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Tapentadol Extended-Release Tablets

DEA Controlled Substance Schedule C-II

TABLE OF CONTENTS

1. DESCRIPTION 8. ADVERSE REACTIONS
2. INDICATIONS AND USAGE 9. DRUG ABUSE AND DEPENDENCE
3. DOSAGE AND ADMINISTRATION 10. OVERDOSAGE
4. CONTRAINDICATIONS 11. DRUG INTERACTIONS
5. MECHANISM OF ACTION 12. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. WARNINGS AND PRECAUTIONS  

 


WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL

Abuse Potential

Tapentadol, is an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions]. Assess each patient’s risk for opioid abuse or addiction prior to prescribing tapentadol ER. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depressive disorder). Routinely monitor all patients receiving tapentadol ER for signs of misuse, abuse, and addiction during treatment [see Drug Abuse and Dependence].

Life-threatening Respiratory Depression

Respiratory depression, including fatal cases, may occur with use of tapentadol ER, even when the drug has been used as recommended and not misused or abused [see Warnings and Precautions]. Proper dosing and titration are essential and tapentadol ER should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of tapentadol ER or following a dose increase. Instruct patients to swallow tapentadol ER tablets whole. Crushing, dissolving, or chewing tapentadol ER can cause rapid release and absorption of a potentially fatal dose of tapentadol.

Accidental Exposure

Accidental ingestion of tapentadol ER, especially in children, can result in a fatal overdose of tapentadol [see Warnings and Precautions].

Interaction with Alcohol

The co-ingestion of alcohol with tapentadol ER may result in an increase of plasma levels and potentially fatal overdose of tapentadol [see Warnings and Precautions]. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while on tapentadol ER.


 

1. DESCRIPTION

Tapentadol is a mu-opioid receptor agonist. The chemical name is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride. The structural formula is:

Molecular formula: C14H23NO • HCl - Molecular weight: 257.80

The n-octanol:water partition coefficient log P value is 2.87. The pKa values are 9.34 and 10.45.

Tapentadol ER is supplied in extended-release film-coated tablets for oral administration, containing 58.24, 116.48, 174.72, 232.96, and 291.20 mg of tapentadol hydrochloride in each tablet strength, corresponding to 50, 100, 150, 200, and 250 mg of tapentadol free-base, respectively.

Inactive ingredients: polyethylene oxide, hypromellose, polyethylene glycol and alpha-tocopherol (vitamin E). The film coating is comprised of polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and the colorant FD&C Blue #2 aluminum lake is used for 100-, 150-, 200-, and 250-mg strengths; and additionally, yellow iron oxide is used in 150-mg tablets. Printing inks contain shellac glaze and propylene glycol for all strengths, and black iron oxide (50-, 100-, 150- and 200-mg tablet) or titanium dioxide (250-mg tablet).

2. INDICATIONS AND USAGE

Tapentadol ER is indicated for the management of:

• moderate to severe chronic pain in adults

• neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults

when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Usage

Tapentadol ER is not intended for use:

• As an as-needed (prn) analgesic

• For pain that is mild or not expected to persist for an extended period of time

• For acute pain

• For postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

3. DOSAGE AND ADMINISTRATION

3.1 Initial Dosing

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. Monitor patients closely for respiratory depression, especially within the first 72 hours of initiating therapy with tapentadol ER [see Warnings and Precautions].

Consider the following factors when selecting an initial dose of tapentadol ER:

• Total daily dose, potency, and kind of any prior analgesic the patient has been taking previously;

• Reliability of the relative potency estimate used to calculate the equivalent dose of tapentadol needed (Note: potency estimates may vary with the route of administration);

• Patient's degree of opioid experience and opioid tolerance;

• General condition and medical status of the patient;

• Concurrent medication;

• Type and severity of the patient's pain. Tapentadol ER tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth.

Tapentadol ER is administered at a frequency of twice daily (every 12 hours).

Discontinue all other tapentadol and tramadol products when beginning and while taking tapentadol ER [see Serotonin Syndrome Risk]. Although the maximum approved total daily dose of tapentadol immediate-release formulation is 600 mg per day, the maximum total daily dose of tapentadol ER is 500 mg. Do not exceed a total daily dose of tapentadol ER of 500 mg.

