Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/499
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Sufentanil Citrate (Injection, Solution)
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The dosage of sufentanil should be individualized in each
case according to body weight, physical status, underlying pathological condition,
use of other drugs, and type of surgical procedure and anesthesia. In obese
patients (more than 20% above ideal total body weight), the dosage of sufentanil
citrate should be determined on the basis of lean body weight. Dosage should
be reduced in elderly and debilitated patients (see PRECAUTIONS). Vital
signs should be monitored routinely. Intravenous
Use Sufentanil Citrate may be administered
intravenously by slow injection or infusion 1) in doses of up to 8 mcg/kg
as an analgesic adjunct to general anesthesia, and 2) in doses���8
mcg/kg as a primary anesthetic agent for induction and maintenance of anesthesia
(see Dosage Range Chart). If benzodiazepines, barbiturates,
inhalation agents, other opioids or other central nervous system depressants
are used concomitantly, the dose of sufentanil and/or these agents should
be reduced (see PRECAUTIONS). In all cases dosage should be titrated to individual
patient response. Usage
In Children: For induction and maintenance of anesthesia in children
less than 12 years of age undergoing cardiovascular surgery, an anesthetic
dose of 10-25 mcg/kg administered with 100% oxygen is generally recommended.
Supplemental dosages of up to 25-50 mcg are recommended for maintenance, based
on response to initial dose and as determined by changes in vital signs indicating
surgical stress or lightening of anesthesia. 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). In patients administered high doses of sufentanil citrate,
it is essential that qualified personnel and adequate facilities are available
for the management of postoperative respiratory depression. Also
see WARNINGS and PRECAUTIONS sections. For purposes
of administering small volumes of sufentanil citrate injection accurately,
the use of a tuberculin syringe or equivalent is recommended. Epidural Use in Labor and Delivery Proper
placement of the needle or catheter in the epidural space should be verified
before sufentanil is injected to assure that unintentional intravascular or
intrathecal administration does not occur. Unintentional intravascular injection
of sufentanil could result in a potentially serious overdose, including acute
truncal muscular rigidity and apnea. Unintentional intrathecal injection of
the full sufentanil, bupivacaine epidural doses and volume could produce effects
of high spinal anesthesia including prolonged paralysis and delayed recovery.
If analgesia is inadequate, the placement and integrity of the catheter should
be verified prior to the administration of any additional epidural medications.
Sufentanil should be administered by slow injection. Respiration should be
closely monitored following each administration of an epidural injection of
sufentanil. Dosage for Labor and Delivery: The recommended
dosage is sufentanil 10-15 mcg administered with 10 mL bupivacaine 0.125%
with or without epinephrine. Sufentanil and bupivacaine should be mixed together
before administration. Doses can be repeated twice (for a total of three doses)
at not less than one-hour intervals until delivery. Parenteral
drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
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Sufentanil Citrate Injection, USP is a sterile, nonpyrogenic
solution of sufentanil citrate in water for injection. Sufentanil Citrate
is a potent opioid analgesic which is administered either epidurally or by
intravenous injection. Each mL contains sufentanil
citrate equivalent to 50 mcg of sufentanil. May contain sodium hydroxide and/or
hydrochloric acid for pH adjustment. pH 4.2 (3.5 to 6.0). The
solution contains no bacteriostat, antimicrobial agent or added buffer and
is intended for use only as a single-use injection. When smaller doses are
required, the unused portion should be discarded in an appropriate manner. Sufentanil
Citrate, USP, occurs as a white crystalline powder and is chemically designated
as N-[-4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide 2-hydroxy-1,2,3-propanetricarboxylate
(1:1). The molecular formula of sufentanil citrate is
CHNOS���CHOand
the molecular weight is 578.69. Sufentanil Citrate has the following structural
formula:
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Pharmacology Sufentanil
citrate is an opioid analgesic. When used in balanced general anesthesia sufentanil
has been reported to be as much as 10 times as potent as fentanyl. When administered
intravenously as a primary anesthetic agent with 100% oxygen, sufentanil is
approximately 5 to 7 times as potent as fentanyl. Assays
of histamine in patients administered sufentanil have shown no elevation in
