CLINICAL PHARMACOLOGY
Enter section text here
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. Cholesterol and triglycerides circulate in the
bloodstream as part of lipoprotein complexes. With ultracentrifugation, these
complexes separate into HDL (high-density lipoprotein), IDL
(intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL
(very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in
the liver are incorporated into VLDL and released into the plasma for delivery
to peripheral tissues. LDL is formed from VLDL and is catabolized primarily
through the high-affinity LDL receptor. Clinical and pathologic studies show
that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol
(LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk
factors for developing cardiovascular disease, while increased levels of HDL-C
are associated with a decreased cardiovascular risk.
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. LIPITOR reduces LDL-C in some patients with homozygous
familial hypercholesterolemia (FH), a population that rarely responds to other
lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of
total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human
atherosclerosis. Similarly, decreased levels of HDL-C (and its transport
complex, apo A) are associated with the development of atherosclerosis.
Epidemiologic investigations have established that cardiovascular morbidity and
mortality vary directly with the level of total-C and LDL-C, and inversely with
the level of HDL-C.
LIPITOR reduces total-C, LDL-C, and apo B in patients with homozygous and
heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed
dyslipidemia. LIPITOR also reduces VLDL-C and TG and produces variable increases
in HDL-C and apolipoprotein A-1. LIPITOR reduces total-C, LDL-C, VLDL-C, apo B,
TG, and non-HDL-C, and increases HDL-C in patients with isolated
hypertriglyceridemia. LIPITOR reduces intermediate density lipoprotein
cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including
VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote
atherosclerosis. Elevated plasma triglycerides are frequently found in a triad
with low HDL-C levels and small LDL particles, as well as in association with
non-lipid metabolic risk factors for coronary heart disease. As such, total
plasma TG has not consistently been shown to be an independent risk factor for
CHD. Furthermore, the independent effect of raising HDL or lowering TG on the
risk of coronary and cardiovascular morbidity and mortality has not been
determined.
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, Nursing Mothers (4.4)
and
Use in Specific Populations, Nursing Mothers
].
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 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, Geriatric Use
].
Pediatric: Pharmacokinetic data in the
pediatric population are not available.
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, Dosage in Patients
with Renal Impairment
,
Warnings and Precautions, Skeletal Muscle
].
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 3. 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 |
† Lopinavir
400 mg BID/ ritonavir 100 mg BID, 14 days |
20 mg QD for 4 days |
↑ 5.9 fold |
↑ 4.7 fold |
† Ritonavir
400 mg BID/ saquinavir 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 |
† Itraconazole 200 mg QD, 4 days |
40 mg SD |
↑ 3.3 fold |
↑ 20% |
† 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 QD, 4 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% |
* 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. ‡ 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.
TABLE 4. 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 - ethinyl estradiol 35µg |
↑ 28% ↑ 19% |
↑ 23% ↑ 30% |
* See Section 7 for clinical significance.
NONCLINICAL TOXICOLOGY
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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.
Studies in 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
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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%. 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 5). 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 5. Overview of Efficacy Results in TNT
Endpoint |
Atorvastatin 10 mg (N=5006) |
Atorvastatin 80 mg (N=4995) |
HR * (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
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) |
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 invervals 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
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 5). 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 5). 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 (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
LIPITOR reduces total-C, LDL-C, VLDL-C, apo B, and TG, and
increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia.
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 6.)
TABLE 6. 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 |
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 |
* Results are pooled from 2 dose-response studies.
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 7).
TABLE 7. 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 |
-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 |
* 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
The impact on clinical outcomes of the differences in lipid-altering effects
between treatments shown in Table 7 is not known. Table 7 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 (Fredrickson Type IV)
The response to LIPITOR in 64 patients with isolated
hypertriglyceridemia treated across several clinical trials is shown in the
table below (Table 8). For the LIPITOR-treated patients,
median (min, max) baseline TG level was 565 (267–1502).
TABLE 8. 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 (Fredrickson Type III)
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 9).
TABLE 9. 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 Hypercholoesterolemia
In a study without a concurrent control group, 29 patients ages 6
to 37 years with homozygous FH 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 postmenarchal girls 10–17 years of age (mean age
14.1 years) with heterozygous familial hypercholesterolemia (FH) 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 80 (57.1%).
LIPITOR significantly decreased plasma levels of total-C, LDL-C,
triglycerides, and apolipoprotein B during the 26-week double-blind phase (see
Table 10).
TABLE 10. 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.
The safety and efficacy of doses above 20 mg have not been studied in
controlled trials in children. The long-term efficacy of LIPITOR therapy in
childhood to reduce morbidity and mortality in adulthood has not been
established.
|