Ofirmev.com2
Day surgery discharge instructions
For medications containing acetaminophen in adults weighing ≥ 50 kg
During your procedure, you were given OFIRMEV® (acetaminophen) injection 1000 mg (1 g) for pain control
at AM/PM. If you need additional pain medication at home, take as directed by your physican.
(checked below) no sooner than
It is important that you do not exceed the maximum amount of acetaminophen, 4000 mg (4 g), in the
remaining 24 hours.
Total tablets remaining
amount per tablet
(acetaminophen amount)
Tylenol® Regular Strength*(acetaminophen tablets)1
9 tablets (2925 mg)
Tylenol® Extra Strength*(acetaminophen tablets)2
6 tablets (3000 mg)
Tylenol® #3 (30 mg/300 mg)*(codeine and acetaminophen tablets)3
10 tablets (3000 mg)
Norco® (5 mg/325 mg)*(hydrocodone and acetaminophen tablets)4
8 tablets (2600 mg)
Percocet® (5 mg/325 mg)*(oxycodone and acetaminophen tablets)5
9 tablets (2925 mg)
Ultracet® (37.5 mg/325 mg)*(tramadol and acetaminophen tablets)6
8 tablets (2600 mg)
Vicodin® (5 mg/300 mg)
8 tablets (2400 mg)
(hydrocodone and acetaminophen tablets)7
XARTEMISTM XR (7.5 mg/325 mg)
4 tablets (1300 mg)
(oxycodone HCI and acetaminophen tablets)8
* Including generic formulationsThese instructions are designed to serve as a guide and are not meant to be a comprehensive directory of all available acetaminophen-containing products. It is important to review each
product's list of ingredients to determine whether and how much acetaminophen is contained within. Please refer to individual product labels for specific dosing quidelines.
OFIRMEV® (acetaminophen) injection is used to treat pain that is mild to moderately painful,
XARTEMISTM XR (oxycodone HCl and acetaminophen) Extended-Release Tablets (CII) is
and to reduce fever. OFIRMEV is also used with opioid (narcotic) medications to treat more
used to treat pain that is not expected to last a long time but painful enough to need
serious pain.
this type of medicine. XARTEMIS XR is an opioid (narcotic). It has risks of addiction,
IMPORTANT RISK INFORMATION
abuse, misuse, overdose, and death, even when taken at the dose your doctor pre-
scribed. Because of this, XARTEMIS XR should be used only when other medicines don't
WARNING: RISK OF MEDICATION MISTAKES AND LIVER TOXICITY
OFIRMEV contains acetaminophen, which can harm the liver and kill you if you
IMPORTANT RISK INFORMATION
take too much. Your healthcare provider will take care to avoid accidentally
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING BREATHING
giving you too much acetaminophen (overdose). Be sure to tell your doctor
PROBLEMS; ACCIDENTAL USE; WITHDRAWAL SYNDROME IN NEWBORNS; and
about all medications you take because they may also contain acetaminophen.
LIVER TOXICITY
Addiction, Abuse, and Misuse: Addiction, abuse, and misuse of XARTEMIS XR can
lead to overdose and death.
Life-threatening Breathing Problems: XARTEMIS XR can cause severe breathing
problems that can kill you. Crushing, chewing, or dissolving XARTEMIS XR can
cause you to get too much medicine, which can kill you.
Accidental Use: Taking XARTEMIS XR by mistake can cause overdose and death,
especially in children.
Withdrawal Syndrome in Newborns: Taking XARTEMIS XR while pregnant can
cause withdrawal in your newborn baby. It may kill them if they are not treated.
Liver Toxicity: XARTEMIS XR contains acetaminophen, which can harm the liver
and kill you if you take too much.
Please see additional Important Risk Information, including boxed warnings, in accompanying Full Prescribing Information.
References: 1. Regular Strength Tylenol® [Directions for use]. Fort Washington, PA: McNeil Consumer Healthcare LLC; 2012. 2. Extra Strength Tylenol® [Directions for use]. Fort Washington, PA: McNeil Consumer Healthcare LLC; 2012.
3. Tylenol® with Codeine No. 3 [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013. 4. Norco® [package insert]. Corona, CA: Watson Pharma, Inc.; 2011. 5. Percocet® [package insert]. Malvern, PA: Endo Pharmaceuticals; 2013
6. Ultracet® [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013. 7. Vicodin® [package insert]. North Chicago, IL: AbbVie, Inc., 2013. 8. XARTEMISTM XR [package insert]. Hazelwood, MO: Mallinckrodt Pharmaceuticals, 2014.
These instructions are provided as an educational service by Mallinckrodt Pharmaceuticals. All brand names used in this communication are trademarks of their respective owners.
OFIRMEV® (acetaminophen) injection is used to treat pain that is mild to moderately
XARTEMIS™ XR (oxycodone HCl and acetaminophen) Extended-Release Tablets (CII) is
painful, and to reduce fever. OFIRMEV is also used with opioid (narcotic) medications
used to treat pain that is not expected to last a long time but painful enough to need
to treat more serious pain.
this type of medicine. XARTEMIS XR is an opioid (narcotic). It has risks of addiction,
IMPORTANT RISK INFORMATION
abuse, misuse, overdose, and death, even when taken at the dose your doctor
prescribed. Because of this, XARTEMIS XR should be used only when other medicines
DO NOT USE OFIRMEV IF:
You are allergic to acetaminophen or any other ingredient in OFIRMEV.
IMPORTANT RISK INFORMATION
You have serious liver problems or if you currently have serious liver disease.
DO NOT USE XARTEMIS XR IF:
Taking too much acetaminophen can cause liver problems that can kill you. Your
You are allergic to oxycodone, acetaminophen, or any other ingredient.
healthcare provider will take care to avoid accidentally giving you too much
You have severe asthma or other breathing problems.
acetaminophen (overdose). Be sure to tell your doctor about all medications you
You have a bowel blockage.
take because they may also contain acetaminophen. Tell your doctor if you have
serious liver or kidney problems, drink alcohol, are not drinking enough fluids
(dehydrated) or eating enough food (malnourished), or recently lost a lot of
XARTEMIS XR is a controlled substance. It has risks of abuse, misuse, and
addiction like other opioid medicines used for pain. Crushing, chewing, snorting,
or injecting XARTEMIS XR can cause overdose and death. Injecting the inactive
Rarely, acetaminophen can cause serious skin reactions that can kill you.
ingredients in XARTEMIS XR can damage your heart and lungs, which can kill you.
Signs of an allergic reaction to this medicine include swelling of the face, mouth,
Drug abuse by injection can also cause the spread of diseases such as hepatitis
and throat, trouble breathing, rash, and itching.
and HIV (AIDS).
OFIRMEV may hide signs of fever.
XARTEMIS XR can cause severe breathing problems that can kill you, even when
it is used as your doctor prescribed. The risk of severe breathing problems is
Serious side effects may include liver damage, serious skin reactions, and
highest when you first start taking XARTEMIS XR or when your dose is increased.
allergic reactions.
People who are elderly or who already have severe breathing problems have a
higher chance of having severe breathing problems when they take XARTEMIS XR.
Common side effects in adults include nausea, vomiting, headache, and
trouble sleeping. Common side effects in children include nausea, vomiting,
The use of XARTEMIS XR could result in low blood pressure.
constipation, itching, feeling irritated, and lung collapse.
Low blood pressure, excessive sedation, severe breathing problems, and death
USE IN CERTAIN POPULATIONS
can occur if you take XARTEMIS XR with other medicines. These include drugs to
treat anxiety or help you sleep, similar pain medicines, or alcohol.
OFIRMEV passes into breast milk. This may cause your baby to have side effects
from the medication.
Taking too much XARTEMIS XR can cause serious liver problems that can kill you.
The chance of having serious liver problems is higher if you already have liver
OFIRMEV is not approved for children less than 2 years old.
problems or drink alcohol. Do not take over-the-counter medicines that contain
acetaminophen while on XARTEMIS XR.
Rarely, the acetaminophen in XARTEMIS XR can cause serious skin reactions that
can kill you. Stop taking XARTEMIS XR and seek medical help if you get a rash on
XARTEMIS XR may complicate head injuries.
Signs of an allergic reaction to this medicine include swelling of the face,
mouth, and throat, trouble breathing, hives, itching, and throwing up. Stop using
XARTEMIS XR and seek medical help if you get symptoms of an allergic reaction.
Talk to your doctor about other possible treatments if you have trouble
swallowing. Do not lick XARTEMIS XR or get it wet before you take it. Take one
tablet at a time with plenty of water. Swallow right away after you place it in your
Use of certain other medicines with XARTEMIS XR may cause you to have more
or less oxycodone in your body. Tell your doctor and pharmacist about all the
medicines you take.
XARTEMIS XR could affect your ability to drive a car, use machinery, or do other
dangerous tasks.
Serious side effects of XARTEMIS XR are serious breathing problems and liver
Common side effects of XARTEMIS XR are nausea, dizziness, headache, vomiting,
constipation, and tiredness.
USE IN CERTAIN POPULATIONS•
Babies born to mothers who use opioids like XARTEMIS XR could have trouble
breathing and symptoms of withdrawal.
XARTEMIS XR passes into breast milk. It may harm your baby if you breastfeed.
XARTEMIS XR is not approved for children.
To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt Pharmaceuticals, at 1.800.778.7898 or FDA at 1.800.FDA.1088 or www.fda.gov/medwatch.
Please see Important Risk Information, including complete boxed warnings for both OFIRMEV® and XARTEMISTM XR, in accompanying Full Prescribing
Information for both products.
2014 Mallinckrodt.
acetaminophen-containing products including combination FULL PRESCRIBING INFORMATION
Recommended Dosage: Children
Use caution when administering acetaminophen in patients
Treatment-Emergent Adverse Reactions
products) may result in hepatic injury, including the risk of liver
Children 2 to 12 years of age: the recommended dosage of
with the following conditions: hepatic impairment or active
Occurring in ≥ 3% of OFIRMEV-treated Patients
failure and death. (5.1)
WARNING: Risk of Medication Errors and Hepatotoxicity
OFIRMEV is 15 mg/kg every 6 hours or 12.5 mg/kg every
hepatic disease, alcoholism, chronic malnutrition, severe
and at a greater frequency than Placebo in
HIGHLIGHTS OF PRESCRIBING INFORMATION
Do not exceed the maximum recommended daily dose
Take care when prescribing, preparing, and admin-
4 hours, with a maximum single dose of OFIRMEV of 15 mg/kg,
hypovolemia (e.g., due to dehydration or blood loss), or severe
Placebo-Controlled, Repeated Dose Studies
of acetaminophen (by all routes of administration and all
istering OFIRMEV Injection to avoid dosing errors
renal impairment (creatinine clearance ≤ 30 mL/min) [see Use
These highlights do not include all the information needed
a minimum dosing interval of 4 hours, and a maximum daily
System Organ Class – Preferred Term
acetaminophen-containing products including combination
which could result in accidental overdose and death. In
in Specific Populations (8.6, 8.7)].
to use OFIRMEV® safely and effectively. See full prescribing
dose of acetaminophen of 75 mg/kg per day.
information for OFIRMEV.
particular, be careful to ensure that:
Table 2. Dosing for Children
Take care when prescribing, preparing, and administering
• the dose in milligrams (mg) and milliliters (mL) is
Serious Skin Reactions
OFIRMEV (acetaminophen) Injection
OFIRMEV injection to avoid dosing errors which could result in
Age group
Maximum Maximum total
Rarely, acetaminophen may cause serious skin reactions
Initial U.S. Approval: 1951
accidental overdose and death. (5.3)
• the dosing is based on weight for patients under
daily dose of
such as acute generalized exanthematous pustulosis (AGEP),
• Use caution when administering acetaminophen in patients with
Stevens-Johnson Syndrome (SJS), and toxic epidermal
RISK OF MEDICATION ERRORS AND HEPATOTOXICITY
the following conditions: hepatic impairment or active hepatic
• infusion pumps are properly programmed; and
(by all routes)
necrolysis (TEN), which can be fatal. Patients should be
General Disorders and
See full prescribing information for complete boxed warning
disease, in cases of alcoholism, chronic malnutrition, severe
• the total daily dose of acetaminophen from all
12.5 mg/kg 15 mg/kg 15 mg/kg 75 mg/kg in
informed about the signs of serious skin reactions, and use of
Administration Site Conditions
hypovolemia, or severe renal impairment (creatinine clearance
the drug should be discontinued at the first appearance of skin
Take care when prescribing, preparing, and administering
sources does not exceed maximum daily limits.
2 to 12 years
≤ 30 mL/min). (5.1)
rash or any other sign of hypersensitivity.
