Pivotal Phase 3 Study Compares Tapentadol Extended Release Tablets to Placebo in Patients with Chronic Osteoarthritis Knee Pain

RARITAN, N.J., Aug. 30 /PRNewswire/ -- Phase 3 safety and efficacy data comparing tapentadol extended release (ER) tablets, an investigational pain medication, to placebo in patients with moderate to severe chronic osteoarthritis knee pain have been published by Clinical Drug Investigation. In addition, this study compared oxycodone controlled release (CR) to placebo as an active control.  

Tapentadol ER vs. Placebo

The study demonstrated that a significantly higher percentage of patients receiving tapentadol ER tablets achieved at least a 50 percent improvement in average pain intensity compared to placebo (32 percent vs. 24.3 percent, respectively; nominal p = 0.027), indicating a clinically significant improvement in pain intensity.

To measure perceived change in overall health status, patients also were asked to report their pain at Weeks 5 and 9 of the maintenance period and at the end of treatment. Results of this patient global impression of change (PGIC) analysis indicated that patients receiving tapentadol ER tablets showed statistically significant improvements compared with placebo (nominal p<0.001).

Primary endpoints for the study were the changes in average daily pain intensity from baseline (11-point numerical rating scale) over the last week of maintenance and over the study's entire 12-week maintenance period. Tapentadol ER significantly reduced average pain intensity from baseline to Week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95 percent confidence interval], -0.7 [-1.04, -0.33]), and throughout the maintenance period (-0.7 [-1.00, -0.33]).

The incidence of patients who reported at least one treatment-emergent adverse event (TEAE) was 61.1 percent for placebo and 75.9 percent for tapentadol ER. The percentages of tapentadol ER patients experiencing common TEAEs (reported by ≥10 percent in any group of the study) included 18.9 percent with constipation, 21.5 percent with nausea, 5.2 percent with vomiting, 10.8 percent with somnolence, 17.7 percent with dizziness, 14.8 percent with headache, 10.8 percent with fatigue, and 7.0 percent with pruritus.

The rate of patient discontinuations from the study due to all TEAEs was 19.2 percent for patients in the tapentadol ER group and 6.5 percent for the placebo group. For all gastrointestinal-related TEAEs, the discontinuation rate for patients in the tapentadol ER group was 7.3 percent versus 1.8 percent for patients in the placebo group. Specifically, 4.1 percent of tapentadol ER patients discontinued due to nausea, 1.7 percent because of constipation, and 1.2 percent due to vomiting.

"We are pleased that the study indicates that tapentadol ER may be effective in the treatment of moderate to severe osteoarthritis knee pain, and that a low number of patients discontinued the study due to gastrointestinal side effects," said Dr. Bruce Moskovitz, Therapeutic Area Leader for Pain, Ortho-McNeil Janssen Scientific Affairs, LLC. "We look forward to our ongoing discussions with the FDA regarding the potential approval of this investigational medication."

Patients in this study were randomized in a 1:1:1 ratio to receive twice daily, controlled, adjustable, oral doses of tapentadol ER (100-250 mg), oxycodone HCl CR (20-50 mg) or placebo during a 15-week double-blind treatment period. There were 1,023 patients in the study that received at least one dose of study medication (placebo, n=337; tapentadol ER, n=344; oxycodone CR, n=342). Demographic and baseline characteristics were balanced across groups.

Oxycodone CR vs. Placebo

The oxycodone CR arm was compared to placebo as an active control.  The study found oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95 percent confidence interval], -0.3 [-0.67, -0.00]), but not at Week 12 (-0.3 [-0.68, 0.02]). A significantly lower percentage of patients achieved at least a 50 percent improvement in average pain intensity in the oxycodone CR group compared to placebo (17.3 percent vs. 24.3 percent, respectively; nominal p = 0.023).

The rate of oxycodone CR patient discontinuations from the study due to all TEAEs was 42.7 percent. For gastrointestinal-related TEAEs, the discontinuation rate for patients in the oxycodone CR group was 26.9 percent. Discontinuation rates for specific gastrointestinal-related TEAEs in this group included 14.3 percent due to nausea, 9.4 percent due to constipation, and 8.5 percent due to vomiting.

The incidence of oxycodone CR patients who reported at least one TEAE was 87.4 percent. The percentages of oxycodone CR patients experiencing common TEAEs included the 36.8 percent with constipation, 36.5 percent with nausea, 17.8 percent with vomiting, 19.6 percent with somnolence, 19 percent with dizziness, 14.6 percent with headache, 10.2 percent experiencing fatigue, and 12.6 with pruritus.

