Included as part of the PRECAUTIONS section.
XARTEMIS XR is not interchangeable with other
oxycodone/acetaminophen products because of differing pharmacokinetic profiles
that affect the frequency of administration.
Addiction, Abuse, And Misuse
XARTEMIS XR contains oxycodone, a Schedule II controlled
substance. As an opioid, XARTEMIS XR exposes users to the risks of addiction,
abuse, and misuse [see Drug Abuse and Dependence]. Although the risk of
addiction in any individual is unknown, it can occur in patients appropriately
prescribed XARTEMIS XR and in those who obtain the drug illicitly. Addiction
can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse,
or misuse prior to prescribing XARTEMIS XR, and monitor all patients receiving
XARTEMIS XR for the development of these behaviors or conditions. Risks are
increased in patients with a personal or family history of substance abuse (including
drug or alcohol addiction or abuse) or mental illness (e.g., major depression).
The potential for these risks should not, however, prevent the prescribing of
XARTEMIS XR for the proper management of pain in any given patient. Patients at
increased risk may be prescribed modifiedrelease opioid formulations such as
XARTEMIS XR, but use in such patients necessitates intensive counseling about
the risks and proper use of XARTEMIS XR along with intensive monitoring for
signs 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 [see
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory
depression has been reported with the use of opioids, even when used as
recommended. Respiratory depression from opioid use, if not immediately recognized
and treated, may lead to respiratory arrest and death. Management of
respiratory depression may include close observation, supportive measures, and
use of opioid antagonists, depending on the patient's clinical status [see
OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory
depression can exacerbate the sedating effects of opioids.
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. Closely
monitor patients for respiratory depression when initiating therapy with
XARTEMIS XR and following dose increases.
To reduce the risk of respiratory depression, proper dosing
and titration of XARTEMIS XR are essential [see DOSAGE AND ADMINISTRATION].
Overestimating the XARTEMIS XR dose when converting patients from another
opioid product can result in fatal overdose with the first dose.
Accidental consumption of XARTEMIS XR, especially by
children, can result in respiratory depression and death due to an overdose of
Neonatal Opioid Withdrawal Syndrome
Prolonged use of XARTEMIS XR during pregnancy can result
in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike
opioid withdrawal syndrome in adults, may be lifethreatening 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.
Neonatal opioid withdrawal syndrome presents as
irritability, hyperactivity and abnormal sleep pattern, high pitched cry,
tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and
severity of neonatal opioid withdrawal syndrome vary based on the specific
opioid used, duration of use, timing and amount of last maternal use, and rate
of elimination of the drug by the newborn.
Interactions With Central Nervous System Depressants
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 (e.g., sedatives,
anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of XARTEMIS XR in a patient
taking a CNS depressant, assess the duration use of the CNS depressant and the
patient's response, including the degree of tolerance that has developed to CNS
depression. Additionally, evaluate the patient's use of alcohol or illicit
drugs that cause CNS depression. If the decision to begin XARTEMIS XR is made,
start with XARTEMIS XR 1 tablet every 12 hours, monitor patients for signs of
sedation and respiratory depression, and consider using a lower dose of the
concomitant CNS depressant [see DRUG INTERACTIONS].
Elderly, Cachectic, And Debilitated Patients
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.
Monitor such patients closely, particularly when initiating and titrating XARTEMIS
XR and when XARTEMIS XR is given concomitantly with other drugs that depress respiration
[see Life-threatening Respiratory Depression].
Use In Patients With Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and patients having a substantially
decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory
depression for respiratory depression, particularly when initiating therapy and
titrating with XARTEMIS XR, as in these patients, even usual therapeutic doses
of XARTEMIS XR may decrease respiratory drive to the point of apnea [see Life-threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in
these patients if possible.
XARTEMIS XR contains oxycodone and 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 4000 milligrams per day, and
often involve more than one acetaminophen-containing product. The excessive
intake of acetaminophen may be intentional to cause self-harm or unintentional
as patients attempt to obtain more pain relief or unknowingly take other
acetaminophen-containing products. The typical daily acetaminophen contribution
from XARTEMIS XR is 1300 mg.
The risk of acute liver failure is higher in individuals
with underlying liver disease and in individuals who ingest alcohol while
Instruct patients to look for acetaminophen or APAP on
package labels and not to use more than one product that contains
acetaminophen. Instruct patients to seek medical attention immediately upon ingestion
of more than 4000 milligrams of acetaminophen per day, even if they feel well.
Serious Skin Reactions
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.
Inform patients about the signs of serious skin reactions, and use of the drug
should be discontinued at the first appearance of skin rash or any other sign
Head Injury And Increased Intracranial Pressure
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. Furthermore, narcotics produce adverse
reactions which may obscure the clinical course of patients with head injuries.
