Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
NUCYNTA® ER contains tapentadol, a Schedule II controlled
substance. As an opioid, NUCYNTA® ER exposes users to the risks of addiction,
abuse, and misuse [see Drug Abuse and Dependence]. As modified-release
products such as NUCYNTA® ER deliver the opioid over an extended period of
time, there is a greater risk for overdose and death due to the larger amount
of tapentadol present.
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed NUCYNTA® ER and in
those who obtain the drug illicitly. Addiction can occur at recommended doses
and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse,
or misuse prior to prescribing NUCYNTA® ER, and monitor all patients receiving NUCYNTAR®
ER 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 addiction or abuse) or mental illness (e.g., major depression). The
potential for these risks should not, however, prevent the prescribing of
NUCYNTA® ER for the proper management of pain in any given patient. Patients at
increased risk may be prescribed modified-release opioid formulations such as
NUCYNTA® ER, but use in such patients necessitates intensive counseling about
the risks and proper use of NUCYNTA® ER along with intensive monitoring for
signs of addiction, abuse, and misuse.
Abuse or misuse of NUCYNTA® ER by crushing, chewing,
snorting, or injecting the dissolved product will result in the uncontrolled
delivery of tapentadol and can result in overdose and death [see OVERDOSAGE].
Opioid agonists such as NUCYNTA® ER are sought by drug
abusers and people with addiction disorders and are subject to criminal
diversion. Consider these risks when prescribing or dispensing NUCYNTA® ER.
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.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory
depression has been reported with the use of modified-release opioids, even
when used as recommended. Respiratory depression from opioid use, 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
While serious, life-threatening, or fatal respiratory
depression can occur at any time during the use of NUCYNTA® ER, the risk is
greatest during the initiation of therapy or following a dose increase. Closely
monitor patients for respiratory depression when initiating therapy with
NUCYNTA® ER and following dose increases.
To reduce the risk of respiratory depression, proper
dosing and titration of NUCYNTA® ER are essential [see DOSAGE AND ADMINISTRATION].
Overestimating the NUCYNTA® ER dose when converting patients from another
opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of NUCYNTA® ER,
especially by children, can result in respiratory depression and death due to
an overdose of tapentadol.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of NUCYNTA® ER during pregnancy can result
in withdrawal signs 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. 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.
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.
Interactions With Central Nervous System Depressants
Patients must not consume alcoholic beverages or
prescription or non-prescription products containing alcohol while on NUCYNTAR®
ER therapy. The co-ingestion of alcohol with NUCYNTA® ER may result in
increased plasma tapentadol levels and a potentially fatal overdose of
tapentadol [see CLINICAL PHARMACOLOGY].
Hypotension, profound sedation, coma, respiratory
depression, and death may result if NUCYNTA® ER is used concomitantly with
alcohol or other central nervous system (CNS) depressants (e.g., sedatives,
anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of NUCYNTA® ER in a patient
taking a CNS depressant, assess the duration of use of the CNS depressant and
the patient's response, including the degree of tolerance that has developed to
CNS depression. Additionally, evaluate the patient's use of alcohol or illicit
drugs that cause CNS depression. If the decision to begin NUCYNTA® ER is made,
start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation
and respiratory depression, and consider using a lower dose of the concomitant
CNS depressant [see DRUG INTERACTIONS].
Use In Elderly, Cachectic, And 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 patients.
Therefore, closely monitor such patients, particularly when initiating and
titrating NUCYNTA® ER and when NUCYNTA® ER is given concomitantly with other
drugs that depress respiration [see Life-Threatening Respiratory Depression].
Use In Patients With Chronic Pulmonary Disease
Monitor for respiratory depression those patients with
significant chronic obstructive pulmonary disease or cor pulmonale, and
patients having a substantially decreased respiratory reserve, hypoxia,
hypercarbia, or pre-existing respiratory depression, particularly when
initiating therapy and titrating with NUCYNTA® ER, as in these patients, even
usual therapeutic doses of NUCYNTA® ER may decrease respiratory drive to the
point of apnea [see Life-Threatening Respiratory Depression]. Consider the use of
alternative non-opioid analgesics in these patients if possible.
