Phase 3 Data Show NUCYNTA® ER (tapentadol) Extended-Release Tablets Provide Pain Management for Patients with Diabetic Peripheral Neuropathy (DPN)

RARITAN, N.J., May 17, 2012 /PRNewswire/ -- Janssen Pharmaceuticals, Inc. today announced the results of an investigational Phase 3 study suggesting NUCYNTA® ER (tapentadol) extended-release tablets were significantly more effective than placebo in providing pain management among adults with chronic moderate to severe, painful diabetic peripheral neuropathy (DPN). Results of the study were presented at the 31st Annual Scientific Meeting of the American Pain Society being held May 16-19 in Honolulu, Hawaii.

Diabetes affects nearly 26 million people in the United States(1)– and its prevalence is expected to grow significantly during the coming decades(2). Over time, people with diabetes can develop a type of nerve damage called neuropathy. Approximately 60 to 70 percent of people with diabetes have some form of neuropathy(3). The most common type is diabetic peripheral neuropathy, which causes pain or loss of feeling in the toes, feet, legs, hands, and arms.

The study found, among patients who had at least a one-point reduction in pain intensity during three weeks of treatment with tapentadol ER, those who continued on an optimized dose of tapentadol ER (100-250 mg twice daily) for an additional 12 weeks experienced significantly better pain control compared to those who switched to placebo(4). Treatment-emergent adverse events reported in 10 percent or more of tapentadol ER-treated patients during the double-blind maintenance period included nausea (21.1 percent) and vomiting (12.7 percent)(4).

"Painful DPN is a common and burdensome complication of diabetes, and controlling pain in people with DPN can be challenging," said Aaron I. Vinik, M.D., Ph.D., FCP, MACP, Director of Research and Neuroendocrine Unit at Strelitz Diabetes Center for Endocrine and Metabolic Disorders at Eastern Virginia Medical School, and lead investigator of the study. "These data suggest tapentadol ER provides a significant reduction in chronic pain in adult patients with DPN."

The findings of this study are consistent with those of another Janssen-sponsored study published early last year, which found tapentadol ER to be effective versus placebo for relieving moderate to severe chronic pain associated with diabetic peripheral neuropathy.

"We are pleased the Phase 3 data presented today showed tapentadol ER was effective at providing pain management for patients with chronic, moderate to severe pain associated with DPN," said Christine Rauschkolb, M.D., Ph.D., Vice President and Head of Integrated Operations, Janssen Research & Development, LLC and one of the study's authors. "Janssen has a long history of helping physicians provide responsible treatment for patients to relieve their acute and chronic pain. We are committed to developing new pain management options for the millions of Americans who have painful DPN."

About the Study

This Phase 3 clinical trial was a randomized-withdrawal, placebo-controlled study.  It enrolled adult patients who had moderate to severe, chronic painful DPN for six months or more and a history of analgesic use for painful DPN for three months or more. This trial had three phases: an open-label phase, which included a 3-week titration period during which the individually optimized tapentadol ER dose (100-250 mg two times per day) was determined for each patient; a 12-week, double-blind maintenance phase, during which patients with a one-point or greater reduction in pain intensity from beginning to end of titration were randomized either to continue taking tapentadol ER (at their optimal dose) or to receive placebo; and a follow-up period with a clinic visit at four days and a telephone interview at 10 to 14 days after discontinuation of study drug.

The primary efficacy endpoint of the study was the mean change in average pain intensity from baseline (point of randomization) to the last week of the 12-week, double-blind maintenance phase, as determined by an 11-point pain rating scale or numerical rating scale (NRS; 0='no pain,' 10='pain as bad as you can imagine'). Safety assessments were performed on the open-label and double-blind safety populations (all patients who received greater than or equal to 1 dose of open-label and double-blind treatment, respectively). Treatment-emergent adverse events (TEAEs), defined as any AEs (new or worse in intensity) that occurred after the first intake of study drug during the open-label or double-blind phase, were monitored throughout the study.

