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Tapentadol

Medically reviewed by Drugs.com. Last updated on Jun 5, 2020.

Pronunciation

(ta PEN ta dol)

Index Terms

  • CG5503
  • Tapentadol HCl
  • Tapentadol Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Nucynta: 50 mg, 75 mg [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Nucynta: 100 mg [contains fd&c yellow #6 aluminum lake]

Tablet Extended Release 12 Hour, Oral:

Nucynta ER: 50 mg

Nucynta ER: 100 mg, 150 mg, 200 mg, 250 mg [contains fd&c blue #2 aluminum lake]

Brand Names: U.S.

  • Nucynta
  • Nucynta ER

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

Binds to μ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine, which also modifies the ascending pain pathway

Absorption

Rapid and complete

Distribution

Vd: IV: 442-638 L

Metabolism

Extensive metabolism, including first pass metabolism; metabolized primarily via phase 2 glucuronidation to glucuronides (major metabolite: tapentadol-O-glucuronide); minimal phase 1 oxidative metabolism; also metabolized to a lesser degree by CYP2C9, CYP2C19, and CYP2D6; all metabolites pharmacologically inactive

Excretion

Urine (99%: 70% conjugated metabolites; 3% unchanged drug)

Time to Peak

Plasma: Immediate release: 1.25 hours; Long acting formulations: 3-6 hours

Half-Life Elimination

Immediate release: ~4 hours; Long acting formulations: ~5-6 hours

Protein Binding

~20%

Special Populations: Renal Function Impairment

In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O-glucuronide are 1.5-, 2.5-, and 5.5-fold higher, respectively, compared with healthy renal function.

Special Populations: Hepatic Function Impairment

Administration of tapentadol resulted in higher exposures to and serum levels of tapentadol in subjects with impaired hepatic function The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.

Special Populations: Elderly

Cmax is 16% lower than in younger subjects.

Use: Labeled Indications

Neuropathic pain associated with diabetic peripheral neuropathy: Extended-release: Management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Note: Tapentadol ER is generally not recommended as first or second line therapy due to a high risk for addiction and safety concerns compared to modest pain reduction (Pop-Busui 2017).

Pain management:

Immediate release: Management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate in adults.

Extended release: Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatments are inadequate.

Limitations of use: Reserve tapentadol for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Tapentadol ER is not indicated as an as-needed analgesic.

Contraindications

Hypersensitivity (eg, anaphylaxis, angioedema) to tapentadol or any component of the formulation; significant respiratory depression; acute or severe asthma or hypercapnia in unmonitored settings or in absence of resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected); use with or within 14 days of MAO inhibitors.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to opioids; acute respiratory depression, cor pulmonale; obstructive airway; known or suspected gastrointestinal obstruction or any disease/condition that affects bowel transit (eg, ileus of any type, strictures); suspected surgical abdomen (eg, acute appendicitis, pancreatitis); severe renal impairment (CrCl <30 mL/minute); severe hepatic impairment (Child-Pugh class C); mild, intermittent, or short-duration pain that can be managed with alternative pain medication; management of perioperative pain (extended-release tablets); acute alcoholism, delirium tremens, and seizure disorders; severe CNS depression, increased cerebrospinal or intracranial pressure or head injury; pregnancy; breast-feeding; use during labor/delivery

Dosing: Adult

Note: Dose and dosage intervals should be individualized according to pain severity with respect to patient’s previous experience with similar opioid analgesics. In patients receiving tapentadol ER, immediate-release opioid or nonopioid medication may be used for rescue relief of breakthrough pain and during dosage adjustments. Opioid tolerance is defined as: Patients already taking at least morphine 60 mg orally daily, oxymorphone 25 mg orally daily, transdermal fentanyl 25 mcg per hour, oxycodone 30 mg orally daily, hydromorphone 8 mg orally daily, hydrocodone 60 mg orally daily or an equivalent dose of another opioid for at least 1 week.

Neuropathic pain associated with diabetic peripheral neuropathy: Oral: Extended release:

Opioid naive (use as the first opioid analgesic or use in patients who are not opioid tolerant): Initial: 50 mg every 12 hours

Conversion from other opioids to tapentadol ER: Initial: 50 mg every 12 hours

Conversion from tapentadol immediate release to ER: Convert using same total daily dose but divide into 2 equal doses and administer every 12 hours.

