ST. LOUIS--(BUSINESS WIRE)--Mallinckrodt (NYSE: MNK) today announced that clinical data for its investigational opioid, MNK-155 (hydrocodone bitartrate and acetaminophen) and approved opioid combination product XARTEMIS™ XR (oxycodone hydrochloride and acetaminophen) Extended-Release Tablets (CII) will be presented at PAINWeek 2014, a national conference on pain for frontline practitioners, September 2-6, in Las Vegas, Nevada.
MNK-155 is an investigational extended-release oral formulation of hydrocodone and acetaminophen being studied for the management of moderate to moderately severe acute pain where the use of an opioid analgesic is appropriate. MNK-155 is formulated with both immediate- and extended-release components. The NDA for MNK-155 was accepted for review by the U.S. Food and Drug Administration (FDA) in May 2014.
XARTEMIS XR, approved by the FDA in March 2014, is the first and only immediate- and extended-release oral combination of two clinically proven pain medications -- oxycodone and acetaminophen. It is indicated for the management of acute pain severe enough to require opioid treatment and for which alternative treatment options (e.g., non-opioid analgesics) are ineffective, not tolerated or would otherwise be inadequate. XARTEMIS XR is formulated with both immediate- and extended-release components to provide onset of pain relief in less than one hour and to allow twice daily dosing. Other than XARTEMIS XR, currently available commonly used oral acute pain options containing an opioid are dosed every 4 to 6 hours.
XARTEMIS XR research presented at the meeting includes pooled safety data from Phase 3 clinical trials and describes the pharmacokinetics in various populations and the potential impact on dosing for clinical practice. Clinical data for MNK-155 include results from a Human Abuse Liability (HAL) study to evaluate the extent to which MNK-155 intact or crushed versus immediate-release hydrocodone-acetaminophen produce certain subjective effects that have been associated with drug abuse in recreational opioid users, such as drug-liking, high, and good drug effects. Efficacy, safety and pharmacokinetic study results will also be presented.
“Since acute pain can have a profound impact on a person’s life, opioid combination treatments dosed every four to six hours may pose difficulties for some patients, such as the sleep disruption that can be caused by a 4-6 hour dosing interval. That is why Mallinckrodt is committed to developing and providing patients and physicians with longer-lasting treatment options,” said Mark Trudeau, President and CEO of Mallinckrodt. “The data we are presenting at PAINWeek will help clinicians gain insight into the efficacy, pharmacokinetics, release characteristics and implications of the drug-delivery technology for these extended-release opioid combinations.”
Research to be presented at the meeting for MNK-155 and XARTEMIS XR is as follows:
- Comparison of Subjective Drug Effects of Orally Administered MNK-155 Extended-Release Hydrocodone Bitartrate/Acetaminophen (HB/APAP ER) Tablets versus Immediate-Release Hydrocodone Bitartrate/Acetaminophen Tablets in Recreational Users of Prescription Opioids
- Influence of Pharmacokinetic Differences on Pharmacodynamic Measures of Abuse Liability: Comparison of MNK-155 Extended-Release Hydrocodone Bitartrate/Acetaminophen Tablets and Immediate-Release Hydrocodone Bitartrate/Acetaminophen Tablets in Recreational Users of Prescription Opioids
- Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of the Safety and Analgesic Efficacy of MNK-155, Extended-Release hydrocodone Bitartrate/Acetaminophen Tablets, in an Acute Pain Model
- Open-Label Safety of MNK-155, Extended-Release Hydrocodone Bitartrate/Acetaminophen Tablets (HB/APAP ER), in Patients with Osteoarthritis or Chronic Low Back Pain
- Single- and Multiple-Dose Pharmacokinetics of Extended-Release Hydrocodone Bitartrate/Acetaminophen Tablets (MNK-155) With and Without Loading Dose Compared With Marketed Immediate-Release Hydrocodone Bitartrate/Ibuprofen Tablets and Immediate-Release Tramadol HCI/Acetaminophen Tablets
- Single- and Multiple-Dose Pharmacokinetics of 1 and 2 Tablets of Extended-Release Hydrocodone Bitartrate/Acetaminophen (MNK-155) Compared With Immediate-Release Hydrocodone Bitartrate/Acetaminophen
- Single-Dose Pharmacokinetics of 2 or 3 Tablets of Extended-Release Hydrocodone Bitartrate/ Acetaminophen (MNK-155) Under Fed and Fasted Conditions
XARTEMIS XR abstracts
- Safety and Tolerability of Extended-Release Oxycodone/Acetaminophen Tablets in Phase 3 Clinical Trials
- Respiratory Rates and O2 Saturation After Administration of MNK-795 (Oxycodone/Acetaminophen Extended-Release Tablets)
- Population Pharmacokinetics of Oxycodone and Acetaminophen Following Multiple Oral Doses of Extended-Release Oxycodone/Acetaminophen Tablets
- Population Pharmacokinetics of Oxycodone and Acetaminophen Following a Single Oral Dose of Extended-Release Oxycodone/Acetaminophen Tablets
XARTEMIS™ XR (oxycodone HCl and acetaminophen) Extended-Release Tablets, for oral use, CII
INDICATIONS AND USAGE
XARTEMIS TM 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 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.