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. Administer XARTEMIS XR with caution
to patients in circulatory shock, since vasodilation produced by the drug may
further reduce cardiac output and blood pressure. XARTEMIS XR may produce orthostatic
hypotension in ambulatory patients [see DRUG INTERACTIONS].
Use With Other Acetaminophen-containing Products
The typical daily acetaminophen-contribution from
XARTEMIS XR is 1300 mg. 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.
There have been post-marketing reports of
hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical
signs included swelling of the face, mouth, and throat, respiratory distress, urticaria,
rash, pruritus, and vomiting. There were infrequent reports of life-threatening
anaphylaxis requiring emergency medical attention. Instruct patients to
discontinue XARTEMIS XR immediately and seek medical care if they experience
these symptoms. Do not prescribe XARTEMIS XR for patients with acetaminophen
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 presoak, 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.
XARTEMIS XR is contraindicated in patients with known or
suspected paralytic ileus. Opioids diminish propulsive peristaltic waves in the
gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel
motility in post-operative patients receiving opioids. The administration of XARTEMIS
XR may obscure the diagnosis or clinical course in patients with acute
abdominal conditions. Oxycodone may cause spasm of the Sphincter of Oddi.
Monitor patients with biliary tract disease, including acute pancreatitis.
Cytochrome P450 3A4 Inhibitors And Inducers
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
Inhibition of CYP3A4 activity by its inhibitors, such as
macrolide antibiotics (e.g., erythromycin), azoleantifungal agents (e.g.,
ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations
of oxycodone and prolong opioid effects. These effects could be more pronounced
with concomitant use of CYP 2D6 and 3A4 inhibitors.
Cytochrome P450 inducers, such as rifampin,
carbamazepine, and phenytoin, may induce the metabolism of oxycodone and,
therefore, may cause increased clearance of the drug which could lead to a
decrease in oxycodone plasma concentrations, resulting in a potential lack of
If co-administration is necessary, caution is advised
when initiating XARTEMIS XR treatment in patients currently taking, or
discontinuing CYP3A4 inhibitors or inducers. Evaluate these patients at frequent
intervals and consider dose adjustments until stable drug effects are achieved [see
Driving And Operating Machinery
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
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Provide the following information to patients receiving
XARTEMIS XR or their caregivers:
Inform patients that XARTEMIS XR is not interchangeable
with other forms of oxycodone/acetaminophen.
Inform patients XARTEMIS XR is a narcotic pain reliever
and must be taken only as directed.
Inform patients to take each tablet with enough water to
ensure complete swallowing immediately after placing in the mouth, and not to
pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth.
Inform patients that XARTEMIS XR tablets must be
swallowed whole. Do not crush or dissolve. Do not use XARTEMIS XR for
administration via nasogastric, gastric, or other feeding tubes as it may cause
obstruction of feeding tubes.
Inform patients that if they miss a dose to take it as
soon as possible. If it is almost time for the next dose, skip the missed dose
and take the next dose at the regularly scheduled time. Do not take more than 2
tablets at once unless instructed by their healthcare provider. If they are not
sure about their dosing, call their healthcare provider.
Inform patients not to adjust the dose of XARTEMIS XR
without consulting with a physician or other healthcare professional.
Inform patients not to not take more than 4000 milligrams
of acetaminophen per day and to call their doctor if they took more than the
Addiction, Abuse, And Misuse
Inform patients that the use of XARTEMIS XR, even when
taken as recommended, can result in addiction, abuse, and misuse, which can
lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct
patients not to share XARTEMIS XR with others and to take steps to protect XARTEMIS
XR from theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening
respiratory depression, including information that the risk is greatest when
starting XARTEMIS XR or when the dose is increased, and that it can occur even
at recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how
to recognize respiratory depression and to seek medical attention if breathing
Inform patients that accidental exposure, especially in
children, may result in respiratory depression or death [see WARNINGS AND
PRECAUTIONS]. Instruct patients to take steps to store XARTEMIS XR securely
and to dispose of unused XARTEMIS XR by flushing the tablets down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
prolonged use of XARTEMIS XR during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and
treated [see WARNINGS AND PRECAUTIONS].
Interactions With Alcohol And Other CNS Depressants
Inform patients that potentially serious additive effects
may occur if XARTEMIS XR is used with alcohol or other CNS depressants, and not
to use such drugs unless supervised by a health care provider.
Impairment Of Mental Or Physical Ability
Inform patients that XARTEMIS XR may cause drowsiness,
dizziness, or lightheadedness and may impair mental and/or physical ability
required for the performance of potentially hazardous tasks (e.g., driving,
operating heavy machinery). Advise patients started on XARTEMIS XR or patients
whose dose has been adjusted to refrain from any potentially dangerous activity
until it is established that they are not adversely affected.
