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FDA Approves Mallinckrodt Inc.'s EXALGO®  
8/27/2012 8:34:28 AM

ST. LOUIS--(BUSINESS WIRE)-- The U.S. Food and Drug Administration (FDA) has notified Mallinckrodt, the pharmaceuticals business of Covidien (COV), that it has approved a 32 mg tablet strength of EXALGO® (hydromorphone HCI) Extended-Release Tablets (CII) for opioid-tolerant patients with moderate-to-severe chronic pain requiring continuous around-the-clock opioid analgesia for an extended period of time. The FDA approved the 8, 12 and 16 mg tablets of EXALGO in March 2010 and the Supplemental New Drug Application (sNDA) for the 32 mg tablet was submitted in January 2012 with post-marketing data to support the original application’s compendium of clinical trials demonstrating efficacy and tolerability. The EXALGO 32 mg tablet strength will be available in the next few weeks.

“We believe that the new 32 mg tablet - delivered by the same extended-release OROS® technology used with the 8, 12, and 16 mg tablets - will provide an established pharmacologic profile and analgesic potency of once-daily hydromorphone. This new EXALGO 32 mg tablet represents an important milestone as 32 mg was the median effective dose upon which patients were stabilized during the pivotal trial,” said Thomas Smith, M.D., Chief Medical Officer, Mallinckrodt. “By providing a variety of tablet strengths, we hope that physicians and opioid-tolerant patients can work together to develop and tailor a treatment regimen that adequately and appropriately controls their chronic pain.”

EXALGO utilizes the OROS drug delivery system designed to release the opioid analgesic at a controlled rate. By providing a steady release of hydromorphone throughout the day once steady-state is achieved after three to four days, the drug is formulated to help minimize the peaks and valleys that are sometimes experienced by chronic pain patients who rely on immediate-release products that are dosed at more frequent intervals. Additionally, the physical properties of EXALGO may make it difficult to extract the active ingredient using common forms of physical and chemical tampering, including chewing, crushing and dissolving. OROS technology has been used in products for various therapeutic areas for more than 30 years.

There are an estimated 116 million Americans1 with chronic pain. According to a survey of 1,000 patients, many people have made life-altering changes such as taking disability leave from work, changing jobs altogether, getting help with activities of daily living and moving to a home that is easier to manage.2 While opioid therapy to help reduce their pain levels is not appropriate for all of these patients, it is critically important for all patients to work with their physicians to find the right treatment, including the right dosing regimen if medications are used.

“Physicians may try as many as five types of opioids before finding a treatment plan that provides pain relief to patients,” said Dr. Joseph Shurman, Chairman, Pain Management, at Scripps Memorial Hospital. “Sustained release treatments like EXALGO help patients avoid fluctuations in blood plasma levels and a new tablet strength provides more options for physicians to use with their opioid-tolerant patients."

All EXALGO dosage strengths, including the new 32 mg tablet, are subject to the recently approved Risk Evaluation and Mitigation Strategy (REMS) program for all long-acting and extended-release opioids. The three primary components of this REMS program are: training for prescribers in the form of continuing medical education (CME) initiatives, which will be available by March 2013; updated medication guides for each opioid and a patient counseling document; and assessment and auditing to ensure the reach and effectiveness of prescriber training.

Mallinckrodt fully supports the efforts coordinated by the White House Office of National Drug Control Policy to address the abuse, misuse and overdose of these opioid analgesics.

In order to ensure a smooth transition to the class-wide REMS program, Mallinckrodt will maintain the current EXALGO REMS program web site at www.exalgorems.com and continue to provide important EXALGO prescribing information, with a focus on appropriate patient selection and dosing, to new prescribers. In addition, Mallinckrodt continues to provide to health care professionals, patients and caregivers more than 60 educational tools, at no cost, on the safe and appropriate prescribing, dispensing and use of opioids at www.caresalliance.org.

