Side effects of welchol

Contents

PMC

Currently available binding resins used for symptomatic bile salt malabsorption are generally poorly tolerated because of unpalatability and associated gastrointestinal side effects. We suggest that there is now a viable alternative, colesevelam hydrochloride (WelChol, Sankyo Pharmaceuticals Inc., Japan).

A 30 year old man presented with steatorrhoea, progressive weight loss, marked abdominal bloating, and lethargy after a right hemicolectomy following a road traffic accident in 1966.

Physical examination, relevant blood tests, barium follow through, colonoscopy, and microscopic examination of colonic biopsies were normal. A trial of cholestyramine in preference to a SeCHAT scan caused cessation of diarrhoea on one sachet per day. However, his abdominal bloating continued unabated and he found the treatment unpalatable. Cholestyramine was therefore changed to colesevelam 2.5 g/3.75 g on alternate days. This was well tolerated, with complete cessation of his steatorrhoea and lethargy, and no side effects. In addition, he rapidly gained weight.

A further four patients with markedly symptomatic bile salt malabsorption resistant to antidiarrhoeal agents and intolerant of cholestyramine were subsequently commenced on colesevelam (table 1 ▶). In all of these cases colesevelam was well tolerated with no side effects.

Table 1

 Characteristics of four patients with markedly symptomatic bile salt malabsorption resistant to antidiarrhoeal agents and intolerant of cholestyramine given colesevelam

Age (y) Sex Reason for bile salt malabsorption Outcome with cholestyramine Outcome with colesevelam Duration of colesevelam treatment (months) Current dose of colesevelam
37 M Idiopathic Diarrhoea improved but not tolerated because it induced severe dyspepsia Diarrhoea resolved, no side effects 7 3.75 g/day
59 F Right hemicolectomy Diarrhoea improved but not tolerated due to unpalatability Diarrhoea resolved, no side effects 3 3.75 g/day
68 F Radiation enteritis and right hemicolectomy Diarrhoea improved although suffered intractable vomiting Diarrhoea resolved, no side effects 2 2.5 g/day
40 F Radiation enteritis Diarrhoea improved although suffered intractable nausea Diarrhoea resolved, no side effects 2 1.25 g/day

Colesevelam is a non-absorbed water insoluble polymer which sequesters bile.1 It has been approved for usage by the US FDA, and has been received as a valuable alternative for lowering cholesterol.2 Colesevelam has high affinity for dihydroxy and trihydroxy bile acids in the intestine which causes increased faecal bile acid secretion, reducing the enterohepatic circulation of bile acids.2 This allows 7-hydroxylase, the rate limiting enzyme in bile acid synthesis, to increase the conversion of hepatic cholesterol to bile acids.2 It has not yet been approved for use in the UK. One abstract suggests that colesevelam may be beneficial for patients with diarrhoea who have undergone small bowel resection for Crohn’s disease.3 There are no other published data to support its role in bile salt induced diarrhoea. Colesevelam is reported to be 4–6 times as potent as traditional bile salt sequestrants, possibly due to its greater binding affinity for glycocholic acid.4 It is administered in tablet form, and in one study the rate of compliance with colesevelam was 93%.4 The unique hydrogel polymeric structure enables greater tolerability with less potential drug interactions than with resins.1

Reported adverse events from the largest clinical trial to date include flatulence, dyspepsia, and diarrhoea although the incidence of adverse events does differ significantly from that observed with placebo, and is lower than with cholestyramine.2 It is rarely associated with constipation, unlike cholestyramine.4 Colesevelam is non-absorbed and is excreted entirely via the gastrointestinal tract, preventing systemic side effects.5 Furthermore, there is little evidence for clinically significant interactions involving colesevelam.4 Pharmacokinetic studies with colesevelam have not shown clinically significant effects of absorption of six other coadministered drugs.6

There is a theoretical risk of fat soluble vitamin deficiency following such efficient bile acid sequestration. None of our patients developed any significant change in fasting triglycerides or fat soluble vitamin levels to date.

Each film coated tablet contains colesevelam 625 mg (active ingredient).2 The recommended starting dose for monotherapy for hypercholesteraemia is 3.75 g once a day or 1.875 g twice per day, although the optimal dose is 4.375 g in adults.2 The optimal dose for bile salt malabsorption is not clear but an effective dose has varied between two and six tablets/day in our series. Colesevelam was obtained from IDIS Ltd.

