Approved Drug Label (PDF)
Boxed Warning
Additions
and/or revisions underlined:
Risk Evaluation and Mitigation Strategy
(REMS)
Because
of the risk for accidental exposure, misuse, abuse, addiction, and overdose,
SUBSYS is available only through a restricted program required by the Food and
Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS).
Under the Transmucosal Immediate Release Fentanyl (TIRF) REMS, pharmacies,
outpatients, and healthcare professionals who prescribe to outpatients
must enroll in the program. Inpatient pharmacies must develop policies and
procedures to verify opioid tolerance in inpatients who require SUBSYS while
hospitalized [see Warnings and
Precautions (5.7)]. Further information is available at www.TIRFREMSaccess.com
or by calling 1-866-822-1483.
5
Warnings and Precautions
5.1 Life-Threatening Respiratory Depression
Additions and/or revisions underlined:
… Accidental
ingestion of even one dose of SUBSYS, especially by children, can result in
respiratory depression and death due to an overdose of fentanyl.
Educate patients
and caregivers on how to recognize respiratory depression and emphasize the
importance of calling 911 or getting emergency medical help right away in the
event of a known or suspected overdose [see
Patient Counseling Information (17)].
Opioids can cause
sleep-related breathing disorders including central sleep apnea (CSA) and
sleep-related hypoxemia. Opioid use increases the risk of CSA in a
dose-dependent fashion. In patients who present with CSA, consider decreasing
the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.4)].
Newly added information:
Patient Access to
Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the
availability of naloxone for the emergency treatment of opioid overdose with
the patient and caregiver and assess the potential need for access to naloxone,
both when initiating and renewing treatment with SUBSYS. Inform patients and
caregivers about the various ways to obtain naloxone as permitted by individual
state naloxone dispensing and prescribing requirements or guidelines (e.g., by
prescription, directly from a pharmacist, or as part of a community-based
program). Educate patients and caregivers on how to recognize respiratory
depression and emphasize the importance of calling 911 or getting emergency
medical help, even if naloxone is administered [see Patient Counseling Information (17)].
Consider prescribing
naloxone, based on the patient’s risk factors for overdose, such as concomitant
use of CNS depressants, a history of opioid use disorder, or prior opioid
overdose. The presence of risk factors for overdose should not prevent the
proper management of pain in any given patient. Also consider prescribing
naloxone if the patient has household members (including children) or other
close contacts at risk for accidental ingestion or overdose. If naloxone is
prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.4, 5.6),
Patient Counseling Information (17)].
5.4 Risks from Concomitant Use with Benzodiazepines or
Other CNS Depressants
Additions and/or revisions underlined:
… 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.
If concomitant use
is warranted, consider prescribing naloxone for the emergency treatment of
opioid overdose [see Dosage and
Administration (2.2), Warnings and Precautions (5.1)].
5.6 Addiction, Abuse, and Misuse
Additions and/or revisions underlined:
… Patients at
increased risk may be prescribed opioids such as SUBSYS, but use in such
patients necessitates intensive counseling about the risks and proper use of SUBSYS
along with intensive monitoring for signs of addiction, abuse, and misuse. Consider
prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2),
Warnings and Precautions (5.1)].
5.7 Transmucosal Immediate Release Fentanyl (TIRF)
Risk Evaluation and Mitigation Strategy (REMS)
Additions and/or revisions underlined:
Because of the
risk of accidental exposure, misuse, abuse, addiction, and overdose [see Warnings and Precautions (5.1)],
SUBSYS is available only through a restricted program under a REMS called the
TIRF REMS. Under the TIRF REMS, healthcare professionals who prescribe to
outpatients, the outpatients themselves, and pharmacies, are required
to enroll in the program.
Notable
requirements
of the TIRF REMS are:
Prescribers for outpatient use must be certified with
the REMS program by enrolling and completing training. Prescribers must
document opioid tolerance with every SUBSYS prescription.
Outpatients
must be enrolled in the REMS program and must be opioid tolerant to
receive SUBSYS [see Dosage and
Administration (2.1)].
Outpatient pharmacies must be certified with the REMS
program and verify documentation of opioid tolerance with every SUBSYS prescription.
Inpatient pharmacies must be certified with the REMS
program and develop policies and procedures to verify opioid tolerance in
inpatients who require SUBSYS while hospitalized.
Wholesalers
and distributers must enroll in the REMS program and distribute only to certified
pharmacies.
Further
information, including a list of qualified certified pharmacies/and enrolled
distributors, is available at www.tirfremsaccess.com or by calling
1-866-822-1483.
