Included as part of the PRECAUTIONS section.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory
depression has been reported with the use of opioids, including fentanyl, even
when used as recommended. Respiratory depression, if not immediately recognized
and treated, may lead to respiratory arrest and death. Management of
respiratory depression may include close observation, supportive measures, and
use of opioid antagonists, depending on the patient's clinical status [see
OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory
depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory
depression can occur at any time during the use of IONSYS, the risk is greatest
during the initiation of therapy. Monitor patients closely for respiratory depression,
especially within the first 2472
hours of initiating therapy with IONSYS.
Accidental exposure to the hydrogel component of IONSYS,
especially in children, can result in respiratory depression and death due to
an overdose of fentanyl.
Following accidental contact with IONSYS or its
components, immediately rinse the affected area thoroughly with water. Do not
use soap, alcohol, or other solvent because they may enhance the drug's ability
to penetrate the skin. The individual exposed should be monitored for signs of
respiratory or central nervous system depression.
If IONSYS is not handled correctly using gloves,
healthcare professionals are at risk of accidental exposure to a fatal overdose
IONSYS is for hospital use only. Use of IONSYS outside of
the hospital setting can lead to accidental exposure in others for whom it is
not prescribed, causing fatal respiratory depression. Prior to the patient
leaving the hospital, medical personnel must remove IONSYS and dispose of it
IONSYS Risk Evaluation And Mitigation Strategy (REMS)
IONSYS is available only through a restricted program
under a REMS called the IONSYS REMS Program because of the risk of respiratory
depression resulting from accidental exposure [see Life-Threatening Respiratory Depression].
Notable requirements of the IONSYS REMS Program include
- Healthcare facilities that dispense and administer IONSYS
must be certified in the IONSYS REMS program and comply with the REMS
- Hospitals must only dispense IONSYS for hospital use.
Further information about the IONSYS REMS Program is
available at www.ionsysrems.com, or by calling 1-877-488-6835.
Addiction, Abuse, And Misuse
IONSYS contains fentanyl, a Schedule II controlled
substance. As an opioid, IONSYS exposes users to the risks of addiction, abuse,
and misuse [see Drug Abuse and Dependence].
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed IONSYS. Addiction
can occur at recommended dosages and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse,
or misuse, prior to prescribing IONSYS, and monitor all patients receiving
IONSYS for the development of these behaviors or conditions. Risks are increased
in patients with a personal or family history of substance abuse (including
drug or alcohol abuse or addiction) or mental illness (e.g., major depression).
The potential for these risks should not, however, prevent the proper
management of pain in any given patient. Patients at increased risk may be prescribed
opioids, such as IONSYS, but use in such patients necessitates intensive counseling
about the risks and proper use of IONSYS along with intensive monitoring for
signs 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 prescribing or dispensing IONSYS. 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.
Risks Of Concomitant Use Or Discontinuation Of Cytochrome
P450 3A4 Inhibitors And Inducers
Concomitant use of IONSYS 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 fentanyl, and prolong opioid adverse reactions, depression [see
Life-Threatening Res piratory Depression] , particularly when an inhibitor is added after a
stable dose of IONSYS is achieved. Similarly, discontinuation of a CYP3A4
inducer, such as rifampin, carbamazepine, and phenytoin, in IONSYS-treated
patients may increase fentanyl plasma concentrations and prolong opioid adverse
reactions. When using IONSYS with CYP3A4 inhibitors or discontinuing CYP3A4
inducers in IONSYS-treated patients, monitor patients closely at frequent
intervals for respiratory depression and sedation [see DRUG INTERACTIONS].
Concomitant use of IONSYS with CYP3A4 inducers or
discontinuation of a CYP3A4 inhibitor could decrease fentanyl plasma
concentrations, decrease opioid efficacy or, possibly lead to a withdrawal syndrome
in a patient who had developed physical dependence to fentanyl. When using
IONSYS with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor
patients closely at frequent intervals and consider increasing the opioid
dosage if needed to maintain adequate analgesia or if symptoms of opioid
withdrawal occur [see DRUG INTERACTIONS].
