Included as part of the "PRECAUTIONS" Section
Risk Of Accidental Overdose And Death Due To Medication Errors
Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from
confusion between mg and mL when prescribing, dispensing, and administering NUCYNTA oral
solution. Ensure that the dose is communicated clearly and dispensed accurately. Always use the
enclosed calibrated syringe when administering NUCYNTA to ensure the dose is measured and
administered accurately. Do not use a teaspoon or a tablespoon to measure a dose. A household
teaspoon or tablespoon is not an adequate measuring device. Given the inexactitude of the
household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which
could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated
measuring device. Health care providers should recommend a calibrated device that can measure
and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in
measuring the dosage.
Addiction, Abuse, And Misuse
NUCYNTA oral solution contains tapentadol, a Schedule II controlled substance.
As an opioid, NUCYNTA oral solution exposes users to the risks of addiction, abuse, and misuse
[see Drug Abuse And Dependence].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately
prescribed NUCYNTA oral solution. 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 NUCYNTA
oral solution and monitor all patients receiving NUCYNTA oral solution for the development of
these behaviors and 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 NUCYNTA
oral solution, but use in such patients necessitates intensive counseling about the risks and proper use
of NUCYNTAoral solution along with intensive monitoring for signs of addiction, abuse, and
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal
diversion. Consider these risks when prescribing or dispensing NUCYNTA oral solution. 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 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 OVERDOSE]. 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
NUCYNTA oral solution, 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 NUCYNTA oral solution.
To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA oral solution
are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the NUCYNTA oral solution
dosage when converting patients from another opioid product can result in a fatal overdose with the
Accidental ingestion of even one dose of NUCYNTA oral solution, especially by children, can result
in respiratory depression and death due to an overdose of tapentadol.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of NUCYNTA oral solution during pregnancy can result in withdrawal in the neonate.
Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be lifethreatening
if not recognized and treated, and requires management according to protocols developed
by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and
manage accordingly. Advise pregnant women using opioids a prolonged period of the risk of
neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use In Specific Population, PATIENT INFORMATION].
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of
NUCYNTA oral solution with benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine
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
NUCYNTA oral solution 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 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].
Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease
Or In Elderly, Cachectic, Or Debilitated Patients
The use of NUCYNTA oral solution 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
NUCYNTA oral solution-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 NUCYNTA oral
solution [see Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease
Or In Elderly, Cachectic, Or Debilitated Patients].
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 In Patients With Chronic Pulmonary Disease
Or In Elderly, Cachectic, Or Debilitated Patients].
Monitor such patients closely, particularly when initiating and titrating NUCYNTA® and when
NUCYNTA oral solution is given concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease
Or In Elderly, Cachectic, Or Debilitated Patients]. Alternatively, consider the use of non-opioid analgesics in these
Serotonin Syndrome With Concomitant Use Of Serotonergic Drugs
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during
concurrent use of tapentadol 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
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) and/or gastrointestinal symptoms (e.g., nausea,
vomiting, diarrhea) and can be fatal [see DRUG INTERACTIONS] The onset of symptoms generally
occurs within several hours to a few days of concomitant use, but may occur later than that.
Discontinue NUCYNTA oral solution if serotonin syndrome is suspected.
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than
one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and
signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If
adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.
If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of
corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue
corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases
reported use of a different opioid without recurrence of adrenal insufficiency. The information
available does not identify any particular opioids as being more likely to be associated with adrenal
NUCYNTA oral solution 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
NUCYNTA oral solution. In patients with circulatory shock, NUCYNTA oral solution may cause
vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA
oral solution 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), NUCYNTA oral solution 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 NUCYNTA oral solution.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of
NUCYNTA oral solution in patients with impaired consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
NUCYNTA oral solution is contraindicated in patients with known or suspected gastrointestinal
obstruction, including paralytic ileus.
The tapentadol in NUCYNTA oral solution 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 tapentadol in NUCYNTA oral solution 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 NUCYNTA oral solution therapy.
Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial
agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic,
including NUCYNTA oral solution. In these patients, mixed agonist/antagonist and partial agonist
analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see DRUG INTERACTIONS].
When discontinuing NUCYNTA oral solution in a physically-dependent patient, gradually taper the
dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue NUCYNTA in these
patients [see Drug Abuse And Dependence].
Risks Of Driving And Operating Machinery
NUCYNTA oral solution 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 oral solution and
know how they will react to the medication.
Interactions With Alcohol, Other Opioids, And Drugs Of Abuse
Due to its mu-opioid agonist activity, NUCYNTA oral solution may be expected to have additive
effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central
nervous system depression, respiratory depression, hypotension, and profound sedation, coma or
death [see DRUG INTERACTIONS]. Instruct patients not to consume alcoholic beverages or use
prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse
while on NUCYNTA oral solution therapy [see DRUG INTERACTIONS].
Risk Of Toxicity In Patients With Hepatic Impairment
A study with NUCYNTA oral solution in subjects with hepatic impairment showed higher
serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of
NUCYNTAoral solution in patients with severe hepatic impairment. Reduce the dose of
NUCYNTA oral solution 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 receiving
NUCYNTA oral solution.
Risk Of Toxicity In Patients With Renal Impairment
Use of NUCYNTA oral solution 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).
Instruct patients how to measure and take the correct dose of NUCYNTA oral solution, and to
always use the enclosed syringe when administering NUCNYNTA oral solution to ensure the dose is
measured and administered accurately [see WARNINGS AND PRECAUTIONS].
Advise patients that NUCYNTA oral solution is available in 20 mg/mL. Provide detailed instruction
on how to measure and take the correct dose of NUCYNTA oral solution, and to always use the
enclosed measuring device when administering NUCYNTA oral solution, to ensure that the dose is
measured and administered accurately.
If the prescribed concentration is changed, instruct patients on how to correctly measure the new
dose to avoid errors which could result in accidental overdose and death.
Addiction, Abuse, And Misuse
Inform patients that the use of NUCYNTA oral solution, 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 NUCYNTA oral solution with others and to
take steps to protect NUCYNTA oral solution 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 oral solution 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 they are experiencing
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
oral solution securely and to dispose of unused NUCYNTA oral solution by flushing the oral
solution down the toilet.
Interactions With Benzodiazepines And Other CNS Depressants
Inform patients that potentially fatal serious additive effects may occur if NUCYNTA oral solution is
used with benzodiazepines or other CNS depressants, including alcohol, and not to use these
concomitantly drugs unless supervised by a health care provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
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 provider if they are taking, or plan to take serotonergic
medications [see DRUG INTERACTIONS].
Inform patients not to take NUCYNTA oral solution while using any drugs that inhibit monoamine
oxidase. Patients should not start MAOIs while taking NUCYNTA oral solution [see WARNINGS AND PRECAUTIONS]
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
Instruct patients how to properly take NUCYNTA oral solution, including the following:
- Advise patients to always use the enclosed calibrated oral syringe when administering
NUCYNTA oral solution to ensure the dose is measured and administered accurately.
- Advise patients never to use household teaspoons or tablespoons to measure NUCYNTA oral
- Advise patients not to adjust the dose of NUCYNTA oral solution without consulting with a
physician or other healthcare professional.
- If patients have been receiving treatment with NUCYNTA oral solution for more than a few
weeks and cessation of therapy is indicated, counsel them on the importance of safely
tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal
symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the
medication [see DOSAGE AND ADMINISTRATION].
Inform patients that NUCYNTA oral solution 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]
Inform patients that anaphylaxis has been reported with ingredients contained in NUCYNTA oral
solution. Advise patients to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of NUCYNTA oral solution
during pregnancy 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].
Inform female patients of reproductive potential that NUCYNTAoral solution can (or may) cause
fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use In Specific Populations].
