TAPENTADOL: 29,208 Adverse Event Reports & Safety Profile

Tapentadol tablets are a mu-opioid receptor agonist, available in immediate-release film-coated tablets for oral administration, containing 58.24, 87.36 and 116.48 mg of tapentadol hydrochloride in each tablet strength, equivalent to 50, 75, and 100 mg of tapentadol free-base, respectively. The chemical name is 3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2- methylpropyl] phenol monohydrochloride, and it has the following chemical structure: The molecular weight of tapentadol hydrochloride is 257.80, and the molecular formula is C 14 H 23 NO·HCl. The n-octanol: water partition coefficient log P value is 2.87. The pKa values are 9.34 and 10.45. The inactive ingredients in tapentadol tablets include: colloidal silicon dioxide, copovidone, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The film coatings for all tablet strengths contain macrogol/peg 4000, polyvinyl alcohol-part hydrolyzed, talc, titanium dioxide; the film coatings for the 50 mg tablets also contain caramel; the film coatings for the 75 mg tablets contain D&C yellow #10 aluminum lake and FD&C red #40/allura red AC aluminum lake; the film coatings for the 100 mg tablets contain FD&C red #40/allura red AC aluminum lake and FD&C yellow #6/sunset yellow FCF aluminum lake. structure-formula.jpg

AND USAGE NUCYNTA ER (tapentadol) is indicated for the management of: Severe and persistent pain in adults that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. Severe and persistent neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. NUCYNTA ER is an opioid agonist indicated for the management of: severe and persistent pain in adults that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. ( 1 ) severe and persistent neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults that requires opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including NUCYNTA ER, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 ) NUCYNTA ER is not indicated as an as-needed (prn) analgesic. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ] , reserve opioid analgesics, including NUCYNTA ER, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. NUCYNTA ER is not indicated as an as-needed (prn) analgesic.

AND ADMINISTRATION NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Reserve titration to higher doses of NUCYNTA tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) NUCYNTA tablets can be taken with or without food ( 2.1 ). Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating andrenewing treatment with NUCYNTA tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) Dosing in adults: See full prescribing information for detailed dosing instructions. ( 2.3 ) Dosing in Pediatric Patients aged 6 years and older with a body weight of at least 40 kg and who are able to swallow tablets: See full prescribing information for detailed dosing instructions. ( 2.4 )

Moderate Hepatic

Impairment in Adult Patients: Initiate treatment with 50 mg no more than once every 8 hours (maximum of three doses in 24 hours). Regularly evaluate for respiratory and central nervous system depression. ( 2.4 ) Periodically reassess patients receiving NUCYNTA tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.6 ) Do not rapidly reduce or abruptly discontinue NUCYNTA tablets in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.6 , 5.14 )

2.1 IMPORTANT DOSAGE AND ADMINISTRATION INSTRUCTIONS NUCYNTA tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span> . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of NUCYNTA tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient&apos;s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with NUCYNTA tablets. Consider this risk when selecting an initial dose and when making dose adjustments <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span> . NUCYNTA tablets can be taken with or without food [ see Clinical Pharmacology (12.3) ].

2.2 PATIENT ACCESS TO AN OPIOID OVERDOSE REVERSAL AGENTAGENT FOR THE EMERGENCY TREATMENT OF OPIOID OVERDOSE Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2 , 5.3) ]</span> . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

2.3 INITIAL DOSAGE IN ADULTS Initiating Treatment with NUCYNTA Tablets Initiate treatment with NUCYNTA tablets in a dosing range of 50 mg to 100 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient&apos;s response to their initial dose of NUCYNTA tablets. On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability. Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are not recommended. NUCYNTA tablets may be given with or without food <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Conversion from NUCYNTA Tablets to NUCYNTA ER Patients can be converted from NUCYNTA tablets to NUCYNTA ER using the equivalent total daily dose of NUCYNTA tablets and dividing it into two equal doses of NUCYNTA ER separated by approximately 12-hour intervals. As an example, a patient receiving 50 mg of NUCYNTA tablets four times per day (200 mg/day) may be converted to 100 mg NUCYNTA ER twice a day. Conversion to NUCYNTA ER may lead to increased risk of excessive sedation and respiratory depression.

