Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Life-Threatening
Respiratory Depression
Additions and/or
revisions underlined:
… Management of
respiratory depression may include close observation, supportive measures, and use
of opioid overdose reversal agents (e.g., naloxone, nalmefene),
depending on the patient's clinical status [see Overdosage (10)]. Carbon
dioxide (CO2) retention from opioid-induced respiratory depression can
exacerbate the sedating effects of opioids.
…
![]()
5.3 Risks from
Concomitant Use with Benzodiazepines or Other CNS Depressants
Additions and/or
revisions underlined:
…
Profound sedation, respiratory depression, coma,
and death may result from concomitant use of Sufentanil Citrate Injection with
benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine
sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general
anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and
other opioids).
…
5.11 Risks of Gastrointestinal Complications
Additions and/or revisions underlined:
…
Cases
of opioid-induced esophageal dysfunction (OIED) have been reported in patients
taking opioids. The risk of OIED may increase as the dose and/or duration of
opioids increases. Regularly evaluate patients for signs and symptoms of OIED
(e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary,
adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].
6
Adverse Reactions
6.2 Postmarketing Experience
Additions
and/or revisions underlined:
…
Opioid-induced
esophageal dysfunction (OIED): Cases of OIED have been reported in
patients taking opioids and may occur more frequently in patients taking higher
doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.11)].
7
Drug Interactions
Additions
and/or revisions to Table 3, please refer to label for complete information.
8
Use in Specific Populations
8.1 Pregnancy
Additions
and/or revisions underlined:
…
Clinical
Considerations
…
Labor or Delivery
Opioids
cross the placenta and may produce respiratory depression and
psycho-physiologic effects in neonates. An opioid overdose reversal agent, such
as naloxone or nalmefene, must be available for reversal of
opioid-induced respiratory depression in the neonate.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Addiction, Abuse, and Misuse
Additions and revisions underlined:
Opioids are sought for
nonmedical use and
are subject to diversion from legitimate prescribed use.
5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury
Additions and revisions underlined:
In
patients who may be susceptible to the intracranial effects of CO2
retention (e.g., those with evidence of increased intracranial pressure or
brain tumors), Sufentanil Citrate Injection may reduce respiratory drive, and
the resultant CO2 retention can further increase intracranial
pressure. Monitor such patients for signs of sedation and respiratory
depression, particularly when initiating therapy with Sufentanil Citrate
Injection.
Opioids may also obscure
the clinical course in a patient with a head injury.
5.13 Risks of Driving and Operating Machinery
Additions and revisions underlined:
Sufentanil
Citrate Injection may impair the mental or physical abilities needed to perform
potentially hazardous activities such as driving a car or operating machinery.
Warn patients not to drive or operate dangerous machinery unless they are
tolerant to the effects of Sufentanil Citrate Injection and know how
they will react to the medication.
5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Additions and revisions underlined:
Profound
sedation, respiratory depression, coma, and death may result from the
concomitant use of Sufentanil Citrate Injection with benzodiazepines and/or
other CNS depressants including alcohol (e.g., nonbenzodiazepine
sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general
anesthetics, antipsychotics, other opioids).
Observational
studies have demonstrated that concomitant use of opioid analgesics and
benzodiazepines increases the risk of drug-related mortality compared to use of
opioid analgesics alone. Because of
similar pharmacological properties, it is reasonable to expect similar risk
with the concomitant use of other CNS depressant drugs with opioid analgesics [see
Drug Interactions (7)].
If
the decision is made to manage postoperative pain with Sufentanil Citrate
Injection concomitantly with a benzodiazepine or other CNS depressant, start
dosing with the lowest effective dosage and titrate based on clinical response.
Monitor patients closely for signs and symptoms of respiratory
depression, sedation, and hypotension. Fluids or other measures to counter
hypotension should be available. [see
Drug Interactions (7)]
5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
Additions and revisions underlined:
Concomitant
use of Sufentanil Citrate Injection with CYP3A4 inducers or discontinuation of
an CYP3A4 inhibitor could result in lower than expected sufentanil plasma
concentrations, decreased efficacy, or, possibly, lead to a withdrawal
syndrome in a patient who had developed physical dependence to sufentanil.
