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Fentanyl Buccal

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Life-Threatening Respiratory
Depression

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 [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 fentanyl buccal tablets, 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 fentanyl buccal tablets.

To reduce the risk of
respiratory depression, proper dosing and titration of fentanyl buccal tablets
are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the
fentanyl buccal tablets dosage can result in a fatal overdose with the first
dose. The substitution of fentanyl buccal tablets for any other fentanyl
product may result in fatal overdose [see Risk of Medication Errors].

Fentanyl buccal tablets could
be fatal to individuals for whom it is not prescribed and for those who are not
opioid-tolerant.

Accidental ingestion of even
one dose of fentanyl buccal tablets, especially by children, can result in
respiratory depression and death due to an overdose of fentanyl.

Increased Risk Of Overdose In Children
Due To Accidental Ingestion Or Exposure

Death has been reported in
children who have accidentally ingested transmucosal immediate-release fentanyl
products.

Patients and their caregivers
must be informed that fentanyl buccal tablets contain a medicine in an amount
which can be fatal to a child. Healthcare providers 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 [see PATIENT INFORMATION].

Detailed instructions for the
proper storage, administration, disposal, and important instructions for managing
an overdose of fentanyl buccal tablets are provided in the fentanyl buccal
tablets Medication Guide. Encourage patients to read this information in its
entirety and give them an opportunity to have their questions answered.

Risks Of Concomitant Use Or Discontinuation
Of Cytochrome P450 3A4 Inhibitors And Inducers

Concomitant use of fentanyl
buccal tablets 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 [see Life-Threatening Respiratory Depression], particularly when an
inhibitor is added after a stable dose of fentanyl buccal tablets is achieved.
Similarly, discontinuation of a CYP3A4 inducer, such as rifampin,
carbamazepine, and phenytoin, in fentanyl buccal tablets-treated patients may
increase fentanyl plasma concentrations and prolong opioid adverse reactions.
When using fentanyl buccal tablets with CYP3A4 inhibitors or discontinuing
CYP3A4 inducers in fentanyl buccal tablets-treated patients, monitor patients
closely at frequent intervals and consider dosage reduction of fentanyl buccal
tablets until stable drug effects are achieved [see DRUG INTERACTIONS].

Concomitant use of fentanyl
buccal tablets 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 fentanyl buccal tablets 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 CNS Depressants (including Alcohol)

Profound sedation, respiratory
depression, coma, and death may result from the concomitant use of fentanyl
buccal tablets 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 [see DRUG INTERACTIONS].

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 fentanyl
buccal tablets are 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 disorders, including opioid abuse and misuse, and warn them of
the risk for overdose and death associated with the use of additional CNS
depressants including alcohol and illicit drugs [see DRUG INTERACTIONS and
PATIENT INFORMATION].

Risk Of Medication Errors

When prescribing, do not
convert a patient to fentanyl buccal tablets from any other fentanyl product on
a mcg per mcg basis as fentanyl buccal tablets and other fentanyl products are
not equivalent on a microgram per microgram basis.

Fentanyl buccal tablets are not
a generic version of other transmucosal immediate release fentanyl (TIRF)
formulations. When dispensing, do not substitute a fentanyl buccal tablets
prescription for any other TIRF formulation under any circumstances. Other TIRF
formulations and fentanyl buccal tablets are not equivalent. Substantial
differences exist in the pharmacokinetic profile of fentanyl buccal tablets
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 fentanyl
buccal tablets or any other fentanyl product may result in a fatal overdose.

There are no safe conversion
directions available for patients on any other fentanyl products except ACTIQ
(Note: This includes oral, transdermal, or parenteral formulations of
fentanyl.) [see DOSAGE AND ADMINISTRATION].Therefore, for opioid
tolerant patients, the initial dose of fentanyl buccal tablets should always be
100 mcg. Individually titrate each patient’s dose to provide adequate analgesia
while minimizing side effects [see DOSAGE AND ADMINISTRATION].

