Lipitor
Generic Name: atorvastatin calcium
Dosage Form: tablet, film coated
Indications and Usage for Lipitor
Therapy with lipid-altering agents should be only
one component of multiple risk factor intervention in individuals at significantly
increased risk for atherosclerotic vascular disease due to
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 CHD or
multiple risk factors for CHD, Lipitor can be started simultaneously with diet.
Prevention of Cardiovascular Disease
in Adults
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-C, or a family history of
early coronary heart disease, Lipitor is indicated to:
· Reduce the risk of
myocardial infarction
· Reduce the risk of stroke
· Reduce the risk for revascularization
procedures and angina
In adult 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, Lipitor is indicated to:
· Reduce the risk of
myocardial infarction
· Reduce the risk of stroke
In adult patients with clinically evident coronary
heart disease, Lipitor 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 CHF
· Reduce the risk of angina
Hyperlipidemia
Lipitor is indicated:
§ As an adjunct to diet to
reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in
adult 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 adult patients with elevated serum TG levels (Fredrickson Type IV);
§ For the treatment of adult
patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not
respond adequately to diet;
§ To reduce total-C and
LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) 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 pediatric patients, 10 years to 17
years of age, with heterozygous familial hypercholesterolemia (HeFH) if after
an adequate trial of diet therapy the following findings are present:
i. LDL-C remains ≥ 190 mg/dL
or
ii.
LDL-C remains ≥ 160 mg/dL and:
i. there is a positive family
history of premature cardiovascular disease or
ii. two or more other CVD risk
factors are present in the pediatric patient
Limitations of Use
Lipitor has not been studied in conditions where
the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).
SLIDESHOW
The
Lowdown on Lipitor: What You Need To Know
Lipitor Dosage and Administration
Hyperlipidemia and Mixed Dyslipidemia
The recommended starting dose of Lipitor 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 Lipitor is 10 to
80 mg once daily. Lipitor can be administered as a single dose at any time of
the day, with or without food. The starting dose and maintenance doses of
Lipitor should be individualized according to patient characteristics such as
goal of therapy and response. After initiation and/or upon titration of
Lipitor, lipid levels should be analyzed within 2 to 4 weeks and dosage
adjusted accordingly.
Heterozygous Familial
Hypercholesterolemia in Pediatric Patients (10 Years to17 Years of Age)
The recommended starting dose of Lipitor is 10
mg/day; the usual dose range is 10 to 20 mg orally once daily [see Clinical Studies (14.6)]. Doses should be
individualized according to the recommended goal of therapy [see Indications and Usage (1.2) and Clinical Pharmacology (12)]. Adjustments should be
made at intervals of 4 weeks or more.
Homozygous Familial
Hypercholesterolemia
The dosage of Lipitor in patients with HoFH is 10
to 80 mg daily. Lipitor 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
Lipitor may be used with bile acid resins. The
combination of HMG-CoA reductase inhibitors (statins) and fibrates should
generally be used with caution [see Warnings and Precautions (5.1) and Drug Interactions (7)].
Dosage in Patients with Renal
Impairment
Renal disease does not affect the plasma
concentrations nor LDL-C reduction of Lipitor; thus, dosage adjustment in
patients with renal dysfunction is not necessary [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Dosage in Patients Taking
Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors
In patients taking cyclosporine or the HIV protease
inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor
(telaprevir), therapy with Lipitor should be avoided. In patients with HIV
taking lopinavir plus ritonavir, caution should be used when prescribing
Lipitor and the lowest dose necessary employed. 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, therapy with Lipitor should be limited to 20 mg,
and appropriate clinical assessment is recommended to ensure that the lowest
dose necessary of Lipitor is employed. In patients taking the HIV protease
inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy
with Lipitor should be limited to 40 mg, and appropriate clinical assessment is
recommended to ensure that the lowest dose necessary of Lipitor is
employed [see Warnings and Precautions (5.1) and Drug Interactions (7)].
Dosage Forms and Strengths
Lipitor tablets are white elliptical, film-coated,
and are available in four strengths (see Table 1).
Table 1: Lipitor Tablet Strengths and Identifying Features
|
|
Tablet Strength
|
Identifying Features
|
|
10
mg of atorvastatin
|
"PD
155" on one side and "10" on the other
|
|
20
mg of atorvastatin
|
"PD
156" on one side and "20" on the other.
|
|
40
mg of atorvastatin
|
"PD
157" on one side and "40" on the other
|
|
80
mg of atorvastatin
|
"PD
158" on one side and "80" on the other
|
Contraindications
· Active
Liver Disease, Which May Include Unexplained Persistent Elevations in Hepatic
Transaminase Levels
· Hypersensitivity
to Any Component of This Medication
· Pregnancy [see Use in Specific Populations (8.1)].
· Lactation [see Use in Specific Populations (8.2)].
Warnings and Precautions
Skeletal Muscle
Rare cases of rhabdomyolysis with
acute renal failure secondary to myoglobinuria have been reported with Lipitor
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 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 myopathy/rhabdomyolysis.
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, and/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 Lipitor. Lipitor therapy
should be discontinued if markedly elevated CPK levels occur or myopathy is
diagnosed or suspected.
The risk of myopathy during treatment with drugs in
this class 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
Lipitor 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 (7)]. 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 (2.6), Drug Interactions (7),
and Clinical Pharmacology (12.3)].
Table 2. Drug Interactions Associated with Increased Risk of
Myopathy/Rhabdomyolysis
|
|
Interacting Agents
|
Prescribing Recommendations
|
|
*
Use with caution and with the lowest dose
necessary (12.3)
|
|
Cyclosporine,
HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease
inhibitor (telaprevir)
|
Avoid
atorvastatin
|
|
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
|
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 Interactions (7.11)].
Lipitor 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 (e.g., severe acute
infection, hypotension, major surgery, trauma, severe metabolic, endocrine and
electrolyte disorders, and uncontrolled seizures).
Liver Dysfunction
Statins, like 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
Lipitor 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, respectively.
One patient in clinical trials 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 of Lipitor.
It is recommended that liver enzyme tests be
obtained prior to initiating therapy with Lipitor 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 Lipitor, promptly interrupt therapy. If an
alternate etiology is not found, do not restart Lipitor.
Lipitor 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 Lipitor [see Contraindications (4)].
Endocrine Function
Increases in HbA1c and fasting serum glucose levels
have been reported with HMG-CoA reductase inhibitors, including Lipitor.
