Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
Fentanyl Citrate Injection contains fentanyl, a Schedule
CII controlled substance. As an opioid, Fentanyl Citrate Injection exposes
users to the risks of addiction, abuse, and misuse [see Drug Abuse and
Opioids are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion. Consider these risks
when handling Fentanyl Citrate Injection. 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.
Life-Threatening Respiratory Depression
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. Adequate facilities should be
available for postoperative monitoring and ventilation of patients administered
anesthetic doses of Fentanyl Citrate Injection. 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 antagonists, depending on the patient's clinical status [see OVERDOSAGE].
Carbon dioxide (CO2) retention from opioidinduced respiratory depression can
exacerbate the sedating effects of opioids.
To reduce the risk of respiratory depression, proper
dosing and titration of Fentanyl Citrate Injection are essential [see DOSAGE
AND ADMINISTRATION]. As with other potent opioids, the respiratory
depressant effect of fentanyl may persist longer that the measured analgesic
effect. The total dose of all opioid agonists administered should be considered
by the practitioner before ordering opioid analgesics during recovery from
Certain forms of conduction anesthesia, such as spinal
anesthesia and some peridural anesthetics, can alter respiration by blocking
intercostal nerves. Through other mechanisms [see CLINICAL PHARMACOLOGY]
Fentanyl Citrate Injection can also alter respiration. Therefore, when Fentanyl
Citrate Injection is used to supplement these forms of anesthesia, the anesthetist
should be familiar with the physiological alterations involved, and be prepared
to manage them in the patients selected for these forms of anesthesia.
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 Fentanyl Citrate Injection. Elderly, cachectic, or
debilitated patients may have altered pharmacokinetics or altered clearance
compared to younger, healthier patients resulting in greater risk for
Monitor such patients closely including vital signs,
particularly when initiating and titrating Fentanyl Citrate Injection and when
Fentanyl Citrate Injection is given concomitantly with other drugs that depress
respiration. To reduce the risk of respiratory depression, proper dosing and
titration of Fentanyl Citrate Injection are essential [see DOSAGE AND
Risks Of Concomitant Use Or Discontinuation Of Cytochrome
P450 3A4 Inhibitors And Inducers
Concomitant use of Fentanyl Citrate Injection with a
CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal
agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may
increase plasma concentrations of fentanyl and prolong opioid adverse
reactions, which may exacerbate respiratory depression [see Life-Threatening Respiratory Depression], particularly when an inhibitor is added after a stable dose
of Fentanyl Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4
inducer, such as rifampin, carbamazepine, and phenytoin, in Fentanyl Citrate
Injection-treated patients may increase fentanyl plasma concentrations and
prolong opioid adverse reactions. When using Fentanyl Citrate Injection with
CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Fentanyl Citrate Injection-treated
patients, monitor patients closely at frequent intervals and consider dosage
reduction of Fentanyl Citrate Injection [see DOSAGE AND ADMINISTRATION, DRUG
Concomitant use of Fentanyl Citrate Injection with CYP3A4
inducers, or discontinuation of a CYP3A4 inhibitor, could result in lower than
expected fentanyl plasma concentrations and decrease efficacy. When using
Fentanyl Citrate Injection with CYP3A4 inducers or discontinuation of a CYP3A4
inhibitor, monitor patients closely at frequent intervals and consider
increasing the fentanyl dosage. [see DOSAGE AND ADMINISTRATION, DRUG
Risks From Concomitant Use With Benzodiazepines Or Other
Central Nervous System Depressants
When benzodiazepines or other CNS depressants are used
with Fentanyl Citrate Injection, 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 Fentanyl Citrate Injection are employed, even relatively small
dosages of diazepam may cause cardiovascular depression.
When Fentanyl Citrate Injection 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.
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of Fentanyl Citrate Injection with
benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics,
anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids, alcohol).
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. Follow 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].
Risks Of Muscle Rigidity And Skeletal Muscle Movement
Fentanyl Citrate Injection may cause muscle rigidity,
particularly involving the muscles of respiration. The incidence and severity
of muscle rigidity is dose related. These effects are related to the dose and speed
of injection. Skeletal muscle rigidity also has been reported to occur or recur
infrequently in the extended postoperative period usually following high dose
administration. In addition, skeletal muscle movements of various groups in the
extremities, neck, and external eye have been reported during induction of
anesthesia with Fentanyl Citrate Injection; these reported movements have, on
rare occasions, been strong enough to pose patient management problems.
