CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-3 04
`
`' LABELING
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TRADENAME“ safely and effectively. See full prescribing information
`for TRADENAME".
`
`TRADENAME'I (tapentadol) immediate release oral tablets
`Initial U.S. Approval : 2008
`-----------------INDICATIONS AND USAGE-—--—-—----—----------
`TRADENAMETM is an opioid analgesic indicated for the relief of moderate to
`severe acute pain in patients 18 years of age or older. (I)
`-------------DOSAGE AND ADMINISTRATION------—-——--—-—--
`0 As with many centrally-acting analgesic medications, the dosing regimen
`of TRADENAMETM should be individualized according to the severity of
`pain being treated, the previous experience with similar drugs and the
`ability to monitor the patient. (2)
`g
`' - Initiate TRADENAMETM with or without food at a dose of 50 mg, 75 mg,
`or 100 mg every 4 to 6 hours depending upon pain intensity. On the first
`day of dosing, the second dose may be administered as soon as one hour
`after the first dose, if adequate pain relief is not attained with the first dose.
`Subsequent closing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and
`should be adjusted to maintain adequate analgesia with acceptable
`tolerability. Daily doses greater than 700 mg on the first day of therapy and
`600 mg on subsequent days have not been studied and are, therefore, not
`recommended. (2)
`
`-—----———-—-DOSAGE FORMS AND STRENGTHS--—--—-——--v--
`Tablets: 50 mg, 75 mg, 100 mg (3)
`-—--——-----—--—---—-CONTRAINDICATIONS--------------------
`o Impaired pulmonary function (significant respiratory depression, acute or
`severe bronchial asthma or hypercapnia in unmonitored settings or the
`absence of resuscitative equipment) (4.1)
`o Paralytic ileus (4.2)
`o Concomitant use with monoamine oxidase inhibitors (MAOI) or use within
`14 days (4.3)
`
`—--------------WARNINGS AND PRECAUTIONS------------
`0 Respiratory depression: Increased risk in elderly, debilitated patients, those
`suffering from conditions accompanied by hypoxia, hypercapnia, or upper
`airway obstruction. (5.1)
`0 CNS effects: Additive CNS depressive effects when used in conjunction
`with alcohol, other opioids, or illicit drugs. (5.2)
`0 Elevation of intracranial pressure: May be markedly exaggerated in the
`presence of head injury, other intracranial lesions. (53)
`
`.
`
`0 Abuse potential may occur. Monitor patients closely for signs of abuse and
`addiction. (5.4)
`o Impaired mental/physical abilities: Caution must be used with potentially
`hazardous activities. (5.5)
`o Seizures: Use with caution in patients with a history of seizures. (5.7)
`- Serotonin Syndrome: Potentially life-threatening condition could result
`from concomitant serotonergic administration. (5.8)
`------------------ADVERSE REACTIONS--—--—---—--—-—-—-—-—
`The most common adverse events were nausea, dizziness, vomiting and
`somnolence. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact PriCara,
`Division of Ortho-McNeiI-Janssen Pharmaceuticals, Inc. at 1-800-526-
`7736 or FDA at 1-800-FDA-1088 or www.1dmgav/ingdwggh.
`—--—-----------DRUG INTERACTIONS-----------------
`0 Use TRADENAME'” with caution in patients currently using specified
`centrally-acting drugs or alcohol. (7.3)
`0 Do not use TRADENAMETM in patients currently using or within 14 days
`of using a monoamine oxidase inhibitor (MAOI). (7.4)
`------------USE IN SPECIFIC POPULATIONSn—-----------
`0 Labor and delivery: should not use during and immediately prior to labor
`and delivery. Monitor neonates, whose mothers have been taking
`TRADENAMET“, for respiratory depression. (8.2)
`I Nursing mothers: should not breast-feed. (8.3)
`0 Pediatric use: safety and effectiveness not established in patients less than
`18 years of age. (8.4)
`.
`0 Renal or hepatic impairment: not recommended in patients with severe
`renal or hepatic impairment. Use with caution in patients with moderate
`hepatic impairment (8.6, 8.7)
`o Elderly: care should be taken when selecting an initial dose. (2.3)
`See 17 for PATIENT COUNSELING INFORMATION AND
`MEDICATION GUIDE.
`
`Revised: 11/2008
`
`M
