nger subjects treated with ezetimibe.
Atorvastatin
Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
Hepatic impairment
Ezetimibe
After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 or 6), compared to healthy subjects. In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the mean AUC for total ezetimibe was increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. No dose adjustment is necessary for patients with mild hepatic insufficiency. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe (Child-Pugh score > 9) hepatic insufficiency, ezetimibe is not recommended in these patients (see sections 4.2 and 4.4).
Atorvastatin
Plasma concentrations of atorvastatin and its active metabolites are markedly increased (approx. 16-fold in Cmax and approx. 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh B).
Renal impairment
Ezetimibe
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30 ml/min/1.73 m2), the mean AUC for total ezetimibe was increased approximately 1.5-fold, compared to healthy subjects (n=9).
An additional patient in this study (post-renal transplant and receiving multiple medicinal products, including ciclosporin) had a 12-fold greater exposure to total ezetimibe.
Atorvastatin
Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Gender
Ezetimibe
Plasma concentrations for total ezetimibe are slightly higher (approximately 20%) in women than in men. LDL-C reduction and safety profile are comparable between men and women treated with ezetimibe.
Atorvastatin
Concentrations of atorvastatin and its active metabolites in women differ from those in men (women: approx. 20% higher for Cmax and approx. 10% lower for AUC). These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.
SLCO1B1 polymorphism
Atorvastatin
Hepatc uptake of all HMG-CoA reductase inhibitors, including atorvastatin, involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism there is a risk of increased exposure of atorvastatin, which may lead to an increased risk of rhabdomyolysis (see section 4.4). Polymorphism in the gene encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher atorvastatin exposure (AUC) than in individuals without this genotype variant (c.521TT). A genetically impaired hepatic uptake of atorvastatin is also possible in these patients. Possible consequences for the efficacy are unknown.
5.3 Preclinical safety data
ATOZET
In three-month coadministration studies in rats and dogs with ezetimibe and atorvastatin, the toxic effects observed were essentially those typically associated with statins. The statin-like histopathologic findings were limited to the liver. Some of the toxic effects were more pronounced than those observed during treatment with statins alone. This is attributed to pharmacokin |
