Cholestagel

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Cholestagel uses



Warnings and Precautions (5.6) 5/2013

Cholestagel is a bile acid sequestrant indicated as an adjunct to diet and exercise to


Important Limitations of Use (1.3):

1.1 Primary Hyperlipidemia

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

Cholestagel 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


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 .

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.

1.2 Type 2 Diabetes Mellitus

Cholestagel is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus .

Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted .

1.3 Important Limitations of Use

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2 DOSAGE AND ADMINISTRATION

2.1 Primary Hyperlipidemia

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

The recommended dose of Cholestagel 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 ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Cholestagel for Oral Suspension should be taken with meals. To avoid esophageal distress, Cholestagel 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 Cholestagel for Oral Suspension.

Cholestagel can be dosed at the same time as a statin or the two drugs can be dosed apart .

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

2.2 Type 2 Diabetes Mellitus

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

The recommended dose of Cholestagel 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 ½ to 1 cup (4 to 8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Cholestagel for Oral Suspension should be taken with meals. To avoid esophageal distress, Cholestagel for Oral Suspension should not be taken in its dry form.

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3 DOSAGE FORMS AND STRENGTHS


Tablets: 625 mg (3)

Oral suspension: 3.75 gram packet, 1.875 gram packet (3)

4 CONTRAINDICATIONS

Cholestagel is contraindicated in patients with

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5 WARNINGS AND PRECAUTIONS

5.1 General

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

5.2 Serum Triglycerides

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

Cholestagel had small effects on serum TG in trials of patients with primary hyperlipidemia .

In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when Cholestagel was used as monotherapy (median increase 9.7% compared to placebo) and when Cholestagel was used in combination with pioglitazone (median increase 11% compared to placebo in combination with pioglitazone), sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas), and insulin (median increase 22% compared to placebo in combination with insulin) . 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 Cholestagel 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 Cholestagel 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 Cholestagel. In addition, the use of Cholestagel is contraindicated in patients with TG levels >500 mg/dL . Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting Cholestagel and periodically thereafter. Cholestagel should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis .

5.3 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 Cholestagel on the absorption of co-administered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered Cholestagel 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 Cholestagel. 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.

5.4 Gastrointestinal Disorders

Because of its constipating effects, Cholestagel 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, Cholestagel Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Cholestagel for Oral Suspension should not be taken in its dry form. Always mix Cholestagel for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting.

5.5 Drug Interactions

Cholestagel reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with Cholestagel should be administered at least 4 hours prior to Cholestagel. Drugs that have not been tested for interaction with Cholestagel, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Cholestagel. Alternatively, the physician should monitor drug levels of the co-administered drug .

5.6 Phenylketonurics

Cholestagel for Oral Suspension contains 13.5 mg phenylalanine per 1.875 gram packet and 27 mg phenylalanine per 3.75 gram packet .

5.7 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with Cholestagel or any other antidiabetic drugs.

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6 ADVERSE REACTIONS

In clinical trials, the most common adverse reactions with Cholestagel included constipation, dyspepsia, and nausea.

Postmarketing reports with concomitant Cholestagel administration include:


Other postmarketing reports include bowel obstruction, dysphagia, esophageal obstruction, fecal impaction, hypertriglyceridemia, pancreatitis, and increased transaminases (5.5, 6.2, 7, 12.3).

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.

6.1 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.

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 Cholestagel 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years).

In clinical trials for the reduction of LDL-C, 68% of patients receiving Cholestagel vs. 64% of patients receiving placebo reported an adverse reaction.

Number of Patients (%)
Cholestagel

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 Cholestagel tablets (1.9-3.8 g, daily) or placebo tablets .

Number of Patients (%)
Cholestagel

N = 129

Placebo

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 Cholestagel 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%) .

Type 2 Diabetes Mellitus: The safety of Cholestagel in patients with type 2 diabetes mellitus was evaluated in 5 add-on combination and 1 monotherapy double-blind, 12-26 week, placebo-controlled clinical trials [see Clinical Studies (14.2)]. In these studies 1022 patients were exposed to Cholestagel. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of Cholestagel per day. The mean age of patients exposed to Cholestagel was 55.7 years, 52.8 percent of the population was male and 61.9% were Caucasian, 4.8% were Asian, and 15.9% were Black or African American. At baseline the population had a mean HbA1C of 8.2% and 26% had past medical history suggestive of microvascular complications of diabetes. Baseline characteristics in the placebo group were comparable.

