Colesevelam Drug Information

Testing Prior to Initiation of Colesevelam Hydrochloride

Obtain lipid parameters, including triglyceride (TG) levels, before starting colesevelam hydrochloride. The recommended dosage of colesevelam hydrochloride for adults with type 2 diabetes mellitus is 3.75 grams daily. Colesevelam hydrochloride should be taken as follows: Tablets Take 6 tablets once daily or 3 tablets twice daily.

Due to tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population. For Oral Suspension Take one packet once daily.

Important Dosing Information for Primary Hyperlipidemia

Colesevelam hydrochloride can be dosed at the same time as a statin, or colesevelam hydrochloride and the statin can be dosed apart. Monitor lipid levels within 4 to 6 weeks after initiation of colesevelam hydrochloride.

Administration Instructions Tablets

Take colesevelam hydrochloride tablets with a meal and liquid. For patients with difficulty swallowing tablets, use colesevelam hydrochloride for oral suspension. For Oral Suspension To prepare, empty the entire contents of one packet into a glass or cup.

Add 1 cup (8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Take colesevelam hydrochloride oral suspension with meals.

Do not take colesevelam hydrochloride oral suspension in its dry form.

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. Table 1 Clinical Studies of Colesevelam Hydrochloride for Primary Hyperlipidemia: Adverse Reactions Reported in ≥ 2% of Patients and More Commonly than in Placebo 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 (1.9-3.8 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 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%).

The mean exposure duration was 20 weeks (total exposure 393 patient-years). Patients were to receive 3.8 grams of colesevelam hydrochloride per day. At baseline the population had a mean hemoglobin A1c (HbA1c) of 8.2%, and 26% had past medical history suggestive of microvascular complications of diabetes.

Table 3 shows adverse reactions associated with the use of colesevelam hydrochloride in patients with type 2 diabetes. These adverse reactions were not present at baseline, occurred more commonly on colesevelam hydrochloride than on placebo, and occurred in at least 2% of patients treated with colesevelam hydrochloride. Table 3 Clinical Studies of Colesevelam Hydrochloride for Type 2 Diabetes: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Placebo A total of 5.3% of colesevelam hydrochloride-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 colesevelam hydrochloride, which may represent a hypersensitivity reaction to colesevelam hydrochloride. Hypertriglyceridemia Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials.

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 colesevelam hydrochloride group and 162 mg/dL in the placebo group. In comparison, colesevelam hydrochloride resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial. Fasting TG concentrations ≥500 mg/dL occurred in 0.9% of colesevelam hydrochloride-treated patients compared to 0.7% of placebo-treated patients in the diabetes trials.

Cardiovascular Adverse Reactions During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1022) in the colesevelam hydrochloride 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.

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: 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

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 coadministered with colesevelam hydrochloride.

There have been postmarketing reports of increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Intervention: Administer phenytoin 4 hours prior to colesevelam hydrochloride. There have been postmarketing reports of elevated thyroid-stimulating hormone (TSH) in patients receiving thyroid hormone replacement therapy.

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. Intervention: Monitor INR frequently during colesevelam hydrochloride initiation then periodically thereafter.

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 coadministered with colesevelam hydrochloride. Intervention: Administer olmesartan medoxomil 4 hours prior to colesevelam hydrochloride.

Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins A, D, E, and K. Intervention: Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to colesevelam hydrochloride.

Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication Table 5 Colesevelam Hydrochloride Drug Interactions that Increase the Exposure of the Concomitant Medication Metformin Extended Release (ER) Clinical Impact: In vivo drug interactions studies showed an increase in metformin extended release (ER) when coadministered with colesevelam hydrochloride. Intervention: Monitor patients' glycemic control.

Pregnancy Risk Summary Colesevelam hydrochloride is not absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug. Limited available data on the use of colesevelam hydrochloride are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of either maternal or fetal toxicity was found in rats or rabbits exposed to colesevelam hydrochloride during the period of fetal organogenesis at 8 and 5 times, respectively, the maximum recommended human dose (MRHD) of 3.75 g/day, based on body surface area (mg/m 2 ).

No adverse effects on offspring survival and development were observed in rats administered 5 times the MRHD (see Data ). Colesevelam hydrochloride may decrease the absorption of fat-soluble vitamins. There are no data available on the effect of colesevelam hydrochloride on the absorption of fat-soluble vitamins in pregnant women.

If the patient becomes pregnant while taking colesevelam hydrochloride, the patient should be advised of the lack of known clinical benefit with continued use during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Data Human Data There are no adequate and well-controlled studies of colesevelam hydrochloride use in pregnant women. In the postmarketing setting there have been infrequent reports of pregnancy with use of colesevelam hydrochloride and a causal association with congenital anomalies has not been established.

Pediatric Use Primary Hyperlipidemia The safety and effectiveness of colesevelam hydrochloride to reduce LDL-C levels in boys and postmenarchal girls 10 to 17 years of age with HeFH who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification have been established. Use of colesevelam hydrochloride for this indication is supported by a study in 129 colesevelam hydrochloride-treated pediatric patients aged 10 to 17 years with HeFH. Adverse reactions commonly observed in pediatric patients compared to placebo, but not in adults, included headache (3.9%), creatine phosphokinase increase (2.3%), and vomiting (2.3%).

There were no significant effects on fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo.Due to colesevelam hydrochloride tablet size, colesevelam hydrochloride for oral suspension is recommended for use in the pediatric population. The safety and effectiveness of colesevelam hydrochloride in pediatric patients with HeFH less than 10 years of age or in premenarchal females have not been established. Type 2 Diabetes Mellitus The safety and effectiveness of colesevelam hydrochloride to improve glycemic control in pediatric patients with type 2 diabetes mellitus have not been established.

Colesevelam hydrochloride is contraindicated in patients with: Serum TG concentrations >500 mg/dL History of hypertriglyceridemia-induced pancreatitis A history of bowel obstruction Patients with serum triglyceride levels >500 mg/dL Patients with a history of hypertriglyceridemia-induced pancreatitis Patients with a history of bowel obstruction

Colesevelam hydrochloride is not absorbed and the risk of systemic toxicity is low. Excessive doses of colesevelam hydrochloride may cause more severe local gastrointestinal effects (e.g., constipation).