nbsp;0.010
* 6% were uptitrated to ezetimibe/simvastatin 10/80 mg.
† 27% were uptitrated to simvastatin 80 mg.
‡ Kaplan-Meier estimate at 7 years.
Homozygous Familial Hypercholesterolaemia (HoFH)
A double-blind, randomised, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=36) receiving atorvastatin 40 mg at baseline. Increasing the dose of atorvastatin from 40 to 80 mg (n=12) produced a reduction of LDL-C of 2% from baseline on atorvastatin 40 mg. Coadministered ezetimibe and atorvastatin equivalent to ATOZET (10/40 and 10/80 pooled, n=24), produced a reduction of LDL-C of 19% from baseline on atorvastatin 40 mg. In those patients coadministered ezetimibe and atorvastatin equivalent to ATOZET (10/80, n=12), a reduction of LDL-C of 25% from baseline on atorvastatin 40 mg was produced.
After completing the 12-week study, eligible patients (n=35), who were receiving atorvastatin 40 mg at baseline, were assigned to coadministered ezetimibe and atorvastatin equivalent to ATOZET 10/40 for up to an additional 24 months. Following at least 4 weeks of treatment, the atorvastatin dose could be doubled to a maximum dose of 80 mg. At the end of the 24 months, ATOZET (10/40 and 10/80 pooled) produced a reduction of LDL-C that was consistent with that seen in the 12-week study.
The European Medicines Agency has waived the obligation to submit the results of studies with ATOZET in all subsets of the paediatric population in the treatments of hypercholesterolaemia and mixed hyperlipidaemia (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
ATOZET
ATOZET has been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets.
Absorption
ATOZET
The effects of a high-fat meal on the pharmacokinetics of ezetimibe and atorvastatin when administered as ATOZET tablets are comparable to those reported for the individual tablets.
Ezetimibe
After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.
Concomitant food administration (high-fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as 10-mg tablets.
Atorvastatin
Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95% to 99% bioavailable compared to the oral solution. The absolute bioavailability of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Distribution
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are bound 99.7% and 88 to 92% to human plasma proteins, respectively.
Atorvastatin
Mean volume of distribution of atorvasta |