Study researchers also conducted additional secondary statistical analyses, which may be found in the full article, published in Clinical Drug Investigation and accessible online at:  http://adisonline.com/druginvestigation/Abstract/2010/30080/Efficacy_and_Safety_of_Tapentadol_Extended_Release.1.aspx.

Worldwide, osteoarthritis pain affects as many as one in four adults who are older than 65 years of age and it is one of the most common causes of disability and pain among older adults. Opioid analgesics have demonstrated efficacy in the management of moderate to severe pain and are recommended by current guidelines for chronic pain associated with osteoarthritis.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) and Grunenthal GmbH conducted this study, which J&JPRD has included as part of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tapentadol ER tablets for the management of moderate to severe chronic pain in patients 18 years of age or older. The FDA currently is reviewing this application and, if approved, PriCara^®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., will market tapentadol ER in the United States.

About tapentadol

Tapentadol is a centrally acting oral analgesic that binds to mu-opioid receptors and inhibits norepinephrine re-uptake. Although the exact mechanism of action is not known, these two mechanisms, which affect established pain pathways, are thought to be responsible for pain relief with tapentadol. The tapentadol molecule is classified as Schedule II of the Controlled Substances Act.

NUCYNTA^® (tapentadol immediate release) was approved by the FDA on November 20, 2008, and is available by prescription only for the relief of moderate to severe acute pain in patients 18 years of age or older. On December 1, 2009, J&JPRD submitted its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tapentadol extended release (ER) tablets for the management of moderate to severe chronic pain in patients 18 years of age or older. The tapentadol ER tablet formulation is designed to provide a high degree of mechanical resistance, such as to crushing or chewing. The NDA filing is part of the ongoing commitment of J&JPRD and PriCara^® to bring new and innovative products to patients and physicians for the treatment and management of pain.

IMPORTANT SAFETY INFORMATION FOR NUCYNTA^® (tapentadol)

Contraindications

Like other drugs with mu-opioid agonist activity, NUCYNTA^® is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.  NUCYNTA^® is contraindicated in patients who have or are suspected to have paralytic ileus.  NUCYNTA^® is also contraindicated in patients currently using or within 14 days of using monoamine oxidase inhibitors (MAOIs) due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

Warnings & Precautions

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 the elderly, debilitated patients, and 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, 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.  

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.

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 susceptible to the effects of raised cerebrospinal fluid pressure such as those with 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.

NUCYNTA^® 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 mu-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.  All patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction.  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.

Experience with NUCYNTA^® overdose is very limited. Management of overdose should be focused on treating symptoms of mu-opioid agonism. Primary attention should be given to reestablishment of a patent airway and institution of assisted or controlled ventilation when overdose of NUCYNTA^® 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.

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.

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.

The development of a potentially life-threatening serotonin syndrome may occur with use of SNRI products, including NUCYNTA^®, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, and with drugs which impair metabolism of serotonin (including MAOIs).  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^®.

Pregnancy Category C.  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. NUCYNTA^® is not recommended for use in women during and immediately prior to labor and delivery. Neonates whose mothers have been taking NUCYNTA^® should be monitored for respiratory depression. NUCYNTA^® should not be used during breastfeeding.

NUCYNTA^® is not recommended in patients with severe renal or hepatic impairment.  NUCYNTA^® should be used with caution in patients with moderate hepatic impairment.  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.

Adverse Events

The most common adverse events are nausea, dizziness, vomiting, somnolence and headache. To see the NUCYNTA^® full prescribing information, go to http://www.nucynta.com/nucynta/assets/Nucynta-PI.pdf.

PriCara^®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.

PriCara^®, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., is a major health care company in the United States dedicated to the needs of primary care providers who serve a vital role on the frontline of medicine. For more information about the company, please visit www.PriCara.com.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., (J&JPRD) is a wholly owned subsidiary of Johnson & Johnson, the world's most broadly based producer of health care products. J&JPRD is headquartered in Raritan, N.J., and has facilities throughout Europe, the United States and Asia. J&JPRD is leveraging drug discovery and drug development in a variety of therapeutic areas, including CNS, Internal Medicine and Oncology, to address unmet medical needs worldwide. More information can be found at www.jnjpharmarnd.com.  

SOURCE PriCara(R), Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.

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