General
Since the vasodilation induced by the amlodipine component of CADUET is gradual
in onset, acute hypotension has rarely been reported after oral administration of
amlodipine. Nonetheless, caution should be exercised when administering CADUET as
with any other peripheral vasodilator particularly in patients with severe aortic
stenosis.
Use in Patients with Congestive Heart Failure
In general, calcium channel blockers should be used with caution in patients with
heart failure. The amlodipine component of CADUET (5-10 mg per day) has been studied
in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure
(see CLINICAL PHARMACOLOGY) on stable doses of ACE inhibitor, digoxin, and
diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There
was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening
arrhythmia, acute myocardial infarction, or hospitalization for worsened 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 LVEF.
Beta-Blocker Withdrawal
The amlodipine component of CADUET is not a beta-blocker and therefore gives no
protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal
should be by gradual reduction of the dose of beta-blocker.
Endocrine Function
Statins, such as the atorvastatin component of CADUET 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. Caution should be exercised if a statin
is administered concomitantly with drugs that may decrease the levels or activity
of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
CNS Toxicity
Studies with atorvastatin: Brain hemorrhage was seen in a female dog
treated with atorvastatin calcium for 3 months at a dose equivalent to 120 mg atorvastatin/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 of atorvastatin
calcium equivalent to up to 280 mg atorvastatin/kg/day. The 120 mg/kg dose of atorvastatin
resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve
(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 with atorvastatin calcium at a dose
equivalent to 10 mg atorvastatin/kg/day and one at a dose equivalent to 120 mg atorvastatin/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 of atorvastatin calcium equivalent to up to 400 mg atorvastatin/kg/day
or in rats at doses equivalent to up to 100 mg atorvastatin/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 of 80 mg atorvastatin/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear
cell infiltration of perivascular spaces, have been observed in
dogs treated with other members of the statins class. 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.
Use in Patients with Recent Stroke or TIA
Studies with atorvastatin: 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 nonfatal 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, The Atorvastatin Component of CADUET).
Information for Patients
Due to the risk of myopathy with statins, the drug class to which
the atorvastatin component of CADUET belongs, patients should be advised to report
promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied
by malaise or fever.
Drug Interactions
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 coadministered. 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 was 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:
Studies with Amlodipine:
In vitro data in human plasma indicate that amlodipine has no effect on the
protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin).
Cimetidine: Co-administration of amlodipine with cimetidine did not alter
the pharmacokinetics of amlodipine.
Maalox® (antacid): Co-administration of the antacid
Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics
of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil (Viagra®)
in subjects with essential hypertension had no effect on the pharmacokinetic parameters
of amlodipine. When amlodipine and sildenafil were used in combination, each agent
independently exerted its own blood pressure lowering effect.
Digoxin: Co-administration of amlodipine with digoxin did not change serum
digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant
effect on the pharmacokinetics of ethanol.
Warfarin: Co-administration of amlodipine with warfarin did not change the
warfarin prothrombin response time.
In clinical trials, amlodipine has been safely administered with thiazide diuretics,
beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual
nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics,
and oral hypoglycemic drugs.
Studies with Atorvastatin:
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 CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors,
and itraconazole) (see WARNINGS, Skeletal Muscle, and CLINICAL PHARMACOLOGY).
Strong Inhibitors of CYP 3A4: Atorvastatin is metabolized by cytochrome
P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent
of interaction and potentiation of effects depends on the variability of effect
on CYP 3A4.
Clarithromycin: 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, caution should be used when the atorvastatin dose exceeds 20 mg (see WARNINGS,
Skeletal Muscle, and DOSAGE AND ADMINISTRATION).
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin
40 mg with ritonavir plus saquinavir (400 mg twice daily) or atorvastatin 20 mg with lopinavir
plus ritonavir (400 mg + 100 mg twice daily) compared to that of atorvastatin alone (see CLINICAL PHARMACOLOGY). Therefore, in patients taking HIV protease inhibitors, caution should be used when the atorvastatin dose exceeds 20 mg (see WARNINGS, Skeletal Muscle, and DOSAGE AND ADMINISTRATION).
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg (see CLINICAL PHARMACOLOGY). Therefore, in patients taking itraconazole, cautions should be used when the atorvastatin dose exceeds 20 mg (see WARNINGS, Skeletal Muscle, and DOSAGE AND ADMINISTRATION).
Grapefruit juice: Contains one or more components that inhibit CYP 3A4 and
can increase plasma concentrations of atorvastatin, especially with excessive grapefruit
juice consumption (>1.2 liters per day).
Cyclosporine: 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). In cases where co-administration of atorvastatin with cyclosporine is necessary,
the dose of atorvastatin should not exceed 10 mg (see WARNINGS, Skeletal Muscle).
