VA Class:CN101

AHFS Class:

• Opioid Agonists 28:08.08

Generic Name(s):

• Tapentadol Hydrochloride

Chemical Name:

• 3-[(1 R , 2 R )-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride

Molecular Formula:

• C₁₄H₂₃NO HCL

Associated Monographs

• Opiate Agonists General Statement

Tapentadol hydrochloride is a synthetic, centrally active analgesic.1,6,8,9

Pain

Conventional (immediate-release) formulations of tapentadol hydrochloride are used for the relief of acute pain that is severe enough to require an opiate analgesic;1,2,3,9,20 because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, conventional preparations of tapentadol should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, opiate-containing fixed combinations) have not been, or are not expected to be, adequate or tolerated.1,20

Tapentadol hydrochloride extended-release tablets are used for the relief of pain, including neuropathic pain associated with diabetic peripheral neuropathy, that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic.21,22,23,24,25 Because of the risks of addiction, abuse, and misuse associated with opiates, even at recommended dosages, and because of the greater risks of overdosage and death associated with extended-release opiate formulations, extended-release tapentadol should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.21 Extended-release tapentadol is not intended for use on an as-needed (“prn”) basis.21

Acute Pain

Efficacy and safety of conventional preparations of tapentadol for the relief of acute pain have been established in 2 phase 3, randomized, double-blind, placebo- and active-controlled clinical studies in adults with moderate to severe pain secondary to either bunionectomy or end-stage degenerative joint disease.1,2,3

In the first study, 603 patients with moderate to severe pain (defined as a baseline pain score of at least 4 on an 11-point rating scale) following unilateral first metatarsal bunionectomy were randomized to receive conventional tablets of tapentadol (50, 75, or 100 mg), oxycodone hydrochloride (15 mg), or placebo every 4-6 hours for 72 hours.1,2 On day 1, patients were allowed a second dose of study drug as early as 1 hour after the first dose, with subsequent doses administered every 4-6 hours.1,2 At each dosage level studied, tapentadol provided a greater reduction in pain intensity, as assessed by the sum of pain intensity difference (SPID) over the first 48 hours of therapy, compared with placebo.1,2 In addition, at each dosage level studied, a greater proportion of tapentadol-treated patients experienced at least a 30 or 50% reduction in pain intensity at 48 hours compared with placebo recipients.1,2 A post-hoc noninferiority analysis found that tapentadol 100 mg was comparable to oxycodone hydrochloride 15 mg in analgesic efficacy, and tapentadol 100 mg was associated with a lower incidence of adverse GI effects (i.e., nausea, vomiting) compared with oxycodone hydrochloride 15 mg.2,6,11 Although analgesic efficacy of tapentadol 75 mg was inferior to that of oxycodone hydrochloride 15 mg in this study,2 another phase 3 study in patients undergoing bunionectomy found that tapentadol 50 and 75 mg provided analgesic efficacy comparable to that of oxycodone hydrochloride 10 mg.12

In the second study, 674 patients with moderate to severe pain associated with end-stage degenerative joint disease of the hip or knee (defined as a 3-day mean pain score of at least 5 on an 11-point rating scale) were randomized to receive conventional tablets of tapentadol (50 or 75 mg), oxycodone hydrochloride (10 mg), or placebo every 4-6 hours during waking hours for 10 days.1,3 Patients who had received a stable regimen of a nonopiate analgesic for at least 28 days prior to the screening period were allowed to continue receiving that regimen throughout the study.1,3 At each dosage level studied, tapentadol provided a greater reduction in pain intensity, as assessed by the SPID over the first 5 days of therapy, compared with placebo.1,3 In addition, at each dosage level studied, a greater proportion of tapentadol-treated patients experienced at least a 30 or 50% reduction in pain intensity at day 5 of therapy compared with placebo recipients.1,3 In a prespecified noninferiority analysis, tapentadol 50 and 75 mg provided analgesic efficacy comparable to that of oxycodone hydrochloride 10 mg, and the incidence of adverse GI effects (i.e., nausea, vomiting, constipation) was lower with tapentadol compared with oxycodone.3,6

For further information on the role of opiate analgesics in the management of acute pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Chronic Pain

Efficacy of tapentadol extended-release tablets for the relief of pain requiring long-term, daily, around-the-clock use of an opiate analgesic was established in 3 randomized, double-blind studies, including one placebo- and active-controlled study in adults with chronic low back pain and 2 placebo-controlled studies in patients with diabetic peripheral neuropathy.21,23,24,25

