Fentanyl Citrate Injection, USP

Rx only

DESCRIPTION
Fentanyl Citrate Injection, USP is a potent o p i o i d ag o nis t . Each milliliter of solution contains fentanyl citrate
equivalent to 50 mcg of fentanyl base, adjusted to pH 4.0 to 7.5 with sodium hydroxide. Fentanyl citrate is
chemically identified as N-(1-phenethyl-4-piperidyl) propionanilide citrate (1:1) with a molecular weight of
528.60. The empirical formula is C22H28N2O • C6H8O7. The structural formula of fentanyl citrate is:

Fentanyl Citrate Injection, USP is a sterile, non-pyrogenic, preservative free aqueous solution for intravenous or
intramuscular injection.
CLINICAL PHARMACOLOGY
Fentanyl citrate is a potent opioid agonist. A dose of 100 mcg (0.1 mg) (2.0 mL) is approximately equivalent in
analgesic activity to 10 mg of morphine or 75 mg of meperidine. The principal actions of therapeutic value are
analgesia and sedation. Alterations in respiratory rate and alveolar ventilation, associated with opioid analgesics,
may last longer than the analgesic effect. As the dose of fentanyl is increased, the decrease in pulmonary exchange
becomes greater. Large doses may produce apnea. Fentanyl appears to have less emetic activity than either
morphine or meperidine. Histamine assays and skin wheal testing in man indicate that clinically significant
histamine release rarely occurs with fentanyl. Recent assays in man show no clinically significant histamine release
in dosages up to 50 mcg/kg (0.05 mg/kg) (1 mL/kg). Fentanyl preserves cardiac stability, and blunts stress-related
hormonal changes at higher doses.
The pharmacokinetics of fentanyl can be described as a three-compartment model, with a distribution time of 1.7
minutes, redistribution of 13 minutes and a terminal elimination half-life of 219 minutes. The volume of distribution
for fentanyl is 4 L/kg.
Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may
affect its distribution between plasma and the central nervous system. It accumulates in skeletal muscle and fat, and
is released slowly into the blood. Fentanyl, which is primarily transformed in the liver, demonstrates a high first pass
clearance and releases approximately 75% of an intravenous dose in urine, mostly as metabolites with less than 10%
representing the unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.
The onset of action of fentanyl is almost immediate when the drug is given intravenously; however, the maximal
analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the
analgesic effect is 30 to 60 minutes after a single intravenous dose of up to 100 mcg (0.1 mg) (2.0 mL). Following
intramuscular administration, the onset of action is from seven to eight minutes, and the duration of action is one to
two hours. As with longer acting opioid analgesics, the duration of the respiratory depressant effect of fentanyl may
be longer than the analgesic effect. The following observations have been reported concerning altered respiratory
response to CO2 stimulation following administration of fentanyl citrate to man.

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 1. DIMINISHED SENSITIVITY TO CO2 STIMULATION MAY PERSIST LONGER THAN DEPRESSION OF
RESPIRATORY RATE. (Altered sensitivity to CO2 stimulation has been demonstrated for up to four hours
following a single dose of 600 mcg (0.6 mg) (12 mL) fentanyl to healthy volunteers.) Fentanyl frequently slows the
respiratory rate, duration and degree of respiratory depression being dose related.
2. The peak respiratory depressant effect of a single intravenous dose of fentanyl citrate is noted 5 to 15 minutes
following injection. See also WARNINGS and PRECAUTIONS concerning respiratory depression.

INDICATIONS AND USAGE

Fentanyl Citrate Injection, USP is indicated:
- for analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance,
and in the immediate postoperative period (recovery room) as the need arises.
- for use as a opioid analgesic supplement in general or regional anesthesia.
- for administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia and as an
adjunct in the maintenance of general and regional anesthesia.
- for use as an anesthetic agent with oxygen in selected high risk patients, such as those undergoing open heart
surgery or certain complicated neurological or orthopedic procedures.
CONTRAINDICATIONS
Fentanyl Citrate Injection, USP is contraindicated in patients with known intolerance to the drug or other opioid
agonists.
WARNINGS
FENTANYL CITRATE SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN
THE USE OF INTRAVENOUS ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF
POTENT OPIOIDS.
AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD
BE READILY AVAILABLE.
See also discussion of opioid antagonists in PRECAUTIONS and OVERDOSAGE.
If fentanyl is administered with a tranquilizer, the user should become familiar with the special properties of each
drug, particularly the widely differing duration of action. In addition, when such a combination is used, fluids and
other countermeasures to manage hypotension should be available.
As with other potent opioids, the respiratory depressant effect of fentanyl may persist longer than the measured
analgesic effect. The total dose of all opioid agonists administered should be considered by the practitioner before
ordering opioids analgesics during recovery from anesthesia. It is recommended that opioids, when required, should
be used in reduced doses initially, as low as 1/4 to 1/3 those usually recommended.
Fentanyl may cause muscle rigidity, particularly involving the muscles of respiration. This rigidity 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; these reported movements have, on rare occasions, been strong enough
to pose patient management problems. This effect is 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; 2) administration of a full paralyzing dose of a
neuromuscular blocking agent following loss of eyelash reflex when fentanyl is used in anesthetic doses titrated by
slow intravenous infusion; or, 3) simultaneous administration of fentanyl citrate and a full paralyzing dose of a
neuromuscular blocking agent when fentanyl citrate is used in rapidly administered anesthetic dosages. The
neuromuscular blocking agent used should be compatible with the patient’s cardiovascular status.
Adequate facilities should be available for postoperative monitoring and ventilation of patients administered
anesthetic doses of fentanyl. Where moderate or high doses are used (above 10 mcg/kg), there must be adequate
facilities for postoperative observation, and ventilation if necessary, of patients who have received fentanyl. It is
essential that these facilities be fully equipped to handle all degrees of respiratory depression.

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 Fentanyl may also produce other signs and symptoms characteristic of opioid agonists including euphoria, miosis,
bradycardia and bronchoconstriction.
Severe and unpredictable potentiation by MAO inhibitors has been reported for other opioid agonists. Although this
has not been reported for fentanyl, there are insufficient data to establish that this does not occur with fentanyl.
Therefore, when fentanyl is administered to patients who have received MAO inhibitors within 14 days, appropriate
monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is indicated.
Head Injuries and Increased Intracranial Pressure — Fentanyl should be used with caution in patients who may
be particularly susceptible to respiratory depression, such as comatose patients who may have a head injury or brain
tumor. In addition, fentanyl may obscure the clinical course of patients with head injury.
PRECAUTIONS
General: The initial dose of fentanyl citrate should be appropriately reduced in elderly and debilitated patients. The
effect of the initial dose should be considered in determining incremental doses.
Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of fentanyl.
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 can also alter respiration. Therefore, when fentanyl 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.
When a tranquilizer is used with fentanyl, 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 are employed, even relatively small dosages of diazepam may cause cardiovascular depression.
When fentanyl is used with a tranquilizer, hypotension can occur. If it occurs, the possibility of hypovolemia should
also be considered and managed with appropriate parenteral fluid therapy. Repositioning the patient to improve
venous return to the heart should be considered when operative conditions permit. Care should be exercised 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, the administration of pressor agents other than
epinephrine should be considered. Epinephrine may paradoxically decrease blood pressure in patients treated with a
neuroleptic that blocks alpha adrenergic activity.
Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of
fentanyl 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 anesthesia.
When fentanyl is used with a neuroleptic and the EEG is used for postoperative monitoring, it may be found that the
EEG pattern returns to normal slowly.
Many neuroleptic agents have been associated with QT prolongation, torsades de pointes, and cardiac arrest.
Neuroleptic agents should be administered 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 I 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.
ECG monitoring is indicated when a neuroleptic agent is used in conjunction with fentanyl as an anesthetic
premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.
Vital signs should be monitored routinely.
Respiratory depression caused by opioids can be reversed by opioid antagonists such as naloxone. Because the
duration of respiratory depression produced by fentanyl may last longer than the duration of the opioid antagonist
action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied
by respiratory depression and diminished sensitivity to CO2 stimulation which may persist into or recur in the
postoperative period. Respiratory depression secondary to chest wall rigidity has been reported in the postoperative