OFIRMEV Injection to avoid dosing errors which could result
OFIRMEV contains acetaminophen. Acetaminophen
Nervous System Disorders
• Discontinue OFIRMEV immediately at the first appearance of skin
in accidental overdose and death.
has been associated with cases of acute liver failure, at
rash and if symptoms associated with allergy or hypersensitivity
Instructions for Intravenous Administration
Risk of Medication Errors
OFIRMEV contains acetaminophen. Acetaminophen has been
times resulting in liver transplant and death. Most of
occur. Do not use in patients with aceta minophen allergy. (5.2, 5.4)
For adult and adolescent patients weighing ≥ 50 kg Take care when prescribing, preparing, and administering
associated with cases of acute liver failure, at times resulting in
the cases of liver injury are associated with the use of
requiring 1000 mg doses of OFIRMEV, administer the dose
OFIRMEV (acetaminophen) Injection in order to avoid dosing
liver transplant and death. Most of the cases of liver injury are
acetaminophen at doses that exceed the maximum daily
by inserting a vented intravenous set through the septum
errors which could result in accidental overdose and death. In
associated with the use of acetaminophen at doses that exceed
The most common adverse reactions in patients treated with
limits, and often involve more than one acetaminophen-
* Pyrexia adverse reaction frequency data is included in order
of the 100 mL vial. OFIRMEV may be administered without
particular, be careful to ensure that:
the recommended maximum daily limits, and often involve
OFIRMEV were nausea, vomiting, headache, and insomnia in adult
containing product [see Warnings and Precautions (5.1)].
to alert healthcare practitioners that the antipyretic effects of
further dilution. Examine the vial contents before dose
• the dose in milligrams (mg) and milliliters (mL) is not
more than one acetaminophen-containing product (5.1).
patients and nausea, vomiting, constipation, pruritus, agitation, and
OFIRMEV may mask fever.
atelectasis in pediatric patients. (6.1)
preparation or administering. DO NOT USE if particulate
------------------------- INDICATIONS AND USAGE -------------------------
matter or discoloration is observed. Administer the contents
Other Adverse Reactions Observed During Clinical Studies of
To report SUSPECTED ADVERSE REACTIONS, contact 1
INDICATIONS AND USAGE
• the dosing is based on weight for patients under
OFIRMEV (acetaminophen) injection is indicated for the
of the vial intravenously over 15-minutes. Use aseptic
OFIRMEV in Adults
Mallinckrodt Hospital Products Inc. at 1-800-778-7898 or FDA at
OFIRMEV® (acetaminophen) injection is indicated for
• Management of mild to moderate pain (1)
technique when preparing OFIRMEV for intravenous
The following additional treatment-emergent adverse
• infusion pumps are properly programmed; and
• the management of mild to moderate pain
• Management of moderate to severe pain with adjunctive opioid
infusion. Do not add other medications to the OFIRMEV vial
the total daily dose of acetaminophen from all
reactions were reported by adult subjects treated with
• the management of moderate to severe pain with
or infusion device.
sources does not exceed maximum daily limits [see
OFIRMEV in all clinical trials (n=1020) that occurred with
• Substances that induce or regulate hepatic cytochrome enzyme
adjunctive opioid analgesics
• Reduction of fever (1)
Dosage and Administration (2)].
an incidence of at least 1% and at a frequency greater than
CYP2E1 may alter the metabolism of acetaminophen and increase
• the reduction of fever.
For doses less than 1000 mg, the appropriate dose must
--------------------- DOSAGE AND ADMINISTRATION ---------------------
placebo (n=525).
its hepatotoxic potential. (7.1)
be withdrawn from the vial and placed into a separate
Allergy and Hypersensitivity
• OFIRMEV may be given as a single or repeated dose. (2.1)
• Chronic oral acetaminophen use at a dose of 4000 mg/day has
container prior to administration. Using aseptic technique,
Blood and lymphatic system disorders: anemia
DOSAGE AND ADMINISTRATION
There have been post-marketing reports of hypersensitivity
• OFIRMEV should be administered only as a 15-minute intravenous
been shown to cause an increase in international normalized
withdraw the appropriate dose (650 mg or weight-based)
and anaphylaxis associated with the use of acetaminophen.
General disorders and administration site conditions: fatigue,
General Dosing Information
ratio (INR) in some patients who have been stabilized on sodium
from an intact sealed OFIRMEV vial and place the measured
Clinical signs included swelling of the face, mouth, and
infusion site pain, edema peripheral
Adults and Adolescents Weighing 50 kg and Over:
OFIRMEV may be given as a single or repeated dose for the
warfarin as an anticoagulant. (7.2)
dose in a separate empty, sterile container (e.g. glass bottle,
throat, respiratory distress, urticaria, rash, and pruritus. There
Investigations: aspartate aminotransferase increased, breath
• 1000 mg every 6 hours or 650 mg every 4 hours to a maximum of
treatment of acute pain or fever. No dose adjustment is
plastic intravenous container, or syringe) for intravenous
---------------------- USE IN SPECIFIC POPULATIONS ---------------------
were infrequent reports of life-threatening anaphylaxis sounds abnormal
4000 mg per day. Minimum dosing interval of 4 hours. (2.2)
required when converting between oral acetaminophen and
infusion to avoid the inadvertent delivery and administration
• Pregnancy: Category C. There are no studies of intravenous
requiring emergent medical attention. Discontinue OFIRMEV
Adults and Adolescents Weighing Under 50 kg:
OFIRMEV dosing in adults and adolescents who weigh 50 kg
of the total volume of the commercially available container.
Metabolism and nutrition disorders: hypokalemia
acetaminophen in pregnant women. Use only if clearly needed.
immediately if symptoms associated with allergy or
• 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maxi mum
and above. Calculated maximum daily dose of acetaminophen
The entire 100 mL vial of OFIRMEV is not intended for use in
hypersensitivity occur. Do not use OFIRMEV in patients with
Musculoskeletal and connective tissue disorders: muscle
of 75 mg/kg per day. Minimum dosing interval of 4 hours. (2.2)
is based on all routes of administration (i.e., intravenous,
patients weighing less than 50 kg. OFIRMEV is a single-use vial
• Nursing Mothers: Caution should be exercised when admin-
Children:
oral, and rectal) and all products containing acetaminophen.
and the unused portion must be discarded.
istered to a nursing woman. (8.3)
Psychiatric disorders: anxiety
• Children 2 to 12 years of age: 15 mg/kg every 6 hours or
Exceeding the maximum mg/kg daily dose of acetaminophen
• Pediatric Use: The effectiveness of OFIRMEV for the treatment of
Place small volume pediatric doses up to 60 mL in volume in a
12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day.
as described in Tables 1 and 2 may result in hepatic injury,
Respiratory, thoracic and mediastinal disorders: dyspnea
acute pain and fever has not been studied in pediatric patients less
syringe and administer over 15 minutes using a syringe pump.
6 ADVERSE
Minimum dosing interval of 4 hours. (2.3)
including the risk of liver failure and death. To avoid the risk
than 2 years of age. The safety and effectiveness of OFIRMEV in
The following serious adverse reactions are discussed Vascular disorders: hypertension, hypotension
of overdose, ensure that the total amount of acetaminophen
Monitor the end of the infusion in order to prevent the
-------------------- DOSAGE FORMS AND STRENGTHS -------------------
pediatric patients older than 2 years is supported by evidence from
elsewhere in the labeling:
from all routes and from all sources does not exceed the
possibility of an air embolism, especially in cases where the
• Injection for intravenous infusion.
adequate and well controlled studies in adults with additional
maximum recommended dose.
OFIRMEV infusion is the primary infusion.
Hepatic Injury [see Warnings and Precautions (5.1)]
Each 100 mL glass vial contains 1000 mg acetaminophen
A total of 355 pediatric patients (47 neonates, 64 infants,
safety and pharmacokinetic data for this age group. (8.4)
• Serious Skin Reactions [see Warnings and Precautions
Once the vacuum seal of the glass vial has been penetrated, or
171 children, and 73 adolescents) have received OFIRMEV
• Geriatric Use: No overall differences in safety or effectiveness were
Recommended Dosage: Adults and Adolescents
the contents transferred to another container, administer the
in active-controlled (n=250) and open-label clinical trials
observed between geriatric and younger subjects. (8.5)
Adults and adolescents weighing 50 kg and over: the
dose of OFIRMEV within 6 hours.
Allergy and Hypersensitivity [see Warnings and (n=225), including 59.7% (n=212) who received 5 or more
Acetaminophen is contraindicated:
• Hepatic Impairment: OFIRMEV is contraindicated in patients with
recommended dosage of OFIRMEV is 1000 mg every
doses and 43.1% (n=153) who received more than 10 doses.
• In patients with known hypersensitivity to acetaminophen or to
severe hepatic impairment or severe active liver disease and
6 hours or 650 mg every 4 hours, with a maximum single
Do not add other medications to the OFIRMEV solution.
Pediatric patients received OFIRMEV doses up to 15 mg/kg on
any of the excipients in the IV formulation. (4)
should be used with caution in patients with hepatic impairment
dose of OFIRMEV of 1000 mg, a minimum dosing interval
Diazepam and chlorpromazine hydrochloride are physically
6.1 Clinical
an every 4 hours, every 6 hours, or every 8 hours schedule. The
• In patients with severe hepatic impairment or severe active liver
or active liver disease. (4, 5.1, 8.6)
of 4 hours, and a maximum daily dose of acetaminophen
incompatible with OFIRMEV, therefore do not administer
Because clinical trials are conducted under widely varying
maximum exposure was 7.7, 6.4, 6.8, and 7.1 days in neonates,
• Renal Impairment: In cases of severe renal impairment, longer
of 4000 mg per day (includes all routes of administration
conditions, adverse reaction rates observed cannot be directly
infants, children, and adolescents, respectively.
dosing intervals and a reduced total daily dose of acetaminophen
and all acetaminophen-containing products including
compared to rates in other clinical trials and may not reflect
DOSAGE FORMS AND STRENGTHS
The most common adverse events (incidence ≥ 5%) in
Administration of acetaminophen in doses higher than
may be warranted. (5.1, 8.7)
the rates observed in practice.
OFIRMEV is a sterile, clear, colorless, non pyrogenic,
pediatric patients treated with OFIRMEV were nausea,
recommended (by all routes of administration and from all
Adults and adolescents weighing under 50 kg: the recom-
preservative free, isotonic formulation of acetaminophen Adult Population
vomiting, constipation, pruritus, agitation, and atelectasis.
mended dosage of OFIRMEV is 15 mg/kg every 6 hours or
intended for intravenous infusion. Each 100 mL glass vial
A total of 1020 adult patients have received OFIRMEV in
12.5 mg/kg every 4 hours, with a maximum single dose of
Other Adverse Reactions Observed During Clinical Studies of
FULL PRESCRIBING INFORMATION: CONTENTS*
8.2 Labor and Delivery
contains 1000 mg acetaminophen (10 mg/mL).
clinical trials, including 37.3% (n=380) who received 5 or more
OFIRMEV of 15 mg/kg, a minimum dosing interval of 4 hours, and
OFIRMEV in Pediatrics
WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY
doses, and 17.0% (n=173) who received more than 10 doses.
a maximum daily dose of acetaminophen of 75 mg/kg per day
1 INDICATIONS AND USAGE
Most patients were treated with OFIRMEV 1000 mg every
The following additional treatment-emergent adverse reactions
2 DOSAGE AND ADMINISTRATION
(includes all routes of administration and all acetaminophen-
Acetaminophen is contraindicated:
6 hours. A total of 13.1% (n=134) received OFIRMEV 650 mg
were reported by pediatric subjects treated with OFIRMEV
2.1 General Dosing Information
8.6 Patients with Hepatic Impairment
containing products including combination products).
(n=355) that occurred with an incidence of at least 1%.
in patients with known hypersensitivity to every 4 hours.
2.2 Recommended Dosage: Adults and Adolescents
8.7 Patients with Renal Impairment
Table 1. Dosing for Adults and Adolescents
acetaminophen or to any of the excipients in the
All adverse reactions that occurred in adult patients Blood and lymphatic system disorders: anemia
2.3 Recommended Dosage: Children
treated with either OFIRMEV or placebo in repeated dose,
Cardiac disorders: tachycardia
2.4 Instructions for Intravenous Administration
Age group
Dose given Dose given Maximum Maximum total
• in patients with severe hepatic impairment or severe
placebo-controlled clinical trials at an incidence ≥ 3% and
3 DOSAGE FORMS AND STRENGTHS
12 CLINICAL PHARMACOLOGY
single dose daily dose of
Gastrointestinal disorders: abdominal pain, diarrhea
active liver disease [see Warnings and Precautions
at a greater frequency than placebo are listed in Table 3. The
12.1 Mechanism of Action
most common adverse events in adult patients treated with
General disorders and administration site conditions: injection
5 WARNINGS AND PRECAUTIONS
(by all routes)
OFIRMEV (incidence ≥ 5% and greater than placebo) were
site pain, edema peripheral, pyrexia
Adults and
WARNINGS AND PRECAUTIONS
nausea, vomiting, headache, and insomnia.
Investigations: hepatic enzyme increase
5.2 Serious Skin Reactions
13 NONCLINICAL TOXICOLOGY
adolescents
5.1 Hepatic
5.3 Risk of Medication Errors
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Metabolism and nutrition disorders:
hypoalbuminemia,
(13 years and
Administration of acetaminophen in doses higher than
5.4 Allergy and Hypersensitivity
14 CLINICAL STUDIES
kalemia, hypomagnesemia, hypophosphatemia,
older) weighing
recommended may result in hepatic injury, including the
6 ADVERSE
14.1 Adult Acute Pain
≥ 50 kg
risk of liver failure and death [see Overdosage (10)]. Do
not exceed the maximum recommended daily dose of
Musculoskeletal and connective tissue disorders: muscle
14.3 Pediatric Acute Pain and Fever
Adults and
12.5 mg/kg 15 mg/kg
acetaminophen [see Dosage and Administration (2)]. The
spasm, pain in extremity
7.1 Effects of other Substances on Acetaminophen
16 HOW SUPPLIED/STORAGE AND HANDLING
adolescents
maximum recommended daily dose of acetaminophen
7.2 Anticoagulants
Nervous system disorders: headache
*Sections or subsections omitted from the full prescribing
(13 years and
includes all routes of acetaminophen administration and all
8 USE IN SPECIFIC POPULATIONS
information are not listed.
older) weighing
Psychiatric disorders: insomnia
acetaminophen-containing products administered, including
< 50 kg
Renal and urinary disorders: oliguria
Respiratory, thoracic and mediastinal disorders: pulmonary
be used in such settings only after a careful benefit-risk
At therapeutic levels, binding of acetaminophen to plasma
to placebo for reduction in pain intensity over 24 hours. There
edema, hypoxia, pleural effusion, stridor, wheezing
Acetaminophen is a non-salicylate antipyretic and non-
proteins is low (ranging from 10% to 25%). Acetaminophen
was an attendant decrease in opioid consumption, the clinical
Skin and subcutaneous tissue disorders: periorbital edema,
opioid analgesic agent. Its chemical name is N-acetyl-p-
appears to be widely distributed throughout most body
benefit of which was not demonstrated.
