PriCara™, Ortho-McNeil-Janssen Pharmaceuticals, Inc.: Phase 3 Open-Label Study Comparing Tapentadol Extended Release Tablets to Oxycodone Controlled Release Tablets Published by Pain Practice
Published: Jul 19, 2010
The study found tapentadol ER was associated with a lower overall incidence of gastrointestinal adverse events than oxycodone CR (tapentadol ER, 52.0 percent; oxycodone CR, 64.1 percent) in patients with chronic knee or hip osteoarthritis pain or chronic low back pain, including:
- Constipation (tapentadol ER, 22.6 percent; oxycodone CR, 38.6 percent);
- Nausea (tapentadol ER, 18.1 percent; oxycodone CR, 33.2 percent); and
- Vomiting (tapentadol ER, 7.0 percent; oxycodone CR, 13.5 percent).
The median duration of treatment was substantially longer with tapentadol ER (268 days) than with oxycodone CR (59 days), and the incidence of overall gastrointestinal treatment-emergent adverse events (TEAEs) leading to study discontinuation was approximately 2.5 times greater in the oxycodone CR group than in the tapentadol ER group (oxycodone CR, 21.5 percent; tapentadol ER, 8.6 percent). In addition, the incidence of constipation leading to study discontinuation was 4.5 times greater in the oxycodone CR group than in the tapentadol ER group (oxycodone CR, 7.2 percent; tapentadol ER, 1.6 percent).
The study also found tapentadol ER provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis pain or chronic low back pain for up to one year. At baseline, mean pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 and 7.6; at endpoint, they had decreased to 4.4 and 4.5.
"We are encouraged by these study results as they illustrate the tolerability of tapentadol ER compared with oxycodone CR, a standard chronic pain treatment," said Dr. Bruce Moskovitz, Therapeutic Area Leader for Pain, Ortho-McNeil Janssen Scientific Affairs, LLC. "We are pleased about the possibility of bringing this important investigational compound forward to patients in the future."
This study of tapentadol ER examined its long-term safety and tolerability compared to oxycodone CR and the primary objective of this study was to evaluate the safety of twice-daily doses of tapentadol ER (100 to 250 mg) over one year. Patients were randomized in a 4:1 ratio to receive controlled, adjustable, oral, twice-daily doses of tapentadol ER (100-250 mg) or oxycodone HCl CR (20-50 mg) in open-label treatment for up to one year. There were 1,117 patients in the study that received at least one dose of study medication (tapentadol ER, n=894; oxycodone CR, n=223). Demographic and baseline characteristics were similar in the two treatment groups.
The overall incidence of patients experiencing at least one TEAE in the study was 85.7 percent in the tapentadol ER group and 90.6 percent in the oxycodone CR group. The most common TEAEs (reported in the study by greater than 10 percent in either treatment group) included constipation, nausea, dizziness, somnolence, vomiting, headache, fatigue and pruritus. In addition to the gastrointestinal TEAEs reported above, tapentadol ER was associated with lower incidences of dizziness (tapentadol ER, 14.8 percent; oxycodone CR, 19.3 percent), fatigue (tapentadol ER, 9.7 percent; oxycodone CR, 10.3 percent), and pruritus (tapentadol ER, 5.4 percent; oxycodone CR, 10.3 percent). Oxycodone CR was associated with lower incidences of somnolence (tapentadol ER, 14.9 percent; oxycodone CR, 11.2 percent) and headache (tapentadol ER, 13.3; oxycodone CR, 7.6). In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1 percent and 36.8 percent of patients.
Chronic pain, affecting an estimated 100 million Americans, continues to be a significant medical challenge in the United States. Osteoarthritis pain and low back pain are particularly prevalent osteoarthritis pain affects 27 million Americans, and chronic low back pain is the most common cause of disability in developed countries.
Although currently available long-acting opioid analgesics have been shown to provide relief for moderate to severe chronic pain, many are associated with high incidences of side effects, which can cause patients to discontinue their treatment. Research also shows that physicians are uncomfortable prescribing opioids due to these opioid-related side effects.
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.
The full article in Pain Practice can be accessed online at http://www3.interscience.wiley.com/cgi-bin/fulltext/123567330/PDFSTART.
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)
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.
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.
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.
Grunenthal, a privately owned pharmaceutical company based in Aachen, Germany, discovered and started development of tapentadol. Grunenthal and J&JPRD have shared development responsibilities for tapentadol for acute and chronic pain conditions since the companies signed a licensing agreement for tapentadol in 2003. Grunenthal licensed marketing rights to tapentadol to Ortho-McNeil-Janssen Pharmaceuticals, Inc. for the United States, Canada and Japan. Grunenthal maintains marketing rights in Europe and other parts of the world.