5.7 Opioid-Induced Hyperalgesia and Allodynia
Newly added subsection:
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid
analgesic paradoxically causes
an increase in pain, or
an increase in sensitivity to pain. This condition differs from tolerance,
which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH
include (but may not be limited to) increased levels of pain upon opioid dosage
increase, decreased levels of pain upon opioid dosage decrease, or pain from
ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only
if there is no evidence of underlying disease progression, opioid tolerance,
opioid withdrawal, or addictive behavior.
Cases of OIH have been reported,
both with short-term and longer-term use of opioid analgesics. Though the
mechanism of OIH is not fully understood, multiple biochemical pathways have
been implicated. Medical literature suggests a strong biologic plausibility
between opioid analgesics and OIH and allodynia. If a patient is suspected to
be experiencing OIH, carefully consider appropriately decreasing the dose of
the current opioid analgesic or opioid rotation (safely switching the patient
to a different opioid moiety) [see Dosage
and Administration (2), Warnings and Precautions (5.2)].
5.8 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
Additions and revisions underlined:
Serotonin syndrome symptoms may include mental status
changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations
(e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea) and can be fatal.
6
Adverse Reactions
Additions and revisions underlined:
The
following serious adverse reactions are described, or described in greater
detail, in other sections:
•
Addiction, Abuse, and Misuse [see
Warnings and Precautions (5.1)]
•
Life-Threatening Respiratory Depression [see
Warnings and Precautions (5.2)]
•
Skeletal Muscle Rigidity and Skeletal Muscle Movement [see Warnings and Precautions (5.5)]
•
Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)]
• Severe Cardiovascular Depression [see
Warnings and Precautions (5.6)]
• Opioid-Induced Hyperalgesia and Allodynia [see
Warnings and Precautions (5.7)]
•
Serotonin Syndrome [see Warnings and
Precautions (5.8)]
•
Gastrointestinal Adverse Reactions [see
Warnings and Precautions (5.11)]
•
Seizures [see Warnings and Precautions
(5.12)]
8
Use in Specific Populations
8.1 Pregnancy
Additions and revisions underlined:
Risk Summary
Use of opioid analgesics for an extended
period of time during pregnancy may cause neonatal
opioid withdrawal syndrome.
8.2 Lactation
Additions and revisions underlined:
Clinical Considerations
Monitor infants exposed to Sufentanil Citrate
Injection through breast milk for excess sedation and respiratory depression.
8.3 Females and Males of Reproductive Potential
Additions and revisions underlined:
Infertility
Use of opioids for an
extended period of time may cause reduced fertility in females and males of
reproductive potential.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Newly added subsection:
Addiction, Abuse, and Misuse
Inform patients that the use of
Sufentanil Citrate Injection, even when taken as recommended, can result in
addiction, abuse, and misuse, which can lead to overdose and death [see
Warnings and Precautions (5.1)].
Life-Threatening Respiratory
Depression
Inform patients of the risk of
life-threatening respiratory depression, including information that the risk is
greatest when starting Sufentanil Citrate Injection or when the dosage is
increased, and that it can occur even at recommended dosages.
Hyperalgesia and
Allodynia
Advise patients to inform their
healthcare provider if they experience symptoms of hyperalgesia, including
worsening pain, increased sensitivity to pain, or new pain [see Warnings and
Precautions (5.7), Adverse Reactions (6)].
Serotonin Syndrome
Inform patients that opioids
could cause a rare but potentially life-threatening condition called serotonin
syndrome resulting from concomitant administration of serotonergic drugs. Warn
patients of the symptoms of serotonin syndrome and to seek medical attention
right away if symptoms develop after discharge from the hospital. Instruct
patients to inform their healthcare provider if they are taking, or plan to
take serotonergic medications [see
Warnings and Precautions (5.8), Drug Interactions (7)].
Constipation
Advise patients of the potential
for severe constipation, including management instructions and when to seek
medical attention [see Adverse Reactions
(6), Clinical Pharmacology (12.2)].
Approved Drug Label (PDF)
Boxed Warning
Additions
and/or revisions to incorporate the opioid analgesic template language.