In clinical trials of type 2 diabetes, 57% of patients receiving Cholestagel vs. 52% of patients receiving placebo reported an adverse reaction.

Table 3 shows common adverse reactions associated with the use of Cholestagel in the 1015 patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on Cholestagel than on placebo, and occurred in at least 2% of patients treated with Cholestagel.

Number of Patients (%)
Cholestagel

N = 1015

Placebo

N = 1010

Constipation 66 (6.5) 22 (2.2)
Hypoglycemia 35 (3.4) 31 (3.1)
Dyspepsia 28 (2.8) 10 (1.0)
Nausea 26 (2.6) 16 (1.6)
Hypertension 26 (2.6) 19 (1.9)
Back Pain 23 (2.3) 13 (1.3)

A total of 5.3% of WELCHOL-treated patients and 3.6% 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 add-on to sulfonylurea trial discontinued due to body rash and mouth blistering that occurred on the first day of dosing of Cholestagel, which may represent a hypersensitivity reaction to Cholestagel.

Hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the diabetes trials, 1292 (67.7%) patients had baseline fasting serum TG levels less than 200 mg/dL, 426 (22.3%) had baseline fasting serum TG levels between 200 and less than 300 mg/dL, 175 (9.2%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 16 (0.8%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 160 mg/dL; the median post-treatment fasting TG was 180 mg/dL in the Cholestagel group and 162 mg/dL in the placebo group. Cholestagel therapy resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03) in the monotherapy study and of 5% (p=0.22), 11% (p<0.001), 18% (p<0.001), and 22% (p<0.001), when added to metformin, pioglitazone, sulfonylureas, and insulin, respectively . In comparison, Cholestagel resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial .

Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 0.9% of WELCHOL-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with Cholestagel (median 606 mg/dL; interquartile range 570-794 mg/dL) were similar to that observed with placebo (median 663 mg/dL; interquartile range 542-984 mg/dL). Five (0.6%) patients on Cholestagel and 3 (0.3%) patients on placebo developed TG elevations ≥1000 mg/dL. In all Cholestagel 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 Cholestagel .

Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 2.2% (22/1015) in the Cholestagel group and 1% (10/1010) 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.

6.2 Post-marketing Experience

The following additional adverse reactions have been identified during post-approval use of Cholestagel. 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.

7 DRUG INTERACTIONS

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

a Should be administered at least 4 hours prior to Cholestagel
b No significant alteration of warfarin drug levels with warfarin and Cholestagel coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR).
c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to Cholestagel.
d Patients receiving concomitant metformin ER and Cholestagel should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
Drugs with a known interaction with Cholestagel:

Decrease in exposure of coadministered drug

cyclosporinec, glimepiridea, glipizidea, glyburidea,

levothyroxinea, olmesartan medoxomila, and oral

contraceptives containing ethinyl estradiol and

norethindronea

Drugs with a known interaction with Cholestagel:

Increase in exposure of coadministered drug

metformin extended release (ER)d
Drug(s) with postmarketing reports consistent with

potential drug-drug interactions when

coadministered with Cholestagel

phenytoina, warfarinb
Drugs that do not interact with Cholestagel based

on in vitro or in vivo testing

aspirin, atenolol, cephalexin, ciprofloxacin,

digoxin, enalapril, fenofibrate, lovastatin,

metformin, metoprolol, phenytoina, pioglitazone,

rosiglitazone, quinidine, repaglinide, sitagliptin,

valproic acid, verapamil, warfarinb


In an in vivo drug interaction study, Cholestagel and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of Cholestagel and warfarin coadministration on INR. In post-marketing reports, concomitant use of Cholestagel and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating Cholestagel and frequently enough during early Cholestagel 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 .

