tapentadol hydrochloride
Dosage Form: tablet, film coated, extended release
FULL PRESCRIBING INFORMATION
Potential for Abuse
NUCYNTA® ER contains tapentadol, a mu-opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics.
NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when prescribing, or dispensing NUCYNTA® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. (9)
Proper Patient Selection
NUCYNTA® ER is an extended-release formulation of tapentadol indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.
Limitations of Use
NUCYNTA® ER is not intended for use as an as-needed analgesic. (1)
NUCYNTA® ER is not intended for the management of acute or postoperative pain. (1)
NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA® ER tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol. (5)
Patients must not consume alcoholic beverages, prescription or non-prescription medications containing alcohol. Co-ingestion of alcohol with NUCYNTA® ER may result in a potentially fatal overdose of tapentadol. (12.3)
Indications and Usage for Nucynta ER
NUCYNTA® ER is an extended-release formulation of tapentadol indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.
NUCYNTA® ER is NOT intended for use as an as-needed analgesic.
NUCYNTA® ER is not indicated for the management of acute or postoperative pain.
Nucynta ER Dosage and Administration
Selection of patients for treatment with NUCYNTA® ER is governed by the same principles that apply to the use of similar opioid analgesics. Physicians should individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization and Federation of State Medical Boards Model Guidelines.
NUCYNTA® ER tablets must be swallowed whole and must not be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA® ER Tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol.
NUCYNTA® ER tablets must be taken one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)].
Initiating Therapy with NUCYNTA® ER
It is critical to initiate the dosing regimen for each patient individually giving attention to:
- risk factors for abuse or addiction; including whether the patient has a previous or current substance abuse problem, a family history of substance abuse, or a history of mental illness or depression;
- the age, general condition and medical status of the patient;
- the patient's opioid exposure and opioid tolerance (if any);
- the daily dose, potency, and kind of the analgesic(s) the patient has been taking;
- the balance between pain management and adverse reactions.
Discontinue all other tapentadol and tramadol products when beginning and while taking NUCYNTA® ER [see Serotonin Syndrome Risk (5.10)]. Although the maximum approved total daily dose of NUCYNTA® immediate-release formulation is 600 mg per day, the maximum total daily dose of NUCYNTA® ER is 500 mg. Do not exceed a total daily dose of NUCYNTA® ER of 500 mg.
Once therapy with NUCYNTA® ER is initiated, assess pain intensity and adverse reactions frequently.
Titrate patients to adequate analgesia with dose increases of 50 mg no more than twice daily every three days.
During periods of changing analgesic requirements, including initial titration, maintain frequent contact between the healthcare provider and the patient.
Patients Currently Not Taking Opioid Analgesics
The starting dose of NUCYNTA® ER in patients currently not taking opioid analgesics is 50 mg twice a day (approximately every 12 hours). Individually titrate the dose within the therapeutic range of 100 mg to 250 mg twice daily.
Patients Currently Taking Opioid Analgesics
There are no adequate data on the direct conversion from other opioids to NUCYNTA® ER.
The initial dose of NUCYNTA® ER in patients previously taking other opioids is 50 mg titrated to an effective and tolerable dose within the therapeutic range of 100 mg to 250 mg twice daily.
In the dose selection of NUCYNTA® ER in patients currently taking opioids, give attention to the following:
- There is a substantial patient variation in the relative potency of different opioid drugs and formulations;
- It is extremely important to monitor all patients closely when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma.
- The recommended doses are only a starting point, and close observation and titration are indicated until a satisfactory dose is obtained on the new therapy.
Conversion from NUCYNTA® to NUCYNTA® ER
Patients can be converted from NUCYNTA® to NUCYNTA® ER using the equivalent total daily dose of NUCYNTA® and dividing it into two equal doses of NUCYNTA® ER separated by approximately 12-hour intervals. As an example, a patient receiving 50 mg of NUCYNTA® four times per day (200 mg/day) may be converted to 100 mg NUCYNTA® ER twice a day.
Cessation of Therapy
Periodically reassess the continued need for NUCYNTA® ER during chronic therapy. When discontinuing NUCYNTA® ER, potential withdrawal symptoms may be reduced by tapering the dose of NUCYNTA® ER [see Withdrawal (5.11, 9.3)].
