Severe Rhabdomyolysis Associated with the Cerivastatin-Gemfibrozil Combination Therapy

Abstract

Cerivastatin is the new 3rd-generation of the synthetic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, the 1st drugs of choice for treating hypercholesterolemia. A potent inhibitor of HMG-CoA reductase, it possesses a high affinity for liver tissue and decreases plasma low-density lipoprotein cholesterol at microgram doses. Cerivastatin produces reductions in low-density lipoprotein cholesterol of 31.3% and 36.1% at doses of 0.3 and 0.4 mg/day, respectively. It is an uncomplicated agent with regard to its pharmacokinetic profile, low potential for interaction with other drugs, and suitability for use in those with impaired renal function. Most other statins have been implicated in causing rhabdomyolysis, either as mono-therapy or in combination with other agents. We report what to our knowledge is the most profound case yet in the literature of rhabdomyolysis in association with ceriva-statin-gemfibrozil combination therapy, in regard both to the extreme elevation in serum creatinine kinase and to the patient's near-paralytic weakness.

Cerivastatin produces reductions in low-density lipoprotein (LDL) cholesterol of 31.3% and 36.1% at doses of 0.3 and 0.4 mg/day, respectively. ¹ It is an uncomplicated agent with regard to its pharmacokinetic profile, low potential for interaction with other drugs, and suitability for use in those with impaired renal function. Most other statins have been implicated in causing rhabdomyolysis, either as monotherapy or in combination with other agents. We report a case of severe myopathy and rhabdomyolysis associated with cerivastatin-gemfibrozil combination therapy.

Case Report

In January 2000, a 72-year-old white man was admitted to our hospital because of worsening generalized weakness for the past 7 days.

The patient had a history of ischemic cardiomyopathy and hyperlipidemia. He had no history of alcohol abuse. For the past 4 years, he had been treated with several 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors—initially with lovastatin, then with simvastatin, and subsequently with atorvastatin. Due to an elevated triglyceride level, the patient had been started on gemfibrozil, 600 mg twice daily, 18 months before. Daily, he had been taking losartan 50 mg, aspirin 81 mg, digoxin 0.125 mg, amiodarone 200 mg, allopurinol 300 mg, potassium 20 mEq, and atorvastatin 20 mg daily; twice daily, he had been taking carvedilol 3.125 mg, bumetanide 2 mg, and gemfibrozil 600 mg. Two weeks before admission, however, he stopped taking atorvastatin and started taking cerivastatin 0.3 mg daily, due to the availability of free drug samples.

After 7 days of consuming the cerivastatin, the patient started to notice weakness around his hips that progressed to generalized weakness, which was more pronounced in his proximal muscles. He also complained of myalgia and stiffness around his shoulders, hips, and neck. He eventually developed difficulty in keeping his head up at the dining table and in getting out of bed. The patient denied having any swallowing or breathing problems, nor did he have any numbness, syncope, cardiac symptoms, or recent history of trauma.

On physical examination, the patient's temperature was 98 °F, his pulse rate was 76/min, his blood pressure was 110/60 mmHg, and his respiratory rate was 14/min. The patient was a well developed, well oriented man in no distress and was lying in bed with his head elevated. His pupils were anicteric and reactive. A grade 2/6 holosystolic murmur was present at the cardiac apex, which was displaced 2 cm laterally. The abdominal and chest examinations were unremarkable. His speech was fluent and no muscle tremor was discerned. He was not able to raise his hips against gravity; his shoulders, elbows, and knees had 4/5ths of normal strength against some resistance, and his distal muscles had strength close to normal. Deep tendon reflexes were decreased (1+), but were equal bilaterally. Functions of the cerebellum and cranial nerves appeared to be intact.

Pertinent laboratory findings included normal levels of sodium, potassium, chloride, magnesium, calcium, and phosphate. Other results appear in Table I. The patient's urine was amber in color; urinalysis showed a pH of 6.5 and a large quantity of occult blood (3 red blood cells and 1 white blood cell per high-power field). His urine myoglobin level was 85,200 μg/L. The patient's chest radiograph and electrocardiogram were normal.

TABLE I. Laboratory Findings

We discontinued cerivastatin and gemfibrozil and administered an intravenous bicarbonate infusion and diuretics. His creatinine kinase (CK) level continued to rise and peaked at 124,880 U/L on day 6 of admission, before it gradually decreased during his 2-week stay in the hospital. His alanine aminotransferase level reached 1,045 U/L on day 5, but returned to normal on discharge. The patient's kidney function remained stable. On hospital day 7, a nerve-conduction study and electromyogram showed a slight nonspecific reduction in sensory and motor amplitude and in velocity in most of his proximal muscles; a muscle biopsy of his quadriceps was non-yielding (no inflammation, vasculitis, or necrosis). At first, the patient had been unable to open his jaw voluntarily for oral ingestion, or to get out of bed. After 10 days of hospitalization, his general muscle strength returned gradually to 4/5ths of normal, and he was able to walk slowly for progressively longer periods of time. The patient was transferred to the rehabilitation care unit, where his recovery was uneventful. Eighteen days after discontinuation of cerivastatin and gemfibrozil, the patient's CK value, renal function, and physical strength had all returned to normal. This patient was not returned to his previous regimen of atorvastatin and gemfibrozil.

