`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Abuse potential may occur. Monitor patients closely for signs of abuse and
`
` addiction. (5.4)
` • Impaired mental/physical abilities: Caution must be used with potentially
`
` hazardous activities. (5.5)
` • 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-McNeil-Janssen Pharmaceuticals, Inc. at 1-800-526­
`
`
`7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`---------------------------------DRUG INTERACTIONS----------------------------
`• Use TRADENAME™ with caution in patients currently using specified
`
`
`centrally-acting drugs or alcohol. (7.3)
`
`
`• Do not use TRADENAME™ in patients currently using or within 14 days
`
`
`
`of using a monoamine oxidase inhibitor (MAOI). (7.4)
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
`• Labor and delivery: should not use during and immediately prior to labor
`
`
`
`and delivery. Monitor neonates, whose mothers have been taking
`
`
`
`TRADENAME™, for respiratory depression. (8.2)
`• Nursing mothers: should not breast-feed. (8.3)
`
`
`
`• Pediatric use: safety and effectiveness not established in patients less than
`
`
`18 years of age. (8.4)
`
`• 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)
`
`• Elderly: care should be taken when selecting an initial dose. (2.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION AND
`
`
`MEDICATION GUIDE.
`
`
`
`
`Revised: 11/2008
`
`
` 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™ (tapentadol) immediate release oral tablets
`
` Initial U.S. Approval : 2008
`----------------------------INDICATIONS AND USAGE----------------------------
`
`
`
`
` TRADENAME™ is an opioid analgesic indicated for the relief of moderate to
` severe acute pain in patients 18 years of age or older. (1)
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
` • As with many centrally-acting analgesic medications, the dosing regimen
` of TRADENAME™ 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)
`
`
` • Initiate TRADENAME™ 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 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, therefore, not
`
` recommended. (2)
` --------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets: 50 mg, 75 mg, 100 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
` • Impaired pulmonary function (significant respiratory depression, acute or
`
`
` severe bronchial asthma or hypercapnia in unmonitored settings or the
` absence of resuscitative equipment) (4.1)
`
`• Paralytic ileus (4.2)
` • Concomitant use with monoamine oxidase inhibitors (MAOI) or use within
`
` 14 days (4.3)
`---------------------------WARNINGS AND PRECAUTIONS--------------------
`
`
` • Respiratory depression: Increased risk in elderly, debilitated patients, those
` suffering from conditions accompanied by hypoxia, hypercapnia, or upper
`
`
`
` airway obstruction. (5.1)
` • CNS effects: Additive CNS depressive effects when used in conjunction
`
`
` with alcohol, other opioids, or illicit drugs. (5.2)
` • Elevation of intracranial pressure: May be markedly exaggerated in the
`
`
` presence of head injury, other intracranial lesions. (5.3)
`
`
`
`
`
`
`
`
`
`
`1
`
`

