Colesevelam Hydrochloride 625 mg Tablet, Film Coated, 180-count — NDC 0713-0936-81 (Billing 00713-0936-81)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Primary Hyperlipidemia : Colesevelam hydrochloride, the active pharmaceutical ingredient, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors.

These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged. Type 2 Diabetes Mellitus : The mechanism by which colesevelam hydrochloride improves glycemic control is unknown.

12.2Pharmacodynamics A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to colesevelam hydrochloride, as reflected by a reduction in HbA1c, was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

12.3Pharmacokinetics Absorption Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed. Distribution Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract. Elimination Metabolism Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450.

Excretion In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14 C-labeled colesevelam hydrochloride dose was excreted in the urine. Drug Interaction Studies Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride.

Therefore, an in vivo pharmacokinetic interaction of colesevelam hydrochloride with these drugs is unlikely. Colesevelam hydrochloride was found to have no significant effect on the bioavailability of aspirin, atenolol, digoxin, enalapril, fenofibrate, lovastatin, metoprolol, phenytoin, pioglitazone, quinidine, rosiglitazone, sitagliptin, valproic acid, and warfarin. The results of additional in vivo drug interactions of colesevelam hydrochloride are presented in Table 6.

Table 6 Mean Change in Drug Exposure (AUC 0-∞ and C max ) when Administered with Colesevelam Hydrochloride (3.75 g) With verapamil, the dose of colesevelam hydrochloride was 4.5 g. Drug Dose Co-administered 1 hr prior to Colesevelam Hydrochloride 4 hrs prior to Colesevelam Hydrochloride AUC 0-∞ C max AUC 0-∞ C max AUC 0-∞ C max N/A − not available Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A Ethinyl Estradiol Oral contraceptive containing norethindrone and ethinyl estradiol 0.035 mg -24% -24% -18% -1% -12% 0% Glimepiride 4 mg -18% -8% N/A N/A -6% 3% Glipizide 20 mg -12% -13% N/A N/A -4% 0% Glyburide 3 mg -32% -47% -20% -15% -7% 4% Levothyroxine 600 µg -22% -33% 6% -2% 1% 8% Metformin ER 1500 mg 44% 8% N/A N/A N/A N/A Norethindrone 1 mg -1% -20% 5% -3% 6% 7% Olmesartan Medoxomil 40 mg -39% -28% N/A N/A -15% -4% Repaglinide 2 mg -7% -19% -6% -1% N/A N/A Verapamil Sustained Release 240 mg -31% -11% N/A N/A N/A N/A

12.1Mechanism of Action Primary Hyperlipidemia : Colesevelam hydrochloride, the active pharmaceutical ingredient, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors.

These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged. Type 2 Diabetes Mellitus : The mechanism by which colesevelam hydrochloride improves glycemic control is unknown.

12.3Pharmacokinetics Absorption Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed. Distribution Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract. Elimination Metabolism Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450.

Excretion In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14 C-labeled colesevelam hydrochloride dose was excreted in the urine. Drug Interaction Studies Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride.

Therefore, an in vivo pharmacokinetic interaction of colesevelam hydrochloride with these drugs is unlikely. Colesevelam hydrochloride was found to have no significant effect on the bioavailability of aspirin, atenolol, digoxin, enalapril, fenofibrate, lovastatin, metoprolol, phenytoin, pioglitazone, quinidine, rosiglitazone, sitagliptin, valproic acid, and warfarin. The results of additional in vivo drug interactions of colesevelam hydrochloride are presented in Table 6.

Table 6 Mean Change in Drug Exposure (AUC 0-∞ and C max ) when Administered with Colesevelam Hydrochloride (3.75 g) With verapamil, the dose of colesevelam hydrochloride was 4.5 g. Drug Dose Co-administered 1 hr prior to Colesevelam Hydrochloride 4 hrs prior to Colesevelam Hydrochloride AUC 0-∞ C max AUC 0-∞ C max AUC 0-∞ C max N/A − not available Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A Ethinyl Estradiol Oral contraceptive containing norethindrone and ethinyl estradiol 0.035 mg -24% -24% -18% -1% -12% 0% Glimepiride 4 mg -18% -8% N/A N/A -6% 3% Glipizide 20 mg -12% -13% N/A N/A -4% 0% Glyburide 3 mg -32% -47% -20% -15% -7% 4% Levothyroxine 600 µg -22% -33% 6% -2% 1% 8% Metformin ER 1500 mg 44% 8% N/A N/A N/A N/A Norethindrone 1 mg -1% -20% 5% -3% 6% 7% Olmesartan Medoxomil 40 mg -39% -28% N/A N/A -15% -4% Repaglinide 2 mg -7% -19% -6% -1% N/A N/A Verapamil Sustained Release 240 mg -31% -11% N/A N/A N/A N/A

12.2Pharmacodynamics A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to colesevelam hydrochloride, as reflected by a reduction in HbA1c, was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

14 CLINICAL STUDIES

14.1Primary Hyperlipidemia 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 1600 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. Monotherapy 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 9-10% were observed at both colesevelam hydrochloride doses, but the changes were not statistically different from placebo. Table 7 Response to Colesevelam Hydrochloride Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from Baseline Grams/Day N TC LDL-C Apo B HDL-C Median % change from baseline Non-HDL-C TG Placebo 88 +1 0 0 −1 +1 +5 3.8 g (6 tablets) 95 −7 p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline −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. Combination Therapy 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 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 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. Table 8 Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin - Percent Change in Lipid Parameters Dose/Day N TC LDL-C Apo B HDL-C Median % change from baseline Non-HDL-C TG Atorvastatin Trial (4-week) Placebo 19 +4 +3 −3 +4 +4 +10 Atorvastatin 10 mg 18 −27 p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline −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) Placebo 26 +1 0 0 +1 +1 +1 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 d… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice.

In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg). Mutagenesis Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test.

The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation.

The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation. Impairment of Fertility Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

13.2Animal Toxicology and/or Pharmacology 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.