plasma histamine levels and no indication of histamine release. (See
dosage chart for more complete information on the intravenous use of sufentanil.) Pharmacodynamics Intravenous Use At intravenous
doses of up to 8 mcg/kg, sufentanil is an analgesic component of general anesthesia;
at intravenous doses���8 mcg/kg, sufentanil produces a deep level of
anesthesia. Sufentanil produces a dose related attenuation of catecholamine
release, particularly norepinephrine. At intravenous
dosages of���8 mcg/kg, sufentanil produces hypnosis and anesthesia without
the use of additional anesthetic agents. A deep level of anesthesia is maintained
at these dosages, as demonstrated by EEG patterns. Dosages of up to 25 mcg/kg
attenuate the sympathetic response to surgical stress. The catecholamine response,
particularly norepinephrine, is further attenuated at doses of sufentanil
of 25-30 mcg/kg with hemodynamic stability and preservation of favorable myocardial
oxygen balance. Sufentanil has an immediate onset of
action, with relatively limited accumulation. Rapid elimination from tissue
storage sites allows for relatively more rapid recovery as compared with equipotent
dosages of fentanyl. At dosages of 1-2 mcg/kg, recovery times are comparable
to those observed with fentanyl; at dosages of>2-6 mcg/kg, recovery times
are comparable to enflurane, isoflurane and fentanyl. Within the anesthetic
dosage range of 8-30 mcg/kg of sufentanil, recovery times are more rapid compared
to equipotent fentanyl dosages. The vagolytic effects
of pancuronium may produce a dose dependent elevation in heart rate during
sufentanil-oxygen anesthesia. The use of moderate doses of pancuronium or
of a less vagolytic neuromuscular blocking agent may be used to maintain a
stable lower heart rate and blood pressure during sufentanil-oxygen anesthesia.
The vagolytic effects of pancuronium may be reduced in patients administered
nitrous oxide with sufentanil. Preliminary data suggest
that in patients administered high doses of sufentanil, initial dosage requirements
for neuromuscular blocking agents are generally lower as compared to patients
given fentanyl or halothane, and comparable to patients given enflurane. Bradycardia
is infrequently seen in patients administered sufentanil-oxygen anesthesia.
The use of nitrous oxide with high doses of sufentanil may decrease mean arterial
pressure, heart rate and cardiac output. Sufentanil
at 20 mcg/kg has been shown to provide more adequate reduction in intracranial
volume than equivalent doses of fentanyl, based upon requirements for furosemide
and anesthesia supplementation in one study of patients undergoing craniotomy.
During carotid endarterectomy, sufentanil-nitrous oxide/oxygen produced reductionsin cerebral blood flow comparable to those of enflurane-nitrous oxide/oxygen.
During cardiovascular surgery, sufentanil-oxygen produced EEG patterns similar
to fentanyl-oxygen; these EEG changes were judged to be compatible with adequate
general anesthesia. The intraoperative use of sufentanil
at anesthetic dosages maintains cardiac output, with a slight reduction in
systemic vascular resistance during the initial postoperative period. The
incidence of postoperative hypertension, need for vasoactive agents and requirements
for postoperative analgesics are generally reduced in patients administered
moderate or high doses of sufentanil as compared to patients given inhalation
agents. Skeletal muscle rigidity is related to the dose
and speed of administration of sufentanil. This muscular rigidity may occur
unless preventative measures are taken (see WARNINGS). Decreased
respiratory drive and increased airway resistance occur with sufentanil. The
duration and degree of respiratory depression are dose related when sufentanil
is used at sub-anesthetic dosages. At high doses, a pronounced decrease in
pulmonary exchange and apnea may be produced. Epidural Use in Labor and Delivery Onset
of analgesic effect occurs within approximately 10 minutes of administration
of epidural doses of sufentanil and bupivacaine. Duration of analgesia following
a single epidural injection of 10-15 mcg sufentanil and bupivacaine 0.125%
averaged 1.7 hours. During labor and vaginal delivery,
the addition of 10-15 mcg sufentanil to 10 mL 0.125% bupivacaine provides
an increase in the duration of analgesia compared to bupivacaine without an
opioid. Analgesia from 15 mcg sufentanil plus 10 mL 0.125% bupivacaine is
comparable to analgesia from 10 mL of 0.25% bupivacaine alone. Apgar scores
of neonates following epidural administration of both drugs to women in labor
were comparable to neonates whose mothers received bupivacaine without an
opioid epidurally. Pharmacokinetics Intravenous
Use The pharmacokinetics of intravenous sufentanil
can be described as a three-compartment model, with a distribution time of
1.4 minutes, redistribution of 17.1 minutes and an elimination half-life of
164 minutes. The liver and small intestine are the major sites of biotransformation.
