DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. NUCYNTA tablets contain tapentadol, Schedule II controlled substance.. 9.2 Abuse. NUCYNTA tablets contain tapentadol, substance with high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA tablets can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.Prescription drug abuse is the intentional non-therapeutic use of prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes physical withdrawal.Drug seeking behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated loss of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). Doctor shopping (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in patient with poor pain control.Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.NUCYNTA tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by law, is strongly advised.Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.. Risks Specific to Abuse of NUCYNTA TabletsNUCYNTA tablets are for oral use only. Abuse of NUCYNTA tablets poses risk of overdose and death. The risk is increased with concurrent abuse of NUCYNTA tablets with alcohol and other central nervous system depressants.Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.. 9.3 Dependence. Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.Physical dependence results in withdrawal symptoms after abrupt discontinuation or significant dosage reduction of drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine) or partial agonists (e.g., buprenorphine). Physical dependence may not occur to clinically significant degree until after several days to weeks of continued opioid usage.NUCYNTA tablets should not be abruptly discontinued in physically-dependent patient [see Dosage and Administration (2.5)]. If NUCYNTA tablets are abruptly discontinued in physically-dependent patient, withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes clinically significant drug interactions with NUCYNTA tablets.Table 2: Clinically Significant Drug Interactions with NUCYNTA TabletsBenzodiazepines and other Central Nervous System (CNS) DepressantsClinical 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 (5.5)].Examples:Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.Serotonergic DrugsClinical Impact:The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.7]. 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 (5.3)] 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, linezolidMixed Agonist/Antagonist and Partial Agonist Opioid AnalgesicsClinical Impact:May reduce the analgesic effect of NUCYNTA tablets and/or precipitate withdrawal symptoms.Intervention:Avoid concomitant use.Examples:butorphanol, nalbuphine, pentazocine, buprenorphineMuscle RelaxantsClinical 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.DiureticsClinical 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 DrugsClinical 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 AbuseClinical 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 (5.5)].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).. 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).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed, or described in greater detail, in other sections:Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.5)] Serotonin Syndrome [see Warnings and Precautions (5.7)] Adrenal Insufficiency [see Warnings and Precautions (5.8)] Severe Hypotension [see Warnings and Precautions (5.9)] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)] Seizures [see Warnings and Precautions (5.12)] Withdrawal [see Warnings and Precautions (5.13)] Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)] Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.5)] Serotonin Syndrome [see Warnings and Precautions (5.7)] Adrenal Insufficiency [see Warnings and Precautions (5.8)] Severe Hypotension [see Warnings and Precautions (5.9)] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)] Seizures [see Warnings and Precautions (5.12)] Withdrawal [see Warnings and Precautions (5.13)] The most common adverse reactions (incidence >=10%) were nausea, dizziness, vomiting and somnolence. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Collegium Pharmaceutical, Inc. at 1-855-331-5615 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Based on data from nine Phase 2/3 studies that administered multiple doses (seven placebo- and/or active-controlled, one noncontrolled and one Phase active-controlled safety study) the most common adverse reactions (reported by >=10% in any NUCYNTA tablets dose group) were: nausea, dizziness, vomiting and somnolence.The most common reasons for discontinuation due to adverse reactions in the studies described above (reported by >=1% in any NUCYNTA tablets dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for NUCYNTA- and placebo-treated patients, respectively.Seventy-six percent of NUCYNTA-treated patients from the nine studies experienced adverse events.NUCYNTA tablets were studied in multiple-dose, active- or placebo-controlled studies, or noncontrolled studies (n 2178), in single-dose studies (n 870), in open-label study extension (n 483) and in Phase studies (n 597). Of these, 2034 patients were treated with doses of 50 mg to 100 mg of NUCYNTA tablets dosed every to hours.The data described below reflect exposure to NUCYNTA tablets in 3161 patients, including 449 exposed for 45 days. NUCYNTA tablets were studied primarily in placebo- and active-controlled studies (n 2266, and = 2944, respectively). The population was 18 to 85 years old (mean age 46 years), 68% were female, 75% white and 67% were postoperative. Most patients received NUCYNTA tablets doses of 50 mg, 75 mg, or 100 mg every to hours.Table Adverse Reactions Reported by >=1% of NUCYNTA-Treated Patients In Seven Phase 2/3 Placebo- and/or Oxycodone-Controlled, One Non-controlled, and One Phase Oxycodone-Controlled Safety, Multiple-Dose Clinical StudiesSystem/Organ Class MedDRA Preferred TermNUCYNTA21 mg 120 mg(n 2178)%Placebo(n 619)%Gastrointestinal disorders Nausea3013 Vomiting184 Constipation83 Dry mouth4<1 Dyspepsia2<1General disorders and administration site conditions Fatigue3<1 Feeling hot1<1Infections and infestations Nasopharyngitis1<1 Upper respiratory tract infection1<1 Urinary tract infection1<1Metabolism and nutrition disorders Decreased appetite20Nervous system disorders Dizziness248 Somnolence153 Tremor1<1 Lethargy1<1Psychiatric disorders Insomnia2<1 Confusional state10 Abnormal dreams1<1 Anxiety1<1Skin and subcutaneous tissue disorders Pruritus51 Hyperhidrosis3<1 Pruritus generalized3<1 Rash1<1Vascular disorders Hot flush1<1The following adverse drug reactions occurred in less than 1% of NUCYNTA-treated patients in the pooled safety data from nine Phase 2/3 clinical studies:Cardiac disorders: heart rate