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`_|
`2
`
`3
`4
`
`5
`
`6
`
`7
`
`8
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1
`Renal Impairment
`2.2
`Hepatic Impairment
`2.3
`Elderly Patients
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1
`Impaired Pulmonary Function
`4.2
`Paralytic IIeus
`4.3
`Monoamine Oxidase Inhibitors
`WARNINGS AND PRECAUTIONS
`5.1
`Respiratory Depression
`5.2
`CNS Depression
`5.3
`Head Injury and Increased Intracranial
`Pressure
`Misuse and Abuse
`5.4
`Driving and Operating Machinery
`5.5
`Interactions with Alcohol and Drugs of Abuse
`5.6
`Seizures
`5.7
`Serotonin Syndrome Risk
`5.8
`Vlfithdrawal
`5.9
`Hepatic Impairment
`5.10
`Use in Pancreatic/Biliary Tract Disease
`5.11
`ADVERSE REACTIONS
`6.1
`Commonly-Observed Treatment-Emergent
`Adverse Events in Double-Blind Controlled
`Clinical Trials
`.
`Other Adverse Reactions Observed During
`the Premarketing Evaluation of
`TRADENAMET"I
`DRUG INTERACTIONS
`7.1
`Drugs Metabolized by Cytochrome P450
`Enzymes
`Drugs That Inhibit or Induce Cytochrome
`P450 Enzymes
`Centrally—Acting Drugs and Alcohol
`7.3
`Monoamine Oxidase Inhibitors
`7.4
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`6.2
`
`7.2
`
`10
`
`11
`12
`
`13
`
`14
`
`16
`17
`
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Renal Impairment
`8.7
`Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.2
`Abuse
`9.3
`Dependence
`OVERDOSAGE
`10.1
`I-luman Experience
`10.2 Management of Overdose
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharrnacodynamics
`12.3
`Pharmacokinetics
`NON-CLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`Animal Toxicology and/or Pharmacology
`13.2
`CLINICAL STUDIES
`14.1 We Sm - Bunienoetomy
`14.2
`End-Stage Degenerative Joint Disease
`HOW SUPPLIEDISTORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1
`Instructions for Use
`17.2
`Misuse and Abuse
`17.3
`Interference with Cognitive and Motor
`Performance
`Pregnancy
`Nursing
`Monoamine Oxidase Inhibitors
`Seizures
`Serotonin Syndrome
`Alcohol
`Medication Guide
`
`17.4
`17.5
`17.6
`17.7
`17.8
`17.9
`7.10
`
`[*Sections
`subsections omitted from the firll prescribing information are not listed]
`
`or
`
`W
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`TRADENAMET" is indicated for the relief of moderate to severe acute pain in patients 18 years
`of age or older.
`
`2 DOSAGE AND ADMINISTRATION
`
`the dosing regimen should be
`As with many centrally-acting analgesic medications,
`individualized according to the severity of pain being treated, the previous experience with
`similar drugs and the ability to monitor the patient.
`
`The dose is 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity.
`
`On the first day of closing, the second dose may be administered as soon as one hour after the
`first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg,
`75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with
`acceptable tolerability.
`
`Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have
`not been studied and are not recommended.
`
`TRADENAMETM may be given with or without food [see Clinical Pharmacology (12.3)].
`
`2.1 Renal Impairment
`
`No dosage adjustment18 recommended1n patients with mild or moderate renal impairment [see
`Clinical Pharmacology (12 3)]
`
`TRADENAMETM has not been studied in patients with severe renal impairment. The use in this
`population is not recommended.
`
`2.2 Hepatic Impairment
`
`No dosage adjustment is recommended in patients with mild hepatic impairment [see Clinical
`Pharmacology (12.3)].
`
`TRADENAMET" should be used with caution in patients with moderate hepatic impairment.
`Treatment in these patients should be initiated at 50 mg with the interval between doses no less
`than every 8 hours (maximum of three doses in 24 hours). Further treatment should reflect
`maintenance of analgesia with acceptable tolerability, to be achieved by either shortening or
`lengthening the dOSing interval [see Clinical Pharmacology (12.3)].
`
`TRADENAMET" has not been studied in patients with severe hepatic impairment and use in this
`population is not recommended [see Warnings and Precautions (5.10)].
`
`

`

`2.3 Elderly Patients
`
`In general, recommended dosing for elderly patients with normal renal and hepatic function is
`the same as for younger adult patients with normal renal and hepatic function. Because elderly
`patients are more likely to have decreased renal and hepatic fimction, consideration should be
`
`given to starting elderly patients with the lower range of recommended doses.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`TRADENAMETM Tablets are round, biconvex and film-coated and are available in the following
`strengths, colors, and debossings: 50 mg of tapentadol (yellow with “O-M” on one side and “50”
`
`on the other side), 75 mg of tapentadol (yeilow-or—ange with “0M” on one side and “‘75” on the
`
`other side), and 100 mg of tapentadol (orange with “o. ” on one side and “100” on the other
`
`side).
`
`4 CONTRAINDICATIONS
`
`4.1
`
`Impaired Pulmonary Function
`
`Like other drugs with mu-opioid agonist activity, TRADENAMET" is contraindicated in patients
`with significant respiratory depression in unmonitored settings or the absence of resuscitative
`
`equipment. TRADENAMETM is also contraindicated in patients with acute or severe bronchial
`asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment [see
`Warnings and Precautions (5.1)].
`
`4.2 Paralytic lleus
`
`Like drugs with mu-opioid agonist activity, TRADENAMETM is contraindicated in any patient
`who has or is suspected of having paralytic ileus.
`
`4.3 Monoamine Oxidase Inhibitors
`
`TRADENAMETM is contraindicated in patients who are receiving monoamine oxidase (MAO)
`inhibitors or who have taken them within the last 14 days due to potential additive effects on
`norepinephrine levels which may result in adverse cardiovascular events [see Drug Interactions
`(7.4)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Respiratory Depression
`
`Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs
`more frequently in elderly or debilitated patients and in those suffering from conditions
`accompanied by hypoxia, hypercapnia, or upper airway obstruction,
`in whom even moderate
`
`therapeutic doses may significantly decrease pulmonary ventilation.
`
`TRADENAMEW should be administered with caution to patients with conditions accompanied
`by hypoxia, hypercapnia or decreased respiratory reserve such as: asthma, chronic obstructive
`pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema,
`. kyphoscoliosis, central nervous system (CNS) depression, or coma.
`In such patients, even usual
`
`therapeutic doses of TRADENAMETM may increase airway resistance and decrease respiratory
`4
`
`