Use During Pregnancy
Instruct females of reproductive potential who become or
are planning to become pregnant to consult a physician prior to initiating or
continuing therapy with XARTEMIS XR. Advise patients that safe use in pregnancy
has not been established.
Information Regarding Nursing
Advise women to not breastfeed as breastfeeding may cause
sedation in the infant.
Cessation Of Therapy
If patients have been receiving treatment with XARTEMIS
XR for more than a few weeks and cessation of therapy is indicated, counsel
them on the possibility of withdrawal and provide medical support for safe
discontinuation of the product.
Common Side Effects
Advise patients taking XARTEMIS XR of the potential for
severe constipation; appropriate laxatives and/or stool softeners as well as
other appropriate treatments should be initiated from the onset of opioid
Advise patients of the most common adverse reactions that
may occur while taking XARTEMIS XR: nausea, dizziness, headache, vomiting,
constipation and somnolence.
Mallinckrodt, the “M” brand mark, the Mallinckrodt
Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity, mutagenicity, or fertility studies
were conducted with the combination of oxycodone and APAP, the components of
XARTEMIS XR. The following data are based on findings from studies performed
with the individual components.
No animal studies to evaluate the carcinogenic potential
of oxycodone have been conducted. Longterm studies in mice and rats have been
completed by the National Toxicology Program to evaluate the carcinogenic
potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice
were fed a diet containing acetaminophen up to 6000 ppm. Female rats
demonstrated equivocal evidence of carcinogenic activity based on increased
incidences of mononuclear cell leukemia at 0.8 times the maximum human daily
dose (MHDD) of 4 grams/day, based on a body surface area comparison. In
contrast, there was no evidence of carcinogenic activity in male rats that
received up to 0.7 times or mice at up to 1.2-1.4 times the MHDD, on a body
surface area comparison.
Oxycodone hydrochloride was genotoxic in an In vitro
mouse lymphoma assay in the presence of metabolic activation. There was no
evidence of genotoxic potential in an In vitro bacterial reverse mutation assay
(Salmonella typhimurium and Escherichia coli) or in an assay for
chromosomal aberrations (In vivo mouse bone marrow micronucleus assay).
Acetaminophen was not mutagenic in the bacterial reverse
mutation assay (Ames test). In contrast, acetaminophen tested positive for
induction of sister chromatid exchanges and chromosomal aberrations in In vitro
assays using Chinese hamster ovary cells. In the published literature, acetaminophen
has been reported to be clastogenic when administered a dose of 1500 mg/kg/day
to the rat model (3.6-times the MHDD, based on a body surface area comparison).
In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times
the MHDD, based on a body surface area comparison), suggesting a threshold
Impairment Of Fertility
No animal studies to evaluate the effect of oxycodone on
male or female fertility have been conducted.
In studies conducted by the National Toxicology Program,
fertility assessments have been completed in Swiss CD-1 mice via a continuous
breeding study. There were no effects on fertility parameters in mice consuming
up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison.
Although there was no effect on sperm motility or sperm density in the
epididymis, there was a significant increase in the percentage of abnormal
sperm in mice consuming 1.7 times the MHDD (based on a body surface area
comparison) and there was a reduction in the number of mating pairs producing a
fifth litter at this dose, suggesting the potential for cumulative toxicity with
chronic administration of acetaminophen near the upper limit of daily dosing.
Published studies in rodents report that oral
acetaminophen treatment of male animals at doses that are 1.2 times the MHDD
and greater (based on a body surface area comparison) result in decreased testicular
weights, reduced spermatogenesis, reduced fertility, and reduced implantation
sites in females given the same doses. These effects appear to increase with
the duration of treatment. The clinical significance of these findings is not
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of
XARTEMIS XR tablets or oxycodone/acetaminophen in pregnant women.
Epidemiological data on oral acetaminophen use in pregnant women show no
increased risk of major congenital malformations. The incidence of malformations
in human pregnancies has not been established for oxycodone as the data are
limited. All pregnancies, regardless of drug exposure, have a background risk
of 2 to 4% for major birth defects, and 15 to 20% for pregnancy loss.
No animal reproductive or developmental studies were
conducted with the combination of oxycodone and acetaminophen, the components
of XARTEMIS XR. The following data are based on findings from studies performed
with the individual components. Reproductive and developmental studies in rats
and mice from the published literature identified adverse events at clinically
relevant doses with acetaminophen. Treatment of pregnant rats with doses of
acetaminophen approximately equal to the maximum human daily dose (MHDD) showed
evidence of fetotoxicity and increases in bone variations in the fetuses. In another
study, necrosis was observed in the liver and kidney of both pregnant rats and
fetuses at doses approximately equal to the MHDD. In mice treated with acetaminophen
at doses within the clinical dosing range, a reduction in number of litters of
the parental mating pair was observed as well as retarded growth and abnormal
sperm in their offspring and reduced birth weight in the next generation.
