Welchol

W

Dosage Form: tablet, film coated, oral suspension
FULL PRESCRIBING INFORMATION Indications and Usage for Welchol Primary Hyperlipidemia

Welchol is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin).

 Welchol is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
a. LDL-C remains ? 190 mg/dL or
b. LDL-C remains ? 160 mg/dL and

 there is a positive family history of premature cardiovascular disease or  two or more other CVD risk factors are present in the pediatric patient.

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate [See Clinical Studies (14.1)].

In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are < 100 mg/dL. An LDL-C goal of < 70 mg/dL is a therapeutic option on the basis of recent trial evidence. If LDL-C is at goal but the serum triglyceride (TG) value is > 200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C.

Type 2 Diabetes Mellitus

Welchol is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [See Clinical Studies (14.2)].

Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted [See Indications and Usage (1.1) and Warnings and Precautions (5.2)].

Important Limitations of Use Welchol should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis. Welchol has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones. Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.  Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls. Welchol Dosage and Administration Primary Hyperlipidemia

The recommended dose of Welchol Tablets in adults, whether used as monotherapy or in combination with a statin, is 6 tablets once daily or 3 tablets twice daily. Welchol Tablets should be taken with a meal and liquid.

 The recommended dose of Welchol for Oral Suspension, in adults and children 10 to 17 years of age, is one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ? to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Due to tablet size, it is recommended that any patient who has difficulty swallowing tablets use Welchol for Oral Suspension.

Welchol can be dosed at the same time as a statin or the two drugs can be dosed apart [See Clinical Studies (14.1)].

After initiation of Welchol, lipid levels should be analyzed within 4 to 6 weeks.

Type 2 Diabetes Mellitus

The recommended dose of Welchol Tablets is 6 tablets once daily or 3 tablets twice daily. Welchol should be taken with a meal and liquid.

 The recommended dose of Welchol for Oral Suspension is one 3.75 gram packet once daily or one 1.875 gram packet twice daily. To prepare, empty the entire contents of one packet into a glass or cup. Add ? to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Welchol for Oral Suspension should be taken with meals. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form.

Dosage Forms and Strengths Tablets: 625 mg tablets are off-white, oval, film-coated and imprinted with "Sankyo" and "C01" on one side. Oral Suspension: a white to pale yellow powder containing yellow granules packaged in single-dose packets: 3.75 gram single-dose packet, 1.875 gram single-dose packet. Contraindications

Welchol is contraindicated in patients with

A history of bowel obstruction [See Warnings and Precautions (5.4)] Serum TG concentrations >500 mg/dL [See Warnings and Precautions (5.2)] A history of hypertriglyceridemia-induced pancreatitis [See Warnings and Precautions (5.2)] Warnings and Precautions General

The effect of Welchol on cardiovascular morbidity and mortality has not been determined.

Serum Triglycerides (TG)

Welchol, like other bile acid sequestrants, can increase serum TG concentrations.

Welchol had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia [See Adverse Reactions (6.1) and Clinical Studies (14.1)].

In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when Welchol was used in combination with sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas) and when Welchol was used in combination with insulin (median increase 22% compared to placebo in combination with insulin) [See Adverse Reactions (6.1) and Clinical Studies (14.2)]. Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. In patients with type 2 diabetes, the effect of Welchol on LDL-C levels may be attenuated by Welchol’s effects on TG levels and a smaller reduction in non-HDL-C compared to the reduction in LDL-C. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the Welchol clinical trials had baseline TG <300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol. In addition, the use of Welchol is contraindicated in patients with TG levels >500 mg/dL [See Contraindications (4)]. Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting Welchol and periodically thereafter. Welchol should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis [See Adverse Reactions (6.1)].

Vitamin K or Fat-Soluble Vitamin Deficiencies Precautions

Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of Welchol on the absorption of co-administered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins.

Gastrointestinal Disorders

 Because of its constipating effects, Welchol is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction. Because of the tablet size, Welchol Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form. Always mix Welchol for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting.

Drug Interactions

Welchol reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the co-administered drug [See Drug Interactions (7) and Clinical Pharmacology (12.3)].

Phenylketonurics

 Welchol for Oral Suspension contains 24 mg phenylalanine per 1.875 gram packet and 48 mg phenylalanine per 3.75 gram packet [See Description (11)].

Adverse Reactions Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice.

In the lipid-lowering trials, 807 adult patients received at least one dose of Welchol (total exposure 199 patient-years). In the type 2 diabetes trials, 566 patients received at least one dose of Welchol (total exposure 209 patient-years).

In clinical trials for the reduction of LDL-C, 68% of patients receiving Welchol vs. 64% of patients receiving placebo reported an adverse reaction. In clinical trials of type 2 diabetes, 60% of patients receiving Welchol vs. 56% of patients receiving placebo reported an adverse reaction.

