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(amlodipine besylate and atorvastatin calcium) Tablets
CADUET (amlodipine besylate and atorvastatin calcium)
tablets combine the calcium channel blocker amlodipine besylate with the HMG
CoA-reductase inhibitor atorvastatin calcium.
Amlodipine besylate is chemically described as
monobenzenesulphonate. Its empirical formula is C20H25ClN2O5•C6H6O3S.
Atorvastatin calcium is chemically described as [R-(R*,
acid, calcium salt (2:1) trihydrate. Its empirical formula is (C33H34FN2O5)2Ca•3H2O.
The structural formulae for amlodipine besylate and
atorvastatin calcium are shown below.
CADUET contains amlodipine besylate, a white to off-white
crystalline powder, and atorvastatin calcium, also a white to off-white
crystalline powder. Amlodipine besylate has a molecular weight of 567.1 and
atorvastatin calcium has a molecular weight of 1209.42. Amlodipine besylate is
slightly soluble in water and sparingly soluble in ethanol. Atorvastatin
calcium is insoluble in aqueous solutions of pH 4 and below. Atorvastatin
calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer,
and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.
Each film-coated tablet also contains calcium carbonate,
croscarmellose sodium, microcrystalline cellulose, pregelatinized starch,
polysorbate 80, hydroxypropyl cellulose, purified water, colloidal silicon
dioxide (anhydrous), magnesium stearate, Opadry® II White 85F28751 (polyvinyl
alcohol, titanium dioxide, PEG 3000, and talc) or Opadry® II Blue 85F10919
(polyvinyl alcohol, titanium dioxide, PEG 3000, talc, and FD&C blue #2).
CADUET (amlodipine and atorvastatin) is indicated in
patients for whom treatment with both amlodipine and atorvastatin is
Amlodipine is indicated for the treatment of
hypertension, to lower blood pressure. Lowering blood pressure reduces the risk
of fatal and nonfatal cardiovascular events, primarily strokes and myocardial
infarctions. These benefits have been seen in controlled trials of
antihypertensive drugs from a wide variety of pharmacologic classes including
Control of high blood pressure should be part of
comprehensive cardiovascular risk management, including, as appropriate, lipid
control, diabetes management, antithrombotic therapy, smoking cessation,
exercise, and limited sodium intake. Many patients will require more than one
drug to achieve blood pressure goals. For specific advice on goals and
management, see published guidelines, such as those of the National High Blood
Pressure Education Program’s Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of
pharmacologic classes and with different mechanisms of action, have been shown
in randomized controlled trials to reduce cardiovascular morbidity and
mortality, and it can be concluded that it is blood pressure reduction, and not
some other pharmacologic property of the drugs, that is largely responsible for
those benefits. The largest and most consistent cardiovascular outcome benefit
has been a reduction in the risk of stroke, but reductions in myocardial
infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased
cardiovascular risk, and the absolute risk increase per mmHg is greater at
higher blood pressures, so that even modest reductions of severe hypertension
can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the
absolute benefit is greater in patients who are at higher risk independent of
their hypertension (for example, patients with diabetes or hyperlipidemia), and
such patients would be expected to benefit from more aggressive treatment to a
lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure
effects (as monotherapy) in black patients, and many antihypertensive drugs
have additional approved indications and effects (e.g., on angina, heart
failure, or diabetic kidney disease). These considerations may guide selection
Amlodipine may be used alone or in combination with other
Coronary Artery Disease (CAD)
Chronic Stable Angina
Amlodipine is indicated for the symptomatic treatment of
chronic stable angina. Amlodipine may be used alone or in combination with
other antianginal agents.
Vasospastic Angina (Prinzmetal’s Or Variant Angina)
Amlodipine is indicated for the treatment of confirmed or
suspected vasospastic angina. Amlodipine may be used as monotherapy or in
combination with other antianginal agents.
Angiographically Documented CAD
In patients with recently documented CAD by angiography
and without heart failure or an ejection fraction < 40%, amlodipine is
indicated to reduce the risk of hospitalization for angina and to reduce the
risk of a coronary revascularization procedure.
Therapy with HMG CoA-reductase inhibitors (lipid-altering
agents) should be only one component of multiple risk factor intervention in
individuals at significantly increased risk for atherosclerotic vascular
disease from hypercholesterolemia. Drug therapy is recommended as an adjunct to
diet when the response to a diet restricted in saturated fat and cholesterol
and other nonpharmacologic measures alone has been inadequate. In patients with
coronary heart disease (CHD) or multiple risk factors for CHD, atorvastatin can
be started simultaneously with diet restriction.
Prevention Of Cardiovascular Disease (CVD)
In adult patients without clinically evident coronary
heart disease, but with multiple risk factors for coronary heart disease such
as age, smoking, hypertension, low HDL-cholesterol (HDL-C), or a family history
of early coronary heart disease, atorvastatin is indicated to:
Reduce the risk of myocardial infarction (MI)
Reduce the risk of stroke
Reduce the risk for revascularization procedures and
In patients with type 2 diabetes, and without clinically
evident coronary heart disease, but with multiple risk factors for coronary heart
disease such as retinopathy, albuminuria, smoking, or hypertension,
atorvastatin is indicated to:
Reduce the risk of myocardial infarction
Reduce the risk of stroke
In patients with clinically evident coronary heart
disease, atorvastatin is indicated to:
Reduce the risk of non-fatal myocardial infarction
Reduce the risk of fatal and non-fatal stroke
Reduce the risk for revascularization procedures
Reduce the risk of hospitalization for congestive heart
Reduce the risk of angina
Atorvastatin is indicated:
As an adjunct to diet to reduce elevated total
cholesterol (total-C) , LDL-cholesterol (LDL-C), apolipoprotein B (apo B), and
triglycerides (TG) levels and to increase HDL-C in patients with primary
hypercholesterolemia (heterozygous familial and nonfamilial) and mixed
dyslipidemia (Fredrickson Types IIa and IIb)
As an adjunct to diet for the treatment of patients with
elevated serum TG levels (Fredrickson Type IV);
For the treatment of patients with primary
dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to
To reduce total-C and LDL-C in patients with homozygous
familial hypercholesterolemia as an adjunct to other lipid-lowering treatments
(e.g., LDL apheresis) or if such treatments are unavailable
As an adjunct to diet to reduce total-C, LDL-C, and apo B
levels in boys and postmenarchal girls, 10 to 17 years of age, with
heterozygous familial hypercholesterolemia if after an adequate trial of diet
therapy the following findings are present:
LDL-C remains ≥ 190 mg/dL or
LDL-C remains ≥ 160 mg/dL and:
there is a positive family history of premature CVD or
two or more other CVD risk factors are present in the
Limitations Of Use
Atorvastatin has not been studied in conditions where the
major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I
Salt and sodium are the same.See Answer
DOSAGE AND ADMINISTRATION
Dosage of CADUET must be individualized on the basis of
both effectiveness and tolerance for each individual component in the treatment
of hypertension/angina and hyperlipidemia. Select doses of amlodipine and
CADUET may be substituted for its individually titrated
components. Patients may be given the equivalent dose of CADUET or a dose of
CADUET with increased amounts of amlodipine, atorvastatin, or both for
additional antianginal effects, blood pressure lowering, or lipid-lowering
CADUET may be used to provide additional therapy for
patients already on one of its components. CADUET may be used to initiate
treatment in patients with hyperlipidemia and either hypertension or angina.
The usual initial antihypertensive oral dose of
amlodipine is 5 mg once daily, and the maximum dose is 10 mg once daily.
Pediatric (age > 6 years), small adult, fragile, or
elderly patients, or patients with hepatic insufficiency may be started on 2.5
mg once daily and this dose may be used when adding amlodipine to other antihypertensive
Adjust dosage according to blood pressure goals. In
general, wait 7 to 14 days between titration steps. Titration may proceed more
rapidly, however, if clinically warranted, provided the patient is assessed
The recommended dose of amlodipine for chronic stable or
vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and
in patients with hepatic insufficiency. Most patients will require 10 mg for
Coronary Artery Disease
The recommended dose range of amlodipine for patients
with CAD is 5–10 mg once daily. In clinical studies, the majority of patients
required 10 mg [see Clinical Studies].
The effective antihypertensive oral dose of amlodipine in
pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in
excess of 5 mg daily have not been studied in pediatric patients [see CLINICAL
PHARMACOLOGY, Clinical Studies].
Hyperlipidemia (Heterozygous Familial And Nonfamilial) And
Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
The recommended starting dose of atorvastatin is 10 or 20
mg once daily. Patients who require a large reduction in LDL-C (more than 45%)
may be started at 40 mg once daily. The dosage range of atorvastatin is 10 to
80 mg once daily. Atorvastatin can be administered as a single dose at any time
of the day, with or without food. The starting dose and maintenance doses of
atorvastatin should be individualized according to patient characteristics such
as goal of therapy and response (see current NCEP Guidelines). After
initiation and/or upon titration of atorvastatin, lipid levels should be
analyzed within 2 to 4 weeks and dosage adjusted accordingly.
Homozygous Familial Hypercholesterolemia
The dosage range of atorvastatin in patients with
homozygous FH is 10 to 80 mg daily. Atorvastatin should be used as an adjunct
to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or
if such treatments are unavailable.
Concomitant Lipid-Lowering Therapy
Atorvastatin may be used with bile acid resins. Monitor
for signs of myopathy in patients receiving the combination of HMG-CoA
reductase inhibitors (statins) and fibrates [see WARNINGS AND PRECAUTIONS,
Patients With Renal Impairment
Renal disease does not affect the plasma concentrations
nor LDL-C reduction of atorvastatin; thus, dosage adjustment in patients with
renal dysfunction is not necessary [see WARNINGS AND PRECAUTIONS, CLINICAL
Use With Cyclosporine, Clarithromycin, Itraconazole, Or Certain
In patients taking cyclosporine or the HIV protease
inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor
(telaprevir), avoid therapy with atorvastatin. In patients with HIV taking
lopinavir plus ritonavir, use the lowest necessary dose of atorvastatin. In
patients taking clarithromycin, itraconazole, or in patients with HIV taking a
combination of saquinavir plus ritonavir, darunavir plus ritonavir,
fosamprenavir, or fosamprenavir plus ritonavir, limit therapy with atorvastatin
to 20 mg, and make appropriate clinical assessment to ensure that the lowest
dose necessary of atorvastatin is employed. In patients taking the HIV protease
inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, limit
therapy with atorvastatin to 40 mg, and make appropriate clinical assessment to
ensure that the lowest dose necessary of atorvastatin is employed [see WARNINGS
AND PRECAUTIONS, DRUG INTERACTIONS].
Heterozygous Familial Hypercholesterolemia In Pediatric
Patients (10–17 years of age)
The recommended starting dose of atorvastatin is 10
mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg
have not been studied in this patient population). Doses should be
individualized according to the recommended goal of therapy [see current
NCEP Pediatric Panel Guidelines 1, REFERENCES, CLINICAL
PHARMACOLOGY, and INDICATIONS AND USAGE]. Adjustments should be made
at intervals of 4 weeks or more.