Use of Tapentadol ER as the First Opioid Analgesic

Initiate tapentadol ER therapy with the 50 mg tablet twice daily (at 12 hour intervals).

Conversion from Tapentadol to Tapentadol ER

Patients can be converted from tapentadol to tapentadol ER using the equivalent total daily dose of tapentadol and dividing it into two equal doses of tapentadol ER separated by approximately 12-hour intervals. As an example, a patient receiving 50 mg of tapentadol four times per day (200 mg/day) may be converted to 100 mg tapentadol ER twice a day.

Conversion from other Opioids to Tapentadol ER

While there are useful tables of oral and parenteral equivalents, there is substantial inter-patient variation in the relative potency of different opioid drugs and formulations. Specific recommendations are not available because of a lack of systematic evidence for these types of analgesic substitutions. As such, it is safer to underestimate a patient's 24-hour tapentadol ER requirement and provide rescue medication (e.g., immediate-release opioid or non-opioid) than to overestimate and manage an adverse reaction. In general, begin with half of the estimated daily tapentadol requirement as the initial dose, managing inadequate analgesia by supplementation with immediate-release rescue medication.

Published relative potency/equianalgesia data are available and may be referred to in clinical practice guidelines such as those published by authorities in the field of pain medicine, but such ratios are approximations. Consider contacting your specific state medical or pharmacy professional societies for further information on how to safely convert patients from one opioid to another.

3.2 Titration and Maintenance of Therapy

Individually titrate tapentadol ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving tapentadol ER to assess the maintenance of pain control and the relative incidence of adverse reactions. During chronic therapy, especially for non-cancer-related pain (or pain associated with other terminal illnesses), periodically reassess the continued need for the use of opioid analgesics.

Titrate patients to adequate analgesia with dose increases of 50 mg no more than twice daily every three days. In clinical studies, efficacy with tapentadol ER was demonstrated relative to placebo in the dosage range of 100 mg to 250 mg twice daily.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the tapentadol ER dose to decrease the level of pain.

Patients who experience breakthrough pain may require dosage adjustment or rescue medication with an appropriate dose of an immediate-release opioid or non-opioid medication.

If signs of excessive opioid-related adverse reactions are observed, the next dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

During chronic, around-the-clock opioid therapy, especially for non-cancer pain syndromes, reassess the continued need for around-the-clock opioid therapy regularly (e.g., every 6 to 12 months) as appropriate.

3.3 Discontinuation of Tapentadol ER

When the patient no longer requires therapy with tapentadol ER tablets, use a gradual downward titration of the dose to prevent signs and symptoms of withdrawal in the physically-dependent patient.

3.4 Patients with Hepatic Impairment

The use of tapentadol ER in patients with severe hepatic impairment (Child-Pugh Score 10-15) is not recommended.

In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), initiate treatment using 50 mg tapentadol ER and administer no more frequently than once every 24 hours. The maximum recommended dose for patients with moderate hepatic impairment is 100 mg of tapentadol ER once daily.

No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Score 5 to 6) [see Warnings and Precautions].

3.5 Patients with Renal Impairment

No dosage adjustment is recommended in patients with mild or moderate renal impairment. tapentadol ER use in patients with severe renal impairment is not recommended [see Warnings and Precautions].

3.6 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.

3.7 Administration of Tapentadol ER

Instruct patients to swallow tapentadol ER tablets whole. The tablets are not to be cut, crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of tapentadol [see Warnings and Precautions].

Instruct patients to take tapentadol ER one tablet at a time and with enough water to ensure complete swallowing immediately after placing in the mouth [see Warnings and Precautions].

4. CONTRAINDICATIONS

Tapentadol ER is contraindicated in:

• Patients with significant respiratory depression.

• Patients with acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment.

• Patients with known or suspected paralytic ileus.

• Patients with hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product [see Adverse Reactions].

• Patients who are receiving monoamine oxidase inhibitors (MAOI) 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].

