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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.
ULTIVA (NDA-020630)
(REMIFENTANIL HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/22/2025 (SUPPL-31)
5 Warnings and Precautions
5.2 Life-Threatening Respiratory Depression
Additions and/or revisions underlined:
. . .
ULTIVA should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Resuscitative and intubation equipment, oxygen, and opioid overdose reversal agents (e.g., naloxone, nalmefene) must be readily available.
5.3 Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or Other CNS Depressants
Additions and/or revisions underlined:
. . .
Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin and pregabalin], and other opioids). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7)].
. . .
6 Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined:
. . .
Opioid-Induced Esophageal Dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term.
7 Drug Interactions
Additions and/or revisions underlined:
. . .
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.
. . .
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
. . .
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.
. . .
12/22/2025 (SUPPL-33)
5 Warnings and Precautions
5.2 Life-Threatening Respiratory Depression
Additions and/or revisions underlined:
. . .
ULTIVA should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Resuscitative and intubation equipment, oxygen, and opioid overdose reversal agents (e.g., naloxone, nalmefene) must be readily available.
5.3 Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or Other CNS Depressants
Additions and/or revisions underlined:
. . .
Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin and pregabalin], and other opioids). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7)].
. . .
6 Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined:
. . .
Opioid-Induced Esophageal Dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term.
7 Drug Interactions
Additions and/or revisions underlined:
. . .
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.
. . .
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
. . .
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.
. . .
12/15/2023 (SUPPL-30)
5 Warnings and Precautions
5.1 Addiction, Abuse, and MisuseULTIVA contains remifentanil, a Schedule II controlled substance. As an opioid, ULTIVA exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.
Subsection title revised
Additions and revisions underlined:
When benzodiazepines or other CNS depressants are used with ULTIVA, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of ULTIVA are employed, even relatively small dosages of diazepam may cause cardiovascular depression.
When ULTIVA is used with CNS depressants,
hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider
repositioning the patient to improve venous return to the heart. Exercise care
in moving and repositioning of patients because of the possibility of
orthostatic hypotension. If volume expansion with fluids plus other
countermeasures do not correct hypotension, consider administration of pressor
agents other than epinephrine. Epinephrine may paradoxically decrease blood
pressure in patients treated with a neuroleptic that blocks alpha adrenergic
activity.
Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7)].
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].
If the decision is made to manage postoperative pain with ULTIVA concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response.
Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions (7)].
Newly added subsection:
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2), Warnings and Precautions (5.2)].
Additions and revisions underlined:
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal.
6 Adverse Reactions
Additions and revisions underlined:
The following serious adverse reactions are described, or described in greater detail, in other sections:
Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
Interactions with Benzodiazepines or other CNS Depressants [see Warnings and Precautions (5.3)]
Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.4)]
Newly added information:
Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.4)].
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).
8 Use in Specific Populations
8.1 PregnancyRisk Summary
Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.
Newly added information:
Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of ULTIVA slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)]
. . .
This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONNewly added information:
Addiction, Abuse, and Misuse
Inform patients that the use of ULTIVA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)].
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ULTIVA or when the dosage is increased, and that it can occur even at recommended dosages.
Hyperalgesia and Allodynia
Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.4), Adverse Reactions (6)].
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.5), Drug Interactions (7)].
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].
10/07/2019 (SUPPL-20)
5 Warnings and Precautions
5.4 Serotonin Syndrome with Concomitant Use of Serotonergic DrugsAdditions and/or revisions underlined:
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ULTIVA with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
7 Drug Interactions
Table 18: Clinically Significant Drug Interactions with ULTIVA
Serotonergic Drugs
Additions and/or revisions underlined:
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
12/16/2016 (SUPPL-16)
Boxed Warning
(Newly added subsection)
WARNING: ADDICTION, ABUSE, AND MISUSEAddiction, Abuse, and Misuse
ULTIVA exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing ULTIVA.
5 Warnings and Precautions
5.1 Addiction, Abuse, and Misuse(Newly added subsection)
ULTIVA contains remifentanil, a Schedule II controlled substance. As an opioid, ULTIVA exposes users to the risks of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when handling ULTIVA. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
(Newly added subsection title)
(Newly added subsection)
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ULTIVA may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure in spontaneously breathing patients. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ULTIVA.
Opioids may also obscure the clinical course in a patient with a head injury.
(Newly added subsection)
The remifentanil in ULTIVA may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
(Newly added subsection)
The remifentanil in ULTIVA may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ULTIVA therapy.
(Newly added subsection title)
(Newly added subsection title; Additions and/or revisions are underlined)
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.
…Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ULTIVA, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially when initiating therapy with and following dosage increases of ULTIVA.
Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ULTIVA.
Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression.
Monitor such patients closely including vital signs, particularly when initiating and titrating ULTIVA and when ULTIVA is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of ULTIVA are essential.
(Newly added subsection)
Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol). Patients should be advised to avoid alcohol for 24 hours after surgery.
(Newly added subsection)
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ULTIVA with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ULTIVA if serotonin syndrome is suspected.
(Newly added subsection title)
(Newly added subsection title; Additions and/or revisions are underlined)
…Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications and can be treated by decreasing the rate or discontinuing the infusion of ULTIVA or by administering a neuromuscular blocking agent. The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status…
(Newly added subsection)
ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.
(Newly added subsection title)
(Newly added subsection title)