Tapentadol Hydrochloride

Pronunciation

Class: Opiate Agonists
ATC Class: N02AX06
VA Class: CN101
Chemical Name: 3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride
Molecular Formula: C14H23NO HCL
CAS Number: 175591-23-8
Brands: Nucynta

Introduction

Synthetic, centrally active analgesic; structurally and pharmacologically related to tramadol.1 6 8 9 10 15

Uses for Tapentadol Hydrochloride

Acute Pain

Relief of moderate to severe acute pain.1 2 3 9

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Tapentadol Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.1

Dosage

Available as tapentadol hydrochloride; dosage expressed in terms of tapentadol.1

Individualize dosage according to severity of pain, prior experience with similar agents, and clinician's ability to monitor the patient.1

Adults

Acute Pain
Oral

Usually 50–100 mg administered every 4–6 hours depending on pain intensity.1 On day 1, patients not experiencing adequate pain relief may receive a second dose as early as 1 hour following first dose.1 Administer subsequent doses every 4–6 hours; adjust dosage to maintain adequate analgesia and minimize adverse effects.1

Prescribing Limits

Adults

Acute Pain
Oral

Dosages >700 mg on day 1 and dosages >600 mg on subsequent days are not recommended.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary in mild hepatic impairment.1

In patients with moderate hepatic impairment, initial dosage of 50 mg administered no more frequently than once every 8 hours (maximum 3 doses in 24 hours).1 Adjust subsequent dosage by shortening or lengthening the dosing interval to maintain adequate analgesia and minimize adverse effects.1

Not recommended in patients with severe hepatic impairment.1 (See Special Populations under Pharmacokinetics: Absorption and also see under Pharmacokinetics: Elimination.)

Renal Impairment

No dosage adjustment necessary in mild or moderate renal impairment.1 Not recommended in patients with severe renal impairment.1 (See Special Populations under Pharmacokinetics: Elimination.)

Geriatric Patients

Because geriatric patients are more likely to have renal or hepatic impairment, consider initiating tapentadol therapy at the lower end of the usual dosage range.1 (See Geriatric Use under Cautions.)

Cautions for Tapentadol Hydrochloride

Contraindications

  • Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.1 9

  • Substantial respiratory depression in unmonitored settings or in the absence of resuscitative equipment.1

  • Acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.1

  • Known or suspected paralytic ileus.1

Warnings/Precautions

Opiate Agonist Precautions

May cause effects similar to those produced by other opiate agonists;1 2 3 9 12 13 observe many of the usual precautions of opiate agonist therapy.1

Respiratory Depression

The major toxicity associated with opiate agonists.1

Occurs more frequently in geriatric and debilitated patients and those with conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.1

Use with caution in patients having a substantially decreased respiratory reserve, hypoxia, or hypercapnia, including patients with asthma, COPD, cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis, CNS depression, or coma.1 In such patients, even therapeutic tapentadol doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.1 Consider alternative nonopiate agonists; use tapentadol only under careful medical supervision and at the lowest effective dosage.1

If respiratory depression occurs, follow usual guidelines for management of opiate agonist-induced respiratory depression.1

CNS Depression

Performance of activities requiring mental alertness and physical coordination (e.g., driving, operating machinery) may be impaired, especially at the beginning of therapy, during periods of dosage adjustment, or with concomitant use of alcohol or tranquilizers.1 (See Advice to Patients.)

Concurrent use of other CNS depressants may cause additive CNS depression, possibly resulting in respiratory depression, hypotension, profound sedation, coma, or death; if concomitant therapy is necessary, consider reducing the dosage of one or both drugs.1 9 (See Specific Drugs under Interactions.)

