tapentadol 100 MG (as tapentadol hydrochloride) Oral Tablet
DRUG INTERACTIONS
7 Table 2 includes clinically significant drug interactions with NUCYNTA tablets.
Table 2: Clinically Significant Drug Interactions with NUCYNTA Tablets Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.4 )] .
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.6 ].
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.
Discontinue NUCYNTA tablets if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )] Intervention: Do not use NUCYNTA tablets in patients taking MAOIs or within 14 days of stopping such treatment.
If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of NUCYNTA tablets and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUCYNTA tablets and/or the muscle relaxant as necessary.
Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA tablets is used concomitantly with anticholinergic drugs.
Alcohol, Other Opioids, and Drugs of Abuse Clinical Impact: Due to its mu-opioid agonist activity, NUCYNTA tablets 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 Warnings and Precautions ( 5.4 )] .
Intervention: 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 tablets therapy.
Examples: Alcohol, other opioids, illicit drugs Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with NUCYNTA tablets because they reduce analgesic effect of NUCYNTA tablets or precipitate withdrawal symptoms.
( 7 ).
OVERDOSAGE
10 Clinical Presentation Acute overdosage with NUCYNTA tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.
Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] .
Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed.
Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated.
Cardiac arrest or arrhythmias will require advanced life support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose.
For clinically significant respiratory or circulatory depression secondary to tapentadol overdose, administer an opioid antagonist.
Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to tapentadol overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of tapentadol in NUCYNTA tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished.
If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed in the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome.
The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered.
If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
DESCRIPTION
11 NUCYNTA (tapentadol) tablets are a mu-opioid receptor agonist, available in immediate-release film-coated tablets for oral administration, containing 58.24, 87.36 and 116.48 mg of tapentadol hydrochloride in each tablet strength, equivalent to 50, 75, and 100 mg of tapentadol free-base, respectively.
The chemical name is 3-[(1 R ,2 R )-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride, and it has the following chemical structure: The molecular weight of tapentadol HCl is 257.80, and the molecular formula is C 14 H 23 NO∙HCl.
The n-octanol:water partition coefficient log P value is 2.87.
The pKa values are 9.34 and 10.45.
The inactive ingredients in NUCYNTA tablets include: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone.
The film coatings for all tablet strengths contain polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and the colorant FD&C Yellow #6 aluminum lake; the film coatings for the 50 mg and 75 mg tablets also contain the additional colorant D&C Yellow #10 aluminum lake.
NUCYNTA chemical structure
CLINICAL STUDIES
14 The efficacy and safety of NUCYNTA tablets in the treatment of acute pain has been established in two randomized, double-blind, placebo- and active-controlled studies of moderate to severe pain from first metatarsal bunionectomy and end-stage degenerative joint disease.
14.1 Orthopedic Surgery – Bunionectomy A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study demonstrated the efficacy of 50 mg, 75 mg, and 100 mg NUCYNTA tablets given every 4 to 6 hours for 72 hours in patients aged 18 to 80 years experiencing moderate to severe pain following unilateral, first metatarsal bunionectomy surgery.
Patients who qualified for the study with a baseline pain score of ≥4 on an 11-point rating scale ranging from 0 to 10 were randomized to 1 of 5 treatments.
Patients were allowed to take a second dose of study medication as soon as 1 hour after the first dose on study Day 1, with subsequent dosing every 4 to 6 hours.
If rescue analgesics were required, the patients were discontinued for lack of efficacy.
Efficacy was evaluated by comparing the sum of pain intensity difference over the first 48 hours (SPID48) versus placebo.
NUCYNTA tablets at each dose provided a greater reduction in pain compared to placebo based on SPID48 values.
For various degrees of improvement from baseline to the 48-hour endpoint, Figure 1 shows the fraction of patients achieving that level of improvement.
The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%.
Patients who did not complete the 48-hour observation period in the study were assigned 0% improvement.
Figure 1: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by Pain Severity at 48 Hours Compared to Baseline- Post Operative Bunionectomy The proportions of patients who showed reduction in pain intensity at 48 hours of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA tablets at each dose versus placebo.
Figure 1 14.2 End-Stage Degenerative Joint Disease A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study evaluated the efficacy and safety of 50 mg and 75 mg NUCYNTA tablets given every 4 to 6 hours during waking hours for 10 days in patients aged 18 to 80 years, experiencing moderate to severe pain from end stage degenerative joint disease of the hip or knee, defined as a 3-day mean pain score of ≥5 on an 11-point pain intensity scale, ranging from 0 to 10.
