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
]
Liver enzyme abnormalities [see
Warnings
and Precautions
]
> 2%) in patients treated with LIPITOR in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at
(1-800-438-1985 and www.pfizer.com) or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
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Clinical Trial Adverse Experiences
Because clinical trials are conducted under widely varying
conditions, the adverse reaction rates observed in the clinical studies 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 2 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 2. Clinical adverse reactions occurring in ≥ 2% in patents 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
|
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
|
* Adverse Reaction ≥ 2% in any dose greater than placebo
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
] 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
] 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
] 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
] 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
].
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%).
Postmarketing Experience
The following adverse reactions have been identified during
postapproval 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, fatigue, tendon rupture, hepatic failure,
dizziness, memory impairment, depression, and peripheral neuropathy.
Pediatric Patients (ages 10-17 years)
In a 26-week controlled study in boys and postmenarchal girls
(n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the
safety and tolerability profile of LIPITOR 10 to 20 mg daily was generally
similar to that of placebo [see
Clinical
Studies
and
Use in Special
Populations, Pediatric Use
].
|