Dosage Forms And Strengths
CADUET tablets are formulated for oral administration in
the following strength combinations:
Combinations of atorvastatin with 2.5 mg and 5 mg
amlodipine are film-coated white, and combinations of atorvastatin with 10 mg
amlodipine are film-coated blue.
Storage And Handling
CADUET® tablets contain amlodipine besylate and
atorvastatin calcium equivalent to amlodipine and atorvastatin in the dose
strengths described below.
CADUET tablets are differentiated by tablet color/size
and are engraved with a unique number on one side. Combinations of atorvastatin
with 2.5 mg amlodipine are round and film-coated white, combinations of
atorvastatin with 5 mg amlodipine are oval and film-coated white, and
combinations of atorvastatin with 10 mg amlodipine are oval and are film-coated
blue. CADUET tablets are supplied for oral administration in the following
strengths and package configurations:
Table 14: CADUET Packaging Configurations
Tablet Strength mg (amlodipine / atorvastatin)
Engraving Side 1 / Side 2
Bottle of 30
CDT 251 / Blank
Bottle of 30
CDT 252 / Blank
Bottle of 30
CDT 254 / Blank
Bottle of 30
CDT 051 / Pfizer
Bottle of 30
CDT 052 / Pfizer
Bottle of 30
CDT 054 / Pfizer
Bottle of 30
CDT 058 / Pfizer
Bottle of 30
CDT 101 / Pfizer
Bottle of 30
CDT 102 / Pfizer
Bottle of 30
CDT 104 / Pfizer
Bottle of 30
CDT 108 / Pfizer
Store at 25°C (77°F); excursions permitted to 15-30°C
(59-86°F) [see USP Controlled Room Temperature].
1 National Cholesterol Education Program (NCEP):
Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in
Children and Adolescents, Pediatrics. 89(3):495-501. 1992.
Distributed by: Pfizer Labs, Division of Pfizer Inc., NY,
NY 10017. Revised: May 2018
The following serious adverse reactions are discussed in
greater detail in other sections of the label:
Rhabdomyolysis and myopathy [see WARNINGS AND
Liver enzyme abnormalities [see WARNINGS AND
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
CADUET (amlodipine besylate/atorvastatin calcium) has
been evaluated for safety in 1,092 patients in double-blind placebo-controlled
studies treated for co-morbid hypertension and dyslipidemia. In general,
treatment with CADUET was well tolerated. For the most part, adverse reactions
have been mild or moderate in severity. In clinical trials with CADUET, no
adverse reactions peculiar to this combination have been observed. Adverse
reactions are similar in terms of nature, severity, and frequency to those
reported previously with amlodipine and atorvastatin. The following information
is based on the clinical experience with amlodipine and atorvastatin.
Amlodipine has been evaluated for safety in more than
11,000 patients in U.S. and foreign clinical trials. In general, treatment with
amlodipine was well tolerated at doses up to 10 mg daily. Most adverse
reactions reported during therapy with amlodipine were of mild or moderate
severity. In controlled clinical trials directly comparing amlodipine (N=1,730)
at doses up to 10 mg to placebo (N=1,250), discontinuation of amlodipine
because of adverse reactions was required in only about 1.5% of patients and
was not significantly different from placebo (about 1%). The most commonly
reported side effects more frequent than placebo are dizziness and edema. The
incidence (%) of side effects that occurred in a dose-related manner are as
Other adverse reactions that were not clearly dose
related but were reported at an incidence greater than 1.0% in
placebo-controlled clinical trials include the following:
Edema, flushing, palpitations, and somnolence appear to
be more common in women than in men.
The following events occurred in < 1% but > 0.1% of
patients treated with amlodipine in controlled clinical trials or under conditions
of open trials or marketing experience where a causal relationship is
uncertain; they are listed to alert the physician to a possible relationship:
Amlodipine therapy has not been associated with
clinically significant changes in routine laboratory tests. No clinically
relevant changes were noted in serum potassium, serum glucose, total
triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea
nitrogen, or creatinine.
In the atorvastatin placebo-controlled clinical trial
database of 16,066 patients (8,755 atorvastatin vs. 7,311 placebo; age range
10- 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a
median treatment duration of 53 weeks, 9.7% of patients on atorvastatin and
9.5% of the patients on placebo discontinued because of adverse reactions
regardless of causality. The five most common adverse reactions in patients
treated with atorvastatin that led to treatment discontinuation and occurred at
a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea
(0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase
The most commonly reported adverse reactions (incidence
≥ 2% and greater than placebo) regardless of causality, in patients
treated with atorvastatin in placebo-controlled trials (n=8,755) were:
nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity
(6.0%), and urinary tract infection (5.7%).
Table 3 summarizes the frequency of clinical adverse
reactions, regardless of causality, reported in ≥ 2% and at a rate
greater than placebo in patients treated with atorvastatin (n=8,755), from
seventeen placebo-controlled trials.
Table 3: Clinical Adverse Reactions Occurring in ≥2%
in Patients Treated with Any Dose of Atorvastatin and at an Incidence Greater
than Placebo Regardless of Causality (% of Patients)
Pain in extremity
Urinary tract infection
* Adverse Reaction ≥2% in any dose greater than
Other adverse reactions reported in placebo-controlled
Body as a whole: malaise, pyrexia; Digestive
system: abdominal discomfort, eructation, flatulence, hepatitis,
cholestasis; Musculoskeletal system: musculoskeletal pain, muscle
fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases
increase, liver function test abnormal, blood alkaline phosphatase increase,
creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare;
Respiratory system: epistaxis; Skin and appendages: urticaria; Special
senses: vision blurred, tinnitus; Urogenital system: white blood
cells urine positive.
Treating to New Targets Study (TNT)
In TNT [see Clinical Studies] involving 10,001
subjects (age range 29-78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0%
Asians, 2.0% other) with clinically evident CHD treated with atorvastatin 10 mg
daily (n=5,006) or atorvastatin 80 mg daily (n=4,995), serious adverse
reactions and discontinuations because of adverse reactions increased with
dose. Persistent transaminase elevations (≥ 3 x ULN twice within 4-10
days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%)
individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were
low overall, but were higher in the high-dose atorvastatin treatment group (13,
0.3%) compared to the low-dose atorvastatin group (6, 0.1%).
Stroke Prevention By Aggressive Reduction In Cholesterol
In SPARCL involving 4,731 subjects (age range 21-92
years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other)
without clinically evident CHD but with a stroke or transient ischemic attack
(TIA) within the previous 6 months treated with atorvastatin 80 mg (n=2,365) or
placebo (n=2,366) for a median follow-up of 4.9 years, there was a higher
incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice
within 4-10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%).
Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin
group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse
reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects
(3.8%) in the placebo group [see WARNINGS AND PRECAUTIONS].
In a post-hoc analysis, atorvastatin 80 mg reduced the
incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased
the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared
to placebo. The incidence of fatal hemorrhagic stroke was similar between
groups (17 atorvastatin vs. 18 placebo). The incidence of non-fatal hemorrhagic
strokes was significantly greater in the atorvastatin group (38 non-fatal
hemorrhagic strokes) as compared to the placebo group (16 nonfatal hemorrhagic
strokes). Subjects who entered the study with a hemorrhagic stroke appeared to
be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin vs. 2 (4%)
There were no significant differences between the
treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin 80
mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects
who experienced cardiovascular death were numerically smaller in the
atorvastatin 80 mg group (3.3%) than in the placebo group (4.1%). The
proportions of subjects who experienced non-cardiovascular death were
numerically larger in the atorvastatin 80 mg group (5.0%) than in the placebo
In a 26-week controlled study in boys and postmenarchal
girls (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8%
other), the safety and tolerability profile of atorvastatin 10 to 20 mg daily
was generally similar to that of placebo [see Clinical Studies and Use
In Specific Populations].
The following adverse reactions have been identified
during post-approval of amlodipine and atorvastatin. Because these reactions
are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
The following postmarketing event has been reported
infrequently where a causal relationship is uncertain: gynecomastia. In
postmarketing experience, jaundice and hepatic enzyme elevations (mostly
consistent with cholestasis or hepatitis), in some cases severe enough to
require hospitalization, have been reported in association with use of
Postmarketing reporting has also revealed a possible
association between extrapyramidal disorder and amlodipine.
Amlodipine has been used safely in patients with chronic
obstructive pulmonary disease, well-compensated congestive heart failure,
coronary artery disease, peripheral vascular disease, diabetes mellitus, and
abnormal lipid profiles.
Adverse reactions associated with atorvastatin therapy
reported since market introduction that are not listed above, regardless of
causality assessment, include the following: anaphylaxis, angioneurotic edema,
bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and
toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture,
fatal and non-fatal hepatic failure, dizziness, depression, peripheral
neuropathy, pancreatitis and interstitial lung disease.
There have been rare reports of immune-mediated
necrotizing myopathy associated with statin use [see WARNINGS AND
There have been rare postmarketing reports of cognitive
impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment,
confusion) associated with statin use. These cognitive issues have been
reported for all statins. The reports are generally nonserious, and reversible
upon statin discontinuation, with variable times to symptom onset (1 day to
years) and symptom resolution (median of 3 weeks).
2 These events occurred in less than 1% in
placebo-controlled trials, but the incidence of these side effects was between
1% and 2% in all multiple dose studies.
How to Lower Blood Pressure: Exercise Tips See Slideshow
Data from a drug-drug interaction study involving 10 mg
of amlodipine and 80 mg of atorvastatin in 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, which is not clinically meaningful.
No drug interaction studies have been conducted with
CADUET and other drugs, although studies have been conducted in the individual
amlodipine and atorvastatin components, as described below:
Impact Of Other Drugs On Amlodipine
Co-administration with CYP3A inhibitors (moderate and
strong) results in increased systemic exposure to amlodipine and may require
dose reduction. Monitor for symptoms of hypotension and edema when amlodipine
is co-administered with CYP3A inhibitors to determine the need for dose
adjustment [see CLINICAL PHARMACOLOGY].
No information is available on the quantitative effects
of CYP3A inducers on amlodipine. Blood pressure should be closely monitored
when amlodipine is co-administered with CYP3A inducers.
Monitor for hypotension when sildenafil is
co-administered with amlodipine [see CLINICAL PHARMACOLOGY].
Impact Of Amlodipine On Other Drugs
Amlodipine may increase the systemic exposure of
cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough
blood levels of cyclosporine and tacrolimus is recommended and adjust the dose
when appropriate [see CLINICAL PHARMACOLOGY].
The risk of myopathy during treatment with statins is
increased with concurrent administration of fibric acid derivatives,
lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors
(e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see WARNINGS
AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Strong Inhibitors Of CYP3A4
Atorvastatin is metabolized by CYP3A4. Concomitant
administration of atorvastatin with strong inhibitors of CYP3A4 can lead to
increases in plasma concentrations of atorvastatin. The extent of interaction
and potentiation of effects depend on the variability of effect on CYP3A4.
