CLINICAL PHARMACOLOGY
Mechanism Of Action
LIPITOR is a selective,
competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that
converts 3-hydroxy-3methylglutaryl-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].
Pharmacokinetics
Absorption
LIPITOR is rapidly absorbed
after oral administration; maximum plasma concentrations occur within 1 to
2hours. 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].
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 and Use in Specific
Populations].
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]. 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 14hours, but
the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30hours due
to the contribution of active metabolites. Less than2% 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 ≥ 65years)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].
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 10years to 17years 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 and WARNINGS AND PRECAUTIONS].
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].
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& |
#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%** |
MaaloxTC® 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 (coadministered) † |
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 |
& 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 WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION for clinical significance.
* Greater increases in AUC (up to2.5fold)and/or Cmax(up to 71%)have been
reported with excessive grapefruit consumption ( ≥ 750 mL -1.2 liters per
day).
** Single sample taken 8-16h 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.
‡ The dose of saquinavir plus ritonavir in this study is not the clinically
used dose. The increase in atorvastatin exposure when used clinicallyis likely
to be higher than what was observed in this study. Therefore, caution should be
applied and the lowest dose necessary should be used. |
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 |
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 |
↑ 28% |
↑ 23% |
ethinyl estradiol 35μg |
↑ 19% |
↑ 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 |
# See DOSAGE AND ADMINISTRATION for clinical significance. |
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 63years), without a previous myocardial infarction and with TC levels
≤ 251mg/dL (6.5mmol/L). Additionally, all patients had at least 3 of the following
cardiovascular risk factors: male gender (81.1%), age > 55years
(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 mmHg for non-diabetic patients; < 130/80 mmHg for diabetic
patients) and allocated to either LIPITOR10mg 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 10mg/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 non-cardiovascular causes
(p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS),
the effect of LIPITOR on cardiovascular disease (CVD)endpoints was assessed in
2838subjects (94%white, 68% male), ages 40-75with 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 clinicaltrial, subjects were randomly
allocated to either LIPITOR 10mg daily (1429) or placebo (1411) ina1:1ratio 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, unstableangina, 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 HbA1c7.7%; 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 10mg/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. 127events in the placebo group) with a relative risk reduction of 37%,
HR0.63,95%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%
(21events 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 61deaths 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 LIPITOR80 mg/day vs. LIPITOR10 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 cardiacarrest, 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 47mg/dL during treatment with 80 mg of
LIPITOR and 99, 177, 152, 129, and 48mg/dL during treatment with 10mg of LIPITOR.
Treatment with LIPITOR80mg/day
significantly reduced the rate of MCVE(434 events in the 80 mg/day group vs.
548eventsin the 10 mg/day group) with a relative risk reduction of 22%,
HR0.78,95%CI(0.69, 0.89),p=0.0002(see Figure 3 and Table6). The
overallrisk reduction was
consistent regardless of age( < 65, ≥ 65) or gender.
Figure 3:Effect of
LIPITOR 80mg/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) |
HRa
(95% CI) |
PRIMARY ENDPOINT |
n |
(%) |
n |
(%) |
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 procedureb |
904 |
(18.1) |
667 |
(13.4) |
0.72
(0.65, 0.80) |
First documented angina endpointb |
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-CVdeath |
43 |
(0.9) |
58 |
(1.2) |
1.35
(0.91, 2.00) |
Suicide, homicide, and other traumatic non-CVdeath |
9 |
(0.2) |
15 |
(0.3) |
1.67
(0.73, 3.82) |
a Atorvastatin 80 mg:atorvastatin 10 mg
b Component of other secondary endpoints
* Secondary endpoints not included in primary endpoint 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 |
Of the events that comprised the primary efficacy
endpoint, treatment with LIPITOR 80 mg/day significantly reduced the rate of
nonfatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD
death or resuscitated cardiac arrest (Table6). 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 (Table6). 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 non-cardiovascular
death were numerically larger in the LIPITOR80 mg group than in the LIPITOR 10
mg treatment group.
In the Incremental Decrease in
Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with
LIPITOR80mg/day was compared to treatment with simvastatin 20-40 mg/day in
8,888 subjects up to80 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 61.7years, and an average LDL-Cof121.5 mg/dL at
randomization; 76% were on stat in 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 100mg/dL during
treatment with 80 mg of LIPITOR and105,179, 142, 47, and 132mg/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 LIPITOR80 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 80mg/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 non familial)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 doseover 6weeks,significantly reduced total-C, LDL-C,
apo B, and TG.(Pooled results are provided in Table7.)
TABLE 7: Dose Response in Patients With Primary
Hyperlipidemia (Adjusted Mean % Change From Baseline)a
Dose |
N |
TC |
LDL-C |
Apo B |
TG |
HDL-C |
Non-HDL-C/ HDL-C |
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 |
a Results are pooled from 2dose-response
studies. |
In patients with Fredrickson Types IIa and IIb
hyperlipoproteinemia pooled from 24controlled trials, the median (25th
and 75th percentile) percent changes from baseline in HDL-C for LIPITOR 10, 20,
40, and80mg 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 LIPITOR10mgper day or afixed
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 |
Study 1 |
LIPITOR 10 mg |
707 |
-27a |
-36a |
-28a |
-17a |
+7 |
-37a |
Lovastatin 20 mg |
191 |
-19 |
-27 |
-20 |
-6 |
+7 |
-28 |
95% CI for Diff1 |
|
-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 |
-25b |
-35b |
-27b |
-17b |
+6 |
-36b |
Pravastatin 20 mg |
77 |
-17 |
-23 |
-17 |
-9 |
+8 |
-28 |
95% CI for Diff1 |
|
-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 |
-29c |
-37c |
-34c |
-23c |
+7 |
-39c |
Simvastatin 10 mg |
45 |
-24 |
-30 |
-30 |
-15 |
+7 |
-33 |
95% CI for Diff1 |
|
-8.7, -2.7 |
-10.1, -2.6 |
-8.0, -1.1 |
-15.1, -0.7 |
-4.3, 3.9 |
-9.6, -1.9 |
1A 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.
a Significantly different from lovastatin, ANCOVA, p ≤ 0.05
b Significantly different from pravastatin, ANCOVA, p ≤ 0.05
c Significantly different from simvastatin, ANCOVA, p ≤ 0.05 |
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table8is
not known. Table8 does not contain data comparing the effects of LIPITOR10 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 (min, max) at Baseline (mg/dL) |
Median % Change (min, max) |
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 6yearsto37 years with HoFH received maximum daily
doses of 20 to 80mgof LIPITOR. The mean LDL-C reduction in this study was 18%.
Twenty-five patients with a reduction in LDL-Chad a mean response of 20% (range
of 7% to 53%,median of 24%); the remaining 4patientshad 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 3receptor-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, 187boys and
post-menarchal girls 10years to17 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 for26weeks. 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 to230.0 mg/dL (range: 160.0-324.5 mg/dL)in the placebo group. The
dosage of LIPITOR (once daily) was 10mgforthe first 4weeks and uptitrated to 20
mgifthe LDL-C level was > 130mg/dL. The number of LIPITOR-treated patients
who required uptitration to20 mg after Week 4during the double-blind phase
was78(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 130.7mg/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 163patientswith
HeFH who were 10years to 15 years old (82boys and81girls). Allpatients had a
clinical diagnosis of HeFH confirmed by genetic analysis (if not already
confirmed by family history). Approximately 98% were Caucasian, andlessthan1%
were Black or Asian. Mean LDL-Cat baseline was 232mg/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.