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5.2 Phaemacokinetic Properties
Pharmacokinetics and Metabolism
Absorption
In studies with amlodipine/atorvastatin: Following oral
administration of amlodipine/atorvastatin two distinct
peak plasma concentrations were observed. The first,
within 1 to 2 hours of administration, is attributable to
atorvastatin; the second, between 6 and 12 hours
after dosing is attributable to amlodipine. The rate and
extent of absorption (bioavailability) of amlodipine and
atorvastatin from amlodipine/atorvastatin are not
significantly different from the bioavailability of
amlodipine and atorvastatin from co-administration of
amlodipine and atorvastatin tablets as assessed by
Cmax: 101 % (90% CI:98, 104) and AUC: 100% (90%
Cl:97, 103) for the amlodipine component and Cmax:
94% (90% Cl:85, 104) and AUC: 105% (90% Cl:99,
111) for the atorvastatin component, respectively.
The bioavailability of the amlodipine component of
amlodipine/atorvastatin was not affected under the fed
state as assessed by Cmax: 105% (90% CI:99, 111)
and AUC: 101 % (90% Cl:97, 105) relative to the
fasted state. Although food decreases the rate and
extent of absorption of atorvastatin from
amiodipine/atorvastatin by approximately 32% and
11%, respectively, as assessed by Cmax: 68% (90% CI:60, 79) and AUC: 89% (90% CI:83, 95), similar
reductions in plasma concentrations in the fed state
have been seen with atorvastatin taken as
monotherapy without reduction in LDL-C effect
(see below).
In studies with amlodipine: After oral administration of
therapeutic doses, amlodipine is well absorbed with
peak blood levels between 6-12 hours post-dose.
Absolute bioavailability has been estimated to be
between 64 and 80%. The volume of distribution is
approximately 21 l/kg.
In vitro studies have shown that approximately 97.5%
of circulating amlodipine is bound to plasma proteins.
Absorption of amlodipine is unaffected by
consumption of food.
In studies with atorvastatin: Atorvastatin is rapidly
absorbed after oral administration; maximum plasma
concentrations occur within one to two hours. Extent
of absorption and plasma atorvastatin concentrations
increase in proportion to atorvastatin dose.
Atorvastatin tablets are 95% to 99% bioavailable
compared with solutions. The absolute bioavailability
of atorvastatin is approximately 14% 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.
Although food decreases the rate and extent of drug
absorption by approximately 25% and 9%
respectively, as assessed by Cmax and AUC, LDL-C
reduction is similar whether atorvastatin is given with
or without food. Plasma atorvastatin concentrations
are lower (approximately 30% for Cmax and AUC)
following evening drug administration compared with
morning. However, LDL-C reduction is the same
regardless of the time of day of drug administration
(see section 4.2 Posology and Method of
Administration).
Distribution
In studies with amlodipine:
Ex vivo studies have shown
that approximately 93% of the circulating amlodipine
drug is bound to plasma proteins in hypertensive
patients. Steady-state plasma levels of amlodipine
are reached after 7 to 8 days of consecutive daily
dosing.
In studies with atorvastatin: Mean volume of
distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥
98% bound to plasma proteins. A red
blood cell /plasma ratio of approximately 0.25
indicates poor drug penetration into red blood cells.
Metabolism and Excretion
In studies with amlodipine: The terminal plasma
elimination half life is about 35-50 hours and is
consistent with once daily dosing. Steady-state
plasma levels are reached after 7-8 days of
consecutive dosing. Amlodipine is extensively
metabolized by the liver to inactive metabolites with
10% of the parent compound and 60% of metabolites
excreted in the urine.
In studies with atorvastatin: Atorvastatin is extensively
metabolized to ortho- and para-hydroxylated
derivatives and various beta-oxidation products.
In vitro inhibition of HMG-CoA reductase by ortho-
and para-hydroxylated metabolites is equivalent to
that of atorvastatin. Approximately 70% of circulating
inhibitory activity for HMG-CoA reductase is attributed
to active metabolites. In vitro studies suggest the
importance of atorvastatin metabolism by hepatic
cytochrome P450 3A4, consistent with increased
plasma concentrations of atorvastatin in humans
following co-administration with erythromycin, a
known inhibitor of this isozyme. In vitro studies also
indicate that atorvastatin is a weak inhibitor of
cytochrome P450 3A4. Atorvastatin co-administration
did not produce a clinically significant effect in plasma
concentrations of terfenadine, a compound
predominantly metabolized by cytochrome P450 3A4;
therefore, it is unlikely that atorvastatin will
significantly alter the pharmacokinetics of other
cytochrome P450 3A4 substrates (see section 4.5
Interaction with Other Medicaments and Other
Forms of Interaction). In animals, the ortho-hydroxy
metabolite undergoes further glucuronidation.
Atorvastatin and its metabolites are eliminated
primarily in bile following hepatic and/or extrahepatic
metabolism; however, the drug does not appear to
undergo enterohepatic recirculation. Mean plasma
elimination half-life of atorvastatin in humans is
approximately 14 hours, but the half-life of inhibitory
activity for HMG CoA reductase is 20 to 30 hour ; due
to the contribution of active metabolites. Less than 2%
of a dose of atorvastatin is recovered in urine following
oral administration.