5. MECHANISM OF ACTION

Tapentadol is a centrally-acting synthetic analgesic. Although its exact mechanism is unknown, analgesic efficacy is thought to be due to mu-opioid agonist activity and the inhibition of norepinephrine reuptake.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies of tapentadol ER in pregnant women. Tapentadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 1.36 times the plasma exposure at the maximum recommended human dose (MRHD) of 500 mg/day for tapentadol ER 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 0.3, 0.8, and 2.5 times the plasma exposure at the MRHD based on an AUC comparison, respectively] 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 2.28 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. At maternal tapentadol doses •150 mg/kg/day, a dose-related increase in pup mortality was observed to postnatal Day 4. Treatment-related developmental delay was observed in the dead pups, including incomplete ossification. In addition, significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity (150 mg/kg/day and above) was seen throughout lactation.

6.2 Labor and Delivery

Tapentadol ER is not for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor.

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations.

6.3 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 breastfeeding child cannot be excluded.

Because of the potential for adverse reactions in nursing infants from tapentadol ER, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Withdrawal symptoms can occur in breast-feeding infants when maternal administration of tapentadol ER is stopped.

6.4 Pediatric Use

The safety and effectiveness of tapentadol ER in pediatric patients less than 18 years of age have not been established. Tapentadol ER is not recommended in this population.

6.5 Geriatric Use

Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of tapentadol ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger 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.

6.6 Neonatal Withdrawal Syndrome

Chronic maternal use of tapentadol ER during pregnancy can affect the neonate with subsequent withdrawal signs. Neonatal withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration and severity of neonatal withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination drug by the newborn. Neonatal opioid withdrawal syndrome may be life-threatening and should be treated according to protocols developed by neonatology experts.

6.6 Renal Impairment

The safety and effectiveness of tapentadol ER has not been established in patients with severe renal impairment (CLCR < 30 mL/min). Use of tapentadol ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

6.7 Hepatic Impairment

Administration of tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. Tapentadol ER should be used with caution in patients with moderate hepatic impairment [see Dosage and Administration].

Use of tapentadol ER is not recommended in severe hepatic impairment (Child-Pugh Score 10 to 15) [see Warnings and Precautions].

7. WARNINGS AND PRECAUTIONS

7.1 Abuse Potential

Tapentadol ER contains tapentadol, an opioid agonist and a Schedule II controlled substance. Tapentadol can be abused in a manner similar to other opioid agonists legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing tapentadol ER in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.

Assess each patient’s risk for opioid abuse or addiction prior to prescribing tapentadol ER. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.

Misuse or abuse of tapentadol ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death [see Overdosage].

Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

7.2 Life Threatening Respiratory Depression

Respiratory depression is the chief hazard of opioid agonists, including tapentadol ER. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage].

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of tapentadol ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with tapentadol ER and following dose increases. Instruct patients against use by individuals other than the patient for whom tapentadol ER was prescribed and to keep tapentadol ER out of the reach of children, as such inappropriate use may result in fatal respiratory depression.

To reduce the risk of respiratory depression, proper dosing and titration of tapentadol ER are essential [see Dosage and Administration]. Overestimating the tapentadol ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused.

To further reduce the risk of respiratory depression, consider the following:

• Proper dosing and titration are essential and tapentadol ER should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

• Instruct patients to swallow tapentadol ER tablets whole. The tablets are not to be cut, crushed, dissolved, or chewed. The resulting tapentadol dose may be fatal, particularly in opioid-naïve individuals.

• Tapentadol ER is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression [see Contraindications].

7.3 Accidental Exposure

Accidental ingestion of tapentadol ER, especially in children, can result in a fatal overdose of tapentadol.

7.4 Interaction with Alcohol

The co-ingestion of alcohol with tapentadol ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on tapentadol ER therapy.

7.5 Elderly, Cachectic, and Debilitated Patients

Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating tapentadol ER and when tapentadol ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions].