In drug interaction studies, Cholestagel reduced levels of cyclosporine, glimepiride, glipizide, glyburide, levothyroxine, olmesartan medoxomil, and oral contraceptives containing ethinyl estradiol and norethindrone. Cholestagel increased levels of metformin when coadministered with metformin extended release. There have been postmarketing reports of decreases in phenytoin levels in patients receiving phenytoin concomitantly with Cholestagel and decreases in INR in patients receiving warfarin concomitantly with Cholestagel (5.5, 7, 12.3).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. There are no adequate and well-controlled studies of Cholestagel 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 Cholestagel 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, Cholestagel 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.

8.3 Nursing Mothers

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

8.4 Pediatric Use

The safety and effectiveness of Cholestagel as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH . 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, Cholestagel for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when Cholestagel is administered to children 10 to 17 years of age.

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

8.5 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 2048 patients enrolled in the six diabetes studies, 397 (19%) were ≥65 years old, and 36 (2%) were ≥75 years old. In these trials, Cholestagel 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.

8.6 Hepatic Impairment

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

8.7 Renal Impairment

Type 2 Diabetes Mellitus: Of the 2048 patients enrolled in the six diabetes studies, 807 (39%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 61 (3%) 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) in the add-on to metformin, sulfonylureas, and insulin diabetes studies. In the monotherapy study and add-on to pioglitazone study only 3 and 5 patients respectively had moderate renal insufficiency

10 OVERDOSAGE

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

11 DESCRIPTION

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

Cholestagel hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of Cholestagel hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of Cholestagel 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 cross-linking 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. Cholestagel hydrochloride is hydrophilic and insoluble in water.

Cholestagel Tablets are an off-white, oval, film-coated, solid tablet containing 625 mg Cholestagel 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.

Cholestagel 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 Cholestagel 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: Cholestagel for Oral Suspension contains 13.5 mg phenylalanine per 1.875 gram dose and 27 mg phenylalanine per 3.75 gram dose.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Primary Hyperlipidemia: Cholestagel hydrochloride, the active pharmaceutical ingredient in Cholestagel, 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 Cholestagel improves glycemic control is unknown.

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

Absorption: Cholestagel hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.

Distribution: Cholestagel hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.

Metabolism: Cholestagel 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 Cholestagel hydrochloride dose was excreted in the urine.

Drug Interactions: Drug interactions between Cholestagel 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 Cholestagel hydrochloride. Therefore, an in vivo pharmacokinetic interaction of Cholestagel with these drugs is unlikely. Cholestagel 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 Cholestagel are presented in Table 5.

a With verapamil, the dose of Cholestagel was 4.5 g
b Should be administered at least 4 hours prior to Cholestagel [See Drug Interactions (7)].
c Patients receiving concomitant metformin ER and Cholestagel should be monitored for clinical response as is usual for the use of anti-diabetes drugs [See Drug Interactions (7)].
d Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to Cholestagel [See Drug Interactions (7)].
* Oral contraceptive containing norethindrone and ethinyl estradiol.
N/A – Not Available
Drug Dose Co-administered 1 hr prior to

Cholestagel

4 hr prior to

Cholestagel

AUC0-∞ Cmax AUC0-∞ Cmax AUC0-∞ Cmax
Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A
Ethinyl Estradiol* b 0.035 mg -24% -24% -18% -1% -12% 0%
Glimepiride b 4 mg -18% -8% N/A N/A -6% 3%
Glipizide b 20 mg -12% -13% N/A N/A -4% 0%
Glyburide b 3 mg -32% -47% -20% -15% -7% 4%
Levothyroxine b 600 µg -22% -33% 6% -2% 1% 8%
Metformin ER c 1500 mg 44% 8% N/A N/A N/A N/A
Norethindrone* b 1 mg -1% -20% 5% -3% 6% 7%
Olmesartan Medoxomilb 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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: A 104-week carcinogenicity study with Cholestagel 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 Cholestagel 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 (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: Cholestagel 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: Cholestagel 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).

13.2 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 Cholestagel hydrochloride.

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

Cholestagel reduces TC, LDL-C, apolipoprotein 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 Cholestagel 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), Cholestagel 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. Cholestagel at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both Cholestagel doses but the changes were not statistically different from placebo.

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), Cholestagel 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 Cholestagel 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 7, Cholestagel 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.