Pain scores were assessed twice daily and assessed the pain the patient had experienced over the previous 12 hours.
Patients were allowed to continue non-opioid analgesic therapy for which they had been on a stable regimen before screening throughout the study.
Eighty-three percent (83%) of patients in the tapentadol treatment groups and the placebo group took such analgesia during the study.
The 75 mg treatment group was dosed at 50 mg for the first day of the study, followed by 75 mg for the remaining nine days.
Patients requiring rescue analgesics other than study medication were discontinued for lack of efficacy.
Efficacy was evaluated by comparing the sum of pain intensity difference (SPID) versus placebo over the first five days of treatment.
NUCYNTA tablets 50 mg and 75 mg provided improvement in pain compared with placebo based on the 5-Day SPID.
For various degrees of improvement from baseline to the Day 5 endpoint, Figure 2 shows the fraction of patients achieving that level of improvement.
The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%.
Patients who did not complete the 5-day observation period in the study were assigned 0% improvement.
Figure 2: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by Average Pain Severity for the Previous 12 hours, Measured on Study Day 5 Compared to Baseline — End Stage Degenerative Joint Disease The proportions of patients who showed reduction in pain intensity at 5 days of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA tablets at each dose versus placebo.
Figure 2
HOW SUPPLIED
16 /STORAGE AND HANDLING NUCYNTA Tablets are available in the following strengths and packages.
All tablets are round and biconvex-shaped.
50 mg tablets are yellow and debossed with “O-M” on one side and “50” on the other side, and are available in bottles of 100 (NDC 50458-820-04) and hospital unit dose blister packs of 10 (NDC 50458-820-02).
75 mg tablets are yellow-orange and debossed with “O-M” on one side and “75” on the other side, and are available in bottles of 100 (NDC 50458-830-04) and hospital unit dose blister packs of 10 (NDC 50458-830-02).
100 mg tablets are orange and debossed with “O-M” on one side and “100” on the other side, and are available in bottles of 100 (NDC 50458-840-04) and hospital unit dose blister packs of 10 (NDC 50458-840-02).
Storage and Handling Store up to 25°C (77°F); excursions permitted to 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].
Protect from moisture.
Keep NUCYNTA tablets in a secure place out of reach of children.
NUCYNTA tablets that are no longer needed should be destroyed by flushing down the toilet.
RECENT MAJOR CHANGES
Boxed Warning 12/2016 Indications and Usage ( 1 ) 12/2016 Dosage and Administration ( 2 ) 12/2016 Contraindications ( 4 ) 12/2016 Warnings and Precautions ( 5 ) 12/2016
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA tablets, 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 tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.5 )] .
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.
DOSAGE FORMS AND STRENGTHS
3 Tablets: 50 mg, 75 mg, 100 mg.
50 mg: round, biconvex and film-coated yellow tablets with “O-M” on one side and “50” on the other side.
75 mg: round, biconvex and film-coated yellow-orange tablets with “O-M” on one side and “75” on the other side.
100 mg: round, biconvex and film-coated orange tablets with “O-M” on one side and “100” on the other side.
Tablets: 50 mg, 75 mg, 100 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Tapentadol is a centrally-acting synthetic analgesic.
The exact mechanism of action is unknown.
Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI).
Analgesia in animal models is derived from both of these properties.
INDICATIONS AND USAGE
1 NUCYNTA (tapentadol) tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate in adults.
Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions ( 5.1 )] , reserve NUCYNTA tablets for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products: Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia NUCYNTA tablets are an opioid analgesic indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve NUCYNTA tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of NUCYNTA tablets in pediatric patients less than 18 years of age have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category C Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.3 )] .
Available data with NUCYNTA tablets 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.
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, 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 ( 5.3 )] .
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 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 NUCYNTA 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 Animal Data 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 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 0.2, 0.6, and 1.85 times the plasma exposure at the MRHD based on an AUC comparison] 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 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 dose-related increase in pup mortality was observed through postnatal Day 4.
BOXED WARNING
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse NUCYNTA tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.
Assess each patient’s risk prior to prescribing NUCYNTA tablets, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )] .
Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA tablets.
Monitor for respiratory depression, especially during initiation of NUCYNTA tablets or following a dose increase [see Warnings and Precautions ( 5.2 )] .