7
Drug Interactions
Table 6:
Clinically Significant Drug Interactions with SUBSYS
Benzodiazepines
and Other Central Nervous System (CNS) Depressants
Under Intervention, the
following language is added:
If concomitant use is warranted, consider prescribing naloxone for the
emergency treatment of opioid overdose [see Dosage and Administration (2.2),
Warnings and Precautions (5.1, 5.4, 5.6)].
Muscle Relaxants
Under Intervention, the
following language is added:
Due to the risk of respiratory depression with concomitant use of
skeletal muscle relaxants and opioids, consider prescribing naloxone for the
emergency treatment of opioid overdose [see Dosage and Administration (2.2),
Warnings and Precautions (5.1, 5.4)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Important information about SUBSYS:
Additions and/or revisions underlined:
Get emergency help
or call 911 right away if you take too much SUBSYS (overdose). When you first
start taking SUBSYS, when your dose is changed, or if you take too much
(overdose), serious or life-threatening breathing problems that can lead to death
may occur. Talk to your healthcare provider about naloxone, a medicine for
the emergency treatment of an opioid overdose.
Store
SUBSYS securely, out of sight and reach of children, in a location not
accessible by others, including visitors to the home. SUBSYS is available only
through a program called the Transmucosal Immediate Release
Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy
(REMS). To receive SUBSYS, you must:
Before
taking SUBSYS, tell your healthcare provider if you have a history of:
abuse
of street or prescription drugs, alcohol addiction, opioid overdose, or
mental health problems.
Tell
your healthcare provider if you are:
Get
emergency medical help or call 911 right away if you have: …
PATIENT COUNSELING INFORMATION
Storage and
Disposal of Unused and Used SUBSYS [see
Instructions for Use].
Additions and/or revisions underlined:
In the event that
a caregiver requires additional assistance in disposing of excess unusable
units that remain in the home after a patient has expired, instruct them to
call the toll-free number for West Therapeutic Development, LLC.,
1-844-452-9263![]()
or seek assistance from their local DEA office.
Life-Threatening
Respiratory Depression
Newly added information:
Educate patients
and caregivers on how to recognize respiratory depression and emphasize the
importance of calling 911 or getting emergency medical help right away in the
event of a known or suspected overdose [see
Warnings and Precautions (5.1)].
Newly added information:
Patient Access to
Naloxone for the Emergency Treatment of Opioid Overdose
Discuss with the
patient and caregiver the availability of naloxone for the emergency treatment
of opioid overdose, both when initiating and renewing treatment with SUBSYS.
Inform patients and caregivers about the various ways to obtain naloxone as
permitted by individual state naloxone dispensing and prescribing requirements
or guidelines (e.g., by prescription, directly from a pharmacist, or as part of
a community-based program) [see Dosage
and Administrations (2.2), Warnings and Precautions (5.1)].
Educate patients
and caregivers on how to recognize the signs and symptoms of an overdose.
Explain to
patients and caregivers that naloxone’s effects are temporary, and that they
must call 911 or get emergency medical help right away in all cases of known or
suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].
If naloxone is
prescribed, also advise patients and caregivers:
How
to treat with naloxone in the event of an opioid overdose
To
tell family and friends about their naloxone and to keep it in a place where
family and friends can access it in an emergency
To
read the Patient Information (or other educational material) that will come
with their naloxone. Emphasize the importance of doing this before an opioid
emergency happens, so the patient and caregiver will know what to do.
Increased Risk of
Overdose and Death in Children Due to Accidental Exposure
SUBSYS Child Safety Kit
Additions and/or revisions underlined:
Provide patients
and their caregivers with a SUBSYS Child Safety Kit. The kit consists of a
portable carrying case, a lock for the bag and contains a package of cabinet
and drawer child safety latches for securing the storage space at home to help
patients store SUBSYS and other medicines out of the reach of children. To
obtain a supply of Child Safety Kits, health care professionals can call West
Therapeutic Development, LLC., 1-844-452-9263![]()
.
Transmucosal Immediate-Release Fentanyl
(TIRF) REMS
Additions and/or revisions underlined:
SUBSYS is
available only through a restricted program called the Transmucosal Immediate
Release Fentanyl (TIRF) REMS [see
Warnings and Precautions (5.7)]. Inform the patient of the following
notable requirements:
Outpatients must be enrolled in the REMS program
Patients must be opioid-tolerant to receive SUBSYS
SUBSYS is
available only from certified pharmacies participating in this
program. Therefore, provide patients with the telephone number
and website for information on how to obtain the product.
