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Mallinckrodt Pharmaceuticals to Present New Clinical Data at American Pain Society Annual Scientific Meeting

XARTEMIS^™ XR (oxycodone hydrochloride and acetaminophen) Extended-Release Tablets (CII) and PENNSAID^® 2% (diclofenac sodium topical solution 2% w/w) Studies Offer Additional Product Information

TAMPA, Fla.--(BUSINESS WIRE)--Apr. 30, 2014-- Mallinckrodt (NYSE: MNK) will present new data for two of its recently approved pain medications – XARTEMIS^™ XR (oxycodone hydrochloride and acetaminophen) Extended-Release Tablets (CII) and PENNSAID^® 2% (diclofenac sodium topical solution) 2% w/w (PENNSAID 2%) – during the 33rd Annual Scientific Meeting of the American Pain Society (APS) to be held April 30 - May 3, 2014 in Tampa, Florida.

XARTEMIS XR is an oral medication indicated for the management of acute pain severe enough to require opioid treatment in patients for whom alternative treatment options (e.g., non-opioid analgesics) are ineffective, not tolerated or would otherwise be inadequate. It is the first and only oxycodone HCI/acetaminophen combination for acute pain with immediate- and extended-release analgesia, providing fast-acting and long-lasting pain relief with 12-hour dosing for patients. PENNSAID 2% is a topical non-steroidal anti-inflammatory drug (NSAID) approved for the treatment of the pain of osteoarthritis of the knee(s).

The data to be presented on XARTEMIS XR evaluates pharmacokinetics in different populations, as well as pooled safety data from Phase III trials. The first presentation of pivotal efficacy and safety results for PENNSAID 2% in the treatment of pain for osteoarthritis of the knee will also be presented, as well as an assessment of pharmacokinetics and tolerability compared with the 1.5% PENNSAID formulation.

“Mallinckrodt is committed to providing a diverse range of products for patients with different types of pain,” said Mark Trudeau, President and Chief Executive Officer of Mallinckrodt. “The data we are sharing at APS will help further educate physicians about the characteristics and use of our two most recently launched products, XARTEMIS XR and PENNSAID 2%.”

The abstracts to be presented are:

XARTEMIS XR data

• Single-Dose Population Pharmacokinetics of MNK-795 (Oxycodone and Acetaminophen Extended-Release Tablets) Under Fed and Fasted Conditions (Abstract 426)
• Population Pharmacokinetics of Oxycodone Following a Single Oral Dose of MNK-795 (Oxycodone and Acetaminophen Extended-Release Tablets) (Abstract 436)
• Population Pharmacokinetics of Acetaminophen Following a Single Oral Dose of MNK-795 (Oxycodone and Acetaminophen Extended-Release Tablets) (Abstract 434)
• Population Pharmacokinetics of Oxycodone Following Multiple Oral Doses of MNK-795 (Oxycodone and Acetaminophen Extended-Release Tablets) (Abstract 433)
• Variability in the Pharmacokinetics of Acetaminophen Following Multiple Dose Administration of MNK-795 (Oxycodone and Acetaminophen Extended-Release Tablets) Is Affected by Covariates (Abstract 416)
• Safety and Tolerability of MNK-795 (Oxycodone and Acetaminophen Extended-Release Tablets) in Phase III Clinical Trials (Abstract 424)

PENNSAID 2% data

• A Comparison of the Pharmacokinetics and Tolerability of Diclofenac Sodium 2% and 1.5% Topical Solutions (Abstract 485)
• An Assessment of the Efficacy and Tolerability of Diclofenac Sodium 2% Topical Solution for Treating Osteoarthritis of the Knee (Abstract 484)

PENNSAID 2% Pivotal Trial Results

The pivotal data presented at APS supported the January 17, 2014 U.S. Food and Drug Administration approval of PENNSAID 2%. This double-blind, randomized, controlled, parallel-group study assessed the efficacy and tolerability of twice-daily PENNSAID 2% topical solution vs. vehicle in 259 patients with primary osteoarthritis of the knee. After four weeks, PENNSAID 2% produced significantly greater improvements in pain reduction – as measured by reductions in WOMAC^® (Western Ontario and McMaster University Osteoarthritis Index) pain scores (-4.4 [0.4]) vs. (-3.4 [0.4]; P=0.040) – associated with osteoarthritis of the knee compared to vehicle control.

Similar results were observed for secondary endpoints including WOMAC physical function (-13.9 [1.2] vs. -10.7 [1.3]; P=0.061) and stiffness (-1.7 [0.2] vs. -1.3 [0.2]; P=0.097) as well as patient global assessment of osteoarthritis status (-1.1 [0.1] vs. -0.8 [0.1]; P=0.085). None of these measures were statistically significant however. PENNSAID 2% was generally well tolerated. The vehicle control group experienced slightly more adverse events than active treatment (38.8% vs. 31.5%), which primarily involved application site reactions.

About WOMAC^®

WOMAC^® is a registered trademark of Nicholas Bellamy. WOMAC is a proprietary health status questionnaire. For further information visit the WOMAC website at www.WOMAC.com.