In the first study, 981 patients with chronic low back pain and a baseline pain score of at least 5 on an 11-point rating scale were randomized in a 1:1:1 ratio to receive tapentadol extended-release tablets (100-250 mg twice daily), extended-release oxycodone hydrochloride (20-50 mg twice daily), or placebo for 12 weeks following a 3-week dosage titration period.21,23 The mean age of patients in the study was 50 years (range: 18-89 years); the mean baseline pain score was 8, and approximately one-half of the patients had not received opiate analgesics in the past 3 months.21,23 Extended-release tapentadol was initiated at a dosage of 50 mg twice daily, increased to 100 mg twice daily after 3 days, and subsequently titrated over the 3-week titration period up to a maximum dosage of 250 mg twice daily.21,23 Approximately one-half of the patients completed the 15-week study.23 At week 15, patients receiving extended-release tapentadol or extended-release oxycodone had substantially greater pain reduction from baseline compared with those receiving placebo.21,23 The incidence of adverse GI effects (i.e., nausea and/or vomiting, constipation) or pruritus was lower with tapentadol compared with oxycodone.23

In 2 similarly designed studies, patients with chronic pain due to diabetic peripheral neuropathy and a baseline pain score of at least 5 on an 11-point rating scale received open-label treatment with extended-release tapentadol titrated over 3 weeks to a stable dosage in the range of 100-250 mg twice daily.21,24,25 Patients who tolerated the drug and had at least a 1-point improvement in pain score were randomized in a 1:1 ratio to receive continued therapy with extended-release tapentadol or to receive placebo (following a taper to 100 mg twice daily for 3 days) during a 12-week double-blind withdrawal phase.21,24,25 In the 2 studies combined, 709 patients met criteria for entering the double-blind phase.21,24,25 Low-dose extended-release tapentadol (25 mg twice daily as needed for 4 days, then 25 mg once daily as needed) was available to patients in both groups throughout the double-blind phase.21,24,25 The mean age of patients in these studies was 59-60 years,21,24,25 and approximately 67% of the patients had not received opiate analgesics in the past 3 months.21 In both studies, reductions in pain intensity were substantially greater in patients receiving extended-release tapentadol compared with those receiving placebo during the 12-week double-blind phase.21

For further information on the role of opiate analgesics in the management of chronic pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Administration

Tapentadol hydrochloride conventional tablets, extended-release tablets, and oral solution are administered orally without regard to food.1,20,21

Tapentadol extended-release tablets are administered twice daily (approximately every 12 hours).21 The extended-release tablets should be swallowed whole, one at a time, with enough water to ensure that each tablet is completely swallowed immediately after it is placed in the mouth; crushing, chewing, or dissolving the tablets will result in uncontrolled delivery of tapentadol and can result in overdosage and death.21 Patients receiving tapentadol extended-release tablets should not consume alcoholic beverages or use prescription or nonprescription preparations containing alcohol; intake of alcohol with the extended-release tablets may result in increased peak plasma concentrations of tapentadol and ingestion of a potentially toxic dose of the drug.21 Extended-release tablets of tapentadol should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.21

Caution is required when prescribing, dispensing, and administering tapentadol oral solutions to avoid dosing errors.20 Care should be taken to ensure that the appropriate dose is communicated and dispensed; prescriptions should specify the intended total dose of the drug (in mg) along with the corresponding total volume (in mL).20 The calibrated measuring device provided with the particular formulation should always be used to ensure that the dose is measured and administered accurately.20 Use of a household spoon as a measuring device could result in overdosage.20 (See Dispensing and Administration Precautions with Oral Solution under Warnings/Precautions: Warnings, in Cautions.)

Dosage

Dosage of tapentadol hydrochloride is expressed in terms of tapentadol.1,20,21

Opiate analgesics should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.1,20,21,411,413,431,432,435 The dosage regimen should be individualized according to severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.1,20,21 If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.1,20,21,700,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).411,433,434,435 When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.423,431

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.1,20,21 Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.1,20,21

Patients receiving opiate analgesia should be reevaluated continually for adequacy of pain control and for adverse effects, as well for the development of addiction, abuse, or misuse.1,20,21 During long-term therapy, the continued need for opiate analgesics should be periodically reevaluated.21 Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.1,20,21 If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the tapentadol dosage.1,20,21

When tapentadol therapy is discontinued in a patient who may be physically dependent on opiates, the dosage generally should be reduced by 25-50% every 2-4 days.1,20,21 If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly (i.e., by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose).1,20,21

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Conventional (Immediate-release) Preparations

For the management of acute pain that is severe enough to require use of an opiate analgesic, the recommended initial adult dosage of tapentadol as conventional (immediate-release) tablets or oral solution is 50-100 mg administered every 4-6 hours as needed.1,20 On day 1 of therapy, patients with inadequate pain relief may receive a second dose of the drug as soon as 1 hour after the first dose.1,20 Subsequent doses should be administered at intervals of 4-6 hours and should be adjusted to maintain adequate analgesia and minimize adverse effects.1,20 Dosages exceeding 700 mg daily on the first day of therapy or 600 mg daily on subsequent days have not been evaluated and are not recommended by the manufacturer.1,20

Extended-release Tablets

For the management of pain, including neuropathic pain associated with diabetic peripheral neuropathy, that is severe enough to require daily, around-the-clock, long-term opiate analgesia in adults who are opiate-naive or not opiate tolerant, therapy with tapentadol extended-release tablets should be initiated at a dosage of 50 mg every 12 hours.21 The manufacturer states that use of higher initial dosages in patients who are not opiate tolerant may result in fatal respiratory depression.21