Mallinckrodt is committed to ensuring that patients have access to medications that adequately control their pain. If a patient cannot afford their EXALGO prescription, Mallinckrodt may be able to help. More information about the Patient Assistance Program is available by calling 1-800-259-7765. Some rules and restrictions may apply.

Beyond the Patient Assistance Program, Mallinckrodt also offers EXALGO Co-Pay Cards to certain eligible patients. Those eligible patients can show their Co-Pay Card to their pharmacist and save every time they fill their prescription for EXALGO. If a patient did not receive a Co-Pay Card enrollment form from their physician, they can access one by visiting http://www.exalgo.com/patient/exalgo-co-pay-card.aspx.

IMPORTANT RISK INFORMATION

INDICATION

EXALGO® (hydromorphone HCI) Extended-Release Tablets (CII) is indicated for the management of moderate to severe pain in opioid tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time.

IMPORTANT RISK INFORMATION

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION,

and ACCIDENTAL EXPOSURE

Abuse Potential

EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit. Assess each patient’s risk for opioid abuse or addiction prior to prescribing EXALGO. 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 (e.g., major depressive disorder). Routinely monitor all patients receiving EXALGO for signs of misuse, abuse, and addiction during treatment.

Life-threatening Respiratory Depression

Respiratory depression, including fatal cases, may occur with use of EXALGO, even when the drug has been used as recommended and not misused or abused. EXALGO is for use in opioid tolerant patients only. Proper dosing and titration are essential and EXALGO should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of EXALGO or following a dose increase. Crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of hydromorphone.

Accidental Exposure

Accidental ingestion of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

• EXALGO is contraindicated in: • Opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.

• Patients with significant respiratory depression

• Patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

• Patients with known or suspected paralytic ileus

• Patients who have had surgical procedures and/or underlying disease resulting in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction

• Patients with hypersensitivity (e.g., anaphylaxis) to hydromorphone or sulfite-containing medications

• EXALGO is indicated for opioid tolerant patients only. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer.

• EXALGO is not intended for use as an as-needed analgesic and is not indicated for the management of acute or postoperative pain. It is contraindicated in patients who need management of mild pain or pain not expected to persist.

• Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death.

EXALGO may impair the ability to drive a car or operate machinery.

• Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO. • Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insufficiency, Addison’s disease, delirium tremens, myxedema or hypothyroidism, prostatic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings. Consider use of an alternate analgesic in patients with severe renal impairment.

• Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO.

• Serious adverse events could also include hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal. Most common adverse events (>10%) seen in clinical studies (N=2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness.

• Use EXALGO with extreme caution in patients susceptible to intracranial effects of CO2 retention.

• Do not abruptly discontinue EXALGO.

See Full Prescribing Information and Medication Guide at http://www.imaging.covidien.com/WorkArea/DownloadAsset.aspx?id=2147483728.

OROS is a registered trademark of ALZA Corporation.

About Covidien

Covidien is a leading global healthcare products company that creates innovative medical solutions for better patient outcomes and delivers value through clinical leadership and excellence. Covidien manufactures, distributes and services a diverse range of industry-leading product lines in three segments: Medical Devices, Pharmaceuticals and Medical Supplies. With 2011 revenue of $11.6 billion, Covidien has 43,000 employees worldwide in more than 65 countries, and its products are sold in over 140 countries. Please visit www.covidien.com to learn more about our business.

1 American Academy of Pain Medicine (AAPM) Facts and Figures on Pain. American Academy of Pain Medicine website. Retrieved on April 24, 2012 http://www.painmed.org/patient/facts.html.

2 Peter D. Hart Research Associates. (2003). Americans in Pain: A SURVEY AMONG ADULTS NATIONWIDE CONDUCTED FOR RESEARCH!AMERICA. Retrieved on May 15, 2012 from http://www.researchamerica.org/uploads/poll2003pain.pdf.

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