7.6 Use in Patients with Chronic Pulmonary Disease

Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with tapentadol ER, as in these patients, even usual therapeutic doses of tapentadol ER may decrease respiratory drive to the point of apnea [see Warnings and Precautions]. Consider the use of alternative non-opioid analgesics in these patients if possible.

7.7 Interactions with CNS Depressants and Illicit Drugs

Hypotension, and profound sedation, coma or respiratory depression may result if tapentadol ER is used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids and illicit drugs). When considering the use of tapentadol ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol and/or illicit drugs that can cause CNS depression. If tapentadol ER therapy is to be initiated in a patient taking a CNS depressant, start with a lower tapentadol ER dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions].

7.8 Hypotensive Effect

Tapentadol ER may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions]. Monitor these patients for signs of hypotension after initiating or titrating the dose of tapentadol ER. In patients with circulatory shock, tapentadol ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tapentadol ER in patients with circulatory shock.

7.9 Use in Patients with Head Injury or Increased Intracranial Pressure

Monitor patients taking tapentadol ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with tapentadol ER. Tapentadol ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.

Avoid the use of tapentadol ER in patients with impaired consciousness or coma.

7.10 Seizures

Tapentadol ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in tapentadol ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during tapentadol ER therapy.

7.11 Serotonin Syndrome Risk

Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and 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) and can be fatal [see Serotonergic Drugs].

7.12 Use in Patients with Gastrointestinal Conditions

Tapentadol ER is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in tapentadol ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

7.13 Avoidance of Withdrawal

Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including tapentadol ER. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing tapentadol ER, gradually taper the dose [see Dosage and Administration].

7.14 Driving and Operating Heavy Machinery

Tapentadol ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of tapentadol ER and know how they will react to the medication.

7.15 Hepatic Impairment

A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of tapentadol ER in patients with severe hepatic impairment. Reduce the dose of tapentadol ER in patients with moderate hepatic impairment [see Dosage and Administration]. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating tapentadol ER.

7.16 Renal Impairment

Use of tapentadol ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

8. ADVERSE REACTIONS

The following treatment-emergent adverse events are discussed in more detail in other sections of the labeling:

• Respiratory Depression [see Contraindications; Warnings and Precautions]

• CNS Depression [see Warnings and Precautions]

• Hypotension [see Warnings and Precautions]

• Seizures [see Warnings and Precautions]

• Serotonin Syndrome [see Warnings and Precautions].

8.1 Clinical Studies Experience

A causal relationship with tapentadol ER often cannot be reliably established in individual cases. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data described in Table 1 below are based on three pooled, randomized, double-blind, placebo-controlled, parallel group, 15-week studies of tapentadol ER (dosed 100 to 250 mg BID after a 50 mg BID starting dose) in patients with chronic pain due to low back pain (LBP) and osteoarthritis (OA). These trials included 980 tapentadol ER-treated patients and 993 placebo-treated patients. The mean age was 57 years old; 63% were female and 37% were male; 83% were White, 10% were Black, and 5% were Hispanic.

The most common adverse reactions (reported by ≥10% in any tapentadol ER dose group) were: nausea, constipation, headache, dizziness, and somnolence.

The most common reasons for discontinuation due to adverse reactions in nine Phase 2/3 pooled studies reported by ≥1% in any tapentadol ER dose group for tapentadol ER- and placebo-treated patients were nausea (4% vs. < 1%), dizziness (4% vs. < 1%), vomiting (3% vs. < 1%), somnolence (2% vs. < 1%), constipation (1% vs. < 1%), headache (1% vs. < 1%), and fatigue (1% vs. < 1%), respectively.

8.2 Commonly-Observed Adverse Reactions in Double-Blind Controlled Clinical Studies with Tapentadol ER

Table 1 lists the common adverse reactions reported in 1% or more of tapentadol ER-treated patients and greater than placebo-treated patients with chronic moderate to severe pain in the three pooled studies. The types of adverse reactions seen in the study of patients with painful diabetic peripheral neuropathy (DPN) were similar to what was seen in the low back pain and osteoarthritis trials.