increased, heart rate decreasedEye disorders: visual disturbanceGastrointestinal disorders: abdominal discomfort, impaired gastric emptyingGeneral disorders and administration site conditions: irritability, edema, drug withdrawal syndrome, feeling drunkImmune system disorders: hypersensitivityInvestigations: gamma-glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increasedMusculoskeletal and connective tissue disorders: involuntary muscle contractions, sensation of heavinessNervous system disorders: hypoesthesia, paresthesia, disturbance in attention, sedation, dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope, coordination abnormal, seizurePsychiatric disorders: euphoric mood, disorientation, restlessness, agitation, nervousness, thinking abnormalRenal and urinary disorders: urinary hesitation, pollakiuriaRespiratory, thoracic and mediastinal disorders: oxygen saturation decreased, cough, dyspnea, respiratory depressionSkin and subcutaneous tissue disorders: urticariaVascular disorders: blood pressure decreasedIn the pooled safety data, the overall incidence of adverse reactions increased with increased dose of NUCYNTA tablets, as did the percentage of patients with adverse reactions of nausea, dizziness, vomiting, somnolence, and pruritus.. 6.2Post-marketing Experience. The following additional adverse reactions have been identified during post approval use of tapentadol. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Gastrointestinal disorders: diarrheaNervous system disorders: headachePsychiatric disorders: hallucination, suicidal ideation, panic attackCardiac disorders: palpitationsSerotonin syndrome: Cases of serotonin syndrome, potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.Anaphylaxis: Anaphylaxis has been reported with ingredients contained in NUCYNTA tablets.Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

BOXED WARNING SECTION.

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS. WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTSSee 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 patients risk before prescribing and monitor regularly for these behaviors and conditions. (5.1)To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required Risk Evaluation and Mitigation Strategy (REMS) for these products. (5.2)Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following dose increase. (5.3) Accidental ingestion of NUCYNTA tablets, especially by children, can result in fatal overdose of tapentadol. (5.3)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 pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.4)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 (5.5), (7).. NUCYNTA tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patients risk before prescribing and monitor regularly for these behaviors and conditions. (5.1). To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required Risk Evaluation and Mitigation Strategy (REMS) for these products. (5.2). Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following dose increase. (5.3) Accidental ingestion of NUCYNTA tablets, especially by children, can result in fatal overdose of tapentadol. (5.3). 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 pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.4). 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 (5.5), (7).. 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 patients 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)].. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required REMS for these products [see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged tocomplete REMS-compliant education program,counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, andconsider other tools to improve patient, household, and community safety.. complete REMS-compliant education program,. counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,. emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and. consider other tools to improve patient, household, and community safety.. Life-Threatening Respiratory DepressionSerious, 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 dose increase [see Warnings and Precautions (5.3)]. Accidental IngestionAccidental ingestion of even one dose of NUCYNTA tablets, especially by children, can result in fatal overdose of tapentadol [see Warnings and Precautions (5.3)].. Neonatal Opioid Withdrawal SyndromeProlonged 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 prolonged period in 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 (5.4)]. Risks From Concomitant Use With Benzodiazepines Or Other CNS DepressantsConcomitant 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 (5.5) 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.. 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Tapentadol is centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is mu-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties.. 12.2 Pharmacodynamics. Effects on the Central Nervous SystemTapentadol produces respiratory depression by direct action on the brainstem respiratory centers. The respiratory depression involves reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.Tapentadol causes miosis, even in total darkness. Pinpoint pupils are sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.. Effects on the Gastrointestinal Tract and Other Smooth MuscleTapentadol causes reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.. Effects on the Cardiovascular SystemThere was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In randomized, double-blind, placebo- and positive-controlled crossover study, healthy subjects were administered five consecutive doses of NUCYNTA 100 mg every hours, NUCYNTA 150 mg every hours, placebo and single oral dose of moxifloxacin. Similarly, NUCYNTA had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).Tapentadol produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.. Effects on the Endocrine SystemOpioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)]. Effects on the Immune SystemOpioids have been shown to have variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.. Concentration-Efficacy RelationshipsThe minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of tapentadol for any individual patient may increase over time due to an increase in pain, the development of new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1)].. Concentration-Adverse Experience RelationshipsThere is relationship between increasing tapentadol plasma concentration and increasing frequency of dose-related adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2)].. 12.3 Pharmacokinetics. AbsorptionThe mean absolute bioavailability after single-dose administration (fasting) of NUCYNTA is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing.Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range.A multiple (every hour) dose study with doses ranging from 75 to 175 mg tapentadol showed mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite.. Food EffectThe AUC and Cmax increased by 25% and 16%, respectively, when NUCYNTA was administered after high-fat, high-calorie breakfast. NUCYNTA may be given with or without food.. DistributionTapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%.. Elimination. MetabolismIn humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase pathways, and only small amount is metabolized by Phase oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase conjugation.None of the metabolites contribute to the analgesic activity.. ExcretionTapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average hours after oral administration. The total clearance is 1530 +/- 177 mL/min.. Specific Populations. Age: Geriatric PopulationThe mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.. Hepatic ImpairmentAdministration of NUCYNTA resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild hepatic impairment group (Child-Pugh Score to 6) and moderate hepatic impairment group (Child-Pugh Score to 9) in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.. Renal ImpairmentAUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild (CLCR 50 to <80 mL/min), moderate (CLCR 30 to <50 mL/min), and severe (CLCR <30 mL/min) renal impairment, the AUC of tapentadol-O-glucuronide was 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.. Drug Interaction Studies. Pharmacokinetic Drug InteractionsTapentadol is mainly metabolized by Phase glucuronidation, high capacity/low affinity system; therefore, clinically relevant interactions caused by Phase metabolism are unlikely to occur. Naproxen and probenecid increased the AUC of tapentadol by 17% and 57%, respectively. These changes are not considered clinically relevant and no change in dose is required.No changes in the pharmacokinetic parameters of tapentadol were observed when acetaminophen and acetylsalicylic acid were given concomitantly.In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Furthermore, minor amount of NUCYNTA is metabolized via the oxidative pathway. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively.Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 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.. 14.1Orthopedic Surgery Bunionectomy. 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 to 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 baseline pain score of >=4 on an 11-point rating scale ranging from to 10 were randomized to of treatments. Patients were allowed to take second dose of study medication as soon as hour after the first dose on study Day 1, with subsequent dosing every to 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 greater reduction in pain compared to placebo based on SPID48 values.For various degrees of improvement from baseline to the 48-hour endpoint, Figure shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves 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 BunionectomyThe 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. 14.2End-Stage Degenerative Joint Disease. 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 to 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 3-day mean pain score of >=5 on an 11-point pain intensity scale, ranging from 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 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 endpoint, Figure shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves 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 Compared to Baseline -- End Stage Degenerative Joint DiseaseThe proportions of patients who showed reduction in pain intensity at 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 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 dose of 50 mg, 75 mg, or 100 mg every to 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 to 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 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 physically dependent patient. (2.5). 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 dose of 50 mg, 75 mg, or 100 mg every to 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 to 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 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 physically dependent patient. (2.5). 2.1Important 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 patients 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 (5.3)] 2.2Initial Dosage. Initiating Treatment with NUCYNTA TabletsInitiate treatment with NUCYNTA tablets in dosing range of 50 mg to 100 mg every to 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 to 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 ERPatients 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, patient receiving 50 mg of NUCYNTA tablets four times per day (200 mg/day) may be converted to 100 mg NUCYNTA ER twice day.. 2.3Dosage 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 (5.16)].Initiate treatment of patients with moderate hepatic impairment (Child-Pugh Score to 9) with 50 mg no more frequently than once every 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 to 6) [see Clinical Pharmacology (12.3)].. 2.4Titration 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.. 2.5Discontinuation of NUCYNTA Tablets. When 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 to 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 physically-dependent patient [see Warnings and Precautions (5.13), Drug Abuse and Dependence (9.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Addiction, Abuse, and MisuseInform 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 DepressionInform 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 (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.. Accidental ExposureInform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)]. 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 DepressantsInform 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 health care provider [see Warnings and Precautions (5.5), Drug Interactions (7)]. Serotonin SyndromeInform patients that opioids could cause 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 (5.7), Drug Interactions (7)].. MAOI InteractionInform 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 (5.7), Drug Interactions (7)] . Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, 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 constellation of these symptoms [see Warnings and Precautions (5.8)].. Important Administration InstructionsInstruct patients how to properly take NUCYNTA tablets, including the following:Advise patients not to adjust the dose of NUCYNTA tablets without consulting with physician or other healthcare professional.If patients have been receiving treatment with NUCYNTA tablets for more than 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 dose schedule to accomplish gradual discontinuation of the medication [see Dosage and Administration (2.5)].. Advise patients not to adjust the dose of NUCYNTA tablets without consulting with physician or other healthcare professional.. If patients have been receiving treatment with NUCYNTA tablets for more than 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 dose schedule to accomplish gradual discontinuation of the medication [see Dosage and Administration (2.5)].. HypotensionInform 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 sitting or lying position) [see Warnings and Precautions (5.9)].. AnaphylaxisInform patients that anaphylaxis has been reported with ingredients contained in NUCYNTA tablets. Advise patients to recognize such reaction and when to seek medical attention [see Contraindications (4) Adverse Reactions (6.2)].. Pregnancy. Neonatal Opioid Withdrawal SyndromeInform 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 (5.4), Use in Specific Populations (8.1)]. Embryo-Fetal ToxicityInform female patients of reproductive potential that NUCYNTA tablets can cause fetal harm and to inform the healthcare provider of 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)].. InfertilityInform 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 MachineryInform patients that NUCYNTA tablets may impair the ability to perform potentially hazardous activities such as driving 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 (5.14)].. ConstipationAdvise 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 TabletsAdvise patients to dispose of unused NUCYNTA tablets by flushing down the toilet.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Effects on the Central Nervous SystemTapentadol produces respiratory depression by direct action on the brainstem respiratory centers. The respiratory depression involves reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.Tapentadol causes miosis, even in total darkness. Pinpoint pupils are sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.. Effects on the Gastrointestinal Tract and Other Smooth MuscleTapentadol causes reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.. Effects on the Cardiovascular SystemThere was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In randomized, double-blind, placebo- and positive-controlled crossover study, healthy subjects were administered five consecutive doses of NUCYNTA 100 mg every hours, NUCYNTA 150 mg every hours, placebo and single oral dose of moxifloxacin. Similarly, NUCYNTA had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).Tapentadol produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.. Effects on the Endocrine SystemOpioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)]. Effects on the Immune SystemOpioids have been shown to have variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.. Concentration-Efficacy RelationshipsThe minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of tapentadol for any individual patient may increase over time due to an increase in pain, the development of new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1)].. Concentration-Adverse Experience RelationshipsThere is relationship between increasing tapentadol plasma concentration and increasing frequency of dose-related adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe mean absolute bioavailability after single-dose administration (fasting) of NUCYNTA is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing.Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range.A multiple (every hour) dose study with doses ranging from 75 to 175 mg tapentadol showed mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite.. Food EffectThe AUC and Cmax increased by 25% and 16%, respectively, when NUCYNTA was administered after high-fat, high-calorie breakfast. NUCYNTA may be given with or without food.. DistributionTapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%.. Elimination. MetabolismIn humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase pathways, and only small amount is metabolized by Phase oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase conjugation.None of the metabolites contribute to the analgesic activity.. ExcretionTapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average hours after oral administration. The total clearance is 1530 +/- 177 mL/min.. Specific Populations. Age: Geriatric PopulationThe mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.. Hepatic ImpairmentAdministration of NUCYNTA resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild hepatic impairment group (Child-Pugh Score to 6) and moderate hepatic impairment group (Child-Pugh Score to 9) in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t1/2. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.. Renal ImpairmentAUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild (CLCR 50 to <80 mL/min), moderate (CLCR 30 to <50 mL/min), and severe (CLCR <30 mL/min) renal impairment, the AUC of tapentadol-O-glucuronide was 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.. Drug Interaction Studies. Pharmacokinetic Drug InteractionsTapentadol is mainly metabolized by Phase glucuronidation, high capacity/low affinity system; therefore, clinically relevant interactions caused by Phase metabolism are unlikely to occur. Naproxen and probenecid increased the AUC of tapentadol by 17% and 57%, respectively. These changes are not considered clinically relevant and no change in dose is required.No changes in the pharmacokinetic parameters of tapentadol were observed when acetaminophen and acetylsalicylic acid were given concomitantly.In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Furthermore, minor amount of NUCYNTA is metabolized via the oxidative pathway. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively.Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryProlonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. Available data with NUCYNTA tablets are insufficient to inform 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 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 ReactionsProlonged 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 (5.4)].. Labor or DeliveryOpioids 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 DataTapentadol 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 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 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, dose-related increase in pup mortality was observed through postnatal Day 4.

