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July 4, 1990, Vol 264, No. 1 >
ARTICLE | July 4, 1990

Myopathy and Rhabdomyolysis Associated With Lovastatin-Gemfibrozil Combination Therapy FREE

L. Ross Pierce, MD; Diane K. Wysowski, PhD; Thomas P. Gross, MD, MPH
[+] Author Affiliations

This article contains the views of the authors and not necessarily those of the Food and Drug Administration.

Reprint requests to Division of Metabolism and Endocrine Drug Products, HFD-510, Food and Drug Administration, 5600 Fishers Ln, Room 14B03, Rockville, MD 20857 (Dr Pierce).


JAMA. 1990;264(1):71-75. doi:10.1001/jama.1990.03450010075034
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References

The Food and Drug Administration documents the receipt of 12 case reports of severe myopathy or rhabdomyolysis associated with concomitant use of lovastatin and gemfibrozil, including 10 voluntary postmarketing, and 2 required, reports. All patients had serum creatine kinase levels of more than 10 000 U/L, 4 tested showed myoglobinuria, and 5 had acute renal failure. The patients' symptoms resolved when both drugs were discontinued. For the first year of marketing of lovastatin, spontaneous reports of myopathy with documentation of creatine kinase level were reviewed for the use of lovastatin, gemfibrozil, and combination therapy. The median creatine kinase level in reports involving concomitant lovastatin and gemfibrozil use was 15 250 U/L, 20 times that in reports with gemfibrozil use alone and 30 times that in reports with lovastatin use alone. Because of the potential for severe myopathy and life-threatening rhabdomyolysis, and given alternative drug combinations for treating hyperlipoproteinemia, the use of lovastatin in combination with gemfibrozil is to be discouraged.

(JAMA. 1990;264:71-75)