Accidental Ingestion Accidental ingestion of even one dose of NUCYNTA tablets, especially by children, can result in a fatal overdose of tapentadol [see Warnings and Precautions ( 5.2 )] .
Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions ( 5.3 )] .
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )] .
Reserve concomitant prescribing of NUCYNTA tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning.
NUCYNTA tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death.
Assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions.
( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur.
Monitor closely, especially upon initiation or following a dose increase.
( 5.2 ) Accidental ingestion of NUCYNTA tablets, especially by children, can result in a fatal overdose of tapentadol.
( 5.2 ) Prolonged use of NUCYNTA tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
( 5.3 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation ( 5.4 ), ( 7 ).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.
( 5.5 ) Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration.
Discontinue NUCYNTA tablets if serotonin syndrome is suspected.
( 5.6 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
( 5.7 ) Severe Hypotension: Monitor during dosage initiation and titration.
Avoid use of NUCYNTA tablets in patients with circulatory shock.
( 5.8 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression.
Avoid use of NUCYNTA tablets in patients with impaired consciousness or coma.
( 5.9 ) 5.1 Addiction, Abuse, and Misuse NUCYNTA tablets contain tapentadol, a Schedule II controlled substance.
As an opioid, NUCYNTA tablets exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] .
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA 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 NUCYNTA tablets and monitor all patients receiving NUCYNTA tablets 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 tablets, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA 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 NUCYNTA 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 Counseling Information ( 17 )] .
Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
5.2 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 ( 10 )] .
Carbon dioxide (CO 2 ) 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 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 NUCYNTA tablets.
To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA tablets are essential [see Dosage and Administration ( 2.2 )] .
Overestimating the NUCYNTA tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of NUCYNTA tablets, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.
5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA 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 ( 8.1 ), Patient Counseling Information ( 17 )] .
5.4 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 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 ( 7 ) ].
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 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 ( 7 ), Patient Counseling Information ( 17 ) ].
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA 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: NUCYNTA 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 NUCYNTA tablets [see Warnings and Precautions ( 5.2 )].
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 Warnings and Precautions ( 5.2 )] .
Monitor such patients closely, particularly when initiating and titrating NUCYNTA tablets and when NUCYNTA tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.4 )] .
Alternatively, consider the use of non-opioid analgesics in these patients.
5.6 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) [see Drug Interactions ( 7 )] .
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) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal [see Drug Interactions ( 7 )] .
The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that.
Discontinue NUCYNTA tablets if serotonin syndrome is suspected.
5.7 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.
5.8 Severe Hypotension NUCYNTA 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 ( 7 )].
Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA tablets.
In patients with circulatory shock, NUCYNTA tablets may cause vasodilation that can further reduce cardiac output and blood pressure.
Avoid the use of NUCYNTA tablets in patients with circulatory shock.
5.9 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 CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure.
Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA tablets.
Opioids may also obscure the clinical course in a patient with a head injury.
Avoid the use of NUCYNTA tablets in patients with impaired consciousness or coma.
5.10 Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The tapentadol in NUCYNTA 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.
5.11 Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA 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 NUCYNTA tablets therapy.
5.12 Withdrawal 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 tablets.
In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 )] .
When discontinuing NUCYNTA tablets in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.5 )] .
Do not abruptly discontinue NUCYNTA tablets in these patients [see Drug Abuse and Dependence ( 9.3 )] .
5.13 Risks of Driving and Operating Machinery NUCYNTA 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 NUCYNTA tablets and know how they will react to the medication.
5.14 Interactions with Alcohol, Other Opioids, and Drugs of Abuse Due to its mu-opioid agonist activity, NUCYNTA tablets 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 ( 7 )] .
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 tablets therapy [see Drug Interactions ( 7 )] .
5.15 Risk of Toxicity in Patients with Hepatic Impairment A study with NUCYNTA tablets in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function.
Avoid use of NUCYNTA tablets in patients with severe hepatic impairment.
Reduce the dose of NUCYNTA tablets in patients with moderate hepatic impairment [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )] .
Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when receiving NUCYNTA tablets.
5.16 Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA tablets 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 ( 12.3 )] .
INFORMATION FOR PATIENTS
17 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 tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 )] .
Instruct patients not to share NUCYNTA tablets with others and to take steps to protect NUCYNTA tablets 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 tablets or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions ( 5.2 )] Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Accidental Exposure Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.2 )] .