Addiction, Abuse, And Misuse

Fentanyl buccal tablets contain
fentanyl, a Schedule II controlled substance. As an opioid, fentanyl buccal
tablets expose 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
fentanyl buccal tablets. 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 fentanyl buccal
tablets, and monitor all patients receiving fentanyl buccal tablets 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
fentanyl buccal tablets, but use in such patients necessitates intensive
counseling about the risks and proper use of fentanyl buccal tablets 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 fentanyl buccal
tablets. 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 [see PATIENT INFORMATION]. 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.

Transmucosal Immediate Release
Fentanyl (TIRF) Risk Evaluation And Mitigation Strategy (REMS) Access Program

Because of the risk for misuse,
abuse, addiction, and overdose [see Drug Abuse And Dependence], fentanyl
buccal tablets are available only through a restricted program called the TIRF
REMS Access program. Under the TIRF REMS Access program, outpatients,
healthcare professionals who prescribe for outpatient use, 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 fentanyl buccal tablets, patient and prescriber enrollment is not
required.

Required components of the TIRF
REMS Access program are:

  • Healthcare professionals, who prescribe fentanyl buccal
    tablets for outpatient use, must review the prescriber educational materials
    for the TIRF REMS Access program, enroll in the program, and comply with the
    REMS requirements.
  • To receive fentanyl buccal tablets, outpatients must
    understand the risks and benefits and sign a Patient-Prescriber Agreement.
  • Pharmacies that dispense fentanyl buccal tablets must
    enroll in the program and agree to comply with the REMS requirements.
  • Wholesalers and distributors that distribute fentanyl
    buccal tablets must enroll in the program, and distribute only to authorized
    pharmacies.
  • Further information, including a list of qualified
    pharmacies/distributors, is available at www.TIRFREMSAccess.com or by calling
    1-866-822-1483.

Neonatal Opioid Withdrawal
Syndrome

Prolonged use of fentanyl
buccal tablets 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 [see Use In Specific Populations, PATIENT INFORMATION].

Life-Threatening Respiratory
Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic,
Or Debilitated Patients

The use of fentanyl buccal
tablets 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

fentanyl buccal tablets-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 fentanyl buccal tablets [see Life-Threatening Respiratory Depression].

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 [see Life-Threatening Respiratory Depression].

Monitor such patients closely,
particularly when initiating and titrating fentanyl buccal tablets and when
fentanyl buccal tablets are given concomitantly with other drugs that depress
respiration [see Life-Threatening Respiratory Depression]. Alternatively, consider the use of non-opioid analgesics
in these patients.

Serotonin Syndrome With Concomitant
Use Of Serotonergic Drugs

Cases of serotonin syndrome, a
potentially life-threatening condition, have been reported during concomitant
use of fentanyl buccal tablets 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
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 fentanyl buccal tablets if
serotonin syndrome is suspected.

Adrenal Insufficiency

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.

Severe Hypotension

Fentanyl buccal tablets 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 or titrating the
dosage of fentanyl buccal tablets. In patients with circulatory shock, fentanyl
buccal tablets may cause vasodilation that can further reduce cardiac output
and blood pressure. Avoid the use of fentanyl buccal tablets 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), fentanyl buccal
tablets 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
fentanyl buccal tablets.

Opioids may also obscure the
clinical course in a patient with a head injury. Avoid the use of fentanyl
buccal tablets in patients with impaired consciousness or coma.

Risks Of Use In Patients With Gastrointestinal Conditions

Fentanyl buccal tablets are
contraindicated in patients with known or suspected gastrointestinal
obstruction, including paralytic ileus.

The fentanyl in fentanyl buccal
tablets 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 Disorders

The fentanyl in fentanyl buccal
tablets 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 fentanyl buccal tablets therapy.

Risks Of Driving And Operating
Machinery

Fentanyl buccal tablets 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
fentanyl buccal tablets and know how they will react to the medication.

Cardiac Disease

Intravenous fentanyl may
produce bradycardia. Therefore, use fentanyl buccal tablets with caution in
patients with bradyarrhythmias.

Application Site Reactions

Application site reactions
occurred in 10% of patients in clinical trials and ranged from paresthesia to
ulceration and bleeding [see ADVERSE REACTIONS].

MAO Inhibitors

Fentanyl buccal tablets are not
recommended for use in patients who have received MAO inhibitors within 14
days, because severe and unpredictable potentiation by MAO inhibitors has been
reported with opioid analgesics [see DRUG INTERACTIONS].

