reports about the influence of HMG-CoA-reductase inhibitors are conflicting (F7, H42, J8, K22, K29, L15, M3, S33, T5). In general, the effect is minimal or nonexistent some statins, such as simvastatin and lovastatin, are even reported to have an increasing influence (H42, J8, S33, Ul). Fibrates and derivatives are reported to exert a lowering effect (B13, F4, M3). 

Concomitant lipid-lowering therapy- Simvastatin is effective alone or when used concomitantly with bile acid sequestrants. The combined use of simvastatin with gemfibrozil, other fibrates, or lipid-lowering doses (1 g/day or more) of niacin should be avoided unless the benefit of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination. 

However, if simvastatin is used in combination with fibrates or niacin, the dose of simvastatin generally should not exceed 10 mg/day. 

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 (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... 

The incidence of rhabdomyolysis in patients taking different statins and fibrates, alone and in combination, has been estimated using data from 11 managed health care plans across the USA (43). The incidences of rhabdomyolysis were 0.44 per 10 000 person-years of treatment with atorvastatin, pravastatin, or simvastatin, 5.34 with cerivastatin, and 2.82 with fibrates. The incidence increased to 5.98 when atorvastatin, pravastatin, or simvastatin was with a fibrate, and to 1035 when cerivastatin was combined with a fibrate. 

In hepatorenal syndrome (HRS), which is an acute episode, the clearance of renally excreted drugs and metabolites (pravastatin, simvastatin, rosu-vastatin, acipimox, fibrates) may be reduced. During an episode of HRS, anti-hyperlipidaemic medication should be withheld. 

The absorption of highly lipophilic drugs (atorvastatin, simvastatin, ezetimibe, fibrates) may be reduced in cholestasis if they require bile salts for their absorption. 

FIBRATES STATINS Gemfibrozil may t atorvastatin, rosuvastatin and simvastatin levels (risk of myopathy with simvastatin) Uncertain Avoid co-administration of simvastatin and gemfibrozil. When using other statins, warn patients to watch for the features of myopathy... 

The approved starting dose of simvastatin (zocoR)for most patients is 20 mg at bedtime unless the required LDL-C reduction exceeds 45% or the patient is a high-risk secondary prevention patient, in which case a 40-mg starting dose is indicated. The maximal dose is 80 mg, and the drug should be taken at bedtime. In patients taking cyclosporine, fibrates, or niacin, the daily dose should not exceed 20 mg. 

The plasma levels of lovastatin, simvastatin, atorvastatin and pravastatin are increased by gemfibrozil, the levels of fluvastatin are increased by bezaflbrate, and the levels of pravastatin are increased by fenoflbrate. No pharmacokinetic interactions occur with the combinations of fluvastatin with gemfibrozil, lovastatin with bezaflbrate, and pravastatin, rosuvastatin or simvastatin with fenoflbrate. Both statins and fibrates are known to cause rhabdomyolysis, and their concurrent use increases the risk of this reaction. 

In a review of the FDA spontaneous reports of statin-associated rhabdomyolysis covering the period November 1997 to March 2000, fibrates (unspeeified) were potentially implieated in 10 of 73 cases of rhabdomyolysis seen with atorvastatin, 4 of 10 with fluvastatin, 5 of 40 with lovastatin, 6 of 71 with pravastatin, and 33 of 215 with simvastatin. 

Prueksaritanont, T. Tang, C. (Jiu, Y. Mu, L. Subramanian, R. Lin, J.H. Effects of fibrates on metabolism of statins in human hepatocytes, Drug Metab.Dispos., 2002, 30, 1280-1287. [cerivastatin simvastatin atorvastatin rosuvastatin pravastatin]... 

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