`

`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`Renal Impairment
`
`
`2.2
`Hepatic Impairment
`
`
`2.3
`Elderly Patients
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`
`Impaired Pulmonary Function
`4.1
`
`
`4.2
`Paralytic Ileus
`
`
`4.3
`Monoamine Oxidase Inhibitors
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`Respiratory Depression
`
`
`5.2
`CNS Depression
`
`5.3
`Head Injury and Increased Intracranial
`
`
`Pressure
`
`
`5.4
`Misuse and Abuse
`
`
`Driving and Operating Machinery
`5.5
`
`
`5.6
`Interactions with Alcohol and Drugs of Abuse
`
`
`
`5.7
`Seizures
`
`
`5.8
`Serotonin Syndrome Risk
`
`
`
`5.9 Withdrawal
`
`
`5.10 Hepatic Impairment
`
`
`5.11 Use in Pancreatic/Biliary Tract Disease
`
`
`ADVERSE REACTIONS
`
`Commonly-Observed Treatment-Emergent
`6.1
`
`Adverse Events in Double-Blind Controlled
`
`Clinical Trials
`Other Adverse Reactions Observed During
`the Premarketing Evaluation of
`
`
`TRADENAME™
`
`DRUG INTERACTIONS
`
`Drugs Metabolized by Cytochrome P450
`7.1
`
`Enzymes
`
`7.2
`Drugs That Inhibit or Induce Cytochrome
`
`P450 Enzymes
`
`
`7.3
`Centrally-Acting Drugs and Alcohol
`
`
`Monoamine Oxidase Inhibitors
`7.4
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`3
`
`4
`
`
`5
`
`
`6
`
`
`6.2
`
`
`7
`
`
`8
`
`
`
`
`9
`
`
`10
`
`
`11
`
`12
`
`
`13
`
`
`14
`
`
`16
`
`17
`
`
`
`Labor and Delivery
`8.2
`
`
`Nursing Mothers
`
`8.3
`
`
`Pediatric Use
`
`8.4
`
`
`Geriatric Use
`
`8.5
`
`
`Renal Impairment
`
`8.6
`
`
`Hepatic Impairment
`
`8.7
`
`DRUG ABUSE AND DEPENDENCE
`
`
`
`9.1
`Controlled Substance
`
`
`
`9.2
`Abuse
`
`
`
`9.3
`Dependence
`
`
`OVERDOSAGE
`
`
`
`10.1 Human Experience
`
`
`
`10.2 Management of Overdose
`
`
`DESCRIPTION
`
`
`CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`NON-CLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`
`
`
`Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`CLINICAL STUDIES
`
`
`
`14.1 Orthopedic Surgery – Bunionectomy
`
`
`
`14.2 End-Stage Degenerative Joint Disease
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`PATIENT COUNSELING INFORMATION
`
`
`
`
`Instructions for Use
`
`17.1
`
`
`17.2 Misuse and Abuse
`
`
`17.3
`Interference with Cognitive and Motor
`
`
`Performance
`
`
`
`17.4 Pregnancy
`
`
`
`17.5 Nursing
`
`
`17.6 Monoamine Oxidase Inhibitors
`
`
`
`17.7 Seizures
`
`
`
`17.8 Serotonin Syndrome
`
`
`
`17.9 Alcohol
`
`
`
`7.10 Medication Guide
`
`
`
`
`
`
`[*Sections
`or
`
`subsections omitted from the full prescribing information are not listed]
`
`
`
`
`
`
`2
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
` INDICATIONS AND USAGE
`1
`
`
`
` TRADENAME™ is indicated for the relief of moderate to severe acute pain in patients 18 years
`of age or older.
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
` As with many centrally-acting analgesic medications, the dosing regimen should be
` 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 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 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.
`
`TRADENAME™ may be given with or without food [see Clinical Pharmacology (12.3)].
`
`
`2.1 Renal Impairment
`No dosage adjustment is recommended in patients with mild or moderate renal impairment [see
`Clinical Pharmacology (12.3)].
`
`TRADENAME™ 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)].
`
`TRADENAME™ 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)].
`
`
`TRADENAME™ has not been studied in patients with severe hepatic impairment and use in this
`
`population is not recommended [see Warnings and Precautions (5.10)].
`
`
`
`3
`
`

`

`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 function, consideration should be
`
`given to starting elderly patients with the lower range of recommended doses.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`TRADENAME™ 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 (yellow-orange with “O-M” on one side and “75” on the
`
`other side), and 100 mg of tapentadol (orange with “O-M” on one side and “100” on the other
`
`side).
`
`4 CONTRAINDICATIONS
`
`Impaired Pulmonary Function
`4.1
`
`Like other drugs with mu-opioid agonist activity, TRADENAME™ is contraindicated in patients
`
`with significant respiratory depression in unmonitored settings or the absence of resuscitative
`
`
`
`equipment. TRADENAME™ 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 Ileus
`
`Like drugs with mu-opioid agonist activity, TRADENAME™ is contraindicated in any patient
`
`who has or is suspected of having paralytic ileus.
`
`
`4.3 Monoamine Oxidase Inhibitors
`
`TRADENAME™ 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.
`
`TRADENAME™ 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 TRADENAME™ may increase airway resistance and decrease respiratory
`
`
`
`
`4
`
`