4
Contraindications
PLR conversion;
revised as below:
Sufentanil Citrate Injection is
contraindicated in patients with:
- Hypersensitivity to
sufentanil (e.g., anaphylaxis)
5
Warnings and Precautions
PLR conversion
throughout this section:
5.1 Addiction, Abuse, and Misuse
(Newly added information)
Sufentanil
Citrate Injection contains sufentanil, a Schedule II controlled substance. As
an opioid, Sufentanil Citrate Injection exposes users to the risks of
addiction, abuse, and misuse.
Opioids
are sought by drug abusers and people with addiction disorders and are subject
to criminal diversion. Consider these risks when handling Sufentanil Citrate
Injection. Strategies to reduce these risks include proper product storage and
control practices for a C-II drug. Contact local state professional licensing
board or state controlled substances authority for information on how to
prevent and detect abuse or diversion of this product.
5.10 Risks of Use in Patients with Gastrointestinal Conditions
(Newly added information)
Sufentanil
may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum
amylase. Monitor patients with biliary tract disease, including acute
pancreatitis for worsening symptoms.
5.11 Increased Risk of Seizures in Patients with Seizure Disorders
(Newly added information)
Sufentanil
may increase the frequency of seizures in patients with seizure disorders, and
may increase the risk of seizures occurring in other clinical settings associated
with seizures. Monitor patients with a history of seizure disorders for
worsened seizure control during Sufentanil Citrate Injection therapy.
5.12 Risks of Driving and Operating Machinery
(Newly added information)
Sufentanil
Citrate Injection may impair the mental or physical abilities needed to perform
potentially hazardous activities such as driving a car or operating machinery.
Warn patients not to drive or operate dangerous machinery after Sufentanil
Citrate Injection administration.
5.2 Life-Threatening Respiratory Depression
(Newly added information)
Serious,
life-threatening, or fatal respiratory depression has been reported with the
use of opioids, even when used as recommended. Respiratory depression, if not
immediately recognized and treated, may lead to respiratory arrest and death.
Sufentanil Citrate Injection should be administered only by persons
specifically trained in the use of anesthetic drugs and the management of the
respiratory effects of potent opioids, including respiration and cardiac
resuscitation of patients in the age group being treated. Such training must
include the establishment and maintenance of a patent airway and assisted
ventilation. Adequate facilities should be available for postoperative
monitoring … Management of respiratory depression may include close
observation, supportive measures, and use of opioid antagonists, depending on
the patient’s clinical status.. Carbon dioxide (CO2) retention from
opioid-induced respiratory depression can exacerbate the sedating effects of
opioids.
As
with other potent opioids, the respiratory depressant effect of Sufentanil
Citrate Injection may persist longer than the measured analgesic effect. The
total dose of all opioid agonists administered should be considered by the
practitioner before ordering opioid analgesics during recovery from anesthesia.
Certain
forms of conduction anesthesia, such as spinal anesthesia and some epidural
anesthetics …
Patients
with significant chronic obstructive pulmonary disease or cor pulmonale, and
those with a substantially decreased respiratory reserve, hypoxia, hypercapnia,
or pre-existing respiratory depression are at increased risk of decreased
respiratory drive including apnea, even at recommended dosages of Sufentanil
Citrate Injection. Elderly, cachectic,
or debilitated patients may have altered pharmacokinetics or altered clearance
compared to younger, healthier patients resulting in greater risk for
respiratory depression.
Monitor
such patients closely including vital signs, particularly when initiating and
titrating Sufentanil Citrate Injection and when Sufentanil Citrate Injection is
given concomitantly with other drugs that depress respiration. To reduce the
risk of respiratory depression, proper dosing and titration of Sufentanil Citrate
Injection are essential.