REFERENCES

1 +
Mastaglia FL.  Adverse effects of drugs on muscle . Drugs . 1982;;24:304-321.
2 +
Langer T, Levy RI.  Acute muscular syndrome associated with administration of clofibrate . N Engl J Med. 1968;;279:856-858
3 +
Sekowski I, Samuel P.  Clofibrate-induced acute muscular syndrome . Am J Cardiol. 1972;;30:572-574.
4 +
Bridgmen JF, Rosen SM, Thorp JM.  Complications during clofibrate treatment of nephrotic-syndrome hyperlipoproteinemia . Lancet . 1972;;2:506-509.
5 +
Denizot M, Fabre J, Pometta D, Wildi E.  Clofibrate, nephrotic syndrome, and histological changes in muscle . Lancet . 1973;;1:1326.
6 +
Pierides AM, Alvarez-Ude F, Kerr DNS, Skillen AW.  Clofibrate-induced muscle damage in patients with chronic renal failure . Lancet . 1975;;2:1279-1282.
7 +
Kijima Y, Sasaoka T, Kanayama M, Kubota S.  Untoward effects of clofibrate in hemodialyzed patients . N Engl J Med. 1977;;296:515.
8 +
Haubenstock A, Schroecksnadel W, Bauer K, Schmidt P, Gabl F.  Predominance of lactate dehydrogenase isoenzyme 1 in a patient with bezafibrate-induced rhabdomyolysis . Clin Chem. 1984;; 30:1587-1588.
9 +
Rumpf KW, Barth M, Blech M, Kaiser H, Koop I, Arnold R, Scheler F.  Bezafibrate-induzierte myolyse und myoglobinurie bei patienten mit eingeschraenkter nierenfunktion . Klin Wochenschr. 1984;; 62:346-348.
10 +
Yeshurun D, Dakak N, Khoury K, Daher E.  Acute severe myositis due to bezafibrate treatment . Harefuah. 1989;;116:261-263.
11 +
Giraud P, Cassou M, Paul R, Guidet M.  Toxicité musculaire due au fenofibriate: a propos d'un cas . Rev Rheum. 1982;;49:162.
12 +
Tobert JA.  Efficacy and long-term adverse effect pattern of lovastatin . Am J Cardiol. 1988;;62:28J-34J.
13 +
Tobert JA.  Reply (letter) . N Engl J Med. 1988;;318:48.
14 +
Illingworth DR, Bacon S.  Influence of lovastatin plus gemfibrozil on plasma lipids and lipoproteins in patients with heterozygous familial hypercholesterolemia . Circulation . 1989;;79:590-596.
15 +
Norman DJ, Illingworth DR, Munson J, Hosenpud J.  Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin . N Engl J Med. 1988;;318:46-47.
16 +
East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA.  Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation . N Engl J Med. 1988;;318:47-48.
17 +
Corpier CL, Jones PH, Suki WN, et al.  Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients . JAMA . 1988;;260:239-241.
18 +
Reaven P, Witztum JL.  Lovastatin, nicotinic acid, and rhabdomyolysis . Ann Intern Med. 1988;;109:597-598.
19 +
Goldman JA, Fishman AB, Lee JE, Johnson RJ.  The role of cholesterol-lowering agents in druginduced rhabdomyolysis and polymyositis . Arthritis Rheum. 1989;;32:358-359.
20 +
Smith PF, Eydalloth RS, Grossman SG, Schwartz M, Stubbs RJ, MacDonald JS.  HMG-CoA reductase inhibitor-induced myopathy in the rat: a model for drug interactions . Presented at the 10th International Symposium on Drugs Affecting Lipid Metabolism; November 9, 1989 ; Houston, Tex
21 +
Migneco G, Mascarella A, La Ferla A, Attianese R.  Epatite da clofibrato . Minerva Med. 1986;;77:799-800.
22 +
Aron E, Metman EH, Bougnoux Ph.  Hepatite due au procetofene? un cas . Nouv Presse Med. 1979;;8:783.
23 +
Vachon JM.  Hepatite due au procetofene . Nouv Presse Med. 1980;;9:2740.
24 +
Pierce EH, Chesler DL.  Possible association of granulomatous hepatitis with clofibrate therapy . N Engl J Med. 1978;;299:314.
25 +
Transcript: Metabolism and Endocrine Drug Advisory Committee Meeting . Rockville, Md: Food and Drug Administration; (September 29) , 1989;.
26 +
Ayanian JZ, Fuchs CS, Stone RM.  Lovastatin and rhabdomyolysis . Ann Intern Med. 1988;;109: 682-683.
27 +
Frick MH, Elo O, Haapa K, et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease . N Engl J Med. 1987;;317:1237-1245.
28 +
Manninen V, Elo O, Frick MH, et al.  Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study . JAMA . 1988;;260:641-651.
29 +
 Report from the Committee of Principal Investigators: a co-operative trial in the primary prevention of ischaemic heart disease using clofibrate . Br Heart J. 1978;;40:1069-1118.
30 +
Kane JP, Malloy MJ, Tun P, et al.  Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen . N Engl J Med. 1981;;304:251-258.
31 +
Grundy SM, Vega GL, Bilheimer DW.  Influence of combined therapy with mevinolin and interruption of bile-acid reabsorption on low density lipoproteins in heterozygous familial hypercholesterolemia . Ann Intern Med. 1985;;103:339-343.
32 +
Leren TP, Hjermann I, Berg K, Leren P, Foss OP, Viksmoen L.  Effects of lovastatin alone and in combination with cholestyramine on serum lipids and apolipoproteins in heterozygotes for familial hypercholesterolemia . Atherosclerosis . 1988;;73: 135-141.
33 +
Brunzell JD, Bierman EL.  Chylomicronemia syndrome: interaction of genetic and acquired hypertriglyceridemia . Med Clin North Am. 1982;;66: 455-468.
34 +
Vega GL, Grundy SM.  Gemfribrozil therapy in primary hypertriglyceridemia associated with coronary heart disease: effects on metabolism of lowdensity lipoproteins . JAMA . 1985;;253:2398-2403.
35 +
Shepherd J, Caslake MJ, Lorimer AR, Vallance BD, Packard CJ.  Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects . Arteriosclerosis . 1985;;5:162-168.
36 +
Carlson LA, Olsson G, Ballantyne D.  On the rise in low density and high density lipoproteins in response to the treatment of hypertriglyceridemias in type IV and type V hyperlipoproteinaemias . Atherosclerosis . 1977;;26:603-609.
37 +
Garg A, Grundy SM.  Gemfibrozil alone and in combination with lovastatin for treatment of hypertriglyceridemia in NIDDM . Diabetes . 1989;;38:364-372.
38 +
Hulley SB, Rosenman RH, Bawol RD, Brand RJ.  Epidemiology as a guide to clinical decisions: the association between triglyceride and coronary heart disease . N Engl J Med. 1980;;302:1383-1389.
39 +
Austin MA.  Plasma triglyceride as a risk factor for coronary heart disease: the epidemiologic evidence and beyond . Am J Epidemiol. 1989;;129:249-259.
40 +
Greenberg BH, Blackwelder WC, Levy RI.  Primary type V hyperlipoproteinemia: a descriptive study in 32 families . Ann Intern Med. 1977;;87:526-534.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