Approximately 80% of the administered dose is excreted within 24 hours and
only 2% of the dose is eliminated as unchanged drug. Plasma protein binding
of sufentanil, related to the alphaacid glycoprotein concentration,
was approximately 93% in healthy males, 91% in mothers and 79% in neonates. Epidural Use in Labor and Delivery After
epidural administration of incremental doses totaling 5-40 mcg sufentanil
during labor and delivery, maternal and neonatal sufentanil plasma concentrations
were at or near the 0.05 to 0.1 ng/mL limit of detection, and were slightly
higher in mothers than in their infants.
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Sufentanil Citrate Injection is contraindicated in patients
with known hypersensitivity to the drug or known intolerance to other opioid
agonists.
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Sufentanil Citrate Injection, USP equivalent to 50 mcg/mL
sufentanil is supplied in the following single-use containers: 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.] December, 2004 HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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General:: The initial dose of sufentanil should be appropriately reduced
in elderly and debilitated patients. The effect of the initial dose should
be considered in determining supplemental doses. Vital
signs should be monitored routinely. Nitrous oxide may
produce cardiovascular depression when given with high doses of sufentanil
(see CLINICAL PHARMACOLOGY). Bradycardia has been reported
infrequently with sufentanil-oxygen anesthesia and has been responsive to
atropine. Respiratory depression caused by opioid analgesics
can be reversed by opioid antagonists such as naloxone. Because the duration
of respiratory depression produced by sufentanil 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 COstimulation
which may persist into or recur in the postoperative period. Respiratory depression
may be enhanced when sufentanil is administered in combination with volatile
inhalational agents and/or other central nervous system depressants such as
barbiturates, tranquilizers, and other opioids. Appropriate postoperative
monitoring should be employed to ensure that adequate spontaneous breathing
is established and maintained prior to discharging the patient from the recovery
area. Respiration should be closely monitored following each administration
of an epidural injection of sufentanil. Proper placement
of the needle or catheter in the epidural space should be verified before
sufentanil is injected to assure that unintentional intravascular or intrathecal
administration does not occur. Unintentional intravascular injection of sufentanil
could result in a potentially serious overdose, including acute truncal muscular
rigidity and apnea. Unintentional intrathecal injection of the full sufentanil/bupivacaine
epidural doses and volume could produce effects of high spinal anesthesia
including prolonged paralysis and delayed recovery. If analgesia is inadequate,
the placement and integrity of the catheter should be verified prior to the
administration of any additional epidural medications. Sufentanil should be
administered epidurally by slow injection.<br/>Neuromuscular Blocking Agents:: The hemodynamic effects and degree of skeletal muscle relaxation
required should be considered in the selection of a neuromuscular blocking
agent. High doses of pancuronium may produce increases in heart rate during
sufentanil-oxygen anesthesia. Bradycardia and hypotension have been reported
with other muscle relaxants during sufentanil-oxygen anesthesia; this effect
may be more pronounced in the presence of calcium channel and/or beta blockers.