Thus colesevelam is a novel bile acid binding resin in tablet form that maintains the benefits of cholestyramine, yet is palatable, associated with decreased adverse effects, and has greater potency. It provides a very attractive alternative therapy for patients with bile salt malabsorption and further study is warranted.

colesevelam (Colesevelam Hydrochloride, Welchol)

Brand Names: Colesevelam Hydrochloride, Welchol

Generic Name: colesevelam

  • What is colesevelam (Colesevelam Hydrochloride, Welchol)?
  • What are the possible side effects of colesevelam (Colesevelam Hydrochloride, Welchol)?
  • What is the most important information I should know about colesevelam (Colesevelam Hydrochloride, Welchol)?
  • What should I discuss with my healthcare provider before taking colesevelam (Colesevelam Hydrochloride, Welchol)?
  • How should I take colesevelam (Colesevelam Hydrochloride, Welchol)?
  • What happens if I miss a dose (Colesevelam Hydrochloride, Welchol)?
  • What happens if I overdose (Colesevelam Hydrochloride, Welchol)?
  • What should I avoid while taking colesevelam (Colesevelam Hydrochloride, Welchol)?
  • What other drugs will affect colesevelam (Colesevelam Hydrochloride, Welchol)?
  • Where can I get more information (Colesevelam Hydrochloride, Welchol)?

What is colesevelam (Colesevelam Hydrochloride, Welchol)?

Colesevelam lowers “bad” cholesterol in the blood, which is also called LDL (low-density lipoprotein) cholesterol. Lowering your LDL cholesterol may reduce your risk of hardened arteries, which can lead to heart attacks, stroke, and circulation problems.

Colesevelam is sometimes used together with “statin” cholesterol medications such as atorvastatin, lovastatin, simvastatin, Crestor, Lipitor, Pravachol, Zocor, and others.

Colesevelam is also used to improve blood sugar control in people with type 2 diabetes. This medication is not for treating type 1 diabetes.

Colesevelam may also be used for purposes not listed in this medication guide.

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What are the possible side effects of colesevelam (Colesevelam Hydrochloride, Welchol)?

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using colesevelam and call your doctor at once if you have:

  • severe constipation;
  • severe stomach pain; or
  • pancreatitis–severe pain in your upper stomach spreading to your back, nausea and vomiting.

Common side effects may include:

  • mild constipation; or
  • nausea, upset stomach, indigestion.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is the most important information I should know about colesevelam (Colesevelam Hydrochloride, Welchol)?

You should not take this medicine if you have diabetic ketoacidosis, very high triglycerides, a history of bowel obstruction, or a history of pancreatitis caused by high triglycerides.

Welchol

SIDE EFFECTS

The following important adverse reactions are described below and elsewhere in the labeling:

  • Hypertriglyceridemia and Pancreatitis
  • Gastrointestinal Obstruction
  • Vitamin K or Fat-Soluble Vitamin Deficiencies

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

Table 1: Clinical Studies of WELCHOL for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo

Pediatric Patients 10 To 17 Years Of Age

Table 2: Clinical Study of WELCHOL for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo

Type 2 Diabetes Mellitus

In 5 add-on combination and 1 monotherapy double-blind, 12-26 week, placebo-controlled clinical trials in patients with type 2 diabetes mellitus, 1022 patients were treated with WELCHOL. The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of WELCHOL per day. The mean age of patients was 55.7 years, 52.8 percent of the population was male and 61.9% were Caucasian, 4.8% were Asian, and 15.9% were Black or African American. At baseline the population had a mean HbA1C of 8.2% and 26% had past medical history suggestive of microvascular complications of diabetes. Table 3 shows adverse reactions associated with the use of WELCHOL in patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on WELCHOL than on placebo, and occurred in at least 2% of patients treated with WELCHOL.

Table 3: Clinical Studies of WELCHOL for Type 2 Diabetes: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo

A total of 5.3% of WELCHOL-treated patients and 3.6% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation.

One patient in the add-on to sulfonylurea trial discontinued due to body rash and mouth blistering that occurred on the first day of dosing of WELCHOL, which may represent a hypersensitivity reaction to WELCHOL.

Hypertriglyceridemia

Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the diabetes trials, 1292 (67.7%) patients had baseline fasting serum TG levels less than 200 mg/dL, 426 (22.3%) had baseline fasting serum TG levels between 200 and less than 300 mg/dL, 175 (9.2%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 16 (0.8%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 160 mg/dL; the median post-treatment fasting TG was 180 mg/dL in the WELCHOL group and 162 mg/dL in the placebo group. WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03) in the monotherapy study and of 5% (p=0.22), 11% (p<0.001), 18% (p<0.001), and 22% (p<0.001), when added to metformin, pioglitazone, sulfonylureas, and insulin, respectively. In comparison, WELCHOL resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial.