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].
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 NUCYNTAoral solution 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].
Advise patients of the potential for severe constipation, including management instructions and when
to seek medical attention [see ADVERSE REACTIONS].
Disposal Of Unused NUCYNTA Oral Solution
Advise patients to dispose of unused NUCYNTA oral solution by flushing down the toilet.
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 0.2 times the plasma exposure at the maximum recommended human
dose [MRHD] 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 0.2 times in the male rats and 0.6 times in the female rats the MRHD on an
AUCbasis). 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. 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 0.4 times 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
Pregnancy Category C
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal
syndrome [see WARNINGS AND PRECAUTIONS]. . Available data with NUCYNTA oral solution
are insufficient to inform a drug-associated risk for major birth defects and miscarriage.
In animal reproduction studies, embryofetal mortality and structural malformations were observed
with subcutaneous administration of tapentadol during organogenesis to rabbits and delays in
skeletal maturation were observed in rats at exposures equivalent to and less than the maximum
recommended human dose (MRHD), respectively. When administered to pregnant rats during
organogenesis and through lactation, increased pup mortality was noted following oral tapentadol
exposures to doses equivalent to the MRHD [see Data].
Based on animal data, advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown.
Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of
medications. 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.
Fetal/Neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result
in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep
pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration,
and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used,
duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the
newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage
accordingly [see WARNINGS AND 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. NUCYNTA oral solution is not recommended for use in
pregnant women during or immediately prior to labor, when other analgesic techniques are more
appropriate. Opioid analgesics, including NUCYNTA oral solution, 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.
Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following
subcutaneous exposure during 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 times the
plasma exposure at the maximum recommended human dose (MRHD) of 700 mg/day based on an
area under the time-curve (AUC) comparison], no teratogenic effects were observed. Evidence of
embryo fetal 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 0.2, 0.6, and 1.85 times the plasma exposure at the MRHD based on an AUC
comparison] revealed embryo fetal 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 1.7 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. Treatment-related developmental delay was observed, including incomplete ossification,
and significant reductions in pup body weights and body weight gains at doses associated with
maternal toxicity (150 mg/kg/day and above). At maternal tapentadol doses ≥150 mg/kg/day, a doserelated
increase in pup mortality was observed through postnatal Day 4.
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.
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.
The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for NUCYNTA oral solution and any potential adverse effects on the
breastfed infant from NUCYNTA oral solution or from the underlying maternal condition.
Infants exposed to NUCYNTA oral solution through breast milk should be monitored for excess
sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when
maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
Females And Males Of Reproductive Potential
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It
is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].
The safety and effectiveness of NUCYNTA oral solution 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, 19% were 65 and over, while 5% were 75 and over. No overall differences in
effectiveness were observed between these patients and younger patients. The rate of
constipation was higher in subjects greater than or equal to 65 years than those less than 65 years
(12% vs. 7%).
Elderly patients (aged 65 years or older) may have increased sensitivity to tapentadol. In general,
use caution when selecting a dosage for an elderly patient, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of
concomitant disease or other drug therapy.
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 NUCYNTA
oral solution slowly in geriatric patients and monitor closely for signs of central nervous system and
respiratory depression [see WARNINGS AND PRECAUTIONS].
Tapentadol 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.
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]. Use of NUCYNTA oral solution is not recommended in patients
with severe hepatic impairment (Child- Pugh Score 10 to 15). The dose of NUCYNTA oral
solution should be reduced in patients with moderate hepatic impairment (Child-Pugh Score 7 to 9)
[see DOSAGE AND ADMINISTRATION].No dosage adjustment is recommended in patients with mild
hepatic impairment (Child-Pugh Score 5 to 6) [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY]
Use of NUCYNTA oral solution in patients with severe renal impairment (creatinine clearance
less than 30 mL/minute) is not recommended. No dosage adjustment is recommended in patients
with mild or moderate renal impairment (creatinine clearance 30-90 mL/minute) [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].