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 life-threatening respiratory depression, including information that
the risk is greatest when starting fentanyl buccal tablets or when the dosage
is increased, and that it can occur even at recommended dosages [see WARNINGS
AND PRECAUTIONS
].
Advise patients how to recognize respiratory depression and to seek medical
attention if breathing difficulties develop.

Increased Risk Of Overdose And Death
In Children Due To Accidental Ingestion
  • Healthcare providers 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 [see WARNINGS AND PRECAUTIONS].
  • Inform patients that accidental ingestion, especially by
    children, may result in respiratory depression or death [see WARNINGS AND
    PRECAUTIONS
    ].
  • Instruct patients to take steps to store fentanyl buccal
    tablets securely and to dispose of unused fentanyl buccal tablets [see DOSAGE
    AND ADMINISTRATION
    , PATIENT INFORMATION; Disposal of
    Unopened Fentanyl Buccal Tablets Blister Packages When No Longer Needed
    ].
  • Instruct patients and caregivers to keep both used and
    unused fentanyl buccal tablets out of the reach of children [see WARNINGS
    AND PRECAUTIONS
    ].
Interactions With Benzodiazepines
And Other CNS Depressants (including Alcohol)

Inform patients that
potentially fatal additive effects may occur if fentanyl buccal tablets are
used with benzodiazepines or other CNS depressants, including alcohol, and not
to use these concomitantly unless supervised by a health care provider [see WARNINGS
AND PRECAUTIONS
, DRUG INTERACTIONS].

Addiction, Abuse, And Misuse

Inform patients that the use of
fentanyl buccal tablets, even when taken as recommended, can result in
addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS
AND PRECAUTIONS
].
Instruct patients not to share fentanyl buccal tablets with others and to take
steps to protect fentanyl buccal tablets from theft or misuse.

Transmucosal Immediate-Release
Fentanyl (TIRF) REMS

Advise patients of the following
information pertaining to the TIRF REMS

  • Inform outpatients that they must be enrolled in the TIRF
    REMS Access program before they can receive fentanyl buccal tablets.
  • Allow patients the opportunity to ask questions and
    discuss any concerns regarding fentanyl buccal tablets or the TIRF REMS Access
    program.
  • As required by the TIRF REMS Access program, review the
    contents of the fentanyl buccal tablets Medication Guide with every patient
    before initiating treatment with fentanyl buccal tablets.
  • Advise the patient that fentanyl buccal tablets is
    available only from pharmacies that are enrolled in the TIRF REMS Access
    program, and provide them with the telephone number and website for information
    on how to obtain the drug.
  • Advise the patient that only enrolled healthcare
    providers may prescribe fentanyl buccal tablets.
  • Inform the patient that they must sign the
    Patient-Prescriber Agreement to acknowledge that they understand the risks of
    fentanyl buccal tablets.
  • Advise patients that they may be requested to participate
    in a survey to evaluate the effectiveness of the TIRF REMS Access program [see WARNINGS
    AND PRECAUTIONS
    ].
Serotonin Syndrome

Inform patients that opioids
could cause a rare but potentially life-threatening 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 healthcare providers if they are
taking, or plan to take serotonergic medications [see WARNINGS AND
PRECAUTIONS
, DRUG INTERACTIONS].

MAOI Interaction

Inform patients to avoid taking
fentanyl buccal tablets while using any drugs that inhibit monoamine oxidase.
Patients should not start MAOIs while taking fentanyl buccal tablets [see WARNINGS
AND PRECAUTIONS
; DRUG INTERACTIONS].

Adrenal Insufficiency

Inform patients that opioids
could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal
insufficiency may present with non-specific symptoms and signs such as nausea,
vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
Advise patients to seek medical attention if they experience a constellation of
these symptoms [see WARNINGS AND PRECAUTIONS].