In the open-label titration period, 459 patients received one or more doses of tapentadol ER and were included in the open-label safety population. At the start of the 3-week, open-label phase, the majority of patients (87.1 percent) reported severe pain (6 or more on the 11-point NRS) with a mean pain intensity of 7.3. By the end of the open-label phase, the mean pain intensity was reduced to 3.6. Treatment-emergent adverse events (TEAEs) experienced by 10 percent or more of patients during the open-label phase were nausea (24.4 percent), dizziness (17), constipation (11.8) and somnolence (10.7).

A total of 358 patients completed the open-label titration period; 318 were randomized and received one or more dose of study medication (n=152 for placebo, 166 for tapentadol ER).

Following randomization, during the double-blind treatment phase to week 12, pain increased in the placebo group (as demonstrated by the mean change in pain intensity of 1.3), while in the tapentadol ER group, efficacy was maintained, as indicated by the mean change in pain intensity of 0.28. The least-squares mean difference between the tapentadol ER and placebo groups in the change in average pain intensity was -0.95 on the 11-point NRS favoring tapentadol ER (95 percent CI, -1.42 to -0.49; p<0.001, tapentadol ER vs. placebo)(4).

For more details about the study design, please visit www.clinicaltrials.gov (NCT01041859).

Janssen Research & Development, LLC  and Grunenthal GmbH, conducted this study, which Janssen Research & Development, LLC has included as part of its Supplemental New Drug Application (sNDA) submitted on October 28, 2011 to the U.S. Food and Drug Administration (FDA) for tapentadol ER tablets for the management of neuropathic pain associated with DPN in patients 18 years of age or older. The FDA currently is reviewing this supplemental application.

About Tapentadol and NUCYNTA^® ER

Tapentadol is a centrally-acting synthetic analgesic. The tapentadol molecule is classified as Schedule II of the Controlled Substances Act.

NUCYNTA^® ER (tapentadol) extended-release tablets are an oral analgesic available by prescription only and indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. NUCYNTA^® ER is taken twice daily and available in 50 mg, 100 mg, 150 mg, 200 mg and 250 mg strengths.

Outside the United States, tapentadol is marketed by Janssen Inc. in Canada; Grünenthal GmbH discovered tapentadol and markets immediate- and extended-release formulations of tapentadol (PALEXIA^®) in various countries in Europe.

IMPORTANT SAFETY INFORMATION FOR NUCYNTA^® ER (tapentadol) extended-release tablets

WARNING: POTENTIAL FOR ABUSE, PROPER PATIENT SELECTION, AND LIMITATIONS OF USE

Potential for Abuse

NUCYNTA^® ER contains tapentadol, a mu-opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics.

NUCYNTA^® ER can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when prescribing or dispensing NUCYNTA^® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Schedule II opioid substances, which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection

NUCYNTA^® ER is an extended-release formulation of tapentadol indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Use

NUCYNTA^® ER is not intended for use as an as-needed analgesic.

NUCYNTA^® ER is not intended for the management of acute or postoperative pain.

NUCYNTA^® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA^® ER tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol.

Patients must not consume alcoholic beverages, or prescription or nonprescription medications containing alcohol. Co-ingestion of alcohol with NUCYNTA^® ER may result in a potentially fatal overdose of tapentadol.

CONTRADICTIONS

• NUCYNTA^® ER 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^® ER is contraindicated in any patient who has or is suspected of having a paralytic ileus.
• NUCYNTA^® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) 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.
• NUCYNTA^® ER is contraindicated in patients with a known hypersensitivity to the active substance, tapentadol, or any component of the product. Angioedema has been reported in association with use of tapentadol.

