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Tapentadol

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 [contains fd&c blue #2 aluminum lake]

Nucynta ER: 200 mg, 250 mg [scored; 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: The American Diabetes Association guidelines states 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 (ADA 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 tablets and solution: Day 1: 50 to 100 mg (2.5 to 5 mL) 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 (2.5 to 5 mL) 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: Decrease previous daily dose by 25% to 50% each day every 2 to 4 days; monitor carefully for signs/symptoms of withdrawal. If patient displays withdrawal symptoms, increase dose to previous level and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both.

Dosing: Geriatric

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

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Use not recommended.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B):

Immediate release: Initial: 50 mg every 8 hours or longer (maximum: 150 mg/24 hours). Further treatment for maintenance of analgesia may be achieved by either shortening or lengthening the dosing interval.

Extended release: Initial: 50 mg every 24 hours or longer; maximum: 100 mg/day

Severe impairment (Child-Pugh class C): Use not recommended.

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.

Oral solution: Always use the enclosed calibrated oral syringe to ensure the dose is measured and administered accurately.

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

Alvimopan: Opioid Analgesics 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 Analgesics. Monitor therapy

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

Antiemetics (5HT3 Antagonists): May diminish the analgesic effect of Tapentadol. 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. Consider therapy modification

Brimonidine (Topical): 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: Tapentadol may enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Desmopressin: Opioid Analgesics 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 Analgesics may enhance the adverse/toxic effect of Diuretics. Opioid Analgesics 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 (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

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

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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

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

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

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

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

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

Minocycline: 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 Analgesics. Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification

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

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Analgesics. 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

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 Analgesics 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 Analgesics 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

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Serotonin Modulators: Opioid Analgesics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Opioid Analgesics. 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

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

Immediate release:

>10%:

Central nervous system: Dizziness (24%), drowsiness (15%)

Gastrointestinal: Nausea (30%), vomiting (18%)

1% to 10%:

Central nervous system: Fatigue (3%), insomnia (2%), abnormal dreams (1%), anxiety (1%), confusion (1%), lethargy (1%)

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

Endocrine & metabolic: Hot flash (1%)

Gastrointestinal: Constipation (8%), xerostomia (4%), decreased appetite (2%), dyspepsia (2%)

Genitourinary: Urinary tract infection (1%)

Neuromuscular & skeletal: Arthralgia (1%), tremor (1%)

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

Extended release:

>10%:

Central nervous system: Dizziness (17% to 18%), headache (10% to 15%), drowsiness (12% to 14%)

Gastrointestinal: Nausea (21% to 27%), constipation (13% to 17%), vomiting (8% to 12%)

1% to 10%:

Cardiovascular: Hypotension (1%)

Central nervous system: Fatigue (9%), anxiety (2% to 5%), insomnia (4%), irritability (2%), lethargy (2%), abnormal dreams (1% to 2%), vertigo (1% to 2%), chills (1%), depression (1%), hypoesthesia (1%), lack of concentration (1%), nervousness (1%), sedation (1%), withdrawal syndrome (1%)

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

Endocrine & metabolic: Hot flash (2% to 3%)

Gastrointestinal: Diarrhea (7%), xerostomia (7%), decreased appetite (2% to 6%), dyspepsia (1% to 3%), abdominal distress (1%)

Genitourinary: Erectile dysfunction (1%)

Neuromuscular & skeletal: Tremor (1% to 3%), weakness (2%)

Ophthalmic: Blurred vision (1%)

Respiratory: Dyspnea (1%)

Immediate and/or extended release: <1% (Limited to important or life-threatening): Abnormality in thinking, altered mental status, anaphylaxis, angioedema, ataxia, decreased blood pressure, delayed gastric emptying, disorientation, drug withdrawal, dysarthria, euphoria, hallucination, hypersensitivity, hypogonadism (Brennan, 2013; Debono, 2011), impaired consciousness, intoxicated feeling, memory impairment, panic attack, pollakiuria, presyncope, respiratory depression, seizure, syncope, urinary hesitation, visual disturbance

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.

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 sexual dysfunction, infertility, 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-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. 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.

• Oral solution: In order to avoid dosing errors, include the dose in mL and mg when writing prescriptions. Instruct patients to always use the enclosed calibrated oral syringe to ensure the dose is measured and administered accurately.

Other warnings/precautions:

• 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.

• 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.

• Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Taper dose gradually when discontinuing.

Monitoring Parameters

Respiratory and cardiovascular status, blood pressure, heart rate; signs 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]).

Pregnancy Risk Factor

C

Pregnancy Considerations

[U.S. Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate.

Adverse events were observed in some animal reproduction studies. Opioids cross the placenta. Maternal use of opioids may be associated with birth defects, poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). 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.

Agents other than tapentadol are commonly used to treat maternal pain during labor and immediately postpartum (ACOG 177 2017) as well as chronic noncancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009; Kahan 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, itching, dry mouth, headache, or loss of strength and energy. Have patient report immediately to prescriber difficulty breathing, slow breathing, shallow breathing, signs of adrenal gland problems (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, burning or numbness feeling, angina, tachycardia, confusion, sensation of cold, difficult urination, polyuria, shortness of breath, bradycardia, memory impairment, mood changes, severe abdominal pain, suicidal ideation, abnormal movements, twitching, change in balance, difficulty speaking, difficulty swallowing, vision changes, severe fatigue, sweating a lot, feeling overheated, sexual dysfunction (males), decreased libido, amenorrhea, infertility, or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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