Conversion from methadone to tapentadol ER: Close monitoring is required when converting methadone to another opioid. Ratio between methadone and other opioid agonists varies widely according to previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Dosage titration: Titrate in increments of 50 mg no more frequently than twice daily every 3 days to effective dose (therapeutic range: 100 to 250 mg every 12 hours).

Pain management: Oral:

Immediate release: Day 1: 50 to 100 mg every 4 to 6 hours as needed; may administer a second dose ≥1 hour after the initial dose (maximum dose on first day: 700 mg/day); Day 2 and subsequent dosing: 50 to 100 mg every 4 to 6 hours as needed (maximum: 600 mg/day).

Conversion from tapentadol immediate release to ER: Convert using same total daily dose but divide into 2 equal doses and administer every 12 hours.

Extended-release:

Opioid naive (use as the first opioid analgesic or use in patients who are not opioid tolerant): Initial: 50 mg every 12 hours

Conversion from other opioids to tapentadol ER: Initial: 50 mg every 12 hours

Conversion from tapentadol immediate release to ER: Convert using same total daily dose but divide into 2 equal doses and administer every 12 hours.

Conversion from methadone to extended release tapentadol: Close monitoring is required when converting methadone to another opioid. Ratio between methadone and other opioid agonists varies widely according to previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Dosage titration: Titrate in increments of 50 mg no more frequently than twice daily every 3 days to effective dose (therapeutic range: 100 to 250 mg every 12 hours).

Discontinuation of therapy: When discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal universal tapering schedule for all patients has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Tapering schedules should be individualized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered. An even slower taper may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2018).

Dosing: Geriatric

Refer to adult dosing. Initiate therapy at low end of dosing range and use caution.

Administration

Administer with or without food.

ER tablets: Swallow whole; do not split, crush, break, chew, cut, or dissolve. Administer 1 tablet at a time with sufficient water to ensure complete swallowing immediately after placing in mouth.

Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, clinicians are advised to monitor closely for adverse effects and withdrawal symptoms after bariatric surgery. Oral morphine has been shown to have significantly increased Cmax and decreased Tmax in the immediate period (1 to 2 weeks) and long-term (6 months) period after bariatric surgery.

Storage

Store up to 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Protect tablets from moisture.

Drug Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect of Tapentadol. Alcohol (Ethyl) may increase the serum concentration of Tapentadol. Specifically, alcohol may increase the maximum serum concentrations when used with extended-release tapentadol. Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Desmopressin: Opioid Agonists may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Iobenguane Radiopharmaceutical Products: Tapentadol may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer tapentadol until at least 7 days after each iobenguane dose. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Monoamine Oxidase Inhibitors: Tapentadol may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Specifically, the additive effects of norepinephrine may lead to adverse cardiovascular effects. Tapentadol may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Ondansetron: May diminish the analgesic effect of Tapentadol. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interupt oxybate salt treatment during short-term opioid use. Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: Isocarboxazid; Linezolid; Methylene Blue; Moclobemide; Phenelzine; Tranylcypromine. Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%:

Gastrointestinal: Nausea (21% to 30%), vomiting (8% to 18%), constipation (8% to 17%)

Nervous system: Dizziness (17% to 24%), drowsiness (12% to 15%), headache (ER: 10% to 15%)

1% to 10%:

Cardiovascular: Hypotension (ER: 1%)

Dermatologic: Pruritus (1% to 8%), hyperhidrosis (3% to 5%), skin rash (1%)

Endocrine & metabolic: Hot flash (ER: 2% to 3%; IR: 1%)

Gastrointestinal: Diarrhea (ER: 7%), xerostomia (4% to 7%), decreased appetite (ER: 2% to 6%; IR: 2%), dyspepsia (1% to 3%), abdominal distress (≤1%)

Genitourinary: Erectile dysfunction (ER: 1%), urinary tract infection (IR: 1%)

Nervous system: Fatigue (ER: 9%: IR: 3%), anxiety (ER: 2% to 5%; IR: 1%), insomnia (2% to 4%), irritability (≤2%), abnormal dreams (1% to 2%), lethargy (1% to 2%), vertigo (ER: 1% to 2%), chills (ER: 1%), depression (ER: 1%), feeling hot (IR: 1%), confusion (≤1%), disturbance in attention (≤1%), hypoesthesia (≤1%), lack of concentration (≤1%), nervousness (≤1%), sedated state (≤1%), withdrawal syndrome (≤1%)

Neuromuscular & skeletal: Tremor (ER: 1% to 3%; IR: 1%), asthenia (ER: 2%)

Ophthalmic: Blurred vision (ER: 1%)