Statins interfere with cholesterol synthesis and
theoretically might blunt adrenal and/or gonadal steroid production. Clinical
studies have shown that Lipitor 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
Brain hemorrhage was seen in a female dog treated
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-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
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 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 members of this 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
In a post-hoc analysis of the Stroke Prevention by
Aggressive Reduction in Cholesterol Levels (SPARCL) study where Lipitor 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 Lipitor 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 (6.1)].
Adverse Reactions
The following serious adverse reactions are
discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, the 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 clinical practice.
In the Lipitor placebo-controlled clinical trial
database of 16,066 patients (8755 Lipitor vs. 7311 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 Lipitor and 9.5% of the
patients on placebo discontinued due to adverse reactions regardless of
causality. The five most common adverse reactions in patients treated with
Lipitor 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 (0.4%).
The most commonly reported adverse reactions
(incidence ≥ 2% and greater than placebo) regardless of causality, in patients
treated with Lipitor in placebo controlled trials (n=8755) 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 Lipitor (n=8755), from seventeen
placebo-controlled trials.
Table 3. Clinical adverse reactions occurring in ≥ 2% in patients treated with any dose of Lipitor
and at an incidence greater than placebo regardless of causality (% of
patients).
|
|
Adverse Reaction*
|
Any dose
N=8755
|
10 mg
N=3908
|
20 mg
N=188
|
40 mg
N=604
|
80 mg
N=4055
|
Placebo
N=7311
|
|
*
Adverse Reaction ≥ 2% in any dose greater than placebo
|
|
Nasopharyngitis
|
8.3
|
12.9
|
5.3
|
7.0
|
4.2
|
8.2
|
|
Arthralgia
|
6.9
|
8.9
|
11.7
|
10.6
|
4.3
|
6.5
|
|
Diarrhea
|
6.8
|
7.3
|
6.4
|
14.1
|
5.2
|
6.3
|
|
Pain
in extremity
|
6.0
|
8.5
|
3.7
|
9.3
|
3.1
|
5.9
|
|
Urinary
tract infection
|
5.7
|
6.9
|
6.4
|
8.0
|
4.1
|
5.6
|
|
Dyspepsia
|
4.7
|
5.9
|
3.2
|
6.0
|
3.3
|
4.3
|
|
Nausea
|
4.0
|
3.7
|
3.7
|
7.1
|
3.8
|
3.5
|
|
Musculoskeletal
pain
|
3.8
|
5.2
|
3.2
|
5.1
|
2.3
|
3.6
|
|
Muscle
Spasms
|
3.6
|
4.6
|
4.8
|
5.1
|
2.4
|
3.0
|
|
Myalgia
|
3.5
|
3.6
|
5.9
|
8.4
|
2.7
|
3.1
|
|
Insomnia
|
3.0
|
2.8
|
1.1
|
5.3
|
2.8
|
2.9
|
|
Pharyngolaryngeal
pain
|
2.3
|
3.9
|
1.6
|
2.8
|
0.7
|
2.1
|
Other adverse reactions reported in
placebo-controlled studies include:
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.
Anglo-Scandinavian Cardiac Outcomes
Trial (ASCOT)
In ASCOT [see Clinical Studies (14.1)] involving 10,305
participants (age range 40–80 years, 19% women; 94.6% Caucasians, 2.6%
Africans, 1.5% South Asians, 1.3% mixed/other) treated with Lipitor 10 mg daily
(n=5,168) or placebo (n=5,137), the safety and tolerability profile of the
group treated with Lipitor was comparable to that of the group treated with
placebo during a median of 3.3 years of follow-up.
Collaborative Atorvastatin Diabetes
Study (CARDS)
In CARDS [see Clinical Studies (14.1)] involving 2,838
subjects (age range 39–77 years, 32% women; 94.3% Caucasians, 2.4% South
Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with
Lipitor 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in
the overall frequency of adverse reactions or serious adverse reactions between
the treatment groups during a median follow-up of 3.9 years. No cases of
rhabdomyolysis were reported.
Treating to New Targets Study (TNT)
In TNT [see Clinical Studies (14.1)] 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 Lipitor 10 mg
daily (n=5006) or Lipitor 80 mg daily (n=4995), there were more serious adverse
reactions and discontinuations due to adverse reactions in the high-dose
atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the
low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of
4.9 years. Persistent transaminase elevations (≥3 × 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 × 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%).
Incremental Decrease in Endpoints
through Aggressive Lipid Lowering Study (IDEAL)
In IDEAL [see Clinical
Studies (14.1)] involving 8,888 subjects (age
range 26–80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04%
other) treated with Lipitor 80 mg/day (n=4439) or simvastatin 20–40 mg daily
(n=4449), there was no difference in the overall frequency of adverse reactions
or serious adverse reactions between the treatment groups during a median
follow-up of 4.8 years.
Stroke Prevention by Aggressive
Reduction in Cholesterol Levels (SPARCL)
In SPARCL involving 4731 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 Lipitor 80 mg (n=2365) or
placebo (n=2366) for a median follow-up of 4.9 years, there was a higher
incidence of persistent hepatic transaminase elevations (≥ 3 × ULN twice within
4–10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%).
Elevations of CK (>10 × 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 (5.5)].
In a post-hoc analysis, Lipitor 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 Lipitor 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 non-fatal hemorrhagic strokes).
Subjects who entered the study with a hemorrhagic stroke appeared to be at
increased risk for hemorrhagic stroke [7 (16%) Lipitor vs. 2 (4%) placebo].
There were no significant differences between the
treatment groups for all-cause mortality: 216 (9.1%) in the Lipitor 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 Lipitor 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 Lipitor 80
mg group (5.0%) than in the placebo group (4.0%).
Adverse Reactions from Clinical
Studies of Lipitor in Pediatric Patients
In a 26-week controlled study in boys and
postmenarchal girls with HeFH (ages 10 years to 17 years) (n=140, 31% female;
92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and
tolerability profile of Lipitor 10 to 20 mg daily, as an adjunct to diet to
reduce total cholesterol, LDL-C, and apo B levels, was generally similar to
that of placebo [see Use
in Special Populations (8.4) and Clinical
Studies (14.6)].
Postmarketing Experience
The following adverse reactions have been
identified during post-approval use of Lipitor. 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.
Adverse reactions associated with Lipitor 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 Precautions (5.1)].
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).
Drug Interactions
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
and Precautions (5.1) and Clinical
Pharmacology (12.3)].
Strong Inhibitors of CYP 3A4
Lipitor is metabolized by cytochrome P450 3A4.
Concomitant administration of Lipitor with strong inhibitors of CYP 3A4 can
lead to increases in plasma concentrations of atorvastatin. The extent of
interaction and potentiation of effects depend on the variability of effect on
CYP 3A4.
