COLESEVELAM HYDROCHLORIDE (Page 2 of 6)

6.1 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

In 7 double-blind, placebo-controlled clinical trials, 807 patients with primary hyperlipidemia (age range 18 to 86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with colesevelam hydrochloride 1.5 g/day to 4.5 g/day from 4 to 24 weeks (total exposure 199 patient-years).

Table 1 Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo
Colesevelam Hydrochloride
N = 807
Placebo
N = 258
Constipation 11.0% 7.0%
Dyspepsia 8.3% 3.5%
Nausea 4.2% 3.9%
Accidental injury 3.7% 2.7%
Asthenia 3.6% 1.9%
Pharyngitis 3.2% 1.9%
Flu syndrome 3.2% 3.1%
Rhinitis 3.2% 3.1%
Myalgia 2.1% 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 HeFH (n = 194), were treated with colesevelam hydrochloride tablets (1.9 g to 3.8 g, daily) or placebo tablets.

Table 2 Clinical Study of Colesevelam Hydrochloride for Primary Hyperlipidemia in HeFH Pediatric Patients: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo
Colesevelam Hydrochloride
N = 129
Placebo
N = 65
Nasopharyngitis 6.2% 4.6%
Headache 3.9% 3.1%
Fatigue 3.9% 1.5%
Creatine Phosphokinase Increase 2.3% 0.0%
Rhinitis 2.3% 0.0%
Vomiting 2.3% 1.5%

The reported adverse reactions during the additional 18-week open-label treatment period with colesevelam hydrochloride 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%).

6.2 Post-marketing Experience

The following additional adverse reactions have been identified during post-approval use of colesevelam hydrochloride. 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 [see Drug Interactions ( 7)]: Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin, reduced International Normalized Ratio (INR) in patients receiving warfarin therapy, and 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

7 DRUG INTERACTIONS

7.1 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication

Table 4 includes a list of drugs that decrease exposure of the concomitant medication when administered concomitantly with colesevelam hydrochloride and instructions for preventing or managing them.

Table 4 Colesevelam Hydrochloride Drug Interactions that Decrease the Exposure of the Concomitant Medication
Drugs with a Narrow Therapeutic Index
Clinical Impact: Concomitant use with colesevelam hydrochloride may decrease the exposure of the narrow therapeutic index drug. In vivo drug interactions studies showed a decrease in exposure of cyclosporine when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
Intervention: Administer the narrow therapeutic index drug at least 4 hours prior to colesevelam hydrochloride. Monitor drug levels when appropriate.
Examples: Cyclosporine
Phenytoin
Clinical Impact: There have been postmarketing reports of increased seizure activity or decreased phenytoin levels in patients receiving phenytoin [see Adverse Reactions (6.2)].
Intervention: Administer phenytoin 4 hours prior to colesevelam hydrochloride.
Thyroid Hormone Replacement Therapy
Clinical Impact: In vivo drug interactions studies showed a decrease in exposure of levothyroxine when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)] . There have been postmarketing reports of elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy [see Adverse Reactions (6.2)] .
Intervention: Administer thyroid hormone replacement therapy 4 hours prior to colesevelam hydrochloride.
Warfarin
Clinical Impact: There have been postmarketing reports of reduced INR in patients receiving warfarin therapy [see Adverse Reactions (6.2)].
Intervention: Monitor INR frequently during colesevelam hydrochloride initiation then periodically thereafter.
Oral Contraceptives Containing Ethinyl Estradiol and Norethindrone
Clinical Impact: In vivo drug interactions studies showed a decrease in exposure of ethinyl estradiol and norethindrone when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
Intervention: Administer oral contraceptives containing ethinyl estradiol and norethindrone 4 hours prior to colesevelam hydrochloride.
Olmesartan Medoxomil
Clinical Impact: In vivo drug interactions studies showed a decrease in olmesartan medoxomil when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
Intervention: Administer olmesartan medoxomil 4 hours prior to colesevelam hydrochloride.
Sulfonylureas
Clinical Impact: In vivo drug interactions studies showed a decrease in sulfonylureas when co-administered with colesevelam hydrochloride [see Clinical Pharmacology (12.3)].
Intervention: Administer sulfonylureas 4 hours prior to colesevelam hydrochloride.
Examples: Glimepiride, glipizide, and glyburide
Oral Vitamin Supplements
Clinical Impact: Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K [see Warnings and Precautions (5.3)].
Intervention: Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride.

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