*p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
aMedian % change from baseline.
Dose/Day N TC LDL-C Apo B HDL-Ca Non-HDL-C TGa
Atorvastatin Trial (4-week)
Placebo 19 +4 +3 –3 +4 +4 +10
Atorvastatin 10 mg 18 –27* –38* –32* +8 –35* –24*
Cholestagel 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*
Cholestagel 3.8 g/

Simvastatin 10 mg

34 –28* –42* –33* +10* –37* –12*
Simvastatin 20 mg 39 –23* –34* –26* +7* –30* –12*
Cholestagel 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
Cholestagel 2.3 g/

Lovastatin 10 mg

Together

27 –21* –34* –24* +4 –27* –1
Cholestagel 2.3 g/

Lovastatin 10 mg

23 –21* –32* –24* +2 –28* –2
Apart

In all 3 studies, the LDL-C reduction achieved with the combination of Cholestagel and any given dose of statin therapy was statistically superior to that achieved with Cholestagel or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of Cholestagel 3.8 g and atorvastatin 10 mg.

The effect of Cholestagel when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either Cholestagel 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 8.

* p≤0.0002 compared to placebo.
a For triglycerides, median % change from baseline.
b Treated Baseline: following 8-week treatment with open-label fenofibrate 160 mg.
Treatment N TC LDL-C Apo

B

HDL-C Non-HDL-

C

TGa
Placebo + Fenofibrate 160 mg 61 2 2 1 -1 2 -3
Cholestagel + Fenofibrate 160 mg 61 -6* -10* -7* -0 -8* 6

Pediatric Therapy: The safety and efficacy of Cholestagel 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 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (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: Cholestagel 3.8 g/day (n=64), Cholestagel 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, Cholestagel 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).

*p≤0.05 for lipid parameters compared to placebo
Values represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day 1 prior to the first dose of randomized study medication.
a For triglycerides, median % change from baseline.
Results were based on the ITT population with LOCF
Treatment

Difference

TC

(N=128)

LDL-C

(N=128)

Apo B

(N=124)

HDL-C

(N=128)

Non-HDL-

C

(N=128)

TGa

(N=128)

Cholestagel 3.8 g vs

Placebo

-7* -13* -8* +6* –11* +5

During the open-label treatment period patients were treated with Cholestagel 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.

14.2 Type 2 Diabetes Mellitus

Cholestagel has been studied as monotherapy and in combination with metformin, pioglitazone, sulfonylureas, and insulin. In these studies, Cholestagel and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.

Monotherapy: The efficacy of Cholestagel 3.8 g/day as anti-diabetes monotherapy was evaluated in a randomized double-blind, placebo-controlled trial involving 357 patients (176 Cholestagel and 181 placebo) with T2DM who were treatment-naïve or had not received antihyperglycemic medication within 3 months prior to the start of the study. Statin use at baseline was reported in 13% of the WELCHOL-treated patients and 16% of the placebo-treated patients.

Cholestagel resulted in a statistically significant reduction in A1C of 0.27% compared to placebo (Table 10).

The mean baseline LDL-C was 121 mg/dL in the monotherapy trial. Cholestagel treatment resulted in a placebo-corrected 11% reduction in LDL-C. Cholestagel treatment also reduced serum TC, ApoB, and non-HDL-C (Table 11). The mean change in body weight was -0.6 kg for Cholestagel and -0.7 kg for placebo treatment groups.

a Least-squares mean change calculated from an Analysis of Covariance model
bNominal p=value, not controlled for multiplicity testing.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
Cholestagel

3.8 g/day

Placebo
A1C (%), Mean
N 175 169
Baseline 8.25 8.17
Change from baselinea -0.26 0.01
Treatment difference (p-value) -0.27 (p=0.013)
FPG (mg/dL), Mean
N 172 166
Baseline 172 168
Change from baselinea -4.6 5.7
Treatment difference (p-value) -10.3 (p=0.037b)
*p<0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
a Median % change from baseline.
The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.
Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL-C TGa
Cholestagel 3.8 g 162 -3.3* -10.0* -5.6* 1.7 -4.4* 15.5
Placebo 160 1.8 1.2 0.9 -0.1 3.0 5.8

Add-on combination Therapy: The efficacy of Cholestagel 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 5 double-blind, placebo-controlled add-on therapy trials involving a total of 1691 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. Statin use at baseline was reported in 41% of the WELCHOL-treated patients and 48% of the placebo-treated patients.