Clarithromycin
Atorvastatin AUC was significantly increased with
concomitant administration of Lipitor 80 mg with clarithromycin (500 mg twice
daily) compared to that of Lipitor alone [see Clinical
Pharmacology (12.3)]. Therefore, in patients
taking clarithromycin, caution should be used when the Lipitor dose exceeds 20
mg [see Dosage and Administration
(2.6) and Warnings
and Precautions (5.1)].
Combination of Protease Inhibitors
Atorvastatin AUC was significantly increased with
concomitant administration of Lipitor with several combinations of HIV protease
inhibitors, as well as with the hepatitis C protease inhibitor telaprevir,
compared to that of Lipitor alone [see Clinical
Pharmacology (12.3)]. Therefore, in patients
taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C
protease inhibitor telaprevir, concomitant use of Lipitor should be avoided. In
patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution
should be used when prescribing Lipitor 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 Lipitor should not exceed 20 mg and should be used with caution [see Dosage
and Administration (2.6) and Warnings
and Precautions (5.1)]. In patients taking the
HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir,
the dose of Lipitor should not exceed 40 mg and close clinical monitoring is
recommended.
Itraconazole
Atorvastatin AUC was significantly increased with
concomitant administration of Lipitor 40 mg and itraconazole 200 mg [see Clinical
Pharmacology (12.3)]. Therefore, in patients
taking itraconazole, caution should be used when the Lipitor dose exceeds 20
mg [see Dosage and Administration
(2.6) and Warnings
and Precautions (5.1)].
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 Lipitor 10
mg and cyclosporine 5.2 mg/kg/day compared to that of Lipitor alone [see Clinical
Pharmacology (12.3)]. The co-administration of
Lipitor with cyclosporine should be avoided [see Warnings
and Precautions (5.1)].
Gemfibrozil
Due to an increased risk of myopathy/rhabdomyolysis
when HMG-CoA reductase inhibitors are co-administered with gemfibrozil,
concomitant administration of Lipitor with gemfibrozil should be avoided [see Warnings
and Precautions (5.1)].
Other Fibrates
Because it is known that the risk of myopathy
during treatment with HMG-CoA reductase inhibitors is increased with concurrent
administration of other fibrates, Lipitor should be administered with caution
when used concomitantly with other fibrates [see Warnings
and Precautions (5.1)].
Niacin
The risk of skeletal muscle effects may be enhanced
when Lipitor is used in combination with niacin; a reduction in Lipitor dosage
should be considered in this setting [see Warnings
and Precautions (5.1)].
Rifampin or other Inducers of
Cytochrome P450 3A4
Concomitant administration of Lipitor 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 Lipitor
with rifampin is recommended, as delayed administration of Lipitor after
administration of rifampin has been associated with a significant reduction in
atorvastatin plasma concentrations.
Digoxin
When multiple doses of Lipitor and digoxin were
co-administered, steady state plasma digoxin concentrations increased by
approximately 20%. Patients taking digoxin should be monitored appropriately.
Oral Contraceptives
Co-administration of Lipitor and an oral
contraceptive increased AUC values for norethindrone and ethinyl
estradiol [see Clinical Pharmacology
(12.3)]. These increases should be
considered when selecting an oral contraceptive for a woman taking Lipitor.
Warfarin
Lipitor had no clinically significant effect on
prothrombin time when administered to patients receiving chronic warfarin
treatment.
Colchicine
Cases of myopathy, including rhabdomyolysis, have
been reported with atorvastatin co-administered with colchicine, and caution
should be exercised when prescribing atorvastatin with colchicine.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
Lipitor 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, Lipitor may
cause fetal harm when administered to a pregnant woman. Lipitor should be
discontinued as soon as pregnancy is recognized [see Contraindications
(4)]. 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 maximum recommended human dose (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 estimated background risk of major birth
defects and miscarriage for the indicated population is unknown. In theU.S.general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
respectively.
Data
Human Data
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.
Animal Data
Atorvastatin crosses the rat placenta and reaches a
level in fetal liver equivalent to that of maternal plasma. Atorvastatin was
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 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 correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the
human exposure at the MRHD, based on AUC.
Lactation
Risk Summary
Lipitor use is contraindicated during
breastfeeding [see Contraindications
(4)]. 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 Lipitor.
Females and Males of Reproductive
Potential
Contraception
Lipitor may cause fetal harm when administered to a
pregnant woman. Advise females of reproductive potential to use effective
contraception during treatment with Lipitor [see Use
in Specific Populations (8.1)].
Pediatric Use
Heterozygous Familial
Hypercholesterolemia (HeFH)
The safety and effectiveness of Lipitor have been
established in pediatric patients, 10 years to 17 years of age, with HeFH as an
adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels when,
after an adequate trial of diet therapy, the following are present:
· LDL-C ≥ 190 mg/dL, or
· LDL-C ≥ 160 mg/dL and
o
a positive family history of FH, or premature CVD
in a first, or second-degree relative, or
o
two or more other CVD risk factors are present.
Use of Lipitor for this indication is supported by
evidence from [see Dosage and Administration
(2.2), Adverse Reactions (6.1), Clinical
Pharmacology (12.3), and Clinical
Studies (14.6)]:
· A placebo-controlled
clinical trial of 6 months duration in 187 boys and postmenarchal girls, 10
years to 17 years of age. Patients treated with 10 mg or 20 mg daily Lipitor
had an adverse reaction profile generally similar to that of patients treated
with placebo. In this limited controlled study, there was no significant effect
on growth or sexual maturation in boys or on menstrual cycle length in girls.
· A three year open-label
uncontrolled trial that included 163 pediatric patients 10 to 15 years of age
with HeFH who were titrated to achieve a target LDL-C < 130 mg/dL. The
safety and efficacy of Lipitor in lowering LDL-C appeared generally consistent
with that observed for adult patients, despite limitations of the uncontrolled
study design
Advise postmenarchal girls of contraception recommendations,
if appropriate for the patient [see Use
in Specific Populations (8.1), (8.3)].
The long-term efficacy of Lipitor therapy initiated
in childhood to reduce morbidity and mortality in adulthood has not been
established.
The safety and efficacy of Lipitor have not been
established in pediatric patients younger than 10 years of age with HeFH.
Homozygous Familial Hypercholesterolemia
(HoFH)
Clinical efficacy of Lipitor with dosages up to 80
mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH
including 8 pediatric patients [see Clinical
Studies (14.5)].
Geriatric Use
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, Lipitor
should be prescribed with caution in the elderly.
Hepatic Impairment
Lipitor is contraindicated in patients with active
liver disease which may include unexplained persistent elevations in hepatic
transaminase levels [see Contraindications
(4) and Clinical
Pharmacology (12.3)].