`

`drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered
`and TRADENAMETM should be employed only under careful medical supervision at the lowest
`effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-
`opioid agonist-induced respiratory depression [see Overdosage (10.2)].
`
`5.2 CNS Depression
`
`Patients receiving other mu-opioid agonist analgesics, general anesthetics, phenothiazines, other
`tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly
`with TRADENAMETM may exhibit additive CNS depression. Interactive effects resulting in
`respiratory depression, hypotension, profound sedation, coma or death may result if these drugs
`are taken in combination with TRADENAMET“. When such combined therapy is contemplated,
`a dose reduction of one or both agents should be considered.
`
`5.3 Head Injury and Increased Intracranial Pressure
`
`Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with
`carbon dioxide retention. Therefore, TRADENAMETM should not be used in patients who may
`be susceptible to the effects of raised cerebrospinal fluid pressure such as those with evidence of
`
`head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical
`
`course of patients with head injury due to effects on pupillary response and consciousness.
`
`TRADENAMETM should be used with caution in patients with head injury, intracranial lesions,
`
`or other sources of preexisting increased intracranial pressure.
`
`‘
`
`5.4 Misuse and Abuse
`
`Tapentadol is a mu-opioid agonist. Such drugs are sought by drug abusers and people with
`addiction disorders.
`
`TRADENAMETM can be abused in a manner similar to other opioid agonists, legal or illicit. This
`
`should be considered when prescribing or dispensing TRADENAMEW in situations where the
`
`physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns
`about abuse and addiction should not prevent the proper management of pain. However, all
`patients treated with mu-opioid agonists require careful monitoring for signs of abuse and
`addiction, since use of mu-opioid agonist analgesic products carry the risk of addiction even
`under appropriate medical use [see Drug Abuse and Dependence (9.2)].
`
`TRADENAMEW may be abused by crushing, chewing, snorting or injecting the product. These
`practices pose a significant risk to the abuser that could result in overdose and death [see Drug
`Abuse and Dependence (9)].
`
`5.5 Driving and Operating Machinery
`
`Patients should be cautioned that TRADENAMETM may impair the mental and/or physical
`abilities required for the performance of potentially hazardous tasks such as driving a car or
`operating machinery. This is to be expected especially at the beginning of treatment, at any
`
`

`

`change of dosage as well as in combination with alcohol or tranquilizers [see Drug Interactions
`
`(7.3)].
`
`5.6 Interactions with Alcohol and Drugs of Abuse
`
`Due to its mu-opioid agonist activity, TRADENAMETM may be expected to have additive effects
`
`when used in conjunction with alcohol, opioids, or illicit drugs that cause central nervous system
`
`depression, respiratory depression, hypotension, and profound sedation, coma or death [see Drug
`
`Interactions (7. 3)].
`
`5.7 Seizures
`
`TRADENAMET"l has not been systematically evaluated in patients with a seizure disorder, and
`
`such patients were excluded from clinical studies. TRADENAMETM should be prescribed with
`
`care in patients with a history of a seizure disorder or any condition that would put the patient at
`risk of seizures.
`
`5.8 Serotonin Syndrome Risk
`
`The development of a potentially life-threatening serotonin syndrome may occur with use of
`
`Serotoninand Norepinephrine Reuptake Inhibitor (SNRI) products, including TRADENAMETM,
`
`particularly with concomitant use of serotonergic drugs such as Selective Serotonin Reuptake
`
`Inhibitors (SSRIs), SNRIs, tricyclic antidepressants (TCAs), MAOIs and triptans, and with drugs
`
`that
`
`impair metabolism of serotonin (including MAOIs). This may occur within the
`
`recommended dose. 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)
`
`and/or
`
`gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
`
`5.9 Withdrawal
`
`Withdrawal symptoms may occur if TRADENAME”M is discontinued abruptly. These symptoms
`
`tremors, diarrhea, upper
`rigors, pain, nausea,
`insomnia,
`may include: anxiety, sweating,
`respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be
`reduced by' tapering TRADENAMETM [see Drug Abuse and Dependence (9.3)].
`
`5.10 Hepatic Impairment
`
`A study of TRADENAMETM in subjects with hepatic impairment showed higher serum
`
`concentrations than in those with normal hepatic function. TRADENAMEWI should be used with
`
`caution in patients with moderate hepatic impairment [see Dosage and Administration (2.2) and
`
`Clinical Pharmacology (I2. 3)].
`
`TRADENAMETM has not been studied in patients with severe hepatic impairment and, therefore,
`
`use in this population is not recommended.
`
`

`

`5.11 Use in Pancreatic/Biliary Tract Disease
`
`Like other drugs with mu-opioid agonist activity, TRADENAMETM may cause spasm of the
`
`sphincter of Oddi and should be used with caution in patients with biliary tract disease, including
`
`acute pancreatitis.
`
`6 ADVERSE REACTIONS
`
`The following treatment-emergent adverse events are discussed in more detail in other sections
`
`of the labeling:
`
`0 Respiratory Depression [see Contraindications (4.1) and Warnings and Precautions (5.1)]
`
`0 CNS Depression [see Warnings and Precautions (5.2)]
`
`Because clinical studies are conducted under widely varying conditions, adverse event rates
`
`observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
`
`studies of another drug and may not reflect
`
`the rates observed in clinical practice. A
`
`treatment-emergent adverse event refers to any untoward medical event associated with the use
`ofthe drug in humans, whether or not considered drug-related.
`
`-
`
`Based on data from nine Phase 2/3 studies that administered multiple doses
`
`(seven
`
`placebo- and/or active-controlled, one noncontrolled and one Phase 3 active-controlled safety
`
`study) the most common adverse events (reported by 210% in any TRADENAMET“ dose group)
`
`were: nausea, dizziness, vomiting and somnolence.
`
`The most common reasons for discontinuation due to adverse events in the studies described
`
`above (reported by 21% in any TRADENAMETM dose group) were dizziness (2.6% vs. 0.5%),
`
`nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache
`
`(0.9% vs. 0.2%) for TRADENAMEW- and placebo-treated patients, respectively.
`
`Seventy—six percent of TRADENAMEm-treated patients from the nine studies experienced
`adverse events.
`
`TRADENAMETM was studied in multiple-dose, active- or placebo-controlled studies, or
`
`noncontrolled studies (11 = 2178), in single-dose studies (n = 870), in open-label study extension
`
`(n = 483) and in Phase 1 studies (n = 597). Of these, 2034 patients were treated with doses of
`
`50 mg to 100 mg of TRADENAMETM dosed every 4 to 6 hours.
`
`The data described below reflect exposure to TRADENAMET“ in 3161 patients,
`
`including
`
`449 exposed for 45 days. TRADENAMET" was studied primarily in placebo- and active-
`
`controlled studies (n = 2266, and n = 2944, respectively). The population was 18 to 85 years old
`
`(mean age 46 years), 68% were female, 75% white and 67% were postoperative. Most patients
`
`received TRADENAMETM doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours.
`
`

`

`6.1 Commonly-Observed Treatment-Emergent Adverse Events in Double-Blind
`Controlled Clinical Trials
`lists the adverse events reported in 21% or more of TRADENAMETM-treated patients
`
`Table 1
`
`with acute moderate to severe pain in the pooled safety data from nine Phase 2/3 studies that
`
`administered multiple doses (seven placebo- and/or active-controlled, one noncontrolled, and one
`
`Phase 3 active-controlled safety study).
`
`Table l
`
`Treatment-Emergent Adverse Events* Reported by 31% of TRADENAMEW-Treated Patients
`In Seven Phase 2/3 Placebo- and/or Oxycodone-Controlled, One Noncontrolled, and One Phase 3
`0x codone-Controlled Safe Multile-Dose Clinical Studies
`System/Organ Class
`TRADENAME'“
`MedDRA Preferred Term
`21 I. — 11. I]
`(n=2 1 78)
`%
`
`__
`-——_
`
`_—__—1 __
`
`Upper respiratory tract
`infection
`
`.
`
`Urina
`
`tract infection ——
`
`__-
`
`———
`—_—
`
`_—
`Confusional state ——__
`
`Abnormal dreams
`
`* A treatment-emergent adverse event refers to any untoward medical event associated with the use of the drug in
`humans, whether or not considered drug-related.
`
`