Table 1: Adverse Drug Reactions Reported by ≥ 1% of Tapentadol ER-Treated Patients and Greater than Placebo-treated Patients in Pooled Parallel-Group Trials (i.e., Studies LBP-1, OA-1, and OA-2)1

1 MedDRA preferred terms. The trials included forced titration during the first week of dosing.

2 Tapentadol ER dosed between 100 and 250 mg twice daily after a starting dose of 50 mg twice daily.

3 Depressed mood was observed in 1.2% of tapentadol ER-treated subjects vs. 0.5% in placebo group, rash- in 1.1 vs. 0.7 in placebo, and dyspnea- in 1.1 vs. 0.5 in placebo.

8.3 Other Adverse Reactions Observed During the Premarketing Evaluation of Tapentadol ER

The following adverse drug reactions occurred in less than 1% of tapentadol ER-treated patients in nine Phase 2/3 clinical studies:

Nervous System Disorders: Paresthesia, Hypoesthesia, Balance disorder, Sedation, Syncope, Memory impairment, Mental impairment, Depressed level of consciousness, Dysarthria, Coordination abnormal, Presyncope

Gastrointestinal disorders: Impaired gastric emptying

General disorders and administration site conditions: Drug withdrawal syndrome, Irritability, Feeling abnormal, Feeling drunk, Feeling of relaxation

Psychiatric disorders: Perception disturbances, Disorientation, Agitation, Confusional state, Euphoric mood, Drug dependence, Thinking abnormal

Skin and subcutaneous tissue disorders: Urticaria

Metabolism and nutrition disorders: Weight decreased

Cardiac disorders: Heart rate increased, Heart rate decreased

Vascular Disorder: Blood pressure decreased

Respiratory, thoracic and mediastinal disorders: Respiratory depression

Renal and urinary disorders: Pollakiuria, Urinary hesitation

Reproductive system and breast disorders: Sexual dysfunction

Eye disorders: Visual disturbance

Immune system disorders: Drug hypersensitivity

8.4 Post-marketing Experience

The following additional adverse reactions have been identified during post-approval use of tapentadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably.

Gastrointestinal disorders: diarrhea

Immune system disorders: angioedema

Psychiatric disorders: hallucination, suicidal ideation

Cardiac disorders: palpitations

9. DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Tapentadol ER has an abuse potential similar to hydromorphone. Tapentadol ER can be abused and is subject to criminal diversion.

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 of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) 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.

Abuse and addiction are separate and distinct from physical dependence and tolerance. 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 tapentadol ER poses a risk of overdose and death. This risk is increased with concurrent abuse of tapentadol 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]. Use of tapentadol in this population has not been characterized. As tapentadol has mu-opioid agonist activity, infants whose mothers have taken tapentadol, should be carefully monitored.

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, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Tolerance and/or a withdrawal syndrome are more likely to occur the longer a patient is on continuous opioid therapy. In clinical trials, patients who stopped taking tapentadol ER abruptly experienced mild (12%) or moderate (2%) withdrawal. Withdrawal symptoms included: nausea, diarrhea, insomnia, sweating, anxiety, arthralgia, and chills. Withdrawal symptoms may be reduced by tapering tapentadol ER.

10. OVERDOSAGE

10.1 Human Experience

Experience with tapentadol ER overdose is very limited. Preclinical data suggest that symptoms similar to those of other centrally acting analgesics with mu-opioid agonist activity are to be expected upon intoxication with tapentadol. In principle, these symptoms may particularly appear in the clinical setting: miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

10.2 Management of Overdose

Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of tapentadol is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

Pure opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. Respiratory depression following an overdose may outlast the duration of action of the opioid antagonist. Administration of an opioid antagonist is not a substitute for continuous monitoring of airway, breathing, and circulation following an opioid overdose. If the response to opioid antagonists is suboptimal or only brief in nature, an additional antagonist should be administered as directed by the manufacturer of the product.

Gastrointestinal decontamination may be considered in order to eliminate unabsorbed drug. Gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities. Before attempting gastrointestinal decontamination, care should be taken to secure the airway.

11. DRUG INTERACTIONS

Tapentadol 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.

The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively.