Atorvastatin AUC was significantly increased with
concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg
twice daily) compared to that of atorvastatin alone [see CLINICAL
PHARMACOLOGY]. Therefore, in patients taking clarithromycin, avoid
atorvastatin doses >20 mg [see DOSAGE AND ADMINISTRATION and WARNINGS
Combination Of Protease Inhibitors
Atorvastatin AUC was significantly increased with
concomitant administration of atorvastatin with several combinations of HIV
protease inhibitors, as well as with the hepatitis C protease inhibitor
telaprevir, compared to that of atorvastatin alone [see CLINICAL
PHARMACOLOGY]. Therefore, in patients taking the HIV protease inhibitor
tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir,
concomitant use of atorvastatin should be avoided. In patients taking the HIV
protease inhibitor lopinavir plus ritonavir, caution should be used when
prescribing atorvastatin and the lowest dose necessary should be used. In
patients taking the HIV protease inhibitors saquinavir plus ritonavir,
darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the
dose of atorvastatin should not exceed 20 mg [see DOSAGE AND ADMINISTRATION
and WARNINGS AND PRECAUTIONS]. In patients taking the HIV protease
inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose
of atorvastatin should not exceed 40 mg and close clinical monitoring is
Atorvastatin AUC was significantly increased with
concomitant administration of atorvastatin 40 mg and itraconazole 200 mg [see CLINICAL
PHARMACOLOGY]. Therefore, in patients taking itraconazole, avoid
atorvastatin doses >20 mg [see DOSAGE AND ADMINISTRATION and WARNINGS
Contains one or more components that inhibit CYP3A4 and
can increase plasma concentrations of atorvastatin, especially with excessive
grapefruit juice consumption (> 1.2 liters per day).
Atorvastatin and atorvastatin-metabolites are substrates
of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can
increase the bioavailability of atorvastatin. Atorvastatin AUC was
significantly increased with concomitant administration of atorvastatin 10 mg
and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone [see CLINICAL
PHARMACOLOGY]. The co-administration of atorvastatin with cyclosporine
should be avoided [see WARNINGS AND PRECAUTIONS].
Because of an increased risk of myopathy/rhabdomyolysis
when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, avoid
concomitant administration of atorvastatin with gemfibrozil [see WARNINGS
The risk of myopathy during treatment with HMG-CoA
reductase inhibitors is increased with concurrent administration of other
fibrates [see WARNINGS AND PRECAUTIONS].
The risk of skeletal muscle effects may be enhanced when
atorvastatin is used in combination with niacin; consider a reduction in
atorvastatin dosage in this setting [see WARNINGS AND PRECAUTIONS].
Rifampin Or Other Inducers Of CYP3A4
Concomitant administration of atorvastatin with inducers
of CYP3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma
concentrations of atorvastatin. Because of the dual interaction mechanism of
rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended,
as delayed administration of atorvastatin after administration of rifampin has
been associated with a significant reduction in atorvastatin plasma
When multiple doses of atorvastatin and digoxin were
co-administered, steady-state plasma digoxin concentrations increased by
approximately 20%. Monitor digoxin levels.
Co-administration of atorvastatin and an oral
contraceptive increased AUC values for norethindrone and ethinyl estradiol [see
CLINICAL PHARMACOLOGY]. Consider these increases when selecting an oral
contraceptive for a woman taking CADUET.
Atorvastatin had no clinically significant effect on
prothrombin time when administered to patients receiving chronic warfarin
Cases of myopathy, including rhabdomyolysis, have been
reported with atorvastatin co-administered with colchicine.
Warnings & Precautions
Included as part of the PRECAUTIONS section.
Myopathy And Rhabdomyolysis
Rare cases of rhabdomyolysis with acute renal failure
secondary to myoglobinuria have been reported with atorvastatin and with other
drugs in this class. A history of renal impairment may be a risk factor for the
development of rhabdomyolysis. Such patients merit closer monitoring for
skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes
myopathy, defined as muscle aches or muscle weakness in conjunction with
increases in creatine phosphokinase (CPK) values > 10 times upper limit of
normal [ULN]. The concomitant use of higher doses of atorvastatin with certain
drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin,
itraconazole, and HIV protease inhibitors) increases the risk of
There have been rare reports of immune-mediated
necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin
use. IMNM is characterized by: proximal muscle weakness and elevated serum
creatine kinase, which persist despite discontinuation of statin treatment;
muscle biopsy showing necrotizing myopathy without significant inflammation;
improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse
myalgias, muscle tenderness or weakness, or marked elevation of CPK. Patients
should be advised to report promptly unexplained muscle pain, tenderness, or
weakness, particularly if accompanied by malaise or fever or if muscle signs
and symptoms persist after discontinuing CADUET. CADUET therapy should be
discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or
The risk of myopathy during treatment with statins is
increased with concurrent administration of cyclosporine, fibric acid
derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor
telaprevir, combinations of HIV protease inhibitors, including saquinavir plus
ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus
ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole
antifungals. Physicians considering combined therapy with CADUET and fibric
acid derivatives, erythromycin, clarithromycin, a combination of saquinavir
plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir,
fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or
lipid-modifying doses of niacin should carefully weigh the potential benefits
and risks and should carefully monitor patients for any signs or symptoms of
muscle pain, tenderness, or weakness, particularly during the initial months of
therapy and during any periods of upward dosage titration of either drug. Lower
starting and maintenance doses of atorvastatin should be considered when taken
concomitantly with the aforementioned drugs [see DRUG INTERACTIONS].
Periodic creatine phosphokinase (CPK) determinations may be considered in such
situations, but there is no assurance that such monitoring will prevent the
occurrence of severe myopathy.
Prescribing recommendations for interacting agents are
summarized in Table 2 [see DOSAGE AND ADMINISTRATION, DRUG
INTERACTIONS, and CLINICAL PHARMACOLOGY].
Table 2: Atorvastatin Drug Interactions Associated
with Increased Risk of Myopathy/Rhabdomyolysis
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)
HIV protease inhibitor (lopinavir plus ritonavir)
Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)
Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)
Do not exceed 40 mg atorvastatin daily
* Use with caution and with the lowest dose necessary
Cases of myopathy, including rhabdomyolysis, have been
reported with atorvastatin co-administered with colchicine, and caution should
be exercised when prescribing atorvastatin with colchicine [see DRUG
Withhold or discontinue in any patient with an acute,
serious condition suggestive of a myopathy or having a risk factor predisposing
to the development of renal failure secondary to rhabdomyolysis (e.g., severe
acute infection; hypotension; major surgery; trauma; severe metabolic,
endocrine, and electrolyte disorders; and uncontrolled seizures).
Statins, like atorvastatin, and some other lipid-lowering
therapies, have been associated with biochemical abnormalities of liver
function. Persistent elevations (> 3 times the upper limit of normal [ULN]
occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of
patients who received atorvastatin in clinical trials. The incidence of these
abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg,
One patient in clinical trials with atorvastatin
developed jaundice. Increases in liver function tests (LFT) in other patients
were not associated with jaundice or other clinical signs or symptoms. Upon
dose reduction, drug interruption, or discontinuation, transaminase levels
returned to or near pretreatment levels without sequelae. Eighteen of 30
patients with persistent LFT elevations continued treatment with a reduced dose
It is recommended that liver enzyme tests be obtained
prior to initiating therapy with atorvastatin and repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic
failure in patients taking statins, including atorvastatin. If serious liver
injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs
during treatment with CADUET, promptly interrupt therapy. If an alternate
etiology is not found, do not restart CADUET.
Active liver disease or unexplained persistent
transaminase elevations are contraindications to the use of CADUET [see CONTRAINDICATIONS].
Increased Angina And Myocardial Infarction
Worsening angina and acute myocardial infarction can
develop after starting or increasing the dose of amlodipine, particularly in
patients with severe obstructive coronary artery disease.
Symptomatic hypotension is possible with use of
amlodipine, particularly in patients with severe aortic stenosis. Because of
the gradual onset of action, acute hypotension is unlikely.
Increases in HbA1c and fasting serum glucose levels have
been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins interfere with cholesterol synthesis and
theoretically might blunt adrenal and/or gonadal steroid production. Clinical
studies have shown that atorvastatin does not reduce basal plasma cortisol
concentration or impair adrenal reserve. The effects of statins on male
fertility have not been studied in adequate numbers of patients. The effects,
if any, on the pituitary-gonadal axis in premenopausal women are unknown. Avoid
a statin with drugs that may decrease the levels or activity of endogenous
steroid hormones such as ketoconazole, spironolactone, and cimetidine.
Brain hemorrhage was seen in a female dog treated with
atorvastatin for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve
vacuolation were seen in another female dog that was sacrificed in moribund
condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg
dose resulted in a systemic exposure approximately 16 times the human plasma
area-under-thecurve (AUC, 0-24 hours) based on the maximum human dose of 80
mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated
at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions
have been observed in mice after chronic treatment for up to 2 years at doses
up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6
to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the
maximum recommended human dose (MRHD) of 80 mg/day.
CNS vascular lesions, characterized by perivascular
hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces,
have been observed in dogs treated with other statins. A chemically similar
drug in this class produced optic nerve degeneration (Wallerian degeneration of
retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion
at a dose that produced plasma drug levels about 30 times higher than the mean drug
level in humans taking the highest recommended dose.
In a post-hoc analysis of the Stroke Prevention by
Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin 80
mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke
or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke
was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3%
atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The
incidence of fatal hemorrhagic stroke was similar across treatment groups (17
vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of
non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group
(38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline
characteristics, including hemorrhagic and lacunar stroke on study entry, were
associated with a higher incidence of hemorrhagic stroke in the atorvastatin
group [see ADVERSE REACTIONS].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION).
Information For Patients
Because of the risk of myopathy with statins, the drug
class to which atorvastatin belongs, advise patients to report unexplained
muscle pain, tenderness, or weakness, particularly if accompanied by malaise or
Advise patients taking atorvastatin that cholesterol is a
chronic condition and they should adhere to their medication along with their
National Cholesterol Education Program (NCEP)-recommended diet, a regular
exercise program as appropriate, and periodic testing of a fasting lipid panel
to determine goal attainment.
Advise patients about substances they should not take
concomitantly with atorvastatin [see WARNINGS AND PRECAUTIONS]. Patients
should inform other healthcare professionals prescribing a new medication that
they are taking CADUET.
Advise patients starting therapy with CADUET of the risk
of myopathy and to report promptly any unexplained muscle pain, tenderness, or
weakness particularly if accompanied by malaise or fever or if these muscle
signs or symptoms persist after discontinuing CADUET. The risk of this
occurring is increased when taking certain types of medication or consuming
larger quantities (> 1 liter) of grapefruit juice. They should discuss all
medication, both prescription and over the counter, with their healthcare
Advise patients treated with CADUET to report promptly
any symptoms that may indicate liver injury, including fatigue, anorexia, right
upper abdominal discomfort, dark urine, or jaundice.