Renal Impairment
NUCYNTA® ER has not been studied in patients with severe renal impairment; therefore, the use of NUCYNTA® ER in this population is not recommended. No dosage adjustment is recommended in patients with mild or moderate renal impairment [see Clinical Pharmacology (12.3)].
Hepatic Impairment
NUCYNTA® ER has not been studied in patients with severe hepatic impairment. The use of NUCYNTA® ER in this population is not recommended.
Use NUCYNTA® ER with caution in patients with moderate hepatic impairment. Initiate treatment in these patients using 50 mg NUCYNTA® 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 NUCYNTA® ER once daily [see Clinical Pharmacology (12.3)].
No dosage adjustment is recommended in patients with mild hepatic impairment [see Clinical Pharmacology (12.3)].
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.
Dosage Forms and Strengths
NUCYNTA® ER 50 mg, 100 mg, and 150 mg extended-release tablets are available in the following colors and prints:
- 50 mg extended-release tablets are white oblong-shaped with a black print "OMJ 50" on one side
- 100 mg extended-release tablets are light-blue oblong-shaped with a black print "OMJ 100" on one side
- 150 mg extended-release tablets are blue-green oblong-shaped with a black print "OMJ 150" on one side
NUCYNTA® ER 200 mg and 250 mg extended-release tablets are available in the following colors and prints:
- 200 mg extended-release tablets are blue oblong-shaped with a depression in the middle running lengthwise on each side and a black print "OMJ 200" on one side
- 250 mg extended-release tablets are dark blue oblong-shaped with a depression in the middle running lengthwise on each side and a white print "OMJ 250" on one side
Contraindications
NUCYNTA® ER is contraindicated in patients with significant respiratory depression, or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment [see Warnings and Precautions (5.1)].
NUCYNTA® ER is contraindicated in any patient who has or is suspected of having a paralytic ileus.
NUCYNTA® ER 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)].
NUCYNTA® ER is contraindicated in patients with a known hypersensitivity to the active substance, tapentadol, or any component of the product. Angioedema has been reported in association with use of tapentadol.
Warnings and Precautions
Information Essential for Safe Administration
NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, crushed or dissolved NUCYNTA® ER tablets leads to the rapid release and absorption of a potentially fatal dose of tapentadol.
NUCYNTA® ER tablets must be kept in a secure place out of the reach of children. Accidental consumption of NUCYNTA® ER, especially in children, can result in a fatal overdose of tapentadol.
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.
Use NUCYNTA® ER with caution in 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 NUCYNTA® ER may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered and NUCYNTA® ER 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)].
CNS Depression
Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, centrally acting muscle relaxants, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® ER 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 NUCYNTA® ER. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.
Head Injury and Increased Intracranial Pressure
Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, NUCYNTA® ER 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. NUCYNTA® ER should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.
Misuse and Abuse
Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty.
Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.
NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA® ER 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)].
Drug abusers may attempt to abuse NUCYNTA® ER by crushing, chewing, snorting or injecting the product. These practices may result in the uncontrolled delivery of NUCYNTA® ER and pose a significant risk to the abuser that could result in overdose and death [see Drug Abuse and Dependence (9)].
Hypotension
NUCYNTA® ER may cause severe hypotension. Patients at higher risk of hypotension include those with hypovolemia or those taking concurrent products that compromise vasomotor tone (e.g., phenothiazines, general anesthetics).
Driving and Operating Machinery
Patients should be cautioned that NUCYNTA® ER 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)].
Interactions with Alcohol and Drugs of Abuse
NUCYNTA® ER may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, because respiratory depression, hypotension, hypertension, and profound sedation, coma or death may result [see Drug Interactions (7.3)].
Seizures
NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. As with other opioids, NUCYNTA® ER 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.
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 (7.5)].
Withdrawal
Withdrawal symptoms may occur if NUCYNTA® ER 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 NUCYNTA® ER [see Drug Abuse and Dependence (9.3)].
Hepatic Impairment
A study with the immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Tapentadol should be used with caution in patients with moderate hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
NUCYNTA® ER has not been studied in patients with severe hepatic impairment and use in this population is not recommended.
Use in Pancreatic/Biliary Tract Disease
Like other drugs with mu-opioid agonist activity, NUCYNTA® ER may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.
Other Special Risk Groups
NUCYNTA® ER should be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison's disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis.
Adverse Reactions
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Respiratory Depression [see Contraindications (4) and Warnings and Precautions (5.2)]
- CNS Depression [see Warnings and Precautions (5.3)]
- Hypotension [see Warnings and Precautions (5.6)]
- Seizures [see Warnings and Precautions (5.9)]
- Serotonin Syndrome [see Warnings and Precautions (5.10)]
Clinical Studies Experience
A causal relationship with NUCYNTA® 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 NUCYNTA® 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 NUCYNTA® 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 NUCYNTA® 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 NUCYNTA® ER dose group for NUCYNTA® 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.
Commonly-Observed Adverse Reactions in Double-Blind Controlled Clinical Studies with NUCYNTA® ER
Table 1 lists the common adverse reactions reported in 1% or more of NUCYNTA® 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.
| NUCYNTA® ER 50 to 250 mg BID† (n=980) | Placebo (n=993) | |
|---|---|---|
| ||
| Gastrointestinal disorders | ||
| Nausea | 21% | 7% |
| Constipation | 17% | 7% |
| Vomiting | 8% | 3% |
| Dry mouth | 7% | 3% |
| Dyspepsia | 3% | 2% |
| Nervous system disorders | ||
| Dizziness | 17% | 7% |
| Headache | 15% | 13% |
| Somnolence | 12% | 4% |
| Lethargy | 2% | 0% |
| Disturbance in attention | 1% | 0% |
| Tremor | 1% | 0% |
| General disorders and administration site conditions | ||
| Fatigue | 9% | 4% |
| Asthenia | 2% | 1% |
| Chills | 1% | 0% |
| Psychiatric disorders | ||
| Insomnia | 4% | 2% |
| Anxiety | 2% | 1% |
| Depressed mood‡ | 1% | 1% |
| Abnormal dreams | 1% | 0% |
| Depression | 1% | 0% |
| Skin and subcutaneous tissue disorders | ||
| Hyperhidrosis | 5% | 1% |
| Pruritus | 5% | 2% |
| Rash‡ | 1% | 1% |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 2% | 1% |
| Ear and labyrinth disorders | ||
| Vertigo | 2% | 1% |
| Vascular disorders | ||
| Hot flush | 2% | 0% |
| Eye disorders | ||
| Vision blurred | 1% | 0% |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea‡ | 1% | 1% |
| Reproductive system and breast disorders | ||
| Erectile dysfunction | 1% | 0% |
Other Adverse Reactions Observed During the Premarketing Evaluation of NUCYNTA® ER
The following adverse drug reactions occurred in less than 1% of NUCYNTA® 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
Postmarketing Experience
The following 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 reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: diarrhea
Immune system disorders: angioedema
Psychiatric disorders: hallucination, suicidal ideation
Cardiac disorders: palpitations
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 [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)].
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 [see Clinical Pharmacology (12.3)].
Drugs That Inhibit or Induce Cytochrome P450 Enzymes
The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides, a high capacity metabolic pathway. To a lesser extent, 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. 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 [see Clinical Pharmacology (12.3)].
Centrally Acting Drugs and Alcohol
Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, antiemetics, other tranquilizers, sedatives, hypnotics, centrally acting muscle relaxants, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® ER may experience additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with NUCYNTA® ER. If such combined therapy is contemplated, a dose reduction of one or both agents should be considered [see Warnings and Precautions (5.3) and (5.8)].
The co-administration of alcohol with NUCYNTA® ER may result in increased serum levels and a potentially fatal overdose of tapentadol. Do not use NUCYNTA® ER with alcohol [see Clinical Pharmacology (12.3)].
Monoamine Oxidase Inhibitors
NUCYNTA® ER 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)].
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 NUCYNTA® ER is co-administered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® 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 (5.10)].
