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]
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 ocurring in ≥ 2% in patients treated with any dose of LIPITOR and at an incidence greater
than placebo regardless of casusality (% of patients)
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] 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 x ULN twice within 4–10 days) occurred in 62 (1.3%)
individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg.
Elevations of CK (≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin
treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).
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, 0.6% Asians, 3.0% Blacks, 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 x ULN
twice within 4–10 days) in the atorvastatin group (0.9%) compared to
placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin
group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in
144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group
[see Warnings and Precautions].
In a post-hoc analysis, 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].
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, Skeletal Muscle and Clinical Pharmacology].
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]. Therefore, in patients taking
clarithromycin, caution should be used when the LIPITOR dose exceeds 20 mg
[see Warnings and Precautions, Skeletal Muscle and
Dosage and Administration].
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with
concomitant administration of LIPITOR 40 mg with ritonavir plus saquinavir
(400 mg twice daily) or LIPITOR 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily
compared to that of LIPITOR alone [see Clinical Pharmacology]. Therefore, in patients taking HIV protease
inhibitors, caution should be used when the LIPITOR dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle and Dosage and
Administration].
Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration
of LIPITOR 40 mg and itraconazole 200 mg [see Clinical Pharmacology]. Therefore,
in patients taking itraconazole, caution should be used when the LIPITOR dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle
and Dosage and Administration].
Grapefruit Juice: Contains one or more components that inhibit CYP 3A4 and can increase
plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption
(>1.2 liters per day).
Cyclosporine: Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1
transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability
of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of LIPITOR 10 mg and cyclosporine 5.2 mg/kg/day compared to that of LIPITOR alone [see Clinical Pharmacology]. In cases where co-administration of LIPITOR with cyclosporine is necessary, the dose of LIPITOR should not exceed 10 mg [see Warnings and Precautions, Skeletal Muscle].
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 coadministered, 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]. 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.