5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
(Newly added information)
Concomitant
use of Sufentanil Citrate Injection with a CYP3A4 inhibitor, such as macrolide
antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole),
and protease inhibitors (e.g., ritonavir), may increase plasma concentrations
of sufentanil and prolong opioid adverse reactions, which may exacerbate fatal
respiratory depression, particularly when an inhibitor is added after a stable
dose of Sufentanil Citrate Injection is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin,
carbamazepine, and phenytoin, in Sufentanil Citrate Injection-treated patients
may increase sufentanil plasma concentrations and prolong opioid adverse
reactions. When using Sufentanil Citrate Injection with CYP3A4 inhibitors or
discontinuing CYP3A4 inducers in Sufentanil Citrate Injection-treated patients,
monitor patients closely at frequent intervals and consider dosage reduction of
Sufentanil Citrate Injection.
Concomitant
use of Sufentanil Citrate Injection with CYP3A4 inducers or discontinuation of
an CYP3A4 inhibitor could result in lower than expected sufentanil plasma
concentrations, and decrease efficacy. When using Sufentanil Citrate Injection
with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients
closely at frequent intervals and consider increasing the Sufentanil Citrate
Injection dosage.
5.4 Risks of Muscle Rigidity and Skeletal Muscle Movement
(Newly added information)
Intravenous
administration or unintentional intravascular injection during epidural
administration of Sufentanil Citrate Injection may cause muscle rigidity,
particularly involving the muscles of respiration. The incidence and severity
of muscle rigidity is dose related. These effects are related to the dose and
speed of injection. Administration of sufentanil may produce muscular rigidity
with a more rapid onset of action than that seen with fentanyl. Skeletal muscle rigidity also has been
reported to occur or recur infrequently in the extended postoperative period
usually following high dose administration. In addition, skeletal muscle
movements of various groups in the extremities, neck, and external eye have
been reported during induction of anesthesia with Sufentanil Citrate Injection;
these reported movements have, on rare occasions, been strong enough to pose
patient management problems.
The
incidence of skeletal muscle rigidity 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 sufentanil 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. 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.
5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
(Newly added information)
When
benzodiazepines or other CNS depressants are used with Sufentanil Citrate
Injection, pulmonary arterial pressure may be decreased. This fact should be
considered by those who conduct diagnostic and surgical procedures where
interpretation of pulmonary arterial pressure measurements might determine
final management of the patient. When high dose or anesthetic dosages of
Sufentanil Citrate Injection are employed, even relatively small dosages of
diazepam may cause cardiovascular depression.
When
Sufentanil Citrate Injection is used with CNS depressants, hypotension can
occur. If it occurs, consider the possibility of hypovolemia and manage with
appropriate parenteral fluid therapy. When operative conditions permit,
consider repositioning the patient to improve venous return to the heart.
Exercise care in moving and repositioning of patients because of the
possibility of orthostatic hypotension. If volume expansion with fluids plus
other countermeasures do not correct hypotension, consider administration of
pressor agents other than epinephrine. Epinephrine may paradoxically decrease
blood pressure in patients treated with a neuroleptic that blocks alpha
adrenergic activity.
Profound
sedation, respiratory depression, coma, and death may result from the
concomitant use of Sufentanil Citrate Injection with benzodiazepines or other
CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics,
tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other
opioids, alcohol).
If
the decision is made to manage postoperative pain with Sufentanil Citrate
Injection concomitantly with a benzodiazepine or other CNS depressant, start
dosing with the lowest effective dosage and titrate based on clinical response.
Follow patients closely for signs and symptoms of respiratory depression,
sedation, and hypotension. Fluids or other measures to counter hypotension
should be available.
5.6 Severe Cardiovascular Depression
(Newly added information)
Sufentanil
Citrate Injection may cause severe bradycardia, severe hypotension including
orthostatic hypotension, and syncope. There is increased risk in patients whose
ability to maintain blood pressure has already been compromised by a reduced
blood volume or concurrent administration of certain CNS depressant drugs
(e.g., phenothiazines or general anesthetics).
In
patients with circulatory shock, Sufentanil Citrate Injection may cause
vasodilation that can further reduce cardiac output and blood pressure. Monitor
these patients for signs of hypotension after initiating or titrating the
dosage of Sufentanil Citrate Injection.
