Colesevelam Hydrochloride

COLESEVELAM HYDROCHLORIDE- colesevelam hydrochloride tablet
Dr.Reddys Laboratories Inc

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1 INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia

Colesevelam hydrochloride tablets are 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 are 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

Colesevelam hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

1.3 Limitations of Use

  • Colesevelam hydrochloride tablets should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.
  • Colesevelam hydrochloride tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation of Colesevelam Hydrochloride Tablets

Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride tablets. Colesevelam hydrochloride tablets are 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 colesevelam hydrochloride tablets 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 colesevelam hydrochloride tablets for adults with type 2 diabetes mellitus is 3.75 grams daily.

Colesevelam hydrochloride tablets should be taken as follows:

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

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 AND STRENGTHS

Tablets: 625 mg tablets are yellowish oval shaped tablets, and imprinted with logo625 on one side and plain on the other side.

4 CONTRAINDICATIONS

Colesevelam hydrochloride tablets are contraindicated in patients with:

  • Serum TG concentrations >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.

In trials in patients with type 2 diabetes, greater increases in TG levels occurred when colesevelam hydrochloride was used as monotherapy (median increase 9.7% compared to placebo) and when colesevelam hydrochloride 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 colesevelam hydrochloride and periodically thereafter. Colesevelam hydrochloride tablets are 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 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)].

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 to 86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 grams/day to 4.5 grams/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 grams, 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 grams 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, 1,022 patients were treated with colesevelam hydrochloride. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of colesevelam hydrochloride 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 colesevelam hydrochloride in patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on colesevelam hydrochloride than on placebo, and occurred in at least 2% of patients treated with colesevelam hydrochloride.

Table 3 Clinical Studies of Colesevelam Hydrochloride for Type 2 Diabetes: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo

Colesevelam Hydrochloride 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 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<0.001), 18% (p<0.001), and 22% (p<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 >1,000 mg/dL.

Cardiovascular Adverse Reactions

During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1,022)) in the colesevelam hydrochloride group and 1% (10/1,010) 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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