Advise females of reproductive potential of the risk to a
fetus, to use effective contraception during treatment and to inform their
healthcare provider of a known or suspected pregnancy while using CADUET [see CONTRAINDICATIONS
and Use In Specific Populations].
Advise women not to breastfeed during treatment with
CADUET [see CONTRAINDICATIONS and Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Rats and mice treated with amlodipine maleate in the diet
for up to two years, at concentrations calculated to provide daily dosage
levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a
carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m²
basis, similar to the MRHD of 10 mg amlodipine/day.4 For the rat,
the highest dose level was, on a mg/m² basis, about twice the MRHD. 4
Mutagenicity studies conducted with amlodipine maleate
revealed no drug related effects at either the gene or chromosome levels.
There was no effect on the fertility of rats treated
orally with amlodipine maleate (males for 64 days and females for 14 days prior
to mating) at doses up to 10 mg amlodipine/kg/day (8 times the MRHD4 of 10
mg/day on a mg/m² basis).
In a 2-year carcinogenicity study with atorvastatin
calcium in rats at dose levels equivalent to 10, 30, and 100 mg
atorvastatin/kg/day, 2 rare tumors were found in muscle in high-dose females:
in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma.
This dose represents a plasma AUC (0-24) value of approximately 16 times the
mean human plasma drug exposure after an 80 mg oral dose.
A 2-year carcinogenicity study in mice given atorvastatin
calcium at dose levels equivalent to 100, 200, or 400 mg atorvastatin/kg/day
resulted in a significant increase in liver adenomas in high-dose males and
liver carcinomas in high-dose females. These findings occurred at plasma AUC
(0–24) values of approximately 6 times the mean human plasma drug exposure
after an 80 mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic
in the following tests with and without metabolic activation: the Ames test
with Salmonella typhimurium and Escherichia coli, the HGPRT
forward mutation assay in Chinese hamster lung cells, and the chromosomal
aberration assay in Chinese hamster lung cells. Atorvastatin was negative in
the in vivo mouse micronucleus test.
In female rats, atorvastatin at doses up to 225 mg/kg (56
times the human exposure) did not cause adverse effects on fertility. Studies
in male rats performed at doses up to 175 mg/kg (15 times the human exposure)
produced no changes in fertility. There was aplasia and aspermia in the
epididymides of 2 of 10 rats treated with atorvastatin calcium at a dose
equivalent to 100 mg atorvastatin/kg/day for 3 months (16 times the human AUC
at the 80 mg dose); testis weights were significantly lower at 30 and 100
mg/kg/day and epididymal weight was lower at 100 mg/kg/day. Male rats given the
equivalent of 100 mg atorvastatin/kg/day for 11 weeks prior to mating had
decreased sperm motility, spermatid head concentration, and increased abnormal
sperm. Atorvastatin caused no adverse effects on semen parameters, or
reproductive organ histopathology in dogs given doses of atorvastatin calcium
equivalent to 10, 40, or 120 mg atorvastatin/kg/day for two years.
Use In Specific Populations
CADUET is contraindicated in women who are pregnant.
Atorvastatin is contraindicated for use in pregnant women
since safety in pregnant women has not been established and there is no
apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA
reductase inhibitors decrease cholesterol synthesis and possibly the synthesis
of other biologically active substances derived from cholesterol, atorvastatin
may cause fetal harm when administered to a pregnant woman. CADUET should be
discontinued as soon as pregnancy is recognized [see CONTRAINDICATIONS].
Limited published data on the use of atorvastatin are insufficient to determine
a drug-associated risk of major congenital malformations or miscarriage. In
animal reproduction studies in rats and rabbits there was no evidence of
embryo-fetal toxicity or congenital malformations at doses up to 30 and 20
times, respectively, the human exposure at the MRHD of 80 mg, based on body
surface area (mg/m²). In rats administered atorvastatin during gestation and
lactation, decreased postnatal growth and development was observed at doses
≥6 times the MRHD (see Data).
The limited available data based on post-marketing
reports with amlodipine use in pregnant women are not sufficient to inform a
drug-associated risk for major birth defects and miscarriage. There are risks
to the mother and fetus associated with poorly controlled hypertension in
pregnancy (see Clinical Considerations). In animal reproduction studies,
there was no evidence of adverse developmental effects when pregnant rats and
rabbits were treated orally with amlodipine maleate during organogenesis at
doses approximately 10 and 20-times MRHD, respectively. However for rats,
litter size was significantly decreased (by about 50%) and the number of
intrauterine deaths was significantly increased (about 5-fold). Amlodipine has
been shown to prolong both the gestation period and the duration of labor in
rats at this dose (see Data).
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
Hypertension in pregnancy increases the maternal risk for
pre-eclampsia, gestational diabetes, premature delivery, and delivery
complications (e.g., need for cesarean section and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and
intrauterine death. Pregnant women with hypertension should be carefully
monitored and managed accordingly.
Atorvastatin Limited published data on atorvastatin
calcium from observational studies, meta-analyses and case reports have not
shown an increased risk of major congenital malformations or miscarriage. Rare
reports of congenital anomalies have been received following intrauterine
exposure to other HMG-CoA reductase inhibitors. In a review of approximately
100 prospectively followed pregnancies in women exposed to simvastatin or
lovastatin, the incidences of congenital anomalies, spontaneous abortions, and
fetal deaths/stillbirths did not exceed what would be expected in the general
population. The number of cases is adequate to exclude a ≥3 to 4-fold
increase in congenital anomalies over the background incidence. In 89% of the
prospectively followed pregnancies, drug treatment was initiated prior to
pregnancy and was discontinued at some point in the first trimester when
pregnancy was identified.
Atorvastatin crosses the rat placenta and reaches a level
in fetal liver equivalent to that of maternal plasma. When administered to
pregnant rats and rabbits during organogenesis at oral doses up to 300
mg/kg/day and 100 mg/kg/day, respectively, atorvastatin was not teratogenic in
rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day.
These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit)
the human exposure at the MRHD based on surface area (mg/m²). In rats, the
maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss
and decreased fetal body weight. At the maternally toxic doses of 50 and 100
mg/kg/day in rabbits, there was increased post-implantation loss, and at 100
mg/kg/day fetal body weights were decreased.
In a study in pregnant rats administered atorvastatin
calcium at doses equivalent to 20, 100, or 225 mg/kg/day, from gestation day 7
through to lactation day 20 (weaning), there was decreased survival at birth,
postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225
mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was
decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day
91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100
mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and
eye-opening at 225 mg/kg/day). These doses of atorvastatin correspond to 6
times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD,
based on AUC.
No evidence of teratogenicity or other embryo/fetal
toxicity was found when pregnant rats and rabbits were treated orally with
amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and
20 times the MRHD based on body surface area, respectively) during their
respective periods of major organogenesis. However, for rats, litter size was
significantly decreased (by about 50%) and the number of intrauterine deaths
was significantly increased (about 5-fold) in rats receiving amlodipine maleate
at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and
throughout mating and gestation. Amlodipine maleate has been shown to prolong
both the gestation period and the duration of labor in rats at this dose.
CADUET is contraindicated during breastfeeding.
Atorvastatin use is contraindicated during breastfeeding [see
CONTRAINDICATIONS]. There is no available information on the effects of
the drug on the breastfed infant or the effects of the drug on milk production.
It is not known whether atorvastatin is present in human milk, but it has been
shown that another drug in this class passes into human milk and atorvastatin
is present in rat milk. Because of the potential for serious adverse reactions
in a breastfed infant, advise women that breastfeeding is not recommended
during treatment with CADUET.
Limited available data from a published clinical
lactation study reports that amlodipine is present in human milk at an
estimated median relative infant dose of 4.2%. No adverse effects of amlodipine
on the breastfed infant have been observed. There is no available information
on the effects of amlodipine on milk production.
Females And Males Of Reproductive Potential
Atorvastatin may cause fetal harm when administered to a
pregnant woman. Advise females of reproductive potential to use effective contraception
during treatment with CADUET [see Use In Specific Populations].
The safety and effectiveness of CADUET have not been
established in pediatric populations.
Amlodipine (2.5 to 5 mg daily) is effective in lowering
blood pressure in patients 6 to 17 years [see Clinical Studies]. The
effect of amlodipine on blood pressure in patients less than 6 years of age is
Safety and effectiveness in patients 10-17 years of age
with heterozygous familial hypercholesterolemia have been evaluated in a
controlled clinical trial of 6 months’ duration in adolescent boys and
postmenarchal girls. Patients treated with atorvastatin had an adverse experience
profile generally similar to that of patients treated with placebo. The most
common adverse experiences observed in both groups, regardless of causality
assessment, were infections. Doses greater than 20 mg have not been studied in
this patient population. In this limited controlled study, there was no
significant effect on growth or sexual maturation in boys or on menstrual cycle
length in girls [see Clinical Studies, ADVERSE REACTIONS, and DOSAGE
AND ADMINISTRATION]. Adolescent females should be counseled on appropriate
contraceptive methods while on atorvastatin therapy [see CONTRAINDICATIONS
and Use In Specific Populations]. Atorvastatin has not been studied in
controlled clinical trials involving pre-pubertal patients or patients younger
than 10 years of age.
Clinical efficacy with doses of atorvastatin up to 80
mg/day for 1 year have been evaluated in an uncontrolled study of patients with
homozygous FH including 8 pediatric patients [see Clinical Studies].
Safety and effectiveness of CADUET have not been
established in geriatric populations.
Clinical studies of amlodipine did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy. Elderly patients have decreased clearance of amlodipine
with a resulting increase of AUC of approximately 40–60%, and a lower initial
dose may be required [see DOSAGE AND ADMINISTRATION].
Of the 39,828 patients who received atorvastatin in
clinical studies, 15,813 (40%) were ≥ 65 years old and 2,800 (7%) were
≥ 75 years old. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older adults
cannot be ruled out. Advanced age (≥ 65 years) is a predisposing factor
CADUET is contraindicated in patients with active liver
disease which may include unexplained persistent elevations in hepatic
transaminase levels [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].
Overdosage & Contraindications
There is no information on overdosage with CADUET in
Overdosage might be expected to cause excessive
peripheral vasodilation with marked hypotension and possibly a reflex
tachycardia. In humans, experience with intentional overdosage of amlodipine is
Single oral doses of amlodipine maleate equivalent to 40
mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively,
caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg
amlodipine/kg or higher in dogs (11 or more times the MRHD on a mg/m² basis)
caused a marked peripheral vasodilation and hypotension.
If overdose should occur with amlodipine, initiate active
cardiac and respiratory monitoring. Perform frequent blood pressure
measurements. Should hypotension occur, provide cardiovascular support
including elevation of the extremities and administration of fluids. If
hypotension remains unresponsive to these conservative measures, consider
administration of vasopressors (such as phenylephrine) with specific attention
to circulating volume and urine output. As amlodipine is highly protein bound,
hemodialysis is not likely to be of benefit.