5.7 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
Cases
of serotonin syndrome, a potentially life-threatening condition, have been
reported during concomitant use of Sufentanil Citrate Injection with
serotonergic drugs. Serotonergic drugs include selective serotonin reuptake
inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs
that affect the serotonergic neurotransmitter system (e.g., mirtazapine,
trazodone, tramadol), and drugs that impair metabolism of serotonin (including
MAO inhibitors, both those intended to treat psychiatric disorders and also
others, such as linezolid and intravenous methylene blue). This may occur
within the recommended dosage range.
Serotonin
syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood
pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea,
vomiting, diarrhea). The onset of symptoms generally occurs within several
hours to a few days of concomitant use, but may occur later than that.
Discontinue Sufentanil Citrate Injection if serotonin syndrome is suspected.
5.8 Risks due to Improper Epidural Injection
(Newly added information)
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.
5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, or Head Injury
(Newly added information)
In
patients who may be susceptible to the intracranial effects of CO2 retention
(e.g., those with evidence of increased intracranial pressure or brain tumors),
Sufentanil Citrate Injection may reduce respiratory drive, and the resultant
CO2 retention can further increase intracranial pressure. Monitor such patients
for signs of increasing intracranial pressure.
6
Adverse Reactions
(PLR conversion;
additional line listing and new information added)
The
following serious adverse reactions are described, or described in greater
detail, in other sections:
- Addiction, Abuse, and Misuse
- Life-Threatening Respiratory
Depression
- Skeletal Muscle Rigidity and
Skeletal Muscle Movement
- Interactions with
Benzodiazepines or Other CNS Depressants
- Severe Cardiovascular
Depression
- Serotonin Syndrome
- Gastrointestinal Adverse
Reactions
- Seizures
6.1 Clinical Trials Experience
PLR conversion:
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Epidural
use in Labor and Delivery
Epidural
sufentanil was tested in 340 patients in two (one single-center and one
multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg
sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and
without epinephrine 1:200,000. In all cases sufentanil was administered
following a dose of local anesthetic to test proper catheter placement. Since
epidural opioids and local anesthetics potentiate each other, these results may
not reflect the dose or efficacy of epidural sufentanil by itself.
Individual
doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine
provided analgesia during the first stage of labor with a duration of 1 to 2
hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose)
tended to have shorter duration. Analgesia was profound (complete pain relief)
in 80% to 100% of patients and a 25% incidence of pruritus was observed. The
duration of initial doses of sufentanil plus bupivacaine with epinephrine is
approximately 95 minutes, and of subsequent doses, 70 minutes.
There
are insufficient data to critically evaluate neonatal neuromuscular and
adaptive capacity following recommended doses of maternally administered
epidural sufentanil with bupivacaine. However, if larger than recommended doses
are used for combined local and systemic analgesia, e.g. after administration
of a single dose of 50 mcg epidural sufentanil during delivery, then impaired
neonatal adaption to sound and light can be detected for 1 to 4 hours and if a
dose of 80 mcg is used impaired neuromuscular coordination can be detected for
more than 4 hours.
6.2 Postmarketing Experience
PLR conversion:
The
following adverse reactions have been identified during post approval use of
sufentanil. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Serotonin
syndrome:
Cases of serotonin syndrome, a potentially life-threatening condition, have
been reported during concomitant use of opioids with serotonergic drugs.
Adrenal
insufficiency:
Cases of adrenal insufficiency have been reported with opioid use, more often
following greater than one month of use.
Anaphylaxis: Anaphylaxis
has been reported with ingredients contained in Sufentanil Citrate Injection
Androgen
deficiency:
Cases of androgen deficiency have occurred with chronic use of opioids.
7
Drug Interactions
PLR conversion:
Table
2 includes clinically significant drug interactions with Sufentanil Citrate
Injection.
Table
2: Clinically Significant Drug
Interactions with Sufentanil Citrate Injection
(Information converted to table format; please refer to label)
8
Use in Specific Populations
8.1 Pregnancy
PLLR conversion:
Risk
Summary
Prolonged
use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal
syndrome. Available data with Sufentanil Citrate Injection in pregnant women
are insufficient to inform a drug-associated risk for major birth defects and
miscarriage. In animal reproduction studies, embryolethality and maternal
toxicity were noted in rabbits when sufentanil was administered intravenously
at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis. Decreased
live fetuses and pup survival were noted in rats treated with sufentanil late
in gestation and throughout lactation at doses below the human procedural dose
No malformations were observed in either rats or rabbits at doses below the
human procedural dose.
