Tapentadol

INDICATIONS AND USAGE Tapentadol extended-release tablets are indicated for the management of: Severe and persistent pain in adults that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Severe and persistent neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions (5.1) ] , reserve tapentadol extended-release tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. tapentadol extended-release tablets are not indicated as an as-needed (prn) analgesic. Tapentadol extended-release tablet is an opioid agonist indicated for the management of: severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. ( 1 ) severe and persistent neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. ( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, reserve tapentadol extended-release tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tapentadol extended-release tablets are not indicated as an as-needed (prn) analgesic.

DOSAGE AND ADMINISTRATION Tapentadol extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of tapentadol extended-release 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 ( 2.5 ). 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. ( 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tapentadol extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with tapentadol extended-release tablets. Consider prescribing naloxone based on the patient's risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) Instruct patients to swallow tapentadol extended-release tablets intact, and not to cut, break, chew, crush, or dissolve the tablets (risk of potentially fatal overdose). ( 2.1 , 5.1 ) Instruct patients to take tablets one at a time, with enough water to ensure complete swallowing immediately after placing in mouth. ( 2.1 ) Do not exceed a total daily dose of tapentadol extended-release tablets of 500 mg. ( 2.1 ) For opioid-naïve and opioid non-tolerant patients, initiate treatment with 50 mg tablet orally twice daily (approximately every 12 hours). See full prescribing information for instructions on conversion, titration, and maintenance of therapy. ( 2.3 , 2.4 ) Titrate patients with dose increases of 50 mg no more than twice daily every three days. ( 2.4 ) Moderate Hepatic Impairment: Initiate treatment with 50 mg tapentadol extended-release tablet no more than every 24 hours. Do not exceed 100 mg per day. Regularly evaluate for respiratory and central nervous system depression ( 2.5 ) Do not abruptly discontinue tapentadol extended-release tablets in a physically-dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.6 ) 2.1 Important Dosage and Administration Instructions Tapentadol extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting 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 [see Warnings and Precautions (5) ] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of tapentadol extended-release 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. 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 [see Warnings and Precautions (5.1) ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with tapentadol extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2) ] . Instruct patients to swallow tapentadol extended-release tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Crushing, chewing, or dissolving tapentadol extended-release tablets will result in uncontrolled delivery of tapentadol and can lead to overdose or death [see Warnings and Precautions (5.1) ]. Discontinue all other tapentadol and tramadol products when beginning and while taking tapentadol extended-release tablets [see Warnings and Precautions (5.7) ] . Although the maximum approved total daily dose of tapentadol immediate-release formulation is 600 mg per day, the maximum total daily dose of tapentadol extended-release tablets is 500 mg. Do not exceed a total daily dose of tapentadol extended-release tablets of 500 mg. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with tapentadol extended-release tablets [see Warnings and Precautions (5.2) ]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1 , 5.2 , 5.3) ]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Use of tapentadol extended-release tablets as the First Opioid Analgesic (opioid-naïve patients) Initiate treatment with tapentadol extended-release tablets with the 50 mg tablet orally twice daily (approximately every 12 hours). Use of tapentadol extended-release tablets in Patients who are not Opioid Tolerant The starting dose for patients who are not opioid tolerant is tapentadol extended-release tablet 50 mg orally twice daily (approximately every 12 hours). Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression. Conversion from tapentadol to tapentadol extended-release tablets Patients can be converted from tapentadol to tapentadol extended-release tablets using the equivalent total daily dose of tapentadol and dividing it into two equal doses of tapentadol extended-release tablet separated by approximately 12-hour intervals. As an example, a patient receiving 50 mg of tapentadol four times per day (200 mg/day) may be converted to 100 mg tapentadol extended-release tablet twice a day. Conversion from Other Opioids to tapentadol extended-release tablet When tapentadol extended-release tablet therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. There are no established conversion ratios for conversion from other opioids to tapentadol extended-release tablets defined by clinical trials. Initiate dosing using tapentadol extended-release tablet 50 mg orally every 12 hours. It is safer to underestimate a patient's 24-hour oral tapentadol dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral tapentadol requirements which could result in an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the potency of opioid drugs and opioid formulations. Close observation and frequent titration are warranted until pain management is stable on the new opioid. Frequently evaluate patients for signs an

WARNINGS 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 extended-release 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. ( 5.9 ) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of tapentadol extended-release 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 extended-release tablets in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse Tapentadol extended-release tablets contain tapentadol, a Schedule II controlled substance. As an opioid, tapentadol extended-release tablets expose users to the risks of addiction, abuse, and misuse. Because extended-release products such as tapentadol extended-release tablets deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present [see Drug Abuse and Dependence (9) ] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tapentadol extended-release tablets. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing tapentadol extended-release tablets, and reassess all patients receiving tapentadol extended-release 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 prescribing of tapentadol extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as tapentadol extended-release tablets but use in such patients necessitates intensive counseling about the risks and proper use of tapentadol extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] . Abuse or misuse of tapentadol extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death [see Overdosage (10) ] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing tapentadol extended-release 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 the proper disposal of unused drug. Contact the local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10) ] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of tapentadol extended-release 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 extended-release tablets are essential [see Dosage and Administration (2) ] . Overestimating the tapentadol extended-release tablet dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of tapentadol extended-release 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 [see Dosage and Administration (2.6) ]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with tapentadol extended-release tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered . Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [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 Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on tapentadol extended-release tablet therapy. The co-ingestion of alcohol with tapentadol extended-release tablets may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol [see Clinical Pharmacology (12.3) ] . Profound sedation, respiratory depression, coma, and death may result from the concomitant use of tapentadol extended-release tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypn

CONTRAINDICATIONS 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 )

DRUG 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 [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 prescribing naloxone for the emergency treatment of opioid overdose [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, 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 prescribing naloxone for the emergency treatment of opioid overdose [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 non- prescription 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 ).

ADVERSE 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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 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 tapentadol extended-release tablets 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 tapentadol extended-release tablets (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 tapentadol extended-release tablet-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 tapentadol extended-release tablet 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 tapentadol extended-release tablet dose group for tapentadol extended-release tablet- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively. Table 1. Adverse Drug Reactions Reported by ≥ 1% of tapentadol extended-release tablet-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. Tapentadol extended-release tablets 50 to 250 mg BID Tapentadol extended-release tablet 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 tapentadol extended-release tablets 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 tapentadol extended-release tablets (dosed 100 to 250 mg BID) in patients with neuropathic pain associated with diabetic peripheral neuropathy. These trials included 1040 tapentadol extended-release tablet-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 tapentadol extended-release tablet-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache. Table 2 lists the common adverse reactions reported in 1% or more of tapentadol extended-release tablet-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 tapentadol extended-release tablet-Treated Patients and Greater than Placebo-Treated Patients in Pooled Trials (Studies DPN-1 and DPN-2) MedDRA preferred terms. Tapentadol extended-release tablets 50 to 250 mg BID Tapentadol extended-release tablets 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 tapentadol extended-release tablet. (n=1040) Placebo It includes ADR reported in the double-blind maintenance period for the subjects who were randomized to placebo after receiving tapentadol extended-release tablets 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 tapentadol extended-release tablet-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 tapentadol extended-release tablets The following additional adverse drug reactions occurred in less than 1% of tapentadol extended-release tablet-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

Mechanism of Action Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties.