"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
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.
NUCYNTA® 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 NUCYNTA® may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered and NUCYNTA® 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].
Patients receiving other mu-opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® 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®. 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® 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® 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.
NUCYNTA® can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA® 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].
NUCYNTA® 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].
Driving and Operating Machinery
Patients should be cautioned that NUCYNTA®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].
Interactions with Alcohol and Drugs of Abuse
Due to its mu-opioid agonist activity, NUCYNTA® 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].
NUCYNTA® has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. NUCYNTA® 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
The development of a potentially life-threatening serotonin syndrome may occur with use of Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) products, including NUCYNTA®, particularly with concomitant use of serotonergic drugs such as Selective Serotonin Reuptake Inhibitors (SSRIs), SNRIs, tricyclic antidepressants (TCAs), MAOIs and triptans, and with drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Withdrawal symptoms may occur if NUCYNTA® 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® [see Drug Abuse and Dependence
A study of NUCYNTA® in subjects with hepatic impairment showed higher serum concentrations than in those with normal hepatic function. NUCYNTA® should be used with caution in patients with moderate hepatic impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
NUCYNTA® has not been studied in patients with severe hepatic impairment and, therefore, use in this population is not recommended.
Use in Pancreatic/Biliary Tract Disease
Like other drugs with mu-opioid agonist activity, NUCYNTA® may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.
Patient Counseling Information
Physicians are advised to discuss the following issues with patients for whom they prescribe NUCYNTA®:
Instructions for Use
Patients should be advised NUCYNTA® should be taken only as directed and to report episodes of breakthrough pain and adverse experiences occurring during therapy to their physician. Individualization of dosage is essential to make optimal use of this medication. Patients should be advised not to adjust the dose of NUCYNTA® without consulting their physician [see DOSAGE AND ADMINISTRATION]. Patients should be advised that it may be appropriate to taper dosing when discontinuing treatment with NUCYNTA® as withdrawal symptoms may occur [see Drug Abuse and Dependence]. The physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.
Misuse and Abuse
Patients should be advised that NUCYNTA® is a potential drug of abuse. Patients should protect NUCYNTA® from theft, and NUCYNTA® should never be given to anyone other than the individual for whom NUCYNTA® was prescribed [see WARNINGS AND PRECAUTIONS].
Interference with Cognitive and Motor Performance
As NUCYNTA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles [see WARNINGS AND PRECAUTIONS].
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with NUCYNTA® [see Use In Specific Populations].
Patients should be advised not to breast-feed an infant during treatment with NUCYNTA® [see Use In Specific Populations].
Monoamine Oxidase Inhibitors
Patients should be informed not to take NUCYNTA® while using any drugs that inhibit monoamine oxidase. Patients should not start any new medications while taking NUCYNTA® until they are assured by their healthcare provider that the new medication is not a monoamine oxidase inhibitor.
Patients should be informed that NUCYNTA® could cause seizures if they are at risk for seizures or have epilepsy. Such patients should be advised to use NUCYNTA® with care [see WARNINGS AND PRECAUTIONS]. Patients should be advised to stop taking NUCYNTA® if they have a seizure while taking NUCYNTA® and call their healthcare provider right away.
Patients should be informed that NUCYNTA® could cause rare but potentially life-threatening conditions resulting from concomitant administration of serotonergic drugs (including Serotonin Reuptake Inhibitors, Serotonin and Norepinephrine Reuptake Inhibitors and tricyclic antidepressants) [see WARNINGS AND PRECAUTIONS].
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs as there is a potential for interactions [see DRUG INTERACTIONS].
Patients should be advised to avoid alcohol while taking NUCYNTA® [see DRUG INTERACTIONS].
See Medication Guide.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tapentadol was administered to rats (diet) and mice (oral gavage) for two years. In mice, tapentadol HCl was administered by oral gavage at dosages of 50, 100 and 200 mg/kg/day for 2 years (up to 0.2 times the plasma exposure at the maximum recommended human dose [MRHD] on an area under the time-curve [AUC] basis).
No increase in tumor incidence was observed at any dose level.
In rats, tapentadol HCl was administered in diet at dosages of 10, 50, 125 and 250 mg/kg/day for two years (up to 0.2 times in the male rats and 0.6 times in the female rats the MRHD on an AUC basis). No increase in tumor incidence was observed at any dose level.
Tapentadol did not induce gene mutations in bacteria, but was clastogenic with metabolic activation in a chromosomal aberration test in V79 cells. The test was repeated and was negative in the presence and absence of metabolic activation. The one positive result for tapentadol was not confirmed in vivo in rats, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose.
Impairment of Fertility
Tapentadol HCl was administered intravenously to male or female rats at dosages of 3, 6, or 12 mg/kg/day (representing exposures of up to approximately 0.4 times the exposure at the MRHD on an AUC basis, based on extrapolation from toxicokinetic analyses in a separate 4-week intravenous study in rats). Tapentadol did not alter fertility at any dose level. Maternal toxicity and adverse effects on embryonic development, including decreased number of implantations, decreased numbers of live conceptuses, and increased pre- and post-implantation losses occurred at dosages ≥ 6 mg/kg/day.
Use In Specific Populations
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 NUCYNTA® in pregnant women. NUCYNTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of tapentadol on labor and delivery in humans is unknown. NUCYNTA® 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®, neonates whose mothers have been taking NUCYNTA® 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.
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® should not be used during breast-feeding.
The safety and effectiveness of NUCYNTA® in pediatric patients less than 18 years of age have not been established. NUCYNTA® is not recommended in this population.
Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA®, 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].
In patients with severe renal impairment, the safety and effectiveness of NUCYNTA® has not been established. NUCYNTA® is not recommended in this population [see DOSAGE AND ADMINISTRATION].
Administration of NUCYNTA® 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]. NUCYNTA® should be used with caution in patients with moderate hepatic impairment [see DOSAGE AND ADMINISTRATION].
NUCYNTA® has not been studied in patients with severe hepatic impairment, therefore, use of NUCYNTA® is not recommended in this population [see WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 11/20/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Nucynta Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Chronic Pain/Back Pain
Find tips and advances in treatment.