`

`6.2 Other Adverse Reactions Observed During the Premarketing Evaluation of
`TRADENAMEN
`'
`The following adverse drug reactions occurred in <1% of TRADENAMEW-treated patients in
`the pooled safety data from nine Phase 2/3 studies that administered multiple doses (seven were
`
`placebo- and/or active-controlled, one noncontrolled, and one Phase 3 active-controlled safety
`
`study):
`
`Cardiac disorders: heart rate increased, heart rate decreased
`
`Eye disorders: Visual disturbance
`
`Gastrointestinal disorders: abdominal discomfort, impaired gastric emptying
`
`General disorders and administration site conditions: irritability, edema, drug withdrawal
`syndrome, feeling drunk
`
`Immune system disorders: hypersensitivity
`
`Investigations: gamma-glutamyltransferase increased, alanine aminotransferase increased,
`
`aspartate aminotransferase increased
`
`Musculoskeletal and connective tissue disorders: involuntary muscle contractions, sensation
`of heaviness
`
`Nervous system disorders: hypoesthesia, paresthesia, disturbance in attention, sedation,
`
`dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope,
`
`coordination abnormal, seizure
`
`Psychiatric disorders: euphoric mood, disorientation,
`
`restlessness, agitation, nervousness,
`
`thinking abnormal
`
`Renal and urinary disorders: urinary hesitation, pollakiuria
`
`Respiratory,
`
`thoracic and mediastinal disorders: oxygen saturation decreased, cough,
`
`dyspnea, respiratory depression
`
`Skin and subcutaneous tissue disorders: urticaria
`
`Vascular disorders: blood pressure decreased
`
`In the pooled safety data, the overall incidence of adverse reactions increased with increased
`
`dose of TRADENAMET”, as did the percentage of patients with adverse reactions of nausea,
`
`dizziness, vomiting, somnolence, and pruritus.
`
`

`

`7 DRUG INTERACTIONS
`
`TRADENAMETM is mainly metabolized by glucuronidation. The following substances have been
`
`included in a set of interaction studies without any clinically significant finding: acetaminophen,
`
`acetylsalicylic acid, naproxen and probenecid [see Clinical Pharmacology (12. 3)].
`
`The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal
`
`motility were increased by omeprazole and metoclopramide,
`
`respectively [see Clinical
`
`Pharmacology (12. 3)].
`
`7.1 Drugs Metabolized by Cytochrome P450 Enzymes
`
`In vitro investigations indicate that TRADENAMET" does not inhibit or induce P450 enzymes.
`
`Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to
`
`occur [see Clinical Pharmacology (12. 3)].
`
`7.2 Drugs That Inhibit or Induce Cytochrome P450 Enzymes
`
`The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce
`
`glucuronides. To a lesser extent,
`
`tapentadol
`
`is additionally metabolized to N-desmethyl
`
`tapentadol (13%) by CYP2C9 and CYP2C19 to hydroxy tapentadol (2%) by CYP2D6, which are
`
`further metabolized by conjugation. Since only a minor amount of TRADENAMETM is
`
`metabolized via the oxidative pathway clinically relevant
`
`interactions mediated by the
`
`cytochrome P450 system are unlikely to occur [see Clinical Pharmacology (12. 3)].
`
`7.3 Centrally-Acting Drugs and Alcohol
`
`Patients
`
`receiving other opioid agonist analgesics, general anesthetics, phenothiazines,
`
`‘
`
`antiemetics, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including
`
`alcohol) concomitantly with TRADENAMETM ‘may exhibit an additive CNS depression.
`
`Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma
`
`may result if these drugs are taken in combination with TRADENAMET". When such combined
`
`therapy is contemplated, a dose reduction of one or both agents should be considered [see
`
`Warnings and Precautions (5.2) and (5.6)].
`
`7.4 Monoamine Oxidase Inhibitors
`
`TRADENAMET" is' contraindicated in patients who are receiving monoamine oxidase (MAO)
`
`inhibitors or who have taken them within the last 14 days due to potential additive effects on
`
`norepinephrine levels which may result in adverse cardiovascular events [see Contraindications
`
`(4.3)].
`
`[0
`
`