Discussion

Most available HMG-CoA reductase inhibitors, the “statins,” have been implicated in causing rhabdomyolysis, either as monotherapy or in combination with such agents as cyclosporine, erythromycins, niacin, and antifungal drugs. ^2–5 This complication is particularly well recognized when an HMG-CoA reductase inhibitor is combined with gemfibrozil, another lipid-lowering drug.

Differential Diagnosis.

Other causes of rhabdomyolysis, such as hyperthermia, prolonged seizures, trauma, physical muscle damage or stress, dehydration, burns, alcohol abuse, hypophosphatemia, and infections with human immunodeficiency virus, influenza virus, or herpesvirus were not evident in our patient. Our patient's clinical course and laboratory data suggest that the combination of cerivastatin with gemfibrozil was the most probable cause of his severe myopathy. The absence of cross-toxicity with gemfibrozil when this patient had used other HMG-CoA reductase inhibitors suggests that his rhabdomyolysis was not caused by HMG-CoA reductase inhibitors as a class. We believe that this is the 1st reported case of such profound rhabdomyolysis in association with cerivastatin-gemfibrozil combination therapy, in regard both to the extreme elevation in serum creatinine kinase and to the patient's near-paralytic weakness.

Properties of Cerivastatin.

Cerivastatin is the 3rd generation of the synthetic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, which are the 1st drugs of choice for treating hypercholesterolemia. A potent HMG-CoA reductase inhibitor, it decreases plasma low-density lipoprotein cholesterol at microgram doses and is 100 times more potent in vitro than is lovastatin. ⁶ Cerivastatin possesses an uncomplicated pharmacokinetic profile, low potential for interaction with other drugs, and readiness for use in patients with impaired renal function. More than 98% is absorbed via the gastrointestinal tract and excreted almost entirely by the hepatobiliary system. ⁷ Notable for its high affinity for liver tissue, cerivastatin is cleared via a dual metabolic pathway, the isoenzymes 2C8 and 3A4 of the hepatic cytochrome P450. ⁸ Cerivastatin is therefore theoretically less subject to interactions with other drugs and is cleared by both biliary and renal excretion. ⁸ Tolerability and safety in clinical trials did not differ from that of placebo with regard to serum CK levels, and the incidence of drug-induced myopathy was infrequent. ^9–12

Other Reported Cases.

To our knowledge, only 1 similar case has been reported in the literature. In 1999, Pogson and colleagues ¹³ reported a case of a 74-year-old woman who had been taking gemfibrozil 600 mg twice daily. Three weeks after adding cerivastatin 0.3 mg/day, she suffered rhabdomyolysis and renal failure. ¹³ Her CK level reached 16,094 mg/dL and serum creatinine peaked at 4.3 mg/dL. The clinical characteristics that she had in common with our patient included advanced age (early 70s), coronary artery disease, allopurinol therapy, and symptoms of rhabdomyolysis that started shortly after cerivastatin 0.3 mg/day was initiated. On the other hand, our patient's serum CK level was 500 times the upper limit of normal and nearly 8 times higher than that of Pogson's patient. Our patient was also more severely debilitated upon presentation.

Conclusion

Adverse events associated with cerivastatin therapy are similar to those associated with other statins: primarily, they involve the liver and muscle tissue. The pooled safety data ¹⁴ on cerivastatin indicate that elevated levels of CK (5 to 10 times the upper limit of normal) occurred in 0.47% to 0.88% of reported cases; CK levels greater than 10 times the upper limit of normal occurred in only 0.29% to 0.47% of cases. The incidence of rhabdomyolysis associated with cerivastatin is comparable to that of other statins. ¹² Myopathy is believed to occur as a result of the enhanced potential for gemfibrozil, like its well-known counterpart clofibrate, to injure muscle directly. ^15–17 Its interaction with statins greatly increases the risk of muscle damage, particularly in patients with a possible underlying predisposition to myopathy (e.g., heavy users of ethyl alcohol, dehydrated patients, elderly patients). Unlike other statins, the clinically significant abnormalities in CK or liver enzymes associated with the use of cerivastatin do not correlate with dosage.

Cerivastatin is a safe and well-tolerated hypolipidemic agent and an important addition to the armamentarium of lipid-lowering drugs for the treatment of hypercholesterolemia. Its combination with “fibrates” offers favorable lipid modifications, when compared with the use of either drug alone. ^18–20 However, given its potential serious deleterious effects, statin-fibrate combination therapy must be managed prudently and applied only after judicious risk-benefit analysis. Before initiating the statin-gemfibrozil therapy, clinicians must take into account a patient's age, renal function, potassium and thyroid levels, and concomitant use of other drugs such as diuretics, cyclosporine, erythromycins, niacin, and antifungal agents.

Although cerivastatin-induced rhabdomyolysis of such severity as our patient experienced is rare, we strongly recommend that clinicians be aware of the potential for serious muscle and liver injury that is associated with cerivastatin. This drug should be used cautiously, especially in patients receiving gemfibrozil. Future studies should focus on the underlying mechanism of rhabdomyolysis that is associated with cerivastatin, and they should examine more broadly the various responses of patients to different statins. There is also a need to devise better risk stratification for patients who are under consideration for combination therapy involving HMG-CoA reductase inhibitors and gemfibrozil.