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.
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 4000 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.
- 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.
Mallinckrodt is a global specialty pharmaceutical and medical imaging business that develops, manufactures, markets and distributes specialty pharmaceutical products and medical imaging agents. Areas of focus include therapeutic drugs for autoimmune and rare disease specialty areas like neurology, rheumatology, nephrology and pulmonology along with analgesics and central nervous system drugs for prescribing by office- and hospital-based physicians. 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 more than 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.
Statements in this document that are not strictly historical, including statements regarding the Questcor acquisition, future financial and operating results, benefits and synergies of the transaction, future opportunities for the combined businesses and any other statements regarding events or developments that we believe or anticipate will or may occur in the future, may be “forward-looking” statements within the meaning of the Private Securities Litigation Reform Act of 1995, and involve a number of risks and uncertainties. There are a number of important factors that could cause actual events to differ materially from those suggested or indicated by such forward-looking statements and you should not place undue reliance on any such forward-looking statements. These factors include risks and uncertainties related to, among other things: general economic conditions and conditions affecting the industries in which Mallinckrodt and Questcor operate; the commercial success of Mallinckrodt’s and Questcor’s products, including H.P. Acthar® Gel (“Acthar”); Mallinckrodt’s and Questcor’s ability to protect intellectual property rights; Mallinckrodt’s ability to successfully integrate Questcor’s operations and employees with Mallinckrodt’s existing business; the ability to realize anticipated growth, synergies and cost savings; Questcor’s performance and maintenance of important business relationships; the lack of patent protection for Acthar, and the possible United States Food and Drug Administration (“FDA”) approval and market introduction of additional competitive products; Questcor’s reliance on Acthar for substantially all of its net sales and profits; Questcor’s ability to continue to generate revenue from sales of Acthar to treat on-label indications associated with nephrotic syndrome, multiple sclerosis, infantile spasms or rheumatology-related conditions, and Questcor’s ability to develop other therapeutic uses for Acthar; volatility in Questcor’s Acthar shipments, estimated channel inventory, and end-user demand; an increase in the proportion of Questcor’s Acthar unit sales comprised of Medicaid-eligible patients and government entities; Questcor’s research and development risks, including risks associated with Questcor’s work in the areas of nephrotic syndrome and lupus, and Questcor’s efforts to develop and obtain FDA approval of Synacthen™ Depot; Mallinckrodt’s ability to receive procurement and production quotas granted by the U.S. Drug Enforcement Administration; Mallinckrodt’s ability to obtain and/or timely transport molybdenum-99 to its technetium-99m generator production facilities; customer concentration; cost containment efforts of customers, purchasing groups, third-party payors and governmental organizations; Mallinckrodt’s ability to successfully develop or commercialize new products; competition; Mallinckrodt’s ability to achieve anticipated benefits of price increases; Mallinckrodt’s ability to integrate acquisitions of technology, products and businesses generally; product liability losses and other litigation liability; the reimbursement practices of a small number of large public or private issuers; complex reporting and payment obligations 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. Additional information regarding the factors that may cause actual results to differ materially from these forward looking statements is available in (i) Mallinckrodt’s SEC filings, including its Annual Report on Form 10-K for the fiscal year ended September 27, 2013 and its Quarterly Reports on Form 10-Q for the quarterly periods ended December 27, 2013, March 28, 2014 and June 27, 2014; (ii) the SEC filings of Cadence Pharmaceuticals, Inc., which was acquired by Mallinckrodt on March 19, 2014, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2013; and (iii) Questcor’s SEC filings, including its Annual Report on Form 10-K for the year ended December 31, 2013 (and the amendment thereto on Form 10-K/A), its Quarterly Reports on Form 10-Q for the quarterly periods ended March 31, 2014 and June 30, 2014, and its Current Report on Form 8-K filed with the SEC on July 10, 2014. The forward-looking statements made herein speak only as of the date hereof and none of Mallinckrodt, Questcor or any of their respective affiliates assumes any obligation to update or revise any forward-looking statement, whether as a result of new information, future events and developments or otherwise, except as required by law.