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.
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 (Fredrickson Type IIa) as monotherapy or in combination with a hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin).Colesevelam hydrochloride is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and post-menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:a. LDL-C remains ≥190 mg/dL orb. LDL-C remains ≥160 mg/dL andthere is a positive family history of premature cardiovascular disease ortwo or more other CVD risk factors are present in the pediatric patient.Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate [see Clinical Studies (14.1)].In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are <100 mg/dL. An LDL-C goal of <70 mg/dL is a therapeutic option on the basis of recent trial evidence. If LDL-C is at goal but the serum triglyceride (TG) value is >200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C.
1.3 Important Limitations Of Use
- Colesevelam hydrochloride should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.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 pediatric patients with type 2 diabetes.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 Primary Hyperlipidemia
The recommended dose of colesevelam hydrochloride tablets in adults, whether used as monotherapy or in combination with a statin, is 6 tablets once daily or 3 tablets twice daily. Colesevelam hydrochloride tablets should be taken with a meal and liquid.Colesevelam hydrochloride can be dosed at the same time as a statin or the two drugs can be dosed apart [see Clinical Studies (14.1)].After initiation of colesevelam hydrochloride, lipid levels should be analyzed within 4 to 6 weeks.
3 Dosage Forms And Strengths
- 625 mg tablets are off-white to pale yellow film-coated oval tablets, debossed with "L61" on one side and plain on the other side.
- Colesevelam hydrochloride is contraindicated in patients withA history of bowel obstruction [see Warnings and Precautions (5.4)]Serum TG concentrations >500 mg/dL [see Warnings and Precautions (5.2)]A history of hypertriglyceridemia-induced pancreatitis [see Warnings and Precautions (5.2)]
The effect of colesevelam hydrochloride on cardiovascular morbidity and mortality has not been determined.
5.2 Serum Triglycerides
Colesevelam hydrochloride, like other bile acid sequestrants, can increase serum TG concentrations.Colesevelam hydrochloride had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia [see Adverse Reactions (6.1) and Clinical Studies (14.1)].Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the colesevelam hydrochloride clinical trials had baseline TG <300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with colesevelam hydrochloride. In addition, the use of colesevelam hydrochloride is contraindicated in patients with TG levels >500 mg/dL [see Contraindications (4)]. Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting colesevelam hydrochloride and periodically thereafter. Colesevelam hydrochloride should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemia-induced pancreatitis [see Adverse Reactions (6.1)].
5.3 Vitamin K Or Fat-Soluble Vitamin Deficiencies Precautions
Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of colesevelam hydrochloride on the absorption of co-administered dietary or supplemental vitamin therapy. In nonclinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins.
5.4 Gastrointestinal Disorders
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. Because of the tablet size, colesevelam hydrochloride tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders.
5.5 Drug Interactions
Colesevelam hydrochloride reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to colesevelam hydrochloride. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to colesevelam hydrochloride. Alternatively, the physician should monitor drug levels of the co-administered drug [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
5.7 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular disease risk reduction with colesevelam hydrochloride or any other antidiabetic drugs.
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.
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.
7 Drug Interactions
Table 4 lists the drugs that have been tested in in vitro binding, in vivo drug interaction studies with colesevelam and/or drugs with post-marketing reports consistent with potential drug-drug interactions. Orally administered drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to colesevelam hydrochloride. Alternatively, the physician should monitor drug levels of the co-administered drug.Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing ReportsDrugs with a known interaction with colesevelam:Decrease in exposure of co-administered drugcyclosporineCyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to colesevelam hydrochloride., glimepirideShould be administered at least 4 hours prior to colesevelam hydrochloride., glipizide, glyburide, levothyroxine, olmesartan medoxomil, and oral contraceptives containing ethinyl estradiol and norethindroneDrugs with a known interaction with colesevelam: Increase in exposure of coadministered drugmetformin extended release (ER)Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.Drug(s) with post-marketing reports consistent with potential drug-drug interactions when co-administered with colesevelam hydrochloridephenytoin, warfarinNo significant alteration of warfarin drug levels with warfarin and colesevelam hydrochloride co-administration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR) [see Post-Marketing Experience (6.2)].Drugs that do not interact with colesevelam based on in vitro or in vivo testingaspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoin, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarinIn an in vivo drug interaction study, colesevelam hydrochloride and warfarin co-administration had no effect on warfarin drug levels. This study did not assess the effect of colesevelam hydrochloride and warfarin co-administration on INR. In post-marketing reports, concomitant use of colesevelam hydrochloride and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating colesevelam hydrochloride and frequently enough during early colesevelam hydrochloride therapy to ensure that no significant alteration in INR occurs. Once the INR is stable, continue to monitor the INR at intervals usually recommended for patients on warfarin [see Post-Marketing Experience (6.2)].
8.3 Nursing Mothers
Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract.
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 of 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.
8.6 Hepatic Impairment
No special considerations or dosage adjustments are recommended when colesevelam hydrochloride is administered to patients with hepatic impairment.
Doses of colesevelam hydrochloride in excess of 4.5 g/day have not been tested. Because colesevelam hydrochloride is not absorbed, the risk of systemic toxicity is low. However, excessive doses of colesevelam hydrochloride may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses.
Colesevelam hydrochloride is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended 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 off-white to pale yellow film-coated oval tablets, debossed with "L61" on one side and plain on the other side, containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, copovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and talc.
A maximum therapeutic response to the lipid-lowering effects of colesevelam hydrochloride was achieved within 2 weeks and was maintained during long-term therapy.
14.1 Primary Hyperlipidemia
Colesevelam hydrochloride reduces TC, LDL-C, apolipoprotein B (Apo B), and 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.
16 How Supplied/Storage And Handling
- Colesevelam hydrochloride tablets, 625 mg, are supplied as off-white to pale yellow film-coated oval tablets, debossed with "L61" on one side and plain on the other side. Colesevelam hydrochloride tablets are available as follows:Bottles of 180 – NDC 0115-1320-19
17.1 Primary Hyperlipidemia
Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet.
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