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1 +
Mastaglia FL.  Adverse effects of drugs on muscle . Drugs . 1982;;24:304-321.
2 +
Langer T, Levy RI.  Acute muscular syndrome associated with administration of clofibrate . N Engl J Med. 1968;;279:856-858
3 +
Sekowski I, Samuel P.  Clofibrate-induced acute muscular syndrome . Am J Cardiol. 1972;;30:572-574.
4 +
Bridgmen JF, Rosen SM, Thorp JM.  Complications during clofibrate treatment of nephrotic-syndrome hyperlipoproteinemia . Lancet . 1972;;2:506-509.
5 +
Denizot M, Fabre J, Pometta D, Wildi E.  Clofibrate, nephrotic syndrome, and histological changes in muscle . Lancet . 1973;;1:1326.
6 +
Pierides AM, Alvarez-Ude F, Kerr DNS, Skillen AW.  Clofibrate-induced muscle damage in patients with chronic renal failure . Lancet . 1975;;2:1279-1282.
7 +
Kijima Y, Sasaoka T, Kanayama M, Kubota S.  Untoward effects of clofibrate in hemodialyzed patients . N Engl J Med. 1977;;296:515.
8 +
Haubenstock A, Schroecksnadel W, Bauer K, Schmidt P, Gabl F.  Predominance of lactate dehydrogenase isoenzyme 1 in a patient with bezafibrate-induced rhabdomyolysis . Clin Chem. 1984;; 30:1587-1588.
9 +
Rumpf KW, Barth M, Blech M, Kaiser H, Koop I, Arnold R, Scheler F.  Bezafibrate-induzierte myolyse und myoglobinurie bei patienten mit eingeschraenkter nierenfunktion . Klin Wochenschr. 1984;; 62:346-348.
10 +
Yeshurun D, Dakak N, Khoury K, Daher E.  Acute severe myositis due to bezafibrate treatment . Harefuah. 1989;;116:261-263.
11 +
Giraud P, Cassou M, Paul R, Guidet M.  Toxicité musculaire due au fenofibriate: a propos d'un cas . Rev Rheum. 1982;;49:162.
12 +
Tobert JA.  Efficacy and long-term adverse effect pattern of lovastatin . Am J Cardiol. 1988;;62:28J-34J.
13 +
Tobert JA.  Reply (letter) . N Engl J Med. 1988;;318:48.
14 +
Illingworth DR, Bacon S.  Influence of lovastatin plus gemfibrozil on plasma lipids and lipoproteins in patients with heterozygous familial hypercholesterolemia . Circulation . 1989;;79:590-596.
15 +
Norman DJ, Illingworth DR, Munson J, Hosenpud J.  Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin . N Engl J Med. 1988;;318:46-47.
16 +
East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA.  Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation . N Engl J Med. 1988;;318:47-48.
17 +
Corpier CL, Jones PH, Suki WN, et al.  Rhabdomyolysis and renal injury with lovastatin use: report of two cases in cardiac transplant recipients . JAMA . 1988;;260:239-241.
18 +
Reaven P, Witztum JL.  Lovastatin, nicotinic acid, and rhabdomyolysis . Ann Intern Med. 1988;;109:597-598.
19 +
Goldman JA, Fishman AB, Lee JE, Johnson RJ.  The role of cholesterol-lowering agents in druginduced rhabdomyolysis and polymyositis . Arthritis Rheum. 1989;;32:358-359.
20 +
Smith PF, Eydalloth RS, Grossman SG, Schwartz M, Stubbs RJ, MacDonald JS.  HMG-CoA reductase inhibitor-induced myopathy in the rat: a model for drug interactions . Presented at the 10th International Symposium on Drugs Affecting Lipid Metabolism; November 9, 1989 ; Houston, Tex
21 +
Migneco G, Mascarella A, La Ferla A, Attianese R.  Epatite da clofibrato . Minerva Med. 1986;;77:799-800.