Overdosage
There is no specific treatment for Lipitor
overdosage. In the event of an overdose, the patient should be treated
symptomatically, and supportive measures instituted as required. Due to
extensive drug binding to plasma proteins, hemodialysis is not expected to
significantly enhance Lipitor clearance.
Lipitor Description
Lipitor is a synthetic lipid-lowering agent.
Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an
early and rate-limiting step in cholesterol biosynthesis.
Atorvastatin calcium is [R-(R*,
R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic
acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin
calcium is (C33H34 FN2O5)2Ca∙3H2O and its molecular weight
is 1209.42. Its structural formula is:
Atorvastatin calcium is a white to off-white
crystalline powder that 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.
Lipitor Tablets for oral administration contain 10,
20, 40, or 80 mg of atorvastatin and the following inactive ingredients:
calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF;
hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF;
microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose,
polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone
emulsion.
Lipitor - Clinical Pharmacology
Mechanism of Action
Lipitor 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,
including cholesterol. In animal models, Lipitor 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; Lipitor also reduces LDL
production and the number of LDL particles.
Pharmacodynamics
Lipitor, 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 (2)].
Pharmacokinetics
Absorption: Lipitor is rapidly
absorbed after oral administration; maximum plasma concentrations occur within
1 to 2 hours. Extent of absorption increases in proportion to Lipitor 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. Although
food decreases the rate and extent of drug absorption by approximately 25% and
9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar
whether Lipitor is given with or without food. Plasma Lipitor 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 (2)].
Distribution: Mean volume of
distribution of Lipitor is approximately 381 liters. Lipitor 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, Lipitor is
likely to be secreted in human milk [see Contraindications
(4) and Use
in Specific Populations (8.2)].
Metabolism: Lipitor 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 Lipitor.
Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is
attributed to active metabolites. In
vitro studies
suggest the importance of Lipitor metabolism by cytochrome P450 3A4, consistent
with increased plasma concentrations of Lipitor in humans following
co-administration with erythromycin, a known inhibitor of this isozyme [see Drug
Interactions (7.1)]. In animals, the
ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Lipitor 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 Lipitor in
humans is approximately 14 hours, but the half-life of inhibitory activity for
HMG-CoA reductase is 20 to 30 hours due to the contribution of active
metabolites. Less than 2% of a dose of Lipitor is recovered in urine following
oral administration.
Specific Populations
Geriatric: Plasma
concentrations of Lipitor 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 drug in the
elderly patient population compared to younger adults [see Use
in Specific Populations (8.5)].
Pediatric: Apparent oral
clearance of atorvastatin in pediatric subjects appeared similar to that of
adults when scaled allometrically by body weight as the body weight was the
only significant covariate in atorvastatin population PK model with data
including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in
an open-label, 8-week study.
Gender: Plasma concentrations of
Lipitor 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 Lipitor between men and women.
Renal Impairment: Renal disease has no
influence on the plasma concentrations or LDL-C reduction of Lipitor; thus,
dose adjustment in patients with renal dysfunction is not necessary [see Dosage
and Administration (2.5) and Warnings
and Precautions (5.1)].
Hemodialysis: While studies have
not been conducted in patients with end-stage renal disease, hemodialysis is
not expected to significantly enhance clearance of Lipitor since the drug is
extensively bound to plasma proteins.
Hepatic Impairment: In patients with
chronic alcoholic liver disease, plasma concentrations of Lipitor are markedly
increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A
disease. Cmax and AUC are approximately 16-fold and 11-fold increased,
respectively, in patients with Childs-Pugh B disease [see Contraindications
(4)].
TABLE 4. Effect of Co-administered Drugs on the Pharmacokinetics of
Atorvastatin
|
|
Co-administered drug and dosing regimen
|
Atorvastatin
|
|
|
Dose (mg)
|
Change in AUC*
|
Change in Cmax*
|
|
*
Data given
as x-fold change represent a simple ratio between co-administration and
atorvastatin alone (i.e., 1-fold = no change). Data given as % change
represent % difference relative to atorvastatin alone (i.e., 0% = no change).
†
See Sections 5.1 and 7 for clinical significance.
‡
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, caution should be
applied and the lowest dose necessary should be used.
§
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 day).
¶
Single
sample taken 8–16 h post dose.
#
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.
|
|
†Cyclosporine 5.2 mg/kg/day, stable dose
|
10
mg QD for 28 days
|
↑ 8.7 fold
|
↑ 10.7 fold
|
|
†Tipranavir 500 mg BID/ritonavir 200 mg BID, 7
days
|
10
mg, SD
|
↑ 9.4 fold
|
↑ 8.6 fold
|
|
†Telaprevir 750 mg q8h, 10 days
|
20
mg, SD
|
↑ 7.88 fold
|
↑ 10.6 fold
|
|
†, ‡Saquinavir
400 mg BID/ ritonavir 400mg BID, 15 days
|
40
mg QD for 4 days
|
↑ 3.9 fold
|
↑ 4.3 fold
|
|
†Clarithromycin 500 mg BID, 9 days
|
80
mg QD for 8 days
|
↑ 4.4 fold
|
↑ 5.4 fold
|
|
†Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days
|
10
mg QD for 4 days
|
↑ 3.4 fold
|
↑ 2.25 fold
|
|
†Itraconazole 200 mg QD, 4 days
|
40
mg SD
|
↑ 3.3 fold
|
↑ 20%
|
|
†Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14
days
|
10 mg
QD for 4 days
|
↑ 2.53 fold
|
↑ 2.84 fold
|
|
†Fosamprenavir 1400 mg BID, 14 days
|
10
mg QD for 4 days
|
↑ 2.3 fold
|
↑ 4.04 fold
|
|
†Nelfinavir 1250 mg BID, 14 days
|
10
mg QD for 28 days
|
↑ 74%
|
↑ 2.2 fold
|
|
†Grapefruit Juice, 240 mL QD §
|
40
mg, SD
|
↑ 37%
|
↑ 16%
|
|
Diltiazem
240 mg QD, 28 days
|
40
mg, SD
|
↑ 51%
|
No
change
|
|
Erythromycin
500 mg QID, 7 days
|
10
mg, SD
|
↑ 33%
|
↑ 38%
|
|
Amlodipine
10 mg, single dose
|
80
mg, SD
|
↑ 15%
|
↓ 12 %
|
|
Cimetidine
300 mg QID, 2 weeks
|
10
mg QD for 2 weeks
|
↓ Less than 1%
|
↓ 11%
|
|
Colestipol
10 mg BID, 28 weeks
|
40
mg QD for 28 weeks
|
Not
determined
|
↓ 26%¶
|
|
Maalox
TC® 30 mL QD, 17 days
|
10
mg QD for 15 days
|
↓ 33%
|
↓ 34%
|
|
Efavirenz
600 mg QD, 14 days
|
10
mg for 3 days
|
↓ 41%
|
↓ 1%
|
|
†Rifampin 600 mg QD, 7 days
(co-administered) #
|
40
mg SD
|
↑ 30%
|
↑ 2.7 fold
|
|
†Rifampin 600 mg QD, 5 days (doses
separated) #
|
40
mg SD
|
↓ 80%
|
↓ 40%
|
|
†Gemfibrozil 600mg BID, 7 days
|
40mg
SD
|
↑ 35%
|
↓ Less than 1%
|
|
†Fenofibrate 160mg QD, 7 days
|
40mg
SD
|
↑ 3%
|
↑ 2%
|
|
Boceprevir
800 mg TID, 7 days
|
40
mg SD
|
↑2.30 fold
|
↑2.66 fold
|
TABLE 5. Effect of Atorvastatin on the Pharmacokinetics of
Co-administered Drugs
|
|
Atorvastatin
|
Co-administered drug and dosing regimen
|
|
|
Drug/Dose (mg)
|
Change in AUC
|
Change in Cmax
|
|
*
See Section 7 for clinical significance.