Primary Hyperlipidemia: In 7 double-blind, placebo-controlled, clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with Welchol 1.5 g/day to 4.5 g/day from 4 to 24 weeks.

Table 1 Placebo-Controlled Clinical Studies of Welchol for Primary Hyperlipidemia: Adverse Reactions Reported in ? 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) Welchol
N = 807 Placebo
N = 258 Constipation 89 (11.0) 18 (7.0) Dyspepsia 67 (8.3) 9 (3.5) Nausea 34 (4.2) 10 (3.9) Accidental injury 30 (3.7) 7 (2.7) Asthenia 29 (3.6) 5 (1.9) Pharyngitis 26 (3.2) 5 (1.9) Flu syndrome 26 (3.2) 8 (3.1) Rhinitis 26 (3.2) 8 (3.1) Myalgia 17 (2.1) 1 (0.4)

 Pediatric Patients 10 to 17 Years of Age: In an 8-week double-blind, placebo-controlled study boys and post menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with Welchol tablets (1.9-3.8 g, daily) or placebo tablets [See Clinical Studies (14.1)].

 Table 2 Placebo-Controlled Clinical Study of Welchol for Primary Hyperlipidemia in heFH Pediatric Patients: Adverse Reactions Reported in ?2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality    Number of Patients (%)      Welchol  Placebo    N = 129  N = 65  Nasopharyngitis  8 (6.2)  3 (4.6)  Headache  5 (3.9)  2 (3.1)  Fatigue  5 (3.9)  1 (1.5)  Creatine Phosphokinase Increase  3 (2.3)  0 (0.0)  Rhinitis  3 (2.3)  0 (0.0)  Vomiting  3 (2.3)  1 (1.5)

 The reported adverse reactions during the additional 18-week open-label treatment period with Welchol 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%) [See Clinical Studies (14.1)].

Type 2 Diabetes Mellitus: The safety of Welchol in patients with type 2 diabetes mellitus was evaluated in 4 double-blind, 12-26 week, placebo-controlled clinical trials. These trials involved 1128 patients (566 patients on Welchol; 562 patients on placebo) with inadequate glycemic control on metformin, sulfonylurea, or insulin when these agents were used alone or in combination with other anti-diabetic agents. Upon completion of the pivotal trials, 492 patients entered a 52-week open-label uncontrolled extension study during which all patients received Welchol 3.8 g/day while continuing background treatment with metformin, sulfonylurea, or insulin alone or in combination with other anti-diabetic agents.

A total of 6.7% of Welchol-treated patients and 3.2% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation.

One patient in the pivotal trials discontinued due to body rash and mouth blistering that occurred after the first dose of Welchol, which may represent a hypersensitivity reaction to Welchol.

Table 3 Placebo-Controlled Clinical Studies of Welchol Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas: Adverse Reactions Reported in ? 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) Welchol
N = 566 Placebo
N = 562 Constipation 49 (8.7) 11 (2.0) Nasopharyngitis 23 (4.1) 20 (3.6) Dyspepsia 22 (3.9) 8 (1.4) Hypoglycemia 17 (3.0) 13 (2.3) Nausea 17 (3.0) 8 (1.4) Hypertension 16 (2.8) 9 (1.6)

Hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the Welchol group and 177 mg/dL in the placebo group. Welchol therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2)]. In comparison, Welchol resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial [See Clinical Studies (14.1)].

Treatment-emergent fasting TG concentrations ?500 mg/dL occurred in 4.1% of Welchol-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with Welchol (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on Welchol and 2 (0.4%) patients on placebo developed TG elevations ?1000 mg/dL. In all Welchol clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with Welchol [See Contraindications (4) and Warnings and Precautions (5.2)].

Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the Welchol group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown.

Hypoglycemia: Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with Welchol and 2.3% in patients treated with placebo. No Welchol treated patients developed severe hypoglycemia.

Post-marketing Experience

The following additional adverse reactions have been identified during post-approval use of Welchol. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug Interactions with concomitant Welchol administration include:

Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to Welchol. Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during Welchol initiation then periodically thereafter. Elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy. Thyroid hormone replacement should be administered 4 hours prior to Welchol [See Drug Interactions (7)].

Gastrointestinal Adverse Reactions
Bowel obstruction (in patients with a history of bowel obstruction or resection), dysphagia (tablet and oral suspension formulations) or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminases.

Laboratory Abnormalities
Hypertriglyceridemia

Drug Interactions

Table 4 lists the drugs that have been tested in in vitro binding or in vivo drug interaction studies with colesevelam and/or drugs with postmarketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the co-administered drug.

Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports a Should be administered at least 4 hours prior to Welchol b No significant alteration of warfarin drug levels with warfarin and Welchol coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)] c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to Welchol. Drugs with a known interaction with colesevelam Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with Welchol phenytoina, warfarinb Drugs that do not interact with colesevelam based on in vitro or in vivo testing cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil

In an in vivo drug interaction study, Welchol and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of Welchol and warfarin coadministration on INR. In postmarketing reports, concomitant use of Welchol and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating Welchol and frequently enough during early Welchol therapy to ensure that no significant alteration in INR occurs. Once the INR is stable, continue to monitor the INR at intervals usually recommended for patients on warfarin. [See Post-marketing Experience (6.2)]

USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category B. There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed.

In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Nursing Mothers

Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract.

Pediatric Use

 The safety and effectiveness of Welchol as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH [See Clinical Studies (14.1)]. The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo [See Adverse Reactions (6.1)].

 Due to tablet size, Welchol for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when Welchol is administered to children 10 to 17 years of age.

 Welchol has not been studied in children younger than 10 years of age or in pre-menarchal girls.

Geriatric Use

Primary Hyperlipidemia:  Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ?65 years old, and 58 (4%) were ?75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Type 2 Diabetes Mellitus:  Of the 1128 patients enrolled in the four diabetes studies, 249 (22%) were ?65 years old, and 12 (1%) were ?75 years old. In these trials, Welchol 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

No special considerations or dosage adjustments are recommended when Welchol is administered to patients with hepatic impairment.

Renal Impairment

Type 2 Diabetes Mellitus:  Of the 1128 patients enrolled in the four diabetes studies, 696 (62%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 53 (5%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl?50 mL/min (n=1075).

Overdosage

Doses of Welchol in excess of 4.5 g/day have not been tested. Because Welchol is not absorbed, the risk of systemic toxicity is low. However, excessive doses of Welchol may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses.

Welchol Description

Welchol (colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule.

Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:

wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ? 100 to indicate an extended polymer network. A small amount of the amines are dialkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water.

Welchol Tablets are an off-white, oval, film-coated, solid tablet containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink.

Welchol for Oral Suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in single-dose packets containing either 1.875 gram or 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate.

PHENYLKETONURICS: Welchol for Oral Suspension contains 24 mg phenylalanine per 1.875 gram dose and 48 mg phenylalanine per 3.75 gram dose.

Welchol - Clinical Pharmacology Mechanism of Action

Primary Hyperlipidemia:  Colesevelam hydrochloride, the active pharmaceutical ingredient in Welchol, 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-?-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 Welchol improves glycemic control is unknown.

Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of Welchol was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to Welchol, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

Pharmacokinetics

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.

Metabolism:  Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.

Excretion:  In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14C-labeled colesevelam hydrochloride dose was excreted in the urine.

Drug Interactions:  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 Welchol with these drugs is unlikely. Welchol was found to have no significant effect on the bioavailability of digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, pioglitazone, and warfarin. The results of additional in vivo drug interactions of Welchol are presented in Table 5.

Drug interactions between Welchol and other commonly co-administered drugs in patients with type 2 diabetes (including rosiglitazone maleate, glimepiride, glipizide, sitagliptin phosphate, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, sustained-release formulations of anti-diabetic and anti-hypertensive drugs, and aspirin) have not been evaluated.

Table 5 Mean Change in Drug Exposure (AUC0-? and Cmax) when Administered with Welchol (3.75 g)a a With verapamil, the dose of Welchol was 4.5 g b Should be administered at least 4 hours prior to Welchol. [See Drug Interactions (7)] * Oral contraceptive containing norethindrone and ethinyl estradiol. N/A — Not Available
Drug
Dose
Co-administered
1 hr prior to
Welchol
4 hr prior to
Welchol AUC0-? Cmax AUC0-? Cmax AUC0-? Cmax Verapamil sustained-release 240 mg -31% -11% N/A N/A N/A N/A Glyburideb 3 mg -32% -47% -20% -15% -7% 4% Levothyroxineb 600 µg -22% -33% 6% -2% 1% 8% Norethindrone*b 1 mg -1% -20% 5% -3% 6% 7% Ethinyl Estradiol*b 0.035 mg -24% -24% -18% -1% -12% 0% Repaglinide 2 mg -7% -19% -6% -1% N/A N/A Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A Nonclinical Toxicology Carcinogenesis, 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).

Animal 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.

Clinical Studies Primary Hyperlipidemia

Welchol reduces TC, LDL-C, apolipoprotein B (Apo B), and 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 Welchol 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), Welchol was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 6, 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. Welchol at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both Welchol doses but the changes were not statistically different from placebo.

Table 6 Response to Welchol Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from Baseline * p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline. a Median % change from baseline. Grams/Day N TC LDL-C Apo B HDL-Ca Non-HDL-C TGa Placebo 88 +1 0 0 -1 +1 +5 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), Welchol 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 Welchol 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 stu

Welchol

.