alfentanil hydrochloride injection, solution HOSPIRA, INC.
ALFENTANIL INJECTION, USP
Alfentanil Injection, USP is an opioid analgesic chemically
designated as N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide
monohydrochloride (1:1) with a molecular weight of 452.98 and an n-octanol:water
partition coefficient of 128:1 at pH 7.4. The structural formula of Alfentanil
Alfentanil Injection, USP is a sterile,
non-pyrogenic, preservative free aqueous solution containing alfentanil hydrochloride
equivalent to 500 mcg per mL of alfentanil base for intravenous injection.
The solution, which contains sodium chloride for isotonicity, has a pH range
of 4.0 to 6.0.
Alfentanil is an opioid analgesic with a rapid onset of action.
doses of 8-40 mcg/kg for surgical procedures lasting up to 30 minutes, alfentanil
provides analgesic protection against hemodynamic responses to surgical stress
with recovery times generally comparable to those seen with equipotent fentanyl
For longer procedures, doses of up to 75 mcg/kg
attenuate hemodynamic responses to laryngoscopy, intubation and incision,
with recovery time comparable to fentanyl. At doses of 50-75 mcg/kg followed
by a continuous infusion of 0.5-3 mcg/kg/min, alfentanil attenuates the catecholamine
response with more rapid recovery and reduced need for postoperative analgesics
as compared to patients administered enflurane. At doses of 5 mcg/kg, alfentanil
provides analgesia for the conscious but sedated patient. Based on patient
response, doses higher than 5 mcg/kg may be needed. Elderly or debilitated
patients may require lower doses. High intrasubject and intersubject variability
in the pharmacokinetic disposition of alfentanil has been reported.
pharmacokinetics of alfentanil can be described as a three-compartment model
with sequential distribution half-lives of 1 and 14 minutes; and a terminal
elimination half-life of 90-111 minutes (as compared to a terminal elimination
half-life of approximately 475 minutes for fentanyl and approximately 265
minutes for sufentanil at doses of 250 mcg). The liver is the major site of
Alfentanil has an apparent volume
of distribution of 0.4-1 L/kg, which is approximately one-fourth to one-tenth
that of fentanyl, with an average plasma clearance of 5 mL/kg/min as compared
to approximately 8 mL/kg/min for fentanyl.
Only 1% of
the dose is excreted as unchanged drug; urinary excretion is the major route
of elimination of metabolites. Plasma protein binding of alfentanil is approximately
In one study involving 15 patients administered
alfentanil with nitrous oxide/oxygen, a narrow range of plasma alfentanil
concentrations, approximately 310-340 ng/mL, was shown to provide adequate
anesthesia for intra-abdominal surgery, while lower concentrations, approximately
190 ng/mL, blocked responses to skin closure. Plasma concentrations between
100-200 ng/mL provided adequate anesthesia for superficial surgery.
has an immediate onset of action. At dosages of approximately 105 mcg/kg,
alfentanil produces hypnosis as determined by EEG patterns; an anesthetic
ED90 of 182 mcg/kg for alfentanil in unpremedicated patients has
been determined, based upon the ability to block response to placement of
a nasopharyngeal airway. Based on clinical trials, induction dosage requirements
range from 130-245 mcg/kg. For procedures lasting 30-60 minutes, loading
dosages of up to 50 mcg/kg produce the hemodynamic response to endotracheal
intubation and skin incision as comparable to those from fentanyl. A pre-intubation
loading dose of 50-75 mcg/kg prior to a continuous infusion attenuates the
response to laryngoscopy, intubation and incision. Subsequent administration
of alfentanil infusion administered at a rate of 0.5-3 mcg/kg/min with nitrous
oxide/oxygen attenuates sympathetic responses to surgical stress with more
rapid recovery than enflurane.
Requirements for volatile
inhalation anesthetics were reduced by thirty to fifty percent during the
first 60 minutes of maintenance in patients administered anesthetic doses
(above 130 mcg/kg) of alfentanil as compared to patients given doses of 4-5
mg/kg thiopental for anesthetic induction. At anesthetic induction dosages,
alfentanil provides a deep level of anesthesia during the first hour of anesthetic
maintenance and provides attenuation of the hemodynamic response during intubation
Following an anesthetic induction dose
of alfentanil, requirements for alfentanil infusion are reduced by 30 to 50%
for the first hour of maintenance.