There is no specific treatment for atorvastatin
overdosage. In the event of an overdose, the patient should be treated
symptomatically, and supportive measures instituted as required. Because of
extensive drug binding to plasma proteins, hemodialysis is not expected to
significantly enhance atorvastatin clearance.
Active Liver Disease
Atorvastatin is contraindicated in patients with active
liver disease, which may include unexplained persistent elevations in hepatic
transaminase levels [see WARNINGS AND PRECAUTIONS and CLINICAL
Pregnancy [see Use In Specific Populations]
Lactation [see Use In Specific Populations]
Mechanism Of Action
CADUET is a combination of two drugs, a dihydropyridine
calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor
(atorvastatin). The amlodipine component of CADUET inhibits the transmembrane
influx of calcium ions into vascular smooth muscle and cardiac muscle. The
atorvastatin component of CADUET is a selective, competitive inhibitor of
HMG-CoA reductase, the rate-limiting enzyme that converts
3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols,
Amlodipine binds to both dihydropyridine and
nondihydropyridine binding sites. The contractile processes of cardiac muscle
and vascular smooth muscle are dependent upon the movement of extracellular
calcium ions into these cells through specific ion channels. Amlodipine
inhibits calcium ion influx across cell membranes selectively, with a greater
effect on vascular smooth muscle cells than on cardiac muscle cells. Negative
inotropic effects can be detected in vitro but such effects have not been seen
in intact animals at therapeutic doses. Serum calcium concentration is not
affected by amlodipine.
Amlodipine is a peripheral arterial vasodilator that acts
directly on vascular smooth muscle to cause a reduction in peripheral vascular
resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves
angina have not been fully delineated, but are thought to include the following:
In patients with exertional angina, amlodipine reduces
the total peripheral resistance (afterload) against which the heart works and
reduces the rate pressure product, and thus myocardial oxygen demand, at any
given level of exercise.
Amlodipine has been demonstrated to block constriction
and restore blood flow in coronary arteries and arterioles in response to
calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in
experimental animal models and in human coronary vessels in vitro. This
inhibition of coronary spasm is responsible for the effectiveness of amlodipine
in vasospastic (Prinzmetal’s or variant) angina.
Cholesterol and triglycerides circulate in the
bloodstream as part of lipoprotein complexes. With ultracentrifugation, these
complexes separate into HDL (high-density lipoprotein), IDL
(intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL
(very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in
the liver are incorporated into VLDL and released into the plasma for delivery
to peripheral tissues. LDL is formed from VLDL and is catabolized primarily
through the high-affinity LDL receptor.
Clinical and pathologic studies show that elevated plasma
levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and
apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for
developing cardiovascular disease, while increased levels of HDL-C are
associated with a decreased cardiovascular risk.
Epidemiologic investigations have established that
cardiovascular morbidity and mortality vary directly with the level of total-C and
LDL-C, and inversely with the level of HDL-C.
In animal models, atorvastatin lowers plasma cholesterol
and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol
synthesis in the liver and by increasing the number of hepatic LDL receptors on
the cell surface to enhance uptake and catabolism of LDL; atorvastatin also
reduces LDL production and the number of LDL particles.
Atorvastatin reduces total-C, LDL-C, and apo B in
patients with homozygous and heterozygous familial hypercholesterolemia (FH),
nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin
also reduces VLDL-C and TG and produces variable increases in HDL-C and
apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG, and
non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia.
Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in
patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich
lipoproteins, including VLDL, (IDL), and remnants, can also promote atherosclerosis.
Elevated plasma triglycerides are frequently found in a triad with low HDL-C
levels and small LDL particles, as well as in association with non-lipid
metabolic risk factors for coronary heart disease. As such, total plasma TG has
not consistently been shown to be an independent risk factor for CHD.
Furthermore, the independent effect of raising HDL or lowering TG on the risk
of coronary and cardiovascular morbidity and mortality has not been determined.
Following administration of therapeutic doses to patients
with hypertension, amlodipine produces vasodilation resulting in a reduction of
supine and standing blood pressures. These decreases in blood pressure are not
accompanied by a significant change in heart rate or plasma catecholamine
levels with chronic dosing. Although the acute intravenous administration of
amlodipine decreases arterial blood pressure and increases heart rate in
hemodynamic studies of patients with chronic stable angina, chronic oral
administration of amlodipine in clinical trials did not lead to clinically
significant changes in heart rate or blood pressures in normotensive patients
With chronic once daily oral administration,
antihypertensive effectiveness is maintained for at least 24 hours. Plasma
concentrations correlate with effect in both young and elderly patients. The
magnitude of reduction in blood pressure with amlodipine is also correlated
with the height of pretreatment elevation; thus, individuals with moderate
hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response
than patients with mild hypertension (diastolic pressure 90– 104 mmHg).
Normotensive subjects experienced no clinically significant change in blood
pressures (+1/–2 mmHg).
In hypertensive patients with normal renal function,
therapeutic doses of amlodipine resulted in a decrease in renal vascular
resistance and an increase in glomerular filtration rate and effective renal
plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic
measurements of cardiac function at rest and during exercise (or pacing) in
patients with normal ventricular function treated with amlodipine have
generally demonstrated a small increase in cardiac index without significant
influence on dP/dt or on left ventricular end diastolic pressure or volume. In
hemodynamic studies, amlodipine has not been associated with a negative
inotropic effect when administered in the therapeutic dose range to intact
animals and man, even when co-administered with beta-blockers to man. Similar
findings, however, have been observed in normal or well-compensated patients
with heart failure with agents possessing significant negative inotropic
Amlodipine does not change sinoatrial nodal function or
atrioventricular conduction in intact animals or man. In patients with chronic
stable angina, intravenous administration of 10 mg did not significantly alter
A-H and H-V conduction and sinus node recovery time after pacing. Similar
results were obtained in patients receiving amlodipine and concomitant
beta-blockers. In clinical studies in which amlodipine was administered in
combination with beta-blockers to patients with either hypertension or angina,
no adverse effects on electrocardiographic parameters were observed. In
clinical trials with angina patients alone, amlodipine therapy did not alter
electrocardiographic intervals or produce higher degrees of AV blocks.
Atorvastatin, as well as some of its metabolites, are
pharmacologically active in humans. The liver is the primary site of action and
the principal site of cholesterol synthesis and LDL clearance. Drug dosage,
rather than systemic drug concentration, correlates better with LDL-C
reduction. Individualization of drug dosage should be based on therapeutic
response [see DOSAGE AND ADMINISTRATION].
When amlodipine and sildenafil were used in combination,
each agent independently exerted its own blood pressure lowering effect [see DRUG
After oral administration of therapeutic doses of
amlodipine alone, absorption produces peak plasma concentrations between 6 and
12 hours. Absolute bioavailability has been estimated to be between 64% and
After oral administration alone, atorvastatin is rapidly
absorbed; maximum plasma concentrations occur within 1 to 2 hours. Extent of
absorption increases in proportion to atorvastatin dose. The absolute
bioavailability of atorvastatin (parent drug) 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. 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
DOSAGE AND ADMINISTRATION].
Following oral administration of CADUET, peak plasma
concentrations of amlodipine and atorvastatin are seen at 6 to 12 hours and 1
to 2 hours post dosing, respectively. The rate and extent of absorption
(bioavailability) of amlodipine and atorvastatin from CADUET are not
significantly different from the bioavailability of amlodipine and atorvastatin
administered separately (see above).
The bioavailability of amlodipine from CADUET was not
affected by food. Food decreases the rate and extent of absorption of
atorvastatin from CADUET by approximately 32% and 11%, respectively, as it does
with atorvastatin when given alone. LDL-C reduction is similar whether
atorvastatin is given with or without food.
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.
Mean volume of distribution of atorvastatin is
approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins.
A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into
red blood cells. Based on observations in rats, atorvastatin calcium is likely
to be secreted in human milk [see CONTRAINDICATIONS and Use In Specific
Amlodipine is extensively (about 90%) converted to
inactive metabolites via hepatic metabolism.
Atorvastatin is extensively metabolized to ortho-and
parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition
of HMG-CoA reductase by ortho-and parahydroxylated 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 cytochrome P4503A4, consistent
with increased plasma concentrations of atorvastatin in humans following
co-administration with erythromycin, a known inhibitor of this isozyme [see DRUG
INTERACTIONS]. In animals, the ortho-hydroxy metabolite undergoes further
Elimination from the plasma is biphasic with a terminal
elimination half-life of about 30-50 hours. Ten percent of the parent
amlodipine compound and 60% of the metabolites of amlodipine are excreted in
Atorvastatin and its metabolites are eliminated primarily
in bile following hepatic and/or extra-hepatic 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 hours
because of the contribution of active metabolites. Less than 2% of a dose of
atorvastatin is recovered in urine following oral administration.
Elderly patients have decreased clearance of amlodipine
with a resulting increase in AUC of approximately 40-60%, and a lower initial
dose of amlodipine may be required.
Plasma concentrations of atorvastatin are higher
(approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age
≥65 years) than in young adults. Clinical data suggest a greater degree
of LDL-lowering at any dose of atorvastatin in the elderly population compared
to younger adults [see Use In Specific Populations].
Sixty-two hypertensive patients aged 6 to 17 years
received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted
clearance and volume of distribution were similar to values in adults.
Pharmacokinetic data in the pediatric population are not
Plasma concentrations of atorvastatin in women differ
from those in men (approximately 20% higher for Cmax and 10% lower for AUC);
however, there is no clinically significant difference in LDL-C reduction with
atorvastatin between men and women.
The pharmacokinetics of amlodipine are not significantly
influenced by renal impairment. Patients with renal failure may therefore
receive the usual initial amlodipine dose.
Renal disease has no influence on the plasma
concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of
atorvastatin in patients with renal dysfunction is not necessary [see DOSAGE
AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
While studies have not been conducted in patients with
end-stage renal disease, hemodialysis is not expected to clear atorvastatin or
amlodipine since both drugs are extensively bound to plasma proteins.
Elderly patients and patients with hepatic insufficiency
have decreased clearance of amlodipine with a resulting increase in AUC of
In patients with chronic alcoholic liver disease, plasma
concentrations of atorvastatin are markedly increased. Cmax and AUC are each
4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC of
atorvastatin are approximately 16-fold and 11-fold increased, respectively, in
patients with Childs-Pugh B disease [see CONTRAINDICATIONS].
Atorvastatin is contraindicated in patients with active
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.
Effects Of Other Drugs On CADUET
Co-administered cimetidine, magnesium-and aluminum
hydroxide antacids, sildenafil, and grapefruit juice have no impact on the
exposure to amlodipine.
Co-administration of a 180 mg daily dose of diltiazem
with 5 mg amlodipine in elderly hypertensive patients resulted in a 60%
increase in amlodipine systemic exposure. Erythromycin co-administration in
healthy volunteers did not significantly change amlodipine systemic exposure.
However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may
increase the plasma concentrations of amlodipine to a greater extent [see DRUG
Table 4 shows effects of other drugs on the
pharmacokinetics of atorvastatin.
Table 4: Effect of Co-administered Drugs on the
Pharmacokinetics of Atorvastatin
Co-administered drug and dosing regimen
Change in AUC
Change in Cmax
#Cyclosporine 5.2 mg/kg/day, stable dose
10 mg QD for 28 days
#Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days
10 mg, SD
#Telaprevir 750 mg q8h, 10 days
20 mg, SD
#, ‡Saquinavir 400 mg BID/ritonavir 400mg BID, 15 days
40 mg QD for 4 days
#Clarithromycin 500 mg BID, 9 days
80 mg QD for 8 days
#Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days
10 mg QD for 4 days
#Itraconazole 200 mg QD, 4 days
40 mg SD
#Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days
10 mg QD for 4 days
#Fosamprenavir 1400 mg BID, 14 days
10 mg QD for 4 days
#Nelfinavir 1250 mg BID, 14 days
10 mg QD for 28 days
#Grapefruit Juice, 240 mL QD*
40 mg, SD
Diltiazem 240 mg QD, 28 days
40 mg, SD
Erythromycin 500 mg QID, 7 days
10 mg, SD
Amlodipine 10 mg, single dose
80 mg, SD
Cimetidine 300 mg QID, 2 weeks
10 mg QD for 2 weeks
↓ Less than 1%
Colestipol 10 mg BID, 28 weeks
40 mg QD for 28 weeks
Maalox TC® 30 mL QD, 17 days
10 mg QD for 15 days
Efavirenz 600 mg QD, 14 days
10 mg for 3 days
#Rifampin 600 mg QD, 7 days (coadministered) †
40 mg SD
#Rifampin 600 mg QD, 5 days (doses separated) †
40 mg SD
#Gemfbrozil 600 mg BID, 7 days
↓ Less than 1%
#Fenofibrate 160 mg QD, 7 days
Boceprevir 800 mg TID, 7 days
40 mg SD
# See WARNINGS AND PRECAUTIONS and DRUG
INTERACTIONS for clinical significance.
* Greater increases in AUC (up to 2.5-fold) and/or Cmax (up to 71%) have been
reported with excessive grapefruit consumption (≥ 750 mL – 1.2 liters per
** Single sample taken 8-16 h post dose.
† Because of the dual interaction mechanism of rifampin, simultaneous
co-administration of atorvastatin with rifampin is recommended, as delayed
administration of atorvastatin after administration of rifampin has been
associated with a significant reduction in atorvastatin plasma concentrations.
‡ The dose of saquinavir plus ritonavir in this study is not the clinically
used dose. The increase in atorvastatin exposure when used clinically is likely
to be higher than what was observed in this study. Therefore, use the lowest
Effects Of CADUET On Other Drugs
Amlodipine is a weak inhibitor of CYP3A and may increase
exposure to CYP3A substrates.
In vitro data indicate that amlodipine has no effect on
the human plasma protein binding of digoxin, phenytoin, warfarin, and
Co-administered amlodipine does not affect the exposure
to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.
A prospective study in renal transplant patients (N=11)
showed on an average of 40% increase in trough cyclosporine levels when
concomitantly treated with amlodipine [see DRUG INTERACTIONS].
A prospective study in healthy Chinese volunteers (N=9)
with CYP3A5 expressers showed a 2.5-to 4-fold increase in tacrolimus exposure
when concomitantly administered with amlodipine compared to tacrolimus alone.
This finding was not observed in CYP3A5 non-expressers (N= 6). However, a
3-fold increase in plasma exposure to tacrolimus in a renal transplant patient
(CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of
post-transplant hypertension resulting in reduction of tacrolimus dose has been
reported. Irrespective of the CYP3A5 genotype status, the possibility of an
interaction cannot be excluded with these drugs [see DRUG INTERACTIONS].
Table 5 shows the effects of atorvastatin on the
pharmacokinetics of other drugs.
Table 5: Effect of Atorvastatin on the
Pharmacokinetics of Co-administered Drugs
Co-administered drug and dosing regimen
Change in AUC
Change in Cmax
80 mg QD for 15 days
Antipyrine, 600 mg SD
80 mg QD for 14 days
Digoxin 0.25 mg QD, 20 days
40 mg QD for 22 days
Oral contraceptive QD, 2 months
- norethindrone 1mg
- ethinyl estradiol 35 μg
10 mg, SD
Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days
10 mg QD for 4 days
Fosamprenavir 1400 mg BID, 14 days
10 mg QD for 4 days
Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days
Amlodipine For Hypertension
The antihypertensive efficacy of amlodipine has been
demonstrated in a total of 15 double-blind, placebo-controlled, randomized
studies involving 800 patients on amlodipine and 538 on placebo. Once daily
administration produced statistically significant placebo-corrected reductions
in supine and standing blood pressures at 24 hours postdose, averaging about
12/6 mmHg in the standing position and 13/7 mmHg in the supine position in
patients with mild to moderate hypertension. Maintenance of the blood pressure
effect over the 24-hour dosing interval was observed, with little difference in
peak and trough effect. Tolerance was not demonstrated in patients studied for
up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the
reduction in supine and standing blood pressures was dose related within the
recommended dosing range. Effects on diastolic pressure were similar in young
and older patients. The effect on systolic pressure was greater in older
patients, perhaps because of greater baseline systolic pressure. Effects were
similar in black patients and in white patients.
Two hundred sixty-eight hypertensive patients aged 6 to
17 years were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks
and then randomized again to the same dose or to placebo for another 4 weeks.
Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower
systolic blood pressure than those secondarily randomized to placebo. The
magnitude of the treatment effect is difficult to interpret, but it is probably
less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg
dose. Adverse events were similar to those seen in adults.
Amlodipine For Chronic Stable Angina
The effectiveness of 5–10 mg/day of amlodipine in
exercise-induced angina has been evaluated in 8 placebo-controlled,
double-blind clinical trials of up to 6 weeks duration involving 1038 patients
(684 amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8
studies, significant increases in exercise time (bicycle or treadmill) were
seen with the 10 mg dose. Increases in symptom-limited exercise time averaged
12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine
5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in
several studies and decreased angina attack rate. The sustained efficacy of
amlodipine in angina patients has been demonstrated over long-term dosing. In
patients with angina, there were no clinically significant reductions in blood
pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).
Amlodipine For Vasospastic Angina
In a double-blind, placebo-controlled clinical trial of 4
weeks duration in 50 patients, amlodipine therapy decreased attacks by
approximately 4/week compared with a placebo decrease of approximately 1/week
(p<0.01). Two of 23 amlodipine and 7 of 27 placebo patients discontinued
from the study for lack of clinical improvement.
Amlodipine For Coronary Artery Disease
In PREVENT, 825 patients with angiographically documented
CAD were randomized to amlodipine (5–10 mg once daily) or placebo and followed
for 3 years. Although the study did not show significance on the primary
objective of change in coronary luminal diameter as assessed by quantitative
coronary angiography, the data suggested a favorable outcome with respect to
fewer hospitalizations for angina and revascularization procedures in patients
CAMELOT enrolled 1318 patients with CAD recently
documented by angiography, without left main coronary disease and without heart
failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian,
93% enrolled at U.S. sites, 89% with a history of angina, 52% without PCI, 4%
with PCI and no stent, and 44% with a stent) were randomized to double-blind
treatment with either amlodipine (5–10 mg once daily) or placebo in addition to
standard care that included aspirin (89%), statins (83%), beta-blockers (74%),
nitroglycerin (50%), anticoagulants (40%), and diuretics (32%), but excluded
other calcium channel blockers. The mean duration of follow-up was 19 months.
The primary endpoint was the time to first occurrence of one of the following
events: hospitalization for angina pectoris, coronary revascularization,
myocardial infarction, cardiovascular death, resuscitated cardiac arrest,
hospitalization for heart failure, stroke/TIA, or peripheral vascular disease.
A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine
and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI:
0.540–0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below.
The outcome of this study was largely derived from the prevention of
hospitalizations for angina and the prevention of revascularization procedures
(see Table 6). Effects in various subgroups are shown in Figure 2.
In an angiographic substudy (n=274) conducted within
CAMELOT, there was no significant difference between amlodipine and placebo on
the change of atheroma volume in the coronary artery as assessed by
Figure 1: Kaplan-Meier Analysis of Composite Clinical
Outcomes for Amlodipine versus Placebo
Figure 2: Effects on Primary Endpoint of Amlodipine
versus Placebo across Sub-Groups
Table 6 below summarizes the significant composite
endpoint and clinical outcomes from the composites of the primary endpoint. The
other components of the primary endpoint including cardiovascular death,
resuscitated cardiac arrest, myocardial infarction, hospitalization for heart
failure, stroke/TIA, or peripheral vascular disease did not demonstrate a
significant difference between amlodipine and placebo.
Table 6: Incidence of Significant Clinical Outcomes
Clinical Outcomes N (%)
Risk Reduction (p-value)
Composite CV Endpoint
Hospitalization for Angina*
* Total patients with these events.
Amlodipine For Heart Failure
Amlodipine has been compared to placebo in four 8–12 week
studies of patients with NYHA Class II/III heart failure, involving a total of
697 patients. In these studies, there was no evidence of worsened heart failure
based on measures of exercise tolerance, NYHA classification, symptoms, or left
ventricular ejection fraction. In a long-term (follow-up at least 6 months,
mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine
5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart
failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine
had no effect on the primary endpoint of the study which was the combined
endpoint of all-cause mortality and cardiac morbidity (as defined by
life-threatening arrhythmia, acute myocardial infarction, or hospitalization
for worsened heart failure), or on NYHA classification, or symptoms of heart
failure. Total combined all-cause mortality and cardiac morbidity events were
222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo;
the cardiac morbid events represented about 25% of the endpoints in the study.
Another study (PRAISE-2) randomized patients with NYHA
Class III (80%) or IV (20%) heart failure without clinical symptoms or
objective evidence of underlying ischemic disease, on stable doses of ACE
inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or
amlodipine (n=827) and followed them for a mean of 33 months. There was no
statistically significant difference between amlodipine and placebo in the
primary endpoint of all-cause mortality (95% confidence limits from 8%
reduction to 29% increase on amlodipine). With amlodipine there were more
reports of pulmonary edema.
Atorvastatin For Prevention Of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),
the effect of atorvastatin on fatal and non-fatal coronary heart disease was
assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years),
without a previous myocardial infarction and with TC levels ≤ 251 mg/dL
(6.5 mmol/L). Additionally, all patients had at least 3 of the following
cardiovascular risk factors: male gender (81.1%), age > 55 years (84.5%),
smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative
(26%), TC:HDL > 6 (14.3%), peripheral vascular disease (5.1%), left
ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific
ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind,
placebo-controlled study, patients were treated with anti-hypertensive therapy
(Goal BP < 140/90 mmHg for non-diabetic patients; < 130/80 mm Hg for
diabetic patients) and allocated to either atorvastatin 10 mg daily (n=5168) or
placebo (n=5137), using a covariate adaptive method that took into account the
distribution of nine baseline characteristics of patients already enrolled and
minimized the imbalance of those characteristics across the groups. Patients
were followed for a median duration of 3.3 years.
