Welchol

WELCHOL 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

  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.
  ).
  
• reduce LDL-C levels in boys and postmenarchal girls, 10 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

  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.
  ).
  
• improve glycemic control in adults with type 2 diabetes mellitus (
  
  
  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

  .
  ).
  

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 WELCHOL (
  
  
  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)]

  .
  ).
  
• The recommended dosage for adults and for boys and postmenarchal girls aged 10 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. WELCHOL should be taken as follows (
  
  
  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.
  ,
  
  
  2.4 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.
  ):
  

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

Take one packet once daily with a meal. To prepare, empty the entire contents of one packet into a glass or cup. Add 1 cup of water, fruit juice, or diet soft drinks. Stir well and drink.

• 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.

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

  .
  ).
  
• Gastrointestinal Obstruction:
  Cases of bowel obstruction have occurred. 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 (
  
  
  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.
  ).
  
• Vitamin K or Fat-Soluble Vitamin Deficiencies:
  WELCHOL 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 WELCHOL (
  
  
  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)].
  ).
  
• 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 WELCHOL (
  
  
  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)].
  ,
  
  
  7 DRUG INTERACTIONS

  Concomitant use with WELCHOL 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 WELCHOL. For patients on warfarin, monitor International Normalized Ratio (INR) frequently during initiation then periodically .

  Concomitant use with WELCHOL may increase the exposure of the following drugs:

  Metformin extended release. Monitor patients' glycemic control .

  7.1 WELCHOL 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 WELCHOL and instructions for preventing or managing them.

  Table 4 WELCHOL Drug Interactions that Decrease the Exposure of the Concomitant Medication

  Drugs with a Narrow Therapeutic Index
  Clinical Impact:	Concomitant use with WELCHOL may decrease the exposure of the narrow therapeutic index drug. In vivo drug interactions studies showed a decrease in exposure of cyclosporine when coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
  Intervention:	Administer the narrow therapeutic index drug at least 4 hours prior to WELCHOL. 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 WELCHOL.
  Thyroid Hormone Replacement Therapy
  Clinical Impact:	In vivo drug interactions studies showed a decrease in exposure of levothyroxine when coadministered with WELCHOL [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 WELCHOL.
  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 WELCHOL 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 coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
  Intervention:	Administer oral contraceptives containing ethinyl estradiol and norethindrone 4 hours prior to WELCHOL.
  Olmesartan Medoxomil
  Clinical Impact:	In vivo drug interactions studies showed a decrease in olmesartan medoxomil when coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
  Intervention:	Administer olmesartan medoxomil 4 hours prior to WELCHOL.
  Sulfonylureas
  Clinical Impact:	In vivo drug interactions studies showed a decrease in sulfonylureas when coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
  Intervention:	Administer sulfonylureas 4 hours prior to WELCHOL.
  Examples:	Glimepiride, glipizide, and glyburide
  Oral Vitamin Supplements
  Clinical Impact:	WELCHOL 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 WELCHOL.

  7.2 WELCHOL Drug Interactions that Increase the Exposure of the Concomitant Medication

  Table 5 WELCHOL 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 coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
  Intervention:	Monitor patients' glycemic control.
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  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 WELCHOL with these drugs is unlikely. WELCHOL 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 WELCHOL are presented in Table 6.

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

  Drug	Dose	Co-administered		1 hr prior to WELCHOL		4 hrs prior to WELCHOL
  		AUC0-∞	Cmax	AUC0-∞	Cmax	AUC0-∞	Cmax
  N/A − not available
  Cyclosporine	200 mg	-34%	-44%	N/A	N/A	N/A	N/A
  Ethinyl EstradiolOral contraceptive containing norethindrone and 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 µg	-22%	-33%	6%	-2%	1%	8%
  Metformin ER	1500 mg	44%	8%	N/A	N/A	N/A	N/A
  Norethindrone	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	-11%	-31%	N/A	N/A	N/A	N/A
  ).
  
• Risks in Patients with Phenylketonuria (PKU):
  Phenylalanine can be harmful to patients with phenylketonuria. WELCHOL for oral suspension contains 27 mg phenylalanine per 3.75 gram packet (
  
  
  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.
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  11 DESCRIPTION

  WELCHOL (colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule.

  Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:

  

  wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone cross-linking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ≥100 to indicate an extended polymer network. A small amount of the amines are dialkylated and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water.

  WELCHOL tablets are off-white, oval, film-coated, solid tablets each containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink (<5 calories per 6 tablets).

  WELCHOL for oral suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in a packet containing 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate (<5 calories per 3.75 gram single-dose packet). PHENYLKETONURICS: WELCHOL for oral suspension contains 27 mg phenylalanine per 3.75 gram dose.

  Chemical Structure

  ).