|
|
80
mg QD for 15 days
|
Antipyrine,
600 mg SD
|
↑ 3%
|
↓ 11%
|
|
80
mg QD for 14 days
|
* Digoxin 0.25 mg QD, 20 days
|
↑ 15%
|
↑ 20 %
|
|
40
mg QD for 22 days
|
Oral
contraceptive QD, 2 months
- norethindrone 1mg
- ethinyl estradiol 35µg
|
↑ 28%
↑ 19%
|
↑ 23%
↑ 30%
|
|
10
mg, SD
|
Tipranavir
500 mg BID/ritonavir 200 mg BID, 7 days
|
No
change
|
No
change
|
|
10
mg QD for 4 days
|
Fosamprenavir
1400 mg BID, 14 days
|
↓ 27%
|
↓ 18%
|
|
10
mg QD for 4 days
|
Fosamprenavir
700 mg BID/ritonavir 100 mg BID, 14 days
|
No
change
|
No
change
|
Nonclinical Toxicology
Carcinogenesis, Mutagenesis,
Impairment of Fertility
In a 2-year carcinogenicity study in rats at dose
levels of 10, 30, and 100 mg/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 100,
200, or 400 mg/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 epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3
months (16 times the human AUC at the 80 mg dose); testis weights were
significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100
mg/kg. Male rats given 100 mg/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 10, 40, or 120 mg/kg for two years.
Clinical Studies
Prevention of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial
(ASCOT), the effect of Lipitor 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 mm Hg for non-diabetic patients; <130/80 mm Hg for
diabetic patients) and allocated to either Lipitor 10 mg daily (n=5168) or
placebo (n=5137), using a covariate adaptive method which 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 Lipitor on lipid levels
was similar to that seen in previous clinical trials.
Lipitor significantly reduced the rate of coronary
events [either fatal coronary heart disease (46 events in the placebo group vs.
40 events in the Lipitor group) or non-fatal MI (108 events in the placebo
group vs. 60 events in the Lipitor group)] with a relative risk reduction of
36% [(based on incidences of 1.9% for Lipitor vs. 3.0% for placebo), p=0.0005
(see Figure
1)]. The risk reduction was consistent regardless of age, smoking status,
obesity, or presence of renal dysfunction. The effect of Lipitor was seen
regardless of baseline LDL levels. Due to the small number of events, results
for women were inconclusive.
Figure 1: Effect of Lipitor 10 mg/day on Cumulative Incidence of
Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in
ASCOT-LLA)
|
|
Lipitor also significantly decreased the relative
risk for revascularization procedures by 42% (incidences of 1.4% for Lipitor
and 2.5% for placebo). 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 Lipitor and
2.3% for placebo). There was no significant difference between the treatment
groups for death due to cardiovascular causes (p=0.51) or noncardiovascular
causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study
(CARDS), the effect of Lipitor on cardiovascular disease (CVD) 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 Lipitor 10 mg daily (1429) or placebo (1411)
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 Lipitor 10 mg/day on lipid levels was
similar to that seen in previous clinical trials.
Lipitor significantly reduced the rate of major
cardiovascular events (primary endpoint events) (83 events in the Lipitor 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
2). An effect of Lipitor was seen regardless of age, sex, or baseline
lipid levels.
Lipitor significantly reduced the risk of stroke by
48% (21 events in the Lipitor 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 Lipitor 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 death.
There were 61 deaths in the Lipitor group vs. 82
deaths in the placebo group (HR 0.73, p=0.059).
Figure 2: Effect of Lipitor 10 mg/day on Time to Occurrence of Major
Cardiovascular Event (myocardial infarction, acute CHD death, unstable
angina, coronary revascularization, or stroke) in CARDS
|
|
In the Treating to New Targets Study (TNT), the
effect of Lipitor 80 mg/day vs. Lipitor 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 Lipitor 10 mg/day. Subjects were randomly assigned to either 10
mg/day or 80 mg/day of Lipitor 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 due to 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 Lipitor and 99, 177,
152, 129, and 48 mg/dL during treatment with 10 mg of Lipitor.
Treatment with Lipitor 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
3 and Table 6). The overall risk
reduction was consistent regardless of age (<65, ≥65) or gender.
