Myopathy inhibitors

Category X) and lactation. The HMG-CoA reductase inhibitors are used cautiously in patients with a history of alcoholism, acute infection, hypotension, trauma, endocrine disorders, visual disturbances, and myopathy. 

The HMG-CoA reductase inhibitors have an additive effect when used with the bile acid sequestrants, which may provide an added benefit in treating hypercholesterolemia that does not respond to a single-drug regimen. There is an increased risk of myopathy (disorders of the striated muscle) when the HMG-CoA reductase inhibitors are administered with erythromycin, niacin, or cyclosporin a When the HMG-CoA reductase inhibitors are administered with oral anticoagulants, there is an increased anticoagulant effect. 

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

HMG-CoA reductase inhibitors Coadministration of niacin and HMG-CoA reductase inhibitors (eg, lovastatin) may result in myopathy and rhabdomyolysis. 

Skeletal muscle effects In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. 

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... 

Uses Hypertriglyceridemia, coronary heart Dz Action Fibric acid Dose 1200 mg/d PO bid 30 min ac am pm Caution [C, ] t Warfarin effect, sulfony-lureas t risk of myopathy w/ HMG-CoA reductase inhibitors X effects w/ cyclosporine Contra Renal/hepatic impair (SCr >2.0 mg/dL), gallbladder Dz, primary biliary cirrhosis, use w/ repaglinide (i glucose) Disp Tabs 600 mg SE Cholelithiasis, GI upset Interactions t Effects OF anticoagulants, sulfonylureas t risk of rhabdomyolysis W/ HMG-CoA reductase inhibitors X effects W/ rifampin X effects OF cyclosporine EMS t Effects of anticoagulants OD May... 

Lovastatin (Mevacor/ Altocor) [Antilipemic/HMG-CoA Reductase Inhibitor] Uses Hypercholesterolemia Action HMG-CoA reductase inhibitor Dose 20 mg/d PO w/ PM meal may T at 4-wk intervals to 80 mg/d max or 60 mg ER tab take w/ meals Caution [X, -] Avoid w/ grapefruit juice, gemfibrozil. Contra Active liver Dz Disp Tabs SE HA GI intolerance common promptly report any unexplained muscle pain, tenderness, or weakness (myopathy) Interactions T Effects W/ grapefruit juice T risk of severe myopathy W/ azole antifungals, cyclosporine, erythromycin, gemfibrozil, HMG-CoA inhibitors, niacin T effects OF warfarin >1 effects W/ isradipine, pectin EMS t Risk of photosensitivity Rxns T effects of warfarin concurrent EtOH use t risk of liver tox diltiazem and verapamil can T risk of lovastatin tox OD Unlikely to cause life-threatening Sxs... 

Action HMG-CoA reductase inhibitor Dose 5-40 mg PO daily max 5 mg/d w/cyclosporine, 10 mg/d w/gemfibrozil or CrCl <30 mL/min (avoid Al-/Mg-based antacids for 2 h after) Caution [X, /-] Contra Active Uvct Dz, unej lained t LFT Disp Tabs SE Myalgia, constipation, asthenia, abd pain, N, myopathy, rarely rhabdomyolysis Interactions t Effects OF warfarin t risk of myopathy W/ cyclosporine, fibrates, niacin, statins EMS t Effects of warfarin concurrent EtOH use can t risk of liver tox Asian pts have an t risk of advise effects OD Unlikely to cause life-threatening Sxs... 

The risk of myopathy appears to be increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Lovastatin is metabolized by the CYP isoform 3A4. Certain drugs, that share this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. These include cyclosporine, itraconazole, ketoconazole and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (greater than 1 quart daily)... 

Myopathy caused by drug interactions The incidence and severity of myopathy are increased by concomitant administration of HMG-CoA reductase inhibitors with drugs that can cause myopathy when given alone, such as gemfibrozil and other fibrates, and lipid-lowering doses (greater than or equal to 1 g/day) of niacin (nicotonic acid). 

Minor increases in creatine kinase (CK) activity in plasma are observed in some patients receiving reductase inhibitors, frequently associated with heavy physical activity. Rarely, patients may have marked elevations in CK activity, often accompanied by generalized discomfort or weakness in skeletal muscles. If the drug is not discontinued, myoglobinuria can occur, leading to renal injury. Myopathy may occur with monotherapy, but there is an increased incidence in patients... 

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. 

Rare adverse effects of fibrates include rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase. A few patients show decreases in white blood count or hematocrit. Both agents potentiate the action of coumarin and indanedione anticoagulants, and doses of these agents should be adjusted. Rhabdomyolysis has occurred rarely. Risk of myopathy increases when fibrates are given with reductase inhibitors. The use of fenofibrate with rosuvastatin appears to minimize this risk. Fibrates should be avoided in patients with hepatic or renal dysfunction. There appears to be a modest increase in the risk of cholesterol gallstones. 

Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on hepatocytes modest reduction in triglycerides Atherosclerotic vascular disease (primary and secondary prevention) t acute coronary syndromes Oral duration 12-24 h Toxicity Myopathy, hepatic dysfunction Interactions CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors... 

The effectiveness of immunosuppressive drugs in autoimmune disorders varies widely. Nonetheless, with immunosuppressive therapy, remissions can be obtained in many instances of autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes, Hashimoto s thyroiditis, and temporal arteritis. Improvement is also often seen in patients with systemic lupus erythematosus, acute glomerulonephritis, acquired factor VIII inhibitors (antibodies), rheumatoid arthritis, inflammatory myopathy, scleroderma, and certain other autoimmune states. 

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... 

Sinzinger H, Schmid P, O Grady J. Two different types of exercise-induced muscle pain without myopathy and CK-elevation during HMG-Co-enzyme-A-reductase inhibitor treatment. Atherosclerosis 1999 143(2) 459-60. 

In a meta-analysis of megatrials with simvastatin, the overall incidence of myopathy was 0.025% (32). The authors suggested that potent inhibitors of CYP3A4 greatly increase the risk, but that weak inhibitors do not. Episodes of gout occurred in three of nine patients with chronic renal insufficiency who took simvastatin (33). 

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