Respiratory: Nasopharyngitis (IR: 1%), upper respiratory tract infection (IR: 1%), dyspnea (≤1%)

<1%: Abnormality in thinking, agitation, altered mental status, ataxia, balance impairment, cough, decreased blood pressure, decreased heart rate, delayed gastric emptying, disorientation, drug dependence, dysarthria, edema, euphoria, feeling abnormal, feeling of heaviness, hallucination, hypersensitivity reaction, hypogonadism (Brennan 2013; Debono 2011), illusion, impaired consciousness, increased gamma-glutamyl transferase, increased heart rate, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, intoxicated feeling, left bundle branch block, memory impairment, muscle spasm, nightmares, oxygen desaturation, palpitations, paresthesia, pollakiuria, presyncope, respiratory depression, restlessness, seizure, sexual difficulty, syncope, urinary hesitancy, urticaria, visual disturbance, weight loss

Frequency not defined:

Nervous system: Drug abuse, neonatal withdrawal

Postmarketing: Anaphylaxis, panic attack, suicidal ideation

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

Tapentadol exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing tapentadol and monitor all patients regularly for the development of these behaviors or conditions.

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 FDA has required a 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 health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program and counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of tapentadol. Monitor for respiratory depression, especially during initiation of tapentadol or following a dose increase. Instruct patients to swallow tapentadol ER tablets whole; crushing, chewing, or dissolving tapentadol can cause rapid release and absorption of a potentially fatal dose of tapentadol.

Accidental ingestion:

Accidental ingestion of even one dose of tapentadol, especially by children, can result in a fatal overdose of tapentadol.

Neonatal opioid withdrawal syndrome:

Prolonged use of tapentadol during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Interaction with alcohol (extended-release):

Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking tapentadol ER. The coingestion of alcohol with tapentadol ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tapentadol and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Swallow ER tablets whole; crushing, chewing, or dissolving can cause rapid release and a potentially fatal dose. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with concomitant use of tapentadol and serotonergic agents (eg, SSRIs, SNRIs, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause spasm of the sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Serum concentrations are increased in hepatic impairment; use with caution in patients with moderate hepatic impairment (dosage adjustment required). Not recommended for use in severe hepatic impairment.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).

• Obesity: Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with mild to moderate renal impairment. Not recommended for use in severe renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating and titrating therapy;; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizures: Use caution in patients with a history of seizures or conditions predisposing patients to seizures; may cause or exacerbate preexisting seizures.

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tapentadol and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Ethanol use: Extended release: [US Boxed Warning]: Patients should not consume alcoholic beverages or medication containing ethanol while taking tapentadol ER; ethanol may increase tapentadol plasma levels resulting in a potentially fatal overdose.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of nonopioid analgesics in these patients.

• Elderly: Use opioids with caution in the elderly; consider decreasing initial dose. Use opioids for chronic pain with caution in this age group; monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Consider the use of nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Extended release tablets: Therapy should only be prescribed by healthcare professionals familiar with the use of potent opioids for chronic pain.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent to opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances and provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.

• Abuse/misuse/diversion: [US Boxed Warning]: Tapentadol exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk for misuse include younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

• Accidental exposure: Extended release tablets: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of tapentadol.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, NSAIDs, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]).

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• REMS program: [US Boxed Warning]: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required. Drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Monitoring Parameters

Relief of symptoms; respiratory and mental status, blood pressure, heart rate; bowel function; signs/symptoms of misuse, abuse, or addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Reproductive Considerations

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women (Brennan 2013).

Pregnancy Considerations

Opioids cross the placenta.

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). Information related to tapentadol exposure in pregnancy is limited (Stollenwerk 2018).

[US Boxed Warning]: Prolonged use of tapentadol during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.

Tapentadol is not commonly used to treat pain during labor (ACOG 209 2019) or chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009).

Patient Education

What is this drug used for?

• It is used to ease pain.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Vomiting

• Itching

• Diarrhea

• Lack of appetite

• Dry mouth

• Headache

• Loss of strength and energy

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Trouble breathing

• Slow breathing

• Shallow breathing

• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss.

• Severe dizziness

• Passing out

• Seizures

• Severe constipation

• Chest pain

• Fast heartbeat

• Confusion

• Shortness of breath

• Mood changes

• Severe abdominal pain

• Trouble walking

• Severe fatigue

• Feeling overheated

• Sexual dysfunction (males)

• Decreased sex drive

• No menstrual periods

• Trouble getting pregnant

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.