fentanyl citrate injection, solution Hospira, Inc.
FENTANYL CITRATE INJECTION,
Fentanyl citrate is a potent narcotic analgesic.
Each milliliter of solution contains fentanyl (as the citrate) 50
mcg (0.05 mg), 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 528.61. The structural formula of fentanyl citrate is:
Fentanyl citrate injection
is a sterile, nonpyrogenic, preservative free aqueous solution for
intravenous or intramuscular injection.
Fentanyl citrate is a narcotic analgesic. A dose
of 100 mcg (0.1 mg) (2 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 narcotic
analgesics, may last longer than the analgesic effect. As the dose
of narcotic 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 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 narcotic 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.
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.
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
INDICATIONS AND USAGE
Fentanyl citrate injection 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
for use as a narcotic analgesic supplement in general
or regional anesthesia.
for administration with a neuroleptic such as droperidol
injection 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.
Fentanyl citrate injection is contraindicated in
patients with known intolerance to the drug.
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.
discussion of narcotic antagonists in PRECAUTIONS and OVERDOSAGE.
If fentanyl is administered with a tranquilizer such as
droperidol, 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.
with other potent narcotics, the respiratory depressant effect of
fentanyl may persist longer than the measured analgesic effect. The
total dose of all narcotic analgesics administered should be considered
by the practitioner before ordering narcotic analgesics during recovery
from anesthesia. It is recommended that narcotics, when required,
should be used in reduced doses initially, as low as 1/4 to 1/3 those
Fentanyl may cause muscle
rigidity, particularly involving the muscles of respiration. 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 nondepolarizing 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
Fentanyl may also produce other
signs and symptoms characteristic of narcotic analgesics including
euphoria, miosis, bradycardia, and bronchoconstriction.
Severe and unpredictable potentiation by MAO inhibitors
has been reported for other narcotic analgesics. 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.
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 such as droperidol 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 such as droperidol, 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 positioning 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. Because
of the alpha-adrenergic blocking action of droperidol, epinephrine
may paradoxically decrease the blood pressure in patients treated
Elevated blood pressure, with
and without preexisting hypertension, has been reported following
administration of fentanyl citrate combined with droperidol. 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 droperidol is used with fentanyl and the EEG is used for postoperative
monitoring, it may be found that the EEG pattern returns to normal
Vital signs should be monitored routinely.
Respiratory depression caused by opioid analgesics 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. 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,
narcotics 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.
Other CNS depressant drugs (e.g., barbiturates, tranquilizers,
narcotics, 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
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 dosed group (1.25 mg/kg-12.5X
human dose) in which one of twenty animals became pregnant.
Pregnancy – Category
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
Labor and Delivery:
There are insufficient data to support the use of
fentanyl in labor and delivery. Therefore, such use is not recommended.
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
The safety and efficacy of fentanyl citrate 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 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.
As with other narcotic analgesics, 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, laryngospasm,
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
such as droperidol 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 antiparkinson agents. Postoperative drowsiness is also frequently
reported following the use of droperidol.
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.
Manifestations: The manifestations of fentanyl overdosage are an extension of its
pharmacologic actions (see CLINICAL PHARMACOLOGY) as with other opioid
analgesics. 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 narcotic 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 narcotic antagonist action. Consult the package
insert of the individual narcotic antagonists for details about use.
DOSAGE AND ADMINISTRATION
50 mcg = 0.05 mg = 1 mL
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.
Premedication (to be appropriately modified in the elderly, debilitated,
and those who have received other depressant drugs)—50 mcg
to 100 mcg (0.05 mg to 0.1 mg) (1 mL 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 mcg to 100 mcg (0.05 mg to 0.1 mg) (1 mL to 2 mL)
may be administered intramuscularly or slowly intravenously, over
one to two minutes, when additional analgesia is required.
room) — 50 mcg to 100 mcg (0.05 mg to 0.1 mg) (1
mL 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 mcg/kg
to 3 mcg/kg is recommended.
DOSAGE RANGE CHART
TOTAL DOSAGE (expressed as fentanyl base)
Low Dose -
High Dose -
2 mcg/kg (0.002 mg/kg) (0.04 mL/kg) Fentanyl,
in small doses is most useful for minor, but painful, surgical procedures.
In addition to the analgesia during surgery, Fentanyl may also provide
some pain relief in the immediate postoperative period.
2-20 mcg/kg (0.002-0.02 mg/kg) (0.04-0.4
mL/kg) Where surgery becomes more major, a larger dose is required.
With this dose, in addition to adequate analgesia, one would expect
to see some abolition of the stress response. However, respiratory
depression will be such that artificial ventilation during anesthesia
is necessary and careful observation of ventilation postoperatively
20-50 mcg/kg (0.02-0.05 mg/kg) (0.4-1
mL/kg) During open heart surgery and certain more complicated neurosurgical
and orthopedic procedures where surgery is more prolonged, and in
the opinion of the anesthesiologist, the stress response to surgery
would be detrimental to the well being of the patient, dosages of
20-50 mcg/kg (0.02-0.05 mg/kg) (0.4-1 mL/kg) of fentanyl with nitrous
oxide/oxygen have been shown to attenuate the stress response as defined
by increased levels of circulating growth hormone, catecholamine,
ADH, and prolactin. When dosages in this range have been used during
surgery, postoperative ventilation and observation are essential due
to extended postoperative respiratory depression. The main objective
of this technique would be to produce “stress-free”
DOSAGE RANGE CHART
MAINTENANCE DOSAGE (expressed as fentanyl base)
Low Dose -
High Dose -
2 mcg/kg (0.002 mg/kg) (0.04 mL/kg) Additional
dosages of fentanyl are infrequently needed in these minor procedures.
2-20 mcg/kg (0.002-0.02 mg/kg) (0.04-0.4
mL/kg) 25-100 mcg (0.025 to 0.1 mg) (0.5 to 2 mL) may be administered
intravenously or intramuscularly when movement and/or changes in vital
signs indicate surgical stress or lightening of analgesia.
20-50 mcg/kg (0.02-0.05 mg/kg) (0.4-1.0
mL/kg) Maintenance dosage (ranging from 25 mcg (0.025 mg) (0.5 mL)
to one half the initial loading dose) will be dictated by the changes
in vital signs which indicate 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 mcg/kg to 100 mcg/kg (0.05
mg/kg to 0.1 mg/kg) (1 mL/kg 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.
drug products should be inspected visually for particulate matter
and discoloration prior to administration, whenever solution and container
Fentanyl citrate injection, USP, equivalent to 50
mcg (0.05 mg) fentanyl per mL is supplied as:
mcg Fentanyl/total mL
Quantity per box
Carpuject® with Luer Lock
100 mcg/2 mL
Carpujects are packaged in the Slim-Pak® tamper detection package.
PROTECT FROM LIGHT.
Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room