Muscle relaxants with no clinically significant effect on heart rate (at recommended
doses) would not counteract the vagotonic effect of sufentanil, therefore
a lower heart rate would be expected. Rare reports of bradycardia associated
with the concomitant use of succinylcholine and sufentanil have been reported.<br/>Interaction With Calcium Channel and Beta Blockers:: The incidence and degree of bradycardia and hypotension
during induction with sufentanil may be greater in patients on chronic calcium
channel and beta blocker therapy. (See Neuromuscular Blocking Agents).<br/>Interaction With Other Central Nervous System Depressants:: Both the magnitude and duration of central nervous system
and cardiovascular effects may be enhanced when sufentanil is administered
to patients receiving barbiturates, tranquilizers, other opioids, general
anesthetics or other CNS depressants. In such cases of combined treatment,
the dose of sufentanil and/or these agents should be reduced. The
use of benzodiazepines with sufentanil during induction may result in a decrease
in mean arterial pressure and systemic vascular resistance. Head Injuries: Sufentanil
may obscure the clinical course of patients with head injuries. Impaired Respiration: Sufentanil 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, sufentanil
citrate should be administered with caution due to the importance of these
organs in the metabolism and excretion of sufentanil.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:: No long-term animal studies of sufentanil have been performed
to evaluate carcinogenic potential. The micronucleus test in female rats revealed
that single intravenous doses of sufentanil as high as 80 mcg/kg (approximately
2.5 times the upper human intravenous dose) produced no structural chromosome
mutations. The Ames Salmonella typhimurium metabolic
activating test also revealed no mutagenic activity. See Animal Toxicology
for reproduction studies in rats and rabbits.<br/>Pregnancy: Teratogenic Effects:: Pregnancy Category C: Sufentanil
has been shown to have an embryocidal effect in rats and rabbits when given
in doses 2.5 times the upper human intravenous dose for a period of 10 days
to over 30 days. These effects were most probably due to maternal toxicity
(decreased food consumption with increased mortality) following prolonged
administration of the drug. No evidence of teratogenic
effects have been observed after administration of sufentanil citrate in rats
or rabbits.<br/>Labor and Delivery:: The use of epidurally administered sufentanil in combination
with bupivacaine 0.125% with or without epinephrine is indicated for labor
and delivery. (See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections.)
Sufentanil is not recommended for intravenous use or for use of larger epidural
doses during labor and delivery because of potential risks to the newborn
infant after delivery. In clinical trials, one case of severe fetal bradycardia
associated with maternal hypotension was reported within 8 minutes of maternal
administration of sufentanil 15 mcg plus bupivacaine 0.125% (10 mL total volume).<br/>Nursing Mothers:: It is not known whether sufentanil is excreted in human milk.
Because fentanyl analogs are excreted in human milk, caution should be exercised
when sufentanil citrate is administered to a nursing woman.<br/>Pediatric Use:: The safety and efficacy of intravenous sufentanil citrate
in pediatric patients under two years of age undergoing cardiovascular surgery
has been documented in a limited number of cases.
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Overdosage is manifested by an extension of the pharmacological
actions of sufentanil (see CLINICAL PHARMACOLOGY) as with other potent opioid
analgesics. The most serious and significant effect of overdose for both intravenous
and epidural administration of sufentanil is respiratory depression. Intravenous
administration of an opioid antagonist such as naloxone should be employed
as a specific antidote to manage respiratory depression. The duration of respiratory
depression following overdosage with sufentanil may be longer than the duration
of action of the opioid antagonist. Administration of an opioid antagonist
should not preclude more immediate countermeasures. In the event of overdosage,
oxygen should be administered and ventilation assisted or controlled as indicated
for hypoventilation or apnea. A patent airway must be maintained, and a nasopharyngeal
airway or endotracheal tube may be indicated. If depressed respiration is
associated with muscular rigidity, a neuromuscular blocking agent may be required
to facilitate assisted or controlled respiration. Intravenous fluids and vasopressors
for the treatment of hypotension and other supportive measures may be employed.
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Sufentanil Citrate
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Sufentanil Citrate (Injection, Solution)
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The most common adverse reactions of opioids are respiratory
depression and skeletal muscle rigidity, particularly of the truncal muscles.
Sufentanil 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.