SPL MEDGUIDE SECTION.

Medication GuideNUCYNTA (new-SINN-tah)(tapentadol) tablets CII This Medication Guide has been approved by the U.S. Food and Drug AdministrationNUC-022-C.1 Issued: 12/2016NUCYNTA tablets are:A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short term (acute) pain in adults, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.Important information about NUCYNTA tablets:Get emergency help right away if you take too much NUCYNTA (overdose) tablets. When you first start taking NUCYNTA tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Taking NUCYNTA tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.Never give anyone else your NUCYNTA tablets. They could die from taking it. Store NUCYNTA tablets away from children and in safe place to prevent stealing or abuse. Selling or giving away NUCYNTA tablets is against the law.Do not take NUCYNTA tablets if you have:severe asthma, trouble breathing, or other lung problems. bowel blockage or have narrowing of the stomach or intestines.Before taking NUCYNTA tablets, tell your healthcare provider if you have history of: head injury, seizures problems urinatingliver, kidney, thyroid problems pancreas or gallbladder problemsabuse of street or prescription drugs, alcohol addiction, or mental health problems. Tell your healthcare provider if you are:pregnant or planning to become pregnant. Prolonged use of NUCYNTA tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.breastfeeding. NUCYNTA tablets pass into breast milk and may harm your baby.taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking NUCYNTA tablets with certain other medicines can cause serious side effects that could lead to death.When taking NUCYNTA tablets:Do not change your dose. Take NUCYNTA tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Take your prescribed dose every 4-6 hours, at the same time every day. Do not take more than your prescribed dose. If you miss dose, take your next dose at your usual time.Call your healthcare provider if the dose you are taking does not control your pain.If you have been taking NUCYNTA tablets regularly, do not stop taking NUCYNTA tablets without talking to your healthcare provider.After you stop taking NUCYNTA tablets, flush any unused tablets down the toilet.While taking NUCYNTA tablets DO NOT: Drive or operate heavy machinery, until you know how NUCYNTA tablets affect you. NUCYNTA tablets can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with NUCYNTA tablets may cause you to overdose and die. The possible side effects of NUCYNTA tablets:constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.Get emergency medical help if you have:trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.These are not all the possible side effects of NUCYNTA tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.govDistributed by: Collegium Pharmaceutical, Inc., 100 Technology Center Drive Suite 300, Stoughton, MA, 02072, www.collegiumpharma.com or call 1-855-331-5615.. strong prescription pain medicine that contains an opioid (narcotic) that is used to manage short term (acute) pain in adults, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.. Get emergency help right away if you take too much NUCYNTA (overdose) tablets. When you first start taking NUCYNTA tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Taking NUCYNTA tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.. Never give anyone else your NUCYNTA tablets. They could die from taking it. Store NUCYNTA tablets away from children and in safe place to prevent stealing or abuse. Selling or giving away NUCYNTA tablets is against the law.. severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines.. head injury, seizures problems urinating. liver, kidney, thyroid problems pancreas or gallbladder problems. abuse of street or prescription drugs, alcohol addiction, or mental health problems. pregnant or planning to become pregnant. Prolonged use of NUCYNTA tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.. breastfeeding. NUCYNTA tablets pass into breast milk and may harm your baby.. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking NUCYNTA tablets with certain other medicines can cause serious side effects that could lead to death.. Do not change your dose. Take NUCYNTA tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Take your prescribed dose every 4-6 hours, at the same time every day. Do not take more than your prescribed dose. If you miss dose, take your next dose at your usual time.. Call your healthcare provider if the dose you are taking does not control your pain.. If you have been taking NUCYNTA tablets regularly, do not stop taking NUCYNTA tablets without talking to your healthcare provider.. After you stop taking NUCYNTA tablets, flush any unused tablets down the toilet.. Drive or operate heavy machinery, until you know how NUCYNTA tablets affect you. NUCYNTA tablets can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with NUCYNTA tablets may cause you to overdose and die.. constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.. trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1)Lactation: Closely monitor infants of nursing women receiving NUCYNTA tablets. (8.2)Severe Renal or Hepatic Impairment: Not recommended. (8.6, 8.7). Pregnancy: Based on animal data, may cause fetal harm. (8.1). Lactation: Closely monitor infants of nursing women receiving NUCYNTA tablets. (8.2). Severe Renal or Hepatic Impairment: Not recommended. (8.6, 8.7). 8.1 Pregnancy. Risk SummaryProlonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. Available data with NUCYNTA tablets are insufficient to inform 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 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 ReactionsProlonged 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 (5.4)].. Labor or DeliveryOpioids 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 DataTapentadol 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 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 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, dose-related increase in pup mortality was observed through postnatal Day 4.. 