CRESTOR (Page 7 of 9)

14.5 Homozygous Familial Hypercholesterolemia

Dose-Titration Study: In an open-label, forced-titration study, homozygous FH patients (n=40, 8‑63 years) were evaluated for their response to CRESTOR 20 to 40 mg titrated at a 6‑week interval. In the overall population, the mean LDL‑C reduction from baseline was 22%. About one-third of the patients benefited from increasing their dose from 20 mg to 40 mg with further LDL lowering of greater than 6%. In the 27 patients with at least a 15% reduction in LDL‑C, the mean LDL-C reduction was 30% (median 28% reduction). Among 13 patients with an LDL‑C reduction of <15%, 3 had no change or an increase in LDL‑C. Reductions in LDL‑C of 15% or greater were observed in 3 of 5 patients with known receptor negative status.

14.6 Pediatric Patients with Homozygous Familial Hypercholesterolemia

CRESTOR was studied in a randomized, double-blind, placebo-controlled, multicenter, cross-over study in 14 children and adolescents with homozygous familial hypercholesterolemia. The study included a 4-week dietary lead-in phase during which patients received CRESTOR 10 mg daily, a cross-over phase that included two 6-week treatment periods with either CRESTOR 20 mg or placebo in random order, followed by a 12-week open-label phase during which all patients received CRESTOR 20 mg. Patients ranged in age from 7 to 15 years of age (median 11 years), 50% were male, 71% were Caucasian, 21% were Asian, 7% were Black, and no patients were of Hispanic ethnicity. Fifty percent were on apheresis therapy and 57% were taking ezetimibe. Patients who entered the study on apheresis therapy or ezetimibe continued the treatment throughout the entire study. Mean LDL-C at baseline was 416 mg/dL (range 152 to 716 mg/dL). A total of 13 patients completed both treatment periods of the randomized cross-over phase; one patient withdrew consent due to inability to have blood drawn during the cross-over phase.

CRESTOR 20 mg significantly reduced LDL-C, total cholesterol, ApoB, and non-HDL-C compared to placebo (Table 11).

Table 11. Lipid-modifying Effects of Rosuvastatin in Pediatric Patients 7 to 15 years of Age with Homozygous Familial Hypercholesterolemia After 6 Weeks

Placebo

(N=13)

CRESTOR 20 mg

(N=13)

Percent difference (95% CI)

LDL-C (mg/dL)

481

396

-22.3% (-33.5, -9.1)1

Total-C (mg/dL)

539

448

-20.1% (-29.7, -9.1)2

Non-HDL-C (mg/dL)

505

412

-22.9% (-33.7, ‑10.3)2

ApoB (mg/dL)

268

235

-17.1% (-29.2, -2.9)3

% Difference estimates are based on transformations of the estimated mean difference in log LDL measurements between CRESTOR and placebo using a mixed model adjusted for study period

1 p=0.005, 2 p=0.003, 3 p=0.024

14.7 Pediatric Patients with Heterozygous Familial Hypercholesterolemia

In a double-blind, randomized, multicenter, placebo-controlled, 12 week study, 176 (97 male and 79 female) children and adolescents with heterozygous familial hypercholesterolemia were randomized to rosuvastatin 5, 10 or 20 mg or placebo daily. Patients ranged in age from 10 to 17 years (median age of 14 years) with approximately 30% of the patients 10 to 13 years and approximately 17%, 18%, 40%, and 25% at Tanner stages II, III, IV, and V, respectively. Females were at least 1 year postmenarche. Mean LDL-C at baseline was 233 mg/dL (range of 129 to 399). The 12-week double blind phase was followed by a 40-week open label dose-titration phase, where all patients (n=173) received 5 mg, 10 mg or 20 mg rosuvastatin daily.

Rosuvastatin significantly reduced LDL-C (primary end point), total cholesterol and ApoB levels at each dose compared to placebo. Results are shown in Table 12 below.

Table 12. Lipid-Modifying Effects of Rosuvastatin in Pediatric Patients 10 to 17 years of Age with Heterozygous Familial Hypercholesterolemia (Least-Squares Mean Percent Change from Baseline to Week 12)
Dose (mg) N LDL-C HDL-C Total-C TG * ApoB
*
Median percent change
Difference from placebo not statistically significant

Placebo

46

-1%

+7%

0%

-7%

-2%

5

42

-38%

+4%

-30%

-13%

-32%

10

44

-45%

+11%

-34%

-15%

-38%

20

44

-50%

+9%

-39%

16%

-41%

At the end of the 12-week, double blind treatment period, the percentage of patients achieving the LDL-C goal of less than 110 mg/dL (2.8 mmol/L) was 0% for placebo, 12% for rosuvastatin 5 mg, 41% for rosuvastatin 10 mg and 41% for rosuvastatin 20 mg. For the 40-week, open-label phase, 71% of the patients were titrated to the maximum dose of 20 mg and 41% of the patients achieved the LDL-C goal of 110 mg/dL.

Rosuvastatin was also studied in a two year open-label, uncontrolled, titration to goal trial that included 175 children and adolescents with heterozygous familial hypercholesterolemia who were 8 to 17 years old (79 boys and 96 girls). All patients had a documented genetic defect in the LDL receptor or in Apo B. Approximately 89% were Caucasian, 7% were Asian, 1% were Black, and fewer than 1% were Hispanic. Mean LDL-C at baseline was 236 mg/dL. Fifty-eight (33%) patients were prepubertal at baseline. The starting rosuvastatin dosage for all children and adolescents was 5 mg once daily. Children 8 to less than 10 years of age (n=41 at baseline) could titrate to a maximum dosage of 10 mg once daily, and children and adolescents 10 to 17 years of age could titrate to a maximum dosage of 20 mg once daily.

The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous experience in both adult and pediatric controlled trials.

The long-term efficacy of rosuvastatin therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.

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