Figure 3: Effect of Lipitor 80 mg/day
vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
TABLE 6. Overview of Efficacy Results in TNT
|
|
Endpoint
|
Atorvastatin
10 mg
(N=5006)
|
Atorvastatin
80 mg
(N=4995)
|
HR* (95%CI)
|
|
PRIMARY ENDPOINT
|
n
|
(%)
|
n
|
(%)
|
|
|
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
|
|
*
Atorvastatin
80 mg: atorvastatin 10 mg
†
Secondary
endpoints not included in primary endpoint
‡
Component of other secondary endpoints
|
|
First
major cardiovascular endpoint
|
548
|
(10.9)
|
434
|
(8.7)
|
0.78 (0.69, 0.89)
|
|
Components of the Primary Endpoint
|
|
|
|
|
|
|
CHD death
|
127
|
(2.5)
|
101
|
(2.0)
|
0.80 (0.61, 1.03)
|
|
Non-fatal,
non-procedure related MI
|
308
|
(6.2)
|
243
|
(4.9)
|
0.78 (0.66, 0.93)
|
|
Resuscitated
cardiac arrest
|
26
|
(0.5)
|
25
|
(0.5)
|
0.96 (0.56, 1.67)
|
|
Stroke
(fatal and non-fatal)
|
155
|
(3.1)
|
117
|
(2.3)
|
0.75 (0.59, 0.96)
|
|
SECONDARY ENDPOINTS†
|
|
|
|
|
|
|
First
CHF with hospitalization
|
164
|
(3.3)
|
122
|
(2.4)
|
0.74 (0.59, 0.94)
|
|
First
PVD endpoint
|
282
|
(5.6)
|
275
|
(5.5)
|
0.97 (0.83, 1.15)
|
|
First
CABG or other coronary revascularization procedure‡
|
904
|
(18.1)
|
667
|
(13.4)
|
0.72 (0.65, 0.80)
|
|
First
documented angina endpoint‡
|
615
|
(12.3)
|
545
|
(10.9)
|
0.88 (0.79, 0.99)
|
|
All-cause
mortality
|
282
|
(5.6)
|
284
|
(5.7)
|
1.01 (0.85, 1.19)
|
|
Components of All-Cause Mortality
|
|
|
|
|
|
|
Cardiovascular
death
|
155
|
(3.1)
|
126
|
(2.5)
|
0.81 (0.64, 1.03)
|
|
Noncardiovascular
death
|
127
|
(2.5)
|
158
|
(3.2)
|
1.25 (0.99, 1.57)
|
|
Cancer
death
|
75
|
(1.5)
|
85
|
(1.7)
|
1.13 (0.83, 1.55)
|
|
Other
non-CV death
|
43
|
(0.9)
|
58
|
(1.2)
|
1.35 (0.91, 2.00)
|
|
Suicide,
homicide, and other traumatic non-CV death
|
9
|
(0.2)
|
15
|
(0.3)
|
1.67 (0.73, 3.82)
|
Of the events that comprised the primary efficacy
endpoint, treatment with Lipitor 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 6). Of the predefined secondary
endpoints, treatment with Lipitor 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 CHF.
There was no significant difference between the
treatment groups for all-cause mortality (Table 6). The proportions of subjects
who experienced cardiovascular death, including the components of CHD death and
fatal stroke, were numerically smaller in the Lipitor 80 mg group than in the
Lipitor 10 mg treatment group. The proportions of subjects who experienced
noncardiovascular death were numerically larger in the Lipitor 80 mg group than
in the Lipitor 10 mg treatment group.
In the Incremental Decrease in Endpoints Through
Aggressive Lipid Lowering Study (IDEAL), treatment with Lipitor 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 Lipitor 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 Lipitor 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 Lipitor 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 Lipitor 80 mg group and
the simvastatin 20–40 mg group.
Hyperlipidemia and Mixed Dyslipidemia
Lipitor reduces total-C, LDL-C, VLDL-C, apo B, and
TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial
and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb).
Therapeutic response is seen within 2 weeks, and maximum response is usually
achieved within 4 weeks and maintained during chronic therapy.
Lipitor 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, Lipitor given as a
single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG.
(Pooled results are provided in Table 7.)
TABLE 7. Dose Response in Patients With Primary Hyperlipidemia
(Adjusted Mean % Change From Baseline)*
|
|
Dose
|
N
|
TC
|
LDL-C
|
Apo B
|
TG
|
HDL-C
|
Non-HDL-C/ HDL-C
|
|
*
Results are pooled from 2 dose-response studies.
|
|
Placebo
|
21
|
4
|
4
|
3
|
10
|
-3
|
7
|
|
10
|
22
|
-29
|
-39
|
-32
|
-19
|
6
|
-34
|
|
20
|
20
|
-33
|
-43
|
-35
|
-26
|
9
|
-41
|
|
40
|
21
|
-37
|
-50
|
-42
|
-29
|
6
|
-45
|
|
80
|
23
|
-45
|
-60
|
-50
|
-37
|
5
|
-53
|
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 Lipitor 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, Lipitor was compared to other statins. After
randomization, patients were treated for 16 weeks with either Lipitor 10 mg per
day or a fixed dose of the comparative agent (Table 8).
TABLE 8. Mean Percentage Change From Baseline at Endpoint (Double-Blind,
Randomized, Active-Controlled Trials)
|
|
Treatment
(Daily Dose)
|
N
|
Total-C
|
LDL-C
|
Apo B
|
TG
|
HDL-C
|
Non-HDL-C/ HDL-C
|
|
*
Significantly
different from lovastatin, ANCOVA, p ≤0.05
†
A negative
value for the 95% CI for the difference between treatments favors Lipitor for
all except HDL-C, for which a positive value favors Lipitor. If the range
does not include 0, this indicates a statistically significant difference.
‡
Significantly
different from pravastatin, ANCOVA, p ≤0.05
§
Significantly different from simvastatin, ANCOVA,
p ≤0.05
|
|
Study 1
|
|
|
|
|
|
|
|
|
Lipitor
10 mg
|
707
|
-27*
|
-36*
|
-28*
|
-17*
|
+7
|
-37*
|
|
Lovastatin
20 mg
|
191
|
-19
|
-27
|
-20
|
-6
|
+7
|
-28
|
|
95%
CI for Diff†
|
|
-9.2, -6.5
|
-10.7, -7.1
|
-10.0, -6.5
|
-15.2, -7.1
|
-1.7, 2.0
|
-11.1, -7.1
|
|
Study 2
|
|
|
|
|
|
|
|
|
Lipitor
10 mg
|
222
|
-25‡
|
-35‡
|
-27‡
|
-17‡
|
+6
|
-36‡
|
|
Pravastatin
20 mg
|
77
|
-17
|
-23
|
-17
|
-9
|
+8
|
-28
|
|
95%
CI for Diff†
|
|
-10.8, -6.1
|
-14.5, -8.2
|
-13.4, -7.4
|
-14.1, -0.7
|
-4.9, 1.6
|
-11.5, -4.1
|
|
Study 3
|
|
|
|
|
|
|
|
|
Lipitor
10 mg
|
132
|
-29§
|
-37§
|
-34§
|
-23§
|
+7
|
-39§
|
|
Simvastatin
10 mg
|
45
|
-24
|
-30
|
-30
|
-15
|
+7
|
-33
|
|
95%
CI for Diff†
|
|
-8.7, -2.7
|
-10.1, -2.6
|
-8.0, -1.1
|
-15.1, -0.7
|
-4.3, 3.9
|
-9.6, -1.9
|
The impact on clinical outcomes of the differences
in lipid-altering effects between treatments shown in Table 8 is not known.
