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.

BUPIVACAINE HYDROCHLORIDE (NDA-018053)

(BUPIVACAINE HYDROCHLORIDE)

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

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03/09/2021 (SUPPL-61)

Approved Drug Label (PDF)

Boxed Warning

Additions underlined:

WARNING: RISK OF CARDIAC ARREST WITH USE OF BUPIVACAINE HYDROCHLORIDE INJECTION IN OBSTETRICAL ANESTHESIA

There have been reports of cardiac arrest with difficult resuscitation or death during use of Bupivacaine Hydrochloride Injection for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of Bupivacaine Hydrochloride Injection is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary [see Warnings and Precautions (5.1)].

4 Contraindications

Additions underlined:

…

intravenous regional anesthesia (Bier Block) [see Warnings and Precautions (5.7)].
…

5 Warnings and Precautions

The following subsections created to comply with Physician Labeling Rule (PLR)

5.1 Risk of Cardiac Arrest with Use of Bupivacaine Hydrochloride Injection in Obstetrical Anesthesia

5.2 Dose-Related Toxicity

5.3 Methemoglobinemia

5.4 Antimicrobial Preservatives in Multiple-Dose Vials

5.5 Chondrolysis with Intra-Articular Infusion

5.6 Risk of Adverse Reactions Due to Drug Interactions with Bupivacaine Hydrochloride and Epinephrine Injection

5.7 Risk of Cardiac Arrest with Intravenous Regional Anesthesia Use (Bier Block)

5.8 Allergic-Type Reactions to Sulfites in Bupivacaine Hydrochloride and Epinephrine Injection

5.9 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection

5.10 Risk of Toxicity in Patients with Hepatic Impairment

5.11 Risk of Use in Patients with Impaired Cardiovascular Function

5.12 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply

5.13 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation Anesthetics

5.14 Risk of Adverse Reactions with Use in Head and Neck Area

5.15 Risk of Respiratory Arrest with Use in Ophthalmic Surgery

5.16 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental Applications

7 Drug Interactions

The following subsections created to comply with Physician Labeling Rule (PLR)

7.1 Local Anesthetics

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

7.3 Ergot-Type Oxytocic Drugs

7.4 Nonselective Beta-Adrenergic Antagonists

7.5 Drugs Associated with Methemoglobinemia

7.6 Potent Inhalation Anesthetics

7.7 Phenothiazines and Butyrophenones

8 Use in Specific Populations

8.6 Hepatic Impairment

New subsection added

Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see Warnings and Precautions (5.10)].

8.7 Renal Impairment

New subsection added

Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. This should be considered when selecting the Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection dosage [see Use in Specific Populations (8.5)].

8.1 Pregnancy

PLLR conversion, please refer to label for complete information

8.2 Lactation

PLLR conversion

Risk Summary

Lactation studies have not been conducted with bupivacaine. Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection should be administered to lactating women only if clearly indicated. Studies assessing the effects of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in breastfed children have not been performed. Studies to assess the effect of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection on milk production or excretion have not been performed. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for bupivacaine and any potential adverse effects on the breastfed child from bupivacaine or from the underlying maternal condition.

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

PATIENT COUNSELING INFORMATION

New section added

Allergic-Type Reactions

Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see Contraindications (4), Warnings and Precautions (5.8), Adverse Reactions (6)].

Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia.

Instructions After Dental Injection of Bupivacaine Hydrochloride Injection

Advise patients receiving dental injections of Bupivacaine Hydrochloride Injection not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see Warnings and Precautions (5.16)].

Methemoglobinemia

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.3)].

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

Other

Physician Labeling Rule (PLR) conversion

11/02/2018 (SUPPL-60)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

(additions underlined)

…

Use in Dentistry: Because of the long duration of anesthesia, when Bupivacaine Hydrochloride 0.5% with epinephrine is used for dental injections, patients should be cautioned about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting or probing.

WARNINGS

(additions underlined)

…

Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Bupivacaine Hydrochloride and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

…

7 Drug Interactions

Clinically Significant Drug Interactions

(additions underlined)

…

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:

Examples of Drugs Associated with Methemoglobinemia:

(please refer to label to view examples)

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

Information for Patients:

(additions underlined)

…

Patients receiving dental injections of Bupivacaine Hydrochloride should be cautioned not to chew solid foods or test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours).