Colesevelam Hydrochloride

Colesevelam hydrochloride is a bile acid sequestrant indicated as an adjunct to diet and exercise to:

• reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (
  
  
  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 post-menarchal girls, 10 years 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.
  ).
  
• reduce LDL-C levels in boys and post-menarchal girls, 10 years to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH), unable to reach LDL-C target levels despite an adequate trial of diet and lifestyle modification (
  
  
  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 post-menarchal girls, 10 years 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.
  ).
  
• improve glycemic control in adults with type 2 diabetes mellitus (
  
  
  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.
  ).
  

Limitations of Use (

• Do not use for treatment of type 1 diabetes or for diabetic ketoacidosis.
• Not studied in Fredrickson Type I, III, IV, and V dyslipidemias.

• Obtain lipid parameters, including serum triglyceride (TG) levels, before starting colesevelam hydrochloride tablets (
  
  
  2.1 Testing Prior to Initiation of Colesevelam Hydrochloride Tablets

  Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride tablets. Colesevelam hydrochloride is contraindicated in patients with TG levels > 500 mg/dL

  [see Contraindications (4)

  and

  Warnings and Precautions (5.1)]

  .
  )
  
• The recommended dosage for adults and for boys and post-menarchal girls aged 10 years to 17 years with primary hyperlipidemia is 3.75 grams daily. The recommended dosage for adults with type 2 diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride tablets should be taken as follows (
  
  
  2.2 Recommended Dosage in Primary Hyperlipidemia and Type 2 Diabetes Mellitus

  The recommended dosage of colesevelam hydrochloride for adults and for boys and post-menarchal girls aged 10 years to 17 years with primary hyperlipidemia is 3.75 grams daily. The recommended dosage of colesevelam hydrochloride 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.
  , 
  
  
  2.4 Administration Instructions

  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)].
  ):
  

Take 6 tablets once daily or 3 tablets twice daily with a meal and liquid.

• Tablets: 625 mg tablets are white to off-white, oval-shaped, film-coated tablets and printed with “COL” on one side with black ink.

Colesevelam hydrochloride is not absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug. Limited available data on the use of colesevelam hydrochloride are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of either maternal or fetal toxicity was found in rats or rabbits exposed to colesevelam hydrochloride during the period of fetal organogenesis at 8 and 5 times, respectively, the maximum recommended human dose (MRHD) of 3.75 g/day, based on body surface area (mg/m
²). No adverse effects on offspring survival and development were observed in rats administered 5 times the MRHD

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

• Hypertriglyceridemia and Pancreatitis:
  Colesevelam hydrochloride can increase TG. Hypertriglyceridemia can cause acute pancreatitis. Monitor lipids, including TG. Instruct patients to discontinue colesevelam hydrochloride and seek prompt medical attention if the symptoms of acute pancreatitis occur (
  
  
  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 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 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)]

  .
  ).
  
• Gastrointestinal Obstruction:
  Cases of bowel obstruction have occurred. 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 (
  
  
  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.
  ).
  
• Vitamin K or Fat-Soluble Vitamin Deficiencies
  :
   Colesevelam hydrochloride may decrease absorption of fat-soluble vitamins. 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. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride (
  
  
  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)].
  ).
  
• Drug Interactions:
  Due to the potential for decreased absorption of other drugs that have not been tested for interaction, consider administering at least 4 hours prior to colesevelam hydrochloride (
  
  
  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)].
  ,
  
  
  7 DRUG INTERACTIONS

  Concomitant use with colesevelam hydrochloride may decrease the exposure of the following drugs:

  Drugs with a narrow therapeutic index (e.g., cyclosporine), phenytoin, thyroid hormone replacement therapy, warfarin, oral contraceptives containing ethinyl estradiol and norethindrone, olmesartan medoxomil, and sulfonylureas (glimepiride, glipizide, glyburide). Administer these drugs 4 hours prior to colesevelam hydrochloride. For patients on warfarin, monitor International Normalized Ratio (INR) frequently during initiation then periodically .

  Concomitant use with colesevelam hydrochloride may increase the exposure of the following drugs:

  Metformin extended release. Monitor patients' glycemic control .

  7.1 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication

  Table 4 includes a list of drugs that decrease exposure of the concomitant medication when administered concomitantly with colesevelam hydrochloride and instructions for preventing or managing them.