Risks From Concomitant Use With Benzodiazepines Or Other
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of IONSYS with benzodiazepines or
other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics,
tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other
opioids, alcohol). Because of these risks, reserve concomitant prescribing of
these drugs for use in patients for whom alternative treatment options are
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
If the decision is made to prescribe a benzodiazepine or
other CNS depressant concomitantly with an opioid analgesic, prescribe the
lowest effective dosages and minimum durations of concomitant use. In patients
already receiving an opioid analgesic, prescribe a lower initial dose of the
benzodiazepine or other CNS depressant than indicated in the absence of an
opioid, and titrate based on clinical response.ÃÂ If an opioid analgesic is
initiated in a patient already taking a benzodiazepine or other CNS depressant,
prescribe a lower initial dose of the opioid analgesic, and titrate based on
clinical response. Follow patients closely for signs and symptoms of
respiratory depression and sedation.
Risk Of Injury During Magnetic Resonance Imaging (MRI)
The IONSYS device is considered MR Unsafe. IONSYS
contains metal parts and must be removed and properly disposed of before an MRI
procedure to avoid injury to the patient and damage to IONSYS. It is unknown if
exposure to an MRI procedure increases release of fentanyl from IONSYS. Monitor
any patients wearing IONSYS with inadvertent exposure to an MRI for signs of
central nervous system and respiratory depression.
Risk Of IONSYS Use During Other Procedures Or Near
Cardioversion, Defibrillation, Radiographic Imaging
Procedures Other Than MRI, Or Diathermy
Use of IONSYS during cardioversion, defibrillation,
X-ray, CT, or diathermy can damage IONSYS from the strong electromagnetic
fields set up by these procedures. IONSYS contains radio-opaque components and
may interfere with an X-ray image or CT scan. Remove and properly dispose of IONSYS
prior to cardioversion, defibrillation, X-ray, CT, or diathermy [see DOSAGE
Synthetic Materials And Electronic Security Systems
Avoid contact with synthetic materials (such as carpeted
flooring) to reduce the possibility of electrostatic discharge and damage to
IONSYS. Avoid exposing IONSYS to electronic security systems to reduce the
possibility of damage to IONSYS. See IONSYS Important Device Instructions for additional
Communications Equipment And Radio Frequency
Use of IONSYS near communications equipment (e.g., base
stations for radio telephones and land mobile radios, amateur radio, AM and FM
radio broadcast and TV broadcast Radio) and Radio Frequency Identification
(RFID) transmitters can damage IONSYS. Depending on the rated maximum output
power and frequency of the transmitter, the recommended separation distance
between IONSYS and communications equipment or the RFID transmitter ranges
between 0.12 and 23 meters. See IONSYS Important Device Instructions for
detailed instructions regarding recommended separation distances.
Other Electromechanical Devices Including Pacemakers Or Electrical
The low-level electrical current provided by IONSYS does
not result in electromagnetic interference with other electromechanical devices
like pacemakers or electrical monitoring equipment.
If exposure to the procedures listed above, electronic
security systems, electrostatic discharge, communications equipment, or RFID
transmitters occurs, and if IONSYS does not appear to function normally [see
DOSAGE AND ADMINISTRATION] , remove IONSYS and replace with a new IONSYS.
See IONSYS Important Device Instructions for additional details including
information on troubleshooting device malfunction and electromagnetic
Life-Threatening Respiratory Depression In Patients With Chronic
Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of IONSYS in patients with acute or severe
bronchial asthma in an unmonitored setting or in the absence of resuscitative
equipment is contraindicated.
Patients With Chronic Pulmonary Disease
IONSYS-treated 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 the recommended dosage of IONSYS [see Life-Threatening Res piratory Depression].
Elderly, Cachectic, Or Debilitated Patients
Life -threatening respiratory depression is more likely
to occur in elderly, cachectic, or debilitated patients as they may have
altered pharmacokinetics or altered clearance compared to younger, healthier
Monitor such patients closely; particularly when
initiating IONSYS and when IONSYS is used concomitantly with other drugs that
depress respiration [see ]. Alternatively,
consider theLife-Threatening Res piratory Depression use of non-opioid analgesics in these patients.
Serotonin Syndrome With Concomitant Use Of Serotonergic
Cases of serotonin syndrome, a potentially
life-threatening condition, have been reported during concomitant use of
fentanyl, the active opioid ingredient of IONSYS, 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) [see DRUG INTERACTIONS]. This may occur at the
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 IONSYS if serotonin syndrome is suspected.
