Safety of a fixed-dose combination of fenofibrate/pravastatin 160 mg/40 mg in patients
with mixed hyperlipidaemia: a pooled analysis from a database of clinical trials.
BACKGROUND: Fenofibrate can be prescribed concomitantly with an HMG-CoA reductase
inhibitor (statin) to improve achievement of lipid goals in patients with atherogenic
mixed hyperlipidaemia. However, some safety concerns, particularly an increased risk
of myopathy, have been reported when these drugs are taken together. OBJECTIVE: The
aim of this analysis was to assess the general safety and tolerability of a fenofibrate/pravastatin
(FF/PRA) 160 mg/40 mg fixed-dose combination (FDC) capsule based on a pooled database
of phase III clinical trials in patients with mixed hyperlipidaemia. METHODS: Safety
data were pooled from five phase III studies (four double-blind with an uncontrolled
extension and one open) of >/=12 to 64 weeks' duration. Adverse event (AE) profiles
of FF/PRA 160 mg/40 mg (n=645 in the double-blind cohort) were evaluated relative
to comparators (statins, n=519 or fenofibrate, n=122). Absolute incidence rates were
calculated in both the double-blind cohort and the all-studies cohort (FF/PRA 160
mg/40 mg, n=1566) for all AEs, drug-related AEs, serious AEs, discontinuations due
to AEs, AEs of specific interest including abnormal laboratory data, and deaths. RESULTS:
The frequency and/or intensity of overall AEs, drug-related AEs, serious AEs and discontinuations
due to AEs were not significantly increased for the FDC (36.0%, 12.3%, 1.7% and 5.1%,
respectively) versus the statin (28.7%, 8.9%, 0.8% and 2.7%, respectively) and fenofibrate
(59.0%, 21.3%, 0% and 4.9%, respectively) monotherapies. No deaths were reported during
the course of treatment in clinical trials. Nevertheless, three deaths were reported
more than 30 days after the patients completed the study; none of these deaths were
assessed as being related to FF/PRA 160 mg/40 mg treatment. Among the AEs of special
interest, no myopathy or rhabdomyolysis were reported; no patients were considered
to have experienced a drug-induced liver injury; no case of pancreatitis occurred
in the double-blind cohort and four patients reported pancreatitis in the all-studies
cohort, two of them being study-treatment related; no case of pulmonary embolism was
reported in the double-blind cohort and two patients presented with pulmonary embolism,
unrelated to the study drug, in the all-studies cohort; there were more cases of decreased
creatinine clearance in the FF/PRA 160 mg/40 mg group (1.7%) than in the statin group
(0.6%). CONCLUSION: Within the limitations of this database (notably low percentage
of very elderly patients, limited sample size of patients with mild renal insufficiency,
and mode of selection in the clinical trials), no particular safety concern was raised
with FF/PRA 160 mg/40 mg in the double-blind cohort as compared with statin and fenofibrate
monotherapies. The acceptable long-term safety profile of FF/PRA 160 mg/40 mg was
confirmed with a low frequency of AEs of interest, comparable to that observed in
the 12-week double-blind cohort. Emergent effects possibly related to FF/PRA 160 mg/40
mg were mainly those attributable to fenofibrate (decrease in creatinine clearance
and pancreatitis).