Welchol

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 singledose packets: 3.75 gram single-dose packet, 1.875 gram single-dose packet.

Storage And Handling

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

Bottles of 180 - NDC 65597-701-18

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.

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

1.875 gram single-dose packet Cartons of 60 packets – NDC 65597-903-60
3.75 gram single-dose packet Cartons of 30 packets – NDC 65597-902-30

Storage

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

Marketed by: Daiichi Sankyo, Inc. Parsippany, New Jersey 07054. Revised: Jan 2014

Primary Hyperlipidemia

WELCHOL is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoproteincholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with a 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:

1. LDL-C remains ≥ 190 mg/dL or
2. 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 whenresponse 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, LDLC 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 serumTG 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.

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

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 in combination with a dipeptidyl peptidase 4 inhibitor.
• WELCHOL has not been studied in pediatric patients with type 2 diabetes.
• 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.

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 ½ 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.

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 ½ 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.

WELCHOL is contraindicated in patients with

• A history of bowel obstruction
• Serum TG concentrations > 500 mg/dL
• A history of hypertriglyceridemia-induced pancreatitis

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

General

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

Serum Triglycerides

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.

In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when WELCHOL was used as monotherapy (median increase 9.7% compared to placebo) and when WELCHOL 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 WELCHOL on LDLC 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. 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.

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 coadministered 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 withcolesevelam 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.

Phenylketonurics

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

Macrovascular Outcomes

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

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 druginduced 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).

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. 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.

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 2048 patients enrolled in the six diabetes studies, 397 (19%) were ≥ 65 years old, and 36 (2%) 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 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

WELCHOL reduces gastrointestinal absorption of some drugs. Drugs with a known interaction withcolesevelam 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.

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.

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction ratesobserved 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 WELCHOL 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 WELCHOL vs. 64% of patients receiving placebo reported an adverse reaction.

Table 1 : Placebo-Controlled Clinical Studies of WELCHOL for Primary Hyperlipidemia: Advers e Reactions Reported in ≥ 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality

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.

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

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%).

Type 2 Diabetes Mellitus

The safety of WELCHOL 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. In these studies 1022 patients were exposed to WELCHOL. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of WELCHOL per day. The mean age of patients exposed to WELCHOL 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 WELCHOL vs. 52% of patients receiving placebo reported an adverse reaction.

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

Table 3 : Placebo-Controlled Clinical Studies of WELCHOL for Type 2 Diabetes : Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality

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 WELCHOL, which may represent a hypersensitivity reaction to WELCHOL.

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 WELCHOL group and 162 mg/dL in the placebo group. WELCHOL 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, 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.

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 WELCHOL (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 WELCHOL and 3 (0.3%) 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.

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 WELCHOL 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.

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.

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

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.

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.

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.