Drug Safety-related Labeling Changes (SrLC)
Get Email Alerts |
Guide
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.
EXPAREL (NDA-022496)
(BUPIVACAINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
11/09/2023 (SUPPL-44)
03/22/2021 (SUPPL-35)
11/02/2018 (SUPPL-30)
5 Warnings and Precautions
5.1 Warnings and Precautions for Bupivacaine Containing Products(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 central nervous system and cardiovascular adverse effects, includi
seizures,
coma, arrhythmias, and death. Discontinue EXPAREL and anyoxidizing 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
(additions underlined)
…
Patients who are administered local anesthetics may be 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)
PATIENT COUNSELING INFORMATION(additions
underlined)
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.
…
04/06/2018 (SUPPL-9)
5 Warnings and Precautions
5.2 Warnings and Precautions Specific for EXPAREL(Additions and/or revisions are underlined)
Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL.
EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for these types of analgesia or routes of administration.
- epidural
- intrathecal
- regional nerve blocks other than interscalene brachial plexus nerve block
- intravascular or intra-articular use
EXPAREL has not been evaluated for use in the following patient population and, therefore, is not recommended for administration to these groups.
patients younger than 18 years old
pregnant patients
The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days as seen in clinical trials.
6 Adverse Reactions
6. ADVERSE REACTIONS(Additions and/or revisions are underlined)
The following serious adverse reactions have been associated with bupivacaine hydrochloride in clinical trials and are described in greater detail in other sections of the labeling:
Central Nervous System Reactions
Cardiovascular System Reactions
Allergic Reactions
Chondrolysis
Accidental intravascular injection
(Table has been revised; please refer to label)
(Table has been added; please refer to label)
(Subsection title has been revised; additions and/or revisions are underlined)
Because adverse reactions reported during postmarketing 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.
These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes (SOCs): Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy,7 Drug Interactions
7 Drug Interactions(Additions and/or revisions are underlined)
The toxic effects of local anesthetics are additive and their co-administration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL.
Bupivacaine
Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2.
Non-Bupivacaine Local Anesthetics
EXPAREL should not be admixed with local anesthetics other than bupivacaine. Non- bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. There are no data to support administration of other local anesthetics prior to administration of EXPAREL.
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
Of the total number of patients in the EXPAREL local infiltration clinical studies (N=823), 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. Of the total number of patients in the EXPAREL nerve block clinical studies (N=531), 241 patients were greater than or equal to 65 years of age and 60 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical experience with EXPAREL has not identified differences in efficacy or safety between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to bupivacaine may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, this should be considered when performing dose selection of EXPAREL.
(Additions and/or revisions are underlined)
Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic disease, 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 increased monitoring for local anesthetic systemic toxicity in subjects with moderate to severe hepatic disease.
(Additions and/or revisions are underlined)
Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. This should be considered when performing dose selection of EXPAREL.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Inform patients in advance that EXPAREL can cause temporary loss of sensation or motor activity that may last for up to 5 days.