The effect of 10 mg/day of atorvastatin on lipid levels
was similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of coronary
events [either fatal coronary heart disease (46 events in the placebo group vs.
40 events in the atorvastatin group) or non-fatal MI (108 events in the placebo
group vs. 60 events in the atorvastatin group)] with a relative risk reduction
of 36% [(based on incidences of 1.9% for atorvastatin vs. 3.0% for placebo),
p=0.0005 (see Figure 3)]. The risk reduction was consistent regardless of age,
smoking status, obesity, or presence of renal dysfunction. The effect of
atorvastatin was seen regardless of baseline LDL levels. Because of the small
number of events, results for women were inconclusive.
Figure 3: Effect of Atorvastatin 10 mg/day on
Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart
Disease Death (in ASCOT-LLA)
Atorvastatin also significantly decreased the relative
risk for revascularization procedures by 42%. Although the reduction of fatal
and non-fatal strokes did not reach a pre-defined significance level (p=0.01),
a favorable trend was observed with a 26% relative risk reduction (incidences
of 1.7% for atorvastatin and 2.3% for placebo). There was no significant
difference between the treatment groups for death from cardiovascular causes
(p=0.51) or noncardiovascular causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS),
the effect of atorvastatin on cardiovascular disease endpoints was assessed in
2838 subjects (94% white, 68% male), ages 40–75 with type 2 diabetes based on
WHO criteria, without prior history of cardiovascular disease, and with LDL
≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects
had 1 or more of the following risk factors: current smoking (23%),
hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria
(3%). No subjects on hemodialysis were enrolled in the study. In this
multicenter, placebo-controlled, double-blind clinical trial, subjects were
randomly allocated to either atorvastatin 10 mg daily (1,429) or placebo
(1,411) in a 1:1 ratio and were followed for a median duration of 3.9 years.
The primary endpoint was the occurrence of any of the major cardiovascular
events: myocardial infarction, acute CHD death, unstable angina, coronary
revascularization, or stroke. The primary analysis was the time to first
occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62
years; mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG
151 mg/dL; median HDL-C 52 mg/dL.
The effect of atorvastatin 10 mg/day on lipid levels was
similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of major
cardiovascular events (primary endpoint events) (83 events in the atorvastatin
group vs. 127 events in the placebo group) with a relative risk reduction of
37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 4). An effect of
atorvastatin was seen regardless of age, sex, or baseline lipid levels.
Atorvastatin significantly reduced the risk of stroke by
48% (21 events in the atorvastatin group vs. 39 events in the placebo group),
HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38
events in the atorvastatin group vs. 64 events in the placebo group), HR 0.58,
95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between
the treatment groups for angina, revascularization procedures, and acute CHD
There were 61 deaths in the atorvastatin group vs. 82
deaths in the placebo group (HR 0.73, p=0.059).
Figure 4: Effect of Atorvastatin 10 mg/day on Time to
Occurrence of Major Cardiovascular Events (myocardial infarction, acute CHD
death, unstable angina, coronary revascularization, or stroke) in CARDS
In the Treating to New Targets Study (TNT), the effect of
atorvastatin 80 mg/day vs. atorvastatin 10 mg/day on the reduction in
cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38%
≥ 65 years) with clinically evident coronary heart disease who had
achieved a target LDL-C level < 130 mg/dL after completing an 8-week,
open-label, run-in period with atorvastatin 10 mg/day. Subjects were randomly
assigned to either 10 mg/day or 80 mg/day of atorvastatin and followed for a
median duration of 4.9 years. The primary endpoint was the time to first
occurrence of any of the following major cardiovascular events (MCVE): death
from CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and
fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL
cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during
treatment with 80 mg of atorvastatin and 99, 177, 152, 129, and 48 mg/dL during
treatment with 10 mg of atorvastatin.
Treatment with atorvastatin 80 mg/day significantly
reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in
the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI
(0.69, 0.89), p=0.0002 (see Figure 5 and Table 7). The overall risk reduction
was consistent regardless of age (< 65, ≥ 65) or gender.
Figure 5: Effect of Atorvastatin 80 mg/day vs. 10
mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
Table 7: Overview of Efficacy Results in TNT
Atorvastatin 10 mg
Atorvastatin 80 mg
HRa (95% CI)
First major cardiovascular endpoint
0.78 (0.69, 0.89)
Components of the Primary Endpoint
0.80 (0.61, 1.03)
Non-fatal, non-procedure related MI
0.78 (0.66, 0.93)
Resuscitated cardiac arrest
0.96 (0.56, 1.67)
Stroke (fatal and non-fatal)
0.75 (0.59, 0.96)
First CHF with hospitalization
0.74 (0.59, 0.94)
First PVD endpoint
0.97 (0.83, 1.15)
First CABG or other coronary revascularization procedureb
0.72 (0.65, 0.80)
First documented angina endpointb
0.88 (0.79, 0.99)
1.01 (0.85, 1.19)
Components of All-Cause Mortality
0.81 (0.64, 1.03)
1.25 (0.99, 1.57)
1.13 (0.83, 1.55)
Other non-CV death
1.35 (0.91, 2.00)
Suicide, homicide, and other traumatic non-CV death
1.67 (0.73, 3.82)
mg: atorvastatin 10 mg
b Component of other secondary endpoints
* Secondary endpoints not included in primary endpoint HR=hazard ratio;
CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction;
CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular
disease; CABG=coronary artery bypass graft Confidence intervals for the
Secondary Endpoints were not adjusted for multiple comparisons.
Of the events that comprised the primary efficacy
endpoint, treatment with atorvastatin 80 mg/day significantly reduced the rate
of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not
CHD death or resuscitated cardiac arrest (Table 7). Of the predefined secondary
endpoints, treatment with atorvastatin 80 mg/day significantly reduced the rate
of coronary revascularization, angina, and hospitalization for heart failure,
but not peripheral vascular disease. The reduction in the rate of CHF with
hospitalization was only observed in the 8% of patients with a prior history of
There was no significant difference between the treatment
groups for all-cause mortality (Table 7). The proportions of subjects who
experienced cardiovascular death, including the components of CHD death and
fatal stroke, were numerically smaller in the atorvastatin 80 mg group than in
the atorvastatin 10 mg treatment group. The proportions of subjects who
experienced noncardiovascular death were numerically larger in the atorvastatin
80 mg group than in the atorvastatin 10 mg treatment group.
In the Incremental Decrease in Endpoints Through
Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin 80 mg/day
was compared to treatment with simvastatin 20–40 mg/day in 8,888 subjects up to
80 years of age with a history of CHD to assess whether reduction in CV risk
could be achieved. Patients were mainly male (81%), white (99%) with an average
age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76%
were on statin therapy. In this prospective, randomized, open-label, blinded
endpoint (PROBE) trial with no run-in period, subjects were followed for a
median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL
cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during
treatment with 80 mg of atorvastatin and 105, 179, 142, 47, and 132 mg/dL
during treatment with 20–40 mg of simvastatin.
There was no significant difference between the treatment
groups for the primary endpoint, the rate of first major coronary event (fatal
CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the
atorvastatin 80 mg/day group vs. 463 (10.4%) in the simvastatin 20–40 mg/day
group, HR 0.89, 95% CI ( 0.78, 1.01), p=0.07.
There were no significant differences between the
treatment groups for all-cause mortality: 366 (8.2%) in the atorvastatin 80
mg/day group vs. 374 (8.4%) in the simvastatin 20–40 mg/day group. The
proportions of subjects who experienced CV or non-CV death were similar for the
atorvastatin 80 mg group and the simvastatin 20–40 mg group.
Atorvastatin For Hyperlipidemia (Heterozygous Familial And
Nonfamilial) And Mixed Dyslipidemia (Fredrickson Types IIa And IIb)
Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, and
TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia.
Therapeutic response is seen within 2 weeks, and maximum response is usually
achieved within 4 weeks and maintained during chronic therapy.
Atorvastatin is effective in a wide variety of patient
populations with hyperlipidemia, with and without hypertriglyceridemia, in men
and women, and in the elderly.
In two multicenter, placebo-controlled, dose-response
studies in patients with hyperlipidemia, atorvastatin given as a single dose
over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG. (Pooled
results are provided in Table 8.)
Table 8: Dose Response in Patients with Primary
Hyperlipidemia (Adjusted Mean % Change From Baseline)a
a Results are pooled from 2 dose-response
In patients with Fredrickson Types IIa and IIb
hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and
75th percentile) percent changes from baseline in HDL-C for
atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0,
16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled
data demonstrated consistent and significant decreases in total-C, LDL-C, TG,
total-C/HDL-C, and LDL-C/HDL-C.
In three multicenter, double-blind studies in patients
with hyperlipidemia, atorvastatin was compared to other statins. After
randomization, patients were treated for 16 weeks with either atorvastatin 10
mg per day or a fixed dose of the comparative agent (Table 9).
Table 9: Mean Percentage Change from Baseline at
Endpoint (Double-Blind, Randomized, Active-Controlled Trials)
Treatment (Daily Dose)
Atorvastatin 10 mg
Lovastatin 20 mg
95% CI for Diff1
.5 6. - 9. -
Atorvastatin 10 mg
Pravastatin 20 mg
95% CI for Diff1
Atorvastatin 10 mg
Simvastatin 10 mg
95% CI for Diff1
1 A negative value for the 95% CI for the
difference between treatments favors atorvastatin for all except HDL-C, for
which a positive value favors atorvastatin. If the range does not include 0,
this indicates a statistically significant difference.
a Significantly different from lovastatin, ANCOVA, p ≤ 0.05
b Significantly different from pravastatin, ANCOVA, p ≤ 0.05
c Significantly different from simvastatin, ANCOVA, p ≤ 0.05
The impact on clinical outcomes of the differences in
lipid-altering effects between treatments shown in Table 9 is not known. Table
9 does not contain data comparing the effects of atorvastatin 10 mg and higher
doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the
studies summarized in the table are not necessarily interchangeable.
Atorvastatin For Hypertriglyceridemia (Fredrickson Type
The response to atorvastatin in 64 patients with isolated
hypertriglyceridemia treated across several clinical trials is shown in the
table below (Table 10). For the atorvastatin-treated patients, median (min,
max) baseline TG level was 565 (267–1502).
Table 10: Combined Patients with Isolated Elevated TG:
Median (min, max) Percentage Change From Baseline
Atorvastatin 10 mg
Atorvastatin 20 mg
Atorvastatin 80 mg
-12.4 (-36.6, 82.7)
-41.0 (-76.2, 49.4)
-38.7 (-62.7, 29.5)
-51.8 (-82.8, 41.3)
-2.3 (-15.5, 24.4)
-28.2 (-44.9, -6.8)
-34.9 (-49.6, -15.2)
-44.4 (-63.5, -3.8)
3.6 (-31.3, 31.6)
-26.5 (-57.7, 9.8)
-30.4 (-53.9, 0.3)
-40.5 (-60.6, -13.8)
3.8 (-18.6, 13.4)
13.8 (-9.7, 61.5)
11.0 (-3.2, 25.2)
7.5 (-10.8, 37.2)
-1.0 (-31.9, 53.2)
-48.8 (-85.8, 57.3)
-44.6 (-62.2, -10.8)
-62.0 (-88.2, 37.6)
-2.8 (-17.6, 30.0)
-33.0 (-52.1, -13.3)
-42.7 (-53.7, -17.4)
-51.5 (-72.9, -4.3)
Atorvastatin For Dysbetalipoproteinemia (Fredrickson Type III)
The results of an open-label crossover study of 16
patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson
Type III) are shown in the table below (Table 11).