Table 8 does not contain data comparing the effects of Lipitor 10 mg and higher
doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the
studies summarized in the table are not necessarily interchangeable.
Hypertriglyceridemia
The response to Lipitor in 64 patients with
isolated hypertriglyceridemia (Fredrickson Type IV) treated
across several clinical trials is shown in the table below (Table 9). For the
Lipitor-treated patients, median (min, max) baseline TG level was 565
(267–1502).
TABLE 9. Combined Patients With Isolated Elevated TG: Median (min,
max) Percentage Change From Baseline
|
|
|
Placebo
(N=12)
|
Lipitor 10 mg
(N=37)
|
Lipitor 20 mg
(N=13)
|
Lipitor 80 mg
(N=14)
|
|
Triglycerides
|
-12.4
(-36.6, 82.7)
|
-41.0
(-76.2, 49.4)
|
-38.7
(-62.7, 29.5)
|
-51.8
(-82.8, 41.3)
|
|
Total-C
|
-2.3
(-15.5, 24.4)
|
-28.2
(-44.9, -6.8)
|
-34.9
(-49.6, -15.2)
|
-44.4
(-63.5, -3.8)
|
|
LDL-C
|
3.6
(-31.3, 31.6)
|
-26.5
(-57.7, 9.8)
|
-30.4
(-53.9, 0.3)
|
-40.5
(-60.6, -13.8)
|
|
HDL-C
|
3.8
(-18.6, 13.4)
|
13.8
(-9.7, 61.5)
|
11.0
(-3.2, 25.2)
|
7.5
(-10.8, 37.2)
|
|
VLDL-C
|
-1.0
(-31.9, 53.2)
|
-48.8
(-85.8, 57.3)
|
-44.6
(-62.2, -10.8)
|
-62.0
(-88.2, 37.6)
|
|
non-HDL-C
|
-2.8
(-17.6, 30.0)
|
-33.0
(-52.1, -13.3)
|
-42.7
(-53.7, -17.4)
|
-51.5
(-72.9, -4.3)
|
Dysbetalipoproteinemia
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 10).
TABLE 10. Open-Label Crossover Study of 16 Patients With
Dysbetalipoproteinemia (Fredrickson Type III)
|
|
|
|
Median % Change (min, max)
|
|
|
Median (min, max) at Baseline (mg/dL)
|
Lipitor 10 mg
|
Lipitor 80 mg
|
|
Total-C
|
442 (225, 1320)
|
-37 (-85, 17)
|
-58 (-90, -31)
|
|
Triglycerides
|
678 (273, 5990)
|
-39 (-92, -8)
|
-53 (-95, -30)
|
|
IDL-C
+ VLDL-C
|
215 (111, 613)
|
-32 (-76, 9)
|
-63 (-90, -8)
|
|
non-HDL-C
|
411 (218, 1272)
|
-43 (-87, -19)
|
-64 (-92, -36)
|
Homozygous Familial Hypercholesterolemia
In a study without a concurrent control group, 29
patients ages 6 years to 37 years with HoFH received maximum daily doses of 20
to 80 mg of Lipitor. 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%.
Heterozygous Familial
Hypercholesterolemia in Pediatric Patients
In a double-blind, placebo-controlled study
followed by an open-label phase, 187 boys and post-menarchal girls 10 years to
17 years of age (mean age 14.1 years) with heterozygous familial
hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to
Lipitor (n=140) or placebo (n=47) for 26 weeks and then all received Lipitor
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 Lipitor group compared to 230.0 mg/dL (range: 160.0–324.5 mg/dL)
in the placebo group. The dosage of Lipitor (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 Lipitor-treated patients who required uptitration to 20 mg after
Week 4 during the double-blind phase was 78 (55.7%).
Lipitor significantly decreased plasma levels of
total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week
double-blind phase (see Table
11).
TABLE 11. Lipid-altering Effects of Lipitor in Adolescent Boys and
Girls with Heterozygous Familial Hypercholesterolemia or Severe
Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in
Intention-to-Treat Population)
|
|
DOSAGE
|
N
|
Total-C
|
LDL-C
|
HDL-C
|
TG
|
Apolipoprotein B
|
|
Placebo
|
47
|
-1.5
|
-0.4
|
-1.9
|
1.0
|
0.7
|
|
Lipitor
|
140
|
-31.4
|
-39.6
|
2.8
|
-12.0
|
-34.0
|
The mean achieved LDL-C value was 130.7 mg/dL
(range: 70.0–242.0 mg/dL) in the Lipitor 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.
Atorvastatin was also studied in a three year
open-label, uncontrolled trial that included 163 patients with HeFH who were 10
years to 15 years old (82 boys and 81 girls). All patients had a clinical
diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by
family history). Approximately 98% were Caucasian, and less than 1% were Black
or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin
dosage was 10 mg once daily and doses were adjusted to achieve a target of <
130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally
consistent across age groups within the trial as well as with previous clinical
studies in both adult and pediatric placebo-controlled trials.
The long-term efficacy of Lipitor therapy in childhood
to reduce morbidity and mortality in adulthood has not been established.
How Supplied/Storage and Handling
10 mg tablets (10 mg of
atorvastatin): coded "PD 155" on one side and "10" on the
other.
NDC 0071-0155-23 bottles of 90
NDC 0071-0155-34 bottles of 5000
NDC 0071-0155-40 10 × 10 unit dose blisters
NDC 0071-0155-10 bottles of 1000
20 mg tablets (20 mg of
atorvastatin): coded "PD 156" on one side and "20" on the
other.
NDC 0071-0156-23 bottles of 90
NDC 0071-0156-40 10 × 10 unit dose blisters
NDC 0071-0156-94 bottles of 5000
NDC 0071-0156-10 bottles of 1000
40 mg tablets (40 mg of
atorvastatin): coded "PD 157" on one side and
"40" on the other.
NDC 0071-0157-23 bottles of 90
NDC 0071-0157-73 bottles of 500
NDC 0071-0157-88 bottles of 2500
NDC 0071-0157-40 10 × 10 unit dose blisters
80 mg tablets (80 mg of
atorvastatin): coded "PD 158" on one side and
"80" on the other.
NDC 0071-0158-23 bottles of 90
NDC 0071-0158-73 bottles of 500
NDC 0071-0158-88 bottles of 2500
NDC 0071-0158-92 8 × 8 unit dose blisters
Storage
Store at controlled room temperature 20 – 25°C (68
– 77°F) [see USP].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Patient Information).
Patients taking Lipitor should be advised 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.
Patients should be advised about
substances they should not take concomitantly with atorvastatin [see Warnings
and Precautions (5.1)].