Fasting TG concentrations ≥500 mg/dL occurred in 0.9% of WELCHOL-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials. Among these patients, the TG concentrations with WELCHOL (median 606 mg/dL; interquartile range 570-794 mg/dL) were similar to that observed with placebo (median 663 mg/dL; interquartile range 542-984 mg/dL). Five (0.6%) patients on WELCHOL and 3 (0.3%) patients on placebo developed TG elevations ≥1000 mg/dL.

Cardiovascular Adverse Reactions

During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1015)) in the WELCHOL group and 1% (10/1010) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown.

Post-Marketing Experience

The following additional adverse reactions have been identified during post-approval use of WELCHOL. 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
  • Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin.
  • Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy.
  • 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

Read the entire FDA prescribing information for Welchol (Colesevelam Hcl)

Welchol works in the digestive tract and is not broken down by the liver

What is Welchol (colesevelam HCI)?

Welchol, along with diet and exercise, lowers LDL or “bad” cholesterol.

Welchol lowers LDL cholesterol in boys, and in girls who have had a menstrual period, ages 10 to 17 years, with a condition known as heterozygous familial hypercholesterolemia (a genetic disorder that causes high cholesterol).

Welchol, along with diet and exercise, also lowers blood sugar levels in adult patients with type 2 diabetes mellitus.

Welchol should not be used to treat type 1 diabetes or diabetic ketoacidosis.

Welchol has not been shown to prevent heart disease or heart attacks.

Welchol has not been studied with all anti-diabetes medications.

Welchol has not been studied in all types of hypercholesterolemia.

Welchol has not been studied in children younger than 10 years old or in girls who have not had a menstrual period.

Important Safety Information About Welchol (colesevelam HCI)

Welchol is available by prescription only. Ask your HCP if Welchol is right for you.

Welchol is not for everyone, especially those with:

  • blood triglyceride levels of greater than 500 mg/dL,
  • a history of pancreatitis (inflammation of the pancreas) due to high triglyceride levels, or
  • a history of intestinal blockage.

Tell your health care provider (HCP) if you have high triglycerides (greater than 300 mg/dL). High levels of triglycerides in your blood can cause acute pancreatitis (inflammation of the pancreas). Discontinue Welchol and seek prompt medical attention if the symptoms of acute pancreatitis occur.

Welchol should not be taken if you have stomach or intestinal problems, including gastroparesis (when the stomach takes too long to empty its contents), abnormal contractions of the digestive system, a history of major gastrointestinal tract surgery, if you have trouble swallowing, by those who might be at risk for intestinal blockage, or if you have vitamin A, D, E, or K deficiencies. Tell your HCP if you have any of these conditions.

Cases of intestinal blockage have occurred. Discontinue Welchol and seek medical attention if severe abdominal pain or severe constipation occurs.

Welchol has known interactions with cyclosporine, glimepiride, glipizide, glyburide, levothyroxine, certain birth control pills, olmesartan medoxomil, and metformin extended-release (ER). Welchol has not been studied with all combinations of drugs and supplements. Please tell your HCP about all medications and vitamins/supplements you may be taking before beginning Welchol, as your HCP may tell you to take your other medications and vitamins/supplements 4 hours before taking Welchol.

Remember to tell your HCP if you are pregnant, plan to become pregnant, or are breastfeeding.

Welchol (colesevelam HCl) for Oral Suspension should not be taken in its dry form.

Welchol for Oral Suspension is recommended for, but not limited to, use in appropriate pediatric patients, as well as any patient who has difficulty swallowing.

Phenylketonurics: Welchol for Oral Suspension contains 27 mg phenylalanine per 3.75 gram packet. Phenylalanine can be harmful to patients with phenylketonuria (PKU).

In clinical trials, the adverse reactions observed in ≥2% of patients, and more commonly with Welchol than placebo (“sugar pill”), regardless of investigator assessment of causality seen in:

  • Adult patients with high LDL (“bad” cholesterol) were:
    constipation, indigestion (dyspepsia), nausea, accidental injury, weakness, sore throat, flu-like symptoms, runny nose, and muscle aches
  • Pediatric patients with high LDL (“bad” cholesterol) were:
    inflamed nasal passages and throat, headache, fatigue, creatine phosphokinase (a muscle enzyme) increase, runny nose, and vomiting
  • Adult patients with Type 2 Diabetes were:
    constipation, low blood sugar (hypoglycemia), indigestion (dyspepsia), nausea, high blood pressure (hypertension), and back pain

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see full Prescribing Information for Welchol® (colesevelam HCl).