These effects are related to the dose and speed of
injection and its incidence can be reduced by: 1) administration of up to 1/4
of the full paralyzing dose of a non-depolarizing neuromuscular blocking agent
just prior to administration of Fentanyl Citrate Injection; 2) administration
of a full paralyzing dose of a neuromuscular blocking agent following loss of
eyelash reflex when Fentanyl Citrate Injection is used in anesthetic doses
titrated by slow intravenous infusion; or, 3) simultaneous administration of Fentanyl
Citrate Injection and a full paralyzing dose of a neuromuscular blocking agent
when Fentanyl Citrate Injection is used in rapidly administered anesthetic
dosages. The neuromuscular blocking agent used should be compatible with the
patient's cardiovascular status.
Severe Cardiovascular Depression
Fentanyl Citrate Injection may cause severe bradycardia,
severe hypotension including orthostatic hypotension, and syncope. There is
increased risk in patients whose ability to maintain blood pressure has already
been compromised by a reduced blood volume or concurrent administration of
certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see
DRUG INTERACTIONS]. In patients with circulatory shock, Fentanyl Citrate
Injection may cause vasodilation that can further reduce cardiac output and
blood pressure. Monitor these patients for signs of hypotension after
initiating or titrating the dosage of Fentanyl Citrate Injection.
Serotonin Syndrome With Concomitant Use Of Serotonergic
Cases of serotonin syndrome, a potentially
life-threatening condition, have been reported during concomitant use of
fentanyl 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) [see DRUG
INTERACTIONS]. 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 Fentanyl Citrate Injection if serotonin syndrome is suspected.
Cases of adrenal insufficiency have been reported with
opioid use, more often following greater than one month of use. Presentation of
adrenal insufficiency may include non-specific symptoms and signs including
nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
pressure. If adrenal insufficiency is suspected, confirm the diagnosis with
diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed,
treat with physiologic replacement doses of corticosteroids. Wean the patient off
of the opioid to allow adrenal function to recover and continue corticosteroid
treatment until adrenal function recovers. Other opioids may be tried as some
cases reported use of a different opioid without recurrence of adrenal
insufficiency. The information available does not identify any particular
opioids as being more likely to be associated with adrenal insufficiency.
Risks Of Use In Patients With Increased Intracranial
Pressure, Brain Tumors, Or Head Injury
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 for signs of increasing intracranial pressure.
Risks Of Use In Patients With Gastrointestinal Conditions
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.
Increased Risk Of Seizures In Patients With Seizure
Fentanyl 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
Fentanyl Citrate Injection therapy.
Risks Of Driving And Operating Machinery
Fentanyl may impair the mental or physical abilities
needed to perform potentially hazardous activities such as driving a car or
operating machinery. Warn patients not to drive or operate dangerous machinery after
Fentanyl Citrate Injection administration.
Risks Due To Interaction With Neuroleptic Agents
Many neuroleptic agents have been associated with QT
prolongation, torsades de pointes, and cardiac arrest. Administer neuroleptic
agents with extreme caution in the presence of risk factors for development of
prolonged QT syndrome and torsades de pointes, such as: 1) clinically
significant bradycardia (less than 50 bpm), 2) any clinically significant
cardiac disease, including baseline prolonged QT interval, 3) treatment with
Class 1 and Class III antiarrhythmics, 4) treatment with monoamine oxidase
inhibitors (MAOI's), 5) concomitant treatment with other drug products known to
prolong the QT interval and 6) electrolyte imbalance, in particular hypokalemia
and hypomagnesemia, or concomitant treatment with drugs (e.g. diuretics) that
may cause electrolyte imbalance.
Elevated blood pressure, with and without pre-existing
hypertension, has been reported following administration of Fentanyl Citrate
Injection combined with a neuroleptic. This might be due to unexplained
alterations in sympathetic activity following large doses; however, it is also
frequently attributed to anesthetic and surgical stimulation during light
ECG monitoring is indicated when a neuroleptic agent is
used in conjunction with Fentanyl Citrate Injection as an anesthetic
premedication, for the induction of anesthesia, or as an adjunct in the maintenance
of general or regional anesthesia.
When Fentanyl Citrate Injection is used with a
neuroleptic and an EEG is used for postoperative monitoring, the EEG pattern
may return to normal slowly.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies in animals to evaluate the carcinogenic
potential of Fentanyl Citrate Injection have not been conducted.
Studies in animals to evaluate the mutagenic potential of
fentanyl citrate injection have not been conducted.
Impairment Of Fertility
Decreased pregnancy rates occurred in a multigenerational
study in which pregnant rats were treated subcutaneously during the first 21
days of pregnancy with 160 mcg/kg to 1250 mcg/kg fentanyl (0.26 times to 2.0
times a human dose of 100 mcg/kg based on body surface area).
