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 ?
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.
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 ---------------------
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.
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
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
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.
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.
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.
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.
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.
• 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
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.
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.
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.
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.
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
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.
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