Heart Beat: Dual duty for WelChol

Heart Beat

Dual duty for WelChol

Published: April, 2008

Few people with type 2 diabetes have the “luxury” of controlling only their blood sugar. Most also struggle to keep their blood pressure and cholesterol in check. Colesevelam (WelChol) may help with two of these three tasks. It is the first drug to get approval from the FDA for reducing both harmful LDL cholesterol and blood sugar. WelChol works by latching onto bile acids in the intestine and locking them into a watery goo that is excreted in the stool. In clinical trials, it reduced the level of hemoglobin A1C (HbA1C), a marker that reflects the average amount of glucose to which blood cells have been exposed during the previous month or so. It also lowers LDL by 15% to 20%. WelChol alone won’t control blood sugar; it is usually taken with metformin, insulin, or other medication. As is the case for Zetia, so far no trials have been completed to show whether WelChol’s effects on cholesterol or blood sugar translate into fewer heart attacks or a longer life.

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CLINICAL PHARMACOLOGY

Mechanism Of Action

Colesevelam hydrochloride, the active pharmaceutical ingredient in WELCHOL, 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.

The mechanism by which WELCHOL improves glycemic control is unknown.

Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of WELCHOL was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to WELCHOL, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near maximal effect after 12-18 weeks of treatment.

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.

Metabolism

Colesevelam 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 Interactions

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 5.

Table 5 : Mean Change in Drug Exposure (AUC0-∞ and Cmax ) when Administered with WELCHOL (3.75 g)a

Animal Toxicology And/Or Pharmacology

Reproductive Toxicology Studies

Reproduction 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.

Clinical Studies

WELCHOL 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 WELCHOL 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), WELCHOL was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 6, 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. WELCHOL at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both WELCHOL doses but the changes were not statistically different from placebo.

Table 6 : Response to WELCHOL Monotherapy in a 24-Week Trial Percent Change in Lipid Parameters from Baseline

In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), WELCHOL 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 WELCHOL and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDLC 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 7, WELCHOL 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.

Table 7 : Response to WELCHOL in Combination with Atorvastatin, Simvastatin, or Lovastatin Percent Change in Lipid Parameters

In all 3 studies, the LDL-C reduction achieved with the combination of WELCHOL and any given dose of statin therapy was statistically superior to that achieved with WELCHOL or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of WELCHOL 3.8 g and atorvastatin 10 mg.

The effect of WELCHOL when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥ 115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label runin period and then randomly assigned to receive fenofibrate 160 mg plus either WELCHOL 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 8.

Table 8 : Response to WELCHOL Added to Fenofibrate in Patients with Mixed Hyperlipidemia (Mean % Change from Treated Baseline at 6 Weeks )

Pediatric Therapy: The safety and efficacy of WELCHOL 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 heterozygous familial hypercholesterolemia (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, parallelgroup, 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.

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

During the open-label treatment period patients were treated with WELCHOL 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.

WELCHOL has been studied as monotherapy and in combination with metformin, pioglitazone, sulfonylureas, and insulin. In these studies, WELCHOL and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.

The efficacy of WELCHOL 3.8 g/day as anti-diabetes monotherapy was evaluated in a randomized double-blind, placebo-controlled trial involving 357 patients (176 WELCHOL and 181 placebo) with T2DM who were treatment-naïve or had not received antihyperglycemic medication within 3 months prior to the start of the study. Statin use at baseline was reported in 13% of the WELCHOL-treated patients and 16% of the placebo-treated patients.

WELCHOL resulted in a statistically significant reduction in A1C of 0.27% compared to placebo (Table 10).

The mean baseline LDL-C was 121 mg/dL in the monotherapy trial. WELCHOL treatment resulted in a placebo-corrected 11% reduction in LDL-C. WELCHOL treatment also reduced serum TC, ApoB, and non-HDL-C (Table 11). The mean change in body weight was -0.6 kg for WELCHOL and -0.7 kg for placebo treatment groups.

