Reproductive Toxicology Studies
Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.
Colesevelam hydrochloride reduces total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia. Approximately 1,600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy.
In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), colesevelam hydrochloride was given for 24 weeks in divided doses with the morning and evening meals.
As shown in Table 7, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Colesevelam hydrochloride at both doses increased HDL-C by 3%. Increases in TG of 9 to 10% were observed at both colesevelam hydrochloride doses, but the changes were not statistically different from placebo.
|Grams/Day||N||TC||LDL-C||Apo B||HDL-C *||Non-HDL-C||TG *|
|3.8 g (6 tablets)||95||–7 †||–15 †||–12 †||+3 †||–10 †||+10|
|4.5 g (7 tablets)||94||–10 †||–18 †||–12 †||+3||–13 †||+9|
In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), colesevelam hydrochloride 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.
Co-administration of colesevelam hydrochloride and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156 to 236 mg/dL), 171 mg/dL in the lovastatin study (range 115 to 247 mg/dL), and 188 mg/dL in the simvastatin study (range 148 to 352 mg/dL). As demonstrated in Table 8, colesevelam hydrochloride doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.
|Dose/Day||N||TC||LDL-C||Apo B||HDL-C *||Non-HDL-C||TG *|
|Atorvastatin Trial (4-week)|
|Atorvastatin 10 mg||18||–27 †||–38 †||–32 †||+8||–35 †||–24 †|
|Colesevelam hydrochloride 3.8 g/Atorvastatin 10 mg||18||–31 †||–48 †||–38 †||+11||–40 †||–1|
|Atorvastatin 80 mg||20||–39 †||–53 †||–46 †||+6||–50 †||–33 †|
|Simvastatin Trial (6-week)|
|Placebo||33||–2||–4||–4 †||–3||–2||+6 †|
|Simvastatin 10 mg||35||–19 †||–26 †||–20 †||+3 †||–24 †||–17 †|
|Colesevelam hydrochloride 3.8 g/ Simvastatin 10 mg||34||–28 †||–42 †||–33 †||+10 †||–37 †||–12 †|
|Simvastatin 20 mg||39||–23 †||–34 †||–26 †||+7 †||–30 †||–12 †|
|Colesevelam hydrochloride 2.3 g/ Simvastatin 20 mg||37||–29 †||–42 †||–32 †||+4 †||–37 †||–12 †|
|Lovastatin Trial (4-week)|
|Lovastatin 10 mg||26||–14 †||–22 †||–16 †||+5||–19 †||0|
|Colesevelam hydrochloride 2.3 g/ Lovastatin 10 mg Together||27||–21 †||–34 †||–24 †||+4||–27 †||–1|
|Colesevelam hydrochloride 2.3 g/ Lovastatin 10 mg Apart||23||–21 †||–32 †||–24 †||+2||–28 †||–2|
In all 3 studies, the LDL-C reduction achieved with the combination of colesevelam hydrochloride and any given dose of statin therapy was statistically superior to that achieved with colesevelam hydrochloride or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of colesevelam hydrochloride 3.8 g and atorvastatin 10 mg.
The safety and efficacy of colesevelam hydrochloride in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10 to 17 years of age (mean age 14.1 years) with HeFH, taking a stable dose of an FDA-approved statin (with LDL-C > 130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C > 160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL.
During the double-blind treatment period, patients were assigned randomly to treatment: Colesevelam hydrochloride 3.8 g/day (n = 64), colesevelam hydrochloride 1.9 g/day (n = 65), or placebo (n = 65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).
|Treatment Difference|| TC |
(N = 128)
| LDL-C |
(N = 128)
| Apo B |
(N = 124)
| HDL-C |
(N = 128)
| Non-HDL-C |
(N = 128)
(N = 128)
|Colesevelam hydrochloride 3.8 g vs Placebo||-7 †||-13 †||-8 †||+6 †||-11 †||+5|
During the open-label treatment period patients were treated with colesevelam hydrochloride 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.
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