Patients with compromised
liver function and those over 65 years of age have been found to have reduced
plasma clearance and extended terminal elimination for alfentanil, which may
prolong postoperative recovery. Repeated or continuous administration of alfentanil
produces increasing plasma concentrations and an accumulation of the drug,
particularly in patients with reduced plasma clearance.
may be seen in patients administered alfentanil. The incidence and degree
of bradycardia may be more pronounced when alfentanil is administered in conjunction
with non-vagolytic neuromuscular blocking agents or in the absence of anticholinergic
agents such as atropine.
Administration of intravenous
diazepam immediately prior to or following high doses of alfentanil has been
shown to produce decreases in blood pressure that may be secondary to vasodilation;
recovery may also be prolonged.
doses up to 200 mcg/kg of alfentanil have shown no significant increase in
histamine levels and no clinical evidence of histamine release.
muscle rigidity is related to the dose and speed of administration of alfentanil.
Muscular rigidity will occur with an immediate onset following anesthetic
induction dosages. Preventative measures (see WARNINGS) may reduce the rate
The duration and degree of respiratory
depression and increased airway resistance usually increase with dose, but
have also been observed at lower doses. Although higher doses may produce
apnea and a longer duration of respiratory depression, apnea may also occur
at low doses.
During monitored anesthesia care (MAC),
attention must be given to the respiratory effects of alfentanil. Decreased
oxygen saturation, apnea, decreased respiratory rate, and upper airway obstruction
can occur. (See WARNINGS)
INDICATIONS AND USAGE
Alfentanil Injection is indicated:
an analgesic adjunct given in incremental doses in the maintenance of anesthesia
with barbiturate/nitrous oxide/oxygen.
as an analgesic
administered by continuous infusion with nitrous oxide/oxygen in the maintenance
of general anesthesia.
as a primary anesthetic agent
for the induction of anesthesia in patients undergoing general surgery in
which endotracheal intubation and mechanical ventilation are required.
the analgesic component for monitored anesthesia care (MAC).
DOSAGE CHART FOR MORE COMPLETE INFORMATION ON THE USE OF ALFENTANIL INJECTION.
Alfentanil is contraindicated in patients with known hypersensitivity
to the drug or known intolerance to other opioid agonists.
ALFENTANIL SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY
TRAINED IN THE USE OF INTRAVENOUS AND GENERAL ANESTHETIC AGENTS AND IN THE
MANAGEMENT OF RESPIRATORY EFFECTS OF POTENT OPIOIDS.
OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD
BE READILY AVAILABLE.
BECAUSE OF THE POSSIBILITY OF
DELAYED RESPIRATORY DEPRESSION, MONITORING OF THE PATIENT MUST CONTINUE WELL
Alfentanil administered in initial dosages
up to 20 mcg/kg may cause skeletal muscle rigidity, particularly of the truncal
muscles. The incidence and severity of muscle rigidity is usually dose-related.
Administration of alfentanil at anesthetic induction dosages (above 130 mcg/kg)
will consistently produce muscular rigidity with an immediate onset. The onset
of muscular rigidity occurs earlier than with other opioids. Alfentanil may
produce muscular rigidity that involves all skeletal muscles, including those
of the neck and extremities. The incidence may be reduced by: 1) routine
methods of administration of neuromuscular blocking agents for balanced opioid
anesthesia; 2) administration of up to 1/4 of the full paralyzing dose
of a neuromuscular blocking agent just prior to administration of alfentanil
at dosages up to 130 mcg/kg; following loss of consciousness, a full paralyzing
dose of a neuromuscular blocking agent should be administered; or 3) simultaneous
administration of alfentanil and a full paralyzing dose of a neuromuscular
blocking agent when alfentanil is used in rapidly administered anesthetic
dosages (above 130 mcg/kg).
The neuromuscular blocking
agent used should be appropriate for the patient’s cardiovascular status.
Adequate facilities should be available for postoperative monitoring and ventilation
of patients administered alfentanil. It is essential that these facilities
be fully equipped to handle all degrees of respiratory depression.
RECEIVING MONITORED ANESTHESIA CARE (MAC) SHOULD BE CONTINUOUSLY MONITORED
BY PERSONS NOT INVOLVED IN THE CONDUCT OF THE SURGICAL OR DIAGNOSTIC PROCEDURE;
OXYGEN SUPPLEMENTATION SHOULD BE IMMEDIATELY AVAILABLE AND PROVIDED WHERE
CLINICALLY INDICATED; OXYGEN SATURATION SHOULD BE CONTINUOUSLY MONITORED;
THE PATIENT SHOULD BE OBSERVED FOR EARLY SIGNS OF HYPOTENSION, APNEA, UPPER
AIRWAY OBSTRUCTION AND/OR OXYGEN DESATURATION.
and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been
reported for other opioid analgesics, and rarely with alfentanil. Thereforewhen alfentanil 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 recommended.
