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.

ALOXI (NDA-021372)

(PALONOSETRON HYDROCHLORIDE)

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

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04/01/2020 (SUPPL-21)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

ALOXI is contraindicated in patients known to have hypersensitivity to palonosetron.

5 Warnings and Precautions

5.1 Hypersensitivity Reactions

(Additions and/or revisions underlined)

Hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported with administration of ALOXI injection. These reactions occurred in patients with or without known hypersensitivity to other 5-HT3 receptor antagonists. If hypersensitivity reactions occur, discontinue ALOXI injection and initiate appropriate medical treatment. Do not reinitiate ALOXI injection in patients who have previously experienced symptoms of hypersensitivity.

6 Adverse Reactions

(Additions and/or revisions underlined)

Serious or otherwise clinically significant adverse reactions reported in other sections of labeling:

Hypersensitivity Reactions
Serotonin Syndrome

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval use of palonosetron HCl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticaria, anaphylaxis and anaphylactic shock
Injection site reactions: including burning, induration, discomfort and pain

7 Drug Interactions

7.1 Serotonergic Drugs

(Newly added subsection)

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If symptoms occur, discontinue ALOXI and initiate supportive treatment.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions are underlined)

Risk Summary

There are no available data on palonosetron HCl use in pregnant women to inform a drug-associated risk.

In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron HCl during the period of organogenesis at doses up to 1,894 and 3,789 times the recommended human intravenous dose in rats and rabbits, respectively.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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

Animal Data

In animal reproduction studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron HCl at doses up to 60 mg/kg/day (1,894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3,789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions are underlined)

Risk Summary

There are no data on the presence of palonosetron in human milk, the effects of palonosetron on the breastfed infant, or the effects of palonosetron on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ALOXI and any potential adverse effect on the breastfed infant from palonosetron or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions underlined)

Chemotherapy-Induced Nausea and Vomiting

Safety and effectiveness of ALOXI injection have been established in pediatric patients aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including HEC. Use is supported by a clinical trial where 165 pediatric patients aged 2 months to less than 17 years were randomized to receive a single dose of ALOXI injection 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy. While this study demonstrated that pediatric patients require a higher palonosetron dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults.

Safety and effectiveness of ALOXI in neonates (less than 1 month of age) have not been established. Postoperative Nausea and Vomiting Studies

Safety and effectiveness have not been established in pediatric patients for prevention of postoperative nausea and vomiting. Two pediatric trials were performed.

Pediatric Study 1, a dose finding study was conducted to compare two doses of palonosetron, 1 mcg/kg (maximum 0.075 mg) versus 3 mcg/kg (maximum 0.25 mg). A total of 150 pediatric surgical patients participated, age range 1 month to less than 17 years. No dose response was observed.

Pediatric Study 2, a multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared intravenous palonosetron HCl (1 mcg/kg, maximum 0.075 mg) versus intravenous ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to less than 17 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given the pre-specified non- inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 1374 adult cancer patients in clinical studies of intravenously administered palonosetron HCl, 316 (23%) were 65 years and over, while 71 (5%) were at least 75 years and over. Of the 1520 adult patients in clinical studies of intravenously administered palonosetron HCl, 73 (5%) were at least 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity in some older individuals cannot be ruled out. Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients 65 years of age and older compared to younger patients. No dose adjustment is required for geriatric patients.

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

17. PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients with or without known hypersensitivity to other 5-HT3 receptor antagonists. Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur with administration of ALOXI injection.

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of ALOXI injection 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.