8.3 Nursing
aminophenol. Acetaminophen has a molecular weight of
tissues except fat.
While studies with OFIRMEV have not been conducted,
Pain Study 2 evaluated the analgesic efficacy of repeated
151.16. Its structural formula is:
Vascular disorders: hypertension, hypotension
acetaminophen is secreted in human milk in small quantities
Metabolism and Excretion
doses of OFIRMEV 1000 mg every 6 hours or 650 mg every
after oral administration. Based on data from more than
Acetaminophen is primarily metabolized in the liver by
4 hours for 24 hours versus placebo in the treatment of
first-order kinetics and involves three principal separate
244 patients with moderate to severe postoperative pain after
15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 – 2% of the maternal dose.
pathways: Conjugation with glucuronide, conjugation with
abdominal laparoscopic surgery. Patients receiving OFIRMEV
Effects of other Substances on Acetaminophen
There is one well-documented report of a rash in a breast-fed
sulfate, and oxidation via the cytochrome P450 enzyme
experienced a statistically significant greater reduction in pain
Substances that induce or regulate hepatic cytochrome enzyme
infant that resolved when the mother stopped acetaminophen
pathway, primarily CYP2E1, to form a reactive intermediate
intensity over 24 hours compared to placebo.
CYP2E1 may alter the metabolism of acetaminophen and
use and recurred when she resumed acetaminophen use.
metabolite (N-acetyl-p-benzoquinone imine or NAPQI). With
increase its hepatotoxic potential. The clinical consequences
14.2 Adult
Caution should be exercised when OFIRMEV is administered
therapeutic doses, NAPQI undergoes rapid conjugation with
of these effects have not been established. Effects of ethanol
The efficacy of OFIRMEV 1000 mg in the treatment of adult
to a nursing woman.
glutathione and is then further metabolized to form cysteine
are complex, because excessive alcohol usage can induce
OFIRMEV injection is a sterile, clear, colorless, non pyrogenic,
fever was evaluated in one randomized, double-blind,
and mercapturic acid conjugates.
hepatic cytochromes, but ethanol also acts as a competitive
8.4 Pediatric
isotonic formulation of acetaminophen intended for
placebo-controlled clinical trial. The study was a 6-hour,
Acetaminophen metabolites are mainly excreted in the urine.
inhibitor of the metabolism of acetaminophen.
single-dose, endotoxin-induced fever study in 60 healthy
The safety and effectiveness of OFIRMEV for the treatment
intravenous infusion. It has a pH of approximately 5.5 and an osmolality of approximately 290 mOsm/kg. Each 100 mL
Less than 5% is excreted in the urine as unconjugated (free)
adult males. A statistically significant antipyretic effect of
of acute pain and fever in pediatric patients ages 2 years
contains 1000 mg acetaminophen, USP, 3850 mg mannitol,
acetaminophen and more than 90% of the administered dose
OFIRMEV was demonstrated through 6 hours in comparison to
Chronic oral acetaminophen use at a dose of 4000 mg/day has
and older is supported by evidence from adequate and well-
USP, 25 mg cysteine hydrochloride, monohydrate, USP, and
is excreted within 24 hours.
placebo. The mean temperature over time is shown in Figure 1.
been shown to cause an increase in international normalized
controlled studies of OFIRMEV in adults. Additional safety
10.4 mg dibasic sodium phosphate, USP. pH is adjusted with
ratio (INR) in some patients who have been stabilized on
and pharmacokinetic data were collected in 355 patients
hydrochloric acid and/or sodium hydroxide.
13 NONCLINICAL
sodium warfarin as an anticoagulant. As no studies have
across the full pediatric age strata, from premature
13.1 Carcinogenesis, Mutagenesis, Impairment of
been performed evaluating the short-term use of OFIRMEV in
neonates (≥ 32 weeks post menstrual age) to adolescents.
12 CLINICAL
patients on oral anticoagulants, more frequent assessment of
The effectiveness of OFIRMEV for the treatment of acute
INR may be appropriate in such circumstances.
pain and fever has not been studied in pediatric patients
12.1 Mechanism of Action
< 2 years of age [see Dosage and Administration (2.3) and
The precise mechanism of the analgesic and antipyretic
Long-term studies in mice and rats have been completed by
properties of acetaminophen is not established but is thought
the National Toxicology Program to evaluate the carcinogenic
USE IN SPECIFIC POPULATIONS
to primarily involve central actions.
potential of acetaminophen. In 2-year feeding studies,
8.5 Geriatric
F344/N rats and B6C3F1 mice were fed a diet containing
Pregnancy Category C.
Of the total number of subjects in clinical studies of OFIRMEV,
acetaminophen up to 6000 ppm. Female rats demonstrated
There are no studies of intravenous acetaminophen in 15% were age 65 and over, while 5% were age 75 and
Acetaminophen has been shown to have analgesic and equivocal evidence of carcinogenic activity based on increased
pregnant women; however, epidemiological data on oral
over. No overall differences in safety or effectiveness were
antipyretic activities in animal and human studies.
incidences of mononuclear cell leukemia at 0.8 times the
Figure 1: Mean Temperature (°C) Over Time
acetaminophen use in pregnant women show no increased
observed between these subjects and younger subjects,
Single doses of OFIRMEV up to 3000 mg and repeated
maximum human daily dose (MHDD) of 4 grams/day, based
risk of major congenital malformations. Animal reproduction
and other reported clinical experience has not identified
doses of 1000 mg every 6 hours for 48 hours have not been
on a body surface area comparison. In contrast, there was no
14.3 Pediatric Acute Pain and Fever
studies have not been conducted with IV acetaminophen, and
differences in responses between the elderly and younger
shown to cause a significant effect on platelet aggregation.
evidence of carcinogenic activity in male rats (0.7 times) or
OFIRMEV was studied in 355 pediatric patients in two active-
it is not known whether OFIRMEV can cause fetal harm when
patients, but greater sensitivity of some older individuals
Acetaminophen does not have any immediate or delayed
mice (1.2-1.4 times the MHDD, based on a body surface area
controlled and three open-label safety and pharmacokinetic
administered to a pregnant woman. OFIRMEV should be given
cannot be ruled out.
effects on small-vessel hemostasis. Clinical studies of both
trials [see Use in Specific Populations (8.4)].
to a pregnant woman only if clearly needed.
Patients with Hepatic Impairment
healthy subjects and patients with hemophilia showed no
HOW SUPPLIED/STORAGE AND HANDLING
The results from a large population-based prospective Acetaminophen is contraindicated in patients with severe significant changes in bleeding time after receiving multiple
Acetaminophen was not mutagenic in the bacterial reverse
cohort, including data from 26,424 women with live born
NDC 43825-102-01 - OFIRMEV® (acetaminophen) Injection
hepatic impairment or severe active liver disease and should
doses of oral acetaminophen.
mutation assay (Ames test). In contrast, acetaminophen tested
singletons who were exposed to oral acetaminophen during
is supplied in a 100 mL glass vial containing 1000 mg
be used with caution in patients with hepatic impairment or
positive in the in vitro mouse lymphoma assay and the in vitro
the first trimester, indicate no increased risk for congenital
acetaminophen (10 mg/mL) in cartons of 24 vials.
active liver disease [see Warnings and Precautions (5.1) and
chromosomal aberration assay using human lymphocytes. In
malformations, compared to a control group of unexposed
Clinical Pharmacology (12)]. A reduced total daily dose of
The pharmacokinetics of OFIRMEV have been studied in
the published literature, acetaminophen has been reported to
OFIRMEV should be stored at 20°C to 25°C (68°F to 77°F) [see
children. The rate of congenital malformations (4.3%) was
acetaminophen may be warranted.
patients and healthy subjects from premature neonates up to
be clastogenic when administered a dose of 1500 mg/kg/day
USP Controlled Room Temperature].
similar to the rate in the general population. A population-
adults 60 years old. The pharmacokinetic profile of OFIRMEV
to the rat model (3.6-times the MHDD, based on a body surface
For single use only. The product should be used within 6 hours
based, case-control study from the National Birth Defects
Patients with Renal Impairment
has been demonstrated to be dose proportional in adults
area comparison). In contrast, no clastogenicity was noted at a
after opening. Do not refrigerate or freeze.
Prevention Study showed that 11,610 children with prenatal
In cases of severe renal impairment (creatinine clearance
following administration of single doses of 500, 650, and
dose of 750 mg/kg/day (1.8-times the MHDD, based on a body
exposure to acetaminophen during the first trimester ≤ 30 mL/min), longer dosing intervals and a reduced total daily
Manufactured for:
surface area comparison), suggesting a threshold effect.
had no increased risk of major birth defects compared to
dose of acetaminophen may be warranted.
Mallinckrodt Hospital Products Inc.
Impairment of Fertility
4,500 children in the control group. Other epidemiological
The maximum concentration (Cmax) occurs at the end of the
Hazelwood, MO 63042 USA
In studies conducted by the National Toxicology Program,
data showed similar results.
15 minute intravenous infusion of OFIRMEV. Compared to
the same dose of oral acetaminophen, the C
fertility assessments have been completed in Swiss mice
While animal reproduction studies have not been conducted
Signs and Symptoms
administration of OFIRMEV is up to 70% higher, while overall
via a continuous breeding study. There were no effects on
Mallinckrodt, the "M" brand mark, the Mallinckrodt
with intravenous acetaminophen, studies in pregnant rats that
In acute acetaminophen overdosage, dose-dependent, exposure (area under the concentration time curve [AUC]) is
fertility parameters in mice consuming up to 1.7 times the
Pharmaceuticals logo and other brands are trademarks of a
received oral acetaminophen during organogenesis at doses
potentially fatal hepatic necrosis is the most serious adverse
very similar.
MHDD of acetaminophen, based on a body surface area
up to 0.85 times the maximum human daily dose (MHDD =
effect. Renal tubular necrosis, hypoglycemic coma, and
comparison. Although there was no effect on sperm motility
2014 Mallinckrodt.
4 grams/day, based on a body surface area comparison) showed
Pharmacokinetic parameters of OFIRMEV (AUC, C
thrombocytopenia may also occur. Plasma acetaminophen
or sperm density in the epididymis, there was a significant
evidence of fetotoxicity (reduced fetal weight and length) and
elimination half-life [T
U.S. PATENT NUMBERS:
levels > 300 mcg/mL at 4 hours after oral ingestion were
½], systemic clearance [CL], and volume
increase in the percentage of abnormal sperm in mice
a dose-related increase in bone variations (reduced ossification
of distribution at steady state [Vss]) following administration
6,028,222; 6,992,218
associated with hepatic damage in 90% of patients;
consuming 1.7 times the MHDD (based on a body surface
and rudimentary rib changes). Offspring had no evidence of
of a s ingle intravenous dose of 15 mg/kg for the pediatric
minimal hepatic damage is anticipated if plasma levels at
area comparison) and there was a reduction in the number of
external, visceral, or skeletal malformations. When pregnant
population and 1000 mg in adults are summarized in Table 4.
4 hours are < 150 mcg/mL or < 37.5 mcg/mL at 12 hours
mating pairs producing a fifth litter at this dose, suggesting the
rats received oral acetaminophen throughout gestation at
after ingestion. Early symptoms following a potentially
Table 4. OFIRMEV Pharmacokinetic Parameters
potential for cumulative toxicity with chronic administration
doses of 1.2-times the MHDD (based on a body surface area
hepatotoxic overdose may include: nausea, vomiting,
of acetaminophen near the upper limit of daily dosing.
comparison), areas of necrosis occurred in both the liver and
Mean (SD)
diaphoresis, and general malaise. Clinical and laboratory
Published studies in rodents report that oral acetaminophen
kidney of pregnant rats and fetuses. These effects did not occur
evidence of hepatic toxicity may not be apparent until 48 to
treatment of male animals at doses that are 1.2 times the MHDD
in animals that received oral acetaminophen at doses 0.3-times
72 hours post-ingestion.
(μg × h/mL) (μg/mL)
and greater (based on a body surface area comparison) result
the MHDD, based on a body surface area comparison.