Increased Intracranial Pressure or Head Injury

The respiratory depressant effects of tapentadol (with carbon dioxide retention and secondary elevation of CSF pressure) may be markedly exaggerated in the presence of head injury or other intracranial lesions.1

Opiate agonists produce effects (e.g., pupillary changes, altered consciousness) that may obscure neurologic signs of a further increase in pressure in patients with head injuries.1

Use with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.1 Avoid use in patients susceptible to effects of increased CSF pressure (e.g., those with evidence of head injury and increased intracranial pressure).1

Dependence and Abuse

Physical and psychic dependence and tolerance may develop with repeated administration; abuse potential exists.1 13

Abuse potential similar to that of hydromorphone.1 9 Abuse of tapentadol poses a risk of overdose and death; concurrent abuse of alcohol and other substances increases risk of toxicity.1

Consider abuse potential when prescribing or dispensing tapentadol in situations where increased risk of misuse and abuse may be present.1 Carefully monitor all patients receiving opiate agonists for signs of abuse and addiction; however, concerns about abuse and addiction should not prevent the proper management of pain.1

Abrupt cessation of therapy may result in withdrawal symptoms (e.g., anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and, rarely, hallucinations).1 6 7 To reduce symptoms, taper dosage when discontinuing the drug.1

Seizures

Seizures reported in <1% of tapentadol-treated patients in clinical studies.1

Not systematically evaluated in patients with seizure disorders; such patients were excluded from clinical studies.1 Use with caution in patients with a history of seizure disorder and those at increased risk for seizures.1 (See Advice to Patients.)

Serotonin Syndrome

Potentially life-threatening serotonin syndrome with SNRIs, including tapentadol, particularly with concurrent use of other serotonergic drugs (e.g., 5-HT1 receptor agonists [“triptans”], SSRIs, tricyclic antidepressants) or drugs that impair serotonin metabolism (e.g., MAO inhibitors).1 4 5 (See Actions.)

Serotonin syndrome may occur with usual dosages of tapentadol.1 Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 4 5

Pancreatic and Biliary Disease

May cause spasm of the sphincter of Oddi.1 Use with caution in patients with biliary tract disease, including acute pancreatitis.1

Specific Populations

Pregnancy

Category C.1

Effect on labor and delivery unknown.1 Not recommended for use during and immediately prior to labor and delivery.1 Neonates born to women who have received tapentadol 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

Lactation

May distribute into milk; do not use in nursing women.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 Not recommended for use in this population.1

Geriatric Use

No overall differences in efficacy of tapentadol in those ≥65 years of age compared with younger adults.1 Incidence of constipation was higher in patients ≥65 years of age compared with those <65 years of age (12 versus 7%).1 (See Special Populations under Pharmacokinetics: Absorption.)

Because of possible renal or hepatic impairment in geriatric patients, consider initiating therapy at the lower end of the recommended dosage range.1

Hepatic Impairment

Higher serum tapentadol concentrations reported in patients with hepatic impairment compared with individuals without impairment.1 (See Special Populations under Pharmacokinetics: Absorption.) Use with caution in moderate hepatic impairment.1 Not studied and, therefore, not recommended in severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Safety and efficacy not established in severe renal impairment; use in this population not recommended.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea,1 2 3 7 9 dizziness,1 2 3 7 9 vomiting,1 2 3 7 9 somnolence,1 2 3 7 9 constipation,1 2 3 7 pruritus,1 2 3 7 dry mouth,1 7 hyperHIDrosis,1 2 fatigue1 3 7 . In several clinical studies, adverse GI effects (nausea, vomiting, constipation) reported more commonly with oxycodone than with tapentadol.2 3 6 7

Interactions for Tapentadol Hydrochloride

Metabolized primarily by glucuronidation.1 6 8

Metabolized to a lesser extent by CYP isoenzymes 2C9, 2C19, and 2D6.1 8

Does not induce CYP isoenzymes 1A2, 2D6, or 3A4 and does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2E1, or 3A4 in vitro.1 6 8 Inhibits CYP2D6 to a limited extent in vitro.8

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically relevant CYP-mediated interactions are unlikely.1 6 8

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome) with serotonergic agents.1 4 5 (See Serotonin Syndrome under Cautions and see Actions.)