Cases of adrenal insufficiency have been reported with opioid
use, more often following greater than one month of use. Presentation of
adrenal insufficiency may include non-specific symptoms and signs including
nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
pressure. If adrenal insufficiency is suspected, confirm the diagnosis with
diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed,
treat with physiologic replacement doses of corticosteroids. Wean the patient
off of the opioid to allow adrenal function to recover and continue
corticosteroid treatment until adrenal function recovers. Other opioids may be
tried as some cases reported use of a different opioid without recurrence of
adrenal insufficiency. The information available does not identify any
particular opioids as being more likely to be associated with adrenal
IONSYS may cause severe hypotension including orthostatic
hypotension and syncope in ambulatory patients. 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) [see DRUG
INTERACTIONS]. Monitor these patients for signs of hypotension after
initiating IONSYS. In patients with circulatory shock, IONSYS may cause vasodilation
that can further reduce cardiac output and blood pressure. Avoid the use of
IONSYS in patients with circulatory shock.
Risks Of Use In Patients With Increased Intracranial
Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness
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). IONSYS 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 IONSYS.
Opioids may also obscure the clinical course in a patient
with a head injury.
Avoid the use of IONSYS in patients with impaired
consciousness or coma. IONSYS is not suitable for use in patients who are not
alert and able to follow directions.
Risks Of Use In Patients with Gastrointestinal Conditions
IONSYS is contraindicated in patients with known or
suspected gastrointestinal obstruction, including paralyticileus.
The fentanyl in IONSYS 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.
Increased Risk Of Seizures In Patients With Seizure
The fentanyl in IONSYS 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 IONSYS therapy.
Topical Skin Reactions
Topical skin reactions (erythema, sweating, vesicles,
papules/pustules) may occur with use of IONSYS and are typically limited to the
application site area. If a severe skin reaction is observed, remove IONSYS and
discontinue further use.
IONSYS may produce bradycardia in some patients. Monitor
patients with bradyarrhythmias closely for changes in heart rate, particularly
when initiating therapy with IONSYS.
Avoid the use of mixed agonist/antagonist (e.g.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine)
analgesics in patients who are receiving a full opioid agonist analgesic, including
IONSYS. In these patients, mixed agonist/antagonist and partial agonist
analgesics may reduce the analgesic effect and/or precipitate withdrawal
Do not abruptly discontinue IONSYS [see Drug Abuse and
Insufficient data are available on the use of IONSYS in
patients with impaired hepatic function. Since fentanyl is eliminated by
hepatic metabolism and fentanyl clearance may decrease in patients with hepatic
disease, monitor patients with hepatic impairment for signs of sedation and
respiratory depression [see Use in Specific Populations and CLINICAL
A clinical pharmacology study with intravenous fentanyl
in patients undergoing kidney transplantation has shown that patients with high
blood urea nitrogen level had low fentanyl clearance. Monitor for signs of
sedation and respiratory depression in patients with renal impairment [see
Use in Specific Populations and CLINICAL PHARMACOLOGY].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of IONSYS during pregnancy can result in
withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid
withdrawal syndrome in adults, may be lifethreatening if not recognized
and treated, and requires management according to protocols developed by
neonatology experts. Observe newborns for signs of neonatal opioid withdrawal
syndrome and manage accordingly. Advise pregnant women using opioids for a
prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure
that appropriate treatment will be available [see Use in Specific
Populations, PATIENT INFORMATION].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Life-Threatening Respiratory Depression
- Inform patients of the risk of respiratory depression,
including information that the risk is greatest when starting IONSYS, and that
it can occur even at the recommended dosage [see WARNINGS AND PRECAUTIONS].
Advise patients how to recognize respiratory depression and to seek medical attention
if breathing difficulties develop.
- Advise patients not to leave the hospital with IONSYS [see
WARNINGS AND PRECAUTIONS].
- Advise patients not to let anyone else activate the
dosing button on the IONSYS since only the patient knows how much pain he or
she is experiencing. Patients should be cautioned that allowing others to activate
the device may result in a potentially fatal overdose [see DOSAGE AND
- Inform patients that accidental exposure, especially in
children, may result in respiratory depression or death [see WARNINGS AND
- Advise patients not to let anyone touch IONSYS if it
falls off accidentally and to contact their nurse, pharmacist, or doctor
immediately. Accidental exposure to the fentanyl hydrogel may result in a fatal
overdose of fentanyl.
- Instruct patients not to remove or reposition IONSYS and
that IONSYS must be removed only by medical personnel [see WARNINGS AND
- Instruct patients not to touch the sticky side of IONSYS
and not to touch the gels. Caution patients that fentanyl is rapidly absorbed
by the eyes and mouth and could be harmful or fatal if absorbed this way.
Advise patients to inform a health care provider if accidental exposure occurs
and to immediately rinse the affected area with copious amounts of water. Soap,
alcohol, or other solvents should not be used because they may enhance
permeability [see WARNINGS AND PRECAUTIONS].