  Table 4 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication

  Drugs with a Narrow Therapeutic Index
  Clinical Impact:	Concomitant use with colesevelam hydrochloride may decrease the exposure of the narrow therapeutic index drug. In vivo drug interactions studies showed a decrease in exposure of cyclosporine when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
  Intervention:	Administer the narrow therapeutic index drug at least 4 hours prior to colesevelam hydrochloride. Monitor drug levels when appropriate.
  Examples:	Cyclosporine
  Phenytoin
  Clinical Impact:	There have been postmarketing reports of increased seizure activity or decreased phenytoin levels in patients receiving phenytoin [see Adverse Reactions (6.2)].
  Intervention:	Administer phenytoin 4 hours prior to colesevelam hydrochloride.
  Thyroid Hormone Replacement Therapy
  Clinical Impact:	In vivo drug interactions studies showed a decrease in exposure of levothyroxine when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)] . There have been postmarketing reports of elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy [see Adverse Reactions (6.2)] .
  Intervention:	Administer thyroid hormone replacement therapy 4 hours prior to colesevelam hydrochloride.
  Warfarin
  Clinical Impact:	There have been postmarketing reports of reduced INR in patients receiving warfarin therapy [see Adverse Reactions (6.2)].
  Intervention:	Monitor INR frequently during colesevelam hydrochloride initiation then periodically thereafter.
  Oral Contraceptives Containing Ethinyl Estradiol and Norethindrone
  Clinical Impact:	In vivo drug interactions studies showed a decrease in exposure of ethinyl estradiol and norethindrone when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
  Intervention:	Administer oral contraceptives containing ethinyl estradiol and norethindrone 4 hours prior to colesevelam hydrochloride.
  Olmesartan Medoxomil
  Clinical Impact:	In vivo drug interactions studies showed a decrease in olmesartan medoxomil when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
  Intervention:	Administer olmesartan medoxomil 4 hours prior to colesevelam hydrochloride.
  Sulfonylureas
  Clinical Impact:	In vivo drug interactions studies showed a decrease in sulfonylureas when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
  Intervention:	Administer sulfonylureas 4 hours prior to colesevelam hydrochloride.
  Examples:	Glimepiride, glipizide, and glyburide
  Oral Vitamin Supplements
  Clinical Impact:	Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K [see Warnings and Precautions (5.3)].
  Intervention:	Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride.

  7.2 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication

  Table 5 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication

  Metformin Extended-Release (ER)
  Clinical Impact:	In vivo drug interactions studies showed an increase in metformin extended release (ER) when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
  Intervention:	Monitor patients' glycemic control.
  ,
  
  
  12.3 Pharmacokinetics

  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.

  Elimination

  Metabolism

  Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P450.

  Excretion

  In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single¹⁴C-labeled colesevelam hydrochloride dose was excreted in the urine.

  Drug Interaction Studies

  Drug interactions between colesevelam 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 colesevelam hydrochloride. Therefore, an

  in vivo

  pharmacokinetic interaction of colesevelam hydrochloride with these drugs is unlikely. Colesevelam hydrochloride 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 colesevelam hydrochloride are presented in Table 6.

  Table 6 Mean Change in Drug Exposure (AUC_0-∞and C_max) when Administered with Colesevelam Hydrochloride (3.75 g)With verapamil, the dose of colesevelam hydrochloride was 4.5 g.

  Drug	Dose	Co-administered		1 hr prior to Colesevelam Hydrochloride		4 hrs prior to Colesevelam Hydrochloride
  		AUC0-∞	Cmax	AUC0-∞	Cmax	AUC0-∞	Cmax
  Cyclosporine	200 mg	-34%	-44%	N/A	N/A	N/A	N/A
  Ethinyl Estradiol†	0.035 mg	-24%	-24%	-18%	-1%	-12%	0%
  Glimepiride	4 mg	-18%	-8%	N/A	N/A	-6%	3%
  Glipizide	20 mg	-12%	-13%	N/A	N/A	-4%	0%
  Glyburide	3 mg	-32%	-47%	-20%	-15%	-7%	4%
  Levothyroxine	600 mcg	-22%	-33%	6%	-2%	1%	8%
  Metformin ER	1,500 mg	44%	8%	N/A	N/A	N/A	N/A
  NorethindroneOral contraceptive containing norethindrone and ethinyl estradiol	1 mg	-1%	-20%	5%	-3%	6%	7%
  Olmesartan Medoxomil	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

  NA - not available
  ).