NUCYNTA® ER may cause severe hypotension. There is an
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 dose of NUCYNTA® ER. In patients with
circulatory shock, NUCYNTA® ER may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of NUCYNTA® ER in patients
with circulatory shock.
Use In Patients With Head Injury Or Increased
Monitor patients taking NUCYNTA® ER who may be
susceptible to the intracranial effects of CO2 retention (e.g., those with
evidence of increased intracranial pressure or brain tumors) for signs of
sedation and respiratory depression, particularly when initiating therapy with
NUCYNTA® ER. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2
retention can further increase intracranial pressure. Opioids may also obscure
the clinical course in a patient with a head injury.
Avoid the use of NUCYNTA® ER in patients with impaired
consciousness or coma.
NUCYNTA® ER has not been evaluated in patients with a predisposition
to a seizure disorder, and such patients were excluded from clinical studies.
The active ingredient tapentadol in NUCYNTA® ER may aggravate convulsions in
patients with convulsive disorders, and may induce or aggravate seizures in
some clinical settings. Monitor patients with a history of seizure disorders
for worsened seizure control during NUCYNTA® ER therapy.
Cases of life-threatening serotonin syndrome have been
reported with the concurrent use of tapentadol and serotonergic drugs.
Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs),
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic
antidepressants (TCAs), triptans, drugs that affect the serotonergic
neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs
that impair metabolism of serotonin (including MAOIs). This may occur within
the recommended dose. Serotonin syndrome 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) and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea) and can be fatal [see DRUG INTERACTIONS].
Use In Patients With Gastrointestinal Conditions
NUCYNTA® ER is contraindicated in patients with GI
obstruction, including paralytic ileus. The tapentadol in NUCYNTA® ER may cause
spasm of the sphincter of Oddi. Monitor patients with biliary tract disease,
including acute pancreatitis, for worsening symptoms.
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine)
analgesics in patients who have received or are receiving a course of therapy
with a full opioid agonist analgesic, including NUCYNTA® ER. In these patients,
mixed agonists/antagonists and partial agonist analgesics may reduce the
analgesic effect and/or may precipitate withdrawal symptoms. When discontinuing
NUCYNTA® ER, gradually taper the dose [see DOSAGE AND ADMINISTRATION].
Driving And Operating Heavy Machinery
NUCYNTA® ER 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 NUCYNTA® ER and know how they will
react to the medication.
A study with an immediate-release formulation of
tapentadol in subjects with hepatic impairment showed higher serum
concentrations of tapentadol than in those with normal hepatic function. Avoid
use of NUCYNTA® ER in patients with severe hepatic impairment. Reduce the dose
of NUCYNTA® ER in patients with moderate hepatic impairment [see DOSAGE AND
ADMINISTRATION and CLINICAL PHARMACOLOGY]. Closely monitor patients
with moderate hepatic impairment for respiratory and central nervous system
depression when initiating and titrating NUCYNTA® ER.
Use of NUCYNTA® ER in patients with severe renal
impairment is not recommended due to accumulation of a metabolite formed by
glucuronidation of tapentadol.
The clinical relevance of the elevated metabolite is not
known [see CLINICAL PHARMACOLOGY].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Addiction, Abuse, and Misuse
Inform patients that the use of NUCYNTA® ER, even when
taken as recommended, can result in addiction, abuse, and misuse, which can
lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct
patients not to share NUCYNTA® ER with others and to take steps to protect
NUCYNTA® ER from theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening
respiratory depression, including information that the risk is greatest when
starting NUCYNTA® ER or when the dose is increased, and that it can occur even
at recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how
to recognize respiratory depression and to seek medical attention if breathing
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 NUCYNTA® ER securely
and to dispose of unused NUCYNTA® ER by flushing the tablets down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and
treated [see WARNINGS AND PRECAUTIONS].
Interactions with Alcohol and other CNS Depressants
Instruct patients not to consume alcoholic beverages, as
well as prescription and over-the counter products that contain alcohol, during
treatment with NUCYNTA® ER. The co-ingestion of alcohol with NUCYNTA® ER may
result in increased plasma tapentadol levels and a potentially fatal overdose
of tapentadol [see WARNINGS AND PRECAUTIONS].
Inform patients that potentially serious additive effects
may occur if NUCYNTA® ER is used with alcohol or other CNS depressants, and not
to use such drugs unless supervised by a health care provider.