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 period. Intraoperative hyperventilation may further alter postoperative response to CO2. Appropriate postoperative
monitoring should be employed to ensure that adequate spontaneous breathing is established and maintained in the
absence of stimulation prior to discharging the patient from the recovery area.
Impaired Respiration: Fentanyl should be used with caution in patients with chronic obstructive pulmonary
disease, patients with decreased respiratory reserve, and others with potentially compromised respiration. In such
patients, opioids may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this
can be managed by assisted or controlled respiration.
Impaired Hepatic or Renal Function: Fentanyl citrate should be administered with caution to patients with liver
and kidney dysfunction because of the importance of these organs in the metabolism and excretion of drugs.
Cardiovascular Effects: Fentanyl may produce bradycardia, which may be treated with atropine. Fentanyl should
be used with caution in patients with cardiac bradyarrhythmias.
Drug Interactions: Other CNS depressant drugs (e.g. barbiturates, tranquilizers, opioids and general anesthetics)
will have additive or potentiating effects with fentanyl. When patients have received such drugs, the dose of fentanyl
required will be less than usual. Following the administration of fentanyl citrate, the dose of other CNS depressant
drugs should be reduced.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity or mutagenicity studies have been
conducted with fentanyl citrate. Reproduction studies in rats revealed a significant decrease in the pregnancy rate of
all experimental groups. This decrease was most pronounced in the high dose group (1.25 mg/kg — 12.5X human
dose) in which one of twenty animals became pregnant.
Pregnancy — Category C: Fentanyl citrate has been shown to impair fertility and to have an embryocidal effect in
rats when given in doses 0.3 times the upper human dose for a period of 12 days. No evidence of teratogenic effects
have been observed after administration of fentanyl citrate to rats. There are no adequate and well-controlled studies
in pregnant women. Fentanyl should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Labor and Delivery: There are insufficient data to support the use of fentanyl in labor and delivery. Therefore, such
use is not recommended.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when fentanyl citrate is administered to a nursing woman.
Pediatric Use: The safety and efficacy of fentanyl citrate in children under two years of age have 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 established.
ADVERSE REACTIONS
As with opioid agonists, the most common serious adverse reactions reported to occur with fentanyl are respiratory
depression, apnea, rigidity, and bradycardia; if these remain untreated, respiratory arrest, circulatory depression or
cardiac arrest could occur. Other adverse reactions that have been reported are hypertension, hypotension, dizziness,
blurred vision, nausea, emesis, diaphoresis, pruritus, urticaria, laryngospasm and anaphylaxis.
It has been reported that secondary rebound respiratory depression may occasionally occur postoperatively. Patients
should be monitored for this possibility and appropriate countermeasures taken as necessary.
When a tranquilizer is used with fentanyl citrate, the following adverse reactions can occur: chills and/or shivering,
restlessness, and postoperative hallucinatory episodes (sometimes associated with transient periods of mental
depression); extrapyramidal symptoms (dystonia, akathisia, and oculogyric crisis) have been observed up to 24
hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with anti-parkinson
agents. Postoperative drowsiness is also frequently reported following the use of neuroleptics with fentanyl citrate.
Cases of cardiac dysrhythmias, cardiac arrest, and death have been reported following the use of fentanyl citrate
with a neuroleptic agent.

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 DRUG ABUSE AND DEPENDENCE
Fentanyl citrate injection is a Schedule II controlled drug substance that can produce drug dependence of the
morphine type and therefore has the potential for being abused.

OVERDOSAGE
Manifestations: The manifestations of fentanyl overdosage are an extension of its pharmacologic actions (see
CLINICAL PHARMACOLOGY) as with other opioids. The intravenous LD50 of fentanyl is 3 mg/kg in rats, 1
mg/kg in cats, 14 mg/kg in dogs and 0.03 mg/kg in monkeys.

Treatment: In the presence of hypoventilation or apnea, oxygen should be administered and respiration should be
assisted or controlled as indicated. A patent airway must be maintained; an oropharyngeal airway or endotracheal
tube might be indicated. If depressed respiration is associated with muscular rigidity, an intravenous neuromuscular
blocking agent might be required to facilitate assisted or controlled respiration. The patient should be carefully
observed for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is
severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral
fluid therapy. A specific opioid antagonist such as naloxone should be available for use as indicated to manage
respiratory depression. This does not preclude the use of more immediate countermeasures.
The duration of respiratory depression following overdosage of fentanyl may be longer than the duration of the
opioid antagonist action. Consult the package insert of the individual opioid antagonists for details about use.
DOSAGE AND ADMINISTRATION
50 mcg = 0.05 mg = 1 mL
Dosage should be individualized. Some of the factors to be considered in determining the dose are age, body weight,
physical status, underlying pathological condition, use of other drugs, type of anesthesia to be used and the surgical
procedure involved. Dosage should be reduced in elderly or debilitated patients (see PRECAUTIONS).
Vital signs should be monitored routinely.
I. Premedication — Premedication (to be appropriately modified in the elderly, debilitated and those who
have received other depressant drugs) — 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 mL) may be
administered intramuscularly 30 to 60 minutes prior to surgery.
II. Adjunct to General Anesthesia — See Dosage Range Chart
III. Adjunct to Regional Anesthesia - 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 mL) may be administered
intramuscularly or slowly intravenously, over one to two minutes, when additional analgesia is
required.
IV. Postoperatively (recovery room) - 50 to 100 mcg (0.05 to 0.1 mg) (1 to 2 mL) may be administered
intramuscularly for the control of pain, tachypnea and emergence delirium. The dose may be repeated
in one to two hours as needed.