Patients should also be advised to inform other healthcare professionals
prescribing a new medication that they are taking Lipitor.
Muscle Pain
All patients starting therapy with Lipitor should
be advised of the risk of myopathy and told 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 Lipitor.
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 professional.
Liver Enzymes
It is recommended that liver enzyme tests be
performed before the initiation of Lipitor and if signs or symptoms of liver
injury occur. All patients treated with Lipitor should be advised to report
promptly any symptoms that may indicate liver injury, including fatigue,
anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Embryofetal Toxicity
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 [see Contraindications
(4) and Use
in Specific Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment
with Lipitor [see Contraindications
(4) and Use
in Specific Populations (8.2)].
This product's label may have been updated. For
current full prescribing information, please visit www.pfizer.com.
LAB-0021-33.0
PATIENT INFORMATION
Lipitor®
atorvastatin calcium
tablets
(LIP-ih-tore))
Read the Patient Information that comes with
Lipitor before you start taking it and each time you get a refill. There may be
new information. This leaflet does not take the place of talking with your
doctor about your condition or treatment.
If you have any questions about Lipitor, ask your
doctor or pharmacist.
What is Lipitor?
Lipitor is a prescription medicine that lowers
cholesterol in your blood. It lowers the LDL-C ("bad" cholesterol)
and triglycerides in your blood. It can raise your HDL-C ("good"
cholesterol) as well. Lipitor is for adults and children over 10 whose
cholesterol does not come down enough with exercise and a low-fat diet alone.
Lipitor can 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
HDL-C, heart disease in the family.
Lipitor can lower the risk for heart attack or
stroke in patients with diabetes and risk factors such as:
eye problems, kidney problems,
smoking, or high blood pressure.
Lipitor starts to work in about 2 weeks.
What is Cholesterol?
Cholesterol and triglycerides are fats that are
made in your body. They are also found in foods. You need some cholesterol for
good health, but too much is not good for you. Cholesterol and triglycerides
can clog your blood vessels. It is especially important to lower your
cholesterol if you have heart disease, smoke, have diabetes or high blood
pressure, are older, or if heart disease starts early in your family.
Who Should Not Take Lipitor?
Do not take Lipitor if you:
are pregnant or think you may be
pregnant, or are planning to become pregnant. Lipitor may harm your unborn
baby. If you get pregnant, stop taking Lipitor and call your doctor right
away.are breast feeding. Lipitor can pass into your
breast milk and may harm your baby.have liver problems.are allergic to Lipitor or any of
its ingredients. The active ingredient is atorvastatin. See the end of
this leaflet for a complete list of ingredients in Lipitor.
Lipitor dosing has not been established in children
under 10 years of age.
Before You Start Lipitor
Tell your doctor if you:
have muscle aches or weaknessdrink more than 2 glasses of
alcohol dailyhave diabeteshave a thyroid problemhave kidney problems
Some medicines should not be taken with Lipitor.
Tell your doctor about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. Lipitor and
certain other medicines can interact causing serious side effects. Especially
tell your doctor if you take medicines for:
your immune systemcholesterolinfectionsbirth controlheart failureHIV or AIDS
Know all the medicines you take. Keep a list of
them with you to show your doctor and pharmacist.
How Should I Take Lipitor?
Take Lipitor exactly as prescribed
by your doctor. Do not change your dose or stop Lipitor without talking to
your doctor. Your doctor may do blood tests to check your cholesterol
levels during your treatment with Lipitor. Your dose of Lipitor may be
changed based on these blood test results.Take Lipitor each day at any time
of day at about the same time each day. Lipitor can be taken with or
without food.
Don't break Lipitor tablets before taking.Your doctor should start you on a
low-fat diet before giving you Lipitor. Stay on this low-fat diet when you
take Lipitor.If you miss a dose of Lipitor, take
it as soon as you remember. Do not take Lipitor if it has been more than
12 hours since you missed your last dose. Wait and take the next dose at
your regular time. Do not take 2 doses of Lipitor at the same time.If you take too much Lipitor or
overdose, call your doctor or Poison Control Center right away. Or go to
the nearest emergency room.
What Should I Avoid While Taking
Lipitor?
Talk to your doctor before you
start any new medicines. This includes prescription and non-prescription
medicines, vitamins, and herbal supplements. Lipitor and certain other
medicines can interact causing serious side effects.Do not get pregnant. If you get
pregnant, stop taking Lipitor right away and call your doctor.
What are the Possible Side Effects of
Lipitor?
Lipitor can cause serious side
effects. These side effects have happened 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 Lipitor is stopped. These serious side effects include:
Muscle
problems. Lipitor
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 with Lipitor.Liver
problems. Your
doctor should do blood tests to check your liver before you start taking
Lipitor and if you have symptoms of liver problems while you take Lipitor.
Call your doctor right away if you have the following symptoms of liver
problems:
o
feel tired or weak
o
loss of appetite
o
upper belly pain
o
dark amber colored urine
o
yellowing of your skin or the whites of your eyes
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 Lipitor. 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.nausea and vomiting.passing brown or dark-colored
urine.you feel more tired than usualyour skin and whites of your eyes
get yellow.stomach pain.allergic skin reactions.
In clinical studies, patients reported the
following common side effects while taking Lipitor: diarrhea, upset stomach,
muscle and joint pain, and alterations in some laboratory blood tests.
The following additional side effects have been
reported with Lipitor:
tiredness, tendon problems, memory loss, and
confusion.
Talk to your doctor or pharmacist if you have side
effects that bother you or that will not go away.
These are not all the side effects of Lipitor. Ask
your doctor or pharmacist for a complete list.
How do I store Lipitor
Store Lipitor at room temperature,
68 to 77°F (20 to 25°C).Do not keep medicine that is out of
date or that you no longer need.Keep
Lipitor and all medicines out of the reach of children. Be sure that if you throw
medicine away, it is out of the reach of children.
General Information About Lipitor
Medicines are sometimes prescribed for conditions
that are not mentioned in patient information leaflets. Do not use Lipitor for
a condition for which it was not prescribed. Do not give Lipitor to other
people, even if they have the same problem you have. It may harm them.
This leaflet summarizes the most important
information about Lipitor. If you would like more information, talk with your
doctor. You can ask your doctor or pharmacist for information about Lipitor
that is written for health professionals. Or you can go to the Lipitor website
at www.Lipitor.com.
What are the Ingredients in Lipitor?
Active Ingredient: atorvastatin calcium
Inactive Ingredients: calcium carbonate,
USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose,
NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline
cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc,
titanium dioxide); polysorbate 80, NF; simethicone emulsion.
LAB-0348-9.0
June 2017