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1 6 8

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Acetaminophen did not affect pharmacokinetics of tapentadol1 14

Alcohol

Additive CNS effects causing CNS depression, cognitive/physical impairment, respiratory depression, hypotension, profound sedation, coma, death1

Increased risk of overdosage and death with concurrent abuse1

Avoid concomitant use1

Antidepressants, SSRIs or other SNRIs

Potentially life-threatening serotonin syndrome1

Antidepressants, tricyclics (TCAs)

Potentially life-threatening serotonin syndrome1

Aspirin

Aspirin did not affect pharmacokinetics of tapentadol1 14

CNS depressants (e.g., other opiate agonists, general anesthetics, antiemetics, tranquilizers, sedatives and hypnotics, phenothiazines)

Additive CNS depression with possible respiratory depression, hypotension, profound sedation, coma, or death1 9

If concomitant therapy is necessary, consider reducing dosage of one or both agents1

5-HT1 receptor agonists (“triptans”)

Potentially life-threatening serotonin syndrome1 4

MAO inhibitors

Potentially life-threatening serotonin syndrome1

Potential adverse cardiovascular effects secondary to increased norepinephrine levels1 9

Tapentadol contraindicated in patients currently receiving or having recently (within 2 weeks) received MAO inhibitors1 9

Metoclopramide

Metoclopramide did not affect pharmacokinetics of tapentadol1

Naproxen

Naproxen increased tapentadol AUC by 17%; not considered clinically relevant1 14

Dosage adjustments not necessary1

Omeprazole

Omeprazole did not affect pharmacokinetics of tapentadol1

Probenecid

Probenecid increased tapentadol AUC by 57%; not considered clinically relevant1

Dosage adjustments not necessary1

Tapentadol Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Mean absolute bioavailablity is approximately 32% following a single oral dose.1 6 Peak plasma concentration and AUC are dose proportional over dosing range of 50–150 mg.1 Peak plasma concentrations attained approximately 1.25 hours following oral administration.1

Food

High-fat, high-calorie meal increases tapentadol AUC by 25% and peak plasma concentration by 16%.1

Special Populations

Mean peak plasma tapentadol concentrations were 16% lower in geriatric patients compared with younger adults; AUCs were similar.1

In patients with mild hepatic impairment, tapentadol AUC and peak plasma concentration were increased 1.7- and 1.4-fold, respectively; in those with moderate hepatic impairment, AUC and peak plasma concentration were increased 4.2- and 2.5-fold, respectively.1

Distribution

Extent

Widely distributed throughout the body.1

May distribute into human milk.1

Plasma Protein Binding

Approximately 20%.1 6 8

Elimination

Metabolism

Principally undergoes conjugation with glucuronic acid to form inactive metabolites; major inactive metabolite, tapentadol-O-glucuronide, formed via uridine diphosphate-glucuronosyltransferase enzymes (UGT) 1A9 and 2B7.1 6 8

Metabolized to a lesser extent by CYP2C9 and CYP2C19 to form N-desmethyl tapentadol and by CYP2D6 to form hydroxytapentadol, both of which undergo secondary conjugation.1 8

Elimination Route

Tapentadol and its metabolites are excreted primarily (99%) by the kidneys.1 6 Following oral administration, approximately 70% of a dose is excreted in urine as conjugates (55% as O-glucuronide and 15% as sulfate conjugate of tapentadol); 3% of a dose is eliminated as unchanged drug.1 6

Half-life

Mean terminal half-life is 4 hours.1

Special Populations

In patients with increased hepatic impairment, rate of formation of tapentadol-O-glucuronide was reduced.1 Tapentadol half-life was increased 1.2- or 1.4-fold in patients with mild or moderate hepatic impairment, respectively.1

In patients with mild, moderate, or severe renal impairment, AUC of tapentadol-O-glucuronide is 1.5-, 2.5-, or 5.5-fold higher, respectively, than AUC in patients with normal renal function.1

Stability

Storage

Oral

Tablets

≤25°C (may be exposed to 15–30°C).1 Protect from moisture.1

Actions

  • Precise mechanism of analgesic action unknown; thought to be related to agonist activity at the μ-opiate receptor and inhibition of norepinephrine reuptake.1 6 7 8 9 10 16 17

  • Also inhibits serotonin reuptake, but serotonergic activity is much lower than noradrenergic activity.10 16 17

  • Inhibition of norepinephrine reuptake may work synergistically with μ-receptor activation to enhance analgesic efficacy and/or attenuate adverse effects seen with traditional opiate analgesics (e.g., GI effects) by reducing the requirement for μ-receptor activation.6 10

  • Drug is 18 times less potent than morphine in μ-receptor binding in humans;1 animal data indicate that tapentadol is almost as potent as venlafaxine in inhibiting the reuptake of norepinephrine.10

