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DAIICHI SANKYO,
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65597090230

brand welchol 3.75g packet

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Uses

Dyslipidemias

Primary Hypercholesterolemia

Colesevelam hydrochloride, alone or combined with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (i.e., statin), is used as an adjunct to dietary therapy and exercise to decrease elevated serum low-density lipoprotein (LDL)-cholesterol concentrations in the management of primary hypercholesterolemia (Frederickson type IIa). The effect of colesevelam, alone or in combination with a statin, on cardiovascular morbidity and mortality has not been established.

The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated. For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., bile acid sequestrants) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. However, nonstatin drugs may be useful as adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations of 190 mg/dL or higher, patients with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy. When a nonstatin drug is required, selection of the nonstatin drug should be based on a favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects and drug interactions) and patient preferences. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

The safety and efficacy of colesevelam for the management of Fredrickson type I, III, IV, or V dyslipidemia have not been established.

Reductions in total cholesterol and LDL-cholesterol concentrations achieved with usual dosages of colesevelam hydrochloride substantially exceed those of placebo. Mean reductions of 7-10% in total cholesterol, 15-19% in LDL-cholesterol, and 12% in apolipoprotein B (apo B) concentrations, and mean increases of 3-8% in high-density lipoprotein (HDL)-cholesterol concentrations have been reported in controlled and uncontrolled studies of patients with primary hypercholesterolemia who received recommended daily dosages of colesevelam hydrochloride (3.75-4.5 g) for at least 6 weeks. Like other bile acid sequestrants, therapy with colesevelam has been associated with slight increases (5-10%) in triglyceride concentrations.

Colesevelam appears to be equally effective in reducing LDL-cholesterol concentrations whether the daily dosage is given as 1 or 2 divided doses. In patients who received 3.75 g of colesevelam hydrochloride as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner, mean reductions in LDL-cholesterol concentrations of 18, 15, and 18% respectively, were observed.

Data from several randomized, placebo-controlled studies indicate that combination therapy with colesevelam and other antilipemic agents (e.g., statins, fenofibrate) may produce additive antilipemic effects. The addition of colesevelam hydrochloride (2.3-3.75 g daily) to usual dosages of various statins (i.e., atorvastatin, lovastatin, simvastatin) further reduced total cholesterol and LDL-cholesterol concentrations by 4-9 and 8-16%, respectively. Reductions in LDL-cholesterol concentrations produced by concomitant low-dose atorvastatin (10 mg daily) and colesevelam hydrochloride (3.75 g daily) were not substantially different from those achieved with high-dose atorvastatin (80 mg daily) therapy. The addition of colesevelam hydrochloride (3.8 g daily) to current fenofibrate therapy (160 mg daily) in patients with mixed dyslipidemia reduced total and LDL-cholesterol concentrations by 6 and 10%, respectively, but increased triglyceride concentrations by 6%.

For additional information on the use of colesevelam or other antilipemic agents in the treatment of lipoprotein disorders, prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.

Diabetes Mellitus

Colesevelam hydrochloride is used in combination with metformin, sulfonylurea, or insulin monotherapy or in combinations of these and other oral antidiabetic agents as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus. Safety and efficacy of colesevelam as monotherapy or in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor have not been established in the management of type 2 diabetes mellitus, and colesevelam has not been studied extensively in combination with thiazolidinediones. In addition to adequate glycemic control, intensive control of dyslipidemia is warranted in patients with diabetes mellitus.

Data from several randomized, placebo-controlled studies of 16-26 weeks' duration in patients with type 2 diabetes mellitus inadequately controlled with metformin, sulfonylurea, or insulin monotherapy or combinations of these agents with other oral antidiabetic agents indicate that add-on therapy with colesevelam hydrochloride (3.75 g daily) produced an average reduction in hemoglobin A1c (HbA1c) of 0.5% from baseline compared with that observed with placebo. Fasting plasma glucose concentrations were reduced by an average of 14 mg/dL from baseline following the addition of colesevelam to metformin- or sulfonylurea-based therapy; such reduction in glucose concentrations was not observed following the addition of colesevelam to insulin-based therapy. Add-on colesevelam therapy in diabetic patients receiving metformin, sulfonylurea, or insulin therapy reduced serum LDL-cholesterol concentrations by 12-16%, a reduction of similar magnitude to that observed in patients receiving colesevelam for primary hypercholesterolemia.

The addition of colesevelam to insulin- or sulfonylurea-based therapy increased serum triglyceride concentrations by a median of 20-25% from baseline; no appreciable increase in serum triglyceride concentrations occurred with addition of colesevelam to metformin-based therapy.(See Contraindications under Cautions.)

Colesevelam is not effective as sole therapy for type 1 diabetes mellitus or diabetic ketoacidosis.

Dosage and Administration

General

Patients with primary hyperlipidemia should be placed on a standard lipid-lowering diet before initiation of colesevelam therapy and should remain on this diet during treatment with the drug.