2.4 DOSAGE IN PEDIATRIC PATIENTS 6 YEARS AND OLDER WITH BODY WEIGHT OF AT LEAST 40 KG Pediatric patients who are at least 6 years old, weigh at least 40 kg, and are able to swallow oral tablets: For patients weighing 40 to 59 kg, administer 50 mg every 4 hours. Do not exceed a maximum single dose of 50 mg. If adequate analgesia is not achieved with a 50 mg NUCYNTA tablet every 4 hours, do not increase to a 75 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution. For patients weighing 60 to 79 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 75 mg. If adequate analgesia is not achieved with a 75 mg NUCYNTA tablet every 4 hours, do not increase to a 100 mg NUCYNTA tablet. Instead consider use of another NUCYNTA product that allows for more flexible dosing, such as NUCYNTA oral solution. For patients weighing greater than or equal to 80 kg, initiate treatment with 50 mg every 4 hours. Increase the dose if needed to 75 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. If adequate pain relief is not attained with a 75 mg NUCYNTA tablet every 4 hours, increase the dose to 100 mg every 4 hours to maintain adequate analgesia with acceptable tolerability. Do not exceed a maximum single dose of 100 mg. The maximum daily dose is 7.5 mg/kg/day (i.e., six 1.25 mg/kg doses over 24 hours). Daily doses greater than 600 mg have not been studied in pediatric patients and are not recommended. In pediatric patients with high body mass index (BMI), the maximum daily dose must not exceed the calculated maximum dose for a body weight at the 97th percentile for a given age. The efficacy and safety of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight (maximum single dose of 100 mg) have not been studied; therefore, the use of NUCYNTA (tapentadol) tablets at doses higher than 1.25 mg/kg body weight is not recommended <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> . Dose reductions may be considered over time as acute pain decreases. NUCYNTA tablets are not recommended for use in pediatric patients who weigh less than 40 kg as the recommended dose cannot be achieved with available tablet strengths. Consider use of another NUCYNTA product, such as NUCYNTA oral solution, in patients who cannot swallow oral tablets or who weigh less than 40 kg <span class="opacity-50 text-xs">[see Pediatric Use (8.4) ]</span> . Duration of Treatment NUCYNTA (tapentadol) tablets are intended for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. As with all symptomatic treatments, the continued use of tapentadol must be evaluated on an ongoing basis. In pediatric patients, the duration of treatment should not exceed 3 days as the safety and effectiveness of longer treatment have not been established. Hepatic or Renal Impairment NUCYNTA (tapentadol) tablets have not been studied in pediatric patients with hepatic or renal impairment; therefore, use in these populations is not recommended <span class="opacity-50 text-xs">[see Pediatric Use (8.4) ]</span> .

2.5 DOSAGE MODIFICATIONS IN ADULT PATIENTS WITH HEPATIC IMPAIRMENT The safety and efficacy of NUCYNTA tablets have not been studied in patients with severe hepatic impairment (Child-Pugh Score 10-15) and use in this population is not recommended <span class="opacity-50 text-xs">[see Warnings and Precautions (5.17) ]</span> . Initiate treatment of patients with moderate hepatic impairment (Child-Pugh Score 7 to 9) with 50 mg no more frequently than once every 8 hours (maximum of three doses in 24 hours). Further treatment should reflect maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or lengthening the dosing interval. Regularly evaluate patients for respiratory and central nervous system depression <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

2.6 TITRATION AND MAINTENANCE OF THERAPY Individually titrate NUCYNTA tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving NUCYNTA tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassess for the development of addiction, abuse, or misuse <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.14) ]</span> . 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 after increase the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.7 SAFE REDUCTION OR DISCONTINUATION OF NUCYNTA TABLETS Do not rapidly reduce or abruptly discontinue NUCYNTA tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking NUCYNTA tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including NUCYNTA tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on NUCYNTA tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic <span class="opacity-50 text-xs">[see Warnings and Precautions (5.14) , Drug Abuse and Dependence (9.3) ]</span>.

