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New Phase 3 Study of Tapentadol Immediate Release Tablets Published in Current Medical Research and Opinion Journal


Data Confirm Tapentadol Efficacy and Tolerability for Acute Pain Patients

Raritan, NJ .- It is estimated that up to 30 percent of all people who have surgery experience gastrointestinal side effects, such as nausea and vomiting. The use of opioid pain medicines during and after surgery is a leading risk factor for experiencing these side effects. Nausea and vomiting are uncomfortable and bothersome and can have an impact on a patient’s recovery.

According to a new Phase 3 clinical study published in the June 2009 issue of Current Medical Research and Opinion, and in an online version of the journal, tapentadol immediate release (IR) tablets provided patients with equivalent efficacy in pain relief following orthopedic surgery and significant reduction in nausea and/or vomiting compared to oxycodone IR.

Results from the new Phase 3 study of tapentadol IR tablets, a prescription oral analgesic approved by the U.S. Food and Drug Administration (FDA) in November 2008, showed that patients receiving 50-mg or 75-mg of the medication experienced significant relief of moderate to severe acute pain after a bunionectomy, one of the most common foot surgeries, compared with placebo. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD), Raritan, NJ, and Grunenthal GmbH, Aachen, Germany, supported this study.

The overall difference in the intensity of pain experienced by patients recovering from bunionectomy was examined during the first 12, 24, 48 and 72 hours after initiating treatment with tapentadol IR. Both tapentadol IR treatment groups showed a statistically significant improvement in pain compared to patients who received placebo, during all of these time periods (P less than 0.001), achieving both the primary efficacy endpoint of the sum of pain intensity difference (SPID) at 48 hours and secondary efficacy endpoints (SPID(12), SPID(24), SPID(72)).

Treatment with 50-mg or 75-mg of tapentadol IR resulted in 77.5 percent and 76 percent of patients, respectively, experiencing at least a 30 percent improvement in pain intensity at 48 hours. This is comparable to the 75 percent of patients who experienced the same percentage of improvement with 10-mg of oxycodone IR. Results were similar for patients who experienced a 50 percent improvement in pain intensity at 48 hours: 65 percent in the tapentadol IR 50-mg group, 64 percent in the tapentadol IR 75-mg group and 64 percent in the oxycodone IR 10-mg group.

The most common treatment-emergent adverse events in all active treatment groups included nausea, vomiting, dizziness, headache, somnolence (drowsiness) and constipation. Compared to oxycodone IR, the incidence of nausea and/or vomiting was significantly lower with tapentadol IR 50-mg: 35 percent compared to 59 percent respectively (P less than 0.001). In addition, the percentage of patients who experienced nausea and/or vomiting in the tapentadol IR 75-mg group was slightly lower than the oxycodone 10-mg group: 51 percent versus 59 percent (P=0.057).

“We are encouraged by this Phase 3 study because it shows that patients treated with tapentadol IR experienced effective analgesic relief of moderate to severe acute pain with fewer incidences of nausea and/or vomiting compared with a comparable dose of oxycodone IR, a standard pain treatment,” said lead study author David Upmalis, M.D., Senior Director, J&JPRD. “Side effects are an important consideration in pain management. If healthcare professionals have a treatment option that offers the possibility for fewer side effects, it could lead to better patient outcomes.”

On November 20, 2008, the FDA approved tapentadol immediate release tablets for the relief of moderate to severe acute pain in patients 18 years of age or older. Tapentadol IR tablets have been approved in 50-mg, 75-mg and 100-mg doses. The FDA-approved trade name for tapentadol is NUCYNTA(TM) (pronounced ’new-sinn-tah’), and the U.S. Drug Enforcement Agency has placed tapentadol into Schedule II of the Controlled Substances Act.

Tapentadol 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. It is also being developed in an extended release formulation for chronic pain.

Study Design
This Phase 3, double-blind, randomized, active- and placebo-controlled, parallel group, multi-center trial of 901 patients with moderate-to-severe pain following bunionectomy studied the safety and efficacy of tapentadol IR for postoperative analgesia. Patients were randomly assigned in a 4:4:4:1 ratio to receive tapentadol IR 50-mg, tapentadol IR 75-mg, oxycodone HCl IR 10-mg, or placebo every four to six hours over a 72-hour period following surgery. The primary efficacy endpoint was the sum of pain intensity difference (SPID) over the first 48 hours of treatment. The secondary endpoints included SPID over the first 12, 24, and 72 hours of treatment, responder rates at 48 hours based on the reduction of pain intensity compared with baseline, and patient overall status using a 7-point patient global impression of change numerical rating scale. The current study differs from the previously completed Phase 3 bunionectomy study in allowing two doses of acetaminophen 1 g in the first 12 hours of the double-blind treatment period. The allowed use of acetaminophen was intended to improve completion rates in the current study.

Like other drugs with mu-opioid activity, NUCYNTA(TM) is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment. NUCYNTA(TM) is contraindicated in patients with suspected or confirmed cases of paralytic ileus. NUCYNTA(TM) is also contraindicated in patients currently using or within 14 days of using monoamine oxidase inhibitors (MAOI) 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(TM) 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(TM) may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered and NUCYNTA(TM) 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, other opioids or illicit drugs) concomitantly with NUCYNTA(TM) 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(TM). 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(TM) 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(TM) should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.

NUCYNTA(TM) 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(TM) can be abused in a manner similar to other mu-opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA(TM) 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 addition. NUCYNTA(TM) 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.

Patients should be cautioned that NUCYNTA(TM) 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(TM) has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. NUCYNTA(TM) 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(TM), 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).

Pregnancy-Category C. There are no adequate and well-controlled studies of NUCYNTA(TM) in pregnant women. NUCYNTA(TM) should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus.

Withdrawal symptoms may occur if NUCYNTA(TM) 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(TM).

NUCYNTA(TM) is not recommended in patients with severe renal or hepatic impairment. NUCYNTA(TM) should be used with caution in patients with moderate hepatic impairment. Like other drugs with mu-opioid agonist activity, NUCYNTA(TM) 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.


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