WARNINGS & PRECAUTIONS

• NUCYNTA^® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, crushed, or dissolved NUCYNTA^® ER tablets leads to the rapid release and absorption of a potentially fatal dose of tapentadol. 
• NUCYNTA^® ER tablets must be kept in a secure place out of the reach of children. Accidental consumption of NUCYNTA^® ER, especially in children, can result in a fatal overdose of tapentadol.
• 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.
• Use NUCYNTA^® ER with caution in 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, central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA^® ER may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non–mu-opioid agonist analgesics should be considered, and NUCYNTA^® ER 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 opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, centrally acting muscle relaxants, or other CNS depressants (including alcohol) concomitantly with NUCYNTA^® ER 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^® ER. 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^® ER should not be used in patients who may be susceptible to the effects of raised cerebrospinal fluid pressure, such as those with evidence of 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^® ER should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.
• Tapentadol 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.
• Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.
• NUCYNTA^® ER can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA^® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction, since use of mu-opioid agonist analgesic products carries the risk of addiction even under appropriate medical use.
• Drug abusers may attempt to abuse NUCYNTA^® ER by crushing, chewing, snorting, or injecting the product. These practices may result in the uncontrolled delivery of NUCYNTA^® ER and pose a significant risk to the abuser that could result in overdose and death.
• NUCYNTA^® ER may cause severe hypotension. Patients at higher risk of hypotension include those with hypovolemia or those taking concurrent products that compromise vasomotor tone (eg, phenothiazines, general anesthetics).
• Patients should be cautioned that NUCYNTA^® ER 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^® ER may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause CNS depression, because respiratory depression, hypotension, hypertension, and profound sedation, coma, or death may result.
• NUCYNTA^® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. As with other opioids, NUCYNTA^® ER 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.
• Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea), and can be fatal.
• Withdrawal symptoms may occur if NUCYNTA^® ER 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^® ER.
• A study with the immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Tapentadol should be used with caution in patients with moderate hepatic impairment.
• NUCYNTA^® ER has not been studied in patients with severe hepatic impairment, and use in this population is not recommended.
• Like other drugs with mu-opioid agonist activity, NUCYNTA^® ER may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.
• NUCYNTA^® ER should be used with caution in the following conditions: adrenocortical insufficiency (eg, Addison's disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis.
• Pregnancy Category C. There are no adequate and well-controlled studies of NUCYNTA^® ER in pregnant women. NUCYNTA^® ER should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus.

ADVERSE REACTIONS

• The most common (greater than equal to 10%) adverse reactions were nausea, constipation, headache, dizziness, and somnolence.

About Janssen Pharmaceuticals, Inc. and Janssen Research and Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop and bring innovative products, services and solutions to people throughout the world.

Janssen Pharmaceuticals, Inc., and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies.

Janssen Pharmaceuticals, Inc. provides medicines for an array of health concerns in several therapeutic areas. Innovative therapies Janssen Pharmaceuticals, Inc. offers currently include ACIPHEX^® (rabeprazole sodium), DORIBAX^® (doripenem for injection), ELMIRON^® (pentosan polysulfate sodium), NUCYNTA^® (tapentadol), NUCYNTA^® ER (tapentadol) extended-release tablets and XARELTO^® (rivaroxaban) tablets. The full prescribing information for NUCYNTA^® ER, including boxed warnings, is available here; the full prescribing information for XARELTO^®, including boxed warnings, is available here.

For more information on Janssen Pharmaceuticals, Inc., visit us at www.janssenpharmaceuticalsinc.com or follow us on Twitter at www.twitter.com/JanssenUS.

For more information on Janssen Research & Development, LLC, visit us at http://www.janssenrnd.com/.

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* Dr. Vinik was compensated for his work as a clinical investigator in the clinical trials for NUCYNTA^® ER.

1.    Centers for Disease Control and Prevention. 2011 Diabetes Fact Sheet: Diagnosed and undiagnosed diabetes in the United States, all ages, 2010. http://www.cdc.gov/diabetes/pubs/estimates11.htm#1.

2.    International Diabetes Federation.  2009 Diabetes Fact Sheet.  http://www.idf.org/diabetesatlas/diabetes.  Updated August 2009.

3.    National Diabetes Information Clearinghouse. Diabetic Neuropathies: The Nerve Damage of Diabetes. http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/index.aspx#peripheralneuropathy. Updated February 2009.

4.    Vinik A., et al. Efficacy and Tolerability of Tapentadol Extended Release (ER) in Patients With Chronic, Painful Diabetic Peripheral Neuropathy (DPN): Results of a Phase 3, Randomized-Withdrawal, Placebo-Controlled Study. Abstract.

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