22 +
Aron E, Metman EH, Bougnoux Ph.  Hepatite due au procetofene? un cas . Nouv Presse Med. 1979;;8:783.
23 +
Vachon JM.  Hepatite due au procetofene . Nouv Presse Med. 1980;;9:2740.
24 +
Pierce EH, Chesler DL.  Possible association of granulomatous hepatitis with clofibrate therapy . N Engl J Med. 1978;;299:314.
25 +
Transcript: Metabolism and Endocrine Drug Advisory Committee Meeting . Rockville, Md: Food and Drug Administration; (September 29) , 1989;.
26 +
Ayanian JZ, Fuchs CS, Stone RM.  Lovastatin and rhabdomyolysis . Ann Intern Med. 1988;;109: 682-683.
27 +
Frick MH, Elo O, Haapa K, et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease . N Engl J Med. 1987;;317:1237-1245.
28 +
Manninen V, Elo O, Frick MH, et al.  Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study . JAMA . 1988;;260:641-651.
29 +
 Report from the Committee of Principal Investigators: a co-operative trial in the primary prevention of ischaemic heart disease using clofibrate . Br Heart J. 1978;;40:1069-1118.
30 +
Kane JP, Malloy MJ, Tun P, et al.  Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen . N Engl J Med. 1981;;304:251-258.
31 +
Grundy SM, Vega GL, Bilheimer DW.  Influence of combined therapy with mevinolin and interruption of bile-acid reabsorption on low density lipoproteins in heterozygous familial hypercholesterolemia . Ann Intern Med. 1985;;103:339-343.
32 +
Leren TP, Hjermann I, Berg K, Leren P, Foss OP, Viksmoen L.  Effects of lovastatin alone and in combination with cholestyramine on serum lipids and apolipoproteins in heterozygotes for familial hypercholesterolemia . Atherosclerosis . 1988;;73: 135-141.
33 +
Brunzell JD, Bierman EL.  Chylomicronemia syndrome: interaction of genetic and acquired hypertriglyceridemia . Med Clin North Am. 1982;;66: 455-468.
34 +
Vega GL, Grundy SM.  Gemfribrozil therapy in primary hypertriglyceridemia associated with coronary heart disease: effects on metabolism of lowdensity lipoproteins . JAMA . 1985;;253:2398-2403.
35 +
Shepherd J, Caslake MJ, Lorimer AR, Vallance BD, Packard CJ.  Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects . Arteriosclerosis . 1985;;5:162-168.
36 +
Carlson LA, Olsson G, Ballantyne D.  On the rise in low density and high density lipoproteins in response to the treatment of hypertriglyceridemias in type IV and type V hyperlipoproteinaemias . Atherosclerosis . 1977;;26:603-609.
37 +
Garg A, Grundy SM.  Gemfibrozil alone and in combination with lovastatin for treatment of hypertriglyceridemia in NIDDM . Diabetes . 1989;;38:364-372.
38 +
Hulley SB, Rosenman RH, Bawol RD, Brand RJ.  Epidemiology as a guide to clinical decisions: the association between triglyceride and coronary heart disease . N Engl J Med. 1980;;302:1383-1389.
39 +
Austin MA.  Plasma triglyceride as a risk factor for coronary heart disease: the epidemiologic evidence and beyond . Am J Epidemiol. 1989;;129:249-259.
40 +
Greenberg BH, Blackwelder WC, Levy RI.  Primary type V hyperlipoproteinemia: a descriptive study in 32 families . Ann Intern Med. 1977;;87:526-534.

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