`

`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`'
`
`Pregnancy Category C.
`
`Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following
`
`intravenous and subcutaneous exposure during the period of embryofetal organogenesis. When
`
`tapentadol was administered twice daily by the subcutaneous route in rats at dose levels of
`10, 20, or 40 mg/kg/day [producing up to 1
`times the plasma exposure at
`the maximum
`recommended human dose (MRHD) of 700 mg/day based on an area under the time-curve
`
`(AUC) comparison], no teratogenic effects were observed. Evidence Of embryofetal toxicity
`
`included transient delays in skeletal maturation (i.e. reduced ossification) at the 40 mg/kg/day
`
`dose which was associated with significant maternal toxicity. Administration of tapentadol HCl
`
`in rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection [producing 0.2, 0.6, and
`
`1.85 times the plasma exposure at the MRHD based on an AUC comparison]
`
`revealed
`
`embryofetal toxicity at doses 2 10 mg/kg/day. Findings included reduced fetal viability, skeletal
`
`delays and other variations.
`
`In addition,
`
`there were multiple malformations
`
`including
`
`gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate at doses 2 10 mg/kg/day
`
`and above, and ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day.
`
`Embryofetal toxicity,
`
`including malformations, may be secondary to the significant maternal
`
`toxicity observed in the study.
`
`In a study of pre- and postnatal development in rats, oral administration of tapentadol at doses of
`
`20, 50, 150, or 300 mg/kg/day to pregnant and lactating rats during the late gestation and early
`
`postnatal period [resulting in up to 1.7 times the plasma exposure at the MRHD on an AUC
`
`basis] did not influence physical or reflex development, the outcome of neurobehavioral tests or
`
`reproductive parameters.
`
`Treatment-related developmental delay was observed,
`
`including
`
`incomplete ossification, and significant reductions in pup body weights and body weight gains at
`
`doses associated with maternal toxicity (150 mg/kg/day and above). At maternal tapentadol
`
`doses 2 150 mg/kg/day, a dose-related increase in pup mortality was observed through postnatal
`
`Day 4.
`
`There are no adequate and well controlled studies of TRADENAMETM in pregnant women.
`
`TRADENAMET“ should be used during pregnancy only if the potential benefit justifies the
`
`potential risk to the fetus.
`
`8.2 Labor and Delivery
`The effect of tapentadol on labor and delivery in humans is unknown. TRADENAMEW is not
`
`recommended for use in women during and immediately prior to labor and delivery. Due to the
`
`mu-opioid receptor agonist activity of TRADENAMET", neonates whose mothers have been
`
`taking TRADENAMETM should be monitored for respiratory depression. A specific opioid
`
`antagonist, such as naloxone, should be available for reversal of opioid induced respiratory
`
`depression in the neonate.
`
`II
`
`

`

`8.3 Nursing Mothers
`
`There is insufficient/limited information on the excretion of tapentadol in human or animal
`
`breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol
`
`point
`
`to excretion in breast milk and risk to the suckling child cannot be excluded.
`
`TRADENAMEW' should not be used during breast-feeding.
`
`8.4 Pediatric Use
`
`The safety and effectiveness of TRADENAMETM in pediatric patients less than 18 years .of age
`
`have not been established. TRADENAMETM is not recommended in this population.
`
`8.5 Geriatric Use
`
`Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of
`
`TRADENAMET", 19% were 65 and over, while 5% were 75 and over. No overall differences in
`
`effectiveness were observed between these patients and younger patients.
`
`The rate of
`
`constipation was higher in subjects greater than or equal to 65 years than those less than 65 years
`
`(12% vs. 7%).
`
`In general, recommended dosing for elderly patients with normal renal and hepatic function is
`
`the same as for younger adult patients with normal renal and hepatic function. Because elderly
`
`patients are more likely to have decreased renal and hepatic function, consideration should be
`
`given to starting elderly patients with the lower range of recommended doses [see Clinical
`
`Pharmacology (12.3)].
`
`8.6 Renal Impairment
`
`In patients with severe renal impairment, the safety and effectiveness of TRADENAMET“ has
`
`not been established. TRADENAMETM is not recommended in this population [see Dosage and
`
`Administration (2.1)].
`
`'
`
`‘
`8.7 Hepatic Impairment
`Administration of TRADENAMETM resulted in higher exposures and serum levels to tapentadol
`
`in subjects with impaired hepatic fimction compared to subjects with normal hepatic function
`
`[see Clinical Pharmacology (12.3)]. TRADENAMET" should be used with caution in patients
`
`with moderate hepatic impairment [see Dosage and Administration (2.2)].
`
`TRADENAMET“ has not been studied in patients with severe hepatic impairment, therefore, use
`
`of TRADENAMETM is not recommended in this population [see Warnings and Precautions
`
`(5.10)].
`
`9 DRUG ABUSE AND DEPENDENCE ‘
`
`9.1 Controlled Substance
`
`TRADENAMET" contains tapentadol, a mu-opioid agonist. TRADENAMET“ has an abuse
`
`potential similar to hydromorphone, can be abused and is subject to criminal diversion.
`
`12
`
`

