Tapentadol Hydrochloride

Boxed Warning 12/2025 Indications and Usage ( 1 ) 12/2025 Dosage and Administration ( 2.2 , 2.7 ) 12/2025 Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.12 , 5.14 ) 12/2025

1 INDICATIONS AND USAGE Tapentadol tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate in adults. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dose or duration [see Warnings and Precautions (5.1)], and persist over the course of therapy, reserve opioid analgesics, including tapentadol tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Pediatric use information is approved for Collegium Pharmaceutical, Inc.’s NUCYNTA tablets. However, due to Collegium Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. Tapentadol tablets are an opioid analgesic indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate in adults. ( 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 tapentadol tablets 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 )

2 DOSAGE AND ADMINISTRATION • Tapentadol 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 tapentadol 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 tapentadol tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2) • Tapentadol 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 and renewing treatment with tapentadol 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 ) • 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 tapentadol 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 tapentadol 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 • Tapentadol 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 [see Warnings and Precautions (5) ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of tapentadol 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'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 a …

3 DOSAGE FORMS AND STRENGTHS Tablets: 50 mg, 75 mg, 100 mg. 50 mg: round biconvex, beige film-coated tablet debossed "50" above “ ” on one side and plain on the other side. 75 mg: round biconvex, pink-orange film-coated tablet debossed "75" above “ ” on one side and plain on the other side. 100 mg: round biconvex, orange film-coated tablet debossed "100" above “ ” on one side and plain on the other side. Tablets: 50 mg, 75 mg, 100 mg ( 3 ) imprint.jpg imprint.jpg imprint.jpg

4 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 )

6 ADVERSE REACTIONS The following adverse reactions are discussed, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions 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 adverse reactions were Adults (incidence ≥10%) were nausea, dizziness, vomiting and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Adults 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 practice. Based on data from nine Phase 2/3 studies that administered multiple doses (seven placebo-and/or active-controlled, one noncontrolled and one Phase 3 active-controlled safety study) the most common adverse reactions (reported by ≥10% in any tapentadol tablets dose group) were: nausea, dizziness, vomiting and somnolence. The most common reasons for discontinuation due to adverse reactions in the studies described above (reported by ≥1% in any tapentadol tablets dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for tapentadol- and placebo-treated patients, respectively. Seventy-six percent of tapentadol-treated patients from the nine studies experienced adverse events. Tapentadol tablets were studied in multiple-dose, active- or placebo-controlled studies, or noncontrolled studies (n = 2,178), in single-dose studies (n = 870), in open-label study extension (n = 483) and in Phase 1 studies (n = 597). Of these, 2,034 patients were treated with doses of 50 mg to 100 mg of tapentadol tablets dosed every 4 to 6 hours. The data described below reflect exposure to tapentadol tablets in 3,161 patients, including 449 exposed for 45 days. Tapentadol tablets were studied primarily in placebo- and active-controlled studies (n = 2,266, and n = 2,944, respectively). The population was 18 to 85 years old (mean age 46 years), 68% were female, 75% white and 67% were postoperative. Most patients received tapentadol tablets doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours. Table 1. Adverse Reactions Reported by ≥1% of Tapentadol-Treated Patients In Seven Phase 2/3 Placebo- and/or Oxycodone-Controlled, One Non-controlled, and One Phase 3 Oxycodone-Controlled Safety, Multiple-Dose Clinical Studies System/Organ Class MedDRA Preferred Term Tapentadol 21 mg to 120 mg (n = 2,178) % Placebo (n = 619) % Gastrointestinal disorders Nausea 30 13 Vomiting 18 4 Constipation 8 3 Dry mouth 4 <1 Dyspepsia 2 <1 General disorders and administration site conditions Fatigue 3 <1 Feeling hot 1 <1 Infections and infestations Nasopharyngitis 1 <1 Upper respiratory tract infection 1 <1 Urinary tract infection 1 <1 Metabolism and nutrition disorders Decreased appetite 2 0 Nervous system disorders Dizziness 24 8 Somnolence 15 3 Tremor 1 <1 Lethargy 1 <1 Psychiatric disorders Insomnia 2 <1 Confusional state 1 0 Abnormal dreams 1 <1 Anxiety 1 <1 Skin and subcutaneous tissue disorders Pruritus 5 1 Hyperhidrosis 3 <1 Pruritus generalized 3 <1 Rash 1 <1 Vascular disorders Hot flu …

7 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 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 …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Closely monitor infants of nursing women receiving tapentadol tablets. ( 8.2 ) Severe Renal or Hepatic Impairment: Not recommended. ( 8.6 , 8.7 ) Pediatric Patients with Hepatic or Renal Impairment: Use not recommended. ( 8.4 ) Pediatric use information is approved for Collegium Pharmaceutical, Inc.’s NUCYNTA tablets. However, due to Collegium Pharmaceutical, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4 )] . Available data with tapentadol tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are risks to the mother and infant associated with use of tapentadol tablets for an extended period of time during pregnancy (see Clinical Considerations). In animal reproduction studies, embryofetal mortality and structural malformations were observed with subcutaneous administration of tapentadol during organogenesis to rabbits and delays in skeletal maturation were observed in rats at exposures equivalent to and less than the maximum recommended human dose (MRHD), respectively. When administered to pregnant rats during organogenesis and through lactation, increased pup mortality was noted following oral tapentadol exposures to doses equivalent to the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse reaction. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4)]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Tapentadol tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including tapentadol tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following subcutaneous exposure during organogenesis. When tapentadol was administered twice daily by the subcutaneous route in rats at dose levels of 10, 20, or 40 mg/kg/day [producing up to 1 times the plasma exposure at the ma …

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

11 DESCRIPTION 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

10 OVERDOSAGE Clinical Presentation Acute overdosage with tapentadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology (12.2) ]. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of tapentadol in tapentadol tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed in the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be begun with care and by titration with smaller than usual doses of the reversal agent.

16 HOW SUPPLIED/STORAGE AND HANDLING Tapentadol tablets are available in the following strengths and packages. All tablets are round and biconvex-shaped. 50 mg tablets are round biconvex, beige film-coated tablet debossed "50" above “ ” on one side and plain on the other side, are available in bottles of 100 (NDC 42806-626-01). 75 mg tablets are round biconvex, pink-orange film-coated tablet debossed "75" above “ ” on one side and plain on the other side, are available in bottles of 100 (NDC 42806-627-01). 100 mg tablets are round biconvex, orange film-coated tablet debossed "100" above “ ” on one side and plain on the other side, are available in bottles of 100 (NDC 42806-628-01). Storage and Handling Store at 20oC to 25°C (68°F to 77oF); excursions permitted to 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature]. Protect from moisture. Keep tapentadol tablets in a secure place out of reach of children. Tapentadol tablets that are no longer needed should be destroyed by flushing down the toilet. Store tapentadol tablets securely and dispose of properly [see Patient Counseling Information (17) ]. imprint.jpg imprint.jpg imprint.jpg