DELAYED RESPIRATORY DEPRESSION, RESPIRATORY ARREST, BRADYCARDIA,
ASYSTOLE, ARRHYTHMIAS AND HYPOTENSION HAVE ALSO BEEN REPORTED. THEREFORE,
VITAL SIGNS MUST BE MONITORED CONTINUOUSLY.
The initial dose of alfentanil should be appropriately reduced
in elderly and debilitated patients. The effect of the initial dose should
be considered in determining supplemental doses. In obese patients (more than
20% above ideal total body weight), the dosage of alfentanil should be determined
on the basis of lean body weight.
In one clinical trial,
the dose of alfentanil required to produce anesthesia, as determined by appearance
of delta waves in EEG, was 40% lower in geriatric patients than that needed
in healthy young patients.
In patients with compromised
liver function and in geriatric patients, the plasma clearance of alfentanil
may be reduced and postoperative recovery may be prolonged.
doses of alfentanil should be administered slowly (over three minutes). Administration
may produce loss of vascular tone and hypotension. Consideration should be
given to fluid replacement prior to induction.
administered immediately prior to or in conjunction with high doses of alfentanil
may produce vasodilation, hypotension and result in delayed recovery.
produced by alfentanil may be treated with atropine. Severe bradycardia and
asystole have been successfully treated with atropine and conventional resuscitative
The hemodynamic effects of a particular muscle
relaxant and the degree of skeletal muscle relaxation required should be considered
in the selection of a neuromuscular blocking agent.
an anesthetic induction dose of alfentanil, requirements for volatile inhalation
anesthetics or alfentanil infusion are reduced by 30 to 50% for the first
hour of maintenance.
Alfentanil infusions should be
discontinued at least 10-15 minutes prior to the end of surgery during general
anesthesia. During administration of alfentanil for Monitored Anesthesia Care
(MAC), infusions may be continued to the end of the procedure.
depression caused by opioid analgesics can be reversed by opioid antagonists
such as naloxone. Because the duration of respiratory depression produced
by alfentanil 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, particularly after infusions and large doses of alfentanil,
to ensure that adequate spontaneous breathing is established and maintained
in the absence of stimulation prior to discharging the patient from the recovery
Head Injuries: Alfentanil
should be used with caution in patients with head injury or increased intracranial
pressure, due to the increased risk of respiratory depression. As with all
opioids, alfentanil may obscure the clinical course of patients with head
injuries and should be used only if clinically indicated.
Impaired Respiration: Alfentanil should be used
with caution in patients with pulmonary disease, decreased respiratory reserve
or 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: In patients
with liver or kidney dysfunction, alfentanil should be administered with caution
due to the importance of these organs in the metabolism and excretion of alfentanil.
Both the magnitude and duration of central nervous system
and cardiovascular effects may be enhanced when alfentanil is administered
in combination with other CNS depressants such as barbiturates, tranquilizers,
opioids, or inhalation general anesthetics. Postoperative respiratory depression
may be enhanced or prolonged by these agents. In such cases of combined treatment,
the dose of one or both agents should be reduced. Limited clinical experience
indicates that requirements for volatile inhalation anesthetics are reduced
by 30 to 50% for the first sixty (60) minutes following alfentanil induction.
concomitant use of erythromycin with alfentanil can significantly inhibit
alfentanil clearance and may increase the risk of prolonged or delayed respiratory
Cimetidine reduces the clearance of alfentanil.
Therefore smaller alfentanil doses will be required with prolonged administration
and the duration of action of alfentanil may be extended.
administration of drugs affecting hepatic blood flow or enzyme function may
reduce plasma clearance and prolong recovery.
Carcinogenesis, Mutagenesis and Impairment of Fertility:
No long-term animal studies of alfentanil have been performed
to evaluate carcinogenic potential. No structural chromosome mutations were
produced in the in vivo micronucleus
test in female rats at single intravenous doses of alfentanil as high as 20
mg/kg body weight (approximately 40 times the upper human dose), equivalent
to a dose of 103 mg/m2 body surface area. No dominant lethal mutations
were produced in the in vivo dominant
lethal test in male and female mice at the maximum intravenous dose of 20 mg/kg
(60 mg/m2). No mutagenic activity was revealed in the in vitro Ames Salmonella
typhimurium test, with and without metabolic activation.
Pregnancy Category C:
Alfentanil has been shown to have an embryocidal effect in
rats and rabbits when given in doses 2.5 times the upper human dose for a
period of 10 days to over 30 days. These effects could have been due
to maternal toxicity (decreased food consumption with increased mortality)
following prolonged administration of the drug.
of teratogenic effects has been observed after administration of alfentanil
in rats or rabbits.
There are no adequate and well-controlled
studies in pregnant women. Alfentanil 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 alfentanil
in labor and delivery. Placental transfer of the drug has been reported; therefore,
use in labor and delivery is not recommended.
In one study of nine women undergoing postpartum tubal ligation,
significant levels of alfentanil were detected in colostrum four hours after
administration of 60 mcg/kg of alfentanil, with no detectable levels present
after 28 hours. Caution should be exercised when alfentanil is administered
to a nursing woman.
Adequate data to support the use of alfentanil in children
under 12 years of age are not presently available.
The most common adverse reactions of opioids are respiratory
depression and skeletal muscle rigidity, particularly of the truncal muscles.
Alfentanil may produce muscular rigidity that involves the skeletal muscles
of the neck and extremities. See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS
on the management of respiratory depression and skeletal muscle rigidity.
adverse experience profile from 696 patients receiving alfentanil for Monitored
Anesthesia Care (MAC) is similar to the profile established with alfentanil
during general anesthesia. Respiratory events reported during MAC included
hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving
alfentanil for MAC, in order of decreasing frequency, were nausea, hypotension,
vomiting, pruritus, confusion, somnolence and agitation.
following adverse reaction information is derived from controlled and open
clinical trials in 785 patients who received intravenous alfentanil during
induction and maintenance of general anesthesia. The controlled trials included
treatment comparisons with fentanyl, thiopental sodium, enflurane, saline
placebo and halothane. The incidence of certain side effects is influenced
by the type of use, e.g., chest wall rigidity has a higher reported incidencein clinical trials of alfentanil induction, and by the type of surgery, e.g.,
nausea and vomiting have a higher reported incidence in patients undergoing
gynecologic surgery. The overall reports of nausea and vomiting with alfentanil
were comparable to fentanyl.
Greater than 1% − Probably Causally Related (Derived from
Alfentanil is a Schedule II controlled drug substance that
can produce drug dependence of the morphine type and therefore has the potential
for being abused.
Opioid analgesics have been associated
with abuse and dependence in health care providers and others with ready access
to such drugs. Alfentanil should be handled accordingly.
Overdosage would be manifested by extension of the pharmacological
actions of alfentanil (see CLINICAL PHARMACOLOGY) as with other potent opioid
analgesics. No experience of overdosage with alfentanil was reported during
clinical trials. The intravenous LD50 of alfentanil is 43-51 mg/kg
in rats, 72-74 mg/kg in mice, 72-82 mg/kg in guinea pigs and 60-88 mg/kg in
dogs. Intravenous administration of an opioid antagonist such as naloxone
should be employed as a specific antidote to manage respiratory depression.
duration of respiratory depression following overdosage with alfentanil may
be longer than the duration of action of the opioid antagonist. Administration
of an opioid antagonist should not preclude immediate establishment of a patent
airway, administration of oxygen, and assisted or controlled ventilation as
indicated for hypoventilation or apnea. If respiratory depression is associated
with muscular rigidity, a neuromuscular blocking agent may be required to
facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive
agents may be required to manage hemodynamic instability.
DOSAGE AND ADMINISTRATION
The dosage of alfentanil injection should be individualized
and titrated to the desired effect in each patient according to body weight,
physical status, underlying pathological condition, use of other drugs, and
type and duration of surgical procedure and anesthesia. In obese patients
(more than 20% above ideal total body weight), the dosage of alfentanil injection
should be determined on the basis of lean body weight. The dose of alfentanil
injection should be reduced in elderly or debilitated patients (see PRECAUTIONS).
signs should be monitored routinely.
See Dosage Guidelines
for the use of alfentanil injection: 1) by incremental injection as an analgesic
adjunct to anesthesia with barbiturate/nitrous oxide/oxygen for short surgical
procedures (expected duration of less than one hour); 2) by continuous infusion
as a maintenance analgesic with nitrous oxide/oxygen for general surgical
procedures; and 3) by intravenous injection in anesthetic doses for the induction
of anesthesia for general surgical procedures with a minimum expected duration
of 45 minutes; and 4) by intravenous injection as the analgesic component
for monitored anesthesia care (MAC).