For patients receiving conventional (immediate-release) tapentadol preparations, the total daily dosage of the drug should be calculated and given as tapentadol extended-release tablets in 2 divided doses at 12-hour intervals.1,20,21,22

In patients who are being switched from other opiate analgesics to tapentadol extended-release tablets, the recommended initial dosage of tapentadol extended-release tablets is 50 mg every 12 hours, since dosage conversion factors have not been established in clinical trials.21 Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.21

When therapy with tapentadol extended-release tablets is initiated, all other tapentadol- or tramadol-containing preparations should be discontinued.21

Because there is substantial interpatient variability in the relative potency of opiate analgesics and analgesic formulations, it is preferable to underestimate the patient's 24-hour opiate requirements and provide “rescue” therapy with an immediate-release opiate analgesic than to overestimate the requirements and manage an adverse reaction.21 Patients who experience breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., “rescue” therapy with an immediate-release analgesic).21

Dosage adjustments may be made in increments of 50 mg no more than twice daily at intervals of every 3 days, to a level that provides adequate analgesia and minimizes adverse effects.21 Dosage should not exceed 500 mg daily (i.e., 250 mg twice daily).21 Dosage of extended-release tapentadol in clinical trials ranged from 100-250 mg twice daily.21,23,24,25

Special Populations

No dosage adjustment is needed in patients with mild or moderate renal impairment (creatinine clearance 30-90 mL/minute).1,20,21 Tapentadol is not recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) because of accumulation of a glucuronide metabolite.1,20,21 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh score 5-6).1,20,21 In patients with moderate hepatic impairment (Child-Pugh score 7-9), conventional preparations of tapentadol should be initiated at a dosage of 50 mg given no more frequently than once every 8 hours for a maximum of 3 doses in 24 hours; if continued therapy is required, the dosage should be adjusted by lengthening or shortening the dosing interval to maintain adequate analgesia and minimize adverse effects.1,20 In patients with moderate hepatic impairment, extended-release tapentadol should be initiated at a dosage of 50 mg given no more frequently than once every 24 hours; the maximum recommended dosage of extended-release tapentadol in patients with moderate hepatic impairment is 100 mg daily.21 Tapentadol has not been evaluated in patients with severe hepatic impairment (Child-Pugh score 10-15) and, therefore, is not recommended for use in this population.1,20,21 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Geriatric patients may exhibit increased sensitivity to tapentadol.1,20,21 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, dosage selection of tapentadol in such patients should be cautious, usually initiating therapy with dosages in the lower end of the usual range.1,20,21 Dosage of tapentadol should be titrated slowly with close monitoring for CNS and respiratory depression.1,20,21 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

Tapentadol is contraindicated in patients with substantial respiratory depression; acute or severe bronchial asthma or hypercarbia in unmonitored settings or in the absence of resuscitative equipment; known or suspected GI obstruction, including paralytic ileus; or known hypersensitivity (e.g., anaphylaxis, angioedema) to the drug or any ingredient in the formulation.1,20,21 Tapentadol also is contraindicated in patients who are receiving or have recently received (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor.1,9,20,21 (See Drug Interactions: Monoamine Oxidase Inhibitors.)

Warnings/Precautions

Warnings

Addiction, Abuse, and Misuse

Tapentadol exposes patients and other users to the risks of opiate addiction (opiate use disorder [OUD]), abuse, and misuse, which can lead to overdosage and death.1,20,21 Tapentadol has an abuse potential similar to that of other potent opiate agonists (e.g., fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone).1,20,21 (See Description.) Addiction can occur at recommended dosages or may be associated with misuse or abuse.1,20,21 Concurrent abuse of alcohol and other CNS depressants increases the risk of toxicity.1,20,21 Each patient's risk for addiction, abuse, or misuse should be assessed prior to initiating tapentadol therapy, and all patients receiving the drug should be monitored for the development of these behaviors or conditions.1,20,21 Personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.1,20,21 The potential for addiction, abuse, or misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for signs of addiction, abuse, and misuse.1,20,21 Tapentadol should be prescribed in the smallest appropriate quantity and the patient should be instructed on secure storage and proper disposal to prevent theft.1,20,21

Extended-release opiates are associated with a greater risk of overdosage and death because of the larger amount of drug contained in each dosage unit.21 Abuse or misuse of tapentadol extended-release tablets by crushing or chewing the tablets, snorting the powder, or injecting the dissolved contents results in uncontrolled release of tapentadol and can result in fatal overdosage.21 In addition, IV injection of excipients in extended-release tapentadol tablets can result in local tissue necrosis, infection, pulmonary granulomas, embolism, and death and increase the risk of endocarditis and valvular heart injury.21

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression can occur in patients receiving opiates, including tapentadol, even when the drugs are used as recommended.1,20,21 Carbon dioxide retention as a result of opiate-induced respiratory depression can exacerbate sedation and, in certain patients, can lead to elevated intracranial pressure.1,20,21 (See Increased Intracranial Pressure or Head Injury under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) Although respiratory depression can occur at any time during therapy, the risk is greatest during initiation of therapy or following an increase in dosa therefore, patients receiving tapentadol should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.1,20,21

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.1,20,21 Large initial doses in nontolerant patients, overestimation of initial tapentadol dosage when transferring patients from other opiate therapy, or accidental ingestion of even one dose of tapentadol, especially by a child, can result in respiratory depression and death.1,20,21 (See Dosage under Dosage and Administration.)