Instruct patients to take steps to store NUCYNTA tablets securely and to dispose of unused NUCYNTA tablets by flushing the tablets down the toilet.
Interactions with Benzodiazepines and other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if NUCYNTA tablets are used with benzodiazepines or other CNS depressants, including and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )] .
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 ( 5.6 ), Drug Interactions ( 7 )] .
MAOI Interaction Inform patients not to take NUCYNTA tablets while using any drugs that inhibit monoamine oxidase.
Patients should not start MAOIs while taking NUCYNTA tablets [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 )] .
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 ( 5.7 )] .
Important Administration Instructions Instruct patients how to properly take NUCYNTA tablets, including the following: Advise patients not to adjust the dose of NUCYNTA tablets without consulting with a physician or other healthcare professional.
If patients have been receiving treatment with NUCYNTA tablets 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 ( 2.5 )] .
Hypotension Inform patients that NUCYNTA 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 ( 5.8 )] .
Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in NUCYNTA tablets.
Advise patients to recognize such a reaction and when to seek medical attention [ see Contraindications ( 4 ), Adverse Reactions ( 6.2 ) ].
Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of NUCYNTA tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 )].
Embryo-Fetal Toxicity Inform female patients of reproductive potential that NUCYNTA tablets can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )].
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 ( 8.2 )] .
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 ( 8.3 )] Driving or Operating Heavy Machinery Inform patients that NUCYNTA 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 ( 5.13 )] .
Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6.1 )] .
Disposal of Unused NUCYNTA Tablets Advise patients to dispose of unused NUCYNTA tablets by flushing down the toilet.
Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Revised: January 2017 NUC-021-C.2
DOSAGE AND ADMINISTRATION
2 Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
( 2.1 ) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.
( 2.1 ) Initiate treatment with NUCYNTA tablets at a dose of 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity.
On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose.
Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability.
Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are, therefore, not recommended.
( 2.2 ) Moderate Hepatic Impairment : Initiate treatment with 50 mg no more than once every 8 hours (maximum of three doses in 24 hours).
Monitor closely for respiratory and central nervous system depression.
( 2.3 ) Do not stop NUCYNTA tablets abruptly in a physically dependent patient.
( 2.5 ) 2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )].
Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] .
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with NUCYNTA and adjust the dosage accordingly [see Warnings and Precautions ( 5.2 )] 2.2 Initial Dosage Initiating Treatment with NUCYNTA Tablets Initiate treatment with NUCYNTA tablets in a dosing range of 50 mg to 100 mg every 4 to 6 hours as needed for pain.
On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose.
Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability.
Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are not recommended.
NUCYNTA tablets may be given with or without food [see Clinical Pharmacology ( 12.3 )].
Conversion from NUCYNTA Tablets to NUCYNTA ER Patients can be converted from NUCYNTA tablets to NUCYNTA ER using the equivalent total daily dose of NUCYNTA tablets and dividing it into two equal doses of NUCYNTA ER separated by approximately 12-hour intervals.
As an example, a patient receiving 50 mg of NUCYNTA tablets four times per day (200 mg/day) may be converted to 100 mg NUCYNTA ER twice a day.
2.3 Dosage Modifications in Patients with Hepatic Impairment The safety and efficacy of NUCYNTA tablets has not been studied in patients with severe hepatic impairment (Child-Pugh Score 10-15) and use in this population is not recommended [see Warnings and Precautions ( 5.15 )] .
Initiate treatment of patients with moderate hepatic impairment (Child-Pugh Score 7 to 9) with 50 mg no more frequently than once every 8 hours (maximum of three doses in 24 hours).
Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or lengthening the dosing interval.
Monitor closely for respiratory and central nervous system depression [see Clinical Pharmacology ( 12.3 )] .
No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6) [see Clinical Pharmacology ( 12.3 )] .
2.4 Titration and Maintenance of Therapy Continually reevaluate patients receiving NUCYNTA tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 )] .
Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the NUCYNTA tablets dosage.
If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage.
Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
2.5 Discontinuation of NUCYNTA Tablets When a patient who has been taking NUCYNTA tablets regularly and may be physically dependent no longer requires therapy with NUCYNTA tablets, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal.
If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.
Do not abruptly discontinue NUCYNTA tablets in a physically-dependent patient [see Warnings and Precautions ( 5.12 ), Drug Abuse and Dependence ( 9.3 )].