NDC 27808-190 Colesevelam

Colesevelam

NDC Product Code 27808-190

NDC CODE: 27808-190

Proprietary Name: Colesevelam What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Colesevelam What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325 - OFF-WHITE)
Shape: CAPSULE (C48336)
Size(s):
19 MM
Imprint(s):
JX001
Score: 1

NDC Code Structure

  • 27808 - Tris Pharma Inc

NDC 27808-190-01

Package Description: 1 TABLET in 1 BOTTLE

NDC Product Information

Colesevelam with NDC 27808-190 is a a human prescription drug product labeled by Tris Pharma Inc. The generic name of Colesevelam is colesevelam. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Tris Pharma Inc

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Colesevelam Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • COLESEVELAM 180 1/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • AMMONIA (UNII: 5138Q19F1X)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • DIACETYLATED MONOGLYCERIDES (UNII: 5Z17386USF)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)
  • HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • SHELLAC (UNII: 46N107B71O)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Bile Acid Sequestrant - [EPC] (Established Pharmacologic Class)
  • Bile-acid Binding Activity - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Tris Pharma Inc
Labeler Code: 27808
FDA Application Number: ANDA209946 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-19-2020 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Colesevelam Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Primary Hyperlipidemia

Colesevelam hydrochloride 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 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 pre-menarchal girls.

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 >500 mg/dL


[see


Contraindications (4) and


Warnings and Precautions (5.1)]


.

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

  • Tablets: 625 mg tablets are off-white, capsule-shaped, film-coated and imprinted with " JX001" on one side.

4 Contraindications

  • Colesevelam hydrochloride is 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)]

5.1 Hypertriglyceridemia And Pancreatitis

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


N = 807


Placebo


N = 258


Constipation11.0%7.0%Dyspepsia8.3%3.5%Nausea4.2%3.9%Accidental injury3.7%2.7%Asthenia3.6%1.9%Pharyngitis3.2%1.9%Flu syndrome3.2%3.1%Rhinitis3.2%3.1%Myalgia2.1%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 (1.9-3.8 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 PlaceboColesevelam Hydrochloride


N = 129


Placebo


N = 65


Nasopharyngitis6.2%4.6%Headache3.9%3.1%Fatigue3.9%1.5%Creatine Phosphokinase Increase2.3%0.0%Rhinitis2.3%0.0%Vomiting2.3%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%).

6.2 Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of colesevelam hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Adverse Reactions Resulting from Drug Interactions [see


Drug Interactions (7)]:


Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin, reduced International Normalized Ratio (INR) in patients receiving warfarin therapy, and elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy.


Gastrointestinal: Bowel obstruction (in patients with a history of bowel obstruction or resection), dysphagia or esophageal obstruction (occasionally requiring medical intervention), fecal impaction, pancreatitis, abdominal distension, exacerbation of hemorrhoids, and increased transaminases


Laboratory Abnormalities: Hypertriglyceridemia

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 IndexClinical 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 coadministered 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:CyclosporinePhenytoinClinical 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 TherapyClinical Impact:In vivo drug interactions studies showed a decrease in exposure of levothyroxine when coadministered 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.WarfarinClinical 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 NorethindroneClinical Impact:In vivo drug interactions studies showed a decrease in exposure of ethinyl estradiol and norethindrone when coadministered with colesevelam hydrochloride


[see


Clinical Pharmacology (12.3)].


Intervention:Administer oral contraceptives containing ethinyl estradiol and norethindrone 4 hours prior to colesevelam hydrochloride.Olmesartan MedoxomilClinical Impact:In vivo drug interactions studies showed a decrease in olmesartan medoxomil when coadministered 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 coadministered with colesevelam hydrochloride


[see


Clinical Pharmacology (12.3)].


Intervention:Administer sulfonylureas 4 hours prior to colesevelam hydrochloride.Examples:Glimepiride, glipizide, and glyburideOral Vitamin SupplementsClinical 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 coadministered with colesevelam hydrochloride


[see


Clinical Pharmacology (12.3)].


 


Intervention: Monitor patients' glycemic control.

8.1 Pregnancy

Risk SummaryColesevelam 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


(see


Data).


Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins


[see


Warnings and Precautions (5.3)].


There are no data available on the effect of colesevelam hydrochloride on the absorption of fat-soluble vitamins in pregnant women. If the patient becomes pregnant while taking colesevelam hydrochloride, the patient should be advised of the lack of known clinical benefit with continued use during pregnancy.


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.DataHuman DataThere are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and a causal association with congenital anomalies has not been established.Animal DataIn pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days 7 through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were 8 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m


2).


In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days 6 through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m


2).


In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day 6 through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m


2).

8.2 Lactation

Risk SummaryColesevelam hydrochloride is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to colesevelam hydrochloride.

