|
|
| (One intermediate revision by the same user not shown) |
| Line 1: |
Line 1: |
| __NOTOC__
| | #REDIRECT [[Colesevelam#Adverse Reactions]] |
| {{Colesevelam}}
| |
| {{CMG}}; {{AE}} {{SS}}
| |
| | |
| ==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.
| |
| {|
| |
| |-
| |
| |[[File:colesevelam01.jpg|thumb|800px]]
| |
| |-
| |
| |}
| |
| 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)].
| |
| | |
| {|
| |
| |-
| |
| |[[File:colesevelam02.jpg|thumb|800px]]
| |
| |-
| |
| |}
| |
| 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.
| |
| | |
| {|
| |
| |-
| |
| |[[File:colesevelam03.jpg|thumb|800px]]
| |
| |-
| |
| |}
| |
| '''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.
| |
| | |
| {|
| |
| |-
| |
| |[[File:colesevelam04.jpg|thumb|800px]]
| |
| |-
| |
| |}
| |
| | |
| '''[[ 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]]<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = WELCHOL (COLESEVELAM HYDROCHLORIDE) TABLET, FILM COATED WELCHOL (COLESEVELAM HYDROCHLORIDE) FOR SUSPENSION [DAIICHI SANKYO, INC.] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4a06d3b2-7229-4398-baba-5d0a72f63821 | publisher = | date = | accessdate = 10 February 2014 }}</ref>
| |
| </div></div>
| |
| | |
| ==References==
| |
| | |
| {{Reflist|2}}
| |
| {{Lipid modifying agents}}
| |
| | |
| [[Category:Hepatology]]
| |
| [[Category:Bile acid sequestrants]]
| |
| [[Category:Cardiovasuclar Drugs]]
| |
| [[Category:Drugs]]
| |