Pharmacies,
outpatients, and
healthcare professionals who prescribe to outpatients are
required to enroll in the program. Inpatient pharmacies must develop
policies and procedures to verify opioid tolerance in inpatients who require
SUBSYS while hospitalized [see
Warnings and Precautions (5.7)].
Approved Drug Label (PDF)
Boxed Warning
(additions underlined)
WARNING: LIFE-THREATENING
RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; CYTOCHROME P450 3A4
INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS;
RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS
and NEONATAL OPIOID WITHDRAWAL SYNDROME
Life-Threatening
Respiratory Depression
Serious,
life-threatening, and/or fatal respiratory depression has occurred in
patients treated with SUBSYS, including following use in opioid non-tolerant
patients and improper dosing. Monitor for respiratory depression, especially
during initiation of SUBSYS or following a dose increase. The substitution
of SUBSYS for any other fentanyl product may result in fatal overdose
Due to the risk of
respiratory depression, SUBSYS is contraindicated in the management of acute or
postoperative pain including headache/migraine and in opioid non-tolerant
patients.
Accidental
INGESTION
Accidental ingestion of
even one dose of SUBSYS especially by children, can result in a fatal overdose
of fentanyl .
Death has been
reported in children who have accidentally ingested transmucosal immediate-
release fentanyl products. SUBSYS must be kept out of reach of children.
Cytochrome
P450 3A4 Interaction
The concomitant use
of SUBSYS with all cytochrome P450 3A4 inhibitors may result in an
increase in fentanyl plasma concentrations, which could increase or prolong
adverse reactions and may cause potentially fatal respiratory depression. In
addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer
may result in an increase in fentanyl plasma concentration. Monitor patients
receiving SUBSYS and any CYP3A4 inhibitor or inducer.
Risks
From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use
of opioids with benzodiazepines or other central nervous system (CNS)
depressants, including alcohol, may result in profound sedation, respiratory
depression, coma, and death.
• Reserve concomitant
prescribing of SUBSYS and benzodiazepines or other CNS
depressants for use
in patients for whom alternative treatment options are inadequate.
• Limit dosages and
durations to the minimum required.
• Follow patients for
signs and symptoms of respiratory depression and sedation.
Risk
of Medication Errors
Substantial
differences exist in the pharmacokinetic profile of SUBSYS compared to other fentanyl products that result in clinically important differences in
the extent of absorption of fentanyl that could result in fatal overdose
products to SUBSYS.
Addiction,
Abuse, and Misuse
SUBSYS exposes
patients and other users to the risks of opioid addiction, abuse, and misuse,
which can lead to overdose and death. Assess each patient’s risk prior to
prescribing SUBSYS, and monitor all patients regularly for the development of
these behaviors and conditions.
Risk
Evaluation and Mitigation Strategy (REMS) Access Program
Because
of the risk for misuse, abuse, addiction, and overdose, SUBSYS is available
only through a restricted program required by the Food and Drug Administration,
called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal
Immediate Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare
professionals who prescribe to outpatients, pharmacies, and distributors must
enroll in the program. Further
information is available at www.TIRFREMSaccess.com
or
by calling1-866-822-1483.
Neonatal
Opioid Withdrawal Syndrome
Prolonged use of
SUBSYS during pregnancy can result in neonatal opioid withdrawal syndrome,
which may be life-threatening if not recognized and treated, and requires
management according to protocols developed by neonatology experts. If opioid use is required for a prolonged
period in a pregnant woman, advise the patient of the risk of neonatal opioid
withdrawal syndrome and ensure that appropriate treatment will be available
4
Contraindications
(additions underlined)
Opioid non-tolerant patients:
Life-threatening respiratory depression and death could occur at any dose
in opioid non-tolerant patients
Acute or postoperative pain
including headache/migraine and dental pain, or in the emergency department .
Acute or severe bronchial
asthma in an unmonitored setting or in the absence of resuscitative equipment.
Known or suspected
gastrointestinal obstruction, including paralytic ileus.
Known hypersensitivity (e.g., anaphylaxis) to fentanyl or
components of SUBSYS.
5
Warnings and Precautions
5.1 Life-Threatening Respiratory Depression
(additions underlined)
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. 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.
While serious, life-threatening, or fatal respiratory depression can
occur at any time during the use of SUBSYS, the risk is greatest during the
initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72
hours of initiating therapy with and following dosage increases of SUBSYS.
reduce the risk of respiratory depression, proper dosing and titration of
SUBSYS are essential. Overestimating the SUBSYS dosage can result in a fatal
overdose with the first dose. The substitution
of SUBSYS for any other fentanyl product may result in fatal overdose.
