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.

RENVELA (NDA-022318)

(SEVELAMER CARBONATE)

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

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04/30/2020 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Gastrointestinal Adverse Events

(additions underlined)

Patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders, including severe constipation, or major GI tract surgery were not included in the Renvela clinical studies.

…Cases of bowel obstruction, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, and perforation have also been reported with sevelamer use.

Inflammatory disorders may resolve upon Renvela discontinuation. Treatment with Renvela should be re-evaluated in patients who develop severe gastrointestinal symptoms.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

The following adverse reactions have been identified during postapproval use of sevelamer hydrochloride or sevelamer carbonate: hypersensitivity, pruritus, rash, abdominal pain, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, fecal impaction, and uncommon cases of ileus, intestinal obstruction, and intestinal perforation. Appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Advise patients to report new onset or worsening of existing constipation or bloody stools promptly to their physician.

11/25/2016 (SUPPL-8)

Approved Drug Label (PDF)

4 Contraindications

(addition underlined)

Renvela is contraindicated in patients with bowel obstruction.

Renvela is contraindicated in patients with known hypersensitivity to sevelamer carbonate, sevelamer hydrochloride, or to any of the excipients.

5 Warnings and Precautions

5.2 Reductions in Vitamins D, E, K (clotting factors) and Folic Acid Levels (subsection updated; addition underlined)

In preclinical studies in rats and dogs, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, reduced vitamins D, E, and K (coagulation parameters) and

folic acid levels at doses of 6-10 times the recommended human dose. In short-term clinical trials, there was no evidence of reduction in serum levels of vitamins. However, in a one-year clinical trial, 25-hydroxyvitamin D (normal range 10 to 55 ng/mL) fell from 39 ± 22 ng/mL to

34 ± 22 ng/mL (p<0.01) with sevelamer hydrochloride treatment. Most (approximately 75%)

patients in sevelamer hydrochloride clinical trials were receiving vitamin supplements.

6 Adverse Reactions

6.1 Clinical Trials Experience (addition underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

There are limited clinical trial data on the safety of Renvela. However, because it contains the same active ingredient as the hydrochloride salt, the adverse event profiles of the two salts are expected to be similar. In a cross-over study in hemodialysis patients with treatment durations of eight weeks each and no washout, and another cross-over study in hemodialysis patients, with treatment durations of four weeks each and no washout between treatment periods, the adverse reactions on sevelamer carbonate powder were similar to those reported for sevelamer hydrochloride.

In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-comparator group (n=101). Overall adverse reactions among those treated with sevelamer hydrochloride occurring in > 5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). A total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions.

Based on studies of 8-52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3-16%).

In 143 peritoneal dialysis patients studied for 12 weeks using sevelamer hydrochloride, most common adverse reactions were similar to adverse reactions observed in hemodialysis patients. The most frequently occurring treatment emergent serious adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer group and 2 reactions in 2 patients [4%] on active-control). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions.

8 Use in Specific Populations

8.1 Pregnancy (PLLR Conversion)

Risk Summary

Sevelamer carbonate is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug.

Clinical Considerations

Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see Clinical Pharmacology (12.2)]. Consider supplementation.

Data

Animal Data

In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred in mid- and high-dose groups (human equivalent doses approximately equal to 3-4 times the maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100, 500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group (human equivalent dose twice the maximum clinical trial dose).

8.2 Lactation (PLLR conversion)

Risk Summary

envela is not absorbed systemically by the mother following oral administration, and No sbreastfeeding is not expected to result in exposure of the child to Renvela.

Clinical Considerations

Sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see Clinical Pharmacology (12.2)]. Consider supplementation.

8.4 Pediatric Use (addition underlined)

The safety and efficacy of Renvela in lowering serum phosphorus levels was studied in patients

6 years of age and older with CKD. In this study, Renvela was apparently less effective in children with a low baseline serum phosphorus, which described children <13 years of age and children not on dialysis. Given its mechanism of action, Renvela is expected to be effective in lowering serum phosphorus levels in pediatric patients with CKD. Most adverse events that were reported as related, or possibly related, to sevelamer carbonate were gastrointestinal in nature. No new risks or safety signals were identified with the use of sevelamer carbonate in the trial.

Renvela has not been studied in pediatric patients below 6 years of age.

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

17 PATIENT COUNSELING INFORMATION (addition underlined)

Advise patients to report new onset or worsening of existing constipation promptly to their physician.

03/09/2016 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

Renvela is contraindicated in patients with known hypersensitivity to sevelamer carbonate or to any of the excipients.

6 Adverse Reactions

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of sevelamer hydrochloride or sevelamer carbonate:

hypersensitivity…