Geriatric, cachectic, or debilitated patients are at increased risk for life-threatening respiratory depression since pharmacokinetics of the drugs may be altered in these patients.1,20,21 In patients with chronic obstructive pulmonary disease or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, even recommended doses of tapentadol may decrease respiratory drive to the point of apnea.1,20,21 Such patients should be monitored closely, particularly during initiation of tapentadol therapy and dosage titration and when other drugs with respiratory depressant effects are used concomitantly.1,20,21 Alternatively, use of nonopiate analgesics should be considered in such patients.1,20,21 Use of tapentadol in patients with substantial respiratory depression or in those with acute or severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment is contraindicated.1,20,21

For usual guidelines for management of opiate agonist-induced respiratory depression, see Acute Toxicity: Treatment, in the Opiate Agonists General Statement 28:08.08.

Because of the risks associated with opiate overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including tapentadol.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose)411,431,750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate analgesic, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of OUD, those who have experienced a prior opiate overdose).750 (See Naloxone Hydrochloride 28:10.)

Neonatal Opiate Withdrawal Syndrome

Prolonged maternal use of tapentadol during pregnancy can result in neonatal opiate withdrawal syndrome.1,20,21 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may occur when opiate agonists are used concomitantly with benzodiazepines or other CNS depressants.1,20,21,700,701,702 Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate.1,20,21,700,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

Dispensing and Administration Precautions with Oral Solution

Caution is required when prescribing, dispensing, and administering tapentadol oral solution since dosing errors caused by confusion between milligrams (mg) and milliliters (mL) can result in overdosage and death.20 To avoid such medication errors, the prescriber should specify the intended total dose of the drug (in mg) along with the corresponding total volume (in mL).20 Patients and/or caregivers should be instructed to use extreme caution when measuring a dose of tapentadol oral solution.20 (See Dosage and Administration: Administration.)

Interaction of Extended-release Tablets with Alcohol

Concomitant ingestion of alcohol with tapentadol extended-release tablets may result in increased plasma concentrations of the drug and a potentially fatal overdose.21 Patients should not consume alcoholic beverages or use prescription or nonprescription preparations containing alcohol during therapy with tapentadol extended-release tablets.21

Other Warnings and Precautions

General Opiate Agonist Precautions

Administration of tapentadol may cause effects similar to those produced by other opiate agonist drugs,1,2,3,9,12,13,20,21 and the usual precautions of opiate agonist therapy should be observed.1,20,21 (See the Opiate Agonists General Statement 28:08.08.)

Serotonin Syndrome

Potentially serious, sometimes fatal serotonin syndrome may occur with serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including tapentadol, particularly with concurrent use of other serotonergic drugs or drugs that impair the metabolism of serotonin (e.g., MAO inhibitors).1,4,5,20,21,400 (See Description.) Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,4,5,20,21,400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.1,20,21,400 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)

Adrenal Insufficiency

Adrenal insufficiency has been reported in patients receiving opiate agonists or opiate partial agonists.1,20,21,400 Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.1,20,21,400 In many of the reported cases, onset of adrenal insufficiency occurred after at least 1 month of opiate agonist or partial agonist use, although the time to onset has ranged from within 1 day to more than 1 year.400

If adrenal insufficiency is suspected, appropriate laboratory testing should be performed promptly and physiologic (replacement) dosages of corticosteroids provided; therapy with the opiate agonist or partial agonist should be tapered and discontinued to allow recovery of adrenal function.1,20,21,400 If the opiate agonist or partial agonist can be discontinued, follow-up assessment of adrenal function should be performed to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.1,20,21,400

Hypotension

Tapentadol may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.1,20,21 Because the risk is increased in patients whose ability to maintain blood pressure has been compromised by blood volume depletion or concomitant use of certain CNS depressants (e.g., general anesthetics, phenothiazines), such patients should be monitored for hypotension following initiation of tapentadol therapy or an increase in dosage.1,20,21 Use of tapentadol should be avoided in patients with circulatory shock since the drug may cause vasodilation that can further reduce cardiac output and blood pressure.1,20,21

Increased Intracranial Pressure or Head Injury

The respiratory depressant effects of tapentadol promote carbon dioxide retention, which can result in elevation of intracranial pressure.1,20,21 Patients who may be particularly susceptible to these effects (e.g., those with evidence of increased intracranial pressure or brain tumors) should be monitored for sedation and respiratory depression, particularly during initiation of therapy.1,20,21 Opiates also may obscure the clinical course in patients with head injuries.1,20,21 Use of tapentadol should be avoided in patients with impaired consciousness or coma.1,20,21