Table 11: Open-Label Crossover Study of 16 Patients
with Dysbetalipoproteinemia (Fredrickson Type III)
Median (min, max) at Baseline (mg/dL)
Median % Change (min, max)
Atorvastatin 10 mg
Atorvastatin 80 mg
442 (225, 1320)
-37 (-85, 17)
-58 (-90, -31)
678 (273, 5990)
-39 (-92, -8)
-53 (-95, -30)
IDL-C + VLDL-C
215 (111, 613)
-32 (-76, 9)
-63 (-90, -8)
411 (218, 1272)
-43 (-87, -19)
-64 (-92, -36)
Atorvastatin For Homozygous Familial Hypercholesterolemia
In a study without a concurrent control group, 29
patients ages 6 to 37 years with homozygous FH received maximum daily doses of
20 to 80 mg of atorvastatin. The mean LDL-C reduction in this study was 18%.
Twenty-five patients with a reduction in LDL-C had a mean response of 20%
(range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases
in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2
patients also had a portacaval shunt and had no significant reduction in LDL-C.
The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.
Atorvastatin For Heterozygous Familial
Hypercholesterolemia In Pediatric Patients
In a double-blind, placebo-controlled study followed by
an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean
age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe
hypercholesterolemia, were randomized to atorvastatin (n=140) or placebo (n=47)
for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the
study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline
LDL-C level ≥ 160 mg/dL and positive family history of FH or documented
premature cardiovascular disease in a first or second-degree relative. The mean
baseline LDL-C value was 218.6 mg/dL (range: 138.5–385.0 mg/dL) in the
atorvastatin group compared to 230.0 mg/dL (range: 160.0–324.5 mg/dL) in the
placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first
4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The
number of atorvastatin-treated patients who required uptitration to 20 mg after
Week 4 during the double-blind phase was 78 (55.7 %).
Atorvastatin significantly decreased plasma levels of
total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week
double-blind phase (see Table 12).
Table 12: Lipid-Altering Effects of Atorvastatin in
Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or
Severe Hypercholesterolemia (Mean Percentage Change from Baseline at Endpoint
in Intention-to-Treat Population)
The mean achieved LDL-C value was 130.7 mg/dL (range:
70.0–242.0 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range:
152.0–385.0 mg/dL) in the placebo group during the 26-week double-blind phase.
The safety and efficacy of doses above 20 mg have not
been studied in controlled trials in children. The long-term efficacy of
atorvastatin therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
CADUET For Hypertension And Dyslipidemia
In a double-blind, placebo-controlled study, a total of
1660 patients with co-morbid hypertension and dyslipidemia received once daily
treatment with eight dose combinations of amlodipine and atorvastatin (5/10,
10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80 mg), amlodipine alone (5 mg or
10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, or 80 mg), or placebo. In
addition to concomitant hypertension and dyslipidemia, 15% of the patients had
diabetes mellitus, 22% were smokers, and 14% had a positive family history of
cardiovascular disease. At eight weeks, all eight combination-treatment groups
of amlodipine and atorvastatin demonstrated statistically significant
dose-related reductions in systolic blood pressure (SBP), diastolic blood
pressure (DBP), and LDL-C compared to placebo, with no overall modification of
effect of either component on SBP, DBP, and LDL-C (Table 13).
Table 13. Effects of Amlodipine and Atorvastatin on
Blood Pressure and LDL-C
LDL-C (% change)
4 Based on patient weight of 50 kg.
Read the patient information that comes with CADUET
before you start taking it, and each time you get a refill. There may be new
information. This information does not replace talking with your doctor about
your condition or treatment. If you have any questions about CADUET, ask your
doctor or pharmacist.
What is CADUET?
CADUET is a prescription drug that combines Norvasc® (amlodipine
besylate) and Lipitor®
(atorvastatin calcium) in one pill.
CADUET is used in adults who need both Norvasc and
Norvasc is used to treat:
High blood pressure (hypertension) and
Chest pain (angina) and
Blocked arteries of the heart (coronary artery disease)
Lipitor is used to lower the levels of “bad” cholesterol
and triglycerides in your blood. It can also raise the levels of “good”
Lipitor is also used to lower the risk for heart attack,
stroke, certain types of heart surgery, and chest pain in patients who have
heart disease or risk factors for heart disease such as:
age, smoking, high blood pressure, low levels of “good”
cholesterol, heart disease in the family.
Lipitor can lower the risk for heart attack or stroke in
patients with diabetes and risk factors such as:
diabetic eye or kidney problems, smoking, or high blood
CADUET has not been studied in children.
Who should not use CADUET?
Do not use CADUET if you:
Are pregnant or think you may be pregnant, or are
planning to become pregnant. CADUET may harm your unborn baby. If you get
pregnant, stop taking CADUET and call your doctor right away.
Are breastfeeding. CADUET can pass into your breast milk
and may harm your baby. Do not breastfeed if you take CADUET.
Have liver problems.
Are allergic to anything in CADUET. The active
ingredients are atorvastatin calcium and amlodipine besylate. See the end of
this leaflet for a complete list of ingredients.
What should I tell my doctor before taking CADUET?
Tell your doctor about all of your health conditions,
including, if you have:
muscle aches or weakness
or drink more than 2 glasses of alcohol daily
Tell your doctor about all the medicines you take
including prescription and nonprescription medicines, vitamins, and herbal
supplements. CADUET and some other medicines can interact, causing serious side
effects. Especially tell your doctor if you take medicines for:
your immune system
You can use nitroglycerin and CADUET together. If you
take nitroglycerin for chest pain (angina), do not stop taking it while taking
Know all the medicines you take. Keep a list of them with
you to show your doctor and pharmacist.
How should I take CADUET?
Take CADUET once a day, exactly as your doctor tells you.
Do not change your dose or stop CADUET without talking to your doctor.
Take CADUET each day at any time of day, at about the
same time each day. CADUET can be taken with or without food.
Do not break the tablets before taking them. Talk to your
doctor if you have a problem swallowing pills.
Your doctor should start you on a low-fat diet before
giving you CADUET. Stay on this low-fat diet when you take CADUET.
If you miss a dose, take it as soon as you remember. Do
not take CADUET if it has been more than 12 hours since your missed dose. Just
take the next dose at your regular time. Do not take 2 doses of CADUET at the
If too much CADUET is taken by accident, call your doctor
or poison control center, or go to the nearest emergency room.
What should I avoid while taking CADUET?
Avoid getting pregnant. If you get pregnant, stop taking
CADUET right away and call your doctor.
Do not breastfeed. CADUET can pass into your breast milk
and may harm your baby.
What are possible side effects of CADUET?
CADUET can cause serious side effects. These side
effects happen only to a small number of people. Your doctor can monitor you
for them. These side effects usually go away if your dose is lowered or CADUET
is stopped. These serious side effects include:
Muscle problems. CADUET can cause serious muscle
problems that can lead to kidney problems, including kidney failure. You have a
higher chance for muscle problems if you are taking certain other medicines
Liver problems. Your doctor should do blood tests
to check your liver before you start taking CADUET and if you have symptoms of
liver problems while you take CADUET. Call your doctor right away if you have
the following symptoms of liver problems:
feel tired or weak
loss of appetite
upper belly pain
dark amber colored urine
yellowing of your skin or the whites of your eyes
Low blood pressure or dizziness
Muscle rigidity, tremor and/or abnormal muscle
Call your doctor right away if:
you have muscle problems like weakness, tenderness, or
pain that happen without a good reason, especially if you also have a fever or
feel more tired than usual. This may be an early sign of a rare muscle problem.
muscle problems that do not go away even after your
doctor has advised you to stop taking CADUET. Your doctor may do further tests
to diagnose the cause of your muscle problems.
allergic reactions including swelling of the face, lips,
tongue, and/or throat that may cause difficulty in breathing or swallowing
which may require treatment right away
you have nausea and vomiting, stomach pain
you are passing brown or dark-colored urine
you feel more tired than usual
your skin and white of your eyes get yellow
you have allergic skin reactions
Chest pain that does not go away or gets worse. Sometimes
when you start CADUET or increase your dose, chest pain can get worse or a
heart attack can happen. If this happens, call your doctor or go to the
emergency room right away.
Common side effects of CADUET include:
Swelling of your legs or ankles
Muscle and joint pain
Alterations in some laboratory blood tests
Additional side effects have been reported: tiredness,
tendon problems, memory loss, and confusion.
Talk to your doctor or pharmacist about side effects that
bother you or do not go away.
There are other side effects of CADUET. Ask your doctor
or pharmacist for a complete list.
How do I store CADUET?
Store CADUET at room temperature, 68 to 77°F (20 to 25°C).
Do not keep medicine that is out-of-date or that you no
Keep CADUET and all medicines out of the reach of
children. Keep medicines in places where children cannot get it.
General information about CADUET
Medicines are sometimes prescribed for conditions that
are not mentioned in patient information leaflets. Do not use CADUET for a
condition for which it was not prescribed. Do not give CADUET to other people,
even if they have the same problem you have. It may harm them. This leaflet
summarizes the most important information about CADUET. If you want more
information, talk with your doctor. Ask your doctor or pharmacist for
information about CADUET written for health professionals. You can also go to
the CADUET website at www.CADUET.com.
What is high blood pressure (hypertension)?
You have high blood pressure when the force of blood
against the walls of your arteries stays high. This can damage your heart and
other parts of your body. Drugs that lower blood pressure lower your risk of
having a stroke or heart attack.
What is angina (chest pain)?
Angina is a pain that keeps coming back when part of your
heart does not get enough blood. It feels like something is pressing or
squeezing your chest under the breastbone. Sometimes you can feel it in your
shoulders, arms, neck, jaw, or back.
What is cholesterol?
Cholesterol is a fat-like substance made in your body. It
is also found in foods. You need some cholesterol for good health, but too much
is not good for you. Cholesterol can clog your blood vessels.
What is a heart attack?
A heart attack occurs when heart muscle does not get
enough blood. Symptoms include chest pain, trouble breathing, nausea, and
weakness. Heart muscle cells may be damaged or die. The heart cannot pump well
or may stop beating.
What is a stroke?
A stroke occurs when nerve cells in the brain do not get
enough blood. The cells may be damaged or die. The damaged cells may cause
weakness or problems speaking or thinking.
WHAT ARE THE INGREDIENTS IN CADUET?
Active ingredients: amlodipine besylate,