FDA Approves NUCYNTA® ER (tapentadol) Extended-Release Oral Tablets for the Management of Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

Raritan, N.J., August 29 , 2012 – Janssen Pharmaceuticals, Inc. today announced the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for NUCYNTA^® ER (tapentadol) extended-release tablets, an oral analgesic taken twice daily, for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

NUCYNTA^® ER is the first and only opioid approved by the FDA for neuropathic pain associated with DPN. In addition to this new indication, NUCYNTA^® ER is currently approved 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.

Diabetes affects nearly 26 million people in the United States, and approximately 60 to 70 percent of people with diabetes have some form of neuropathy. The most common type of neuropathy is DPN, which causes pain or loss of feeling in the toes, feet, legs, hands and arms; it may also include a persistent burning, tingling or prickling sensation. It is estimated that DPN affects nearly eight million people in the United States. Because the complex pathophysiology of DPN involves both central and peripheral mechanisms, certain patients with DPN may require treatment with multiple agents.

“Pain from DPN can be difficult to manage, leaving some patients and healthcare professionals looking for alternative treatments,” said Keith A. Candiotti, M.D., Professor of Anesthesiology and Internal Medicine, University of Miami School of Medicine.* “NUCYNTA^® ER is a different option than currently approved medications for the management of painful DPN and may be an important new choice for these patients.”

NUCYNTA^® ER is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that NUCYNTA^® ER acts as both a mu-opioid receptor and a norepinephrine reuptake inhibitor.

Data from two randomized-withdrawal, placebo-controlled Phase 3 trials showed, among patients who had at least a one-point reduction in pain intensity during three weeks of treatment with NUCYNTA^® ER, those who continued on the same dose of NUCYNTA^® ER that was titrated to balance individual tolerability and efficacy (100-250mg twice daily) for an additional 12 weeks experienced significantly better pain control compared to those who switched to placebo. The findings also demonstrated that NUCYNTA^® ER was generally well tolerated. The most common (=10% of NUCYNTA^® ER treated patients) adverse reactions were nausea, constipation, vomiting, dizziness, headache and somnolence.

“The approval of NUCYNTA^® ER for DPN pain represents the ongoing commitment of Janssen to bring new and innovative products to patients and physicians for the management of pain,” said Paul Chang, Vice President, Medical Affairs, Janssen Pharmaceuticals, Inc. “It is exciting that our in-depth experience in pain management allows us to continue to provide patients with effective options to treat their pain.”

To support the appropriate and effective management of chronic pain, Janssen Pharmaceuticals, Inc. also believes it is essential to provide educational programs about the safe and responsible use of pain medicines and the prevention of misuse.

Since 2008, the company has supported educational programs that reach a range of audiences, including patients, physicians, caregivers, parents, teens and educators. These include: Prescribe Responsibly (www.PrescribeResponsibly.com) for physicians seeking information on the appropriate prescribing of opioid pain medications, and Smart Moves, Smart Choices (www.SmartMovesSmartChoices.org) to increase awareness among educators, parents and teens about the serious problem of teen prescription drug abuse in the United States.

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 was approved by the FDA in August 2011. It is an oral analgesic available by prescription only for the following indications: the management of moderate to severe chronic pain in adults and the management of neuropathic pain associated with DPN 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 several countries worldwide.

Janssen Research & Development, LLC and Janssen Pharmaceutical KK, Japan, are developing tapentadol in Japan. In addition, Janssen Pharmaceutical companies have rights to develop and market immediate- and extended-release formulations of tapentadol in select European countries and certain countries in Latin America, the Asia-Pacific region, Africa and the Middle East.

IMPORTANT SAFETY INFORMATION FOR NUCYNTA^® ER (tapentadol) Extended-Release Oral Tablets

CONTRAINDICATIONS

• NUCYNTA^® ER is contraindicated in patients with significant respiratory depression.
• NUCYNTA^® ER is contraindicated in patients with acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment.
• NUCYNTA^® ER is contraindicated in patients with known or suspected paralytic ileus.
• NUCYNTA^® ER is contraindicated in patients with hypersensitivity (eg, anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product.
• 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.

