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.

ZOFRAN PRESERVATIVE FREE (NDA-020007)

(ONDANSETRON HYDROCHLORIDE)

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

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06/02/2025 (SUPPL-50)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Ondansetron is unlikely to result in clinically relevant exposures in breastfed infants when administered intravenously at doses up to 4 mg/day to women who are breastfeeding. Available data from a lactation study involving pharmacokinetic samples from 80 lactating women and 20 infants indicate that ondansetron is present at low levels in human milk and in the plasma of breastfed infants. Both the estimated daily infant dose (DID) of ondansetron (0.002 mg/kg/day), and the relative infant dose (RID) (3.7%) were low (see Data).

In the same study, no adverse effects attributed to ondansetron were reported in infants exposed to ondansetron through breast milk. There are no data on the effects of ondansetron on milk production.

Data

A pharmacokinetic study utilizing opportunistic sampling of a convenience sample of 80 lactating women receiving intravenous ondansetron for the treatment of post-operative nausea and vomiting and 20 breastfed infants showed that ondansetron was present in breast milk with an average milk to plasma ratio of 0.91 following a median (range) dose of ondansetron of 4 (4 to 8) mg/dose. Using the average milk concentration over 24 hours to estimate the DID and the RID, the DID was 0.002 mg/kg/day and the RID was 3.7% of a weight-adjusted single maternal dose of 4 mg. Among the 20 infant plasma samples, seven concentrations (35%) were below the limit of quantification. Among the 13 infants with a quantifiable plasma concentration, the median (range) concentration was 0.78 (0 to 7.2) ng/mL. The highest observed concentration among these 13 infants was approximately 10 times lower than the median maximum concentration (76.6 ng/mL) observed in an open-label, single-dose pharmacokinetic study conducted in pediatric surgical patients aged 1 to 24 months who received a single 0.1 mg/kg dose of intravenous ondansetron.

10/20/2021 (SUPPL-49)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Myocardial Ischemia

(Newly added section)

Myocardial ischemia has been reported in patients treated with ondansetron. In some cases, predominantly during intravenous administration, the symptoms appeared immediately after administration but resolved with prompt treatment. Coronary artery spasm appears to be the most common underlying cause. Therefore, do not exceed the recommended infusion rate of ZOFRAN and monitor patients for signs and symptoms of myocardial ischemia during and after administration [see Dosage and Administration (2.1, 2.2) and Adverse Reactions (6.2)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
QT Prolongation [see Warnings and Precautions (5.2)]
Serotonin Syndrome [see Warnings and Precautions (5.3)]
Myocardial Ischemia [see Warnings and Precautions (5.4)]
Masking of Progressive Ileus and Gastric Distension [see Warnings and Precautions (5.5)]

6.2 Postmarketing Experience

(Newly added information)

Myocardial ischemia was reported predominately with intravenous administration [see Warnings and Precautions (5.4)].

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting US- and foreign-controlled clinical trials, 862 were aged 65 years and older. No overall differences in safety or effectiveness were observed between subjects 65 years and older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects [see Clinical Pharmacology (12.3)]. There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65.

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

Patient Counseling Information

(Newly added information)

Myocardial Ischemia

Inform patients that ZOFRAN may cause myocardial ischemia during or after the administration. Advise patients to seek immediate medical help if any symptoms suggestive of a myocardial ischemia occur, such as sudden chest pain or chest tightness [see Warnings and Precautions (5.4)].

04/29/2021 (SUPPL-48)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Masking of Progressive Ileus and Gastric Distension

(Additions and/or revisions underlined)

The use of ZOFRAN in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distention. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

6 Adverse Reactions

(Newly added information)

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hypersensitivity reactions [see Warnings and Precautions (5.1)]
QT prolongation [see Warnings and Precautions (5.2)]
Serotonin syndrome [see Warnings and Precautions (5.3)]

Masking of progressive ileus and gastric distention [see Warnings and Precautions (5.4)]

8 Use in Specific Populations

8.1 Pregnancy

(Extensive changes; please refer to label)

8.2 Lactation

(Additions and/or revisions underlined)

However, it has been demonstrated that ondansetron is present in the milk of rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

03/08/2017 (SUPPL-47)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

Risk Summary

It is not known whether ondansetron is present in human milk. There are no data on the effects of ZOFRAN on the breastfed infant or the effects on milk production. However, it has been demonstrated that ondansetron is present in the milk of rat

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOFRAN and any potential adverse effects on the breast-fed infant from ZOFRAN or from the underlying maternal condition.

8.5 Geriatric Use

(subsection revised, additions underlined)

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting US- and foreign-controlled clinical trials, 862 were aged 65 years and older. No overall differences in safety or effectiveness were observed between subjects 65 years and older and younger subjects. A reduction in clearance and increase in elimination half-life were seen in patients older than 75 years compared with younger subjects. There were an insufficient number of patients older than 75 years of age and older in the clinical trials to permit safety or efficacy conclusions in this age-group. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some 267 older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65.

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

17 PATIENT COUNSELING INFORMATION

(section revised, additions underlined)

QT Prolongation

Patients should be informed that ZOFRAN may cause serious cardiac arrhythmias such as QT prolongation. Patients should be instructed to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.Patients should be informed that the chances of developing severe cardiac arrhythmias such as QT prolongation and Torsade de Pointes are higher in the following people:

Patients with a personal or family history of abnormal heart rhythms, such as congenital long QT syndrome;
Patients who take medications, such as diuretics, which may cause electrolyte abnormalities;

Patients with hypokalemia or hypomagnesemia.

ZOFRAN should be avoided in these patients, since they may be more at risk for cardiac arrhythmias such as QT prolongation and Torsade de Pointes.

Hypersensitivity Reactions

Inform patients that ZOFRAN may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. The patient should report any signs and symptoms of hypersensitivity reactions, including fever, chills, rash, or breathing problems.

Masking of Progressive Ileus and Gastric Distension

Inform patients following abdominal surgery or those with chemotherapy-induced nausea and vomiting that ZOFRAN may mask signs and symptoms of bowel obstruction. Instruct patients to immediately report any signs or symptoms consistent with a potential bowel obstruction to their healthcare provider.

Drug Interactions

Instruct the patient to report the use of all medications, especially apomorphine, to their healthcare provider. Concomitant use of apomorphine and ZOFRAN may cause a significant drop in blood pressure and loss of consciousness.
Advise patients of the possibility of serotonin syndrome with concomitant use of ZOFRAN and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.