Treatment
7.0 (2.7) 0.12 (0.04) 1.1 (0.2)
in decreased testicular weights, reduced spermatogenesis,
In a continuous breeding study, pregnant mice received
If an acetaminophen overdose is suspected, obtain a serum
reduced fertility, and reduced implantation sites in females
29 (24) 4.2 (2.9) 0.29 (0.15) 1.1 (0.3)
0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or
acetaminophen assay as soon as possible, but no sooner
given the same doses. These effects appear to increase with
1430 mg/kg/day). These doses are approximately 0.43, 0.87,
than 4 hours following oral ingestion. Obtain liver function
3.0 (1.5) 0.34 (0.10) 1.2 (0.3)
the duration of treatment. The clinical significance of these
and 1.7 times the MHDD, respectively, based on a body
studies initially and repeat at 24-hour intervals. Administer the
2.9 (0.7) 0.29 (0.08) 1.1 (0.3)
findings is not known.
surface area comparison. A dose-related reduction in body
antidote N-acetylcysteine (NAC) as early as possible. As a guide
28 (21) 2.4 (0.6) 0.27 (0.08) 0.8 (0.2)
weights of fourth and fifth litter offspring of the treated
to treatment of acute ingestion, the acetaminophen level can
14 CLINICAL
mating pair occurred during lactation and post-weaning at all
be plotted against time since oral ingestion on a nomogram
The pharmacokinetic exposure of OFIRMEV observed 14.1 Adul t Acute Pain
doses. Animals in the high dose group had a reduced number
(Rumack-Matthew). The lower toxic line on the nomogram
in children and adolescents is similar to adults, but The efficacy of OFIRMEV in the treatment of acute pain in adults
of litters per mating pair, male offspring with an increased
is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/mL at
higher in neonates and infants. Dosing simulations from
was evaluated in two randomized, double-blind, placebo-
percentage of abnormal sperm, and reduced birth weights in
12 hours. If serum level is above the lower line, administer the
pharmacokinetic data in infants and neonates suggest that
controlled clinical trials in patients with postoperative pain.
the next generation pups.
entire course of NAC treatment. Withhold NAC therapy if the
dose reductions of 33% in infants 1 month to < 2 years of age,
Pain Study 1 evaluated the analgesic efficacy of repeated doses
Labor and Delivery
acetaminophen level is below the lower line.
and 50% in neonates up to 28 days, with a minimum dosing
of OFIRMEV 1000 mg vs. placebo every 6 hours for 24 hours
There are no adequate and well-controlled studies with For additional information, call a poison control center at
interval of 6 hours, will produce a pharmacokinetic exposure
in 101 patients with moderate to severe pain following total
OFIRMEV during labor and delivery; therefore, it should 1-800-222-1222.
similar to that observed in children age 2 years and older.
hip or knee replacement. OFIRMEV was statistically superior
HIGHLIGHTS OF PRESCRIBING INFORMATION
• Accidental exposure, especially in children, can result in fatal overdose
ensure that appropriate treatment will be available [see Warnings
Accidental consumption of XARTEMIS XR, especially by children, can result
clearance of oxycodone which could lead to changes in oxycodone
Respiratory, thoracic and mediastinal disorders: dyspnea, hiccups, Animal Data
With intravenous abuse, the inactive ingredients in XARTEMIS XR can
These highlights do not include all the information needed to use
of oxycodone. (5.2)
and Precautions (5.3)].
in respiratory depression and death due to an overdose of oxycodone.
hypopnea, oropharyngeal pain, throat irritation
No reproductive or developmental studies were conducted with the
result in death, local tissue necrosis, infection, pulmonary granulomas, and
• Interactions with CNS depressants: Concomitant use may
combination of oxycodone and acetaminophen, the components of
increased risk of endocarditis and valvular heart injury. Parenteral drug
XARTEMIS™ XR safely and effectively. See full prescribing information
Neonatal Opioid Withdrawal Syndrome
Inhibition of CYP3A4 activity by its inhibitors, such as macrolide antibiotics
Skin and subcutaneous tissue disorders: dermatitis, ecchymosis, hyper-
cause profound sedation, respiratory depression, and death. If
hidrosis, urticaria
XARTEMIS XR. The following data are based on findings from studies
abuse is commonly associated with transmission of infectious diseases
XARTEMIS XR contains acetaminophen. Acetaminophen has been
Prolonged use of XARTEMIS XR during pregnancy can result in
(e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and
coadministration is required, consider dose reduction of one or both
performed with the individual components.
such as hepatitis and HIV.
XARTEMIS XR (oxycodone hydrochloride and acetaminophen)
associated with cases of acute liver failure, at times resulting in liver
withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome,
protease inhibitors (e.g., ritonavir), may increase plasma concentrations
Vascular disorders: flushing, hypertension
Extended-Release Tablets, for oral use, CII
transplant and death. Most of the cases of liver injury are associated
unlike opioid withdrawal syndrome in adults, may be life-threatening
of oxycodone and prolong opioid effects. These effects could be more
Studies in pregnant rats that received oral acetaminophen during organo-
• Use with caution in patients who are receiving other CNS depressants.
with the use of acetaminophen at doses that exceed the maximum
if not recognized and requires management according to protocols
pronounced with concomitant use of CYP 2D6 and 3A4 inhibitors.
genesis at doses up to 0.85 times the maximum human daily dose
Patients may exhibit tolerance to some of the effects of oxycodone.
Initial U.S. Approval: 1976
daily limit, and often involve more than one acetaminophen-
developed by neonatology experts. If opioid use is required for a
Cytochrome P450 inducers, such as rifampin, carbamazepine, and
(MHDD = 4 grams/day, based on a body surface area comparison) showed
Tolerance is the need for increasing doses of opioids to maintain a
• Elderly, cachectic, debilitated patients, and those with chronic
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING
containing product [see Warnings and Precautions (5.7, 5.11)].
prolonged period in a pregnant woman, advise the patient of the risk
phenytoin, may induce the metabolism of oxycodone and, therefore, may
The concomitant use of XARTEMIS XR with other CNS depressants including
evidence of fetotoxicity (reduced fetal weight and length) and a dose-
defined effect such as analgesia (in the absence of disease progression
pulmonary disease: Monitor closely because of increased risk for life-
of neonatal opioid withdrawal syndrome and ensure that appropriate
cause increased clearance of the drug which could lead to a decrease in
sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines,
related increase in bone variations (reduced ossification and rudimentary
or other external factors). Tolerance may occur to both the desired
RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL
threatening respiratory depression. (5.5, 5.6)
treatment will be available.
other opioids, and alcohol can increase the risk of respiratory depression,
rib changes). Offspring had no evidence of external, visceral, or skeletal
OPIOID WITHDRAWAL SYNDROME; and HEPATOTOXICITY
INDICATIONS AND USAGE
oxycodone plasma concentrations, resulting in a potential lack of efficacy.
and undesired effects of drugs, and may develop at different rates for
• Use caution when administering in patients with hepatic impairment.
profound sedation, coma and death. Monitor patients receiving CNS
malformations. When pregnant rats received oral acetaminophen
XARTEMIS XR is indicated for the management of acute pain severe
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity
If co-administration is necessary, caution is advised when initiating
different effects.
See full prescribing information for complete boxed warning.
depressants and XARTEMIS XR for signs of respiratory depression, sedation
throughout gestation at doses of 1.2-times the MHDD (based on a body
enough to require opioid treatment and for which alternative treatment
and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea
XARTEMIS XR treatment in patients currently taking, or discontinuing
Physical dependence results in withdrawal symptoms symptoms
• XARTEMIS XR exposes users to risks of addiction, abuse, and
• May cause serious skin reactions. Discontinue use if reaction occurs. (5.8)
and hypotension.
surface area comparison), areas of necrosis occurred in both the liver
options are inadequate.
and failure to gain weight. The onset, duration, and severity of neonatal
CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals
after abrupt discontinuation or a significant dose reduction of a drug.
misuse, which can lead to overdose and death. Assess each
• May worsen increased intracranial pressure and obscure its signs, such
opioid withdrawal syndrome vary based on the specific opioid used,
and kidney of pregnant rats and fetuses. These effects did not occur in
and consider dose adjustments until stable drug effects are achieved [see
When combined therapy with any of the above medications is considered,
as level of consciousness or pupillary signs. (5.9)
Limitations of Use
Withdrawal also may be precipitated through the administration of
patient's risk before prescribing, and monitor regularly for
duration of use, timing and amount of last maternal use, and rate of
animals that received oral acetaminophen at doses 0.3-times the MHDD,
Drug Interactions (7.4)].
the dose of one or both agents should be reduced [see Dosage and
drugs with opioid antagonist activity, e.g., naloxone or mixed agonist/
development of these behaviors or conditions. (5.1)
• May cause hypotension. Use with caution in patients at increased risk of
Because of the risks of addiction, abuse, misuse, overdose, and death
elimination of the drug by the newborn.
Administration (2.2) and Warnings and Precautions (5.4)].
based on a body surface area comparison. In a continuous breeding
antagonist analgesics (pentazocine, butorphanol, buprenorphine,
• Serious, life-threatening, or fatal respiratory depression may
hypotension and in patients in circulatory shock. (5.10)
with opioids, even at recommended doses, reserve XARTEMIS XR for
5.16 Driving and Operating Machinery
study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the
nalbuphine). Physical dependence may not occur to a clinically
occur. Monitor closely, especially upon initiation or following a
• Due to the potential for acetaminophen hepatotoxicity at doses
use in patients for whom alternative treatment options (e.g., non-
Interactions with Central Nervous System Depressants
XARTEMIS XR may impair the mental and/or physical abilities required
Neuromuscular Blocking Agents
diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.43,
significant degree until after several days to weeks of continued
dose increase. Instruct patients to swallow tablets whole to avoid
higher than 4000 mg/day, XARTEMIS XR should not be used with other
opioid analgesics) are ineff ective, not tolerated, or would be otherwise
Hypotension, profound sedation, coma, respiratory depression, and death
for the performance of potentially hazardous tasks such as driving a car
Oxycodone, as well as other opioid analgesics, may enhance the
0.87, and 1.7 times the MHDD, respectively, based on a body surface area
opioid usage.
exposure to a potentially fatal dose of oxycodone. (5.2)
acetaminophen-containing products. (5.11)
may result if XARTEMIS XR is used concomitantly with alcohol or other
or operating machinery. The patient using this drug should be cautioned
neuromuscular blocking action of skeletal muscle relaxants and produce
comparison. A dose-related reduction in body weights of fourth and fifth
• Discontinue XARTEMIS XR immediately if symptoms associated
central nervous system (CNS) depressants (e.g., sedatives, anxiolytics,
an increased degree of respiratory depression.
• Accidental consumption of XARTEMIS XR, especially in children,
litter offspring of the treated mating pair occurred during lactation and
The opioid abstinence or withdrawal syndrome is characterized by some
with allergy or hypersensitivity occur. Do not use in patients with
DOSAGE AND ADMINISTRATION
hypnotics, neuroleptics, other opioids).
can result in fatal overdose of oxycodone. (5.2)
Monoamine Oxidase Inhibitors
post-weaning at all doses. Animals in the high dose group had a reduced
or all of the following: restlessness, lacrimation, rhinorrhea, yawning,
acetaminophen allergy. (5.12)
XARTEMIS XR is not interchangeable with other oxycodone/acetaminophen
When considering the use of XARTEMIS XR in a patient taking a CNS
6 ADVERSE
• Prolonged use of XARTEMIS XR during pregnancy can result
Monoamine Oxidase Inhibitors (MAOIs) have been reported to intensify
number of litters per mating pair, male offspring with an increased
perspiration, chills, myalgia, and mydriasis. Other symptoms also may
• Use with caution in patients with biliary tract disease, including acute
products because of differing pharmacokinetic profiles that affect the
depressant, assess the duration use of the CNS depressant and the
The following treatment-emergent adverse reactions are discussed in
the effects of at least one opioid drug causing anxiety, confusion, and
percentage of abnormal sperm, and reduced birth weights in the next
develop, including irritability, anxiety, backache, joint pain, weakness,
in neonatal opioid withdrawal syndrome, which may be life-
pancreatitis. (5.14)
frequency of administration.
patient's response, including the degree of tolerance that has developed
more detail in other sections of the labeling:
significant depression of respiration or coma. The use of XARTEMIS XR is
generation pups. Reproduction studies in Sprague-Dawley rats and New
abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea,
threatening if not recognized and treated. If opioid use is
• Concomitant use of CYP3A4 inhibitors may increase opioid eff ects. (5.15)
or increased blood pressure, respiratory rate, or heart rate. In patients
2.1 Initial
to CNS depression. Additionally, evaluate the patient's use of alcohol
• Respiratory Depression [see Contraindications (4), Warnings and
not recommended for patients taking MAOIs or within 14 days of stopping
Zealand rabbits revealed that when oxycodone was administered orally
required for a prolonged period in a pregnant woman, advise the
• May impair the mental and physical abilities needed to perform
or illicit drugs that cause CNS depression. If the decision to begin
at doses up to 16 mg/kg (approximately 2 times the daily oral dose of
suspected of having significant physical dependence, withdrawal
Initiate the dosing regimen for each patient individually, taking into
Precautions (5.2), and Overdosage (10)]
such treatment.
patient of the risk of neonatal opioid withdrawal syndrome and
potentially hazardous activities such as driving a car or operating
XARTEMIS XR is made, start with XARTEMIS XR 1 tablet every 12 hours,
90 mg for adults based on a body surface area comparison) and 25 mg/kg
symptoms may be reduced by tapering therapy.
account the patient's prior analgesic treatment experience and risk factors
• Hepatotoxicity [see Warnings and Precautions (5.7)]
Agents Affecting Cytochrome P450 Enzymes
ensure that appropriate treatment will be available. (5.3)
machinery. (5.16)
monitor patients for signs of sedation and respiratory depression, and
(approximately 5 times the daily oral dose of 90 mg based on body surface
for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• Use With Other Acetaminophen-containing Products [see Warnings and
Infants born to mothers physically dependent on opioids will also
• XARTEMIS XR contains acetaminophen. Acetaminophen has
consider using a lower dose of the concomitant CNS depressant
CYP3A4 Inhibitors
area comparison), it was non teratogenic or embryo-fetal toxic.
Monitor patients closely for respiratory depression, especially within the
be physically dependent and may exhibit respiratory difficulties and
been associated with cases of acute liver failure, at times
Drug Interactions (7.1)].
