Colesevelam Hydrochloride (Page 2 of 5)

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).

In clinical trials for the reduction of LDL-C, 68% of patients receiving colesevelam hydrochloride vs. 64% of patients receiving placebo reported an adverse reaction.

Table 1 Placebo-Controlled Clinical Studies of Colesevelam Hydrochloride 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 (%)
	Colesevelam Hydrochloride N=807	Placebo 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=129), were treated with colesevelam hydrochloride tablets (1.9 to 3.8 g, daily) or placebo tablets [see Clinical Studies (14.1)] .

Table 2 Placebo-Controlled Clinical Study of Colesevelam Hydrochloride 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 (%)
	Colesevelam Hydrochloride N=129	Placebo 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 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%) [see Clinical Studies (14.1)] .

Hypertriglyceridemia: 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 [see Clinical Studies (14.1)] .

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.

Drug Interactions with concomitant colesevelam hydrochloride administration include:

• Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Phenytoin should be administered 4 hours prior to colesevelam hydrochloride.
• Reduced International Normalized Ratio (INR) in patients receiving warfarin therapy. In warfarin-treated patients, INR should be monitored frequently during colesevelam hydrochloride 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 colesevelam hydrochloride [see Drug Interactions (7)] .

Gastrointestinal Adverse Reactions

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

Table 4 lists the drugs that have been tested in in vitro binding, in vivo drug interaction studies with colesevelam and/or drugs with post-marketing 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 colesevelam hydrochloride. Alternatively, the physician should monitor drug levels of the co-administered drug.

Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports

* Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to colesevelam hydrochloride. † Should be administered at least 4 hours prior to colesevelam hydrochloride. ‡ Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. § No significant alteration of warfarin drug levels with warfarin and colesevelam hydrochloride co-administration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR) [see Post-Marketing Experience (6.2)] .
Drugs with a known interaction with colesevelam: Decrease in exposure of co-administered drug	cyclosporine *, glimepiride †, glipizide †, glyburide †, levothyroxine †, olmesartan medoxomil †, and oral contraceptives containing ethinyl estradiol and norethindrone †
Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug	metformin extended release (ER) ‡
Drug(s) with post-marketing reports consistent with potential drug-drug interactions when co-administered with colesevelam hydrochloride	phenytoin †, warfarin §
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, phenytoin †, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarin §

In an in vivo drug interaction study, colesevelam hydrochloride and warfarin co-administration had no effect on warfarin drug levels. This study did not assess the effect of colesevelam hydrochloride and warfarin co-administration on INR. In post-marketing reports, concomitant use of colesevelam hydrochloride and warfarin has been associated with reduced INR. Therefore, in patients on warfarin therapy, the INR should be monitored before initiating colesevelam hydrochloride and frequently enough during early colesevelam hydrochloride 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 (6.2)].