• Naser U.A.M.A. Abdul-Ghaffar. MRCP.

• Mohammed Riad El-Sonbaty. MRCP.

Case was admitted to Medical Department, Adan Hospital, Kuwait.

Key words : Pancreatitis, rhabdomyolysis, lovastatin, gemfibrozil.

Dr. Mohammed Riad El-Sonbaty.

P.O. Box. 46468

Fehahil 64015

KUWAIT

The most important side effects of Hydroxymethylglutaryl Coenzyme A reductase (HMG CoA reductase) inhibitors, were muscular and hepatic toxicity reported mainly with lovastatin [1-5]. Among the protein toxic side effects of fibric acid derivatives, muscular and hepatic toxicity were the most prominent [1,4,6]. Pancreatitis was also recognized with clofibrate [7,8]. The combination of fibric acid derivatives, and HMG CoA reductase inhibitors, was associated with severe rhabdomyolysis [1,4]. To our knowledge pancreatitis associated with either gemfibrozil or lovastatin was not reported before. Here we report a case of acute pancreatitis complicated with pseudo-pancreatic cyst, and acute rhabdomyolysis, associated with combined use of lovastatin and gemfibrozil.

A 55 year old German lady had combined hyperlipidaemia discovered at 1969. By that time she was put on propranolol 20 mg three times a day (tds) to control her anginal pains and bezafibrate 200 mg tds. She was not diabetic and had normal thyroid functions. The patient was admitted with acute myocardial infarction in December 1991 and went home on propranolol long acting 80 mg twice a day (bds), lovastatin 20 mg bds, and aspirin 100 mg once daily. Hyperlipidaemia was difficult to control with diet and lovastatin 40 mg bds, so gemfibrozil was added in a dose of 300 mg bds in August 1992. Plasma lipids were properly controlled in two weeks time. Eight weeks after starting gemfibrozil the patient was admitted complaining of; epigastric pain, vomiting, muscle pain, and weakness. There was no history of chest pain, fever, or alcohol intake. physical examination revealed a middle aged afebrile lady. Pulse was 90/minute regular and blood pressure was 140/80 mmHg. She had definite epigastric tenderness as well as proximal muscle weakness affecting shoulder and pelvic girdles. Sensations were intact and tendon reflexes were diminished all over. Planters were flexor bilaterally. Physical findings otherwise were not remarkable. Investigations showed; blood sugar 3.6 mmol/L, serum creatinine 85 mmol/L, serum sodium 134 mmol/L, serum potassium 4.3 mmol/L, serum triglycerides (TG) 3.15 mmol/L, serum cholesterol 4.75 mmol/L, serum creatine kinase (CK) 1906 IU/L, CK-MB (specific for the myocardium) 6 IU/L, serum amylase 3001 IU/L, 24 hours urinary amylase 8045 IU/L, serum aspartate transaminase (AST) 35 IU/L, serum lactic dehydrogenase (LD) 198 IU/L. Serial electrocardiograms (ECG) showed no recent changes, and AST, LD and CK-MB were repeatedly normal. Gall stones were carefully excluded by repeated abdominal ultrasonography. Lovastatin and gemfibrozil were stopped on admission, because the combination was suspected to be responsible for the patient illness. Within 11 days serum amylase, urine amylase and CK were back to normal. Patient made very good recovery and went home on nefidipine, metoprolol, and aspirin 100 mg daily. She was restarted four weeks later on lovastatin alone and did well for more than two years now. After discharge the patient developed diabetes mellitus requiring insulin treatment. Computed tomography (CT), done in July 1993 showed pseudo-pancreatic cyst in the region of the body of the pancreas 2.8 x 3.6 centimetre in diameter (figure 1). Abdominal ultrasonography done in March 1995 showed marked reduction in the size of the cyst.

In our case the patient received bezafibrate alone for several years, and lovastatin alone for about nine months without side effects. When gemfibrozil was added to lovastatin, in eight weeks time, the patient developed clear picture of acute rhabdomyolysis associated with acute pancreatitis. The patient illness could not be attributed to the hyperlipidaemia she had because of two reasons. First, the associated acute rhabdomyolysis which is not known to occur with hyperlipidaemia. Second, the plasma TG was normal on admission. The time interval between the start of gemfibrozil and the onset of pancreatitis was comparable with cases reported with clofibrate [7-8]. Recent myocardial infarction was excluded by serial ECGs and cardiac enzymes. The patient recovered after stopping the suspected offending agents, namely lovastatin and gemfibrozil. She was restarted on lovastatin four weeks after recovery, and continued for more than two year now without side effects. Mostly either the combined use of lovastatin and gemfibrozil was responsible for the toxicity, or gemfibrozil alone was the offending agent. It seems more likely that the combined use of the two drugs was responsible because, the patient was exposed to each bezafibrate and lovastatin separately for long time with no side effects. The latter possibility can be ruled out only by re-challenging the patient with gemfibrozil alone which seems to be unethical. It seems that combined use of fibric acid derivatives and HMG CoA reductase inhibitors should be avoided in the future.

1. Raimondeau J, Le Marec H, Chevallier JC, Bouhour JB. Myolyse biologique survenue a l'occasion d'un relais therapeutique fenofibrate-pravastatine. La Presse Medicale 1992;21(14):663-4.
1. Ayanian JZ, Fuchs CS, Stone RM. Lovastatin and rhabdomyolysis. Ann Intern Med 1988; 109:682-683.
1. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62(28):J-34 J.
1. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264:71-75.
1. Federico A, Dotti MT. Treatment of cerebrotendinous xanthomatosis. Neurology 1994; 44(11):2218
1. Lavarenne J, Poinas-Caillaud H. Atteintes musculaires et fibrates: Analyse des donnees de la banque informatique du systeme francais de pharmacovigilance. Therapie 1991; 46:347-9
1. Oliver MF, Geizerova H, Gyarfas I et al. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br. Heart J 1978; 40:1069-1118.
1. Smith RB, Prior IA, Cooke Nj. The effect of clofibrate on raised serum lipid levels. NZ Med J 1968; 68:231.

figure 1 :-