In 3 add-on combination therapy trials (metformin, sulfonylurea and insulin), treatment with Cholestagel resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebo-corrected reductions in A1C occurred in patients who received Cholestagel in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti-diabetic agents. In the pioglitazone trial, treatment with Cholestagel resulted in a statistically significant reduction in A1C of 0.32% compared to placebo. In the metformin, pioglitazone, and sulfonylurea trials, treatment with Cholestagel also resulted in statistically significant reductions in fasting plasma glucose (FPG) of at least 14 mg/dL compared to placebo.

Cholestagel had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. WELCHOL’s effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone).

The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 107 mg/dL in the pioglitazone study (range 48-263 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, Cholestagel treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. Cholestagel treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin, patients on a sulfonylurea, and patients on pioglitazone but not in the study of patients on metformin. The clinical significance of these increases is unknown. Cholestagel is contraindicated in patients with TG levels > 500 mg/dL and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended .

Body weight did not significantly increase from baseline with Cholestagel therapy, compared with placebo, in any of the add-on combination diabetes studies.

Add-on Combination Therapy with Metformin: Cholestagel 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥1,500 mg/day of metformin. In combination with metformin, Cholestagel resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 12). Cholestagel also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 13). The mean percent change in serum LDL-C levels with Cholestagel compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with Cholestagel compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for Cholestagel and -0.3 kg for placebo.

a Least-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
Total Patient

Population

Metformin Alone Metformin in Combination with

Other Oral

Anti-Diabetic Agents

Cholestagel

3.8 g/day

Placebo Cholestagel

3.8 g/day

Placebo Cholestagel

3.8 g/day

Placebo
A1C (%), Mean
N 148 152 79 76 69 76
Baseline 8.1 8.1 8.2 8.2 8.1 8.0
Change from baselinea -0.4 0.2 -0.4 0.0 -0.4 0.3
Treatment difference (p-value) -0.5 (p<0.001) -0.5 (p=0.002) -0.6 (p<0.001)
FPG (mg/dL), Mean
N 149 152 79 76 70 76
Baseline 178 174 184 180 171 168
Change from baselinea -3 11 -7 8 0 13
Treatment difference (p-value) -14 (p=0.01) -14 (p=0.07) -14 (p=0.10)
*p<0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
a Median % change from baseline.
The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.
Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL-

C

TGa
Total Patient Population
Cholestagel 3.8 g 125 -4* -12* -4* 1 -6* 12
Placebo 126 3 4 4 0 5 7
Metformin Alone
Cholestagel 3.8 g 66 -3 -9 -2 1 -4 15
Placebo 61 2 0 1 -2 4 8
Metformin in Combination with Other Oral Anti-diabetic Agents
Cholestagel 3.8 g 59 -6* -15* -6* 1 -7* 8
Placebo 65 4 7 7 2 6 5

Add-on Combination Therapy with pioglitazone: Cholestagel 3.8 g/day or placebo was added to background anti-diabetic therapy in a 24-week trial of 562 patients already receiving treatment with pioglitazone alone (N=51) or pioglitazone in combination with other oral agents (N=511). Of these, most were on dual therapy with metformin (N=298) or triple therapy with metformin and a sulfonylurea (N=139). In combination with pioglitazone-based therapy, Cholestagel resulted in statistically significant reductions in A1C and FPG compared to placebo (Table 14). Cholestagel also reduced TC, LDL-C, Apo B, and non-HDL-C but increased serum TG (Table 15). The mean change in body weight was 0.8 kg for Cholestagel and 0.4 kg for placebo.

a Least-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
Cholestagel

3.8 g/day

Placebo
A1C (%), Mean
N 271 276
Baseline 8.2 8.1
Change from baselinea -0.34 -0.02
Treatment difference (p-value) -0.32 (0.0001)
FPG (mg/dL), Mean
N 268 270
Baseline 155 157
Change from baselinea -4.8 +9.9
Treatment difference (p-value) -14.7 (<0.0001)
*p<0.001 for lipid parameters compared to placebo
a Median % change from baseline
The N given represents the smallest number of patients included in the analysis for any parameter.
Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL-