SHOULD BE INDIVIDUALIZED AND TITRATED
FOR USE DURING GENERAL ANESTHESIA
Induction of Analgesia: 8-20 mcg/kg
of Analgesia: 3-5 mcg/kg q 5-20 min or 0.5 to 1 mcg/kg/min
Total dose: 8-40 mcg/kg
ASSISTED OR CONTROLLED
laryngoscopy and intubation)
Induction of Analgesia: 20-50 mcg/kg
of Analgesia: 5-15 mcg/kg q 5-20 min
Total dose: Up to 75 mcg/kg
attenuation of response
intubation and incision)
Infusion rates are variable and should be titrated
to the desired clinical effect.
SEE INFUSION DOSAGE
of Analgesia: 50-75 mcg/kg
of Analgesia: 0.5 to 3 mcg/kg/min (Average rate 1 to 1.5 mcg/kg/min)
Total dose: Dependent on duration of procedure
Induction of Anesthesia: 130-245 mcg/kg
of Anesthesia: 0.5 to 1.5 mcg/kg/min or general anesthetic
Total dose: Dependent on duration of procedure
At these doses, truncal rigidity should be expected and
a muscle relaxant should be utilized.
Administer slowly (over 3 minutes).
of inhalation agents reduced by 30-50% for initial hour.
sedated and responsive,
Induction of MAC: 3-8
Maintenance of MAC: 3-5 mcg/kg q 5-20 min or 0.25 to 1 mcg/kg/min
Total dose: 3-40 mcg/kg
Infusion: 0.5-3 mcg/kg/min administered with nitrous oxide/oxygen
in patients undergoing general surgery. Following an anesthetic induction
dose of alfentanil injection, infusion rate requirements are reduced by 30-50%
for the first hour of maintenance.
Changes in vital
signs that indicate a response to surgical stress or lightening of anesthesia
may be controlled by increasing the alfentanil to a maximum of 4 mcg/kg/min
and/or administration of bolus doses of 7 mcg/kg. If changes are not controlled
after three bolus doses given over a five minute period, a barbiturate, vasodilator,
and/or inhalation agent should be used. Infusion rates should always be adjusted
downward in the absence of these signs until there is some response to surgical
Rather than an increase in infusion rate,
7 mcg/kg bolus doses of alfentanil injection or a potent inhalation agent
should be administered in response to signs of lightening of anesthesia within
the last 15 minutes of surgery. Alfentanil injection infusion should be discontinued
at least 10-15 minutes prior to the end of surgery.
Usage in Children: Clinical
data to support the use of alfentanil injection in patients under 12 years
of age are not presently available. Therefore, such use is not recommended.
Premedication: The selection of preanesthetic medications
should be based upon the needs of the individual patient.
Neuromuscular Blocking Agents: The neuromuscular
blocking agent selected should be compatible with the patient’s condition,
taking into account the hemodynamic effects of a particular muscle relaxant
and the degree of skeletal muscle relaxation required (see CLINICAL PHARMACOLOGY,
WARNINGS and PRECAUTIONS sections).
In patients administered
anesthetic (induction) dosages of alfentanil injection, it is essential that
qualified personnel and adequate facilities are available for the management
of intraoperative and postoperative respiratory depression.
see WARNINGS and PRECAUTIONS sections.
of administering small volumes of alfentanil injection accurately, the use
of a tuberculin syringe or equivalent is recommended.
physical and chemical compatibility of alfentanil injection have been demonstrated
in solution with normal saline, 5% dextrose in normal saline, 5% dextrose
in water and Lactated Ringers. Clinical studies of alfentanil injection infusion
have been conducted with alfentanil injection diluted to a concentration range
of 25 mcg/mL to 80 mcg/mL.
As an example of the preparation
of alfentanil injection for infusion, 20 mL of alfentanil injection added
to 230 mL of diluent provides 40 mcg/mL solution of alfentanil injection.
drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
SAFETY AND HANDLING
Injection, USP is supplied in individually sealed dosage forms which pose
no known risk to health care providers having incidental contact. Accidental
dermal exposure to alfentanil should be treated by rinsing the affected area
Protect from light. Retain in carton until time of use. Store at 20° to 25°C
(68 to 77°F). [See USP Controlled Room Temperature.]
Alfentanil Injection, USP for intravenous use contains alfentanil
hydrochloride equivalent to 500 mcg of alfentanil base and is available