Reproductive studies in rats and rabbits with doses of oxycodone greater than
clinical doses did not show any teratogenic or embryo-fetal toxic effects. XARTEMIS
XR should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Fetal/Neonatal Adverse Reactions
Prolonged maternal use of opioid analgesics during
pregnancy for medical or nonmedical purposes can result in physical dependence
in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as
poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and
manage accordingly [see WARNINGS AND PRECAUTIONS].
Labor And Delivery
Opioids cross the placenta and may produce respiratory
depression and psycho-physiologic effects in neonates. XARTEMIS XR is not
recommended for use in women during or immediately prior to labor. Neonates,
whose mothers received opioid analgesics during labor, must be observed closely
for signs of respiratory depression. An opioid antagonist such as naloxone,
must be available for reversal of opioid-induced respiratory depression in the
Two large population based studies have evaluated the
safety of acetaminophen in pregnant women during the first trimester; neither
study showed an increased risk of congenital malformations. Available published
data on oxycodone exposure during pregnancy and risk for malformations are limited
and do not allow conclusions regarding a possible association.
No reproductive or developmental studies were conducted
with the combination of oxycodone and acetaminophen, the components of XARTEMIS
XR. The following data are based on findings from studies performed with the
Studies in pregnant rats that received oral acetaminophen
during organogenesis at doses up to 0.85 times the maximum human daily dose
(MHDD = 4 grams/day, based on a body surface area comparison) showed evidence
of fetotoxicity (reduced fetal weight and length) and a dose-related increase
in bone variations (reduced ossification and rudimentary rib changes).
Offspring had no evidence of external, visceral, or skeletal malformations.
When pregnant rats received oral acetaminophen throughout gestation at doses of
1.2-times the MHDD (based on a body surface area comparison), areas of necrosis
occurred in both the liver and kidney of pregnant rats and fetuses. These
effects did not occur in animals that received oral acetaminophen at doses
0.3-times the MHDD, based on a body surface area comparison. In a continuous
breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the
diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.43, 0.87,
and 1.7 times the MHDD, respectively, based on a body surface area comparison.
A dose-related reduction in body weights of fourth and fifth litter offspring
of the treated mating pair occurred during lactation and post-weaning at all
doses. Animals in the high dose group had a reduced number of litters per
mating pair, male offspring with an increased percentage of abnormal sperm, and
reduced birth weights in the next generation pups. Reproduction studies in Sprague-Dawley
rats and New Zealand rabbits revealed that when oxycodone was administered orally
at doses up to 16 mg/kg (approximately 2 times the daily oral dose of 90 mg for
adults based on a body surface area comparison) and 25 mg/kg (approximately 5
times the daily oral dose of 90 mg based on body surface area comparison), it
was non teratogenic or embryo-fetal toxic.
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. Based on
data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen
is approximately 1 to 2% of the maternal dose. There is one well-documented
report of a rash in a breast-fed infant that resolved when the mother stopped
acetaminophen use and recurred when she resumed acetaminophen use. Because of
the potential for serious adverse reactions in nursing infants from XARTEMIS
XR, a decision should be made whether to discontinue nursing or discontinue the
drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of XARTEMIS XR in pediatric
patients under the age of 18 years have not been established.
Of the 607 subjects in the Phase 3 studies treated with
XARTEMIS XR, 63 (10.3%) were older than age 65, of which 10 (1.6%) were older
than age 75. No untoward or unexpected adverse reactions were seen in the
elderly patients who received oxycodone hydrochloride/acetaminophen
extendedrelease tablets. However, special precaution should be given when
determining the dosing amount and frequency of XARTEMIS XR for geriatric
patients, since a greater sensitivity to oxycodone may be observed in this
patient population when compared to younger patients.
XARTEMIS XR contains oxycodone and acetaminophen, which
are extensively metabolized in the liver. Their clearance may be decreased in
patients with hepatic impairment. In patients with hepatic impairment start
with one tablet and adjust the dosage as needed. Monitor closely for
respiratory depression [see CLINICAL PHARMACOLOGY].
Information from oxycodone HCl indicates that patients
with renal impairment (defined as a creatinine clearance < 60 mL/min) had
higher plasma concentrations of oxycodone than subjects with normal renal
In patients with renal impairment start with one tablet
and adjust the dosage as needed. Monitor closely for respiratory depression [see