8.3 Females And Males Of Reproductive Potential

ContraceptionUse of colesevelam hydrochloride may reduce the efficacy of oral contraceptives. Advise patients to take oral contraceptives at least 4 hours prior to taking colesevelam hydrochloride


[see


Drug Interactions (7)].

8.4 Pediatric Use

The safety and effectiveness of colesevelam hydrochloride as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age, with HeFH


[see


Clinical Studies (14.1)]


. The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo


[see


Adverse Reactions (6.1)].


Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population. Dose adjustments are not required when colesevelam hydrochloride is administered to children 10 to 17 years of age.Colesevelam hydrochloride has not been studied in children younger than 10 years of age or in pre-menarchal girls.

8.5 Geriatric Use

Primary Hyperlipidemia Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10 Overdosage

Colesevelam hydrochloride is not absorbed and the risk of systemic toxicity is low. Excessive doses of colesevelam hydrochloride may cause more severe local gastrointestinal effects (e.g., constipation).

11 Description

Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-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.Colesevelam hydrochloride tablets are an off-white, capsule-shaped, film-coated, solid tablet each containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: ammonia, N-butyl alcohol, diacetylated monoglycerides, ferrosoferric oxide, isopropyl alcohol, hypromellose 2910 (5 MPA.S), hypromellose 2910 (15 MPA.S), magnesium stearate, microcrystalline cellulose, propylene glycol, shellac and silicon dioxide.

12.1 Mechanism Of Action

Primary Hyperlipidemia: Colesevelam hydrochloride, the active pharmaceutical ingredient in colesevelam hydrochloride, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.

12.2 Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy.

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.EliminationMetabolismColesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.Excretion:


In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single


14C-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.


DrugDoseCo-administered1 hr prior to Colesevelam Hydrochloride4 hr prior to Colesevelam HydrochlorideAUC


0-∞C


maxAUC


0-∞C


maxAUC


0-∞C


maxTable 6 Mean Change in Drug Exposure (AUC0-∞ and C


max) when Administered with Colesevelam Hydrochloride (3.75 g)


*Cyclosporine200 mg-34%-44%N/AN/AN/AN/AEthinyl Estradiol


†0.035 mg-24%-24%-18%-1%-12%0%Glimepiride4 mg-18%-8%N/AN/A-6%3%Glipizide20 mg-12%-13%N/AN/A-4%0%Glyburide3 mg-32%-47%-20%-15%-7%4%Levothyroxine600 μg-22%-33%6%-2%1%8%Metformin ER1500 mg44%8%N/AN/AN/AN/ANorethindrone


†1 mg-1%-20%5%-3%6%7%Olmesartan Medoxomil40 mg -39%-28%N/AN/A-15%-4%Repaglinide2 mg-7%-19%-6%-1%N/AN/AVerapamil sustained-release240 mg-31%-11%N/AN/AN/AN/A* With verapamil, the dose of colesevelam hydrochloride was 4.5 g † Oral contraceptive containing norethindrone and ethinyl estradiolN/A – Not Available

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).Mutagenesis Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an


in vitro bacterial mutagenesis assay in S. typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.


Impairment of FertilityColesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

13.2 Animal Toxicology And/Or Pharmacology

Reproductive Toxicology StudiesReproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.

14.1 Primary Hyperlipidemia

Colesevelam hydrochloride reduces total cholesterol (TC), LDL-C, apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia.Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy.Monotherapy In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), colesevelam hydrochloride was given for 24 weeks in divided doses with the morning and evening meals.As shown in Table 7, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. Colesevelam hydrochloride at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both colesevelam hydrochloride doses but the changes were not statistically different from placebo.Table 7 Response to Colesevelam Hydrochloride Monotherapy in a 24-Week Trial - Percent Change in Lipid Parameters from BaselineGrams/DayNTCLDL-CApo BHDL-C


*Non-HDL-CTG


*Placebo88+100–1+1+53.8 g (6 tablets)95–7


†–15


†–12


†+3


†–10


†+104.5 g (7 tablets)94–10


†–18


†–12


†+3–13


†+9* Median % change from baseline. † p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), colesevelam hydrochloride 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.Combination Therapy Co-administration of colesevelam hydrochloride and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 8, colesevelam hydrochloride doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.Dose/DayNTCLDL-CApo BHDL-C


*Non-HDL-CTG


*Table 8 Response to Colesevelam Hydrochloride in Combination with Atorvastatin, Simvastatin, or Lovastatin - Percent Change in Lipid ParametersAtorvastatin Trial (4-week)Placebo19+4+3–3+4+4+10Atorvastatin 10 mg18–27