GI Conditions

Tapentadol may increase serum amylase concentrations and cause spasm of the sphincter of Oddi.1,20,21 Patients with biliary tract disease, including those with acute pancreatitis, should be monitored for worsening symptoms during therapy with tapentadol.1,20,21

Tapentadol is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.1,20,21

Seizures

Tapentadol may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in some clinical settings associated with seizures.1,20,21 Patients with seizure disorders should be monitored for worsening of seizure control during tapentadol therapy.1,20,21

Dependence and Tolerance

Both physical dependence and tolerance can develop during long-term opiate therapy.1,13,20,21 Tolerance may not develop uniformly to all opiate effects.1,20,21

In patients who are physically dependent on opiates, abrupt discontinuance of tapentadol or a substantial reduction in dosage may result in manifestations of withdrawal (e.g., restlessness, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increases in blood pressure, respiratory rate, or heart rate).1,20,21 Withdrawal also may be precipitated by concomitant administration of an opiate antagonist or opiate partial agonist.1 (See Drug Interactions: Opiate Partial Agonists.) In a study evaluating the safety of tapentadol administered for periods up to 90 days, objective manifestations of opiate withdrawal, as assessed by the Clinical Opiate Withdrawal Scale (COWS), were absent in 83% of tapentadol-treated patients who abruptly discontinued therapy and were assessed for withdrawal symptoms 2-4 days after drug discontinuance; mild to moderate withdrawal symptoms were noted in 17% of tapentadol-treated patients compared with 29% of oxycodone-treated patients.1,6,7,11 When tapentadol therapy is discontinued in a patient who may be physically dependent on opiates, the dosage should be tapered gradually.1,20,21

Infants born to women who are physically dependent on opiates also will be physically dependent.1,20,21 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

CNS Depression

Tapentadol may impair mental alertness and/or physical coordination required to perform potentially hazardous tasks such as driving or operating machinery.1,20,21 (See Advice to Patients.)

Concurrent use of tapentadol and other CNS depressants may result in profound sedation, respiratory depression, coma, or death.1,20,21,700,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

Hypogonadism

Hypogonadism or androgen deficiency has been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,1,20,21,400,401,402,403,404 although a causal relationship has not been established.1,20,21,400 Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility1,20,21 ) should undergo laboratory evaluation.400

Specific Populations

Pregnancy

Category C.1,20,21 (See Users Guide.)

Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic use of opiate agonists in pregnant women during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.28,29 The manufacturer states that available data regarding use of tapentadol in pregnant women are not sufficient to establish the risk of major birth defects and spontaneous abortion with the drug.1,20,21 In animal studies, embryofetal mortality and structural malformations were observed in rabbits and delays in skeletal maturation and increased pup mortality were observed in rats at exposure levels equivalent to or less than those associated with the maximum recommended human dosage.1,20,21 Based on animal data, patients should be apprised of potential risks to the fetus if tapentadol is used during pregnancy.1,20,21

Use of opiates in pregnant women during labor can result in neonatal respiratory depression.1,20,21 Tapentadol is not recommended for use during or immediately prior to labor and delivery.1,20,21 Neonates exposed to opiates during labor should be monitored for respiratory depression and withdrawal symptoms; an opiate antagonist (e.g., naloxone) should be available to reverse opiate-induced respiratory depression in the neonate.1,20,21

Prolonged maternal use of opiates, including tapentadol, during pregnancy can result in neonatal opiate withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.1,20,21 In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.1,20,21 Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.1,20,21 The onset, duration, and severity of the syndrome vary depending on the specific opiate agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.1,20,21

Lactation

Limited data suggest that tapentadol may be distributed into milk; risk to nursing infants cannot be ruled out.1,20,21 The benefits of breast-feeding and the importance of tapentadol therapy to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1,20 Because of the potential for serious adverse effects (e.g., sedation, respiratory depression) in nursing infants, breast-feeding is not recommended during therapy with tapentadol extended-release tablets.21

Infants exposed to tapentadol through breast milk should be monitored for excessive sedation and respiratory depression.1,20,21 Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.1,20,21

Pediatric Use

Safety and efficacy of tapentadol in children younger than 18 years of age have not been established.1,20,21

Geriatric Use

In clinical studies of tapentadol administered as conventional or extended-release tablets, 19 or 28%, respectively, of patients were 65 years of age or older and 5 or 7%, respectively, were 75 years of age or older.1,21 No overall differences in efficacy were observed between geriatric patients and younger adults;1,21 however, in patients receiving tapentadol conventional tablets, the incidence of constipation was higher in geriatric patients 65 years of age or older compared with those younger than 65 years of age (12 versus 7%).1 Systemic exposure to tapentadol, as measured by area under the plasma concentration-time curve (AUC), was similar in geriatric patients and young adults; the mean peak plasma tapentadol concentration was 16% lower in geriatric patients compared with young adults.1,21 (See Dosage and Administration: Special Populations.)

