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4.5 Interaction with Other Medicaments and
Other Forms of Interaction
Data from a drug drug interaction study involving
10mg of amlodipine and 80mg of atorvastatin n
healthy subjects indicate that the pharmacokinetics
of amlodipine are not altered when the drugs are
co-administered. The effect of amlodipine on the
pharmacokinetics of atorvastatin showed no effect
on the Cmax: 91 % (90% confidence interval: 80 to
103%), but the AUC of atorvastatin increased by
18% (90% confidence interval: 109 to 127%) in the
presence of amlodipine.
No drug interaction studies have been conducted
with amlodipine/atorvastatin and other drugs,
although studies have been conducted using the
individual amlodipine and atorvastatin components,
as described below:
In Studies with Amlodipine
Amlodipirie has been safely administered with
thiazide diuretics, alpha blockers, beta blockers,
angiotensin-converting enzyme inhibitors,
long acting nitrates, sublingual nitroglycerine,
non-steroidal anti-inflammatory drugs, antibiotics,
and oral hypoglycemic drugs.
In vitro data from studies with human plasma
indicate that amlodipine has no effect on protein
binding of the drugs tested (digoxin, phenytoin,
warfarin, or indomethacin
In the following studies listed below, there were no
significant changes in the pharmacokinetics of
either amlodipine or another drug within the study,
when co-administered.
Special Studies: Effect of other agents on amlodipine
Cimetidine: Co -administration of amlodipine with
cimetidine did riot alter the pharmacokinetics of
amlodipine
Grapefruit juice: Co-administration of 240mL of
grapefruit juice with a single oral dose of amlodipine
10 mg in 20 healthy volunteers had no significant
effect on the amlodipine.
Aluminum /magnesium (antacid):
Co-administration of an aluminum/ magnesium
antacid with a single dose of amlodipine had no
significant effect on the pharmacokinetics of
amlodipine.
Sildenafil: A single 100mg dose of sildenafil in
subjects with essential hypertension had no effect
on the pharmacokinetic parameters of amlodipine.
When amlodipine and sildenafil were used in
combination, each agent independently exerted its
own blood pressure lowering effect.
Special Studies: Effect of amlodipine on other
agents
Digoxin: Co-administration of amlodipine with
digoxin did riot change serum digoxin levels or
dig cart renal clearance in normal volunteers.
Ethanol (alcohol): Single and multiple 10mg doses
of amlodipine had no significant effect on the
pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with
warfarin did not change the warfarin prothrombin
response time.
Cyclosporin: Pharmacokinetic studies with cyclosporin have demonstrated that amlodipine
does nut significantly alter the pharmacokinetics of
cyclosporin.
Drug/Laboratory Test Interactions: None known.
In Studies with Atorvastatin
The risk of myopathy during treatment with
HMG-CoA reductase inhibitor drugs is increased
with concurrent administration of cyclosporine,
fibric acid derivatives, erythromycin, azole
antifungals, or niacin (see section 4.4 Special
Warnings and Special Precautions for Use:
Skeletal Muscle Effects).
Antacids
Co-administration of atorvastatin with an
oral antacid suspension containing magnesium and
aluminum hydroxides, decreased atorvastatin
plasma concentrations approximately 35%
however, LDL-C reduction was not altered.
Antipyrine: Because atorvastatin does not affect
the pharmacokinetics of antipyrine, interactions with
other drugs metabolized via the same cytochrome
isozymes are tint expected.
Colestipol: Plasma concentrations of atorvastatin
were lower (approximately 25%) when colestipol
was administered with atorvastatin. However, lipid
effects were greater when atorvastatin and
colestipol were co-administered than when either
drug was given alone.
Digoxin: When multiple doses of digoxin and
10mg atorvastatin were co-administered,
steady state plasma digoxin concentrations were
unaffected However, digoxin concentrations
increased approximately 20% following
administration of digoxin with 80mg atorvastatin
daily. Patients taking digoxin should be monitored
appropriately
Erythromycin/Clarithromycin: Co-administration
of atorvastatin and erythromycin (500 mg four
times daily), or clarithromycin (500 mg twice daily)
known inhibitors of cytochrome P450 3A4, was
associated with higher plasma concentrations of atorvastatin (see section 4.4 Special Warnings
and Special Precautions for Use: Skeletal
Muscle Effects).
Azithromycin: Co-administration of atorvastatin
(10mg once daily) and azithromycin (500mg once daily)
did not alter the plasma concentrations of
atorvastatin.
Terfenadine: Co-administration of atorvastatin and
terfenadine did not produce a clinically significant
effect on the pharmacokinetics of terfenadine.
Oral Contraceptives: Co administration with an oral
contraceptive containing norethindrone and ethinyl
estradiol increased AUC values for norethindrone and
ethinyl estradiol by approximately 30% and 20%
These increases should be considered when selecting
an oral contraceptive for a woman taking atorvastatin.
Warfarie: An atorvastatin interaction study with
warfarin was conducted, and no clinically significant
interactions were observed.
Cimetidine: An atorvastatin interaction study with
cimetidine was conducted, arid no clinically significant
interactions were observed.
Protease inhibitors: Co-administration of atorvastatin and protease inhibitors, known to inhibit
cytochrome P450 3A4, was associated with increased
plasma concentrations of atorvastatin.
Other Concomitant Therapy: In clinical studies, atorvastatin was used concomitantly with
antihypertensive agents and estrogen replacement
therapy without evidence of clinically significant
adverse interactions. Interaction studies with specific
agents have not been conducted.
4.6 Pregnancy and Lactation
Amlodipine/atorvastatin is contraindicated n
pregnancy due to the atorvastatin component. Women
of childbearing potential should use adequate
contraceptive measures.
Amlodipine/atorvastatin should be administered to
women of childbearing age only when such patients
are highly unlikely to conceive and have been
informed of the potential hazards to the fetus.
Amlodipine/atorvastatin is contraindicated while
breast -feeding due to the atorvastatin component. It
is riot known whether atorvastatin is excreted in
human milk. Because of the potential for adverse
reactions in nursing infants, women taking
amlodipine/atorvastatin should not breast toed.
Safety of amlodipine in human pregnancy or lactation
has not been established. Amlodipine does not
demonstrate toxicity in animal reproductive studies
other than to delay parturition and prolong labor in rats
at a dose level fifty times the maximum recommended
dose in humans.
4.7 Effects en Ability to Drive and Use Machines
Based on the available information on amlodipine and
atorvastatin, this medication is unlikely to impair a
patient's ability to drive or use machinery.
4.8 Undesirable Effects
Combination therapy with amlodipine and atorvastatin
has been evaluated for safety in 1092 patients in
double blind, placebo controlled studies treated for
concomitant hypertension and dyslipidemia. In clinical
trials, no adverse events peculiar to combination
therapy with amlodipine and atorvastatin have been
observed. Adverse events have been limited to those
that were reported previously with amlodipine and/or
atorvastatin (please see respective adverse event
experiences below).
In general, combination therapy with amlodipine and
atorvastatin was well tolerated. For the most part,
adverse events have been mild or moderate in
severity. In controlled clinical trials, discontinuation of
therapy due to adverse events or laboratory
abnormalities was required in only 5.1% of patients
treated with both amlodipine and atorvastatin
compared to 4.0% of patients given placebo.
The following information is based on clinical trials
and post marketing experience with amlodipine and
atorvastatin.
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