`

`drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered
`
` and TRADENAME™ 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 TRADENAME™ 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 TRADENAME™. 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, TRADENAME™ 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.
`
`
`
` TRADENAME™ 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.
`
`
`
`
`
` TRADENAME™ can be abused in a manner similar to other opioid agonists, legal or illicit. This
`
` should be considered when prescribing or dispensing TRADENAME™ 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)].
`
` TRADENAME™ 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 TRADENAME™ 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
`
`
`
`5
`
`

`

`change of dosage as well as in combination with alcohol or tranquilizers [see Drug Interactions
`(7.3)].
`
`Interactions with Alcohol and Drugs of Abuse
` 5.6
`
`Due to its mu-opioid agonist activity, TRADENAME™ 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
`
`TRADENAME™ has not been systematically evaluated in patients with a seizure disorder, and
`
`such patients were excluded from clinical studies. TRADENAME™ 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
`Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) products, including TRADENAME™,
`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,
`instability (e.g.,
`hallucinations, coma), autonomic
`tachycardia,
`labile blood pressure,
`
`(e.g., hyperreflexia,
`incoordination) and/or
`hyperthermia), neuromuscular aberrations
`
`gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
`
`
`5.9 Withdrawal
`
`Withdrawal symptoms may occur if TRADENAME™ is discontinued abruptly. These symptoms
`may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper
`
`
`respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be
`
`
`reduced by tapering TRADENAME™ [see Drug Abuse and Dependence (9.3)].
`
`
`
`5.10 Hepatic Impairment
`
`A study of TRADENAME™ in subjects with hepatic impairment showed higher serum
`concentrations than in those with normal hepatic function. TRADENAME™ should be used with
`caution in patients with moderate hepatic impairment [see Dosage and Administration (2.2) and
`Clinical Pharmacology (12.3)].
`
`TRADENAME™ has not been studied in patients with severe hepatic impairment and, therefore,
`
`use in this population is not recommended.
`
`
`
`6
`
`

`

`5.11 Use in Pancreatic/Biliary Tract Disease
`
`Like other drugs with mu-opioid agonist activity, TRADENAME™ may cause spasm of the
`
`
`
`sphincter of Oddi and should be used with caution in patients with biliary tract disease, including
`
`
`acute pancreatitis.
`
`
`ADVERSE REACTIONS
`6
`The following treatment-emergent adverse events are discussed in more detail in other sections
`
`
`of the labeling:
`
`
`• Respiratory Depression [see Contraindications (4.1) and Warnings and Precautions (5.1)]
`
`• 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
`
`of the 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 ≥10% in any TRADENAME™ 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 ≥1% in any TRADENAME™ 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 TRADENAME™- and placebo-treated patients, respectively.
`
`
`Seventy-six percent of TRADENAME™-treated patients from the nine studies experienced
`
`adverse events.
`
`
`TRADENAME™ was studied in multiple-dose, active- or placebo-controlled studies, or
`
`
`noncontrolled studies (n = 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 TRADENAME™ dosed every 4 to 6 hours.
`
`The data described below reflect exposure to TRADENAME™ in 3161 patients, including
`
`449 exposed for 45 days. TRADENAME™ 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 TRADENAME™ doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours.
`
`
`
`
`7
`
`