11.1 Drugs Metabolized by Cytochrome P450 Enzymes

In vitro investigations indicate that tapentadol does not inhibit or induce P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.

11.2 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 tapentadol is metabolized via the oxidative pathway clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.

11.3 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 tapentadol 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 tapentadol. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered [see Warnings and Precautions].

11.4 Monoamine Oxidase Inhibitors

Tapentadol 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].

11.5 Serotonergic Drugs

There have been post-marketing reports of serotonin syndrome with the concomitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when tapentadol ER is co-administered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of tapentadol ER with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warning and Precautions].

11.6 Mixed Agonist/Antagonist Opioid Analgesics

The concomitant use of tapentadol ER with mixed agonist/antagonists (e.g., butorphanol, nalbuphine, and pentazocine) and partial agonists (e.g., buprenorphine) could lead to a reduction of the analgesic effect by competitive blocking of opioid receptors, and/or withdrawal. Therefore, this combination is not recommended.

11.7 Anticholinergics

The use of tapentadol ER with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

12. PHARMACOKINETICS

Absorption

The mean absolute bioavailability after single-dose administration (fasting) of tapentadol ER is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are observed between 3 and 6 hours after administration of tapentadol ER. Dose proportional increases for AUC have been observed after administration of tapentadol ER over the therapeutic dose range.

Steady-state exposure of tapentadol is attained after the third dose (i.e., 24 hours after first twice daily multiple dose administration). Following dosing with 250 mg every 12 hours, minimal accumulation was observed.

Food Effect

The AUC and Cmax increased by 6% and 17%, respectively, when tapentadol ER tablet was administered after a high-fat, high-calorie breakfast. tapentadol ER may be given with or without food.

Distribution

Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%.

Metabolism and Elimination

In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation.

None of the metabolites contribute to the analgesic activity.

Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 5 hours after oral administration. The total clearance of tapentadol is 1603 +/-227 mL/min.

Special Populations

Elderly

The mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.

Renal Impairment

AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild, moderate, and severe renal impairment, the AUC of tapentadol-O-glucuronide was 1.5-, 2.5-, and 5.5-fold higher compared with normal renal function, respectively.

Hepatic Impairment

Administration of tapentadol resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild and moderate hepatic impairment groups in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t½. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.

13. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: NUCYNTA ER, by Janssen Pharms.

b) Generic drugs: None.

2) How Supplied:

NUCYNTA® ER tablets are available in the following strengths and packages:

50 mg extended-release tablets are white oblong-shaped with a black print “OMJ 50” on one side and are available in bottles of 60 with child-resistant closure (NDC 50458-860-01) and unit dose blister packs of 10, for hospital use only (NDC 50458-860-02).

100 mg extended-release tablets are light-blue oblong-shaped with a black print “OMJ 100” on one side and are available in bottles of 60 with child-resistant closure (NDC 50458-861-01) and unit dose blister packs of 10, for hospital use only (NDC 50458-861-02).

150 mg extended-release tablets are blue-green oblong-shaped with a black print “OMJ 150” on one side and are available in bottles of 60 with child-resistant closure (NDC 50458-862-01) and unit dose blister packs of 10, for hospital use only (NDC 50458-862-02).

200 mg extended-release tablets are blue oblong-shaped with a depression in the middle running lengthwise on each side and with a black print “OMJ 200” on one side, and are available in bottles of 60 with child-resistant closure (NDC 50458-863-01) and unit dose blister packs of 10, for hospital use only (NDC 50458-863-02).

250 mg extended-release tablets are dark blue oblong-shaped with a depression in the middle running lengthwise on each side and with a white print “OMJ 250” on one side, and are available in bottles of 60 with child-resistant closure (NDC 50458-864-01) and unit dose blister packs of 10, for hospital use only (NDC 50458-864-02).

3) Storage:

Store up to 25ºC (77ºF); excursions permitted to 15 - 30ºC (59 - 86ºF) [see USP Controlled Room Temperature]. Protect from moisture.

Keep out of reach of children.

NUCYNTA® ER tablets that are no longer needed should be destroyed by flushing down the toilet.

Rx only

Rev 08/12