Lipitor

[Atorvastatin]

Lipitor is effective in a wide variety of patient populations with hypercholesterolemia, with and without hypertriglyceridemia, in men and women, and in the elderly. Experience in pediatric patients has been limited to patients with homozygous FH. In two multicenter, placebo-controlled, dose-response studies in patients with hypercholesterolemia, 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 1).

TABLE 1. Dose Response in Patients with Primary Hypercholesterolemia (Adjusted Mean % Change from Baseline)a
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Dose N TC LDL-C Apo B TG HDL-C Non-HDL-C/HDL-C
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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
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aResults 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 atorvastatin 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 decrease in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.

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In three multicenter, double-blind studies in patients with hypercholesterolemia, Lipitor was compared to other HMG-CoA reductase inhibitors. After randomization, patients were treated for 16 weeks with either Lipitor 10 mg per day or a fixed dose of the comparative agent (Table 2).

TABLE 2. Mean Percent Change from Baseline at End Point
(Double-Blind, Randomized, Active-Controlled Trials)
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Treatment (Daily Dose) N Total C LDL-C Apo B TG HDL-C Non-HDL-C/HDL-C
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Study 1
Atorvastatin 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
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Study 2
Atorvastatin 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
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Study 3
Atorvastatin 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
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1 A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive value favors atorvastatin. 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 Table 2 is not known. Table 2 does not contain data comparing the effects of atorvastatin 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. For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267-1502).

TABLE 3. Combined Patients with Isolated Elevated TG:
Median (min, max) Percent Changes from Baseline
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Placebo
(N=12) Atorvastatin 10 mg
(N=37) Atorvastatin 20 mg
(N=13) Atorvastatin 80 mg
(N=14)
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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)
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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)
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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)
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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)
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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)
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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)
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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 4. Open-Label Crossover Study of 16 Patients
with Dysbetalipoproteinemia (Fredrickson Type III)
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Median % Change (min, max)
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Median (min, max) at Baseline (mg/dL) Atorvastatin 10 mg Atorvastatin 80 mg
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Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31)
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Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30)
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IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8)
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non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36)
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Homozygous Familial Hypercholesterolemia

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 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 up-titrated to 20 mg if the LDLC 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 5).

TABLE 5. Lipid-altering Effects of Lipitor in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia
(Mean Percent Change from Baseline at Endpoint in Intention-to-Treat Population)
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DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B
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Placebo 47 -1.5 -0.4 -1.9 1.0 0.7

Lipitor 140 -31.4 -39.6 2.8 -12.0 -34.0
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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.

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