Hepatic Impairment

Serum concentrations and AUC of tapentadol were increased in patients with hepatic impairment compared with individuals with normal hepatic function; in addition, the rate of formation of the inactive O -glucuronide metabolite was reduced in patients with increased hepatic impairment.1 Tapentadol dosage should be reduced in patients with moderate hepatic impairment (Child-Pugh score 7-9), and the patient should be monitored closely for respiratory and CNS depression.1,20,21 (See Dosage and Administration: Special Populations.) Dosage adjustment is not necessary in patients with mild hepatic impairment (Child-Pugh score 5-6).1,20,21 The drug has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15), and use in such patients is not recommended.1,20,21

Renal Impairment

Peak plasma concentrations and AUC of tapentadol were similar in individuals with normal to severely impaired renal function, but exposure to the O -glucuronide metabolite increased as the degree of renal impairment increased; AUC of the O -glucuronide metabolite was 1.5-, 2.5-, and 5.5-fold higher in patients with mild, moderate, and severe renal impairment, respectively, when compared with individuals with normal renal function.1 Because the clinical relevance of accumulation of the glucuronide metabolite is unknown, use of tapentadol is not recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).1,20,21 No dosage adjustment is needed in patients with mild or moderate renal impairment (creatinine clearance 30-90 mL/minute).1,20,21

Common Adverse Effects

Adverse effects reported in 3% or more of tapentadol-treated patients in clinical studies and more frequently with tapentadol than with placebo include nausea,1,2,3,7,9,21,23,24,25 dizziness,1,2,3,7,9,21,23,24,25 vomiting,1,2,3,7,9,21,23,24,25 somnolence,1,2,3,7,9,21,23,25 constipation,1,2,3,7,21,23,24,25 pruritus,1,2,3,7,21,23 dry mouth,1,7,21,23 hyperhidrosis,1,2,21,23 fatigue,1,3,7,21,23,25 headache,21,23 vomiting,21,23 diarrhea,21,24 decreased appetite,21 anxiety,21,24 insomnia,21,23,24,25 dyspepsia,21,23 and hot flush.21 In several clinical studies, adverse GI effects (nausea, vomiting, constipation) were reported more commonly with oxycodone than with tapentadol (see Uses: Pain).2,3,6,7,23

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Tapentadol is metabolized principally by glucuronidation and to a lesser extent by cytochrome P-450 (CYP) isoenzymes 2C9, 2C19, and 2D6.1,6,8 Tapentadol did not induce CYP isoenzymes 1A2, 2D6, or 3A4 or inhibit isoenzymes 1A2, 2A6, 2C9, 2C19, 2E1, or 3A4 in vitro;1,6,8 tapentadol inhibited CYP2D6 to a limited extent in vitro, but at clinically irrelevant concentrations.8 Clinically important interactions mediated by CYP isoenzymes are unlikely.1,6,8

Benzodiazepines and Other CNS Depressants

Potential pharmacologic interaction (additive CNS depressant effects and increased risk of respiratory depression, hypotension, profound sedation, coma, and death) when tapentadol is used concomitantly with benzodiazepines or other CNS depressants, including other opiate agonists, anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and alcohol.1,9,20,21,416,417,418,700,701,702,703 A substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.416,417,418,435,700,701 Whenever possible, concomitant use of opiate agonists and benzodiazepines should be avoided.410,411,415,435 Concomitant use of opiate analgesics and benzodiazepines or other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.1,20,21,700,703 Concomitant use with alcohol should be avoided.1,20,21,700,703 (See Drug Interactions: Alcohol.)

If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving tapentadol, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.1,20,21,700,703 In patients receiving a CNS depressant, tapentadol, if required, should be initiated at a reduced dosage and titrated based on clinical response.1,20,21,700,703 Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750 (See Respiratory Depression under Warnings/Precautions: Warnings, in Cautions.)

Monoamine Oxidase Inhibitors

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome; respiratory depression, coma, or other manifestations of opiate toxicity).1,9,20,21 Tapentadol is contraindicated in patients who are receiving or have recently (i.e., within 2 weeks) received a monoamine oxidase (MAO) inhibitor.1,9,20,21 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome) when tapentadol is used concurrently with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tramadol, tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone) and MAO inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).1,4,5,20,21,400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.1,20,21,400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,20,21,400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.1,20,21,400

Tapentadol is contraindicated in patients who are receiving or have recently (i.e., within 2 weeks) received an MAO inhibitor.1,9,20,21 (See Drug Interactions: Monoamine Oxidase Inhibitors.) If concomitant use of tapentadol with other serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.1,20,21,400 If serotonin syndrome is suspected, treatment with tapentadol,1,20,21 other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.400

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Opiate Partial Agonists

Use of opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine) should be avoided in patients receiving opiate agonists, since the partial agonist may reduce the analgesic effect of the full opiate agonist and/or precipitate withdrawal symptoms.1,20,21

Acetaminophen

Pharmacokinetics of tapentadol were not altered when a single 80-mg dose of the drug was administered concomitantly with the fifth of 7 doses of acetaminophen (1 g every 6 hours) in healthy individuals.1,14,20,21

