Colesevelam HCL

COLESEVELAM HCL- colesevelam hydrochloride tablet, film coated
Bryant Ranch Prepack

Colesevelam-Struct

1 INDICATIONS & USAGE

1.1 Primary Hyperlipidemia

Colesevelam hydrochloride tablets is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia

Colesevelam hydrochloride tablets 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.

1.3 Limitations of Use

• Colesevelam hydrochloride should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.
• The effect of colesevelam hydrochloride on cardiovascular morbidity and mortality has not been determined.
• Colesevelam hydrochloride has not been studied in type 2 diabetes in combination with a dipeptidyl peptidase 4 inhibitor.
• Colesevelam hydrochloride has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.
• Colesevelam hydrochloride has not been studied in children younger than 10 years of age or in premenarchal girls

2 DOSAGE & ADMINISTRATION

2.1 Testing Prior to Initiation of Colesevelam Hydrochloride

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

2.2 Recommended Dosage in Primary Hyperlipidemia

The recommended dosage of colesevelam tablets for adults and children 10 to 17 years old with primary hyperlipidemia is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows:

Tablets

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

2.3 Important Dosing Information for Primary Hyperlipidemia

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

2.4 Administration Instructions

Tablets

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

3 DOSAGE FORMS & STRENGTHS

• Off-white to light yellow colored, oval, film coated tablets imprinted “C625” on one side.

4 CONTRAINDICATIONS

Colesevelam hydrochloride is contraindicated in patients with:

• Serum TG concentrations greater than 500 mg/dL [see Warnings and Precautions (5.1)]
• History of hypertriglyceridemia-induced pancreatitis [see Warnings and Precautions (5.1)]
• A history of bowel obstruction [see Warnings and Precautions (5.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Hypertriglyceridemia and Pancreatitis

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

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

Obtain lipid parameters, including TG levels before starting colesevelam hydrochloride and periodically thereafter. Colesevelam hydrochloride is contraindicated in patients with TG levels greater than 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 colesevelam hydrochloride and may require additional TG monitoring. Instruct patients to discontinue colesevelam hydrochloride and seek prompt medical attention if the symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). Discontinue colesevelam hydrochloride if TG levels exceed 500 mg/dL [see Adverse Reactions (6.1)].

5.2 Gastrointestinal Obstruction

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

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

5.3 Vitamin K or Fat-Soluble Vitamin Deficiencies

Colesevelam hydrochloride 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 colesevelam hydrochloride.

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

5.4 Drug Interactions

Colesevelam hydrochloride reduces gastrointestinal absorption of some drugs. Administer drugs with a known interaction at least 4 hours prior to colesevelam hydrochloride[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 colesevelam hydrochloride[see Clinical Pharmacology (12.3)].

5.6 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with colesevelam hydrochloride.

6 ADVERSE REACTIONS

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

• Hypertriglyceridemia and Pancreatitis [see Warnings and Precautions (5.1)]
• Gastrointestinal Obstruction [see Warnings and Precautions (5.2)]
• Vitamin K or Fat-Soluble Vitamin Deficiencies [see Warnings and Precautions (5.3)]

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

Table 1

Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo

	Colesevelam hydrochloride 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 colesevelam hydrochloride tablets (1.9 to 3.8 g, daily) or placebo tablets

Table 2

Clinical Study of Colesevelam Hydrochloride for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo

	Colesevelam Hydrochloride 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 colesevelam hydrochloride 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%).

A total of 5.3% of colesevelam hydrochloride-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 colesevelam hydrochloride, which may represent a hypersensitivity reaction to colesevelam hydrochloride.

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 colesevelam hydrochloride group and 162 mg/dL in the placebo group. Colesevelam hydrochloride 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 less than 0.001), 18% (p less than 0.001), and 22% (p less than 0.001), when added to metformin, pioglitazone, sulfonylureas, and insulin, respectively. In comparison, colesevelam hydrochloride 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 colesevelam hydrochloride-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with colesevelam hydrochloride (median 606 mg/dL; interquartile range 570 to 794 mg/dL) were similar to that observed with placebo (median 663 mg/dL; interquartile range 542 to 984 mg/dL). Five (0.6%) patients on colesevelam hydrochloride and 3 (0.3%) patients on placebo developed TG elevations greater than 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 colesevelam hydrochloride 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.