Mixed Agonist/Antagonist Opioid Analgesics
The concomitant use of NUCYNTA® 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.
Anticholinergics
The use of NUCYNTA® ER with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C.
There are no adequate and well-controlled studies of NUCYNTA® ER in pregnant women. NUCYNTA® ER 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 NUCYNTA® 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. 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 to postnatal Day 4.
Labor and Delivery
The effect of tapentadol on labor and delivery in humans is unknown. NUCYNTA® ER is not recommended for use in women during and immediately prior to labor and delivery. Due to the mu-opioid receptor agonist activity of NUCYNTA® ER, neonates whose mothers have been taking NUCYNTA® ER 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.
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. NUCYNTA® ER should not be used during breast-feeding.
Pediatric Use
The safety and effectiveness of NUCYNTA® ER in pediatric patients less than 18 years of age have not been established. NUCYNTA® ER is not recommended in this population.
Geriatric Use
Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA® 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 [see Clinical Pharmacology (12.3)].
Neonatal Withdrawal Syndrome
Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother's last dose, and rate of elimination of the drug from the newborn.
Renal Impairment
The safety and effectiveness of NUCYNTA® ER has not been established in patients with severe renal impairment. NUCYNTA® ER is not recommended in this population [see Dosage and Administration (2.3)].
Hepatic Impairment
Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function [see Clinical Pharmacology (12.3)]. NUCYNTA® ER should be used with caution in patients with moderate hepatic impairment [see Dosage and Administration (2.4)].
NUCYNTA® ER has not been studied in patients with severe hepatic impairment, therefore, use of NUCYNTA® ER is not recommended in this population [see Warnings and Precautions (5.12)].
Drug Abuse and Dependence
Controlled Substance
NUCYNTA® ER contains tapentadol, a mu-opioid agonist and is a Schedule II controlled substance. NUCYNTA® ER has an abuse potential similar to hydromorphone, can be abused and is subject to criminal diversion.
Abuse
Drug addiction 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 risks of misuse and abuse should be considered when prescribing or dispensing NUCYNTA® ER. 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 NUCYNTA® ER poses a risk of overdose and death. This risk is increased with concurrent abuse of NUCYNTA® ER with alcohol and other substances. NUCYNTA® ER tablets are intended for oral use only and must not be administered by any other route. If abused by parenteral routes, the tablet excipients may cause serious or even fatal complications. 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 Use in Special Populations (8.6)]. Use of NUCYNTA® ER in this population has not been characterized. As NUCYNTA® ER has mu-opioid agonist activity, infants whose mothers have taken NUCYNTA® ER should be carefully monitored.
Dependence
Tolerance to opioids is the need for increasing doses of opioids to maintain a constant effect such as analgesia (in the absence of disease progression or other external factors). The first sign of tolerance is usually a reduced duration of effect. Tolerance to different effects of opioids may develop to varying degrees and at varying rates in a given individual. There is also inter-patient variability in the rate and extent of tolerance that develops to various opioid effects, whether the effect is desirable (e.g., analgesia) or undesirable (e.g., nausea). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance occur frequently during chronic opioid therapy.
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 NUCYNTA® 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 NUCYNTA® ER.
Overdosage
Human Experience
Experience with NUCYNTA® 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, the clinical manifestations of opioid overdose include miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest, and death.
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 NUCYNTA® ER is suspected. Supportive measures (including oxygen and vasopressors) should be employed in the management of cardiac and/or pulmonary failure as needed. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
Take the extended-release characteristics of NUCYNTA® ER into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects
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 the initial administration of opioid antagonists is suboptimal or only brief in nature, repeated doses or an alternative antagonist should be administered as directed by the label of the antagonist.
Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to tapentadol overdose. In patients who are physically dependent on any opioid agonist including NUCYNTA® ER, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered.
Nucynta ER Description
NUCYNTA® ER (tapentadol) is a mu-opioid receptor agonist, 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. The chemical name is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride. The structural formula is:
The molecular weight of tapentadol HCl is 257.80, and the molecular formula is C14H23NO•HCl. The n-octanol: water partition coefficient log P value is 2.87. The pKa values are 9.34 and 10.45. In
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