Because the CYP3A4 isoenzyme plays a major role in the metabolism
The most common adverse events with XARTEMIS XR are nausea,
first 24-72 hours of initiating therapy with XARTEMIS XR [see Warnings and
• Interactions with Other CNS Depressants [see Warnings and Precautions
withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].
resulting in liver transplant and death. Most of the cases of liver
of oxycodone, drugs that inhibit CYP3A4 activity may cause decreased
8.3 Nursing
dizziness, headache, vomiting, constipation and somnolence. (6.1)
Elderly, Cachectic, and Debilitated Patients
injury are associated with the use of acetaminophen at doses
clearance of oxycodone which could lead to an increase in oxycodone
Oxycodone is present in human milk and may result in accumulation and
Life-threatening respiratory depression is more likely to occur in
that exceed the maximum daily limit, and often involve more
To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at
Use of XARTEMIS XR as the First Opioid Analgesic
Clinical Studies Experience
plasma concentrations and result in increased or prolonged opioid effects.
toxicities such as sedation and respiratory depression in some infants.
elderly, cachectic, or debilitated patients as they may have altered
Acetaminophen is present in human milk in small quantities. Based on
than one acetaminophen-containing product. (5.7, 5.11)
1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The recommended dose of XARTEMIS XR is 2 tablets every 12 hours
Because clinical studies are conducted under widely varying conditions,
These effects could be more pronounced with concomitant use of CYP2D6
pharmacokinetics or altered clearance compared to younger, healthier
data from more than 15 nursing mothers, the calculated infant daily dose
10.1 Signs and Symptoms
administered with or without food. The second dose of 2 tablets may be
adverse reaction rates observed in the clinical studies of a drug cannot be
and 3A4 inhibitors. If co-administration with XARTEMIS XR is necessary,
patients. Monitor such patients closely, particularly when initiating and
of acetaminophen is approximately 1 to 2% of the maternal dose. There is
Following an acute overdosage, toxicity may result from the oxycodone
----------------------------- INDICATIONS AND USAGE -----------------------------
administered as early as 8 hours after the initial dose if patients require
directly compared to rates in the clinical studies of another drug and may
monitor patients for respiratory depression and sedation at frequent
titrating XARTEMIS XR and when XARTEMIS XR is given concomitantly with
• Concurrent use of other CNS depressants may cause respiratory
one well-documented report of a rash in a breast-fed infant that resolved
or the acetaminophen.
XARTEMIS XR (oxycodone hydrochloride and acetaminophen) Extended-
analgesia at that time. Subsequent doses are to be administered 2 tablets
not reflect the rates observed in clinical practice.
intervals and consider dose adjustments until stable drug effects are
other drugs that depress respiration [see Warnings and Precautions (5.2)].
depression, hypotension, and profound sedation or coma. (7.1)
when the mother stopped acetaminophen use and recurred when she
Release Tablets is a combination of oxycodone, an opioid agonist, and
In safety data from two Phase 3 (one placebo-controlled, one open-label)
achieved [see Clinical Pharmacology (12.3)].
acetaminophen, and is indicated for the management of acute pain severe
• XARTEMIS XR may enhance the neuromuscular blocking action
Use in Patients with Chronic Pulmonary Disease
resumed acetaminophen use. Because of the potential for serious adverse
Acute overdosage with opioids is often characterized by respiratory
XARTEMIS XR is given orally. XARTEMIS XR tablets should be swallowed
trials where multiple doses of XARTEMIS XR were administered for up to
CYP3A4 Inducers
of skeletal muscle relaxants and produce an increased degree of
reactions in nursing infants from XARTEMIS XR, a decision should be
enough to require opioid treatment and for which alternative treatment
depression, somnolence progressing to stupor or coma, skeletal muscle
whole, one tablet at a time, with enough water to ensure complete
Monitor patients with significant chronic obstructive pulmonary disease or
42 days, the most common adverse reactions (reported by ≥10% in any
CYP450 3A4 inducers may induce the metabolism of oxycodone and,
respiratory depression. (7.2)
made whether to discontinue nursing or discontinue the drug, taking into
options are inadequate.
flaccidity, cold and clammy skin, constricted pupils, and, sometimes,
swallowing immediately after placing in mouth [see Patient Counseling
cor pulmonale, and patients having a substantially decreased respiratory
XARTEMIS XR dose group) were: nausea, dizziness and vomiting. The
therefore, may cause increased clearance of the drug which could lead
• Monoamine oxidase inhibitors may intensify the effects of opioids
account the importance of the drug to the mother.
pulmonary edema, bradycardia, hypotension, and death. Marked
Limitations of Use:
Information (17)]. Do not break, chew, crush, cut, dissolve or split the
reserve, hypoxia, hypercapnia, or preexisting respiratory depression for
most common reasons for discontinuation due to AEs in these 2 studies
to a decrease in oxycodone plasma concentrations, lack of efficacy or,
causing anxiety, confusion and significant depression of respiration or
respiratory depression, particularly when initiating therapy and titrating
(reported by ≥1% in any XARTEMIS XR dose group) were vomiting (4.8%)
Because of the risks of addiction, abuse, misuse, overdose, and death
8.4 Pediatric
mydriasis rather than miosis may be seen due to severe hypoxia in
ochloride and ac
tablets. Breaking, chewing, crushing, cutting, dissolving or splitting
possibly, development of a withdrawal syndrome in a patient who had
overdose situations [see Clinical Pharmacology (12.2)].
with opioids, even at recommended doses, reserve XARTEMIS XR for
XARTEMIS XR tablets will result in uncontrolled delivery of oxycodone and
with XARTEMIS XR, as in these patients, even usual therapeutic doses of
and nausea (4.1%); there were no reports of these adverse reactions in the
developed physical dependence to oxycodone. If co-administration with
Safety and effectiveness of XARTEMIS XR in pediatric patients under the
• The CYP3A4 isoenzyme plays a major role in the metabolism of
use in patients for whom alternative treatment options (e.g., non-
can lead to overdose or death [see Warnings and Precautions (5.1)].
XARTEMIS XR may decrease respiratory drive to the point of apnea [see
XARTEMIS XR is necessary, monitor for signs of opioid withdrawal and
age of 18 years have not been established.
XARTEMIS XR; drugs that inhibit CYP3A4 activity may cause decreased
Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid
opioid analgesics) are ineff ective, not tolerated, or would be otherwise
clearance of oxycodone which could lead to an increase in oxycodone
The total daily dose of acetaminophen from all drug products should not
A total of 1028 subjects in 14 clinical studies were treated with
consider dose adjustments until stable drug effects are achieved [see
8.5 Geriatric
In acetaminophen overdosage, dose-dependent potentially fatal hepatic
analgesics in these patients if possible.
plasma concentrations. (7.4)
exceed 4000 milligrams.
XARTEMIS XR during the clinical development program, including 892
Clinical Pharmacology (12.3)].
Of the 607 subjects in the Phase 3 studies treated with XARTEMIS XR,
necrosis is the most serious adverse effect. Renal tubular necrosis,
subjects treated with 15 mg oxycodone and 650 mg acetaminophen. This
------------------------- DOSAGE AND ADMINISTRATION -------------------------
63 (10.3%) were older than age 65, of which 10 (1.6%) were older than
hypoglycemic coma, and coagulation defects may also occur.
• Mixed agonist/antagonist analgesics may reduce the analgesic eff ect
2.2 Hepatic
CYP2D6 Inhibitors
XARTEMIS XR contains oxycodone and acetaminophen. Acetaminophen
dosage regimen of XARTEMIS XR was administered to 607 patients in two
• The recommended dose of XARTEMIS XR is 2 tablets every 12 hours
age 75. No untoward or unexpected adverse reactions were seen in the
of oxycodone and may precipitate withdrawal symptoms in these
Early symptoms following a potentially hepatotoxic overdose may
In patients with hepatic impairment start with one tablet and adjust
Oxycodone is metabolized in part to oxymorphone via the Cytochrome
has been associated with cases of acute liver failure, at times resulting in
Phase 3 studies (one placebo-controlled and one open-label).
without regard to food. (2)
elderly patients who received oxycodone hydrochloride/acetaminophen
include: nausea, vomiting, diaphoresis, and general malaise. Clinical and
dosage as needed. Monitor closely for respiratory depression [see Clinical
P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety
liver transplant and death. Most of the cases of liver injury are associated
In a placebo-controlled post-bunionectomy acute pain trial, 329
• XARTEMIS XR tablets should be swallowed whole. Do not break, chew,
extended-release tablets. However, special precaution should be given
• Anticholinergics may increase risk for urinary retention and severe
laboratory evidence of hepatic toxicity may not be apparent until 48 to
of drugs (e.g., certain cardiovascular drugs, including amiodarone and
with the use of acetaminophen at doses that exceed 4000 milligrams per
patients were dosed with 15 mg oxycodone and 650 mg acetaminophen
crush, cut, dissolve or split, the tablets. Swallow with enough water to
constipation. (7.6)
quinidine, and antidepressants), such blockade has not yet been shown
when determining the dosing amount and frequency of XARTEMIS XR
72 hours post-ingestion.
2.3 Renal
day, and often involve more than one acetaminophen-containing product.
XARTEMIS XR or placebo orally every 12 hours, for approximately
ensure complete swallowing immediately after placing in mouth. (2)
for geriatric patients, since a greater sensitivity to oxycodone may be
(oxycodone hydrochloride and acetaminophen)
to be of clinical significance with this agent. However, clinicians should be
--------------------------USE IN SPECIFIC POPULATIONS --------------------------
In patients with renal impairment start with one tablet and adjust
The excessive intake of acetaminophen may be intentional to cause self-
48 hours (blinded period) [see Clinical Studies (14)]. Table 1 lists the
aware of this possible interaction [see Clinical Pharmacology (12.3)].
observed in this patient population when compared to younger patients.
------------------------DOSAGE FORMS AND STRENGTHS ------------------------
A single or multiple drug overdose with oxycodone and aceta-
• Pregnancy: Based on animal data, may cause fetal harm. (8.1)
dosage as needed. Monitor closely for respiratory depression [see Clinical
harm or unintentional as patients attempt to obtain more pain relief or
adverse reactions reported by ≥1% of XARTEMIS XR-treated patients and
8.6 Hepatic
• Extended-release tablets (oxycodone hydrochloride/acetaminophen):
• Labor and Delivery: Not recommended for use in women immediately
unknowingly take other acetaminophen-containing products. The typical
more frequently in XARTEMIS XR-treated patients compared with placebo.
Mixed Agonist/Antagonist Opioid Analgesics
minophen is a potentially lethal polydrug overdose, and consultation
7.5 mg/325 mg (3)
prior to and during labor and delivery. (8.2)
daily acetaminophen contribution from XARTEMIS XR is 1300 mg.
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol,
XARTEMIS XR contains oxycodone and acetaminophen, which are
with a regional poison control center is recommended. Immediate
2.4 Cessation
Table 1. Treatment-Emergent Adverse Reactions* Reported by ≥1%
and buprenorphine) should be administered with caution to patients who
extensively metabolized in the liver. Their clearance may be decreased
treatment includes support of cardiorespiratory function and
• Nursing Mothers: Discontinue nursing or discontinue drug. (8.3)
When a patient who has been taking XARTEMIS XR regularly and may be
The risk of acute liver failure is higher in individuals with underlying liver
of XARTEMIS XR-Treated Patients and More Frequently than Placebo
have received or are receiving a course of therapy with an opioid agonist
in patients with hepatic impairment. In patients with hepatic impairment
measures to reduce drug absorption. Oxygen, intravenous fluids,
• Patients who have known hypersensitivity to oxycodone, acetamin-
• Geriatric use: Dose with caution as clearance of oxycodone may be
physically dependent no longer requires therapy with XARTEMIS XR use a
disease and in individuals who ingest alcohol while taking acetaminophen.
in XARTEMIS XR-Treated Patients with Postoperative Bunionectomy
analgesic such as XARTEMIS XR. In this situation, mixed agonist/antagonist
start with one tablet and adjust the dosage as needed. Monitor closely for
vasopressors, assisted ventilation, and other supportive measures
ophen or any other components of the product. (4)
slightly reduced in this population. (8.5)
gradual downward titration of the dose of 50% every 2 to 4 days to prevent
Instruct patients to look for acetaminophen or APAP on package labels and
Pain (blinded period)
analgesics may reduce the analgesic effect of XARTEMIS XR and/or may
respiratory depression [see Clinical Pharmacology (12.3)].
should be employed as indicated.
• Patients who have signifi cant respiratory depression. (4)
• Hepatic impairment: Dose initiation should follow a conservative
signs and symptoms of withdrawal. Do not stop XARTEMIS XR abruptly in
not to use more than one product that contains acetaminophen. Instruct
Preferred Term
precipitate withdrawal symptoms in these patients.
8.7 Renal
• Patients who have acute or severe bronchial asthma or hypercarbia. (4)
patients who may be physically dependent.
patients to seek medical attention immediately upon ingestion of more
• Patients who have suspected or known paralytic ileus. (4)
• Renal impairment: Dose initiation should follow a conservative
than 4000 milligrams of acetaminophen per day, even if they feel well.
Information from oxycodone HCl indicates that patients with renal
Primary attention should be given to the reestablishment of
impairment (defined as a creatinine clearance <60 mL/min) had higher
DOSAGE FORMS AND STRENGTHS
Anticholinergics or other medications with anticholinergic activity
adequate respiratory exchange through provision of a patent airway
Serious Skin Reactions
plasma concentrations of oxycodone than subjects with normal renal
XARTEMIS XR is an extended-release tablet for oral administration.
when used concurrently with opioid analgesics may result in increased
and the institution of assisted or controlled ventilation. The opioid
• XARTEMIS XR is not interchangeable with other oxycodone/acetamin-
See 17 for PATIENT COUNSELING INFORMATION and Medication
Rarely, acetaminophen may cause serious skin reactions such as acute
Each tablet contains 7.5 mg oxycodone hydrochloride and 325 mg
risk of urinary retention and/or severe constipation, which may lead
antagonist naloxone hydrochloride is a specific antidote against
ophen products because of diff ering pharmacokinetic profi les that
generalized exanthematous pustulosis (AGEP), Stevens-Johnson
to paralytic ileus.
In patients with renal impairment start with one tablet and adjust the
respiratory depression which may result from overdose or unusual
aff ect the frequency of administration. (5)
Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.
Revised: March 2014
dosage as needed. Monitor closely for respiratory depression [see Clinical
sensitivity to opioids, including oxycodone. Since the duration of
• Controlled substance: XARTEMIS XR is a Schedule II controlled substance
Inform patients about the signs of serious skin reactions, and use of the
USE IN SPECIFIC POPULATIONS
action of oxycodone may exceed that of the antagonist, the patient
with an abuse liability similar to other opioids. (5.1)
drug should be discontinued at the first appearance of skin rash or any
XARTEMIS XR tablets are contraindicated in patients with
should be kept under continued surveillance, and repeated doses
other sign of hypersensitivity.
