Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

WELCHOL (NDA-021176)

(COLESEVELAM HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/20/2021 (SUPPL-49)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Primary Hyperlipidemia

The safety and effectiveness of WELCHOL 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 WELCHOL for this indication is supported by a study in 129 WELCHOL-treated pediatric patients aged 10 to 17 years with HeFH [see Clinical Studies (14.1)]. 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%) [see Adverse Reactions (6.1)]. There were no significant effects on fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo. Due to WELCHOL tablet size, WELCHOL for oral suspension is recommended for use in the pediatric population [see Dosage and Administration (2.2, 2.4)]. The safety and effectiveness of WELCHOL 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 WELCHOL to improve glycemic control in pediatric patients with type 2 diabetes mellitus have not been established. Effectiveness was not demonstrated in a 6-month, adequate and well-controlled study conducted in 141 WELCHOL-treated pediatric patients aged 10 to 17 years with type 2 diabetes mellitus.

05/12/2020 (SUPPL-47)

Approved Drug Label (PDF)

6 Adverse Reactions

Cardiovascular Adverse Reactions

(Additions and/or revisions underlined)

During the diabetes trials, the incidence of patients with serious adverse reactions involving the cardiovascular system was 2.2% (22/1022) in the WELCHOL group and 1% (10/1010) in the placebo group.

8 Use in Specific Populations

Pregnancy

(Additions and/or revisions underlined)

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).

05/21/2019 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypertriglyceridemia and Pancreatitis

(additions underlined)

…

Obtain lipid parameters, including TG levels and non-HDL-C, before starting WELCHOL and periodically thereafter. WELCHOL is contraindicated in patients with TG levels >500 mg/dL or patients with a history of hypertriglyceridemia-induced pancreatitis. Patients with TG levels greater than 300 mg/dL could have greater increases in serum TG levels with WELCHOL and may require additional TG monitoring. Instruct patients to discontinue WELCHOL and seek prompt medical attention if the symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting). Discontinue WELCHOL if TG levels exceed 500 mg/dL.

5.2 Gastrointestinal Obstruction

(additions underlined)

Postmarketing cases of bowel obstruction have occurred with WELCHOL Because of its constipating effects, WELCHOL is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal tract surgery and who may be at risk for bowel obstruction. WELCHOL is contraindicated in patients with a history of bowel obstruction. Instruct patients to promptly discontinue WELCHOL and seek medical attention if severe abdominal pain or severe constipation occurs.

Because of the tablet size, WELCHOL tablets can cause dysphagia or esophageal obstruction. For patients with difficulty swallowing tablets use WELCHOL for oral suspension.

5.5 Risks in Patients with Phenylketonuria

(additions underlined)

Phenylalanine can be harmful to patients with phenylketonuria (PKU). WELCHOL for oral suspension contains phenylalanine, a component of aspartame. Each 3.75 gram packet contains 27 mg of phenylalanine. Before prescribing WELCHOL for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including WELCHOL for oral suspension.

6 Adverse Reactions

(additions underlined)

The following important adverse reactions are described below and elsewhere in the labeling:

Hypertriglyceridemia and Pancreatitis
Gastrointestinal Obstruction
Vitamin K or Fat-Soluble Vitamin Deficiencies

7 Drug Interactions

7.1 WELCHOL Drug Interactions that Decrease the Exposure of the Concomitant Medication

(new subsection added)

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

(please refer to label to view Table 4)

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

(new subsection added)

Table 5

WELCHOL Drug Interactions that Increase the Exposure of the Concomitant Medication

(please refer to label to view Table 5)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(section revised, additions underlined)

Hypertriglyceridemia and pancreatitis:

Inform patients that WELCHOL may increase their serum triglycerides which can lead to hypertriglyceridemia and pancreatitis. Instruct patients to discontinue WELCHOL and seek prompt medical attention if the symptoms of acute pancreatitis occur (e.g., severe abdominal pain with or without nausea and vomiting) .

Gastrointestinal:

Inform patients that WELCHOL may cause bowel obstruction. Instruct patients to promptly discontinue WELCHOL and seek medical attention if severe abdominal pain or severe constipation occurs.

Drug and Vitamin interactions:

Advise patients that WELCHOL has drug interactions and WELCHOL may decrease the absorption of fat- soluble vitamins A, D, E, and K. Instruct patients to take oral vitamins at least 4 hours prior to WELCHOL. Instruct patients to inform their physician about all the drugs and vitamins that they are prescribed or take over the counter.

Hypertriglyceridemia and cardiovascular disease:

Inform patients that WELCHOL may increase serum triglycerides and that the long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain.

Administration :

Tablets:

Advise patients to take WELCHOL tablets with a meal and liquid. Inform patients that WELCHOL tablets can be taken as 6 tablets once daily or 3 tablets twice daily.

For Oral Suspension:

Instruct patients to empty the entire contents of one packet into a glass or cup and add 1 cup (8 ounces) of water, fruit juice, or diet soft drinks. Stir well and drink. Advise patients to take WELCHOL oral suspension with meals. Advise patient to not take WELCHOL oral suspension in its dry form.

Chewable Bars:

Advise patients to take the WELCHOL chewable bar with a meal. Inform patients that WELCHOL Chewable bars contain approximately 80 calories per bar.

…

01/16/2019 (SUPPL-44)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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 3 times the MRHD.

WELCHOL 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 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 post-marketing 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 3 times the human exposure at 3.75 g/day MRHD, based on body surface area (mg/m2).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

WELCHOL is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to WELCHOL.

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Contraception

Use of WELCHOL may reduce the efficacy of oral contraceptives. Advise patients to take oral contraceptives at least 4 hours prior to taking WELCHOL.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Newly Added Subsection)

17.3 Females of Reproductive Potential:

Advise females of reproductive potential that WELCHOL may reduce the effectiveness of oral contraceptives, and to take oral contraceptives at least 4 hours before taking WELCHOL.