Colesevelam adverse reactions

Colesevelam adverse reactions

Clinical data
Trade names	Welchol, Cholestagel
MedlinePlus	a699050
Pregnancy category	B
Routes of administration	Oral
ATC code	C10AC04 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	N/A
Metabolism	Colesevelam is not absorbed and not metabolised.
Elimination half-life	N/A (non-systemic drug)
Excretion	By intestines only, colesevelam is non-systemic.
Identifiers
CAS Number	182815-44-7 Y
PubChem CID	160051
DrugBank	DB00930 Y
ChemSpider	NA N
UNII	P4SG24WI5Q
KEGG	D03582 Y
ChEMBL	ChEMBL1201677 Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
NY (what is this?)  (verify)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

Adverse Reactions

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.

In the lipid-lowering trials, 807 adult patients received at least one dose of WELCHOL (total exposure 199 patient-years). In the add-on combination type 2 diabetes trials, 566 patients received at least one dose of WELCHOL (total exposure 209 patient-years). In the monotherapy type 2 diabetes trial, 175 patients received at least one dose of WELCHOL and had a post baseline follow up (total exposure 69 patient-years).

In clinical trials for the reduction of LDL-C, 68% of patients receiving WELCHOL vs. 64% of patients receiving placebo reported an adverse reaction. In add-on combination clinical trials of type 2 diabetes, 60% of patients receiving WELCHOL vs. 56% of patients receiving placebo reported an adverse reaction. In monotherapy clinical trial for type 2 diabetes, 52% of patients receiving WELCHOL vs. 45% of patients receiving placebo reported an adverse reaction.

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 WELCHOL 1.5 g/day to 4.5 g/day from 4 to 24 weeks.

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 heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with WELCHOL tablets (1.9-3.8 g, daily) or placebo tablets [See Clinical Studies (14.1)].

The reported adverse reactions during the additional 18-week open-label treatment period with WELCHOL 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%) [See Clinical Studies(14.1)].

Type 2 Diabetes Mellitus: The safety of WELCHOL in patients with type 2 diabetes mellitus was evaluated in 4 add-on combination and 1 monotherapy double-blind, 12-26 week, placebo-controlled clinical trials. The add-on combination trials involved 1128 patients (566 patients on WELCHOL; 562 patients on placebo) with inadequate glycemic control on metformin, sulfonylurea, or insulin when these agents were used alone or in combination with other anti-diabetic agents. Upon completion of the add-on combination trials, 492 patients entered a 52-week open-label uncontrolled extension study during which all patients received WELCHOL 3.8 g/day while continuing background treatment with metformin, sulfonylurea, or insulin alone or in combination with other anti-diabetic agents. The monotherapy trial involved 357 patients (176 WELCHOL and 181 placebo) who were on no prior anti-diabetes medication within 3 months of the study.

A total of 6.7% of WELCHOL-treated patients and 3.2% of placebo-treated patients were discontinued from the add-on combination diabetes trials due to adverse reactions. This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation. In the monotherapy diabetes trial, a total of 4.6% of WELCHOL-treated patients and 4.7% of placebo-treated patients were discontinued from the trial due to adverse reactions.

One patient in the pivotal trials discontinued due to body rash and mouth blistering that occurred after the first dose 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 phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the WELCHOL group and 177 mg/dL in the placebo group. WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2)]. 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 [See Clinical Studies (14.1)].

Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of WELCHOL-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with WELCHOL (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on WELCHOL and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In all WELCHOL clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL [See Contraindications (4) and Warnings and Precautions (5.2)].

Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the WELCHOL group and 2% (10/562) 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.

Hypoglycemia: Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with WELCHOL and 2.3% in patients treated with placebo. No WELCHOL treated patients developed severe hypoglycemia.

hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials. In the add-on combination diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the WELCHOL group and 177 mg/dL in the placebo group. WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2)]. In the monotherapy diabetes trial, the distribution of baseline fasting serum TG levels was similar to that from the add-on combination trials. The median baseline fasting TG for the monotherapy study population was 167 mg/dL; the median post- treatment fasting TG concentration was 182mg/dL in the WELCHOL group and 173mg/dL in the placebo group. WELCHOL treatment resulted in a median placebo-corrected increase in serum TG of 9.7% (p=0.03). 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 [See Clinical Studies (14.1)].

Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of WELCHOL-treated patients compared to 2.0% of placebo-treated patients in the add-on combination diabetes trials. Among these patients, the TG concentrations with WELCHOL (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on WELCHOL and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In the monotherapy diabetes trial, a total of 8 (4.4%) patients in the placebo group and 9 (5.1%) patients in the WELCHOL group had a TG level <500 mg/dL at baseline and a treatment-emergent TG ≥500 mg/dL. Among these patients, the TG concentrations with WELCHOL (median 594 mg/dL) were similar to that observed with placebo (median 589 mg/dL). Four (2.4%) patients on WELCHOL and 1 (0.6%) patient on placebo developed TG elevation ≥1000 mg/dL. In all WELCHOL clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia. It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL [See Contraindications (4) and Warnings and Precautions (5.2)].

Cardiovascular adverse events: During the add-on combination diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the WELCHOL group and 2% (10/562) 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. In the monotherapy diabetes trial, one myocardial infarction and one case of unstable angina occurred in the WELCHOL group, and one case of hypotension in the placebo group.

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.

Drug Interactions with concomitant WELCHOL administration include

Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to WELCHOL. Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during WELCHOL initiation then periodically thereafter. Elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy. Thyroid hormone replacement should be administered 4 hours prior to WELCHOL [See Drug Interactions (7)].

Gastrointestinal Adverse Reactions

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

Laboratory Abnormalities

hypertriglyceridemia