Studies in animals to characterize the effect of fentanyl
on male fertility have not been conducted.
Use In Specific Populations
Prolonged use of opioid analgesics during pregnancy may
cause neonatal opioid withdrawal syndrome. Available data with Fentanyl Citrate
Injection in pregnant women are insufficient to inform a drugassociated risk
for major birth defects and miscarriage.
In animal reproduction studies, fentanyl administration
to pregnant rats during organogenesis was embryocidal at doses within the range
of the human recommended dosing. No evidence of malformations was noted in
animal studies completed to date [see Data].The estimated background
risk of major birth defects and miscarriage for the indicated population is
unknown. All pregnancies have a background risk of birth defect, loss, or other
In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for
medical or nonmedical purposes can result in physical dependence in the neonate
and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as
irritability, hyperactivity and abnormal sleep pattern, high pitched cry,
tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and
severity of neonatal opioid withdrawal syndrome vary based on the specific
opioid used, duration of use, timing and amount of last maternal use, and rate
of elimination of the drug by the newborn. Observe newborns for symptoms of
neonatal opioid withdrawal syndrome and manage accordingly.
Labor Or Delivery
Opioids cross the placenta and may produce respiratory
depression and psycho-physiologic effects in neonates. An opioid antagonist,
such as naloxone, must be available for reversal of opioid-induced respiratory
depression in the neonate. Fentanyl Citrate Injection is not recommended for
use in pregnant women during or immediately prior to labor, when other
analgesic techniques are more appropriate. Opioid analgesics, including
Fentanyl Citrate Injection, can prolong labor through actions which temporarily
reduce the strength, duration, and frequency of uterine contractions. However,
this effect is not consistent and may be offset by an increased rate of
cervical dilation, which tends to shorten labor. Monitor neonates exposed to
opioid analgesics during labor for signs of excess sedation and respiratory depression.
Fentanyl has been shown to embryocidal in pregnant rats
at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on
a mg/m² basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100
mcg/kg on a mg/m² basis). There was no evidence of teratogenicity reported.
No evidence of malformations or adverse effects on the
fetus was reported in a published study in which pregnant rats were
administered fentanyl continuously via subcutaneously implanted osmotic
minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to
breeding and throughout pregnancy. The high dose was approximately 0.81 times
the human dose of 100 mcg/kg on a mg/m² basis.
Fentanyl is present in breast milk. However, there is
insufficient information to determine the effects of fentanyl on the breastfed
infant and the effects of fentanyl on milk production.
The developmental and health benefits of breastfeeding
should be considered along with the mother's clinical need for Fentanyl Citrate
Injection and any potential adverse effects on the breastfed infant from Fentanyl
Citrate Injection or from the underlying maternal condition.
Monitor infants exposed to Fentanyl Citrate Injection
through breast milk for excess sedation and respiratory depression. Withdrawal
symptoms can occur in breastfed infants when maternal administration of an
opioid analgesic is stopped, or when breast-feeding is stopped.
Females And Males Of Reproductive Potential
Chronic use of opioids 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, CLINICAL
PHARMACOLOGY, Nonclinical Toxicology].
The safety and efficacy of Fentanyl Citrate Injection in
children under two years of age has not been established.
Rare cases of unexplained clinically significant
methemoglobinemia have been reported in premature neonates undergoing emergency
anesthesia and surgery which included the combined use of fentanyl, pancuronium
and atropine. A direct cause and effect relationship between the combined use
of these drugs and the reported cases of methemoglobinemia has not been
Elderly patients (aged 65 years or older) may have
increased sensitivity to fentanyl. In general, use caution when selecting a
dosage for an elderly patient, usually starting at the low end of the dosing
range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function and of concomitant disease or other drug therapy.
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
coadministered with other agents that depress respiration. Titrate the dosage of
Fentanyl Citrate Injection slowly in geriatric patients and monitor closely for
signs of central nervous system and respiratory depression [see WARNINGS AND
Fentanyl 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.
Fentanyl Citrate Injection should be administered with
caution to patients with liver dysfunction because of the extensive hepatic
metabolism. Reduce the dosage as needed and monitor closely for signs of respiratory
depression, sedation, and hypotension.
Fentanyl Citrate Injection should be administered with
caution to patients with kidney dysfunction because of the renal excretion of
fentanyl and its metabolites. Reduce the dosage as needed and monitor for signs
of respiratory depression, sedation, and hypotension.