WARNINGS and PRECAUTIONS

• NUCYNTA^® ER contains tapentadol, an opioid agonist and a Schedule II controlled substance. Tapentadol can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA^® ER in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.
• Assess each patient’s risk for opioid abuse or addiction prior to prescribing NUCYNTA^® ER. The risk for opioid abuse is increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (eg, major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.
• Misuse or abuse of NUCYNTA^® ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death.
• Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
• Respiratory depression is the chief hazard of opioid agonists, including NUCYNTA^® ER. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.
• While serious, life-threatening or fatal respiratory depression can occur at any time during the use of NUCYNTA^® ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with NUCYNTA^® ER and following dose increases. Instruct patients against use by individuals other than the patient for whom NUCYNTA^® ER was prescribed and to keep NUCYNTA^® ER out of the reach of children, as such inappropriate use may result in fatal respiratory depression.
• To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA^® ER are essential. Overestimating the NUCYNTA^® ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused.
• To further reduce the risk of respiratory depression, consider the following:
  • Proper dosing and titration are essential and NUCYNTA^® ER should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
  • Instruct patients to swallow NUCYNTA^® ER tablets whole. The tablets are not to be cut, crushed, dissolved, or chewed. The resulting tapentadol dose may be fatal, particularly in opioid-naïve individuals.
  • NUCYNTA^® ER is contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression.
• Accidental ingestion of NUCYNTA^® ER, especially in children, can result in a fatal overdose of tapentadol.
• The co-ingestion of alcohol with NUCYNTA^® ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on NUCYNTA^® ER therapy.
• Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Therefore, monitor such patients closely, particularly when initiating and titrating NUCYNTA^® ER and when NUCYNTA^® ER is given concomitantly with other drugs that depress respiration.
• Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with NUCYNTA^® ER, as in these patients even usual therapeutic doses of NUCYNTA^® ER may decrease respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients, if possible.
• Hypotension and profound sedation, coma or respiratory depression may result if NUCYNTA^® ER is used concomitantly with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, muscle relaxants, other opioids, and illicit drugs). When considering the use of NUCYNTA^® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol and/or illicit drugs that can cause CNS depression. If NUCYNTA^® ER therapy is to be initiated in a patient taking a CNS depressant, start with a lower NUCYNTA^® ER dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.
• NUCYNTA^® ER may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of NUCYNTA^® ER. In patients with circulatory shock, NUCYNTA^® ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA^® ER in patients with circulatory shock.
• Monitor patients taking NUCYNTA^® ER who may be susceptible to the intracranial effects of CO₂ retention (eg, those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA^® ER. NUCYNTA^® ER may reduce respiratory drive and the resultant CO₂ retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.
• Avoid the use of NUCYNTA^® ER in patients with impaired consciousness or coma.
• NUCYNTA^® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA^® ER may aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA^® ER therapy.
• 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 (GI) symptoms (eg, nausea, vomiting, diarrhea), and can be fatal.
• NUCYNTA^® ER is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA^® ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
• Avoid the use of mixed agonist/antagonist analgesics (ie, pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA^® ER. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
• When discontinuing NUCYNTA^® ER, gradually taper the dose.
• NUCYNTA^® ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA^® ER and know how they will react to the medication.
• A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA^® ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA^® ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and CNS depression when initiating and titrating NUCYNTA^® ER.
• Use of NUCYNTA^® ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

ADVERSE REACTIONS IN CLINICAL STUDIES

• Management of moderate to severe chronic pain: The most common (=10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence.
• Management of neuropathic pain associated with diabetic peripheral neuropathy (DPN): The most common (=10%) adverse reactions were nausea, constipation, vomiting, dizziness, somnolence, and headache.

For full prescribing information for NUCYNTA^® ER, including boxed warnings, please click here.

About Janssen Pharmaceuticals, Inc. and Janssen Research & 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 of Johnson & Johnson.

Janssen Pharmaceuticals, Inc. provides medicines for an array of health concerns in several therapeutic areas. Innovative therapies Janssen Pharmaceuticals, Inc. offers 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.

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* Dr. Candiotti has been a paid consultant to Janssen Pharmaceuticals, Inc. However, he was not compensated for his comments to media relating to the approval of NUCYNTA^® ER.

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