The manufacturer states that lipoprotein concentrations, including serum triglyceride and non-HDL cholesterol concentrations, should be monitored prior to colesevelam therapy and periodically thereafter. The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline recommends that a fasting lipoprotein profile be obtained prior to initiating bile acid sequestrant therapy, after 3 months of therapy, and every 6-12 months thereafter.

In patients with diabetes mellitus, intensive control of hyperlipidemia is warranted in addition to glycemic control.

Administration

Colesevelam hydrochloride is administered orally once or twice daily with a liquid at mealtime. Unlike other bile acid sequestrants (e.g., cholestyramine, colestipol), colesevelam may be administered simultaneously with statin therapy. Drugs known to interact with colesevelam, as well as drugs that have not been evaluated in formal drug interaction studies with colesevelam, especially those with a narrow therapeutic index, should be administered at least 4 hours prior to colesevelam.(See Drug Interactions.) Alternatively, the clinician should monitor blood concentrations of the concomitantly administered drug.

Dosage

Primary Hypercholesterolemia

The usual dosage of colesevelam hydrochloride as monotherapy or in combination with a statin in adults is 1.875 g (3 tablets) twice daily or 3.75 g (6 tablets) once daily with liquid at mealtime. In most patients with primary hypercholesterolemia, the maximum therapeutic response to colesevelam occurs within 2 weeks and is maintained during long-term (e.g., up to 50 weeks) therapy.

Diabetes Mellitus

When used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, insulin) in patients with type 2 diabetes mellitus, the usual dosage of colesevelam hydrochloride in adults is 1.875 g (3 tablets) twice daily or 3.75 g (6 tablets) once daily with liquid at mealtime. A therapeutic response to colesevelam usually occurs following 4-6 weeks of treatment and reaches maximal or near maximal effect after 12-18 weeks of therapy.

Special Populations

No special population dosage recommendations at this time.

Cautions

Contraindications

Bowel obstruction. Baseline serum triglyceride concentrations exceeding 500 mg/dL. History of hypertriglyceridemia-induced pancreatitis. Known hypersensitivity to colesevelam or any ingredient in the formulation.

Warnings/Precautions

General Precautions

Hypertriglyceridemia

Increased serum triglyceride concentrations have been reported in patients with primary hypercholesterolemia or type 2 diabetes mellitus who were treated with colesevelam. In clinical trials in patients with diabetes mellitus, colesevelam therapy increased serum triglyceride concentrations by a median of 18 or 22% from baseline when added to sulfonylurea or insulin therapy, respectively. Hypertriglyceridemia of sufficient severity can cause pancreatitis. In patients with type 2 diabetes mellitus, the favorable reduction of LDL-cholesterol with colesevelam therapy may be attenuated by elevation of serum triglyceride concentrations and a smaller reduction in non-HDL-cholesterol concentrations than in LDL-cholesterol concentrations.

Use of colesevelam has not been studied in patients with triglyceride concentrations of 300 mg/dL or greater. It is not known whether such patients would experience greater increases in serum triglyceride concentrations with colesevelam therapy. Therefore, the American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline states that colesevelam should be used with caution in patients with baseline triglyceride concentrations of 250-299 mg/dL; a fasting lipoprotein profile should be obtained 4-6 weeks after initiation of therapy. The guideline also recommends that lipoprotein concentrations be monitored periodically during therapy with the drug. The manufacturer states that therapy with colesevelam should be discontinued if serum triglyceride concentrations exceed 500 mg/dL or if hypertriglyceridemia-induced pancreatitis occurs (see Contraindications); however, the ACC/AHA cholesterol management guideline states that colesevelam should be discontinued if serum triglyceride concentrations exceed 400 mg/dL.

Colesevelam should not be used in patients with baseline fasting triglyceride concentrations of 300 mg/dL or greater or in those with primary dysbetalipoproteinemia (Fredrickson type III).

Fat-soluble Vitamin Deficiency

Bile acid sequestrants may decrease absorption of fat-soluble vitamins A, D, E, and K. Effects of colesevelam on concomitantly administered dietary or supplemental vitamin therapy, including such use in pregnant women, have not been established.

Hemorrhage from vitamin K deficiency has been reported in rats receiving colesevelam hydrochloride dosages approximately 30 times the usual human dosage. Use caution in patients susceptible to deficiency of vitamin K (e.g., concomitant warfarin therapy, malabsorption syndromes) or other fat-soluble vitamins.(See Drug Interactions: Fat-soluble Vitamins.)

GI Disorders

The large tablet size of colesevelam may cause dysphagia or esophageal obstruction; use with caution in patients with dysphagia or swallowing disorders. Because of its constipating effects, colesevelam is not recommended in patients with gastroparesis or other GI motility disorders, or in those who have undergone major GI tract surgery and who may be at risk for bowel obstruction.