SUBSYS could be fatal to individuals for whom it is not prescribed and
for those who are not opioid- tolerant.
Accidental ingestion or exposure to even one dose of SUBSYS, especially
in children, can result in respiratory depression and death due to an overdose
of fentanyl.
5.10 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
(subsection added)
Cases of serotonin syndrome, a potentially life-threatening condition,
have been reported during concomitant use of SUBSYS 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 SUBSYS if serotonin syndrome is suspected.
5.11 Adrenal Insufficiency
(subsection added)
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 insufficiency.
5.12 Severe Hypotension
(subsection added)
SUBSYS 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) .Monitor these patients for signs of
hypotension after initiating or titrating the dosage of SUBSYS. In patients
with circulatory shock, SUBSYS may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of SUBSYS in patients with
circulatory shock.
5.13 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
( subsection added)
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), SUBSYS 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 SUBSYS.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of SUBSYS in patients with
impaired consciousness or coma.
5.14 Risks of Use in Patients with Gastrointestinal Conditions
(subsection added)
SUBSYS is contraindicated in patients with known or suspected
gastrointestinal obstruction, including paralytic ileus.
The fentanyl in SUBSYS 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.
5.15 Increased Risk of Seizures in Patients with Seizure Disorders
(subsection added)
The fentanyl in SUBSYS 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 SUBSYS therapy.
5.2 Increased Risk of Overdose in Children Due to Accidental Ingestion
(additions underlined)
Death has been reported in children who have accidentally ingested
transmucosal immediate–release fentanyl products.
Patients and their caregivers must be informed that SUBSYS
contains a medicine in an amount which can be fatal to a child. Physicians and
dispensing pharmacists must specifically question patients or caregivers about
the presence of children in the home (on a full time or visiting basis) and
counsel them regarding the dangers to children from inadvertent exposure.
Patients and their caregivers must be instructed to keep both used and
unused dosage units out of the reach of children. While all units should be
disposed of immediately after use, partially consumed units represent a special
risk to children. In the event that a unit is not completely consumed it must
be properly disposed as soon as possible.
5.3 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers
(additions underlined)
Concomitant use of SUBSYS 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, which may cause potentially
fatal respiratory depression , particularly when an inhibitor is added after a
stable dose of SUBSYS is achieved.
Similarly, discontinuation of a CYP3A4 inducer, such as rifampin,
carbamazepine, and phenytoin, in SUBSYS-treated patients may increase fentanyl
plasma concentrations and prolong opioid adverse reactions. When using SUBSYS with CYP3A4 inhibitors or
discontinuing CYP3A4 inducers in SUBSYS-treated patients, monitor patients
closely at frequent intervals and consider dosage reduction of SUBSYS until
stable drug effects are achieved .
Concomitant use of SUBSYS with CYP3A4 inducers or discontinuation of an
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 SUBSYS 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.
5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
(additions underlined)
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of SUBSYS
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 inadequate.
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 .
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. 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.
Advise both patients and caregivers about the risks of respiratory
depression and sedation when SUBSYS is used with benzodiazepines or other CNS
depressants (including alcohol and illicit drugs). Advise patients not to drive
or operate heavy machinery until the effects of concomitant use of the
benzodiazepine or other CNS depressant have been determined. Screen patients
for risk of substance use.
5.5 Risk of Medication Errors
(subsection added)
When prescribing, DO NOT convert a patient to SUBSYS from any other fentanyl
product on a mcg per mcg basis as SUBSYS and other fentanyl products are not
equivalent on a microgram per microgram basis.
SUBSYS is NOT a generic version of other transmucosal immediate release
fentanyl (TIRF) formulations. When dispensing, DO NOT substitute a SUBSYS
prescription for any other TIRF formulation under any circumstances. Other TIRF
formulations and SUBSYS are not equivalent. Substantial differences exist in
the pharmacokinetic profile of SUBSYS compared to other fentanyl products including
other TIRF formulations that result in clinically important differences in the
rate and extent of absorption of fentanyl. As a result of these differences,
the substitution of SUBSYS for any other fentanyl product may result in a fatal
overdose.
There are no safe conversion directions available for patients on any
other fentanyl products (Note: This includes oral, transdermal, or parenteral
formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial
dose of SUBSYS should always be ONE 100 mcg spray. Individually titrate each
patient’s dose to provide adequate analgesia while minimizing side effects.
