"Nov. 1, 2012 -- Two more drugs made by the New England Compounding Center (NECC) are crawling with various kinds of bacteria, FDA tests reveal.
The NECC is the Massachusetts compounding pharmacy whose drugs are the likely source of th"...
The following treatment-emergent adverse events are discussed in more detail in other sections of the labeling:
- Respiratory Depression [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
- CNS Depression [see WARNINGS AND PRECAUTIONS]
Because clinical studies are conducted under widely varying conditions, adverse event rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. A treatment-emergent adverse event refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.
Based on data from nine Phase 2/3 studies that administered multiple doses (seven placebo- and/or active-controlled, one noncontrolled and one Phase 3 activecontrolled safety study) the most common adverse events (reported by ≥ 10% in any NUCYNTA® dose group) were: nausea, dizziness, vomiting and somnolence.
The most common reasons for discontinuation due to adverse events in the studies described above (reported by ≥ 1% in any NUCYNTA® dose group) were dizziness (2.6% vs. 0.5%), nausea (2.3% vs. 0.6%), vomiting (1.4% vs. 0.2%), somnolence (1.3% vs. 0.2%) and headache (0.9% vs. 0.2%) for NUCYNTA®- and placebo-treated patients, respectively.
Seventy-six percent of NUCYNTA®-treated patients from the nine studies experienced adverse events.
NUCYNTA® was studied in multiple-dose, active- or placebo-controlled studies, or noncontrolled studies (n = 2178), in single-dose studies (n = 870), in open-label study extension (n = 483) and in Phase 1 studies (n = 597). Of these, 2034 patients were treated with doses of 50 mg to 100 mg of NUCYNTA® dosed every 4 to 6 hours.
The data described below reflect exposure to NUCYNTA® in 3161 patients, including 449 exposed for 45 days. NUCYNTA® was studied primarily in placebo- and active-controlled studies (n = 2266, and n = 2944, respectively). The population was 18 to 85 years old (mean age 46 years), 68% were female, 75% white and 67% were postoperative. Most patients received NUCYNTA® doses of 50 mg, 75 mg, or 100 mg every 4 to 6 hours.
Commonly-Observed Treatment-Emergent Adverse Events in Double-Blind Controlled Clinical Trials
Table 1 lists the adverse events reported in ≥ 1% or more of NUCYNTA®-treated patients with acute moderate to severe pain in the pooled safety data from nine Phase 2/3 studies that administered multiple doses (seven placebo- and/or active-controlled, one noncontrolled, and one Phase 3 active-controlled safety study).
Table 1 : Treatment-Emergent Adverse Events* Reported
by ≥ 1% of NUCYNTA®- Treated Patients In Seven Phase 2/3 Placebo- and/or
Oxycodone- Controlled, One Noncontrolled, and One Phase 3 Oxycodone-Controlled
Safety, Multiple-Dose Clinical Studies
|System/Organ Class MedDRA Preferred Term||NUCYNTA® 21 mg - 120 mg
|Dry mouth||4||< 1|
|General disorders and administration site conditions|
|Feeling hot||1||< 1|
|Infections and infestations|
|Upper respiratory tract infection||1||< 1|
|Urinary tract infection||1||< 1|
|Metabolism and nutrition disorders|
|Musculoskeletal and connective tissue disorders|
|Nervous system disorders|
|Abnormal dreams||1||< 1|
|Skin and subcutaneous tissue disorders|
|Pruritus generalized||3||< 1|
|Hot flush||1||< 1|
|* A treatment-emergent adverse event refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.|
Other Adverse Reactions Observed During the Premarketing Evaluation of NUCYNTA®
The following adverse drug reactions occurred in < 1% of NUCYNTA®-treated patients in the pooled safety data from nine Phase 2/3 studies that administered multiple doses (seven were placebo- and/or active-controlled, one noncontrolled, and one Phase 3 active-controlled safety study):
Cardiac disorders: heart rate increased, heart rate decreased
Eye disorders: visual disturbance
Gastrointestinal disorders: abdominal discomfort, impaired gastric emptying
General disorders and administration site conditions: irritability, edema, drug withdrawal syndrome, feeling drunk
Immune system disorders: hypersensitivity
Investigations: gamma-glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increased
Musculoskeletal and connective tissue disorders: involuntary muscle contractions, sensation of heaviness
Nervous system disorders: hypoesthesia, paresthesia, disturbance in attention, sedation, dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope, coordination abnormal, seizure
Psychiatric disorders: euphoric mood, disorientation, restlessness, agitation, nervousness, thinking abnormal
Renal and urinary disorders: urinary hesitation, pollakiuria
Respiratory, thoracic and mediastinal disorders: oxygen saturation decreased, cough, dyspnea, respiratory depression
Skin and subcutaneous tissue disorders: urticaria
Vascular disorders: blood pressure decreased
In the pooled safety data, the overall incidence of adverse reactions increased with increased dose of NUCYNTA®, as did the percentage of patients with adverse reactions of nausea, dizziness, vomiting, somnolence, and pruritus.
The following additional adverse reactions have been identified during post-approval use of NUCYNTA®. 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
Nervous system disorders: headache
Psychiatric disorders: hallucination
Cardiac disorders: palpitations
Read the Nucynta (tapentadol immediate-release oral tablets) Side Effects Center for a complete guide to possible side effects »
NUCYNTA® 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].
The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively [see CLINICAL PHARMACOLOGY].
Drugs Metabolized by Cytochrome P450 Enzymes
In vitro investigations indicate that NUCYNTA® does not inhibit or induce P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur [see CLINICAL PHARMACOLOGY].
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 NUCYNTA® is metabolized via the oxidative pathway clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur [see CLINICAL PHARMACOLOGY].
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 NUCYNTA® 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 NUCYNTA®. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered [see WARNINGS AND PRECAUTIONS].
Monoamine Oxidase Inhibitors
NUCYNTA® 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].
Drug Abuse And Dependence
NUCYNTA® contains tapentadol, a mu-opioid agonist and is a Schedule II controlled substance. NUCYNTA® has an abuse potential similar to hydromorphone, can be abused and is subject to criminal diversion.
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 NUCYNTA® poses a risk of overdose and death. This risk is increased with concurrent abuse of NUCYNTA® 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 NUCYNTA® in this population has not been characterized. As NUCYNTA® has mu-opioid agonist activity, infants whose mothers have taken NUCYNTA®, should be carefully monitored.
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.
Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous opioid therapy. In a safety study where drug was administered up to 90 days, 82.7% of patients taking NUCYNTA® who stopped abruptly without initiating alternative therapy and were assessed 2 to 4 days after discontinuation, did not have objective signs of opioid withdrawal using the Clinical Opiate Withdrawal Scale. Moderate withdrawal symptoms were seen in 0.3% of patients with the rest (17%) experiencing mild symptoms. Withdrawal symptoms may be reduced by tapering NUCYNTA®.
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
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