`

`6.1 Commonly-Observed Treatment-Emergent Adverse Events in Double-Blind
`Controlled Clinical Trials
`Table 1 lists the adverse events reported in ≥1% or more of TRADENAME™-treated patients
`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 1
`
`Placebo
`(n=619)
`%
`
` Treatment-Emergent Adverse Events* Reported by ≥1% of TRADENAME™-Treated Patients
`
`In Seven Phase 2/3 Placebo- and/or Oxycodone-Controlled, One Noncontrolled, and One Phase 3
`Oxycodone-Controlled Safety, Multiple-Dose Clinical Studies
`System/Organ Class
`
`TRADENAME™
`
`MedDRA Preferred Term
`
`
`21 mg – 120 mg
`(n=2178)
`%
`
`30
`18
`
`8
`
`4
`
`2
`
`
`
`13
`4
`
`3
`
`<1
`
`<1
`
`
`Gastrointestinal disorders
`Nausea
`Vomiting
`Constipation
`Dry mouth
`Dyspepsia
`General disorders and
`
`administration site conditions
`Fatigue
`Feeling hot
`
`Infections and infestations
`Nasopharyngitis
`Upper respiratory tract
`
`infection
`
`Urinary tract infection
`Metabolism and nutrition disorders
`Decreased appetite
`Musculoskeletal and connective
`
`tissue disorders
`Arthralgia
`
`Nervous system disorders
`Dizziness
`Somnolence
`Tremor
`Lethargy
`
`Psychiatric disorders
`Insomnia
`Confusional state
`
`Abnormal dreams
`Anxiety
`Skin and subcutaneous tissue
`disorders
`1
`5
`Pruritus
`<1
`3
`Hyperhidrosis
`
`
`
`<1
`3
`Pruritus generalized
`
`
`<1
`1
`Rash
`
`
`Vascular disorders
`
`<1
`1
`Hot flush
`
`
`
`* 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.
`
`
`
`
`
`
`
`
`3
`
`1
`
`
`1
`1
`
`
`1
`
`
`2
`
`
`
`1
`
`24
`15
`1
`1
`
`2
`1
`1
`
`1
`
`
`
`
`
`
`
`
`
`<1
`
`<1
`
`
`<1
`<1
`
`
`<1
`
`
`0
`
`
`
`<1
`
`8
`3
`<1
`<1
`
`<1
`0
`<1
`
`<1
`
`
`
`
`
`
`8
`
`

`

`
` 6.2 Other Adverse Reactions Observed During the Premarketing Evaluation of
`TRADENAME™
`
`
` The following adverse drug reactions occurred in <1% of TRADENAME™-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 TRADENAME™, as did the percentage of patients with adverse reactions of nausea,
`dizziness, vomiting, somnolence, and pruritus.
`
`
`
`9
`
`

`

`7 DRUG INTERACTIONS
`
`TRADENAME™ 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 TRADENAME™ 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 TRADENAME™ 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 TRADENAME™ 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 TRADENAME™. 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
`
`TRADENAME™ 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)].
`
`
`
`10
`
`

`

`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 ≥ 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 ≥ 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 ≥ 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 TRADENAME™ in pregnant women.
`
`
`TRADENAME™ 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. TRADENAME™ is not
`recommended for use in women during and immediately prior to labor and delivery. Due to the
`mu-opioid receptor agonist activity of TRADENAME™, neonates whose mothers have been
`
`taking TRADENAME™ 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.
`
`
`
`11
`
`

`

`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.
`TRADENAME™ should not be used during breast-feeding.
`
`
`8.4 Pediatric Use
`The safety and effectiveness of TRADENAME™ in pediatric patients less than 18 years of age
`
`
`have not been established. TRADENAME™ 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
`
`TRADENAME™, 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 TRADENAME™ has
`
`
`
`not been established. TRADENAME™ is not recommended in this population [see Dosage and
`
`Administration (2.1)].
`
`8.7 Hepatic Impairment
`
`Administration of TRADENAME™ resulted in higher exposures and serum levels to tapentadol
`
`in subjects with impaired hepatic function compared to subjects with normal hepatic function
`[see Clinical Pharmacology (12.3)]. TRADENAME™ should be used with caution in patients
`with moderate hepatic impairment [see Dosage and Administration (2.2)].
`
`TRADENAME™ has not been studied in patients with severe hepatic impairment, therefore, use
`of TRADENAME™ is not recommended in this population [see Warnings and Precautions
`
`
`(5.10)].
`
`9 DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`TRADENAME™ contains tapentadol, a mu-opioid agonist. TRADENAME™ 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.
`
`
`Concerns about abuse and addiction should not prevent the proper management of pain.
`
`However, all patients treated with opioids require careful 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, refusal to undergo appropriate
`
`
`examination, testing or referral, repeated claims of loss