Fluvastatin

Liver

It has been debated whether HMG-CoA reductase inhibitors can occasionally cause liver damage [ ]. Pre- and postmarketing studies have shown rises in hepatic aminotransferase activity in 0.1–3%. However, it is still unclear whether serious hepatic reactions occur more often than expected in the general population. The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) looks for signals in the Italian spontaneous ADR reporting system [ ]. By 31 December 2004, the GIF had received 1260 reports of ADRs related to statins, including 178 of hepatic reactions; 69 were attributed to fluvastatin. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one-third the hepatotoxicity occurred after less than 1 month of therapy. Of the 33 patients 27 were women, and the dose of fluvastatin was 80 mg/day in 81% of the cases in whom complete data on drug dosages were available. This is a preliminary signal; further evaluation is needed to confirm it and to quantify the risk.

Individual cases of suspected hepatotoxicity has been reported with fluvastatin.

• Cholestatic hepatitis developed in a 71-year-old man with nephrotic syndrome [ ]. Hepatic function was normal after several months of fluvastatin 20 mg/day. Some weeks after the dose was increased to 40 mg/day, his gamma-glutamyl transpeptidase activity rose from normal to 1818 IU/l, with negative serology for viruses. After normalization, re-introduction of fluvastatin 20 mg/day was not tolerated, but he did tolerate simvastatin 20 mg/day.

• A 61-year-old woman developed symptoms of acute hepatitis 6 weeks after she began to take fluvastatin sodium 20 mg/day for hypercholesterolemia [ ]. Ultrasonography and liver biopsy confirmed the diagnosis of non-obstructive intrahepatic jaundice. Studies of viral markers and autoimmune factors excluded viral hepatitis and autoimmune hepatitis. There was a high serum concentration of a metabolite of fluvastatin, suggesting a possible anomaly of drug metabolism. All liver function tests normalized 8 weeks after the withdrawal of fluvastatin.

Pancreas

Acute pancreatitis has been attributed to fluvastatin [ ].

• A 36-year-old man took fluvastatin 40 mg/day for 3 months and developed mild acute pancreatitis, which settled with medical treatment. Other causes were ruled out. Some months later, he started taking fluvastatin again and had a recurrence of pancreatitis within a few days.

According to the authors, statin-induced acute pancreatitis can occur on the first day of therapy or after several months. It is generally mild and runs a benign course; no deaths have been reported. Its frequency is unknown but it is probably rare.

Urinary tract

Concerns have recently been raised regarding a potential harmful effect of statins on renal function. The effect of fluvastatin on renal function has been investigated in renal transplant recipients enrolled in the Assessment of Lescol in Renal Transplantation (ALERT) trial [ ]. This was a randomized, double-blind, placebo-controlled study in 1102 patients of the effect of fluvastatin 40–80 mg/day. Fluvastatin had no significant effect compared with placebo on renal function, assessed by serum creatinine, creatinine clearance, or proteinuria.

An analysis of adverse events has also been performed on data from 30 completed clinical trials of fluvastatin in 11 815 patients [ ]. Changes in creatinine clearance and serum creatinine from baseline were similar in fluvastatin-treated patients and placebo-treated patients.