Combination Therapy

When used in combination with metformin, a sulfonylurea, or insulin, consider the cautions, precautions, and contraindications associated with the concomitant agent(s).

Specific Populations

Pregnancy

Category B. Use caution since requirements for vitamins and other nutrients are increased during pregnancy.(See Fat-soluble Vitamin Deficiency under Warnings/Precautions: General Precautions, in Cautions.)

Lactation

No formal studies have been performed in nursing women. However, the manufacturer states that since colesevelam is not absorbed systemically, the drug is not expected to distribute into milk.

Pediatric Use

Safety and efficacy of colesevelam has not been established in children younger than 18 years of age. Because of the large tablet size, colesevelam is not recommended in pediatric patients.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Renal Impairment

In patients with type 2 diabetes mellitus, no overall differences in safety or efficacy were observed between patients with moderate renal insufficiency (creatinine clearance less than 50 mL/minute) and those with mild renal insufficiency (creatinine clearance of at least 50 mL/minute).

Common Adverse Effects

Adverse effects occurring in at least 2% of patients with primary hypercholesterolemia receiving colesevelam hydrochloride in controlled clinical trials and more frequently than with placebo include constipation, dyspepsia, nausea, accidental injury, asthenia, pharyngitis, flu-like syndrome, rhinitis, and myalgia. Adverse GI effects have been reported less frequently with colesevelam than with cholestyramine or colestipol; however, there have been no studies to date directly comparing the relative safety of these agents.

Adverse effects occurring in at least 2% of patients with type 2 diabetes mellitus receiving colesevelam and more frequently than with placebo include constipation, nasopharyngitis, dyspepsia, hypoglycemia, nausea, and hypertension.

Drug Interactions

Antidiabetic Agents

Potential pharmacokinetic interaction (decreased peak plasma concentration and area under the concentration-time curve [AUC] for glyburide). Administer glyburide at least 4 hours prior to colesevelam.

Pharmacokinetic interaction with metformin, repaglinide, and pioglitazone unlikely.

Digoxin

Pharmacokinetic interaction unlikely (i.e., no effect on bioavailability of digoxin).

Fat-soluble Vitamins

Potential pharmacokinetic interaction (decreased absorption of fat-soluble vitamins A, D, E, and K) with concomitant bile acid sequestrants. Administer fat-soluble vitamins at least 4 hours prior to colesevelam.(See Dosage and Administration: Administration.)

Fenofibrate

Pharmacokinetic interaction unlikely (i.e., no effect on bioavailability of fenofibrate). Additive effects in reducing total and LDL cholesterol; increased serum triglyceride concentrations observed in clinical studies with concomitant sulfonylurea or insulin therapy.

HMG-CoA Reductase Inhibitors (Statins)

Pharmacokinetic interaction with lovastatin unlikely (i.e., no effect on bioavailability of lovastatin). Additive antilipemic effects with atorvastatin, lovastatin, or simvastatin; used to therapeutic advantage.(See Description.)

Metoprolol

Pharmacokinetic interaction unlikely (i.e., no effect on bioavailability of metoprolol).

Oral Contraceptives

When concomitantly administered with ethinyl estradiol in combination with norethindrone, potential pharmacokinetic interaction (decreased peak blood concentrations and AUC of ethinyl estradiol, decreased peak blood concentrations of norethindrone). Administer oral contraceptives 4 hours prior to colesevelam.

Phenytoin

Potential pharmacokinetic interaction (decreased blood concentrations of phenytoin) and potential for increased seizure activity. Administer phenytoin 4 hours prior to colesevelam.

Quinidine

Pharmacokinetic interaction unlikely (i.e., no effect on bioavailability of quinidine).

Thyroid Agents

Potential pharmacokinetic interaction (decreased peak blood concentrations and AUC of levothyroxine) resulting in increased thyrotropin (thyroid-stimulating hormone [TSH]) concentrations. Administer thyroid agents 4 hours prior to colesevelam.

Valproic Acid

Pharmacokinetic interaction unlikely (i.e., no effect on bioavailability of valproic acid).

Verapamil (Sustained-Release)

Pharmacokinetic interaction unlikely.

Warfarin

Pharmacokinetic interaction unlikely (i.e., no effect on bioavailability of warfarin). Potential pharmacodynamic interaction (reduced international normalized ratio [INR]).

Monitor INR before colesevelam therapy is initiated and with sufficient frequency during concurrent therapy to ensure that no appreciable alteration in INR occurs; once INR is stable, periodically monitor INR thereafter at intervals recommended for warfarin therapy. Administer warfarin 4 hours prior to colesevelam.

Other Drugs

Pharmacokinetic interaction unlikely with cephalexin or ciprofloxacin.

Potential interactions with drugs that have a narrow therapeutic index have not been evaluated in formal drug interaction studies. Administer these drugs at least 4 hours before colesevelam, or consider monitoring blood concentrations of these drugs.

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