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.

ETHYOL (NDA-020221)

(AMIFOSTINE)

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

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07/25/2019 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

(the following subsections were created to comply with Physician Labeling Rule (PLR); please refer to labeling for complete information)

5.1 Effectiveness of the Chemotherapy Regimen

5.2 Effectiveness of Radiotherapy

5.3 Hypotension and Cardiovascular Events

5.4 Severe Cutaneous Reactions

5.5 Hypersensitivity

5.6 Nausea and Vomiting

5.7 Hypocalcemia

5.8 Embryo-Fetal Toxicity

6 Adverse Reactions

(addition of the following information)

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

Hypotension and Cardiovascular Events
Severe Cutaneous Reactions
Hypersensitivity
Nausea and Vomiting
Hypocalcemia

6.1 Clinical Trials Experience

(Physician Labeling Rule (PLR) conversion with extensive changes; please refer to labeling for complete information)

6.2 Postmarketing Experience

(newly added subsection)

The following adverse reactions have been identified during post-approval use of ETHYOL. 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.

The following reported post-marketing adverse reactions are described elsewhere in the labeling:

Hypotension and Cardiovascular Events
Severe Cutaneous Reactions
Hypersensitivity

Adverse reactions associated with the use of ETHYOL that have been identified in other clinical trials and/or post-marketing reports are described below:

Immune system disorders: Hypersensitivity reactions including pruritus, urticaria, laryngeal edema, anaphylactic reactions, anaphylactoid reactions.

Nervous system disorders: Seizure.

Cardiac disorders: Myocardial ischemia, myocardial infarction, cardiac arrest, arrhythmias including tachycardia, bradycardia, atrial fibrillation/flutter, supraventricular tachycardia, extrasystoles.

Vascular disorders: Transient hypertension and exacerbations of preexisting hypertension.

Respiratory, thoracic and mediastinal disorders: Apnea, dyspnea, hypoxia, respiratory arrest.

Skin and subcutaneous tissue disorders: Erythema multiforme, dermatitis exfoliative, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Renal and urinary disorders: Renal failure.

General disorders and administration site conditions: Chest discomfort and chest pain.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

When ETHYOL is used in combination with cisplatin, refer to the cisplatin full prescribing information for pregnancy information.

Based on findings in animals, ETHYOL can cause fetal harm when administered to a pregnant woman. There are no available data on ETHYOL use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of ETHYOL to pregnant rabbits during organogenesis was embryotoxic at doses approximately sixty percent of the recommended dose in humans based on body surface area. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population.

Data

Animal Data

ETHYOL has been shown to be embryotoxic in rabbits at intravenous doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

When ETHYOL is used in combination with cisplatin, refer to the cisplatin full prescribing information for lactation information.

There are no data on the presence of amifostine or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with ETHYOL.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

When ETHYOL is used in combination with cisplatin, refer to the cisplatin full prescribing information for contraception and infertility information.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating ETHYOL.

Infertility

Males

Based on findings from animal studies, ETHYOL may impair fertility in males of reproductive potential

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

PATIENT COUNSELING INFORMATION

(newly added section)

Hypotension and Cardiovascular Events

Inform the patient that he or she may experience hypotension after ETHYOL infusion. Advise the patient to inform the prescriber if he or she is receiving anti-hypertensive medications or other drugs that could cause or potentiate hypotension.

Severe Cutaneous Reactions

Inform the patient that severe cutaneous reactions may develop during or weeks after initiation of ETHYOL administration. Advise the patient to inform the prescriber if they experience any cutaneous reactions or mucosal lesions outside of the injection site or radiation port, or on the palms or soles, as discontinuation of the drug may be necessary.

Hypersensitivity

Inform the patient that he or she may experience allergic reactions after ETHYOL infusion. ETHYOL might need to be discontinued for severe acute allergic reactions and the patient receive other treatments.

Nausea and Vomiting

Inform the patient that he or she may experience severe nausea and/or vomiting after ETHYOL infusion.

Hypocalcemia

Inform the patient that calcium supplements may be necessary if hypocalcemia is identified. Blood tests may be needed to identify this, and correct the condition.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Refer to the cisplatin full prescribing information for pregnancy and contraception information.

Lactation

Advise lactating women not to breastfed during treatment with ETHYOL. Refer to the cisplatin full prescribing information for lactation information.

Infertility

Advise males of reproductive potential that ETHYOL may impair fertility. Refer to the cisplatin full prescribing information for infertility information.

05/25/2017 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Additions and/or revisions underlined:

Pediatric Use

The safety and effectiveness in pediatric patients have not been established Therefore ETHYOL is not recommended for use in the pediatric population.

WARNINGS

Additions and/or revisions underlined:
4. Cutaneous Reactions

Fatal and serious cutaneous reactions have been reported with ETHYOL treatment, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, toxicoderma, exfoliative dermatitis and drug reaction with biopsy-confirmed eosinophilia and systemic symptoms (DRESS). These reactions have been reported more frequently when ETHYOL is used as a radioprotectant (see ADVERSE REACTIONS). Serious cutaneous reactions may develop weeks after initiation of ETHYOL administration. Monitor patients carefully prior to, during and after ETHYOL administration.

Discontinue ETHYOL for cutaneous reactions or mucosal lesions appearing outside of the injection site or radiation port and for erythematous, edematous or bullous lesions on the palms or soles.

6 Adverse Reactions

Additions and/or revisions underlined:

Controlled Trials

… Other effects, which have been described during or following ETHYOL infusion are … syncope is added to describe loss of consciousness, pyrexia replaces fever, and diarrhea is added

Clinical Trials and Pharmacovigilance Reports

Hypersensitivity and anaphylactic replaces allergic characterized …

Discomfort replaces tightness and pyrexia replaces fever

Hypotension, usually brief systolic and diastolic … seizure replaces convulsion.

Seizures and syncope (loss of consciousness) have been reported rarely.

12/15/2016 (SUPPL-32)

Approved Drug Label (PDF)

6 Adverse Reactions

(additions underlined)

Other effects, which have been described during or following ETHYOL infusion are flushing/feeling of warmth, chills/feeling of coldness, malaise, fever, rash, dizziness, somnolence, hiccups, sneezing, diplopia and blurred vision. These effects have not generally precluded the completion of therapy.

Injection site reactions (including rash/erythema, pruritus, urticaria, pain, inflammation, bruising and local swelling) were also observed.