Aspirin

Pharmacokinetics of tapentadol were not altered when a single 80-mg dose of the drug was administered concomitantly with the second of 2 doses of aspirin (325 mg once daily) in healthy individuals.1,14,20,21

Alcohol

In addition to additive CNS depressant effects that could result in respiratory depression, hypotension, profound sedation, coma, or death1,700,703 (see Drug Interactions: Benzodiazepines and Other CNS Depressants), concomitant use of alcohol with extended-release tapentadol tablets can result in increased plasma tapentadol concentrations and potentially fatal overdosage.21 Administration of tapentadol extended-release tablets with 240 mL of 40% alcohol in the fasted state did not affect the rate of tapentadol absorption but increased mean peak plasma concentration and area under the plasma concentration-time curve (AUC) of the drug by 48 and 17%, respectively following a single 100-mg dose, and by 28 and 16%, respectively, following a single 250-mg dose.21

Concomitant use of extended-release tapentadol tablets with alcohol or products containing alcohol should be avoided.1,700,703

Anticholinergic Agents

Concomitant use of tapentadol and drugs with anticholinergic activity may increase the risk of urinary retention and/or severe constipation, which can lead to paralytic ileus.1,20,21 Patients receiving such concomitant therapy should be monitored for signs or symptoms of urinary retention and reduced GI motility.1,20,21

Diuretics

Opiate agonists may decrease the effects of diuretics by inducing the release of vasopressin (antidiuretic hormone).1,20,21 Patients receiving such concomitant therapy should be monitored for decreased diuretic or hypotensive effects; dosage of the diuretic may be increased if clinically indicated.1,20,21

Metoclopramide

Pharmacokinetics of tapentadol were not affected by metoclopramide.1,20,21

Naproxen

Naproxen increased the AUC of tapentadol by 17% when a single 80-mg dose of tapentadol was administered concomitantly with the third of 4 doses of naproxen (500 mg twice daily) in healthy individuals; this change was not considered to be clinically relevant and dosage adjustments are not necessary.1,14,20,21

Neuromuscular Blocking Agents

Opiates may enhance the neuromuscular blocking action and increase the respiratory depressant effect of neuromuscular blocking agents.1,20,21 Patients receiving such concomitant therapy should be monitored for a greater than expected degree of respiratory depression; dosage of one or both drugs should be decreased as needed.1,20,21

Omeprazole

Pharmacokinetics of tapentadol were not affected by omeprazole.1,20,21

Probenecid

Probenecid increased the AUC of tapentadol by 57%; this change was not considered to be clinically relevant and dosage adjustments are not necessary.1,20,21

Protein-bound Drugs

Pharmacokinetic interactions are unlikely.1,6,8,20,21

Description

Tapentadol is a synthetic, centrally active analgesic that is structurally and pharmacologically related to tramadol.1,6,8,9,10,15 Tapentadol, like tramadol, exhibits agonist activity at the µ-opiate receptor and inhibits norepinephrine and serotonin reuptake;10,16,17 however, animal studies indicate that the serotonergic activity of tapentadol is much lower than its noradrenergic activity.10,16,17 The precise mechanism of the analgesic effect of tapentadol is unknown, but is thought to be related to the drug's opiate agonist activity and inhibition of norepinephrine reuptake.1,6,7,8,9,10,16,17 Studies with selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), and other mixed reuptake inhibitors have indicated that analgesia is more readily obtained by inhibiting the reuptake of norepinephrine rather than serotonin.16 It is thought that inhibition of norepinephrine reuptake may work synergistically with µ-receptor activation to enhance analgesic efficacy and/or attenuate adverse effects associated with traditional opiate analgesics (e.g., GI effects) by reducing the requirement for µ-receptor activation.6,10 Results of rat synaptosomal reuptake assays indicate that tapentadol is almost as potent as venlafaxine in inhibiting the reuptake of norepinephrine.10 In animal models, tapentadol is 2-3 times less potent than morphine in producing analgesia.10 Compared with morphine, tapentadol possesses a reduced emetogenic potential, and produces less physical dependence at equianalgesic doses in animal models.10 The drug has an abuse potential similar to that seen with other potent opiates, including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone,1,9 and exhibits weak antagonist activity for muscarinic receptors.10 Tapentadol appears to have a greater abuse potential than tramadol; unlike tramadol (which originally was not subject to control under the Federal Controlled Substances Act of 1970, but currently is subject to control as a schedule IV drug), tapentadol is subject to control as a schedule II drug.9,13,18