- Instruct patients to keep IONSYS out of the reach of
children at all times [see WARNINGS AND PRECAUTIONS].
Addiction, Abuse And Misuse
- Inform patients that the use of IONSYS, even when taken
as recommended can result in addiction, abuse and misuse, which can lead to
overdose and death [see WARNINGS AND PRECAUTIONS].
Interactions With Benzodiazepines And Other CNS
Inform patients and caregivers that potentially fatal
additive effects may occur if IONSYS is used with benzodiazepines or other CNS
depressants, including alcohol, and not to use these concomitantly unless supervised
by a healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG
Inform patients that opioids could cause a rare but
potentially lifethreatening condition 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. Instruct patients to inform their physicians if they are taking, or
plan to take serotonergic medications [see WARNINGS AND PRECAUTIONS, DRUG
Inform patients to avoid taking IONSYS while using any
drugs that inhibit monoamine oxidase. Patients should not start MAOIs while
taking IONSYS [see DRUG INTERACTIONS].
Important Administration Instructions
Advise patients that the level of current (62 microA/cm²)
provided by IONSYS is generally imperceptible to the patient.
- Inform patients that anaphylaxis have been reported with
ingredients contained in IONSYS. Advise patients how to recognize such a
reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE
- Advise patients to inform the health care provider of any
allergies to fentanyl, cetylpiridinium chloride (e.g., Cepacol®) and or any
components of IONSYS.
Inform patients that chronic use of opioids may cause
reduced fertility. It is not known whether these effects on fertility are
reversible [see Use in Specific Populations].
Disposal Of Unused IONSYS
Advise patients that only their health care provider
should remove IONSYS from them and properly dispose of IONSYS prior to them
leaving the hospital.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a two-year carcinogenicity study conducted in rats,
fentanyl was not associated with an increased incidence of tumors at
subcutaneous doses up to 0.033 mg/kg/day in males or 0.1 mg/kg/day in females. These
lifetime doses in rats are approximately 0.1 and 0.3, respectively, the maximum
recommended human dose (MRHD) of 3.2 mg/day by transdermal administration based
on a mg/m² body surface area comparison and a 60 kg human body weight.
Fentanyl is not mutagenic in the in vitro bacterial
reverse mutation assay (Ames assay), the primary rat hepatocyte unscheduled DNA
synthesis assay, the BALB/c 3T3 transformation test, and the in vitro chromosomal
aberration assays using either human lymphocytes or Chinese hamster ovary
Impairment Of Fertility
The potential effects of fentanyl on male and female
fertility were examined in the rat model via two separate experiments. In the
male fertility study, male rats were treated with fentanyl doses of 0, 0.025, 0.1,
or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2 times, respectively, the MHRD)
via continuous intravenous infusion for 28 days prior to mating; female rats
were not treated. In the female fertility study, female rats were treated with
fentanyl doses of 0, 0.025, 0.1, or 0.4 mg/kg/day (equivalent to 0.08, 0.3, 1.2
times, respectively, the MHRD) via continuous intravenous infusion for 14 days
prior to mating until Day 16 of pregnancy; male rats were not treated. Analysis
of fertility parameters in both studies indicated that an intravenous dose of
fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no
effects on fertility (this dose is approximately 1.2 times the maximum available
daily human dose on a mg/m² basis). In a separate study, a single daily bolus
dose of fentanyl was shown to impair fertility in rats when given in
intravenous doses of 0.3 times the MRHD for a period of 12 days.
Use In Specific Populations
Prolonged use of opioid analgesics during pregnancy may
cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS].
Available data with IONSYS in pregnant women are insufficient to inform a
drug-associated risk for major birth defects and miscarriage.
There are no studies with the use of IONSYS in pregnant
women. Limited published data on fentanyl use during pregnancy are insufficient
to establish any drug-associated risks. In animal reproduction and developmental
studies, at doses within the dosing range of humans, there was an increased
risk for early embryonic lethality, decreased pup survival, and delays in
developmental landmarks of surviving pups [see Data].
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%,
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 [see WARNINGS AND
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. IONSYS is not recommended for use in pregnant women
during or immediately prior to labor, when other analgesic techniques are more
appropriate. Opioid analgesics, including IONSYS, 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 and respiratory
depression. Monitor neonates exposed to opioid analgesics during labor for
signs of excess sedation and respiratory depression.
The potential effects of fentanyl on embryo-fetal
development were studied in rat and rabbit models.