8.2 Lactation. Risk SummaryThere 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 mothers clinical need for NUCYNTA tablets and any potential adverse effects on the breastfed infant from NUCYNTA tablets or from the underlying maternal condition.. Clinical ConsiderationsInfants exposed to NUCYNTA tablets 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 breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential. InfertilityChronic 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 (6.2)]. 8.4 Pediatric Use. The safety and effectiveness of NUCYNTA tablets in pediatric patients less than 18 years of age have not been established.. 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 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 (5.6)].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.. 8.6Hepatic Impairment. 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 (12.3)]. Use of NUCYNTA tablets are not recommended in patients with severe hepatic impairment (Child-Pugh Score 10 to 15) [see Warnings and Precautions (5.16)]. The dose of NUCYNTA tablets should be reduced in patients with moderate hepatic impairment (Child-Pugh Score to 9) [see Dosage and Administration (2.2)]. No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score to 6) [see Warnings and Precautions (5.16), Clinical Pharmacology (12.3)] 8.7Renal Impairment. Use of NUCYNTA tablets 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 (5.17), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

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. (5.6)Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue NUCYNTA tablets if serotonin syndrome is suspected. (5.7)Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.8)Severe Hypotension: Monitor during dosage initiation and titration. Avoid 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: Monitor for sedation and respiratory depression. Avoid use of NUCYNTA tablets in patients with impaired consciousness or coma. (5.10). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.6). Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue NUCYNTA tablets if serotonin syndrome is suspected. (5.7). Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.8). Severe Hypotension: Monitor during dosage initiation and titration. Avoid 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: Monitor for sedation and respiratory depression. Avoid use of NUCYNTA tablets in patients with impaired consciousness or coma. (5.10). 5.1Addiction, Abuse, and Misuse. NUCYNTA tablets contain tapentadol, 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 patients 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 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.. 5.2Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:Complete REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.To obtain further information on the opioid analgesic REMS and for list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.. Complete REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.. 5.3Life-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 patients clinical status [see Overdosage (10)]. 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 tablets, the risk is greatest during the initiation of therapy or following 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 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.. 5.4Neonatal 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 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)].. 5.5Risks 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 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 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 patient already taking benzodiazepine or other CNS depressant, prescribe 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) and Patient Counseling Information (17)].. 5.6Life-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 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 (5.3)]. 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 (5.3)].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 (5.5)]. Alternatively, consider the use of non-opioid analgesics in these patients.. 5.7Serotonin Syndrome with Concomitant Use of Serotonergic Drugs. Cases of serotonin syndrome, 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 few days of concomitant use, but may occur later than that. Discontinue NUCYNTA tablets if serotonin syndrome is suspected.. 5.8Adrenal 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 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.. 5.9Severe 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 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.. 5.10Risks 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 tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA tablets. Opioids may also obscure the clinical course in patient with head injury. Avoid the use of NUCYNTA tablets in patients with impaired consciousness or coma.. 5.11Risks 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.. 5.12Increased 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 history of seizure disorders for worsened seizure control during NUCYNTA tablets therapy. 5.13Withdrawal 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 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 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)].. 5.14Risks of Driving and Operating Machinery NUCYNTA tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving 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.. 5.15Interactions 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)].. 5.16Risk of Toxicity in Patients with Hepatic Impairment. 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.. 5.17Risk of Toxicity in Patients with Renal Impairment. Use of NUCYNTA tablets in patients with severe renal impairment is not recommended due to accumulation of metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known [see Clinical Pharmacology (12.3)].