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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.
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.
Table 1 : Placebo-Controlled Clinical Studies of
WELCHOL for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of
Patients and More Commonly than in Patients Given Placebo, Regardless of
Investigator Assessment of Causality
|Number of Patients (%)|
N = 807
N = 258
|Constipation||89 (11.0)||18 (7.0)|
|Dyspepsia||67 (8.3)||9 (3.5)|
|Nausea||34 (4.2)||10 (3.9)|
|Accidental injury||30 (3.7)||7 (2.7)|
|Asthenia||29 (3.6)||5 (1.9)|
|Pharyngitis||26 (3.2)||5 (1.9)|
|Flu syndrome||26 (3.2)||8 (3.1)|
|Rhinitis||26 (3.2)||8 (3.1)|
|Myalgia||17 (2.1)||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 heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with WELCHOL tablets (1.9-3.8 g, daily) or placebo tablets [See Clinical Studies].
Table 2 : Placebo-Controlled
Clinical Study of WELCHOL for Primary Hyperlipidemia in heFH Pediatric
Patients: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly
than in Patients Given Placebo, Regardless of Investigator Assessment of
|Number of Patients (%)|
N = 129
N = 65
|Nasopharyngitis||8 (6.2)||3 (4.6)|
|Headache||5 (3.9)||2 (3.1)|
|Fatigue||5 (3.9)||1 (1.5)|
|Creatine Phosphokinase Increase||3 (2.3)||0 (0.0)|
|Rhinitis||3 (2.3)||0 (0.0)|
|Vomiting||3 (2.3)||1 (1.5)|
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].
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 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.
Table 3 : Placebo-Controlled Clinical Studies of
WELCHOL Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas:
Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in
Patients Given Placebo, Regardless of Investigator Assessment of Causality
|Number of Patients (%)|
N = 566
N = 562
|Constipation||49 (8.7)||11 (2.0)|
|Nasopharyngitis||23 (4.1)||20 (3.6)|
|Dyspepsia||22 (3.9)||8 (1.4)|
|Hypoglycemia||17 (3.0)||13 (2.3)|
|Nausea||17 (3.0)||8 (1.4)|
|Hypertension||16 (2.8)||9 (1.6)|
Table 4 : Placebo-Controlled
Clinical Study of WELCHOL Monotherapy: Adverse Reactions Reported in ≥ 2%
of WELCHOL Patients and More Commonly than in Patients Given Placebo,
Regardless of Investigator Assessment of Causality
|Number of Patients (%)|
N = 175
N = 171
|Back pain||9 (5.1)||1 (0.6)|
|Headache||8 (4.6)||5 (2.9)|
|Diarrhea||7 (4.0)||3 (1.8)|
|Hypoglycemia||7 (4.0)||1 (0.6)|
|C-reactive protein increased||6 (3.4)||4 (2.3)|
|Constipation||6 (3.4)||3 (1.8)|
|Upper respiratory tract infection||6 (3.4)||2 (1.2)|
|Hyperglycemia||5 (2.9)||3 (1.8)|
|Hypertension||4 (2.3)||2 (1.2)|
|Blood creatinine phosphokinase increased||4 (2.3)||1 (0.6)|
|Gastroesophageal reflux disease||4 (2.3)||1 (0.6)|
|Tooth abscess||4 (2.3)||1 (0.6)|
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 and Clinical Studies]. 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].
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 and WARNINGS AND PRECAUTIONS].
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.
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].
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.
Read the Welchol (colesevelam hcl) Side Effects Center for a complete guide to possible side effects
Table 5 lists the drugs that have been tested in in vitro binding, in vivo drug interaction studies with colesevelam and/or drugs with postmarketing 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 WELCHOL. Alternatively, the physician should monitor drug levels of the co-administered drug.
Table 5 : Drugs Tested in In Vitro Binding or In Vivo Drug
Interaction Testing or With Post-Marketing Reports
|Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug||cyclosporinec , glimepiridea, glipizidea , glyburidea , levothyroxinea, olmesartan medoxomila, and oral contraceptives containing ethinyl estradiol and norethindronea|
|Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug||metformin extended release (ER)d|
|Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL||phenytoina , warfarinb|
|Drugs that do not interact with colesevelam based on in vitro or in vivo testing||aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoina , pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarinb|
|a Should be administered at least 4 hours
prior to WELCHOL
bNo significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience]
cCyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
dPatients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
In an in vivo drug interaction study, WELCHOL and warfarin coadministration had no effect on warfarin drug levels. This study did not assess the effect of WELCHOL and warfarin coadministration on INR. In post-marketing reports, concomitant use of WELCHOL and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating WELCHOL and frequently enough during early WELCHOL 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].
Read the Welchol Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 8/5/2013
This monograph has been modified to include the generic and brand name in many instances.
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