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.

EPIPEN (NDA-019430)

(EPINEPHRINE)

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

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02/10/2023 (SUPPL-106)

Approved Drug Label (PDF)

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

PATIENT INFORMATION

Extensive changes; please refer to label for complete information

12/24/2020 (SUPPL-91)

Approved Drug Label (PDF)

6 Adverse Reactions

(Newly added subsection titles)

Cardiovascular Reactions

Reactions from Accidental Injection and/or Improper Technique

Skin and Soft Tissue Infections

7 Drug Interactions

(Newly added subsection titles)

Cardiac Glycosides, Diuretics, and Anti-arrhythmics

Antidepressants, Monoamine Oxidase Inhibitors, Levothyroxine, and Antihistamines

Beta-Adrenergic Blockers

Ergot Alkaloids

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

Patient Counseling Information

(Newly added information)

Advise patients and caregivers to give used EpiPen and EpiPen Jr auto-injectors to their healthcare provider for inspection and proper disposal.

Patient Information

(Additions and/or revisions underlined)

EpiPen and EpiPen Jr are single-dose automatic injection devices (auto- injectors) that contain epinephrine, a medicine used to treat allergic emergencies (anaphylaxis).

Each EpiPen or EpiPen Jr Auto-Injector contains only 1 dose of medicine (single-dose).
EpiPen and EpiPen Jr Auto-Injectors deliver a fixed dose of epinephrine. The auto-injectors cannot be reused. Do not try to reuse EpiPen or EpiPen Jr after the device has been activated. It is normal for most of the medicine to remain in the auto-injector after the dose has been injected. The dose has been injected if the orange tip is extended and the window is blocked.
EpiPen or EpiPen Jr should be injected into the middle of your outer thigh (upper leg). It can be injected through your clothing if needed. Do not inject into a vein or into the buttocks, fingers, toes, hands or feet.
Use your single-dose EpiPen or EpiPen Jr exactly as your healthcare provider tells you to use it. You may need to use a second EpiPen or EpiPen Jr if symptoms continue or recur. Only a healthcare provider should give additional doses of epinephrine if you need more than 2 injections for a single anaphylaxis episode.

Keep the EpiPen Trainer and the real EpiPen and EpiPen Jr Auto- Injectors away from young children. The real EpiPen and EpiPen Jr Auto- injectors and EpiPen Trainer are not toys. For young children, use of the EpiPen Trainer and the real EpiPen and EpiPen Jr Auto-Injectors should be supervised by an adult.

06/17/2020 (SUPPL-89)

Approved Drug Label (PDF)

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

Patient Information

(Additions and/or revisions underlined)

· Caution: Never put your thumb, fingers, or hand over the orange tip. Never press or push the orange tip with your thumb, fingers, or hand. The needle comes out of the orange tip. Accidental injection into finger, hands or feet may cause a loss of blood flow to these areas. If an accidental injection happens, go immediately to the nearest emergency room. Tell the healthcare provider where on your body you received the accidental injection.

· Warning: Do not flip the blue safety release off using a thumb or by pulling it sideways, or by bending and twisting the blue safety release. This may cause the device to activate by accident: a “click” is heard, the orange tip is extended, and the window is blocked. A device that has been activated by accident cannot be used for a patient in an emergency. If this happens, replace it with a new EpiPen or EpiPen Jr.

If you inject a young child with EpiPen or EpiPen Jr, hold their leg firmly in place before and during the injection to prevent injuries. Ask your healthcare provider to show you how to:

Hold the young child firmly in place (restrain).
With one hand, grip the auto-injector with the orange tip pointing down.
With the other hand, pull the blue safety release straight up and away from the auto-injector.

When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal

Visit the FDA’s website (https://www.fda.gov/drugs/safe-disposal- medicines/disposal-unused-medicines-what-you-should-know) for more information about how to throw away (dispose of) unused, unwanted or expired medicines.

- Warning: Do not flip the blue safety release off using a thumb or by pulling it sideways, or by bending and twisting the blue safety release. This may cause the device to activate by accident: a “click” is heard, the orange tip is extended, and the window is blocked. A device that has been activated by accident cannot be used for a patient in an emergency. If this happens, replace it with a new EpiPen or EpiPen Jr.

- When receiving an EpiPen or EpiPen Jr Auto-Injector and before you need to use the EpiPen or EpiPen Jr Auto-Injector, remove the auto- injector from the carrier tube and check the auto-injector to make sure the blue safety release is not raised (see Figure 1 in the Instructions for Use). If the blue safety release is raised, the auto- injector should not be used because the device could activate by accident. Do not try to push the blue safety release back down. Put the auto-injector back in the carrier tube and replace it with a new EpiPen or EpiPen Jr.

08/23/2018 (SUPPL-74)

Approved Drug Label (PDF)

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 adequate and well controlled studies of the acute effect of epinephrine in pregnant women. In animal reproductive studies, epinephrine administered by the subcutaneous route to rabbits, mice, and hamsters during the period of organogenesis was teratogenic at doses 7 times and higher than the maximum recommended human intramuscular and subcutaneous dose on a mg/m2 basis. Epinephrine is the first-line medication of choice for the treatment of anaphylaxis during pregnancy in humans. Epinephrine should be used for treatment of anaphylaxis during pregnancy in the same manner as it is used in non-pregnant patients.

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.

Clinical Considerations:

Disease-associated and embryo/fetal risk:

During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. The prevalence of anaphylaxis occurring during pregnancy is reported to be approximately 3 cases per 100,000 deliveries.

Management of anaphylaxis during pregnancy is similar to management in the general population. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in pregnant and non-pregnant patients. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care.

Data:

Animal Data:

In an embryofetal development study with rabbits dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including gastroschisis and embryonic lethality) at doses approximately 40 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days).

In an embryofetal development study with mice dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including embryonic lethality) at doses approximately 8 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at approximately 4 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days).

In an embryofetal development study with hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine was shown to be teratogenic at doses approximately 7 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There is no information on the presence of epinephrine in human milk, the effects on breastfed infants, or the effects on milk production. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in breastfeeding and non- breastfeeding patients.

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

Patient Information

(Newly Added Section; please refer to labeling)

04/28/2017 (SUPPL-67)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions are underlined)

Rare cases of stress cardiomyopathy have been reported in patients treated with epinephrine.

05/18/2016 (SUPPL-61)

Approved Drug Label (PDF)

5 Warnings and Precautions

Injection-Related Complications

Hold leg firmly during injection.
Lacerations, bent needles, and embedded needles have been reported when epinephrine has been injected into the thigh of young children who are uncooperative and kick or move during an injection. To minimize the risk of injection related injury when administering {insert product name} to young children, instruct caregivers to hold the child’s leg firmly in place and limit movement prior to and during injection.

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 {insert product name} into the buttock [see Warnings and Precautions (5.2)]. 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

Lacerations, bent needles, and embedded needles have been reported when Adrenaclick has been injected into the thigh of young children who are uncooperative and kick or move during an injection.
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.