Approved Drug Label (PDF)
5
Warnings and Precautions
5.2
Life-Threatening Respiratory Depression
Additions and/or
revisions underlined:
. . .
It is essential that these facilities be fully
equipped to handle all degrees of respiratory depression. Management of
respiratory depression may include close observation, supportive measures, and
use of opioid overdose reversal agents (e.g., naloxone, nalmefene),
depending on the patient’s clinical status [see Overdosage (10)]. Carbon
dioxide (CO2) retention from opioid-induced respiratory depression
can exacerbate the sedating effects of opioids.
. . .
5.3 Risks from Concomitatnt
Use with Benzodiazepines or Other CNS Depressants
Additions and/or
revisions underlined:
.
. .
Profound sedation, respiratory depression,
coma, and death may result from the concomitant use of Fentanyl Citrate
Injection with benzodiazepines and/or other CNS depressants, including alcohol
(e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers,
muscle relaxants, general anesthetics, antipsychotics, gabapentinoids
[gabapentin or pregabalin], and other opioids).
.
. .
5.11 Risks of
Gastrointestinal Complications
Additions and/or
revisions underlined:
Fentanyl
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.
Cases of opioid-induced esophageal
dysfunction (OIED) have been reported in patients taking opioids. The risk of
OIED may increase as the dose and/or duration of opioids increases. Regularly
evaluate patients for signs and symptoms of OIED (e.g., dysphagia,
regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy
as clinically appropriate [see Clinical
Pharmacology (12.2)].
6
Adverse Reactions
Additions and/or
revisions underlined:
. . .
The following adverse reactions associated with the
use of fentanyl were identified in clinical studies or postmarketing reports.
Because some of these reactions were 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.
. . .
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 [see Warnings and
Precautions (5.11)].
7
Drug Interactions
Additions and/or
revisions underlined:
.
. .
Benzodiazepines
and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle
relaxants, general anesthetics, antipsychotics, gabapentinoids
(gabapentin
or pregabalin), other
opioids, alcohol.
.
. .
Muscle
Relaxants
.
. .
Examples: Cyclobenzaprine,
metaxalone
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or
revisions underlined:
.
. .
Labor or Delivery
There
are insufficient data to support the use of fentanyl in labor or delivery.
Therefore, such use is not recommended. 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
.
. .
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Addiction, Abuse, and Misuse
Additions and revisions underlined:
Opioids are sought
for nonmedical use
and are subject
to diversion from
legitimate prescribed use.
5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury
Additions and revisions underlined:
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), Fentanyl Citrate
Injection may reduce respiratory drive, and the resultant CO2 retention can further increase
intracranial pressure. Monitor such patients closely,
particularly when initiating and titrating
Fentanyl Citrate Injection and when Fentanyl Citrate Injection is given
concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2), Drug Interactions (7)].
Opioids may also obscure the clinical course in a patient with a head injury.
5.13 Risks of Driving and Operating Machinery
Additions and revisions underlined:
Fentanyl Citrate Injection may impair
the mental or physical abilities needed to perform potentially hazardous activities
such as driving a car or operating machinery after Fentanyl
Citrate Injection administration. Warn patients not to drive
or operate dangerous machinery unless they are tolerant to the effects
of Fentanyl Citrate Injection and know how they will react to the medication.
5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Additions and revisions underlined:
. . .
Profound
sedation, respiratory depression, coma, and death may result from the
concomitant use of Fentanyl Citrate
Injection
with benzodiazepines and/or other CNS depressants, including alcohol
(e.g., nonbenzodiazepine
sedatives/hypnotics,
anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids).
.
. .
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 Fentanyl
Citrate Injection 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)].
5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
Additions and revisions underlined:
Concomitant use of Fentanyl Citrate
Injection with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could
result in lower than expected fentanyl plasma concentrations, decreased
efficacy or, possibly, lead to a withdrawal syndrome in a patient who had
developed physical dependence to fentanyl.
5.7 Opioid-Induced Hyperalgesia and Allodynia
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
nonpainful 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)].
5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
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:
Androgen deficiency: Cases of androgen
deficiency have occurred
with use of opioids for an extended
period of time.
[see Clinical Pharmacology (12.2)].
Hyperalgesia and Allodynia: Cases
of hyperalgesia and allodynia have been reported
with opioid therapy
of any duration [see Warnings and Precautions (5.7)]
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).
7
Drug Interactions
Changes to tables; please refer to
label
8
Use in Specific Populations
8.1 Pregnancy
Additions and revisions underlined:
Risk Summary
Use of opioid analgesics
for an extended period of time during pregnancy may cause neonatal opioid
withdrawal syndrome. Available data with Fentanyl Citrate Injection in pregnant
women are insufficient to inform a drug-associated risk for major birth
defects and miscarriage or adverse maternal
outcomes. There are adverse outcomes
reported with fetal exposure to opioid analgesics (see Clinical Considerations).
. . .
Use of opioid analgesics for an extended
period of time during pregnancy for medical or nonmedical purposes
can result in physical
dependence in the neonate and neonatal opioid withdrawal syndrome shortly after
birth.
8.3 Females and Males of Reproductive Potential
Additions and revisions underlined:
Infertility
Use of opioids for an extended
period of time may cause reduced
fertility in females and males of reproductive potential. It is not known whether these effects on fertility
are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2), Nonclinical
Toxicology (13.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and revisions underlined:
Addiction, Abuse, and Misuse
Inform patients that the use of Fentanyl Citrate
Injection, 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 Fentanyl Citrate Injection
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 (5.7), 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 (5.8), 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)].
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