The
estimated background risk of major birth defects and miscarriage for the
indicated population is unknown. All pregnancies have a background risk of
birth defect, loss, or other adverse outcomes. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical
Considerations
Fetal/Neonatal
Adverse Reactions
Prolonged
use of opioid analgesics during pregnancy for medical or nonmedical purposes
can result in physical dependence in the neonate and neonatal opioid withdrawal
syndrome shortly after birth.
Neonatal opioid withdrawal syndrome
presents as irritability, hyperactivity and abnormal sleep pattern, high
pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset,
duration, and severity of neonatal opioid withdrawal syndrome vary based on the
specific opioid used, duration of use, timing and amount of last maternal use,
and rate of elimination of the drug by the newborn. Observe newborns for
symptoms of neonatal opioid withdrawal syndrome and manage accordingly.
Labor
or Delivery
Opioids cross the placenta and may
produce respiratory depression and psycho-physiologic effects in neonates. An
opioid antagonist, such as naloxone, must be available for reversal of
opioid-induced respiratory depression in the neonate. Sufentanil Citrate
Injection is not recommended for use in pregnant women during or immediately
prior to labor, when other analgesic techniques are more appropriate. Opioid
analgesics, including Sufentanil Citrate Injection, can prolong labor through
actions which temporarily reduce the strength, duration, and frequency of
uterine contractions. However, this effect is not consistent and may be offset
by an increased rate of cervical dilation, which tends to shorten labor.
Monitor neonates exposed to opioid analgesics during labor for signs of excess
sedation and respiratory depression. The use of epidurally administered
sufentanil in combination …
Data
Animal
Data
Pregnant rats were treated with
intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.03, 0.1, or
0.4 times the human total procedural dose of 30 mcg/kg based on body surface
area, respectively). No malformations or embryotoxic effects were noted despite
maternal toxicity (increased mortality in the mid- and high-dose group).
Pregnant rabbits were treated with
intravenous sufentanil doses of 0.005, 0.02, or 0.08 mg/kg/day (0.05, 0.2, or
0.9 times the human total procedural dose of 30 mcg/kg based on body surface
area, respectively). Decreased live fetuses per litter and decreased litter
size in the high dose group were noted in the presence of maternal toxicity
(decreased body weight gain and mortality in the high-dose group).
No evidence of malformations or adverse
effects on the fetus was reported in a published study in which pregnant rats
were administered 10, 50, or 100 mcg/kg/day sufentanil (0.05, 0.27, or 0.54
times the human procedural dose of 30 mcg/kg/day based on body surface area)
continuously from Gestation Day 5 through Gestation Day 20 via subcutaneously
implanted osmotic minipumps.
Pregnant rats were treated intravenously
with sufentanil 0.005, 0.02, or 0.08 mg/kg/day (0.03,0.1, or 0.4 times the
human total procedural dose of 30 mcg/day based on body surface area,
respectively) rom Gestation Day 16 through Lactation Day 21. Sufentanil reduced
birth weights in the mid- and high-dose groups, decreased live fetuses in the
high-dose group, and decreased pup survival in all groups in the presence of
maternal toxicity (decreased weight gain and increased mortality in all
groups).
8.2 Lactation
PLLR
conversion:
Risk Summary
The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for
Sufentanil Citrate Injection and any potential adverse effects on the breastfed
infant from Sufentanil Citrate Injection or from the underlying maternal
condition.
Clinical Considerations
Infants exposed to Sufentanil Citrate
Injection through breast milk should be monitored for excess sedation and
respiratory depression. Withdrawal symptoms can occur in breastfed infants when
maternal administration of an opioid analgesic is stopped, or when breast-
feeding is stopped.
8.3 Females and Males of Reproductive Potential
PLLR conversion:
Infertility
Chronic use of opioids may cause reduced
fertility in females and males of reproductive potential. It is not known
whether these effects on fertility are reversible.
Other
PLR
conversion and additional revisions to incorporate the opioid analgesic
template language.
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