Special Populations
Hepatic Insufficiency
In studies with amlodipine: Elderly patients and
patients with hepatic insufficiency have decreased
clearance of amlodipin with a resulting increase in
AUC of approximately 40-60%, and a lower initial
dose may be required.
In studies with atorvastatin: Plasma concentrations of atorvastatin are markedly increased (approximately
to fold in Cmax and ft fold in AUC) in patients with
chronic alcoholic liver disease (Childs-Pugh B) (see
section 4.3 Contraindications).
Renal Insufficiency (see section 4.2 Posology and
Method of Administration)
In studies with amlodipine: Changes in amlodipine
plasma concentrations are not correlated with degree
of renal impairment. Amlodipine is not dialyzable.
In studies with atorvastatin: Renal disease has no
influence on the plasma concentrations or lipid effects
of atorvastatin. Thus, dose adjustment in patients with
renal dysfunction is not necessary.
Hemodialysis
While studies have not been conducted in patients
with end stage renal disease, hemodialysis is not
expected to significantly enhance clearance of
atorvastatin and/or amlodipine since both drugs are
extensively bound to plasma proteins.
Heart Failure
In studies with amlodipine: In patients with moderate
to severe heart failure, the increase in AUC for
amlodipine was similar to that seen in the elderly and
in patients with hepatic insufficiency.
Gender
In studies with atorvastatin: Plasma concentrations
of atorvastatin in women differ (approximately 20%
higher for Cmax and 10% lower for AUC) from those
n men. However, there were no clinically significant
differences in lipid effects between men and women.
Elderly
In studies with amlodipine: The time to reach peak
plasma concentrations of amlodipine is similar in
elderly and younger subjects. Amlodipine clearance
tends to be decreased with resulting increases in AUC
and elimination half-life in elderly patients. Increases
in AUC and elimination half life in patients with
congestive heart failure were as expected for the
patient age group studied. Amlodipine, used at
similar doses in elderly or younger patients, is equally
well tolerated.
In studies with atorvastatin: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax
and 30% for AUC) in healthy, elderly subjects (aged
≥
65 years) than in young adults. The ACCESS study
specifically evaluated elderly patients with respect to
reaching their NCEP treatment goals. The study
included 1087 patients under 65 years of age, 815
patients over 65 years of age, and 185 patients over
75 years of age. No differences in safety, efficacy or
lipid treatment goal attainment were observed
between elderly patients and the overall population.
5.3 Preclinical Safety Data
Carcinogenesis
In studies with amlodipine: Rats and mice treated
with amlodipine in the diet for two years, at
concentrations calculated to provide daily dosage
levels of 0.5,1.25, and 2.5mg/kg/day showed no
evidence of carcinogenicity. The highest dose (for
mice, similar to, and for rats twice* the maximum
recommended clinical dose of 10 mg on a mg/m2
basis) was close to the maximum tolerated dose for
mice but not for rats.
In studies with atorvastatin: Atorvastatin was not
carcinogenic in rats. The maximum dose used was
63 fold higher than the highest human dose
(80mg/day) on a mg/kg body weight basis and 8- to
16 fold higher based on AUC(0-24) values. In a
2-year study in mice, incidences of hepatocellular
adenomas in males and hepatocellular carcinomas
in females were increased at the maximum dose
used, which was 250-fold higher than the highest
human dose on a mg/kg body weight basis.
Systemic exposure was 6- to 11-fold higher based
on AUC (0-24).
All other chemically similar drugs in this class have
induced tumors in both mice and rats at multiples of
12 to 125 times their highest recommended clinical
doses, on a mg kg body weight basis.
Mutagenesis
In studies with amlodipine: Mutagenicity studies
revealed no drug related effects at either the gene or
chromosome levels.
In studies with atorvastatin: Atorvastatin did not
demonstrate mutagenic or clastogenic potential in
four in vitro tests with and without metabolic
activation or in one in vivo assay. It was negative in the
Ames test with Salmonella typhimurium and
Escherichia coli, and in the in vitro HGPRT forward
mutation assay in Chinese hamster lung cells.
Atorvastatin did not produce significant increases in
chromosomal aberrations in the in vitro Chinese
hamster lung cell assay and was negative in the
in vivo mouse micronucleus test.
Impairment of Fertility
In studies with amlodipine: There was no effect on the
fertility of rats treated with amlodipine (males for 64
days and females 14 days prior to mating) at
doses up to 10mg/kg/day (8 times* the maximum
recommended human dose of 10mg on a mg/m2
basis).
*Based on patient weight of 50 kg.
In studies with atorvastatin: No adverse effects on
fertility or reproduction were observed in male rats
given doses of atorvastatin up to 175 mg/kg/day or in
female rats given doses up to 225 mg/kg/day. These
doses are 100 to 140 times the maximum
recommended human dose on a mg/kg basis. Atorvastatin caused no adverse effects on sperm or
semen parameters, or on reproductive organ
histopathology in dogs given doses of 10, 40, or 120
mg/kg for two years.
6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Tablet Core: Calcium Carbonate, Croscarmellose
Sodium, Microcrystalline Cellulose, Pregelatinised
Starch, Polysorbate 80, Hydroxypropyl Cellulose,
Silicone Dioxide, Colloidal, Magnesium Stearate
Film-Coat: Opadry II White 85F28751, or Opadry II
Blue 85F10919
6.2 Incompatibilities
None
6.3 Shelf Life
36 months
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