Tapentadol undergoes extensive first-pass metabolism with a mean absolute bioavailability following a single oral dose of approximately 32%.1,6,20,21 Peak plasma concentrations of tapentadol are attained 1.25 hours after administration as conventional (immediate-release) preparations1,20 and 3-6 hours after administration as extended-release tablets.21 Peak plasma tapentadol concentration and area under the plasma concentration-time curve (AUC) are dose proportional over the dosing range of 50-150 mg for conventional preparations;1 AUC also is dose proportional over the therapeutic dosage range for extended-release tablets.21 Following oral administration of extended-release tablets every 12 hours, steady-state tapentadol exposure is attained after the third dose.21 Administration of conventional preparations of tapentadol with a high-fat, high-calorie meal increases peak plasma concentration and AUC of the drug by 16 and 25%, respectively;1,20 when the extended-release tablets are administered with a high-fat, high-calorie meal, peak plasma concentration and AUC are increased by 17 and 6%, respectively.21 The manufacturer states that conventional or extended-release formulations may be administered without regard to food.1,20,21 The drug distributes widely throughout the body1 and is approximately 20% bound to plasma proteins.1,6,8 Tapentadol undergoes extensive metabolism, principally by glucuronidation; its major metabolite, tapentadol- O -glucuronide, is formed via uridine diphosphate-glucuronosyltransferase enzymes 1A9 and 2B7.1,6,8 The drug also is metabolized to a lesser extent by cytochrome P-450 (CYP) isoenzymes 2C9 and 2C19 to a desmethyl metabolite and by CYP2D6 to a hydroxide metabolite; both metabolites undergo secondary conjugation.1,8 None of the metabolites contribute to the analgesic activity of the drug.1,6,8,10 The average terminal half-life of tapentadol is 4 or 5 hours following oral administration of conventional preparations or extended-release tablets, respectively.1 Following oral administration, approximately 70% of a dose is excreted in urine as glucuronide or sulfate conjugates and only 3% is excreted unchanged.1,6 Tapentadol and its inactive metabolites are eliminated mainly by the kidneys (99%).1,6

Advice to Patients

Importance of reading the patient information (medication guide) provided by the manufacturer before initiating therapy and each time the prescription is refilled.1

Importance of taking tapentadol only as directed; importance of not adjusting the dosage of tapentadol without consulting a clinician and of not discontinuing the drug abruptly as withdrawal symptoms may occur.1,20,21

Importance of instructing patients on proper administration of the drug.1,20,21 Importance of always using the calibrated oral syringe when administering tapentadol oral solution and of not using a household spoon to measure the dose.20

Importance of instructing patients to swallow extended-release tablets whole with enough water to ensure complete swallowing of the tablet immediately after it is placed in the mouth.21 Importance of not cutting, crushing, chewing, or dissolving extended-release tablets.21

Importance of informing patients that tapentadol is an opiate and carries the risk of addiction, abuse, and misuse, which can lead to overdosage and death, even when used as recommended.1,20,21 Importance of informing patients that this drug should never be given to anyone other than the individual for whom it was prescribed, that the drug should be protected from theft or misuse, and that any unused drug should be disposed of properly.1

Risk of potentially fatal respiratory depression.1,20,21 Importance of informing patients that the risk is greatest following initiation of therapy and dosage increases, and may occur even at recommended dosages.1,20,21 Importance of advising patient to seek immediate medical attention if signs or symptoms of respiratory depression occur.1,20,21 Patients should be advised of the benefits of naloxone administration following an overdose and of their options for obtaining the drug.750

Risk of respiratory depression or death if accidentally ingested, particularly by a child.1,20,21 Importance of keeping tapentadol out of reach of children.1,20,21

Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly. Importance of avoiding concomitant use unless such use is supervised by clinician.700,703 Importance of advising patients that tapentadol should not be combined with alcohol.1,700

Risk of orthostatic hypotension and syncope.1,20,21

Potential for tapentadol to impair mental alertness and/or physical coordination; driving or operating machinery should be avoided until the drug's effects on the individual are known.1

Importance of informing patients that severe constipation may develop and advising patients on appropriate management.1,20,21

Potential risk of serotonin syndrome with concurrent use of tapentadol and other serotonergic agents.1,20,21,400 (See Interactions.) Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.1,20,21,400

Potential risk of adrenal insufficiency.1,20,21,400 Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.1,20,21,400

Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.400 Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.400

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1,20,21 Importance of avoiding concomitant therapy with monoamine oxidase (MAO) inhibitors.1,20,21

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,20,21 Importance of informing women that tapentadol may cause fetal harm and that chronic use during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated.1,20,21 Importance of immediately seeking medical attention if an infant exposed to tapentadol through breast milk exhibits symptoms of opiate overdosage (e.g., sedation, difficulty breathing, hypotonia).1,20 Importance of advising patients that breast-feeding during therapy with extended-release tapentadol is not recommended.21

Importance of informing patients with a history of seizures that tapentadol may precipitate seizures and of advising them to use tapentadol with care.21 Importance of advising patients to discontinue tapentadol if seizures occur and to contact their clinician immediately.21

Importance of informing patients of other important precautionary information.1,20,21 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Depomed, Inc. Nucynta^® (tapentadol) immediate-release tablets prescribing information. Newark, CA; 2016 Dec.

2. Daniels SE, Upmalis D, Okamoto A et al. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain *. Curr Med Res Opin . 2009; 25:765-76. [PubMed 19203298]

3. Hartrick C, Van Hove I, Stegmann JU et al. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther . 2009; 31:260-71. [PubMed 19302899]

4. Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephirne reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website. [Web]

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