`

`9.2 Abuse
`
`Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and
`environmental factors influencing its development and manifestations. It is characterized by
`behaviors that include one or more of the following: impaired control over drug use, compulsive
`use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a
`multidisciplinary approach, but relapse is common.
`
`the proper management of pain.
`Concerns about abuse and addiction should not prevent
`However, all patients treated with opioids require carefiil monitoring for signs of abuse and
`addiction, because use of opioid analgesic products carries the risk of addiction even under
`
`appropriate medical use.
`
`'
`
`“Drug seeking” behavior is very common in addicts, and drug abusers. Drug-seeking tactics
`include emergency calls or visits near the end of office hours, refiisal to undergo appropriate
`examination,
`testing or referral, repeated claims of loss of prescriptions,
`tampering with
`prescriptions and reluctance to provide prior medical records or contact information for other
`treating physicialfis). “Doctor shopping” (visiting- multiple preseribers) to obtain additional
`prescriptions is common among drug abusers and people suffering from untreated addiction.
`Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with
`poor pain control.
`
`from physical dependence and tolerance.
`Abuse and addiction are separate and distinct
`Physicians should be aware that addiction may not be accompanied by concurrent tolerance and
`symptoms of physical dependence in all addicts. In addition, abuse of mu—opioid agonists can
`occur in the absence of true addiction and is characterized by misuse for non-medical purposes,
`often in combination with other psychoactive substances. Careful recordkeeping of prescribing
`information, including quantity, frequency, and renewal requests is strongly advised.
`
`Abuse of TRADENAMETM poses a risk of overdose and death. This risk is increased with
`
`concurrent abuse of TRADENAME‘“ with alcohol and other substances. In addition, parenteral
`drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and
`HIV.
`
`Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,
`and proper dispensing and storage are appropriate measures that help to limit abuse of drugs with
`mu-opioid agonist properties.
`
`Infants born to mothers physically dependent on opioids will also be physically dependent and
`may exhibit respiratory difficulties and withdrawal symptoms [see Warnings and Precautions
`(5.1)]. Use of TRADENAMET"
`in this population has not been characterized. As
`
`TRADENAMET" has mu-opioid agonist
`
`activity,
`
`infants whose mothers have
`
`taken
`
`TRADENAMET", should be carefully monitored.
`
`[3
`
`

`

`9.3 Dependence
`
`Tolerance is the need for increasing doses of opioids to maintain a defined effect such as
`
`analgesia (in the absence of disease progression or other external factors). Physical dependence
`
`is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon
`
`administration of an antagonist.
`
`The opioid abstinence or withdrawal syndrome is characterized by some or all of the following:
`
`restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other
`
`symptoms also may develop,
`
`including irritability, anxiety, backache, joint pain, weakness,
`
`abdominal cramps,
`
`insomnia, nausea, anorexia, v