Welchol (Page 2 of 6)

6.2 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.

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 WELCHOL 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 WELCHOL and instructions for preventing or managing them.

Table 4 WELCHOL Drug Interactions that Decrease the Exposure of the Concomitant Medication
Drugs with a Narrow Therapeutic Index
Clinical Impact: Concomitant use with WELCHOL 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 WELCHOL [see Clinical Pharmacology (12.3)].
Intervention: Administer the narrow therapeutic index drug at least 4 hours prior to WELCHOL. 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 WELCHOL.
Thyroid Hormone Replacement Therapy
Clinical Impact: In vivo drug interactions studies showed a decrease in exposure of levothyroxine when coadministered with WELCHOL [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 WELCHOL.
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 WELCHOL 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 coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
Intervention: Administer oral contraceptives containing ethinyl estradiol and norethindrone 4 hours prior to WELCHOL.
Olmesartan Medoxomil
Clinical Impact: In vivo drug interactions studies showed a decrease in olmesartan medoxomil when coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
Intervention: Administer olmesartan medoxomil 4 hours prior to WELCHOL.
Sulfonylureas
Clinical Impact: In vivo drug interactions studies showed a decrease in sulfonylureas when coadministered with WELCHOL [see Clinical Pharmacology (12.3)].
Intervention: Administer sulfonylureas 4 hours prior to WELCHOL.
Examples: Glimepiride, glipizide, and glyburide
Oral Vitamin Supplements
Clinical Impact: WELCHOL 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 WELCHOL.

7.2 WELCHOL Drug Interactions that Increase the Exposure of the Concomitant Medication

Table 5 WELCHOL 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 WELCHOL [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients’ glycemic control.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

WELCHOL 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 WELCHOL 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/m2). No adverse effects on offspring survival and development were observed in rats administered 5 times the MRHD (see Data). WELCHOL may decrease the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3)]. 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 WELCHOL, 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 2% to 4% and 15% to 20%, 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 WELCHOL and a causal association with congenital anomalies has not been established.

Animal Data

In pregnant rats given dietary doses of 0.3, 1.0, 3.0 g/kg/day colesevelam hydrochloride from gestation days 7 through 17, no teratogenic effects were observed. Exposures at 3.0 g/kg/day were 8 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).

In pregnant rabbits given oral gavage doses of 0.1, 0.5, 1.0 g/kg/day colesevelam hydrochloride from gestation days 6 through 18, no teratogenic effects were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).

In pregnant rats given oral gavage doses of 0.1, 0.3, 1.0 g/kg/day colesevelam hydrochloride from gestation day 6 through lactation day 21 (weaning), no adverse effects on survival and development were observed. Exposures at 1.0 g/kg/day were 5 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).

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