• Known hypersensitivity to oxycodone, acetaminophen, or any other
Pregnancy Category C
DRUG ABUSE AND DEPENDENCE
of the antagonist should be administered as needed to maintain
FULL PRESCRIBING INFORMATION: CONTENTS*
Neuromuscular Blocking Agents
component of this product [see Warnings and Precautions (5.12)].
Head Injury and Increased Intracranial Pressure
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING
Monoamine Oxidase Inhibitors
9.1 Controlled
• Significant respiratory depression
The respiratory depressant effects of narcotics and their capacity to elevate
RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL
Agents Affecting Cytochrome P450 Enzymes
There are no adequate and well-controlled studies of XARTEMIS XR tablets
Opioid antagonists should not be administered in the absence of
XARTEMIS XR contains oxycodone, a mu-opioid agonist of the morphine
• Acute or severe bronchial asthma or hypercarbia
cerebrospinal fluid pressure may be markedly exaggerated in the presence
OPIOID WITHDRAWAL SYNDROME; and HEPATOTOXICITY
Mixed Agonist/Antagonist Opioid Analgesics
or oxycodone/acetaminophen in pregnant women. Epidemiological data
clinically significant respiratory or circulatory depression. Administer
type and is a Schedule II controlled substance. XARTEMIS XR is subject
• Known or suspected paralytic ileus
of head injury, other intracranial lesions, or a pre-existing increase in
INDICATIONS AND USAGE
on oral acetaminophen use in pregnant women show no increased risk of
opioid antagonists cautiously to persons who are known, or suspected
intracranial pressure. Furthermore, narcotics produce adverse reactions
to misuse, abuse, addiction and criminal diversion [see Warnings and
DOSAGE AND ADMINISTRATION
USE IN SPECIFIC POPULATIONS
major congenital malformations. The incidence of malformations in human
to be, physically dependent on XARTEMIS XR. In such cases, an abrupt
WARNINGS AND PRECAUTIONS
which may obscure the clinical course of patients with head injuries.
pregnancies has not been established for oxycodone as the data are
or complete reversal of opioid effects may precipitate an acute
XARTEMIS XR is not interchangeable with other oxycodone/acetamin-
Labor and Delivery
5.10 Hypotensive Effect
9.2 Abuse
abstinence syndrome. In an individual physically dependent on opioids,
limited. All pregnancies, regardless of drug exposure, have a background
ophen products because of differing pharmacokinetic profiles that affect
Oxycodone may cause severe hypotension particularly in individuals
risk of 2 to 4% for major birth defects, and 15 to 20% for pregnancy loss.
All patients treated with opioids require careful monitoring for signs of
administration of the usual dose of the antagonist will precipitate an acute
the frequency of administration.
whose ability to maintain blood pressure has been compromised by a
No animal reproductive or developmental studies were conducted with
abuse and addiction, because use of opioid analgesic products carries the
withdrawal syndrome. The severity of the withdrawal syndrome produced
DOSAGE FORMS AND STRENGTHS
Addiction, Abuse, and Misuse
depleted blood volume, or after concurrent administration with drugs
Pruritus generalized
the combination of oxycodone and acetaminophen, the components
risk of addiction even under appropriate medical use.
will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory
XARTEMIS XR contains oxycodone, a Schedule II controlled substance. As
which compromise vasomotor tone such as phenothiazines. Administer
* A treatment-emergent adverse reaction refers to any untoward medical
of XARTEMIS XR. The following data are based on findings from
Drug abuse is the intentional non-therapeutic use of an over-the-
depression in the physically dependent patient, administration of the
WARNINGS AND PRECAUTIONS
an opioid, XARTEMIS XR exposes users to the risks of addiction, abuse, and
XARTEMIS XR with caution to patients in circulatory shock, since
event associated with the use of the drug in humans, whether or not
studies performed with the individual components. Reproductive and
counter or prescription drug, even once, for its rewarding psychological
agonist should be begun with care and by titration with smaller than usual
Addiction, Abuse, and Misuse
DRUG ABUSE AND DEPENDENCE
misuse [see Drug Abuse and Dependence (9)]. Although the risk of addiction
vasodilation produced by the drug may further reduce cardiac output and
developmental studies in rats and mice from the published literature
or physiological effects. Drug abuse includes, but is not limited to the
doses of the agonist.
Life-Threatening Respiratory Depression
in any individual is unknown, it can occur in patients appropriately
blood pressure. XARTEMIS XR may produce orthostatic hypotension in
identified adverse events at clinically relevant doses with acetaminophen.
following examples: the use of a prescription or over-the-counter drug
6.2 Other Adverse Reactions Observed During the Premarketing
Neonatal Opioid Withdrawal Syndrome
prescribed XARTEMIS XR and in those who obtain the drug illicitly.
ambulatory patients [see Drug Interactions (7.1)].
Treatment of pregnant rats with doses of acetaminophen approximately
to get "high," or the use of steroids for performance enhancement and
Evaluation of XARTEMIS XR
Interactions with Central Nervous System Depressants
Addiction can occur at recommended doses and if the drug is misused
equal to the maximum human daily dose (MHDD) showed evidence of
muscle build-up.
5.11 Use With Other Acetaminophen-containing Products
Gastric decontamination with activated charcoal should be administered
The following adverse drug reactions not listed above occurred in ≥1% of
Elderly, Cachectic, and Debilitated Patients
fetotoxicity and increases in bone variations in the fetuses. In another study,
The typical daily acetaminophen-contribution from XARTEMIS XR is
Drug addiction is a cluster of behavioral, cognitive, and physiological
just prior to N-acetylcysteine (NAC) to decrease systemic absorption if
XARTEMIS XR-treated patients in the pooled safety data from two Phase 3
Use in Patients with Chronic Pulmonary Disease
10.1 Signs and Symptoms
Assess each patient's risk for opioid addiction, abuse, or misuse
necrosis was observed in the liver and kidney of both pregnant rats and
1300 mg. Due to the potential for acetaminophen hepatotoxicity at
phenomena that develop after repeated substance use and include: a
acetaminophen ingestion is known or suspected to have occurred
studies (including a placebo-controlled and an open-label non-controlled
prior to prescribing XARTEMIS XR, and monitor all patients receiving
fetuses at doses approximately equal to the MHDD. In mice treated with
doses higher than 4000 milligrams/day, XARTEMIS XR should not be
strong desire to take the drug, difficulties in controlling its use, persisting
within a few hours of presentation. Serum acetaminophen levels should
safety study) where multiple-doses of XARTEMIS XR were administered
Serious Skin Reactions
XARTEMIS XR for the development of these behaviors or conditions. Risks
acetaminophen at doses within the clinical dosing range, a reduction in
used concomitantly with other acetaminophen-containing products.
in its use despite harmful consequences, a higher priority given to drug
be obtained immediately if the patient presents 4 hours or more after
every 12 hours for up to 42 days:
Head Injury and Increased Intracranial Pressure
12 CLINICAL
are increased in patients with a personal or family history of substance
number of litters of the parental mating pair was observed as well as retarded
use than to other activities and obligations, increased tolerance, and
ingestion to assess potential risk of hepatotoxicity; acetaminophen
12.1 Mechanism of Action
Gastrointestinal disorders: dry mouth, dyspepsia, diarrhea
abuse (including drug or alcohol addiction or abuse) or mental illness
growth and abnormal sperm in their offspring and reduced birth weight in
sometimes a physical withdrawal.
levels drawn less than 4 hours post-ingestion may be misleading. To
5.11 Use With Other Acetaminophen-containing Products
(e.g., major depression). The potential for these risks should not, however,
There have been post-marketing reports of hypersensitivity and
General disorders and administration site conditions: fatigue
the next generation. Reproductive studies in rats and rabbits with doses
"Drug-seeking" behavior is very common in persons with substance abuse
obtain the best possible outcome, NAC should be administered as
prevent the prescribing of XARTEMIS XR for the proper management of
anaphylaxis associated with use of acetaminophen. Clinical signs included
Investigations: hepatic enzyme increased
of oxycodone greater than clinical doses did not show any teratogenic or
disorders. Drug-seeking tactics include emergency calls or visits near the
soon as possible where impending or evolving liver injury is suspected.
13 NONCLINICAL
pain in any given patient. Patients at increased risk may be prescribed
swelling of the face, mouth, and throat, respiratory distress, urticaria, rash,
Psychiatric disorders: insomnia
embryo-fetal toxic effects. XARTEMIS XR should be used during pregnancy
end of office hours, refusal to undergo appropriate examination, testing
Intravenous NAC may be administered when circumstances preclude
Gastrointestinal
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
modified-release opioid formulations such as XARTEMIS XR, but use in
pruritus, and vomiting. There were infrequent reports of life-threatening
only if the potential benefit justifies the potential risk to the fetus.
Respiratory, thoracic and mediastinal disorders: cough
or referral, repeated "loss" of prescriptions, tampering with prescriptions,
5.15 Cytochrome P450 3A4 Inhibitors and Inducers
14 CLINICAL
such patients necessitates intensive counseling about the risks and proper
anaphylaxis requiring emergency medical attention. Instruct patients
The following adverse drug reactions occurred in <1% of XARTEMIS XR-
and reluctance to provide prior medical records or contact information
Vigorous supportive therapy is required in severe intoxication. Procedures
5.16 Driving and Operating Machinery
16 HOW SUPPLIED/STORAGE AND HANDLING
use of XARTEMIS XR along with intensive monitoring for signs of addiction,
to discontinue XARTEMIS XR immediately and seek medical care if they
treated patients in the pooled safety data from the two Phase 3 studies
Fetal/Neonatal Adverse Reactions
for other treating healthcare provider(s). "Doctor shopping" to obtain
to limit the continuing absorption of the drug must be readily performed
6 ADVERSE
17 PATIENT COUNSELING INFORMATION
abuse, and misuse.
experience these symptoms. Do not prescribe XARTEMIS XR for patients
Prolonged maternal use of opioid analgesics during pregnancy for medical
additional prescriptions is common among drug abusers and people
since the hepatic injury is dose-dependent and occurs early in the course
Clinical Studies Experience
with acetaminophen allergy.
* Sections or subsections omitted from the full prescribing
Abuse or misuse of XARTEMIS XR by crushing, chewing, snorting, or
Other Adverse Reactions Observed During the Premarketing
Cardiac disorders: palpitations
or nonmedical purposes can result in physical dependence in the neonate
suffering from untreated addiction.
of intoxication.
information are not listed.
injecting the dissolved product will result in the uncontrolled delivery of
5.13 Difficulty Swallowing
Evaluation of XARTEMIS XR
Eye and ear disorders: tinnitus, vision blurred
and neonatal opioid withdrawal syndrome shortly after birth. Observe
Abuse and addiction are separate and distinct from physical dependence
the oxycodone and can result in overdose and death [see Overdosage (10)].
Due to characteristics of the formulation that cause the tablets to swell
newborns for symptoms of neonatal opioid withdrawal syndrome, such
and tolerance. Healthcare providers should be aware that addiction may
and become sticky when wet, consider use of an alternative analgesic in
Gastrointestinal disorders: abdominal discomfort, abdominal pain,
Life-threatening Respiratory Depression
as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and
not be accompanied by concurrent tolerance and symptoms of physical
patients who have difficulty swallowing and patients at risk for underlying
manage accordingly [see Warnings and Precautions (5.3)].
dependence. In addition, abuse of opioids can occur in the absence of
XARTEMIS XR (oxycodone hydrochloride and acetaminophen) Extended-
Serious, life-threatening, or fatal respiratory depression has been reported
GI disorders resulting in a small gastrointestinal lumen. Instruct patients
General disorders and administration site conditions: asthenia, chest
true addiction.
Release Tablets combine two analgesics, oxycodone hydrochloride 7.5 mg
FULL PRESCRIBING INFORMATION
with the use of opioids, even when used as recommended. Respiratory
Labor and Delivery
increase. Instruct patients to swallow XARTEMIS XR tablets whole;
not to pre-soak, lick or otherwise wet XARTEMIS XR tablets prior to placing
discomfort, chills, contusion, fall, feeling jittery, malaise, non-cardiac chest
and acetaminophen 325 mg for oral administration.
depression from opioid use, if not immediately recognized and treated,
Opioids cross the placenta and may produce respiratory depression and
XARTEMIS XR, like other opioids, can be diverted for non-medical use
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING
crushing, chewing, or dissolving XARTEMIS XR can cause rapid
in the mouth, and to take one tablet at a time with enough water to ensure
may lead to respiratory arrest and death. Management of respiratory
psycho-physiologic effects in neonates. XARTEMIS XR is not recommended
into illicit channels of distribution. Careful record-keeping of prescribing
RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID
release and absorption of a potentially fatal dose of oxycodone [see
complete swallowing immediately after placing in mouth.
Immune system disorders: hypersensitivity
methylmorphinan-6-one hydrochloride, is an opioid agonist which
depression may include close observation, supportive measures, and
for use in women during or immediately prior to labor. Neonates, whose
information, including quantity, frequency, and renewal requests is
WITHDRAWAL SYNDROME; and HEPATOTOXICITY
Warnings and Precautions (5.2)].
occurs as a white, odorless, crystalline powder having a saline, bitter taste.
use of opioid antagonists, depending on the patient's clinical status [see
5.14 Gastrointestinal Effects
Investigations: alanine aminotransferase increased, aspartate amino-
mothers received opioid analgesics during labor, must be observed closely
strongly advised.