Tapentadol tablets are contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2) ]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.8) ]
• Known or suspected gastrointestinal obstruction, including suspected paralytic ileus [see Warnings and Precautions (5.12) ]
• Hypersensitivity to tapentadol (e.g. anaphylaxis, angioedema) or to any other ingredients of the product [see Adverse Reactions (6.2) ].
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Drug Interactions (7) ].
• Significant respiratory depression ( 4 )
• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 )
• Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 )
• Hypersensitivity to tapentadol ( 4 )
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. ( 4 )

REACTIONS The following serious adverse reactions are described, 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 (5.2) ] Interaction with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.3) ]

Neonatal Opioid Withdrawal

Syndrome [see Warnings and Precautions (5.4) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6) ]

Serotonin

Syndrome [see Warnings and Precautions (5.7) ]

Adrenal

Insufficiency [see Warnings and Precautions (5.9) ]

Severe

Hypotension [see Warnings and Precautions (5.10) ]

Gastrointestinal Adverse

Reactions [see Warnings and Precautions (5.12) ] Seizures [see Warnings and Precautions (5.13) ] Withdrawal [see Warnings and Precautions (5.14) ] The most common (≥10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence. ( 6 ) 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 .

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The safety data described in Table 1 below are based on three pooled, randomized, double-blind, placebo-controlled, parallel group, 15-week studies of NUCYNTA ER (dosed 100 to 250 mg BID after a 50 mg BID starting dose) in patients with chronic pain due to low back pain (LBP) and osteoarthritis (OA). These trials included 980 NUCYNTA ER-treated patients and 993 placebo-treated patients. The mean age was 57 years old; 63% were female and 37% were male; 83% were White, 10% were Black, and 5% were Hispanic. The most common adverse reactions (reported by ≥10% in any NUCYNTA ER dose group) were: nausea, constipation, dizziness, headache, and somnolence. The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA ER dose group for NUCYNTA ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. &lt;1%), vomiting (3% vs. &lt;1%), somnolence (2% vs. &lt;1%), constipation (1% vs. &lt;1%), headache (1% vs. &lt;1%), and fatigue (1% vs. &lt;1%), respectively.

Table

1.

Adverse Drug Reactions

Reported by ≥ 1% of NUCYNTA ER-Treated Patients and Greater than Placebo- Treated Patients in Pooled Parallel-Group Trials MedDRA preferred terms. The trials included forced titration during the first week of dosing. NUCYNTA ER 50 to 250 mg BID NUCYNTA ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID (n=980) Placebo (n=993)

Nausea

21% 7% Constipation 17% 7% Dizziness 17% 6% Headache 15% 13% Somnolence 12% 4% Fatigue 9% 4% Vomiting 8% 3% Dry mouth 7% 2% Hyperhidrosis 5% <1% Pruritus 5% 2% Insomnia 4% 2% Dyspepsia 3% 2% Lethargy 2% <1% Asthenia 2% <1% Anxiety 2% 1% Decreased appetite 2% <1% Vertigo 2% <1% Hot flush 2% <1% Disturbance in attention 1% <1% Tremor 1% <1% Chills 1% 0% Abnormal dreams 1% <1% Depression 1% <1% Vision blurred 1% <1% Erectile dysfunction 1% <1% Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The types of adverse reactions seen in the studies of patients with painful diabetic peripheral neuropathy (DPN) were similar to what was seen in the low back pain and osteoarthritis trials. The safety data described in Table 2 below are based on two pooled, randomized withdrawal, double-blind, placebo-controlled, 12-week studies of NUCYNTA ER (dosed 100 to 250 mg BID) in patients with neuropathic pain associated with diabetic peripheral neuropathy. These trials included 1040 NUCYNTA ER-treated patients and 343 placebo- treated patients. The mean age was 60 years old; 40% were female and 60% were male; 76% were White, 12% were Black, and 12% were "Other". The most commonly reported ADRs (incidence ≥10% in NUCYNTA ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache.

Table

2 lists the common adverse reactions reported in 1% or more of NUCYNTA ER-treated patients and greater than placebo-treated patients with neuropathic pain associated with diabetic peripheral neuropathy in the two pooled studies.

Table

2.