  • Tapentadol is 2–3 times less potent than morphine in producing analgesia in animals.1 10

  • Possesses a reduced emetogenic potential compared with morphine and produces less physical dependence at equianalgesic doses.10

  • Abuse potential is similar to that seen with hydromorphone1 9 but appears to be greater than that seen with tramadol;9 13 tapentadol, unlike tramadol, is subject to control under the Federal Controlled Substances Act of 1970 as a scheduled drug.9 13

  • Antinociceptic effect antagonized by μ-receptor antagonists (e.g., naloxone); norepinephrine reuptake inhibition sensitive to norepinephrine modulators.1

  • Possesses weak antagonist activity for muscarinic receptors.10

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 informing clinician of any breakthrough pain or adverse effects (e.g., constipation) that occur during therapy, so that therapy may be adjusted based on individual patient requirements.1

  • Importance of taking tapentadol only as directed; do not increase dosage or abruptly discontinue therapy without consulting a clinician.1

  • Importance of informing patients that tapentadol is a drug of potential abuse and also should be protected from theft.1 Importance of informing patients that this drug should never be given to anyone other than the individual for whom it was prescribed.1

  • Potential for tapentadol to impair mental alertness and/or physical coordination; avoid driving or operating machinery until effects on individual are known.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 Importance of avoiding concomitant therapy with MAO inhibitors and of not combining tapentadol with alcohol.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of avoiding breast-feeding while receiving tapentadol.1

  • Importance of informing patients with a history of seizures that tapentadol may precipitate seizures and of advising them to use tapentadol with care.1 Importance of advising patients to discontinue tapentadol if seizures occur and to contact their clinician immediately.1

  • Importance of informing patients of the potential risk of serotonin syndrome with concurrent use of tapentadol and other serotonergic drugs (e.g., SSRIs, SNRIs, tricyclic antidepressants).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drug.

Tapentadol Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of tapentadol)

Nucynta ( C-II)

Ortho-McNeil-Janssen

75 mg (of tapentadol)

Nucynta ( C-II)

Ortho-McNeil-Janssen

100 mg (of tapentadol)

Nucynta ( C-II)

Ortho-McNeil-Janssen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nucynta 50MG Tablets (JANSSEN): 20/$65.99 or 30/$98.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ortho-McNeil Janssen. Nucynta (tapentadol) immediate-release tablets prescribing information. Raritan, NJ; 2009 Mar.

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; :.

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.

5. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005; 352:1112-20. [PubMed 15784664]

6. Hartrick CT. Tapentadol immediate release for the relief of moderate-to-severe acute pain. Expert Opin Pharmacother. 2009; 10:2687-96. [PubMed 19795998]

7. Hale M, Upmalis D, Okamoto A et al. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009; 25:1095-104. [PubMed 19301989]

8. Kneip C, Terlinden R, Beier H et al. Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes. Drug Metab Lett. 2008; 2:67-75. [PubMed 19356073]

9. . Tapentadol (Nucynta)--a new analgesic. Med Lett Drugs Ther. 2009; 51:61-2. [PubMed 19661853]

10. Tzschentke TM, Christoph T, Kögel B et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007; 323:265-76. [PubMed 17656655]

11. Ortho-McNeil Janssen, Raritan, NJ: Personal communication.

12. Daniels S, Casson E, Stegmann JU et al. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009; 25:1551-61. [PubMed 19445652]

13. Drug Enforcement Administration. Schedules of controlled substances: placement of tapentadol into Schedule II. 21 CFR Part 1308. Final Rule. [Docket No. DEA-319F] Fed Regist. 2009; 74:23790-3.

14. Smit JW, Oh C, Rengelshausen J et al. Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies. Pharmacotherapy. 2010; 30:25-34. [PubMed 20030470]

15. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 22-3304: Summary review for tapentadol. From FDA web site.

16. Guay DR. Is tapentadol an advance on tramadol?. Consult Pharm. 2009; 24:833-40. [PubMed 20092221]

17. Wade WE, Spruill WJ. Tapentadol hydrochloride: a centrally acting oral analgesic. Clin Ther. 2009; 31:2804-18. [PubMed 20110020]

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