5.6 Addiction, Abuse, and Misuse
(subsection added)
SUBSYS contains fentanyl, a Schedule II controlled substance. As an
opioid, SUBSYS exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur
in patients appropriately prescribed SUBSYS. 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 SUBSYS, and monitor all patients receiving SUBSYS 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 SUBSYS, but use in such
patients necessitates intensive counseling about the risks and proper use of SUBSYS
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 SUBSYS. Strategies
to reduce these risks include prescribing the drug in the smallest appropriate
quantity and advising the patient on the proper disposal of unused 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.
5.7 Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and MitigationStrategy (REMS) Access Program
(additions underlined)
Because of the risk of misuse, abuse, addiction, and overdose , SUBSYS is
available only through a restricted program under a REMS called the TIRF REMS
Access program. Under the TIRF REMS Access program, outpatients, healthcare
professionals who prescribe to outpatients, pharmacies, and distributors
must enroll in the program. For inpatient administration (e.g. hospitals,
hospices, and long-term care facilities that prescribe for inpatient use) of
SUBSYS, patient and prescriber enrollment is not required.
Required components of the TIRF REMS Access program are:
• Healthcare professionals who
prescribe SUBSYS must review the prescriber educational materials for the TIRF
REMS Access program, enroll in the program, and comply with the REMS requirements.
• To receive SUBSYS, outpatients
must understand the risks and benefits and sign a Patient-Prescriber Agreement.
• Pharmacies that dispense SUBSYS
must enroll in the program and agree to comply with the REMS arequirements.
• Wholesalers and distributers
that distribute SUBSYS must enroll in the program and distribute only to
authorized pharmacies.
• Further information, including a
list of qualified pharmacies/distributors, is available at
or by calling 1-866-822-1483.
5.8 Neonatal Opioid Withdrawal Syndrome
(subsection added)
Prolonged use of SUBSYS during pregnancy can result in withdrawal in the
neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome
in adults, may be life-threatening 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.
5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
( subsection added)
The use of SUBSYS 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: SUBSYS 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
recommended dosages of SUBSYS.
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in
elderly, cachectic, or debilitated patients because they may have altered
pharmacokinetics or altered clearance compared to younger, healthier patients .
Monitor such patients closely, particularly when initiating and titrating
SUBSYS and when SUBSYS is given concomitantly with other drugs that depress
respiration.
6
Adverse Reactions
6.2 Postmarketing Experience
(subsection added)
The following adverse reactions have been identified during post approval
use of fentanyl. 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 SUBSYS.
Androgen deficiency: Cases of androgen deficiency
have occurred with chronic use of opioids
(additions underlined)
The following serious adverse reactions are described, or described in
greater detail, in other sections:
Life-Threatening Respiratory
Depression
Interactions with
Benzodiazepines and other CNS Depressants
Addiction, Abuse, and Misuse
Neonatal Opioid Withdrawal
Syndrome
Serotonin Syndrome
Adrenal Insufficiency
Severe Hypotension
Gastrointestinal Adverse
Reactions
Seizures
7
Drug Interactions
(Section revised, please refer to label)
8
Use in Specific Populations
8.1 Pregnancy
(PLLR conversion, please refer to label)
8.2 Lactation
Risk Summary
Fentanyl is present in breast milk.
One published lactation study reports a relative infant dose of fentanyl
of 0.024%. However, there is
insufficient information to determine the effects of fentanyl on the breastfed
infant and the effects of fentanyl on milk production.
Because of the potential for serious adverse reactions, including excess
sedation and respiratory depression in a breastfed
infant, advise patients that breastfeeding is not recommended during treatment
with SUBSYS.
Clinical Considerations
Monitor infants exposed to SUBSYS through breast milk 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.
8.5 Geriatric Use
(additions underlined)
Of the 359 patients in clinical studies of SUBSYS in breakthrough cancer
pain, 27% were 60 years of age and older, 17% were 65 years of age and older,
and 3% were 75 years of age and older. No difference
was noted in the safety profile of the group over 65 years of age as
compared to younger patients in
SUBSYS clinical trials.
Elderly patients have been shown to be more sensitive to the effects of
fentanyl when administered
intravenously, compared with the younger population. Therefore, monitor
patients for respiratory depression and CNS effects when titrating SUBSYS in
elderly patients.
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.
Titrate the dosage of SUBSYS slowly in geriatric patients and monitor
closely for signs of central nervous system and respiratory depression.
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Extensive revisions and additions, please refer to
label)
Medication Guide
(Extensive revisions and additions, please refer to
label)
Other
(Revisions to the Package
Insert to incorporate the opioid analgesic template language)
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