Adverse Drug Reactions

Reported by ≥ 1% of NUCYNTA ER-Treated Patients and Greater than Placebo-Treated Patients in Pooled Trials (Studies DPN-1 and DPN-2) MedDRA preferred terms. NUCYNTA ER 50 to 250 mg BID NUCYNTA ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID. It includes ADR reported in the open-label titration period for all subjects and in the double-blind maintenance period for the subjects who were randomized to NUCYNTA ER. (n=1040) Placebo It includes ADR reported in the double-blind maintenance period for the subjects who were randomized to placebo after receiving NUCYNTA ER during the open-label titration period. (n=343)

Nausea

27% 8% Dizziness 18% 2% Somnolence 14% <1% Constipation 13% <1% Vomiting 12% 3% Headache 10% 5% Fatigue 9% <1% Pruritus 8% 0% Dry mouth 7% <1% Diarrhea 7% 5% Decreased appetite 6% <1% Anxiety 5% 4% Insomnia 4% 3% Hyperhidrosis 3% 2% Hot flush 3% 2% Tremor Tremor was observed in 3.4% of NUCYNTA ER-treated subjects vs. 3.2% in placebo group, chills- in 1.3% vs.1.2% in placebo, and feeling cold- in 1.3% vs.1.2% in placebo. 3% 3% Abnormal dreams 2% 0% Lethargy 2% 0% Asthenia 2% <1% Irritability 2% 1% Dyspnea 1% 0% Nervousness 1% 0% Sedation 1% 0% Vision blurred 1% 0% Pruritus generalized 1% 0% Vertigo 1% <1% Abdominal discomfort 1% <1% Hypotension 1% <1% Dyspepsia 1% <1% Hypoesthesia 1% <1% Depression 1% <1% Rash 1% <1% Chills 1% 1% Feeling cold 1% 1% Drug withdrawal syndrome 1% <1% Other Adverse Reactions Observed During the Premarketing Evaluation of NUCYNTA ER The following additional adverse drug reactions occurred in less than 1% of NUCYNTA ER-treated patients in ten Phase 2/3 clinical studies: Nervous system disorders: paresthesia, balance disorder, syncope, memory impairment, mental impairment, depressed level of consciousness, dysarthria, presyncope, coordination abnormal Gastrointestinal disorders: impaired gastric emptying General disorders and administration site conditions: feeling abnormal, feeling drunk Psychiatric disorders: perception disturbances, disorientation, confusional state, agitation, euphoric mood, drug dependence, thinking abnormal, nightmare Skin and subcutaneous tissue disorders: urticaria Metabolism and nutrition disorders: weight decreased Cardiac disorders: heart rate increased, palpitations, heart rate decreased, left bundle branch block Vascular disorder: blood pressure decreased Respiratory, thoracic and mediastinal disorders: respiratory depression Renal and urinary disorders: urinary hesitation, pollakiuria Reproductive system and breast disorders: sexual dysfunction Eye disorders: visual disturbance Immune system disorders: drug hypersensitivity

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tapentadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Psychiatric disorders: hallucination, suicidal ideation, panic attack Serotonin syndrome: Cases of serotonin syndrome, a 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 ER. Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span> Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids, and may occur more frequently in patients taking higher doses of opioid, and/or in patients taking opioids longer term [ see Warnings and Precautions (5.12) ].

Adverse

Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over

12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [ defined in Drug Abuse and Dependence (9.2) ], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

The

5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.

Approximately

17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

AND PRECAUTIONS

• Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. (5.6)
• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs : Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue tapentadol tablets if serotonin syndrome is suspected. ( 5.7 )
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. ( 5.8 )
• Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.8 )
• Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of tapentadol tablets in patients with circulatory shock. ( 5.10)
• 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 tapentadol tablets in patients with impaired consciousness or coma. ( 5.11 )

5.1 Addiction, Abuse, and Misuse Tapentadol tablets contain tapentadol, a Schedule II controlled substance. As an opioid, tapentadol tablets expose users to the risks of addiction, abuse, and misuse <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9) ]</span>. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tapentadol tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span>. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing tapentadol tablets and reassess all patients receiving tapentadol tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as tapentadol tablets, but use in such patients necessitates intensive counseling about the risks and proper use of tapentadol tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ]</span>. Opioids are sought for non-medical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing tapentadol tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug -. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient’s clinical status <span class="opacity-50 text-xs">[see Overdosage (10) ]</span>. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of tapentadol tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of tapentadol tablets are essential <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>. Overestimating the tapentadol tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of tapentadol tablets, especially by children, can result in respiratory depression and death due to an overdose of tapentadol. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span>.

