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.

DIPRIVAN (NDA-019627)

(PROPOFOL)

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

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08/31/2022 (SUPPL-69)

Approved Drug Label (PDF)

4 Contraindications

PLR conversion; additions and/or revisions underlined:

DIPRIVAN is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN components.

DIPRIVAN is contraindicated in patients with a history of anaphylaxis to eggs, egg products, soybeans or soy products.

5 Warnings and Precautions

PLR conversion. Newly created subsection titles below; please refer to label for complete information.

5.1 Anaphylactic and Anaphylactoid Reactions

5.2 Risk of Microbial Contamination

5.3 Risks of Pediatric Neurotoxicity

5.4 Risks of Bradycardia, Asystole, and Cardiac Arrest

5.5 Risk of Seizures

5.6 Neurosurgical Anesthesia

5.7 Cardiac Anesthesia

5.8 Use for Intensive Care Unit Sedation of Intubated, Mechanically Ventilated Adult Patients

5.9 Risks of Propofol Infusion Syndrome in Patients with ICU Sedation

5.10 Risk of Elevations in Serum Triglycerides

5.11 Risks of Zinc Losses

5.12 Use in the Elderly, Debilitated, or ASA-PS III or IV Patients

5.13 Risk of Transient Local Pain

5.14 Risks of Local Reactions

5.15 Risks of Aggregation if Administered through the Same Intravenous Catheter with Blood or Plasma

5.16 Risk of Postoperative Unconsciousness

5.17 Risks of Perioperative Myoclonia

5.18 Risks of Pulmonary Edema

5.19 Risks of Unexplained Postoperative Pancreatitis

6 Adverse Reactions

PLR conversion; please refer to label for complete information.

7 Drug Interactions

PLR conversion. The following subtitles have been added; please refer to label for complete information:

Opioids and Sedatives

Analgesic Agents

Valproate

Common Neuromuscular Blocking Agents

Common Drugs Used as Premedication or Drugs Used During Anesthesia or Sedation

8 Use in Specific Populations

8.1 Pregnancy

PLR and PLLR conversion; please refer to label for complete information

8.2 Lactation

PLR and PLLR conversion; as below:

Risk Summary

Based on data from published studies, propofol is present in human milk. Variable concentrations have been reported in human milk with administration of propofol to nursing mothers in the early post-partum period. Available data have not shown adverse reactions in breastfed infants. There are no data on the effects of propofol on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DIPRIVAN and any potential adverse effects on the breastfed infant form DIPRIVAN or from the underlying maternal condition.

8.4 Pediatric Use

PLR and PLLR conversion; additions and/or revisions underlined:

… In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received DIPRIVAN (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality was not established in this study, DIPRIVAN is not indicated for ICU sedation in pediatric patients until further studies have been performed to document its safety in that population [see Clinical Pharmacology (12.3) and Dosage and Administration (2.1 and 2.2)]. However, propofol infusions are routinely used to provide safe sedation to critically ill pediatric patients in ICUs.

…

8.5 Geriatric Use

PLR conversion; no change to information found in label.

8.6 Hepatic Impairment

PLR conversion; as below:

The long-term administration of DIPRIVAN to patients with hepatic insufficiency has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis compared to adults with normal hepatic function. The effects of acute hepatic failure on the pharmacokinetics of propofol have not been studied.

8.7 Renal Impairment

PLR conversion; as below:

Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with DIPRIVAN containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

DIPRIVAN contains 0.005% disodium edetate. At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules.

The long-term administration of DIPRIVAN to patients with renal failure has not been evaluated.

The pharmacokinetics of propofol do not appear to be different in people with chronic renal impairment compared to adults with normal renal function. The effects of acute renal failure on the pharmacokinetics of propofol have not been studied.

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

PATIENT COUNSELING INFORMATION

PLR conversion. Newly created section as below:

17.1 Impaired Mental Awareness

Advise patients that performance of activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery or signing legal documents may be impaired for some time after general anesthesia or sedation.

17.2 Effect of Anesthetic and Sedation Drugs on Early Brain Development

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Other

PLR and PLLR conversions

04/27/2017 (SUPPL-66)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

(new subsection added)

Pediatric Neurotoxicity

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans.

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

7 Drug Interactions

(additions underlined)

The induction dose requirements of DIPRIVAN may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output.

During maintenance of anesthesia or sedation, the rate of DIPRIVAN administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN.

The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression.

DIPRIVAN does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle relaxants).

No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults. In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN may result in serious bradycardia.

8 Use in Specific Populations

Pediatric Use

(additions underlined)

…

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data

Pregnancy

(PLLR conversion, please refer to label)

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

Information for Patients

(additions underlined)

Risk of Drowsiness

Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle, or hazardous machinery or signing legal documents may be impaired for some time after general anesthesia or sedation.

Effect of Anesthetic and Sedation Drugs on Early Brain Development