Concurrent use of MAOI
Inform patients not to take NUCYNTA® ER while using any
drugs that inhibit monoamine oxidase. Patients should not start MAOIs while
taking NUCYNTA® ER.
Inform patients that NUCYNTA® ER could cause seizures if
they are at risk for seizures or have epilepsy. Patients should be advised to
stop taking NUCYNTA® ER if they have a seizure while taking NUCYNTA® ER and
call their healthcare provider right away.
Inform patients that NUCYNTA® ER could cause a rare but
potentially lifethreatening condition resulting from concomitant administration
of serotonergic drugs (including Serotonin Reuptake Inhibitors, Serotonin and
Norepinephrine Reuptake Inhibitors and tricyclic antidepressants). 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 additional medications including CNS Depressants, MAO
inhibitors, mixed agonists/antagonist opioid analgesics, anticholinergics,
SSRIs, SNRIs, or tricyclic antidepressants.
Important Administration Instructions
Instruct patients how to properly take NUCYNTA® ER,
including the following:
- Swallowing NUCYNTA® ER tablets whole
- Not cutting, crushing, chewing, or dissolving the tablets
- Using NUCYNTA® ER exactly as prescribed to reduce the
risk of life-threatening adverse reactions (e.g., respiratory depression)
- Not discontinuing NUCYNTA® ER without first discussing
the need for a tapering regimen with the prescriber
- To take each tablet with enough water to ensure complete
swallowing immediately after placing in mouth.
Inform patients that NUCYNTA® ER 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).
Driving or Operating Heavy Machinery
Inform patients that NUCYNTA® ER 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.
Advise patients of the potential for severe constipation,
including management instructions and when to seek medical attention.
Inform patients that anaphylaxis has been reported with
ingredients contained in NUCYNTA® ER. Advise patients how to recognize such a
reaction and when to seek medical attention.
Advise female patients that NUCYNTA® ER can cause fetal
harm and to inform the prescriber if they are pregnant or plan to become
Disposal of Unused NUCYNTA® ER
Advise patients to flush the unused tablets down the
toilet when NUCYNTA® ER is no longer needed.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Tapentadol was administered to rats (diet) and mice (oral
gavage) for two years.
In mice, tapentadol HCl was administered by oral gavage
at dosages of 50, 100 and 200 mg/kg/day for 2 years (up to 0.34 times in the
male mice and 0.25 times in the female mice the plasma exposure at the maximum
recommended human dose [MRHD] for NUCYNTA® ER on an area under the time-curve
[AUC] basis). No increase in tumor incidence was observed at any dose level.
In rats, tapentadol HCl was administered in diet at
dosages of 10, 50, 125 and 250 mg/kg/day for two years (up to 0.20 times in the
male rats and 0.75 times in the female rats the plasma exposure at the MRHD on
an AUC basis). No increase in tumor incidence was observed at any dose level.
Tapentadol did not induce gene mutations in bacteria, but
was clastogenic with metabolic activation in a chromosomal aberration test in V79
cells. The test was repeated and was negative in the presence and absence of
metabolic activation. Â The one positive result for tapentadol was not confirmed
in vivo in rats, using the two endpoints of chromosomal aberration and
unscheduled DNA synthesis, when tested up to the maximum tolerated dose.
Impairment of Fertility
Tapentadol HCl was administered intravenously to male or
female rats at dosages of 3, 6, or 12 mg/kg/day (representing exposures of up
to approximately 0.56 times in the male rats and 0.50 times in the female rats
the exposure at the MRHD on an AUC basis, based on extrapolation from
toxicokinetic analyses in a separate 4-week intravenous study in rats).
Tapentadol did not alter fertility at any dose level. Maternal toxicity and
adverse effects on embryonic development, including decreased number of
implantations, decreased numbers of live conceptuses, and increased pre- and
post-implantation losses occurred at dosages ≥ 6 mg/kg/day.
Use In Specific Populations
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. Observe newborns
for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding,
diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly
[see WARNINGS AND PRECAUTIONS].
Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. NUCYNTA® ER should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Tapentadol HCl was evaluated for teratogenic effects in
pregnant rats and rabbits following intravenous and subcutaneous exposure
during the period of embryofetal organogenesis. When tapentadol was
administered twice daily by the subcutaneous route in rats at dose levels of
10, 20, or 40 mg/kg/day [producing up to 1.36 times the plasma exposure at the
maximum recommended human dose (MRHD) of 500 mg/day for NUCYNTA® ER based on an
area under the time-curve (AUC) comparison], no teratogenic effects were
observed. Evidence of embryofetal toxicity included transient delays in
skeletal maturation (i.e., reduced ossification) at the 40 mg/kg/day dose which
was associated with significant maternal toxicity. Administration of tapentadol
HCl in rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection
[producing 0.3, 0.8, and 2.5 times the plasma exposure at the MRHD based on an
AUC comparison, respectively] revealed embryofetal toxicity at doses ≥ 10
mg/kg/day. Findings included reduced fetal viability, skeletal delays and other
variations. In addition, there were multiple malformations including gastroschisis/thoracogastroschisis,
amelia/phocomelia, and cleft palate at doses ≥ 10 mg/kg/day and above, and
ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day.
Embryofetal toxicity, including malformations, may be secondary to the
significant maternal toxicity observed in the study.
In a study of pre- and postnatal development in rats,
oral administration of tapentadol at doses of 20, 50, 150, or 300 mg/kg/day to
pregnant and lactating rats during the late gestation and early postnatal
period [resulting in up to 2.28 times the plasma exposure at the MRHD on an AUC
basis] did not influence physical or reflex development, the outcome of
neurobehavioral tests or reproductive parameters. At maternal tapentadol doses ≥ 150
mg/kg/day, a dose-related increase in pup mortality was observed to postnatal
Day 4. Treatment-related developmental delay was observed in the dead pups,
including incomplete ossification. In addition, significant reductions in pup
body weights and body weight gains at doses associated with maternal toxicity
(150 mg/kg/day and above) were seen throughout lactation.
Labor And Delivery
Opioids cross the placenta and may produce respiratory
depression in neonates. NUCYNTA® ER is not for use in women during and
immediately prior to labor, when shorter acting analgesics or other analgesic
techniques are more appropriate. Opioid analgesics can prolong labor through
actions that 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 dilatation, which tends to shorten labor.
There is insufficient/limited information on the
excretion of tapentadol in human or animal breast milk. Physicochemical and
available pharmacodynamic/ toxicological data on tapentadol point to excretion
in breast milk and risk to the breastfeeding child cannot be excluded. Because
of the potential for adverse reactions in nursing infants from NUCYNTA® ER, a
decision should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
Withdrawal symptoms can occur in breast-feeding infants
when maternal administration of NUCYNTA® ER is stopped.
The safety and efficacy of NUCYNTA® ER in pediatric
patients less than 18 years of age have not been established.
Of the total number of patients in Phase 2/3
double-blind, multiple-dose clinical studies of NUCYNTA® ER, 28% (1023/3613)
were 65 years and over, while 7% (245/3613) were 75 years and over. No overall
differences in effectiveness or tolerability were observed between these
patients and younger patients.
In general, recommended dosing for elderly patients with
normal renal and hepatic function is the same as for younger adult patients
with normal renal and hepatic function. Because elderly patients are more
likely to have decreased renal and hepatic function, consideration should be
given to starting elderly patients with the lower range of recommended doses
[see CLINICAL PHARMACOLOGY].
The safety and effectiveness of NUCYNTA® ER have not been
established in patients with severe renal impairment (CLCR < 30 mL/min). Use
of NUCYNTA® ER in patients with severe renal impairment is not recommended due
to accumulation of a metabolite formed by glucuronidation of tapentadol. The
clinical relevance of the elevated metabolite is not known [see CLINICAL
Administration of tapentadol resulted in higher exposures
and serum levels of tapentadol in subjects with impaired hepatic function
compared to subjects with normal hepatic function [see CLINICAL PHARMACOLOGY].
The dose of NUCYNTA® ER should be reduced in patients with moderate hepatic
impairment (Child-Pugh Score 7 to 9) [see DOSAGE AND ADMINISTRATION].
Use of NUCYNTA® ER is not recommended in severe hepatic
impairment (Child- Pugh Score 10 to 15) [see WARNINGS AND PRECAUTIONS].