Table 10 : Glycemic Parameters in a 24-Week Placebo-Controlled Study of WELCHOL Monotherapy in Patients with Type 2 Diabetes

Table 11 : Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of WELCHOL Monotherapy in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL-C TGa
WELCHOL 3.8 g 162 -3.3* -10.0* -5.6* 1.7 -4.4* 15.5
Placebo 160 1.8 1.2 0.9 -0.1 3.0 5.8
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
†The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy

The efficacy of WELCHOL 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 5 double-blind, placebo-controlled add-on therapy trials involving a total of 1691 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. Statin use at baseline was reported in 41% of the WELCHOLtreated patients and 48% of the placebo-treated patients.

In 3 add-on combination therapy trials (metformin, sulfonylurea and insulin), treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebocorrected reductions in A1C occurred in patients who received WELCHOL in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other antidiabetic agents. In the pioglitazone trial, treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.32% compared to placebo. In the metformin, pioglitazone, and sulfonylurea trials, treatment with WELCHOL also resulted in statistically significant reductions in fasting plasma glucose (FPG) of at least 14 mg/dL compared to placebo.

WELCHOL had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. WELCHOL’s effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone).

The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 107 mg/dL in the pioglitazone study (range 48-263 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, WELCHOL treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. WELCHOL treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin, patients on a sulfonylurea, and patients on pioglitazone but not in the study of patients on metformin. The clinical significance of these increases is unknown. WELCHOL is contraindicated in patients with TG levels > 500 mg/dL and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended .

Body weight did not significantly increase from baseline with WELCHOL therapy, compared with placebo, in any of the add-on combination diabetes studies.

Add-on Combination Therapy With Metformin

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥ 1,500 mg/day of metformin. In combination with metformin, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 12). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 13). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with WELCHOL compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for WELCHOL and -0.3 kg for placebo.

Table 12 : Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

Table 13 : Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL- C TGa
Total Patient Population
WELCHOL 3.8 g 125 -4* -12* -4* 1 -6* 12
Placebo 126 3 4 4 0 5 7
Metformin Alone
WELCHOL 3.8 g 66 -3 -9 -2 1 -4 15
Placebo 61 2 0 1 -2 4 8
Metformin in Combination with Other Oral Anti-diabetic Agents
WELCHOL 3.8 g 59 -6* -15* -6* 1 -7* 8
Placebo 65 4 7 7 2 6 5
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
†The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy With Pioglitazone

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 24-week trial of 562 patients already receiving treatment with pioglitazone alone (N=51) or pioglitazone in combination with other oral agents (N=511). Of these, most were on dual therapy with metformin (N=298) or triple therapy with metformin and a sulfonylurea (N=139). In combination with pioglitazone-based therapy, WELCHOL resulted in statistically significant reductions in A1C and FPG compared to placebo (Table 14). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C but increased serum TG (Table 15). The mean change in body weight was 0.8 kg for WELCHOL and 0.4 kg for placebo.

Table 14 : Glycemic Parameters in a 24-Week Placebo-Controlled Study of WELCHOL in Combination with Pioglitazone Based Therapy in Patients with Type 2 Diabetes

Table 15 : Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of WELCHOL in Combination with Pioglitazone Based Therapy in Patients with Type 2 Diabetes

Add-on Combination Therapy With Sulfonylurea

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 16). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 17). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with WELCHOL compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for WELCHOL and -0.4 kg for placebo.

Table 16 : Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Sulfonylurea in Patients with Type 2 Diabetes

Table 17 : Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination With Sulfonylurea in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL- C TGa
Total Patient Population
WELCHOL 3.8 g 186 -5* -16* -6* 1 -6* 20*
Placebo 193 0 1 1 0 1 1
Sulfonylurea Alone
WELCHOL 3.8 g 57 -5 -14* -5 -1 -6 17
Placebo 68 0 1 1 1 0 -1
Sulfonylurea in Combination with Other Oral Anti-diabetic Agents
WELCHOL 3.8 g 129 -5 -18* -7* 1 -6 21*
Placebo 125 0 0 1 0 1 2
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
†The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy With Insulin

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the WELCHOL group and 65 units in the placebo group. In combination with insulin, WELCHOL resulted in a statistically significant placebo-corrected reduction in A1C (Table 18). WELCHOL also reduced LDL-C and Apo B, but increased serum TG (Table 19). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with WELCHOL compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for WELCHOL and 0.2 kg for placebo.