It is derived from the opium alkaloid thebaine. The structural formula for
Addiction, Abuse, and Misuse
Overdosage (10)]. Carbon dioxide (CO
transferase increased, blood lactate dehydrogenase increased, blood
for signs of respiratory depression. An opioid antagonist such as naloxone,
2) retention from opioid-induced
XARTEMIS XR is contraindicated in patients with known or suspected
Proper assessment of the patient, proper prescribing practices, periodic
Accidental ingestion of XARTEMIS XR, especially in children,
oxycodone hydrochloride is as follows:
XARTEMIS XR exposes patients and other users to the risks of
respiratory depression can exacerbate the sedating effects of opioids.
paralytic ileus. Opioids diminish propulsive peristaltic waves in the
pressure increased, gamma-glutamyltransferase increased, liver functional
must be available for reversal of opioid-induced respiratory depression in
re-evaluation of therapy, and proper dispensing and storage are
can result in a fatal overdose of oxycodone [see Warnings and
opioid addiction, abuse, and misuse, which can lead to overdose
While serious, life-threatening, or fatal respiratory depression can occur at
gastrointestinal tract and decrease bowel motility. Monitor for decreased
the neonate.
appropriate measures that help to limit abuse of opioid drugs.
C18H21NO4 • HCl MW = 351.82
and death. Assess each patient's risk prior to prescribing
Metabolic and nutritional: decreased appetite
any time during the use of XARTEMIS XR, the risk is greatest during the
bowel motility in post-operative patients receiving opioids. The
Risks Specifi c to the Abuse of XARTEMIS XR
XARTEMIS XR, and monitor all patients regularly for the
Neonatal Opioid Withdrawal Syndrome
initiation of therapy or following a dose increase. Closely monitor patients
administration of XARTEMIS XR may obscure the diagnosis or clinical
Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal
XARTEMIS XR is intended for oral use only. Abuse of XARTEMIS XR poses
development of these behaviors or conditions [see Warnings and
Prolonged use of XARTEMIS XR during pregnancy can result
for respiratory depression when initiating therapy with XARTEMIS XR and
course in patients with acute abdominal conditions. Oxycodone may
Two large population based studies have evaluated the safety of
a risk of overdose and death. Abuse may occur by taking intact tablets
in neonatal opioid withdrawal syndrome, which may be life-
following dose increases.
cause spasm of the Sphincter of Oddi. Monitor patients with biliary tract
Nervous system disorders: cognitive disorder, memory impairment,
acetaminophen in pregnant women during the first trimester; neither
in quantities greater than prescribed or without legitimate purpose, by
disease, including acute pancreatitis.
threatening if not recognized and requires management according
To reduce the risk of respiratory depression, proper dosing and titration
migraine, myoclonus, paraesthesia, sedation, tremor
study showed an increased risk of congenital malformations. Available
crushing and chewing, or snorting the crushed formulation, or by injecting
Serious, life-threatening, or fatal respiratory depression may occur
to protocols developed by neonatology experts. If opioid use is
of XARTEMIS XR are essential [see Dosage and Administration (2)].
5.15 Cytochrome P450 3A4 Inhibitors and Inducers
Psychiatric disorders: anxiety, confusional state, disorientation, euphoric
published data on oxycodone exposure during pregnancy and risk for
a solution made from the crushed formulation. The risk of overdose and
with use of XARTEMIS XR. Monitor for respiratory depression,
required for a prolonged period in a pregnant woman, advise the
Overestimating the XARTEMIS XR dose when converting patients from
Since the CYP3A4 isoenzyme plays a major role in the metabolism of
mood, mood altered, sleep disorder, withdrawal syndrome
malformations are limited and do not allow conclusions regarding a
death is increased with concurrent abuse of alcohol or other central
especially during initiation of XARTEMIS XR or following a dose
patient of the risk of neonatal opioid withdrawal syndrome and
another opioid product can result in fatal overdose with the first dose.
XARTEMIS XR, drugs that alter CYP3A4 activity may cause changes in
Renal and urinary disorders: urine flow decreased
possible association.
nervous system depressants.
Acetaminophen, 4'-hydroxyacetanilide, is a white, odorless, crystalline
Food Effect
or sperm density in the epididymis, there was a signifi cant increase in the
Information Regarding Nursing
powder, possessing a slightly bitter taste. The structural formula for
When administered with a high- or low-fat meal, median T
percentage of abnormal sperm in mice consuming 1.7 times the MHDD
Advise women to not breastfeed as breastfeeding may cause sedation in
acetaminophen is as follows:
oxycodone were delayed by 2 hours and 1 hour, respectively. Mean AUC
(based on a body surface area comparison) and there was a reduction in
XARTEMIS™ XR (ZAR-tem-iss) (oxycodone hydrochloride and acetaminophen) Extended-Release Tablets, CII
values are increased by 15 to 16% and peak concentrations are 12 to
the number of mating pairs producing a fi fth litter at this dose, suggesting
Cessation of Therapy
25% higher for oxycodone. Food delayed median acetaminophen T
the potential for cumulative toxicity with chronic administration of
If patients have been receiving treatment with XARTEMIS XR for more
by 1.5 hours. There is no change in mean acetaminophen AUC values and
acetaminophen near the upper limit of daily dosing.
XARTEMIS XR is:
than a few weeks and cessation of therapy is indicated, counsel them
peak concentrations are 23 to 24% lower with food. XARTEMIS XR may be
Published studies in rodents report that oral acetaminophen treatment of
on the possibility of withdrawal and provide medical support for safe
• A strong prescription pain medicine that contains an opioid (narcotic) and the medicine acetaminophen. XARTEMIS XR is used to
administered with or without food.
male animals at doses that are 1.2 times the MHDD and greater (based
discontinuation of the product.
C8H9NO2 MW
treat certain types of short term (acute) pain.
on a body surface area comparison) result in decreased testicular weights,
Common Side Eff ects
XARTEMIS XR is an extended-release tablet for oral administration
Following intravenous administration, the volume of distribution (V
reduced spermatogenesis, reduced fertility, and reduced implantation
Advise patients taking XARTEMIS XR of the potential for severe
• A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose
containing both immediate- and extended-release components. for oxycodone was 2.6 L/kg. Oxycodone was approximately 45% bound
sites in females given the same doses. These eff ects appear to increase
constipation; appropriate laxatives and/or stool softeners as well as
XARTEMIS XR is formulated to immediately release a portion of its
to plasma protein at 37°C and a pH of 7.4. Oxycodone has been found in
with the duration of treatment. The clinical signifi cance of these fi ndings
correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
other appropriate treatments should be initiated from the onset of
oxycodone and acetaminophen doses. XARTEMIS XR is designed to
breast milk [see Use in Specific Populations (8.3)].
is not known.
opioid therapy.
swell in gastric fluid and gradually release the remainder of oxycodone
Acetaminophen appears to be widely distributed throughout most
Important information about XARTEMIS XR:
and acetaminophen to the upper gastrointestinal (GI) tract.
14 CLINICAL
Advise patients of the most common adverse reactions that may occur
body tissues except fat. Its apparent volume of distribution is about
while taking XARTEMIS XR: nausea, dizziness, headache, vomiting,
XARTEMIS XR also contains the following inactive ingredients: 0.9 L/kg. A relative small portion ( 20%) of acetaminophen is bound
Post-Operative Bunionectomy Pain Study
• Get emergency help right away if you take too much XARTEMIS XR (overdose). When you fi rst start taking XARTEMIS XR,
constipation and somnolence.
polyethylene oxide (Polyox), microcrystalline cellulose, hydroxypropyl
to plasma protein.
cacy was demonstrated in one multicenter, randomized, double-blind,
when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to
cellulose, croscarmellose sodium, polyvinyl alcohol, magnesium stearate,
placebo-controlled, parallel-arm, multiple-dose clinical trial comparing
XARTEMIS is a trademark of Mallinckrodt LLC.
titanium dioxide, polyethylene glycol, colloidal silicon dioxide, talc,
XARTEMIS XR and placebo in patients with acute pain following a unilateral
death may occur.
Oxycodone hydrochloride is extensively metabolized to noroxycodone,
pregelatinized starch, FD&C Blue #2 aluminum lake, citric acid anhydrous
fi rst metatarsal bunionectomy. A total of 303 patients with a mean age of
oxymorphone, and their glucuronides. The major circulating metabolite
Mallinckrodt, the "M" brand mark, and the Mallinckrodt Pharmaceuticals
• Never give anyone else your XARTEMIS XR. They could die from taking it. Store XARTEMIS XR away from children and in a safe
powder, and edetate disodium.
43 (range 18 to 73) years, meeting criteria for randomization (pain intensity
is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone.
≥4 on a 0 to 10 numerical pain rating scale) and receiving a fi xed-dose of
logo are trademarks of a Mallinckrodt company.
place to prevent stealing or abuse. Selling or giving away XARTEMIS XR is against the law.
12 CLINICAL
Oxymorphone is present in the plasma only in low concentrations. The
2 tablets of XARTEMIS XR 7.5 mg oxycodone hydrochloride and 325 mg
12.1 Mechanism of Action
analgesic activity profile of other metabolites is not known at present.
acetaminophen tablets or placebo every 12 hours over 48 hours were
2014 Mallinckrodt LLC
• Get emergency help right away if you take more than 4,000 mg of acetaminophen in 1 day. Taking XARTEMIS XR with other
Oxycodone HCl is an opioid agonist and is relatively selective for the mu
The formation of oxymorphone, but not noroxycodone, is mediated by
randomized. There were 36 early discontinuations (9% from XARTEMIS XR,
products that contain acetaminophen can lead to serious liver problems and death.
receptor, although it can interact with other opioid receptors at higher
CYP2D6 and as such its formation can, in theory, be affected by other
13% from placebo). Ibuprofen 400 mg every 4 hours as needed was
doses. The principal therapeutic action of oxycodone is analgesia. Like all
drugs [see Warnings and Precautions (5.4, 5.15)].
allowed as rescue medication.
opioid agonists, there is no ceiling effect to analgesia.
Do not take XARTEMIS XR if you have:
Acetaminophen is primarily metabolized in the liver by first-order kinetics
Mean baseline pain intensity scores were 6.2 in the XARTEMIS XR group
Manufactured for:Mallinckrodt Brand Pharmaceuticals, Inc.
Acetaminophen is a non-opioid, non-salicylate analgesic, and antipyretic.
and involves three principal separate pathways:
(range: 4 to 10) and 6.0 in the placebo group (range: 1 to 10). Approximately
• severe asthma, trouble breathing, or other lung problems.
• allergy to acetaminophen or oxycodone.
Hazelwood, MO 63042
The site and mechanism for the analgesic effect of acetaminophen
a) conjugation with glucuronide;
85% of the 150 subjects treated with XARTEMIS XR and 98% of the 153
has not been determined. The antipyretic effect of acetaminophen is
b) conjugation with sulfate; and
subjects treated with placebo took rescue medication at least once for
• a bowel blockage or have narrowing of the stomach or intestines.
accomplished through the inhibition of endogenous pyrogen action on
c) oxidation via the cytochrome, P450-dependent, mixed-function
pain management during the 48 hours after the fi rst dose. Median rescue
the hypothalamic heat-regulating centers.
oxidase enzyme pathway to form a reactive intermediate
medication use was 2 doses for XARTEMIS XR-treated subjects and 4 doses
Before taking XARTEMIS XR, tell your healthcare provider if you have a history of:
metabolite, which conjugates with glutathione and is then further
for placebo-treated subjects over the 48 hours; rescue medication was
metabolized to form cysteine and mercapturic acid conjugates.
used by less than 50% of the XARTEMIS XR-treated patients after the fi rst
• head injury, seizures
• liver, kidney, thyroid problems
Effects on Central Nervous System
The principal cytochrome P450 isoenzyme involved appears to be CYP2E1,
dose interval. Pain intensity was recorded at 2, 4, 8, and 12 hours after each
Oxycodone produces respiratory depression by direct action on brainstem
with CYP1A2 and CYP3A4 as additional pathways.
dose, with additional recordings at 15, 30, 45, 60, and 90 minutes after the
• problems urinating
• pancreas or gallbladder problems
respiratory centers. The respiratory depression involves both a reduction
fi rst dose. The median time to onset of pain relief was less than one hour
in the responsiveness of the brain stem respiratory centers to increases in
In adults, the majority of acetaminophen is conjugated with glucuronic
for XARTEMIS XR. The primary endpoint was the summed pain intensity
• abuse of street or prescription drugs, alcohol addiction, or mental health problems.
carbon dioxide tension and to electrical stimulation.
acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-,
diff erence (change in pain from baseline) over 48 hours (SPID
and glutathione-derived metabolites lack biologic activity. In premature
Oxycodone depresses the cough reflex by direct effect on the cough
demonstrated improvement in pain from baseline for the XARTEMIS XR
Tell your healthcare provider if you are:
infants, newborns, and young infants, the sulfate conjugate predominates.
center in the medulla. Oxycodone causes miosis, even in total darkness.
treatment group compared to placebo.
• pregnant or planning to become pregnant. Prolonged use during pregnancy can cause life-threatening withdrawal symptoms
Pinpoint pupils are a sign of opioid overdose but are not pathognomonic
(e.g., pontine lesions of hemorrhagic or ischemic origins may produce
Oxycodone and its metabolites are eliminated primarily via the kidney.
HOW SUPPLIED/STORAGE AND HANDLING
in your newborn baby if not recognized and treated.
similar findings). Marked mydriasis rather than miosis may be seen due to
The amounts measured in the urine have been reported as follows:
XARTEMIS XR (oxycodone hydrochloride and acetaminophen) Extended-
• breastfeeding. XARTEMIS XR passes into breast milk and may harm your baby.
hypoxia in overdose situations.
free oxycodone up to 19%; conjugated oxycodone up to 50%; free
Release Tablets are oval shaped tablets with a blue coating, debossed
Effects on Gastrointestinal Tract and Other Smooth Muscle
oxymorphone 0%; and conjugated oxymorphone ≤14%. Both free
with "M" in a box over "115" on one side of the tablet. Each tablet contains
• taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking XARTEMIS XR with certain other
Gastric, biliary, and pancreatic secretions are decreased by oxycodone HCl.
and conjugated noroxycodone have been found in urine but not
7.5 mg oxycodone hydrochloride and 325 mg acetaminophen and is
medicines can cause serious side eff ects.