Patient

Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [ see Warnings and Precautions (5.1, 5.3) ]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [ see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10) ].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of tapentadol tablets with benzodiazepines and/or other CNS depressants including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , Warnings and Precautions (5.2) , Overdosage (10)]</span>. Advise both patients and caregivers about the risks of respiratory depression and sedation when tapentadol 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.4 Neonatal Opioid Withdrawal Syndrome Use of tapentadol tablets for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span>.

5.5 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 a 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 a 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 a 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.

5.6 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect <span class="opacity-50 text-xs">[see Dependence 9.3]</span>. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety) <span class="opacity-50 text-xs">[see Dosage and Administration (2.7), Warnings and Precautions (5.13)]</span>.

5.7 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. 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. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue tapentadol tablets if serotonin syndrome is suspected.

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of tapentadol 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 : Tapentadol tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of tapentadol tablets <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. Regularly evaluate such patients closely, particularly when initiating and titrating tapentadol tablets and when tapentadol tablets are given concomitantly with other drugs that depress respiration <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2, 5.3) , Drug Interactions (7)]</span>. Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.10 Severe Hypotension Tapentadol tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of tapentadol tablets. In patients with circulatory shock, tapentadol tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tapentadol tablets in patients with circulatory shock.

5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tapentadol tablets may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tapentadol tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of tapentadol tablets in patients with impaired consciousness or coma.

5.12 Risks of Gastrointestinal Complications Tapentadol tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The tapentadol in tapentadol tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2)]</span> .

5.13 Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in tapentadol 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during tapentadol tablets therapy.

5.14 Withdrawal Do not rapidly reduce or abruptly discontinue tapentadol tablets in a patient physically dependent on opioids. When discontinuing tapentadol tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of tapentadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain <span class="opacity-50 text-xs">[see Dosage and Administration (2.7) , Drug Abuse and Dependence (9.3) ]</span>. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including tapentadol tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.15 Risks of Driving and Operating Machinery Tapentadol tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of tapentadol tablets and know how they will react to the medication.

5.16 Interactions with Alcohol, Other Opioids, and Drugs of Abuse Due to its mu-opioid agonist activity, tapentadol 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol, other opioids, or drugs of abuse while on tapentadol tablets therapy <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.17 Risk of Toxicity in Patients with Hepatic Impairment A study with tapentadol tablets in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of tapentadol tablets in patients with severe hepatic impairment. Reduce the dose of tapentadol tablets in patients with moderate hepatic impairment <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]</span>. Regularly evaluate patients with moderate hepatic impairment for respiratory and central nervous system depression when receiving tapentadol tablets.

5.18 Risk of Toxicity in Patients with Renal Impairment Use of tapentadol tablets in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

INTERACTIONS Table 2 includes clinically significant drug interactions with tapentadol tablets.

Table

2: Clinically Significant Drug Interactions with Tapentadol Tablets Benzodiazepines and other Central Nervous System (CNS)

Depressants Clinical

Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3) ]. 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. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.2, 5.3)]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.

Serotonergic Drugs Clinical

Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.7 ]. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue tapentadol 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase 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 tapentadol tablets in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of tapentadol tablets and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of tapentadol tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2, 5.3)]. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical

Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when tapentadol tablets is used concomitantly with anticholinergic drugs. Alcohol, Other Opioids, and Drugs of Abuse Clinical Impact: Due to its mu-opioid agonist activity, tapentadol 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 (5.16) ]. Intervention: Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol, other opioids, or drugs of abuse while on tapentadol tablets therapy. Examples: Alcohol, other opioids, illicit drugs

• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with tapentadol tablets because they reduce analgesic effect of tapentadol tablets or precipitate withdrawal symptoms. ( 7 ).