Important Administration
Instructions
[see DOSAGE AND ADMINISTRATION]
  • Instruct patients not to take fentanyl buccal tablets for
    acute pain, postoperative pain, pain from injuries, headache, migraine or any
    other short-term pain, even if they have taken other opioid analgesics for
    these conditions.
  • Instruct patients on the meaning of opioid tolerance and
    that fentanyl buccal tablets are only to be used as a supplemental pain
    medication for patients with pain requiring around-the-clock opioids, who have
    developed tolerance to the opioid medication, and who need additional opioid
    treatment of breakthrough pain episodes.
  • Instruct patients that, if they are not taking an opioid
    medication on a scheduled basis (around-the-clock), they should not take
    fentanyl buccal tablets.
  • Instruct patients that the titration phase is the only
    period in which they may take more than ONE tablet to achieve a desired dose
    (e.g., two 100 mcg tablets for a 200 mcg dose).
  • Instruct patients that, if the breakthrough pain episode
    is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF
    FENTANYL BUCCAL TABLETS USING THE SAME STRENGTH FOR THAT EPISODE. Thus,
    patients should take a maximum of two doses of fentanyl buccal tablets for any
    breakthrough pain episode.
  • Instruct patients that they MUST wait at least 4 hours
    before treating another episode of breakthrough pain with fentanyl buccal
    tablets.
  • Instruct patients NOT to share fentanyl buccal tablets
    and that sharing fentanyl buccal tablets with anyone else could result in the
    other individual’s death due to overdose.
  • Make patients aware that fentanyl buccal tablets contain
    fentanyl which is a strong pain medication similar to hydromorphone, methadone,
    morphine, oxycodone, and oxymorphone.
  • Instruct patients not to open the blister until ready to
    use fentanyl buccal tablets and not to store the tablet in a temporary
    container such as a pill box, once it has been removed from the blister
    package.
  • Instruct patients that fentanyl buccal tablets are not to
    be swallowed whole; this will reduce the effectiveness of the medication.
    Tablets are to be placed between the cheek and gum above a molar tooth or under
    the tongue and allowed to dissolve. After 30 minutes if remnants of the tablet
    still remain, patients may swallow it with a glass of water.
  • Caution patients to talk to their doctor if breakthrough
    pain is not alleviated or worsens after taking fentanyl buccal tablets.
  • Instruct patients to use fentanyl buccal tablets exactly
    as prescribed by their doctor and not to take fentanyl buccal tablets more
    often than prescribed.
  • Provide patients and their caregivers with a Medication
    Guide each time fentanyl buccal tablets are dispensed because new information
    may be available.
Hypotension

Inform patients that fentanyl
buccal tablets may cause orthostatic hypotension and syncope. Instruct patients
how to recognize symptoms of low blood pressure and how to reduce the risk of
serious consequences should hypotension occur (e.g., sit or lie down, carefully
rise from a sitting or lying position) [see WARNINGS AND PRECAUTIONS].

Anaphylaxis

Inform patients that
anaphylaxis have been reported with ingredients contained in fentanyl buccal
tablets. Advise patients how to recognize such a reaction and when to seek
medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS].

Pregnancy

Neonatal Opioid Withdrawal
Syndrome

Inform patients that prolonged
use of fentanyl buccal tablets can result in neonatal opioid withdrawal
syndrome, which may be life-threatening if not recognized and treated [see WARNINGS
AND PRECAUTIONS
, Use In Specific Populations].

Embryo-Fetal Toxicity

Inform female patients of
reproductive potential that fentanyl buccal tablets can cause fetal harm and to
inform the healthcare provider of a known or suspected pregnancy [see Use In
Specific Populations
, Nonclinical Toxicology].

Lactation

Advise nursing mothers to
monitor infants for increased sleepiness (more than usual), breathing
difficulties, or limpness. Instruct nursing mothers to seek immediate medical
care if they notice these signs [see Use In Specific Populations].

Infertility

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].

Driving Or Operating Heavy
Machinery

Inform patients that fentanyl
buccal tablets may impair the ability to perform potentially hazardous
activities such as driving a car or operating heavy machinery. Advise patients
not to perform such tasks until they know how they will react to the medication
[see WARNINGS AND PRECAUTIONS].

Constipation

Advise patients of the
potential for severe constipation, including management instructions and when
to seek medical attention [see ADVERSE REACTIONS, CLINICAL
PHARMACOLOGY
].