Oxycodone, like other opioid analgesics, produces some degree of nausea
quantified. The total plasma clearance was 0.8 L/min for adults. Apparent
packaged in bottles.
and vomiting which is caused by direct stimulation of the chemoreceptor
elimination half-life (mean ± SD) of oxycodone following administration
trigger zone located in the medulla. The frequency and severity of emesis
of XARTEMIS XR was 4.5 ± 0.6 hours as compared to 3.9 ± 0.3 hours for
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see
When taking XARTEMIS XR:
gradually diminishes with time.
USP Controlled Room Temperature].
• Do not change your dose. Take XARTEMIS XR exactly as prescribed by your healthcare provider.
Oxycodone may cause a decrease in the secretion of hydrochloric acid in
Acetaminophen is eliminated from the body primarily by formation of
DEA FORM REQUIRED
the stomach that reduces motility while increasing the tone of the antrum
glucuronide and sulfate conjugates in a dose-dependent manner Less
• Take your prescribed dose every 12 hours, at the same time every day. If you miss a dose, take XARTEMIS XR as soon as possible,
of the stomach, and duodenum. Digestion of food in the small intestine is
than 9% of acetaminophen is excreted unchanged in urine. Following
PATIENT COUNSELING INFORMATION
then take your next dose 12 hours later. If it is almost time for your next dose, skip the missed dose. Take your next dose at the
delayed and propulsive contractions are decreased. Propulsive peristaltic
administration of XARTEMIS XR, the apparent elimination half-life is
See FDA-approved patient labeling (Medication Guide)
waves in the colon are decreased, while tone may be increased to the
5.8 ± 2.1 hours as compared to 4.1 ± 1.1 hours for immediate-release
Provide the following information to patients receiving XARTEMIS XR or
regular time. Do not take more than your prescribed daily dose in 24 hours.
point of spasm resulting in constipation. Other opioid-induced effects
their caregivers:
may include a reduction in biliary and pancreatic secretions, spasm of
Special Populations
• Swallow XARTEMIS XR whole. Do not cut, break, chew, crush, dissolve, snort or inject XARTEMIS XR because this may cause you to
Sphincter of Oddi, and transient elevations in serum amylase.
Elderly: Population pharmacokinetic studies indicate that the plasma
overdose and die. You should not receive XARTEMIS XR through a nasogastric tube or gastric tube (stomach tube).
Inform patients that XARTEMIS XR is not interchangeable with other forms
Effects on Cardiovascular System
concentrations of oxycodone did not appear to be increased in patients
• Take XARTEMIS XR 1 tablet at a time. Do not pre-soak, lick, or wet the tablet before placing in your mouth. Take each XARTEMIS XR
Oxycodone, in therapeutic doses, produces peripheral vasodilation
over the age of 65. A population pharmacokinetic analysis of data
(arterial and venous), decreased peripheral resistance, and inhibits
obtained from a clinical trial in patients with chronic pain which included
Inform patients XARTEMIS XR is a narcotic pain reliever and must be taken
tablet with enough water to be sure that you swallow it completely as soon as you place it in your mouth.
baroreceptor reflexes. Manifestations of histamine release and/or
55 patients between 65 and 75 years of age and 19 patients over
only as directed.
peripheral vasodilation may include pruritus, flushing, red eyes, sweating,
75 years of age, showed no significant changes in the pharmacokinetics of
Inform patients to take each tablet with enough water to ensure complete
• Call your healthcare provider if XARTEMIS XR does not control your pain.
and/or orthostatic hypotension.
acetaminophen in elderly patients with normal renal and hepatic function.
swallowing immediately after placing in the mouth, and not to pre-soak,
• If you have been taking XARTEMIS XR for more than a few days, do not stop taking it without talking to your healthcare
Caution must be used in hypovolemic patients, such as those suffering
Gender: Population pharmacokinetic analyses performed in a clinical study
lick, or otherwise wet the tablet prior to placing in the mouth.
acute myocardial infarction, because oxycodone may cause or further
support the lack of gender effect on the pharmacokinetics of oxycodone.
Inform patients that XARTEMIS XR tablets must be swallowed whole. Do
aggravate their hypotension. Caution must also be used in patients with
Hepatic Impairment: The pharmacokinetics of XARTEMIS XR in patients
not crush or dissolve. Do not use XARTEMIS XR for administration via
• After you stop taking XARTEMIS XR, fl ush any unused tablets down the toilet.
cor pulmonale who have received therapeutic doses of opioids.
with impaired hepatic function has not been studied. Oxycodone and
nasogastric, gastric, or other feeding tubes as it may cause obstruction of
Endocrine System
acetaminophen are extensively metabolized, resulting in decreased
While taking XARTEMIS XR:
Opioid agonists have been shown to have a variety of effects on the
clearance in patients with hepatic impairment [see Use in Specific
Inform patients that if they miss a dose to take it as soon as possible. If it is
secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and
almost time for the next dose, skip the missed dose and take the next dose
• Do not drive or operate heavy machinery, until you know how XARTEMIS XR aff ects you. XARTEMIS XR can make you sleepy, dizzy,
luteinizing hormone (LH) in humans. They also stimulate prolactin, growth
Renal Impairment: The pharmacokinetics of XARTEMIS XR in patients with
at the regularly scheduled time. Do not take more than 2 tablets at once
hormone (GH) secretion, and pancreatic secretion of insulin and glucagon
renal impairment has not been studied. Patients with renal impairment
unless instructed by their healthcare provider. If they are not sure about
or lightheaded.
in humans and other species, rats, and dogs. Thyroid stimulating hormone
(defined as creatinine clearance <60 mL/min) have higher plasma
their dosing, call their healthcare provider.
• Do not drink alcohol.
(TSH) has been shown to be both inhibited and stimulated by opioids.
concentrations of oxycodone than subjects with normal renal function
Inform patients not to adjust the dose of XARTEMIS XR without consulting
[see Use in Specific Populations (8.7)].
Immune System
with a physician or other healthcare professional.
• Do not take other products that contain acetaminophen while taking XARTEMIS XR.
Opioids have been shown to have a variety of effects on components of
Inform patients not to not take more than 4000 milligrams of
the immune system in in vitro and animal models. The clinical significance
13 NONCLINICAL
acetaminophen per day and to call their doctor if they took more than the
The possible side eff ects of XARTEMIS XR are:
of these findings is unknown.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
recommended dose.
12.3 P harmacokinetics
No carcinogenicity, mutagenicity, or fertility studies were conducted
Addiction, Abuse, and Misuse
• nausea, dizziness, headache, vomiting, constipation, sleepiness. Call your healthcare provider if you have any of these symptoms
with the combination of oxycodone and APAP, the components of
XARTEMIS XR is an extended-release bilayer formulation of oxycodone
Inform patients that the use of XARTEMIS XR , even when taken as
XARTEMIS XR. The following data are based on fi ndings from studies
and they are severe.
and acetaminophen (immediate- and extended-release layers) which is
recommended, can result in addiction, abuse, and misuse, which can
performed with the individual components.
not interchangeable with other oxycodone/acetaminophen products
lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct
Get emergency medical help if you have:
because of differing pharmacokinetic profiles that affect the frequency of
patients not to share XARTEMIS XR with others and to take steps to protect
administration. The activity of oxycodone hydrochloride is primarily due to
No animal studies to evaluate the carcinogenic potential of oxycodone
XARTEMIS XR from theft or misuse.
• trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, low
the parent drug oxycodone.
have been conducted. Long-term studies in mice and rats have
Life-threatening Respiratory Depression
blood pressure when changing positions, or you are feeling faint.
been completed by the National Toxicology Program to evaluate the
Inform patients of the risk of life-threatening of respiratory depression,
The oral bioavailability of oxycodone is 60 to 87%. Bioavailability (dose-
carcinogenic potential of acetaminophen. In 2-year feeding studies,
including information that the risk is greatest when starting XARTEMIS XR
• rash with hives, sores in your mouth or eyes, or your skin blisters and peels.
normalized AUC and C
F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen
max) of oxycodone and acetaminophen following
or when the dose is increased, and that it can occur even at recommended
single- and multiple-doses of XARTEMIS XR tablets is comparable to
up to 6000 ppm. Female rats demonstrated equivocal evidence of
doses [see Warnings and Precautions (5.2)]. Advise patients how to
These are not all the possible side eff ects of XARTEMIS XR. Call your doctor for medical advice about side eff ects. You may report side
immediate-release products containing oxycodone or acetaminophen.
carcinogenic activity based on increased incidences of mononuclear
recognize respiratory depression and to seek medical attention if
eff ects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
cell leukemia at 0.8 times the maximum human daily dose (MHDD) of
Oxycodone plasma concentrations from this bilayer product are detectable
culties develop.
4 grams/day, based on a body surface area comparison. In contrast, there
within 30 minutes and reach a maximum concentration (C
XARTEMIS is a trademark of Mallinckrodt LLC.
max) in 3 to 4 hours
was no evidence of carcinogenic activity in male rats that received up
after XARTEMIS XR administration. Maximum plasma concentrations of
to 0.7 times or mice at up to 1.2-1.4 times the MHDD, on a body surface
Inform patients that accidental exposure, especially in children, may
acetaminophen occur in 0.75 to 1 hour after XARTEMIS XR administration.
area comparison.
result in respiratory depression or death [see Warnings and Precautions
Steady-state plasma concentrations of oxycodone and acetaminophen
(5.2)]. Instruct patients to take steps to store XARTEMIS XR securely and
Mallinckrodt Brand Pharmaceuticals, Inc., Hazelwood, MO 63042 USA, www.Mallinckrodt.com or call 1-800-778-7898
are achieved within 24 hours of initiation of dosing of XARTEMIS XR
to dispose of unused XARTEMIS XR by fl ushing the tablets down the toilet.
(prior to the third dose of two XARTEMIS XR tablets administered
Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma
Neonatal Opioid Withdrawal Syndrome
every 12 hours). XARTEMIS XR produces steady-state maximum plasma
assay in the presence of metabolic activation. There was no evidence
This Medication Guide has been approved by the U.S. Food and Drug Administration. Issue: March 2014
Inform female patients of reproductive potential that prolonged
concentrations of oxycodone that are greater than those following the
of genotoxic potential in an in vitro bacterial reverse mutation assay
use of XARTEMIS XR during pregnancy can result in neonatal opioid
first dose, while concentrations of acetaminophen are comparable to the
(Salmonella typhimurium and Escherichia coli) or in an assay for chromo-
withdrawal syndrome, which may be life-threatening if not recognized
first dose (Table 2).
somal aberrations (in vivo mouse bone marrow micronucleus assay).
and treated [see Warnings and Precautions (5.3)].
Acetaminophen was not mutagenic in the bacterial reverse mutation
Table 2. Mean (SD) Pharmacokinetics of XARTEMIS XR (two 7.5 mg
assay (Ames test). In contrast, acetaminophen tested positive for induction
Interactions with Alcohol and other CNS Depressants
oxycodone and 325 mg acetaminophen extended-release tablets;
of sister chromatid exchanges and chromosomal aberrations in in vitro
Inform patients that potentially serious additive eff ects may occur if
after a single dose and multiple doses every 12 hours for 4.5 days)
assays using Chinese hamster ovary cells. In the published literature,
XARTEMIS XR is used with alcohol or other CNS depressants, and not to
acetaminophen has been reported to be clastogenic when administered a
use such drugs unless supervised by a health care provider.
Single Dose Multiple Dose* Single Dose Multiple Dose*
dose of 1500 mg/kg/day to the rat model (3.6-times the MHDD, based on
Impairment of Mental or Physical Ability
a body surface area comparison). In contrast, no clastogenicity was noted
Inform patients that XARTEMIS XR may cause drowsiness, dizziness, or
at a dose of 750 mg/kg/day (1.8-times the MHDD, based on a body surface
lightheadedness and may impair mental and/or physical ability required
0-12h (ng•h/mL)
24924 (5667) 28160 (5807)
area comparison), suggesting a threshold eff ect.
for the performance of potentially hazardous tasks (e.g., driving, operating
Impairment of Fertility
heavy machinery). Advise patients started on XARTEMIS XR or patients
No animal studies to evaluate the eff ect of oxycodone on male or female
whose dose has been adjusted to refrain from any potentially dangerous
Fluctuation (%)†
fertility have been conducted.
activity until it is established that they are not adversely aff ected.
In studies conducted by the National Toxicology Program, fertility
Use During Pregnancy
assessments have been completed in Swiss CD-1 mice via a continuous
Instruct females of reproductive potential who become or are planning to
breeding study. There were no eff ects on fertility parameters in mice
become pregnant to consult a physician prior to initiating or continuing
* Steady-state results on Day 5 (0-12 hours); † Fluctuation = 100•(Cmax-
consuming up to 1.7 times the MHDD of acetaminophen, based on a body
therapy with XARTEMIS XR. Advise patients that safe use in pregnancy has
Cmin)/Cavg; ‡ Median reported for Tmax; NA = not applicable
surface area comparison. Although there was no eff ect on sperm motility
not been established.
Source: http://www.ofirmev.com/downloads/pdf/OFV12731013-IV-to-PO-discharge.pdf
Conférence de consensus sur l'hypertension portale Les Conférences de Consensus © SNFGE, 2004 COMPLICATIONS DE L'HYPERTENSION PORTALE CHEZ L'ADULTE TEXTE LONG - Paris, 4 et 5 décembre 2003 QUESTIONS POSEES AU JURY Question 1 : Comment traiter une hémorragie aiguë par rupture de varices oesophagiennes ? Question 2 : Que doit-on faire pour prévenir les hémorragies par rupture de varices oesophagiennes ?
Pre-Feasibility of a Central Queensland Intermodal Logistics Final Report – Baseline Analysis and Pre-Feasibility Assessment Central Queensland Intermodal Logistics Hub Incorporated Final Report July, 2012 Pre-Feasibility of a Central Queensland Intermodal Freight Hub Final Report