Mallinckrodt plc Receives FDA Approval For XARTEMIS XR (oxycodone hydrochloride and acetaminophen) Extended-Release Tablets (CII)
First and only extended-release oxycodone/acetaminophen medication
approved for acute pain severe enough to require opioid treatment
Built on patented Mallinckrodt formulation platform
DUBLIN--(BUSINESS WIRE)--Mar. 12, 2014--
plc (NYSE: MNK) today announced that the U.S. Food and Drug
Administration (FDA) has approved XARTEMIS™ XR (oxycodone
hydrochloride and acetaminophen) Extended-Release Tablets (CII),
previously known as MNK-795, for the management of acute pain severe
enough to require opioid treatment and in patients for whom alternative
treatment options (e.g., non-opioid analgesics) are ineffective, not
tolerated or would otherwise be inadequate. XARTEMIS XR is the first and
only extended-release oral combination of two clinically proven pain
medications -- oxycodone and acetaminophen.
XARTEMIS XR has both immediate- and extended-release components:
formulated to provide onset of pain relief in less than one hour and to
allow twice daily dosing. The product’s release profile combines
Mallinckrodt’s newly patented technology, including design, formulation,
pharmacokinetic and release characteristics, and Depomed’s advanced
Acuform® drug delivery technology.
The approval is based, in part, on the pivotal Phase 3 efficacy study
conducted in an acute post-surgical pain model. XARTEMIS XR met the
study’s primary endpoint and showed statistically significant
improvement in pain scores compared to placebo from baseline over 48
In addition to the efficacy study, Mallinckrodt conducted extensive lab
testing and a human abuse liability study with XARTEMIS XR. Data from
Mallinckrodt’s studies related to the product were described in 15
scientific presentations at PAINWeek, held September 4-7, 2013. While
the approved label for XARTEMIS XR does not include abuse-deterrent
language, Mallinckrodt will continue working closely with the FDA to
develop more data to characterize abuse-deterrence features of XARTEMIS
XR and other products utilizing this technology platform. The company is
conducting additional studies and will be providing additional data in
the near future.
Pain that is uncontrolled or unmanaged results in ongoing and very
significant costs to U.S. businesses in terms of lost productivity. In
2010, there were over 102 million surgical procedures ordered or
performed at office visits.1 That same year, there were 51
million inpatient surgeries performed.2 The Institute of
Medicine reported in 2011 that 80 percent of patients undergoing surgery
experience postoperative pain. Of these, 88 percent report the pain is
moderate, severe or extreme.3
“Acute pain doesn’t last for only four to six hours, and neither should
its treatment. With the extended-release profile of XARTEMIS XR,
patients may not need to wake in the night to take a dose,” said
Nathaniel Katz, MD, MS, Adjunct Assistant Professor of Anesthesia at
Tufts University School of Medicine. “A long-acting combination
analgesic that can effectively deliver oxycodone and acetaminophen for
acute pain patients experiencing pain throughout the day and night is a
welcome addition to the treatment landscape.”
“The FDA approval of XARTEMIS XR exemplifies Mallinckrodt’s dedication
to developing and providing new treatment options for people with pain,”
said Mark Trudeau, President and Chief Executive Officer of
Mallinckrodt. “Mallinckrodt remains committed to continuing its work to
develop innovative formulations for our product lines to help ensure
access to appropriate pain treatment for the millions of patients
suffering from acute pain, and we will continue to work closely with the
FDA as we engage in further development programs for XARTEMIS XR and
other products utilizing this technology platform.”
Mallinckrodt is dedicated to providing quality medications for treatment
of patients with pain and equally committed to fighting the problems of
opioid misuse and abuse. The company supports a broad range of programs
that encourage and support only appropriate use of pain medications, and
we address diversion and abuse through a multidimensional approach that
includes educational efforts, monitoring for suspicious orders of
controlled substances, drug take-back programs and research into
To support the appropriate use of XARTEMIS XR and other Mallinckrodt
products, the company:
Provides a range of educational resources for patients,
physicians and pharmacists, including education initiatives validated
by measurable outcomes.
Certifies its territory representatives following completion
of robust education and training on all safe use initiatives for
Addresses the safe and environmentally responsible disposal of
unused XARTEMIS XR and other prescription medications through a
unique adsorption technology to render the drugs inactive and unusable.
Maintains a comprehensive anti-diversion program to detect
potential misuse, abuse and diversion of Mallinckrodt products
including XARTEMIS XR.
XARTEMISTM 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
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
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
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,
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
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
Serious adverse events may include respiratory depression and
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
Pediatrics: Safety and effectiveness in pediatric patients under the
age of 18 years have not been established.
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 business that
develops, manufactures, markets and distributes specialty pharmaceutical
products and medical imaging agents. 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 70 countries. The company’s fiscal 2013 revenue totaled $2.2
billion. To learn more about Mallinckrodt, visit www.mallinckrodt.com.
1CDC/NCHS, National Ambulatory Medical Care Survey. Accessed
2CDC, FastStats, accessed 2/25/14: http://www.cdc.gov/nchs/fastats/insurg.htm.
3Relieving Pain in America: A Blueprint for Transforming
Prevention, Care, Education, and Research. Committee on Advancing Pain
Research, Care, and Education; Institute of Medicine. 2011.
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Source: Mallinckrodt plc
Lynn Phillips, 314-654-3263
Senior Vice President, Communications
Vice President, Investor Relations