Urinary retention has been associated with the use of epidural opioids but
was not reported in the clinical trials of epidurally administered sufentanil
due to the use of indwelling catheters. The incidence of urinary retention
in patients without urinary catheters receiving epidural sufentanil is unknown;
return of normal bladder activity may be delayed. The
following adverse reaction information is derived from controlled clinical
trials in 320 patients who received intravenous sufentanil during surgical
anesthesia and in 340 patients who received epidural sufentanil plus bupivacaine
0.125% for analgesia during labor and is presented below. Based on the observed
frequency, none of the reactions occurring with an incidence less than 1%
were observed during clinical trials of epidural sufentanil used during labor
and delivery (N=340). In general cardiovascular and
musculoskeletal adverse experiences were not observed in clinical trials of
epidural sufentanil. Hypotension was observed 7 times more frequently in intravenous
trials than in epidural trials. The incidence of central nervous system, dermatological
and gastrointestinal adverse experiences was approximately 4 to 25 times higher
in studies of epidural use in labor and delivery. Probably Causally Related: Incidence Greater than 1%���Derived from clinical trials (See preceding paragraph) Cardiovascular:
bradycardia*, hypertension*, hypotension*. Musculoskeletal:
chest wall rigidity*. Central Nervous System: somnolence*. Dermatological:
pruritus (25%). Gastrointestinal: nausea*, vomiting*. *
Incidence 3% to 9%. Probably
Causally Related: Incidence Less than 1%���Derived from clinical trials (Adverse events reported in post-marketing surveillance, not seen
in clinical trials, are italicized.) Body as a Whole: anaphylaxis. Cardiovascular:
arrhythmia*, tachycardia*, cardiac arrest. Central
Nervous System: chills*. Dermatological: erythema*. Musculoskeletal: skeletal muscle rigidity of neck and
extremities. Respiratory: apnea*, bronchospasm*,
postoperative respiratory depression*. Miscellaneous:
intraoperative muscle movement*. *0.3% to 1%.
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SUFENTANIL CITRATE INJECTION SHOULD
BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS
AND EPIDURAL ANESTHETICS AND MANAGEMENT OF THE RESPIRATORY EFFECTS OF POTENT
OPIOIDS. AN OPIOID
ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY
AVAILABLE. PRIOR
TO CATHETER INSERTION, THE PHYSICIAN SHOULD BE FAMILIAR WITH PATIENT CONDITIONS
(SUCH AS INFECTION AT THE INJECTION SITE, BLEEDING DIATHESIS, ANTICOAGULANT
THERAPY, ETC.) WHICH CALL FOR SPECIAL EVALUATION OF THE BENEFIT VERSUS RISK
POTENTIAL. Intravenous
Use Intravenous administration or unintentional
intravascular injection during epidural administration of sufentanil citrate
may cause skeletal muscle rigidity, particularly of the truncal muscles. The
incidence and severity of muscle rigidity is dose related. Administration
of sufentanil citrate may produce muscular rigidity with a more rapid onset
of action than that seen with fentanyl. Sufentanil may produce muscular rigidity
that involves the skeletal muscles of the neck and extremities. As with fentanyl,
muscular rigidity has been reported to occur or recur infrequently in the
extended postoperative period. The incidence of muscular rigidity associated
with intravenous sufentanil 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 sufentanil citrate at dosages of up
to 8 mcg/kg, 2) administration of a full paralyzing dose of a neuromuscular
blocking agent following loss of consciousness when sufentanil is used in
anesthetic dosages (above 8 mcg/kg) titrated by slow intravenous infusion,
or, 3) simultaneous administration of sufentanil and a full paralyzing dose
of a neuromuscular blocking agent when sufentanil is used in rapidly administered
anesthetic dosages (above 8 mcg/kg). The neuromuscular
blocking agents used should be compatible with the patient's cardiovascular
status. Adequate facilities should be available for postoperative monitoring
and ventilation of patients administered sufentanil. It is essential that
these facilities be fully equipped to handle all degrees of respiratory depression.
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Sufentanil Citrate Injection, USP is indicated for intravenous
administration: As an analgesic adjunct in the maintenance
of balanced general anesthesia in patients who are intubated and ventilated. As
a primary anesthetic agent for the induction and maintenance of anesthesia
with 100% oxygen in patients undergoing major surgical procedures, in patients
who are intubated and ventilated, such as cardiovascular surgery or neurosurgical
procedures in the sitting position, to provide favorable myocardial and cerebral
oxygen balance or when extended postoperative ventilation is anticipated. Sufentanil
Citrate Injection, USP is indicated for epidural administration as an analgesic
combined with low dose bupivacaine, usually 12.5 mg per administration, during
labor and vaginal delivery. SEE
DOSAGE AND ADMINISTRATION SECTION FOR MORE COMPLETE INFORMATION ON THE USE
OF SUFENTANIL.
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Sufentanil Citrate
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