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Special Populations and Special Considerations
for Dosing
Primary Hypercholesterolemia and Combined
( Mixed) Hyperlipidemia (Atereastatin Studies)
The majority of patients are controlled with 10 mg atorvastatin once a day. A therapeutic response is
evident within two weeks, and the maximum
response is usually achieved within four weeks. The
response is maintained during chronic therapy.
Homozygous Familial Hypercholesterolemia
(Atorvastatin Studies)
In a compassionate use study of patients with
homozygous familial hypercholesterolemia, most
patients responded to 80 mg of atorvastatin with a
greater than 15% reduction in LDL-C (18%-45%)
.
Use in Patients with Impaired Hepatic Function
Amlodipine/atorvastatin should not be used in
patients with hepatic impairment (see section 4.3
Contraindications and section 4.4 Special
Warnings and Special Precautions for Use).
Use in Patients with Impaired Renal Function
No adjustment of the dose is required in patients
with impaired renal function.
Use in the Elderly
No adjustment of the dose is required in elderly
patients.
Use In Children
There have been no studies conducted to
determine the safety or effectiveness of amlodipine/atorvastatin (combination product) in pediatric
populations.
4.3 Contraindications
Amlodipine/atorvastatin is contraindicated in
patients who have
1. Known hypersensitivity to dihydropyridines,
amlodipine, atorvastatin, or any component
of this medication,
2. Active liver disease or unexplained persistent
elevations of serum transaminases exceeding
three times the upper limit of normal,
3. Or who are pregnant, breast-feeding, or of
childbearing potential who are not using
adequate contraceptive measures. Amlodipine/atorvastatin should be administered to women
of childbearing age only when such patients are
highly unlikely to conceive and have been
informed of the potential hazards to the fetus.
4.4 Special Warnings and Special Precautions
for Use
Use in Patients with Heart Failure
In a long-term, placebo controlled study (PRAISE-2)
of amlodipine-treated patients with NYHA III and IV
head failure of non-ischemic etiology, amlodipine
was associated with increased reports of
pulmonary edema despite no significant difference
in the incidence of worsening head failure as
compared to placebo (see section 5.1
Pharmacodynamic Properties).
Use in Patients with Impaired Hepatic Function
(See also section 4.3 Contraindications)
Hepatic Effects
As with other lipid lowering agents of the HMG-CoA
reductase inhibitor class, moderate (>3 x upper
limit of normal [ULN) elevations of serum
transaminases have been reported following
therapy with atorvastatin. Liver function was
monitored during pre-marketing as well as
post mothering clinical studies of atorvastatin given
at doses of 10, 20 , 40 and 80 mg.
Persistent increases in serum transaminases (>3 x
ULN on two or more occasions) occurred in 0.7% of
patients who received atorvastatin in these clinical
trials. The incidence of these abnormalities was
0.2%, 0.2%, 0.6% and 2.3% for 10, 20, 40 and
80mg respectively. Increases were generally not
associated with jaundice or other clinical signs or
symptoms. When the dosage of atorvastatin was
reduced, or drug treatment interrupted or
discontinued, transaminase levels returned to
pre-treatment levels. Most patients continued
treatment on a reduced dose of atorvastatin without
sequelae.
Liver function tests should be performed before the
initiation of treatment and periodically thereafter.
Patients who develop any signs or symptoms
suggesting liver injury should have liver function
tests performed. Patients who develop increased transaminase levels should be monitored until the
abnormality(ies) resolve(s). Should an increase in
ALT or AST of greater than three times the upper
limit of normal persist, reduction of dose or
withdrawal of amlodipine/atorvastatin is
recommended. Atorvastatin can cause an elevation
in transaminases (see section 4.8 Undesirable
Effects).
Amlodipine/atorvastatin should be used with
caution in patients who consume substantial
quantities of alcohol and/or have a history of liver
disease. Active liver disease or unexplained
persistent transaminase elevations are
contraindications to the use of
amlodipine/atorvastatin (see section 4.3
Contraindications).
Increased Angina and/or Myocardial Infarction
Rarely, patients particularly those with severe
obstructive coronary artery disease, have
developed documented increased frequency,
duration and/or severity of angina or acute
myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase.
The mechanism of this effect has not been
elucidated.
Skeletal Muscle Effects
Myalgia has been reported in atorvastatin treated
patients (see section 4.8 Undesirable Effects)
Myopathy, defined as muscle aching or muscle
weakness in conjunction with increases in creatine phosphokinase (CPK) values
>10 ULN, should be
considered in any patient with diffuse myalgias,
muscle tenderness or weakness, and/or marked
elevation of CPK Patients should be advised to
promptly report unexplained muscle pain,
tenderness or weakness, particularly if
accompanied by malaise or fever
Amlodipine/atorvastatin therapy should be
discontinued if markedly elevated CPK levels occur
or myopathy is diagnosed or suspected. The risk of
myopathy during treatment with HMG-CoA
reductase inhibitors is increased with concurrent
administration of cyclosporine, fibric acid
derivatives, erythromycin, niacin, or azole
antifungals. Many of these drugs inhibit cytochrome
P450 3A4 metabolism and/or drug-transport. CYP
3A4 is the primary hepatic isozymes known to be
involved in the biobansformation of atorvastatin.
Physicians considering combined therapy with
atorvastatin and fibric acid derivatives,
erythromycin, immunosuppressive drugs, azole
antifungals, or lipid lowering doses of niacin should
carefully weigh the potential benefits and risks and
should carefully monitor patients for any signs and
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. Periodic creation
phosphokinase (CPK) determinations may be
considered in such situations, but there is no
assurance that such monitoring will prevent the
occurrence of severe myopathy (see section 4.5
Interaction with Other Medicaments and Other
Forms of Interaction). Amlodipine/atorvastatin
may cause an elevation of creative phosphokinase
due to the atorvastatin component (see section 4.8
Undesirable Effects).
As with other drugs in the class of HMG-CoA
reductase inhibitors, rare cases of rhabdomyolysis
with acute renal failure secondary to myoglobinuria,
have been reported. Amlodipine/atorvastatin
therapy should be temporarily withheld or
discontinued 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, (eg., severe
acute infection, hypotension, major surgery, trauma,
severe metabolic, endocrine and electrolyte
disorders, arid uncontrolled seizures). Control of
hypertension may be continued with the
appropriate dose of amlodipine.
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
HMG-CoA reductase inhibitors, 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 HMG-CoA
reductase inhibitors on male fertility have not been
studied in adequate numbers of patients. The
effects, it any, on the pituitary-gonadal axis in
premenopausal women are unknown. Caution
should be exercised if an HMG-CoA reductase
inhibitor 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 female dog treated with atorvastatin
calcium for 3 months at a dose equivalent to 120mg
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 280mg atorvastatin/kg/day.
The 120mg/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
80mg/day. A single tonic convulsion was seen in
each of 2 male dogs (one treated with atorvastatin calcium at a dose equivalent to 10mg atorvastatin/kg/day and one at a dose equivalent
to 120mg atorvastatin/kg/day) in a 2-year study.
No CNS lesions have been observed in mice offer
chronic treatment for up to 2 years at doses of
atorvastatin calcium equivalent to up to 400mg
atorvastatin/kg/day or in rats at doses equivalent
to up to 100mg 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 80mg
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
HMG-CoA reductase 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.
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