Published literature reports that administration of
fentanyl (0, 0.01, 0.1, or 0.5 mg/kg/day) to pregnant female Sprague-Dawley
rats from Gestation Day 7 to 21 via implanted microosmotic minipumps did not produce
any evidence of teratogenicity. The high dose is approximately 1.5 times the
daily maximum recommended human dose (MRHD) of 3.2 mg/day based on a mg/m² body
surface area basis and a 60 kg human body weight.
In contrast, the intravenous administration of fentanyl at
doses of 0, 0.01, or 0.03 mg/kg (equivalent to 0.03 and 0.09 times,
respectively, the MHRD) to pregnant female rats from Gestation Day 6 to 18 resulted
in evidence of embryo toxicity and a slight increase in mean delivery time in
the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.
Pregnant female New Zealand White rabbits were treated
with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from
Gestation Day 6 to 18. Fentanyl produced a slight decrease in the body weight
of the live fetuses at the high dose, which may be attributed to maternal
toxicity (decreased body weight and sedation). Under the conditions of the
assay, there was no evidence for fentanyl-induced adverse effects on
embryo-fetal development at doses up to 0.4 mg/kg (2.4 times the MRHD).
The potential effects of fentanyl on prenatal and
postnatal development were examined in the rat model. Pregnant female Wistar
rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous
infusion (equivalent to 0.08, 0.3, and 1.2 times, respectively, the MRHD) from
Gestation Day 6 through 3 weeks of lactation. Fentanyl treatment (0.4
mg/kg/day) significantly decreased body weight in male and female pups and also
decreased survival in pups at Post-Natal Day 4. Both the mid-dose and high-dose
of fentanyl animals demonstrated alterations in some physical landmarks of
development (delayed incisor eruption and eye opening) and transient behavioral
development (decreased locomotor activity at Post- Natal Day 28 which recovered
by Post-Natal Day 50). No adverse effects were observed at 0.08 times the MRHD.
Limited published literature reports that fentanyl is
present in human milk at low levels, which resulted in an estimated infant dose
of 0.38% of the maternal weight-adjusted dosage. There are no reports of adverse
effects on the breastfed infant and no information on the effects on milk
The developmental and health benefits from breastfeeding
should be considered along with the mother's clinical need for IONSYS and any
potential effects on the breastfed infant from IONSYS or from the underlying
Infants exposed to IONSYS 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 breastfeeding is stopped.
Females And Males Of Reproductive Potential
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 [see ADVERSE REACTIONS, CLINICAL
PHARMACOLOGY, Nonclinical Toxicology].
The efficacy and safety of IONSYS have not been
established in pediatric patients under 18 years of age.
IONSYS 40 mcg has been studied in 499 patients 65 years
or older; 174 of whom were 75 years or older. No major differences in safety or
effectiveness were observed between these subjects and younger subjects.
However, the incidence of the following events was slightly higher ( ≥ 1%)
in patients ≥ 65 years compared with patients who were 18 to 64 years of
age: hypotension (4% versus 3%), confusion (2% versus < 1%), hypokalemia (3%
versus 1%), hypoxia (3% versus 2%), and hypoventilation (2% versus < 1%).
In a pharmacokinetic study of IONSYS conducted in 63
healthy volunteers (25 subjects older than 65 years), age did not significantly
affect the extent of drug absorption. Literature suggests that the clearance of
fentanyl may be reduced and the terminal half-life prolonged in the elderly.
Respiratory depression is the chief risk for elderly
patients treated with opioids, and has occurred after large initial doses were
administered to patients who were not opioid-tolerant or when opioids were co-administered
with other agents that depress respiration and monitor closely for signs of
central nervous system and respiratory depression [see WARNINGS AND
Fentanyl is known to be substantially excreted by the
kidney, and the risk of adverse reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and
it may be useful to monitor renal function.
Insufficient data are available on the use of IONSYS in
patients with impaired hepatic function. Since fentanyl is eliminated by
hepatic metabolism and fentanyl clearance may decrease in patients with hepatic
disease, monitor patients with hepatic impairment closely for signs of central
nervous system and respiratory depression, especially when initiating treatment
Approximately 10% of administered fentanyl is excreted
unchanged by the kidney. Insufficient data are available on the use of IONSYS
in patients with impaired renal function to determine effects on renal clearance
of fentanyl. Monitor patients with renal impairment closely for signs of
central nervous system and respiratory depression, especially when initiating
treatment with IONSYS.