C

TGa
Total Patient Cohort
Cholestagel 3.8 g 262 -3* -9* -5* +3 -5* +14*
Placebo 262 +3 +7 +4 +1 +5 +2

Add-on Combination Therapy with Sulfonylurea: Cholestagel 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, Cholestagel resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 16). Cholestagel also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 17). The mean percent change in serum LDL-C levels with Cholestagel compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with Cholestagel compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for Cholestagel and -0.4 kg for placebo.

a Least-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
Total Patient

Population

Sulfonylurea Alone Sulfonylurea in

Combination with

Other Oral

Anti-diabetic Agents

Cholestagel

3.8 g/day

Placebo Cholestagel

3.8 g/day

Placebo Cholestagel

3.8 g/day

Placebo
A1C (%), Mean
n 218 218 69 80 149 138
Baseline 8.2 8.3 8.2 8.4 8.2 8.3
Change from baselinea -0.3 0.2 -0.3 0.5 -0.4 0.0
Treatment difference (p-value) -0.5 (p<0.001) -0.8 (p<0.001) -0.4 (p<0.001)
FPG (mg/dL), Mean
n 218 217 70 80 148 137
Baseline 177 181 181 186 175 178
Change from baselinea -4 10 3 15 -11 4
Treatment difference (p-value) -14 (p=0.009) -12 (p=0.18) -14 (p=0.03)
*p<0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
a Median % change from baseline.
The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.
Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL-

C

TGa
Total Patient Population
Cholestagel 3.8 g 186 -5* -16* -6* 1 -6* 20*
Placebo 193 0 1 1 0 1 1
Sulfonylurea Alone
Cholestagel 3.8 g 57 -5 -14* -5 -1 -6 17
Placebo 68 0 1 1 1 0 -1
Sulfonylurea in Combination with Other Oral Anti-diabetic Agents
Cholestagel 3.8 g 129 -5 -18* -7* 1 -6 21*
Placebo 125 0 0 1 0 1 2

Add-on Combination Therapy with Insulin: Cholestagel 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the Cholestagel group and 65 units in the placebo group. In combination with insulin, Cholestagel resulted in a statistically significant placebo-corrected reduction in A1C (Table 18). Cholestagel also reduced LDL-C and Apo B, but increased serum TG (Table 19). The mean percent change in serum LDL-C levels with Cholestagel compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with Cholestagel compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for Cholestagel and 0.2 kg for placebo.

a Least-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
Total Patient

Population

Insulin Alone Insulin in Combination

with Oral

Anti-diabetic Agents

Cholestagel

3.8 g/day

Placebo Cholestagel

3.8 g/day

Placebo Cholestagel

3.8 g/day

Placebo
A1C (%), Mean
n 144 136 54 55 90 81
Baseline 8.3 8.2 8.2 8.3 8.3 8.2
Change from baselinea -0.4 0.1 -0.4 0.2 -0.4 0.0
Treatment difference (p-value) -0.5 (p<0.001) -0.6 (p<0.001) -0.4 (p<0.001)
FPG (mg/dL), Mean
n 144 136 54 55 90 81
Baseline 165 151 165 163 165 143
Change from baselinea 2 16 8 17 -4 14
Treatment difference (p-value) -15 (p=0.08) -9 (p=0.51) -18 (p=0.09)
*p<0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
a Median % change from baseline.
The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.
Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL-

C

TGa
Total Patient Population
Cholestagel 3.8 g 129 -3 -12* -4 -1 -3 23*
Placebo 121 1 1 1 0 1 0
Insulin Alone
Cholestagel 3.8 g 46 -3 -12 -5 0 -3 19
Placebo 48 2 4 2 3 2 -2
Insulin in Combination with Oral Anti-diabetic Agents
Cholestagel 3.8 g 83 -4 -13 -4 -1 -3 25*
Placebo 73 -1 -3 0 -1 -1 2

16 HOW SUPPLIED/STORAGE AND HANDLING

Cholestagel (colesevelam hydrochloride) Tablets, 625 mg, are supplied as an off-white, solid tablet imprinted with the word “Sankyo” and “C01” on one side. Cholestagel tablets are available as follows:


Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Brief exposure to 40°C (104°F) does not adversely affect the product. Protect from moisture.