Disposal Of Unopened Fentanyl
Buccal Tablets Blister Packages When No Longer Needed
  • Patients and members of their household must be advised
    to dispose of any unopened blister packages remaining from a prescription as
    soon as they are no longer needed.
  • To dispose of unused fentanyl buccal tablets, remove
    fentanyl buccal tablets from blister packages and flush down the toilet. Do not
    flush the fentanyl buccal tablets blister packages or cartons down the toilet.
  • Detailed instructions for the proper storage,
    administration, disposal, and important instructions for managing an overdose
    of fentanyl buccal tablets are provided in the fentanyl buccal tablets
    Medication Guide. Instruct patients to read this information in its entirety
    and provide an opportunity to have their questions answered.
  • In the event that a caregiver requires additional
    assistance in disposing of excess unusable tablets that remain in the home
    after a patient has expired, instruct them to call the Teva Pharmaceuticals
    toll-free number (1-888-483-8279) or seek assistance from their local DEA
    office.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis,
Impairment Of Fertility

Carcinogenesis

Fentanyl was evaluated for
carcinogenic potential in a 104-week rat study and in a 6-month Tg.AC
transgenic mouse study. In rats, doses up to 50 mcg/kg in males and 100 mcg/kg
in females were administered subcutaneously and no treatment-related neoplasms
were observed (doses are equivalent to 2.3-and 3.4-times the exposure of a
single human dose of 800 mcg per pain episode, respectively, based on an AUC
comparison). In a 26-week transgenic mice model (Tg.AC), at topical doses up to
50 mcg/dose/day, no increase in the occurrence of treatment-related neoplasms
was observed.

Mutagenesis

Fentanyl citrate was not
mutagenic in the Ames reverse mutation assay in S. typhimurium or E. coli, or
the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in
the in vivo mouse micronucleus assay.

Impairment Of Fertility

In a fertility study, female
rats were administered fentanyl subcutaneously for 14 days prior to mating with
untreated males at doses up to 300 mcg/kg and no effects on female fertility
were observed. The systemic exposure at the dose of 300 mcg/kg was
approximately 8.6 times the exposure of a single human dose of 800 mcg per pain
episode, based on an AUC comparison. Males were administered fentanyl
subcutaneously for 28 days prior to mating with untreated females at doses up
to 300 mcg/kg. At 300 mcg/kg, adverse effects on sperm parameters, which affected
fertility, were observed. These effects included decreased percent mobile
sperm, decreased sperm concentrations as well as an increase in the percent
abnormal sperm. The dose in males at which no effects on fertility were
observed was 100 mcg/kg, which is approximately 5.7-times the exposure of a
single human dose of 800 mcg per pain episode, based on an AUC comparison.

Fentanyl has been shown to
impair fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg
subcutaneously. Conversion to the human equivalent doses indicates that this is
within the range of the human recommended dosing for fentanyl buccal tablets.

Use In Specific Populations

Pregnancy

Risk Summary

Prolonged use of opioid
analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS
AND PRECAUTIONS
].
Available data with fentanyl buccal tablets in pregnant women are insufficient
to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies,
fentanyl administration to pregnant rats during organogenesis was embryocidal
at doses within the range of the human recommended dosing. When administered
during gestation through lactation fentanyl administration to pregnant rats
resulted in reduced pup survival at doses within the range of the human
recommended dosing. No evidence of malformations were noted in animal studies
completed to date [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%, 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 of neonatal withdrawal symptoms usually occurs in the first days after
birth. The duration and severity of neonatal opioid withdrawal syndrome may
vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and
manage accordingly [see WARNINGS AND PRECAUTIONS].

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. Fentanyl buccal tablets
are not recommended for use in pregnant women during or immediately prior to
labor, when other analgesic techniques are more appropriate. Opioid analgesics,
including fentanyl buccal tablets, 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.

Data

Human Data

In women treated acutely with
intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory
or neurological depression were no more frequent than would be expected in
infants of untreated mothers.

Transient neonatal muscular
rigidity has been observed in infants whose mothers were treated with
intravenous fentanyl.

Animal Data

Fentanyl (25, 50, or 100 mcg/kg) was administered
subcutaneously to pregnant rats during the period of organogenesis (Gestation
Day, GD 6-17). Maternal toxicity and a decrease in fetal weights were observed
at 100 mcg/kg but no teratogenicity was seen in the study (100 mcg/kg dose is
equivalent to 1.4-times the exposure of a single human dose of 800 mcg per pain
episode, based on an AUC comparison). Fentanyl (50, 100, or 250 mcg/kg) was
also administered subcutaneously to pregnant rabbits during the period of
organogenesis (GD 6-18). Maternal toxicity was noted at doses >100 mcg/kg.
No teratogenicity was seen in the study (250 mcg/kg dose is equivalent to
7.5-times the exposure of a single human dose of 800 mcg per pain episode,
based on an AUC comparison).

Fentanyl has been shown to embryocidal in pregnant rats
at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of fentanyl buccal
tablets on a mg/m² basis) from GD 6 to 18 and 160 mcg/kg subcutaneously (2
times the 800 mcg dose of fentanyl buccal tablets based on a mg/m² basis). No
evidence of teratogenicity was reported.

No evidence of malformations or adverse effects on the fetus
was reported in a published study in which pregnant rats were administered
fentanyl continuously via subcutaneously implanted osmotic minipumps at doses
of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout
pregnancy. The high dose was approximately 6 times the human dose of 800 mcg
fentanyl buccal tablets per pain episode on a mg/m² basis and produced mean
steady-state plasma levels that are approximately 5 times higher than the mean
Cmax observed following administration of 800 mcg dose of fentanyl buccal
tablets in humans.

In a postnatal development
study, pregnant rats were treated from GD 6 through lactation day (LD) 20 with
subcutaneous doses of fentanyl (25, 50, 100, and 400 mcg/kg). Maternal toxicity
was noted at doses >100 mcg/kg. A reduction in pup growth and delayed
attainment of developmental indices were observed at >100 mcg/kg. No
difference in the number of live pups/litter was seen at birth, however, pup
survival at LD 4 was reduced to 48% at 400 mcg/kg and by LD 21 pup survival was
reduced to 30% and 26% at 100 and 400 mcg/kg, respectively. During lactation,
fentanyl-related clinical signs (decreased activity, skin cold to touch, and
moribund appearance) were noted in the F1 pups, most prominently in the 400 mcg/kg
group. Pups from this group also had significantly reduced body weights
throughout the lactation period. The dose of fentanyl administered to rats at
which no developmental toxicity in the F1 generation was seen was 50 mcg/kg
which is approximately equal the exposure of a single human dose of 800 mcg per
pain episode, based on an AUC comparison.

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 fentanyl buccal tablets.

Clinical Considerations

Monitor infants exposed to
fentanyl buccal tablets 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.

Females And Males Of Reproductive
Potential

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 [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Nonclinical
Toxicology
].

Pediatric Use

The safety and efficacy of
fentanyl buccal tablets have not been established in pediatric patients below
the age of 18 years.

Geriatric Use

Of the 304 patients with cancer
in clinical studies of fentanyl buccal tablets, 69 (23%) were 65 years of age
and older. Patients over the age of 65 years tended to titrate to slightly
lower doses than younger patients. Patients over the age of 65 years reported a
slightly higher frequency for some adverse events specifically vomiting,
constipation, and abdominal pain. Therefore, caution should be exercised in
individually titrating fentanyl buccal tablets in elderly patients to provide
adequate efficacy while minimizing risk.

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 fentanyl buccal tablets slowly in geriatric
patients and monitor closely for signs of central nervous system and
respiratory depression [see WARNINGS AND PRECAUTIONS].

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.

Patients With Renal Or Hepatic
Impairment

Insufficient information exists
to make recommendations regarding the use of fentanyl buccal tablets in
patients with impaired renal or hepatic function. Fentanyl is metabolized
primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated
in urine. If the drug is used in these patients, it should be used with caution
because of the hepatic metabolism and renal excretion of fentanyl.

Sex

Both male and female opioid
tolerant patients with cancer were studied for the treatment of breakthrough
cancer pain. No clinically relevant sex differences were noted either in dosage
requirement or in observed adverse reactions.

Race

The pharmacokinetic effects of
race with the use of fentanyl buccal tablets have not been systematically
evaluated. In studies conducted in healthy Japanese subjects, systemic exposure
was generally higher than that observed in U.S. subjects.

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