Rifampin or other Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin
with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable
reductions in plasma concentrations of atorvastatin. Due to 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.
Digoxin: When multiple doses of atorvastatin and digoxin were coadministered,
steady-state plasma digoxin concentrations increased by approximately 20%. Patients
taking digoxin should be monitored appropriately.
Oral Contraceptives: Coadministration of atorvastatin and an oral contraceptive
increased AUC values for norethindrone and ethinyl estradiol (see CLINICAL PHARMACOLOGY). These increases should be considered when selecting an oral contraceptive
for a woman taking CADUET.
Warfarin: Atorvastatin had no clinically significant effect on prothrombin
time when administered to patients receiving chronic warfarin treatment.
Drug/Laboratory Test Interactions
None known.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with amlodipine: 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 maximum recommended human dose of 10 mg amlodipine/day*.
For the rat, the highest dose level was, on a mg/m2 basis,
about twice the maximum recommended human dose*.
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 maximum recommended human
dose of 10 mg/day on a mg/m2 basis).
* Based on patient weight of 50 kg.
Studies with atorvastatin: 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, and 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.
There were no effects on fertility when rats were given atorvastatin calcium at
doses equivalent to up to 175 mg atorvastatin/kg/day (15 times the human exposure).
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.
Pregnancy
Pregnancy Category X (see CONTRAINDICATIONS)
CADUET contains atorvastatin and is therefore contraindicated in women who are pregnant or may become pregnant. The atorvastatin component of CADUET may cause fetal harm when administered to a pregnant woman. CADUET should be
administered to women of child-bearing potential only when such patients are highly
unlikely to conceive and have been informed of the potential hazards. If the woman
becomes pregnant while taking CADUET, it should be discontinued immediately and the patient
advised again as to the potential hazards to the fetus, and the lack of known clinical benefit with continued use during pregnancy.
Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
Studies with amlodipine: 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 (respectively 8 times*
and 23 times* the maximum recommended human dose of 10
mg/day on a mg/m2 basis) during their respective periods
of major organogenesis. However, 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 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.
There are no adequate and well-controlled studies in pregnant women.
* Based on patient weight of 50 kg.
Studies with atorvastatin: There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during 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. Atorvastatin was not
teratogenic in rats at doses of atorvastatin calcium equivalent to up to 300 mg
atorvastatin/kg/day or in rabbits at doses of atorvastatin calcium equivalent to
up to 100 mg atorvastatin/kg/day. These doses resulted in multiples of about 30
times (rat) or
20 times (rabbit) the human exposure based on surface area (mg/m2).
In a study in rats given atorvastatin calcium at doses equivalent to 20, 100, or
225 mg atorvastatin/kg/day, from gestation day 7 through to lactation day 21 (weaning),
there was decreased pup survival at birth, neonate, weaning, and maturity for pups
of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21
for pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth
and at days 4, 21, and 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 AUC at 80 mg/day.
Labor and Delivery
No studies have been conducted in pregnant women on the effect of CADUET, amlodipine
or atorvastatin on the mother or the fetus during labor or delivery, or on the duration
of labor or delivery. Amlodipine has been shown to prolong the duration of labor
in rats.
Nursing Mothers
Studies with amlodipine: It is not known whether the amlodipine component of CADUET is excreted in human
milk.
Studies with atorvastatin: It is not known whether the atorvastatin component of CADUET is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups taking atorvastatin had plasma and liver drug levels of 50%
and 40%, respectively, of that in their mother's milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential
to cause serious adverse reactions in nursing infants, women taking CADUET, which includes atorvastatin, should be advised not to nurse their infants
(see CONTRAINDICATIONS).
Pediatric Use
There have been no studies conducted to determine the safety or effectiveness of
CADUET in pediatric populations.
Studies with amlodipine: The effect of amlodipine on blood pressure in patients
less than 6 years of age is not known.
Studies with atorvastatin: Safety and effectiveness in patients 10-17 years
of age with heterozygous familial hypercholesterolemia have been evaluated in controlled
clinical trials 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 PHARMACOLOGY,
Clinical Studies section; ADVERSE REACTIONS, Pediatric Patients;
and DOSAGE AND ADMINISTRATION, Pediatric Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia. Adolescent females should be
counseled on appropriate contraceptive methods while on atorvastatin therapy (see
CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). 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 PHARMACOLOGY, Clinical Studies, Atorvastatin
Effects in Homozygous Familial Hypercholesterolemia.
Geriatric Use
There have been no studies conducted to determine the safety or effectiveness of
CADUET in geriatric populations.
In studies with amlodipine: 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 of the amlodipine component of CADUET 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).
In studies with atorvastatin: Of the 39,828 patients who received LIPITOR 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. Since advanced age (≥65 years) is a predisposing factor for myopathy, the atorvastatin component of CADUET should be prescribed with caution in the elderly.