Table 18 : Glycemic Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

Table 19 : Percent Change in Lipid Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL- C TGa
Total Patient Population
WELCHOL 3.8 g 129 -3 -12* -4 -1 -3 23*
Placebo 121 1 1 1 0 1 0
Insulin Alone
WELCHOL 3.8 g 46 -3 -12 -5 0 -3 19
Placebo 48 2 4 2 3 2 -2
Insulin in Combination with Oral Anti-diabetic Agents
WELCHOL 3.8 g 83 -4 -13 -4 -1 -3 25*
Placebo 73 -1 -3 0 -1 -1 2
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
†The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Alternative to Statin Titration

Indications

Welchol is indicated as an adjunct to diet and exercise to:

  • reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia
  • reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH)
  • improve glycemic control in adults with type 2 diabetes mellitus

Limitations of Use

  • Welchol should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis
  • The effect of Welchol on cardiovascular morbidity and mortality has not been determined.
  • Welchol has not been studied in type 2 diabetes in combination with a dipeptidyl peptidase-4 inhibitor
  • Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias
  • Welchol has not been studied in children younger than 10 years of age or in premenarchal girls

IMPORTANT SAFETY INFORMATION ABOUT WELCHOL (colesevelam HCI)

Contraindications

Welchol is contraindicated in:

  • those with serum triglyceride (TG) concentrations of >500 mg/dL,
  • those with a history of hypertriglyceridemia-induced pancreatitis, or
  • individuals with a history of bowel obstruction.

Warnings and Precautions

Welchol can increase serum TG concentrations, particularly when used in combination with pioglitazone, sulfonylureas, or insulin. Hypertriglyceridemia can cause acute pancreatitis. Instruct patients to discontinue Welchol and seek prompt medical attention if the symptoms of acute pancreatitis occur. Caution should be exercised when treating patients with TG levels >300 mg/dL.

Welchol is not recommended in patients with gastroparesis, gastrointestinal motility disorders, a history of major gastrointestinal tract surgery, those who might be at risk for bowel obstruction, and when treating patients with dysphagia and swallowing disorders. Postmarketing cases of bowel obstruction have occurred with Welchol. Instruct patients to promptly discontinue Welchol and seek medical attention if severe abdominal pain or severe constipation occurs.

Welchol may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients on oral vitamin supplements should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to vitamin K deficiencies (e.g., patients on warfarin, patients with malabsorption syndromes), or fat-soluble vitamin deficiencies.

Welchol interacts with some drugs. Drugs with a known interaction with colesevelam (cyclosporine, glimepiride, glipizide, glyburide, levothyroxine, olmesartan medoxomil, oral contraceptives , and metformin extended-release ) should be administered at least 4 hours prior to Welchol. Due to the potential for decreased absorption of other drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, consider administering at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the co-administered drug, when appropriate.

Welchol for Oral Suspension should not be taken in its dry form.

Due to tablet size, Welchol for Oral Suspension is recommended for, but not limited to, use in the pediatric population as well as in any patient who has difficulty swallowing tablets.

Phenylketonurics: Welchol for Oral Suspension contains 27 mg phenylalanine per 3.75 gram packet. Phenylalanine can be harmful to patients with phenylketonuria (PKU).

Adverse Reactions

In clinical trials, the adverse reactions observed in ≥2% of patients, and more commonly with Welchol than placebo, regardless of investigator assessment of causality seen in:

  • Adults with Primary Hyperlipidemia were:
    constipation, dyspepsia, nausea, accidental injury, asthenia, pharyngitis, flu syndrome, rhinitis, and myalgia
  • Pediatric patients with HeFH primary hyperlipidemia were:
    nasopharyngitis, headache, fatigue, creatine phosphokinase increase, rhinitis, and vomiting
  • Adult patients with Type 2 Diabetes were:
    constipation, hypoglycemia, dyspepsia, nausea, hypertension, and back pain

Post-marketing experience: Due to the voluntary nature of these reports it is not possible to reliably estimate frequency or establish a causal relationship:

  • Increased seizure activity or decreased phenytoin levels have been reported in patients receiving phenytoin concomitantly with Welchol
  • Reduced International Normalized Ratio (INR) has been reported in patients receiving warfarin concomitantly with Welchol
  • Elevated thyroid-stimulating hormone (TSH) has been reported in patients receiving thyroid hormone replacement therapy
  • Dysphagia has been reported with both tablet and oral suspension formulations

Pregnancy

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.

There are no adequate and well-controlled studies of colesevelam HCl use in pregnant women.

Females and Males of Reproductive Potential

Use of Welchol may reduce the efficacy of oral contraceptives. Patients should be advised to take oral contraceptives at least 4 hours prior to taking Welchol.

Please see full Prescribing Information for Welchol® (colesevelam HCl).

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