1. Continue patient on dietary therapy
2. Establish baseline serum cholesterol and TG levels
3. Carefully monitor patient's cholesterol and TG levels throughout therapy a. LDL should be
   detected at 4-6 weeks until goal achieved

   -Adequate response: Continue with current therapy
   -Inadequate response: Increase dose of drug, switch to a new drug or add another drug

   -MOA -"Statins" block HMG CoA reductase, which is the rate limiting step in cholesterol synthesis, up regulates LDL-C receptors on liver
   -Actions
     1.Lowers total cholesterol, LDL-C, and TG
     2.Raises HDL-C
   -Dosing
   -Adverse effects
     1.Myalgias which may turn into myopathy (elevated CK with myalgia present) may ultimately, if untreated, result in myositis/rhabdomyolysis inhibitors of HMG-CoA reductase, occasionally caused myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10 times the upper limit of normal (ULN).  Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred.  The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.  
~ Creatine kinase (CK) elevations (>10 times upper limit of normal) occurred in 0.2% to 0.4% of patients taking rosuvastatin at doses up to 40 mg in clinical studies.  Treatment-related myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CK values >10 times upper limit of normal, was reported in up to 0.1% of patients taking rosuvastatin doses of up to 40 mg in clinical studies.
a. Increased incidence when used with gemfibrozil, niacin, erythromycin (CYP3A4 inhibitor), azole antifungals or other  (CYP3A4 inhibitor), (significant for lovastatin, simvastatin but not yet proved to be a major problem for fluvastatin, atorvastatin and pravastatin) and cyclosporine antifungals (CYP3A4 inhibitor).
b. Drug-drug interactions: Co-administered with erythromycin, fibrates (e.g., gemfibrozil), cyclosporin (CsA), nicotinic acid (niacin), and azole antifungals increase the risk of myopathy. Before the decision is made to concurrently use the above agents, the potential risks and benefits should be weighed and patients should be carefully monitored for signs and symptoms of myopathy in the initial months of therapy during dose elevation of either drug. Periodic CK monitoring should be considered.
                     ~Not an absolute contraindication to use with these agents.
                     ~Has not been reported with fluvastatin.
c. Also myopathy/rhabdomyalisis is a dose related phenomenon.  EG. with simvastatin, the increase in clinical trials in which pts were carefully monitored and some interacting drugs excluded was about 0.02% at 20 mg, 0.07% at 40 mg, and 0.3% at 80 mg.
d. Specific language may appear for specific statins and their risk of myositis/rhabdo.  For example:
    ~ The risk of myopathy/rhabdomyalisis is increased by concomitant use of simvastatin with the following: 
         - Potent inhibitors of CYP3A4: Cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit joice (>1 quart daily), particularly with higher doses of simvastatin
         - Other drugs: Gemfibrozil particularly with higher doses of simvastatin
         - Other lipid-lowering drugs (other fibrates or >1 g/day of niacin) that can cause myopathy when given alone
         - Amiodarone or verapamil with higher doses of simvastatin
         - The risk of myopathy/rhabdomyolysis is dose related
         - Consequently:
          1. Use of simvastatin concomitantly with itraconazose, ketoconazole, erythromycin, carithromycin, HIV protease inhibitors, nefazodone, or large quantities or grapefruit juice (>1 quart daily) should be avoided.
          2. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil.  The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination.
          3. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine.
          4. The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil.  The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
          5. All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness.  Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected.
          6. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus.  Such patients merit closer monitoring.  Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medicl or surgical condition supervenes.
     2.Headache, flatulence, abdominal pain, nausea, constipation/diarrhea, and rash-- most common side effects 
     3.Increased LFT's (AST, ALT, CK, Alk Phos, and T. bili) - check baseline and periodically often that q4-6 weeks the first year. New guidelines for monitoring HMG's.

Summary of Monitoring for LFT's

Comments:
  ~ Nonlinear dose responses (doubling dose does not lead to doubling of reduction in LDL). You usually see approx. a 6% increase in LDL lowering.
~ Rosuvastain comments:
1. Newer agent with less clinical experience.
2. Unique issues to keep in mind:
    a. appears more potent at LDL, HDL lowering compared to other potent statins (ref. STELLAR study)
        i. In the rosuvastatin clinical trial program, dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients, predominantly in patients dosed above the recommended dose range (ie., 80 mg).  However, this finding was more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator statins, though it was generally transient and was not associated with worsening renal function.  Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin 40 mg therapy with unexplained persistent proteinuria during routine urinanalysis testing.
        ii. Fenofibrate: Coadministration of fenofibrate (67 mg three times daily) with rosuvastatin (10 mg) resulted in no significant changes in plasma concentrations of rosuvastatin or fenofibrate.  
            Gemfibrozil: Coadministration of gemfibrozil (600 mg twice daily for 7 days) with rosuvastatin (80 mg) resulted in a 90% and 120% increase for AUC and C_max of rosuvastatin, respectively. This increase is considered to be clinically significant.

   b.Fenofibrate—Tricor ®
     1.MOA 
        ~Increases lipoproteinlipase activity and trig clearance
        ~Decreases hepatic secretion of VLDL-C and release of fatty acids from adipose tissue-à decreaes transfer of cholesterol from HDL-C to VLDL-C , thus increases HDL-C.
     2.Actions:
        ~Lowers TG
        ~Elevates HDL-C
        ~May lower LDL-C depending on phenotype (may elevate LDL-C also- see table)
     3.Dosing
        ~See table above, usually 1, 60mg/day (micronized)
        ~Dosage adjustment is needed for pts. With Clcr <50ml/hr
     4.Comments:
        ~dyspepsia, abdominal pain, rash cholelithiasis and diarrhea may be issues
        ~caution with patient on "statins" and gemfibrozil +/- fenofibrate)
        ~co administration with warfarin may cause elevated INR’s
        ~Fenofibrate May increase LDL for select patients (Fredrickson’s class IV/V)
        ~VA-HIT applicability to fenofibrate may not be a reasonable explaination

Comments
     ~Hepatic toxicity is mostly thought to be related to select sustained-release (bid) products. Sustained-release products are more expensive and have similar incidence of side effects, so generally SR products are not used as often as IR products - exception NIASPAN (sustained release Niacin given once daily in evening) although the actual incidence of hepatic toxicity is reported to be less with lower doses (max 2-3gm SR daily)
     ~Use with caution in pts with gout, peptic ulcer disease, and diabetes
     ~Alcohol and hot drinks may increase flushing and pruritis
     ~Both IR and SR products are over the counter

Comments
~ Usually used in combination with statins.  To augment LDL (additional 12-18% reduction) lowering effect increase HDL-C (additional 203% elevation) and lowering of TG (additional approx. 9% lowering?)
~ Alone it reduces LDL approx 18%, raises HDL approx. 2-3% and lowers TG by 8-12%.
~ Usually used to augment statins effect if other combinations are not ideal or higher.  Statin doese are not tolerated (elevation in LFTs, myopothic, etc.)

Triglyceride Level	Initial Classification
< 150 mg/dL	Normal
150-199 mg/dL	Borderline-High
200-499 mg/dL	High
> 500 mg/dL	Very High

   d.Complications
       ~Borderline-high and high: Increased risk for CHD
       ~High: Increased risk for pancreatitis
   e.Treatment
       ~Nonpharmacologic therapy
          -Weight reduction
          -Alcohol restriction
          -Increased physical activity
       ~Pharmacologic therapy
          -Nicotinic acid
          -Gemfibrozil
          -Possible fish oils
       ~See Step 9 ATP III Summary

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Last updated: 10/13/2004
Course Director: Robert J. Straka
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