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.

ADRENALIN (NDA-204200)

(EPINEPHRINE)

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

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01/29/2019 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Incorrect Locations of Injections for Anaphylaxis

Addition of the following 5 subsections:

5.3 Extravasation and Tissue Necrosis with Intravenous Infusion

Avoid extravasation of epinephrine into the tissues, to prevent local necrosis. When Adrenalin is administered intravenously, check the infusion site frequently for free flow. Blanching along the course of the infused vein, sometimes without obvious extravasation, may be attributed to vasa vasorum constriction with increased permeability of the vein wall, permitting some leakage. This also may progress on rare occasions to superficial slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside.

There is potential for gangrene in a lower extremity when infusions of catecholamine are given in an ankle vein.

Antidote for Extravasation Ischemia: To prevent sloughing and necrosis in areas in which extravasation has taken place, infiltrate the area with 10 mL to 15 mL of saline solution containing from 5 mg to 10 mg of phentolamine, an adrenergic blocking agent. Use a syringe with a fine hypodermic needle, with the solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard, and pallid appearance. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.

5.4 Hypertension

Because individual response to epinephrine may vary significantly, monitor blood pressure frequently and titrate to avoid excessive increases in blood pressure.

Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may experience severe, prolonged hypertension when given epinephrine.

5.5 Pulmonary Edema

Epinephrine increases cardiac output and causes peripheral vasoconstriction, which may result in pulmonary edema.

5.6 Renal Impairment

Epinephrine constricts renal blood vessels, which may result in oliguria or renal impairment.

5.7 Cardiac Arrhythmias and Ischemia

Epinephrine may induce cardiac arrhythmias and myocardial ischemia in patients, especially patients suffering from coronary artery disease, or cardiomyopathy.

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Drugs Antagonizing Pressor Effects of Epinephrine

a-blockers, such as phentolamine
Vasodilators, such as nitrates
Diuretics
Antihypertensives
Phenothiazine antipsychotics

7.2 Drugs Potentiating Pressor Effects of Epinephrine

Sympathomimetics
ß-blockers, such as propranolol
Tricyclic anti-depressants
Monoamine oxidase (MAO) inhibitors
Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone
Clonidine
Doxapram
Oxytocin

7.3 Drugs Potentiating Arrhythmogenic Effects of Epinephrine

Cardiac arrhythmias are more common among patients receiving any of the following drugs

aß-blockers, such as propranolol
Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane
Antihistamines
Thyroid hormones
Diuretics
Cardiac glycosides, such as digitalis glycosides

Quinidine

7.4 Drugs Potentiating Hypokalemic Effects of Epinephrine

Potassium depleting diuretics
Corticosteroids
Theophylline

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion. Extensively changed; please refer to label for complete information.

8.4 Pediatric Use

Addition of the following statement:

Safety and effectiveness of epinephrine in pediatric patients with septic shock have not been established.

8.5 Geriatric Use

Addition of the following:

Clinical studies of epinephrine for the treatment of hypotension associated with septic shock did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

08/09/2017 (SUPPL-7)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions are underlined)

Cardiovascular: angina, arrhythmias, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, ventricular ectopy and stress cardiomyopathy.

05/18/2016 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

Injection-related Complications

Do not inject into buttock. Injection into the buttock may not provide effective treatment of anaphylaxis and has been associated with the development of Clostridial infections (gas gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk.

Potential for Ophthalmic Injury from Adrenalin® 30 mL multiple-dose vial

The Adrenalin® 30 mL multiple-dose vial is not for ophthalmic use because it contains chlorobutanol which may be harmful to the corneal endothelium.

Serious Infections at the Injection Site

Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Clostridium spores can be present on the skin and introduced into the deep tissue with subcutaneous or intramuscular injection. While cleansing with alcohol may reduce presence of bacteria on the skin, alcohol cleansing does not kill Clostridium spores. To decrease the risk of Clostridium infection, do not inject Adrenalin® into the buttock. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site.

6 Adverse Reactions

Adverse Reactions Associated with Intramuscular/Subcutaneous Use (for Anaphylaxis)

Injection into the buttock has resulted in cases of gas gangrene.
Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection in the thigh.