Welchol

WELCHOL- colesevelam hydrochloride tablet, film coated
WELCHOL- colesevelam hydrochloride for suspension
WELCHOL- colesevelam hydrochloride bar, chewable
Daiichi Sankyo Inc.

1 INDICATIONS AND USAGE

1.1 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.

WELCHOL is indicated to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification.

1.2 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.

1.3 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 Fredrickson Type I, III, IV, and V dyslipidemias.

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation of WELCHOL

Obtain lipid parameters, including triglyceride (TG) levels, before starting WELCHOL. WELCHOL is contraindicated in patients with TG levels >500 mg/dL [see Contraindications (4) and Warnings and Precautions (5.1)].

2.2 Recommended Dosage in Primary Hyperlipidemia and Type 2 Diabetes Mellitus

The recommended dosage of WELCHOL for adults and for boys and postmenarchal girls aged 10 to 17 years with primary hyperlipidemia is 3.75 grams daily. The recommended dosage of WELCHOL for adults with type 2 diabetes mellitus is 3.75 grams daily. WELCHOL should be taken as follows:

Tablets

Take 6 tablets once daily or 3 tablets twice daily. Due to tablet size, WELCHOL for oral suspension is recommended for use in the pediatric population.

For Oral Suspension

Take one packet once daily.

2.3 Important Dosing Information for Primary Hyperlipidemia

WELCHOL can be dosed at the same time as a statin, or WELCHOL and the statin can be dosed apart. Monitor lipid levels within 4 to 6 weeks after initiation of WELCHOL.

2.4 Administration Instructions

Tablets

Take WELCHOL tablets with a meal and liquid. For patients with difficulty swallowing tablets, use WELCHOL for oral suspension [see Warnings and Precautions (5.2)].

For Oral Suspension

To prepare, empty the entire contents of one packet into a glass or cup. Add 1 cup (8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Take WELCHOL oral suspension with meals. Do not take WELCHOL oral suspension in its dry form. Due to tablet size, WELCHOL for oral suspension is recommended for use in the pediatric population.

3 DOSAGE FORMS AND STRENGTHS

  • Tablets: 625 mg tablets are off-white, oval, film-coated and imprinted with “Sankyo” and “C01” on one side.
  • For Oral Suspension: 3.75 gram packet containing a white to pale yellow powder with yellow granules.

4 CONTRAINDICATIONS

WELCHOL is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Hypertriglyceridemia and Pancreatitis

WELCHOL, like other bile acid sequestrants, can increase serum TG concentrations. Hypertriglyceridemia can cause acute pancreatitis.

WELCHOL had effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia.

In 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) [see Adverse Reactions (6.1)].

Obtain lipid parameters, including TG levels, before starting WELCHOL and periodically thereafter. WELCHOL is contraindicated in patients with TG levels >500 mg/dL or patients with a history of hypertriglyceridemia-induced pancreatitis [see Contraindications (4)]. Patients with TG levels greater than 300 mg/dL could have greater increases in serum TG levels with WELCHOL and may require additional TG monitoring. Instruct patients to discontinue WELCHOL and seek prompt medical attention if the symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). Discontinue WELCHOL if TG levels exceed 500 mg/dL [see Adverse Reactions (6.1)].

5.2 Gastrointestinal Obstruction

Postmarketing cases of bowel obstruction have occurred with WELCHOL [see Adverse Reactions (6.2)]. 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. WELCHOL is contraindicated in patients with a history of bowel obstruction [see Contraindications (4)]. Instruct patients to promptly discontinue WELCHOL and seek medical attention if severe abdominal pain or severe constipation occurs.

Because of the tablet size, WELCHOL tablets can cause dysphagia or esophageal obstruction. For patients with difficulty swallowing tablets, use WELCHOL for oral suspension.

5.3 Vitamin K or Fat-Soluble Vitamin Deficiencies

WELCHOL may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins may be at increased risk when taking WELCHOL.

Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to WELCHOL [see Drug Interactions (7.1)].

5.4 Drug Interactions

WELCHOL reduces gastrointestinal absorption of some drugs. Administer drugs with a known interaction at least 4 hours prior to WELCHOL [see Drug Interactions (7)].

Due to the potential for decreased absorption of other drugs that have not been tested for interaction, especially those with a narrow therapeutic index, consider administering at least 4 hours prior to WELCHOL [see Clinical Pharmacology (12.3)].

5.5 Risks in Patients with Phenylketonuria (PKU)

Phenylalanine can be harmful to patients with PKU. WELCHOL for oral suspension contains phenylalanine, a component of aspartame. Each 3.75 gram packet contains 27 mg of phenylalanine. Before prescribing WELCHOL for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including WELCHOL for oral suspension.

6 ADVERSE REACTIONS

The following important adverse reactions are described below and elsewhere in the labeling:

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

Table 1 Clinical Studies of WELCHOL for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo
WELCHOL N=807 Placebo N=258
Constipation 11.0% 7.0%
Dyspepsia 8.3% 3.5%
Nausea 4.2% 3.9%
Accidental injury 3.7% 2.7%
Asthenia 3.6% 1.9%
Pharyngitis 3.2% 1.9%
Flu syndrome 3.2% 3.1%
Rhinitis 3.2% 3.1%
Myalgia 2.1% 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 HeFH (n=194), were treated with WELCHOL tablets (1.9-3.8 g, daily) or placebo tablets.

Table 2 Clinical Study of WELCHOL for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo
WELCHOL N=129 Placebo N=65
Nasopharyngitis 6.2% 4.6%
Headache 3.9% 3.1%
Fatigue 3.9% 1.5%
Creatine Phosphokinase Increase 2.3% 0.0%
Rhinitis 2.3% 0.0%
Vomiting 2.3% 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%).

Type 2 Diabetes Mellitus

In 5 add-on combination and 1 monotherapy double-blind, 12- to 26-week, placebo-controlled clinical trials in patients with type 2 diabetes mellitus, 1022 patients were treated with 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 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 hemoglobin A1c (HbA1c) of 8.2%, and 26% had past medical history suggestive of microvascular complications of diabetes.

Table 3 shows adverse reactions associated with the use of WELCHOL in 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 Clinical Studies of WELCHOL for Type 2 Diabetes: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo
WELCHOL N=1022 Placebo N=1010
Constipation 6.5% 2.2%
Hypoglycemia 3.4% 3.1%
Dyspepsia 2.8% 1.0%
Nausea 2.6% 1.6%
Hypertension 2.6% 1.9%
Back Pain 2.3% 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 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.

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.

Cardiovascular Adverse Reactions

During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1022) 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.

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