Usage in Children: For induction and maintenance in children 2 to 12 years of age, a reduced dose as low as 2 to 3
mcg/kg is recommended.

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 DOSAGE RANGE CHART
TOTAL DOSAGE
Low Dose — 2 mcg/kg Moderate Dose — 2 to 20 High Dose — 20 to 50 stress response as defined
(0.002 mg/kg) (0.04 mL/kg) mcg/kg (0.002 to 0.02 mg/kg) mcg/kg (0.02 to 0.05 mg/kg) by increased levels of
fentanyl. Fentanyl in small (0.04 to 0.4 mL/kg). Where (0.4 to 1 mL/kg). During open circulating growth
doses is most useful for surgery becomes more heart surgery and certain more hormone, catecholamine,
minor, but painful, surgical major, a larger dose is complicated neurosurgical and ADH and prolactin. When
procedures. In addition to required. With this dose, orthopedic procedures where dosages in this range have
the analgesia during in addition to adequate surgery is more prolonged, and been used during surgery,
surgery, fentanyl may also analgesia, one would expect in the opinion of the postoperative ventilation
provide some pain relief in to see some abolition of the anesthesiologist, the stress and observation are
the immediate postoperative stress response. However, response to surgery would essential due to extended
period. respiratory depression will be detrimental to the well postoperative respiratory
be such that artificial being of the patient, dosages depression. The main
ventilation during anesthesia of 20 to 50 mcg/kg (0.02 to objective of this technique
is necessary and careful 0.05 mg) (0.4 to 1 mL) of would be to produce
observation of ventilation fentanyl with nitrous “stress free” anesthesia.
postoperatively is essential oxide/oxygen have been
shown to attenuate the

DOSAGE RANGE CHART

MAINTENANCE DOSAGE
Low Dose — 2 mcg/kg (0.002 mg/kg) Moderate Dose — 2 to 20 mcg/kg High Dose — 20 to 50 mcg/kg
(0.04 mL/kg). (0.002 to 0.02 mg/kg) (0.04 to 0.4 mL/kg). (0.02 to 0.05 mcg/kg) (0.4 to 1.0 mL/kg).
Additional dosages of fentanyl are 25 to 100 mcg (0.025 to 0.1 mg) (0.5 to Maintenance dosage (ranging from 25
infrequently needed in these minor 2.0 mL) may be administered intravenously mcg (0.025 mg) (0.5 mL) to one half the
procedures. or intramuscularly when movement and/or initial loading dose) will be dictated by
changes in vital signs indicate surgical the changes in vital signs which indicate
stress or lightening of analgesia. stress and lightening of analgesia.
However, the additional dosage selected
must be individualized especially if the
anticipated remaining operative time is
short.

As a General Anesthetic
When attenuation of the responses to surgical stress is especially important, doses of 50 to 100 mcg/kg (0.05 to 0.1
mg/kg) (1 to 2 mL/kg) may be administered with oxygen and a muscle relaxant. This technique has been reported to
provide anesthesia without the use of additional anesthetic agents. In certain cases, doses up to 150 mcg/kg (0.15
mg/kg) (3 mL/kg) may be necessary to produce this anesthetic effect. It has been used for open heart surgery and
certain other major surgical procedures in patients for whom protection of the myocardium from excess oxygen
demand is particularly indicated, and for certain complicated neurological and orthopedic procedures.
As noted above, it is essential that qualified personnel and adequate facilities be available for the management of
respiratory depression.
See WARNINGS and PRECAUTIONS for use of fentanyl with other CNS depressants, and in patients with altered
response.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit.
HOW SUPPLIED
Fentanyl Citrate Injection, USP 50 mcg/mL (equivalent to 50 mcg/mL Fentanyl base) is available as:
NDC 17478-030-02 2 mL ampules in packages of 10
NDC 17478-030-05 5 mL ampules in packages of 10
NDC 17478-030-10 10 mL ampules in packages of 5
NDC 17478-030-20 20 mL ampules in packages of 5
NDC 17478-030-25 2 mL ampules in packages of 25
NDC 17478-030-55 5 mL ampules in packages of 25

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 STORAGE: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. PROTECT FROM
LIGHT.

Manufactured by: Akorn, Inc.

Lake Forest, IL 60045

AFCA0N Rev. 11/12

Reference ID: 3336008