title: 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.
abstract: 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%).
  
  
  CONCLUSIONS
  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).
authors.affiliation: Point Mdical, Dijon, France. michelfarnier@nerim.net
authors.forename: Michel
authors.initials: M
authors.lastname: Farnier
authors.forename: David
authors.initials: D
authors.lastname: Marcereuil
authors.forename: Sophie
authors.initials: S
authors.lastname: De Niet
authors.forename: Jean
authors.initials: J
authors.lastname: Ducobu
authors.forename: Armin
authors.initials: A
authors.lastname: Steinmetz
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
authors.forename: Leszek
authors.initials: L
authors.lastname: Bryniarski
authors.forename: Albert
authors.initials: A
authors.lastname: Császár
authors.forename: Francis
authors.initials: F
authors.lastname: Vanderbist
mesh_terms: D000328:Adult; D000368:Aged; D017326:Clinical Trials, Phase III as Topic; D016208:Databases, Factual; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
chemical_list: D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D017035:Pravastatin; D011345:Fenofibrate