†–38


†–32


†+8–35


†–24


†Colesevelam Hydrochloride 3.8 g/Atorvastatin 10 mg18–31


†–48


†–38


†+11–40


†–1Atorvastatin 80 mg20–39


†–53


†–46


†+6–50


†–33


†Simvastatin Trial (6-week)Placebo33–2–4–4


†–3–2+6


†Simvastatin 10 mg35–19


†–26


†–20


†+3


†–24


†–17


†Colesevelam Hydrochloride 3.8 g/Simvastatin 10 mg34–28


†–42


†–33


†+10


†–37


†–12


†Simvastatin 20 mg39–23


†–34


†–26


†+7


†–30


†–12


†Colesevelam Hydrochloride 2.3 g/Simvastatin 20 mg37–29


†–42


†–32


†+4


†–37


†–12


†Lovastatin Trial (4-week)Placebo26+100+1+1+1Lovastatin 10 mg26–14


†–22


†–16


†+5–19


†0Colesevelam Hydrochloride 2.3 g/Lovastatin 10 mg Together27–21


†–34


†–24


†+4–27


†–1Colesevelam Hydrochloride 2.3 g/Lovastatin 10 mg Apart23–21


†–32


†–24


†+2–28


†–2* Median % change from baseline. † p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.In all 3 studies, the LDL-C reduction achieved with the combination of colesevelam hydrochloride and any given dose of statin therapy was statistically superior to that achieved with colesevelam hydrochloride or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of colesevelam hydrochloride 3.8 g and atorvastatin 10 mg.Pediatric Therapy The safety and efficacy of colesevelam hydrochloride in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with HeFH, taking a stable dose of an FDA-approved statin (with LDL-C >130 mg/dL) or naïve to lipid-lowering therapy (with LDL-C >160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-naïve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL.During the double-blind treatment period, patients were assigned randomly to treatment: colesevelam hydrochloride 3.8 g/day (n=64), colesevelam hydrochloride 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, colesevelam hydrochloride 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).Treatment DifferenceTC


(N=128)


LDL-C


(N=128)


Apo B


(N=124)


HDL-C


(N=128)


Non-HDL-C


(N=128)


TG


* (N=128)


Table 9 Response to Colesevelam Hydrochloride 3.8 g Compared to Placebo in Pediatric Patients 10-17 Years of Age – Mean Percent Change in Lipid Parameters from Baseline to Week 8Colesevelam Hydrochloride 3.8 g vs Placebo-7


†-13


†-8


†+6


†–11


†+5* For triglycerides, median % change from baseline † p≤0.05 for lipid parameters compared to placeboValues represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day 1 prior to the first dose of randomized study medication.Results were based on the ITT population with LOCF.During the open-label treatment period patients were treated with colesevelam hydrochloride 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.

16 How Supplied/Storage And Handling

Colesevelam hydrochloride 625 mg tablets are supplied as an off-white, solid tablet imprinted with the word "JX001" on one side and are available as follows:Bottles of 180: NDC 27808-190-01  Store at 20 - 25°C (68 - 77°F); excursions permitted to 15 - 30°C (59 - 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Brief exposure to 40°C (104°F) does not adversely affect colesevelam hydrochloride tablets. Dispense in child-resistant containers.

17 Patient Counseling Information

Hypertriglyceridemia and Pancreatitis Inform patients that colesevelam hydrochloride may increase their serum triglycerides which can lead to hypertriglyceridemia and pancreatitis. 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)


[see


Warnings and Precautions (5.1)].


Gastrointestinal Inform patients that colesevelam hydrochloride may cause bowel obstruction. Instruct patients to promptly discontinue colesevelam hydrochloride and seek medical attention if severe abdominal pain or severe constipation occurs


[see


Warnings and Precautions (5.2)].


Drug and Vitamin interactions: Advise patients that colesevelam hydrochloride has drug interactions and colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K. Instruct patients to take oral vitamins at least 4 hours prior to colesevelam hydrochloride. Instruct patients to inform their physician about all the drugs and vitamins that they are prescribed or take over the counter


[see


Warnings and Precautions (5.3) and


Drug Interactions (7)].


Administration [see


Dosage and Administration (2.4)]:


Tablets:Advise patients to take colesevelam hydrochloride tablets with a meal and liquid. Inform patients that colesevelam hydrochloride tablets can be taken as 6 tablets once daily or 3 tablets twice daily.Females of Reproductive PotentialAdvise females of reproductive potential that colesevelam hydrochloride may reduce the effectiveness of oral contraceptives, and to take oral contraceptives at least 4 hours before taking colesevelam hydrochloride


[see


Drug Interactions (7) and


Use in Specific Populations (8.3)].


Manufactured by:Zhejiang Jingxin Pharmaceutical Co., Ltd.No. 800 Xinchang East RoadZhejiang Province, P.R. ChinaFor: Tris Pharma, Inc.Monmouth Junction, NJ 08852 USAwww.trispharma.comLB8580Rev. 00Revised: May 2020

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