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 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 (total exposure 199 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.
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 Causality
|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 5 add-on combination and 1 monotherapy double-blind, 12-26 week, placebo-controlled clinical trials [see Clinical Studies]. In these studies 1022 patients were exposed to 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 exposed to WELCHOL 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. Baseline characteristics in the placebo group were comparable.
In clinical trials of type 2 diabetes, 57% of patients receiving WELCHOL vs. 52% of patients receiving placebo reported an adverse reaction.
Table 3 shows common adverse reactions associated with the use of WELCHOL in the 1015 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 : Placebo-Controlled Clinical Studies of WELCHOLfor Type 2 Diabetes:: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of CausalityNumber of Patients (%)
N = 1015
N = 1010
|Constipation||66 (6.5)||22 (2.2)|
|Hypoglycemia||35 (3.4)||31 (3.1)|
|Dyspepsia||28 (2.8)||10 (1.0)|
|Nausea||26 (2.6)||16 (1.6)|
|Hypertension||26 (2.6)||19 (1.9)|
|Back Pain||23 (2.3)||13 (1.3)|
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 [See WARNINGS AND PRECAUTIONS and Clinical Studies]. 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 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. 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 diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events 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.
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.