XARTEMIS^™ XR (oxycodone HCl and acetaminophen) Extended-Release Tablets, for oral use, CII

INDICATIONS AND USAGE

XARTEMIS^™ XR (oxycodone HCl and acetaminophen) Extended-Release Tablets (CII) is indicated for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options are inadequate. Because of the risks of addiction, abuse, misuse, overdose, and death with opioids, even at recommended doses, reserve XARTEMIS XR for use in patients for whom alternative treatment options (e.g., non-opioid analgesics) are ineffective, not tolerated or would be otherwise inadequate.

IMPORTANT RISK INFORMATION

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and HEPATOTOXICITY

Addiction, Abuse, and Misuse

XARTEMIS XR exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing XARTEMIS XR, and monitor all patients regularly for the development of these behaviors or conditions.

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of XARTEMIS XR. Monitor for respiratory depression, especially during initiation of XARTEMIS XR or following a dose increase. Instruct patients to swallow XARTEMIS XR tablets whole; crushing, chewing, or dissolving XARTEMIS XR can cause rapid release and absorption of a potentially fatal dose of oxycodone.

Accidental Exposure

Accidental ingestion of XARTEMIS XR, especially in children, can result in a fatal overdose of oxycodone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of XARTEMIS XR during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Hepatotoxicity

XARTEMIS XR contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limit, and often involve more than one acetaminophen-containing product.

CONTRAINDICATIONS

• XARTEMIS XR is contraindicated in patients with:
  • known hypersensitivity to oxycodone, acetaminophen, or any other component of this product.
  • significant respiratory depression.
  • acute or severe bronchial asthma or hypercarbia.
  • known or suspected paralytic ileus.

WARNINGS AND PRECAUTIONS

• XARTEMIS XR contains oxycodone, a Schedule II controlled substance. As an opioid, XARTEMIS XR exposes users to the risks of addiction, abuse, and misuse. Abuse or misuse of XARTEMIS XR by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the oxycodone and can result in overdose and death. With intravenous abuse, the inactive ingredients in XARTEMIS XR can result in death, local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
• Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of XARTEMIS XR, the risk is greatest during the initiation of therapy or following a dose increase. Life-threatening 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. In patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, XARTEMIS XR may decrease respiratory drive to the point of apnea.
• Hypotension, profound sedation, coma, respiratory depression, and death may result if XARTEMIS XR is used concomitantly with alcohol or other central nervous system (CNS) depressants.
• The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.
• Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.
• The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure.
• Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines.
• Due to the potential for acetaminophen hepatotoxicity at doses higher than 4,000 milligrams/day, XARTEMIS XR should not be used concomitantly with other acetaminophen- containing products.
• Hypersensitivity and anaphylaxis associated with use of acetaminophen have been reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting.
• Due to characteristics of the formulation that cause the tablets to swell and become sticky when wet, consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen. Instruct patients not to pre-soak, lick or otherwise wet XARTEMIS XR tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in mouth.
• Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Oxycodone may cause spasm of the Sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.
• Since the CYP3A4 isoenzyme plays a major role in the metabolism of XARTEMIS XR, drugs that alter CYP3A4 activity may cause changes in clearance of oxycodone which could lead to changes in oxycodone plasma concentrations.
• XARTEMIS XR may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.

ADVERSE REACTIONS

• Serious adverse events may include respiratory depression and hepatotoxicity.
• Common adverse events include nausea, dizziness, headache, vomiting, constipation and somnolence.

USE IN SPECIFIC POPULATIONS

• Pregnancy: Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Prolonged use of XARTEMIS XR during pregnancy can result in withdrawal signs in the neonate, which can be life threatening.
• Breast feeding: Oxycodone is present in human milk and may result in accumulation and toxicities such as sedation and respiratory depression in some infants. Acetaminophen is present in human milk in small quantities.
• Pediatrics: Safety and effectiveness in pediatric patients under the age of 18 years have not been established.

See Full Prescribing Information for additional Important Risk Information including boxed warning.

About XARTEMIS XR

XARTEMIS XR is an extended-release oral formulation of oxycodone hydrochloride and acetaminophen with immediate-release and extended-release components. It is not interchangeable with other oxycodone/acetaminophen products because of differing pharmacokinetic profiles that affect the frequency of administration. XARTEMIS XR is a schedule II controlled substance.

PENNSAID^® (diclofenac sodium topical solution) 2% w/w

INDICATIONS AND USAGE

PENNSAID^® (diclofenac sodium topical solution) 2% w/w is a nonsteroidal anti-inflammatory drug (NSAID) indicated for the treatment of pain of osteoarthritis of the knee(s).

IMPORTANT RISK INFORMATION

WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISK

Cardiovascular Risk

• Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
• PENNSAID is contraindicated in the perioperative setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Risk

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.

CONTRAINDICATIONS

• PENNSAID is also contraindicated in patients:
  • with a known hypersensitivity to diclofenac sodium or any other component of PENNSAID.
  • who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal anaphylactic-like reactions to NSAIDs have been reported in such patients.