Cholestagel (colesevelam hydrochloride) for Oral Suspension is a white to pale yellow powder containing yellow granules. Cholestagel for Oral Suspension is available as follows:


Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Dosing: Patients should be advised to take Cholestagel Tablets with a meal and liquid. Cholestagel can be taken as 6 tablets once daily or 3 tablets twice daily. Patients should be advised to take Cholestagel for Oral Suspension as 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 ½ to 1 cup of water, fruit juice, or diet soft drinks. Stir well and drink. Cholestagel for Oral Suspension should be taken with meals. To avoid esophageal distress, Cholestagel for Oral Suspension should not be taken in its dry form. Always mix Cholestagel for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting .

Drug interactions: Drugs with a known interaction with Cholestagel (e.g., cyclosporine, glimepiride, glipizide, glyburide, levothyroxine, olmesartan medoxomil, oral contraceptives) should be administered at least 4 hours prior to Cholestagel. In an in vivo drug interaction study, there was no significant effect on the bioavailability of phenytoin; however, due to its narrow therapeutic index and post-marketing reports consistent with potential drug-drug interactions, phenytoin should be administered at least 4 hours prior to Cholestagel. Drugs that have not been tested for interaction with Cholestagel, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Cholestagel. Alternatively the physician should monitor blood levels of the coadministered drug. Patients receiving concomitant metformin ER and Cholestagel should be monitored for clinical response as is usual for the use of anti-diabetes drugs .

Gastrointestinal: Cholestagel can cause constipation. Cholestagel is contraindicated in patients with a history of bowel obstruction. Cholestagel is not recommended in patients who may be at risk of bowel obstruction, including patients with gastroparesis, other gastrointestinal motility disorders, or a history of major gastrointestinal surgery. Patients should be instructed to consume a diet that promotes bowel regularity. Patients should be instructed to promptly discontinue Cholestagel and seek medical attention if severe abdominal pain or severe constipation occurs. Because of the tablet size, Cholestagel Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders. To avoid esophageal distress, Cholestagel for Oral Suspension should not be taken in its dry form. Always mix Cholestagel for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting .

Hypertriglyceridemia and pancreatitis: Patients should be instructed to discontinue Cholestagel and seek prompt medical attention if the hallmark symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting) .

17.1 Primary Hyperlipidemia:

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet.

17.2 Type 2 Diabetes Mellitus:

General: Patients should be advised that it is important to adhere to dietary instructions, a regular exercise program, and regular testing of blood glucose.

Hypertriglyceridemia and cardiovascular disease: Patients should be informed that Cholestagel may increase serum triglyceride concentrations and that the long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain .

Marketed by: Daiichi Sankyo, Inc.

Parsippany, New Jersey 07054

Active Ingredient: Product of Austria

Package Label - Principal Display Panel – 180 Count Bottle, Cholestagel Tablet

Package Label - Principal Display Panel – 1.875 g Packet, Cholestagel for Suspension

Package Label - Principal Display Panel – 60 Count Box, Cholestagel for Suspension

Package Label - Principal Display Panel – 3.75 g Packet, Cholestagel for Suspension

Package Label - Principal Display Panel – 30 Count Box, Cholestagel for Suspension

Cholestagel pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Cholestagel available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Cholestagel destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Cholestagel Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Cholestagel pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."WELCHOL (COLESEVELAM HYDROCHLORIDE) TABLET, FILM COATED WELCHOL (COLESEVELAM HYDROCHLORIDE) FOR SUSPENSION [DAIICHI SANKYO, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Colesevelam". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
  3. "Colesevelam - DrugBank". http://www.drugbank.ca/drugs/DB0093... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Cholestagel?

Depending on the reaction of the Cholestagel after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cholestagel not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Cholestagel addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Cholestagel, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Cholestagel consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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