"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.
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Interaction with Alcohol [see WARNINGS AND PRECAUTIONS]
- Chronic Pulmonary Disease [see WARNINGS AND PRECAUTIONS]
- Hypotensive Effects [see WARNINGS AND PRECAUTIONS]
- Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Drug abuse, addiction, and dependence [see Drug Abuse and Dependence]
- Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
- Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
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.
Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis
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 placebotreated 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 reasons for discontinuation due to adverse reactions in eight 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 (3% vs. < 1%), vomiting (3% vs. < 1%), somnolence (2% vs. < 1%), constipation (1% vs. < 1%), headache (1% vs. < 1%), and fatigue (1% vs. < 1%), respectively.
Table 1: Adverse Drug Reactions Reported by ≥ 1% of NUCYNTA® ER-Treated Patients and Greater than Placebo-treated Patients in Pooled Parallel-Group Trials1
|NUCYNTA® ER 50 to 250 mg BID2
|Decreased appetite||2%||< 1%|
|Hot flush||2%||< 1%|
|Disturbance in attention||1%||< 1%|
|Abnormal dreams||1%||< 1%|
|Vision blurred||1%||< 1%|
|Erectile dysfunction||1%||< 1%|
|1 MedDRA preferred terms. The trials included forced titration during the first
week of dosing.
2 NUCYNTA® ER dosed between 100 and 250 mg BID after a starting dose of
50 mg BID
Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The types of adverse reactions seen in the studies of patients with painful diabetic peripheral neuropathy (DPN) were similar to what was seen in the low back pain and osteoarthritis trials. The safety data described in Table 2 below are based on two pooled, randomized withdrawal, double-blind, placebocontrolled, 12-week studies of NUCYNTA® ER (dosed 100 to 250 mg BID) in patients with neuropathic pain associated with diabetic peripheral neuropathy. These trials included 1040 NUCYNTA® ER-treated patients and 343 placebotreated patients. The mean age was 60 years old; 40% were female and 60% were male; 76% were White, 12% were Black, and 12% were “Other”. The most commonly reported ADRs (incidence ≥ 10% in NUCYNTA® ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache.
Table 2 lists the common adverse reactions reported in 1% or more of NUCYNTA® ER-treated patients and greater than placebo-treated patients with neuropathic pain associated with diabetic peripheral neuropathy in the two pooled studies.
Table 2: Adverse Drug Reactions Reported by ≥ 1% of
NUCYNTA® ER-Treated Patients and Greater than Placebo-Treated Patients in
Pooled Trials (Studies DPN-1 and DPN-2) 1
|NUCYNTA® ER 50 to 250 mg BID2
|Dry mouth||7%||< 1%|
|Decreased appetite||6%||< 1%|
|Abdominal discomfort||1%||< 1%|
|Drug withdrawal syndrome||1%||< 1%|
|1 MedDRA preferred terms.
2 NUCYNTA® ER dosed between 100 and 250 mg BID after a starting dose of 50 mg BID. It includes ADR reported in the open-label titration period for all subjects and in the double-blind maintenance period for the subjects who were randomized to NUCYNTA® ER.
3 It includes ADR reported in the double-blind maintenance period for the subjects who were randomized to placebo after receiving NUCYNTA® ER during the open-label titration period.
4 Tremor was observed in 3.4% of NUCYNTA® ER-treated subjects vs. 3.2% in placebo group, chills- in 1.3% vs. 1.2% in placebo, and feeling cold- in 1.3% vs. 1.2% in placebo.
Other Adverse Reactions Observed During the Premarketing Evaluation of NUCYNTA® ER
The following additional adverse drug reactions occurred in less than 1% of NUCYNTA® ER-treated patients in ten Phase 2/3 clinical studies:
Gastrointestinal disorders: impaired gastric emptying
General disorders and administration site conditions: feeling abnormal, feeling drunk
Psychiatric disorders: perception disturbances, disorientation, confusional state, agitation, euphoric mood, drug dependence, thinking abnormal, nightmare
Skin and subcutaneous tissue disorders: urticaria
Metabolism and nutrition disorders: weight decreased
Cardiac disorders: heart rate increased, palpitations, heart rate decreased, left bundle branch block
Vascular Disorder: blood pressure decreased
Respiratory, thoracic and mediastinal disorders: respiratory depression
Renal and urinary disorders: urinary hesitation, pollakiuria
Reproductive system and breast disorders: sexual dysfunction
Eye disorders: visual disturbance
Immune system disorders: drug hypersensitivity
The following adverse reactions, not noted in Section 6.1 above, 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.
Psychiatric disorders: hallucination, suicidal ideation
Read the Nucynta ER (tapentadol extended-release film-coated tablets) Side Effects Center for a complete guide to possible side effects »
Concomitant use of alcohol with NUCYNTA® 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 nonprescription products containing alcohol while on NUCYNTA® ER therapy [see CLINICAL PHARMACOLOGY].
Monoamine Oxidase Inhibitors
NUCYNTA® ER is contraindicated in 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 CONTRAINDICATIONS].
Concurrent use of NUCYNTA® ER and other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol can increase the risk of respiratory depression, hypotension, profound sedation or coma. Monitor patients receiving CNS depressants and NUCYNTA® ER for signs of respiratory depression and hypotension. When such combined therapy is contemplated, start NUCYNTA® ER at 1/3 to 1/2 of the usual dosage and consider using a lower dose of the concomitant CNS depressant.
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 WARNINGS AND PRECAUTIONS].
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) may precipitate withdrawal symptoms. Avoid the use of agonist/ antagonists and partial agonists with NUCYNTA® ER.
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.
Drug Abuse And Dependence
NUCYNTA® ER contains tapentadol, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA® ER is subject to misuse, abuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse and misuse.
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 abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get ”high”, or the use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking 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, people suffering from untreated addiction and criminals seeking drugs to sell.
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 opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances.
NUCYNTA® ER can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by law, is strongly advised. 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 opioid drugs.
Both tolerance and physical dependence can develop during chronic opioid therapy. 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). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
NUCYNTA® ER should be discontinued by a gradual downward titration [see DOSAGE AND ADMINISTRATION]. If NUCYNTA® ER is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use In Specific Populations].
Last reviewed on RxList: 10/5/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Nucynta ER Information
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Chronic Pain/Back Pain
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