WARNINGS AND PRECAUTIONS

• Elevation of one or more liver tests may occur during therapy with NSAIDs. PENNSAID should be discontinued immediately if abnormal liver tests persist or worsen.
• Use with caution in patients with fluid retention or heart failure. Hypertension can occur with NSAID treatment. Monitor blood pressure closely with PENNSAID treatment.
• Long-term administration of NSAIDs can result in renal papillary necrosis and other renal injury. Use PENNSAID with caution in patients at greatest risk of this reaction, including the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics and ACE-inhibitors.
• Anaphylactoid reactions may occur in patients without prior exposure to PENNSAID. NSAIDs can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.
• Wash and dry hands before and after use. Avoid contact of PENNSAID with the eyes and mucous membranes.
• PENNSAID was not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise; therefore, concurrent use of PENNSAID under these conditions is not recommended.
• Do not:
  • apply PENNSAID to open wounds.
  • shower for at least 30 minutes after applying PENNSAID.
  • wear clothing over the PENNSAID treated knee until the treated knee is dry.
• Protect treated knee(s) from natural or artificial sunlight. Topicals, such as sunscreen and bug repellent, may be applied after PENNSAID treated knee(s) are completely dry.
• Concurrent use with oral NSAIDs should be avoided unless benefit outweighs risk and periodic laboratory evaluations are conducted.

ADVERSE REACTIONS

• The most common adverse events in a phase 2 clinical trial of PENNSAID 2% were application site reactions, such as dryness (22%), exfoliation (7%), erythema (4%), pruritus (2%), pain (2%), induration (2%), rash (2%), and scabbing (<1%). Other adverse reactions occurring in >1% of patients receiving PENNSAID 2% included urinary tract infection (3%), contusion (2%), sinus congestion (2%), and nausea (2%).
• The most common treatment-related adverse events in patients receiving PENNSAID 1.5% were application site skin reactions including dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In a long term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%. Other common adverse events greater than placebo include: dyspepsia (9%), abdominal pain (6%), flatulence (4%), diarrhea (4%) and nausea (4%).

USE IN SPECIFIC POPULATIONS

• PENNSAID should not be used in pregnant or lactating women and is not approved for use in pediatric patients.

See Full Prescribing Information for additional Important Risk Information including boxed warning.

About PENNSAID 2%

PENNSAID is a registered trademark of Nuvo Research Inc. PENNSAID 2% is a follow-on product to original PENNSAID 1.5%. PENNSAID 2% is a topical non-steroidal anti-inflammatory drug (NSAID) containing 2% diclofenac sodium compared to 1.5% for original PENNSAID 1.5%. It is more viscous than original PENNSAID 1.5%, is supplied in a metered dose pump bottle and has been approved for twice daily dosing compared to four times a day for original PENNSAID 1.5%.

About Mallinckrodt

Mallinckrodt is a global specialty pharmaceutical and medical imaging business that develops, manufactures, markets and distributes specialty pharmaceutical products and medical imaging agents. The company’s core strengths include the acquisition and management of highly regulated raw materials; deep regulatory expertise; and specialized chemistry, formulation and manufacturing capabilities. The company’s Specialty Pharmaceuticals segment includes branded and specialty generic drugs and active pharmaceutical ingredients, and the Global Medical Imaging segment includes contrast media and nuclear imaging agents. Mallinckrodt has approximately 5,500 employees worldwide and a commercial presence in roughly 65 countries. The company’s fiscal 2013 revenue totaled $2.2 billion. To learn more about Mallinckrodt, visit www.mallinckrodt.com.

FORWARD-LOOKING STATEMENTS

Any statements contained in this communication that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include, but are not limited to, statements about future financial condition and operating results, economic, business, competitive and/or regulatory factors affecting our business. Any forward-looking statements contained herein are based on our management's current beliefs and expectations, but are subject to a number of risks, uncertainties and changes in circumstances, which may cause actual results or company actions to differ materially from what is expressed or implied by these statements. The factors that could cause actual future results to differ materially from current expectations include, but are not limited to, our ability to receive procurement and production quotas granted by the U.S. Drug Enforcement Administration, our ability to obtain and/or timely transport molybdenum-99 to our technetium-99m generator production facilities, customer concentration, cost-containment efforts of customers, purchasing groups, third-party payors and governmental organizations, our ability to successfully develop or commercialize new products, our ability to protect intellectual property rights, competition, our ability to integrate acquisitions of technology, products and businesses, product liability losses and other litigation liability, the reimbursement practices of a small number of large public or private issuers, complex reporting and payment obligation under healthcare rebate programs, changes in laws and regulations, conducting business internationally, foreign exchange rates, material health, safety and environmental liabilities, litigation and violations, information technology infrastructure and restructuring activities. These and other factors are identified and described in more detail in the “Risk Factors” section of Mallinckrodt’s Annual Report on Form 10-K for the fiscal year ended September 27, 2013 and in subsequent filings. We disclaim any obligation to update these forward-looking statements other than as required by law.

Source: Mallinckrodt

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