"The the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) will review the risks and benefits of modified- and prolonged-release paracetamol (acetaminophen) tablets, the agency said today.
Addiction, Abuse, And Misuse
XARTEMIS XR contains oxycodone, a Schedule II controlled substance. As an opioid, XARTEMIS XR exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed XARTEMIS XR and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing XARTEMIS XR, and monitor all patients receiving XARTEMIS XR for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of XARTEMIS XR for the proper management of pain in any given patient. Patients at increased risk may be prescribed modifiedrelease opioid formulations such as XARTEMIS XR, but use in such patients necessitates intensive counseling about the risks and proper use of XARTEMIS XR along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of XARTEMIS XR by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the oxycodone and can result in overdose and death [see OVERDOSAGE].
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see OVERDOSAGE]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of XARTEMIS XR, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with XARTEMIS XR and following dose increases.
To reduce the risk of respiratory depression, proper dosing and titration of XARTEMIS XR are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the XARTEMIS XR dose when converting patients from another opioid product can result in fatal overdose with the first dose.
Accidental consumption of XARTEMIS XR, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of XARTEMIS XR during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be lifethreatening if not recognized and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.
Interactions With Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression, and death may result if XARTEMIS XR is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of XARTEMIS XR in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin XARTEMIS XR is made, start with XARTEMIS XR 1 tablet every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see DRUG INTERACTIONS].
Elderly, Cachectic, And Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating XARTEMIS XR and when XARTEMIS XR is given concomitantly with other drugs that depress respiration [see Life-threatening Respiratory Depression].
Use In Patients With Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with XARTEMIS XR, as in these patients, even usual therapeutic doses of XARTEMIS XR may decrease respiratory drive to the point of apnea [see Life-threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in these patients if possible.
XARTEMIS XR contains oxycodone and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The typical daily acetaminophen contribution from XARTEMIS XR is 1300 mg.
The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.
Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.
Serious Skin Reactions
Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Inform patients about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Head Injury And Increased Intracranial Pressure
The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.
Oxycodone may cause severe hypotension particularly in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs which compromise vasomotor tone such as phenothiazines. Administer XARTEMIS XR with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure. XARTEMIS XR may produce orthostatic hypotension in ambulatory patients [see DRUG INTERACTIONS].
Use With Other Acetaminophen-containing Products
The typical daily acetaminophen-contribution from XARTEMIS XR is 1300 mg. Due to the potential for acetaminophen hepatotoxicity at doses higher than 4000 milligrams/day, XARTEMIS XR should not be used concomitantly with other acetaminophen-containing products.
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue XARTEMIS XR immediately and seek medical care if they experience these symptoms. Do not prescribe XARTEMIS XR for patients with acetaminophen allergy.
Due to characteristics of the formulation that cause the tablets to swell and become sticky when wet, consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen. Instruct patients not to presoak, lick or otherwise wet XARTEMIS XR tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in mouth.
XARTEMIS XR is contraindicated in patients with known or suspected paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of XARTEMIS XR may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxycodone may cause spasm of the Sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis.
Cytochrome P450 3A4 Inhibitors And Inducers
Since the CYP3A4 isoenzyme plays a major role in the metabolism of XARTEMIS XR, drugs that alter CYP3A4 activity may cause changes in clearance of oxycodone which could lead to changes in oxycodone plasma concentrations.
Inhibition of CYP3A4 activity by its inhibitors, such as macrolide antibiotics (e.g., erythromycin), azoleantifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid effects. These effects could be more pronounced with concomitant use of CYP 2D6 and 3A4 inhibitors.
Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, may induce the metabolism of oxycodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in oxycodone plasma concentrations, resulting in a potential lack of efficacy.
If co-administration is necessary, caution is advised when initiating XARTEMIS XR treatment in patients currently taking, or discontinuing CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see DRUG INTERACTIONS].
Driving And Operating Machinery
XARTEMIS XR may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Provide the following information to patients receiving XARTEMIS XR or their caregivers:
Inform patients that XARTEMIS XR is not interchangeable with other forms of oxycodone/acetaminophen.
Inform patients XARTEMIS XR is a narcotic pain reliever and must be taken only as directed.
Inform patients to take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth, and not to pre-soak, lick, or otherwise wet the tablet prior to placing in the mouth.
Inform patients that XARTEMIS XR tablets must be swallowed whole. Do not crush or dissolve. Do not use XARTEMIS XR for administration via nasogastric, gastric, or other feeding tubes as it may cause obstruction of feeding tubes.
Inform patients that if they miss a dose to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regularly scheduled time. Do not take more than 2 tablets at once unless instructed by their healthcare provider. If they are not sure about their dosing, call their healthcare provider.
Inform patients not to adjust the dose of XARTEMIS XR without consulting with a physician or other healthcare professional.
Inform patients not to not take more than 4000 milligrams of acetaminophen per day and to call their doctor if they took more than the recommended dose.
Addiction, Abuse, And Misuse
Inform patients that the use of XARTEMIS XR, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share XARTEMIS XR with others and to take steps to protect XARTEMIS XR from theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting XARTEMIS XR or when the dose is increased, and that it can occur even at recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store XARTEMIS XR securely and to dispose of unused XARTEMIS XR by flushing the tablets down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of XARTEMIS XR during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS AND PRECAUTIONS].
Interactions With Alcohol And Other CNS Depressants
Inform patients that potentially serious additive effects may occur if XARTEMIS XR is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider.
Impairment Of Mental Or Physical Ability
Inform patients that XARTEMIS XR may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery). Advise patients started on XARTEMIS XR or patients whose dose has been adjusted to refrain from any potentially dangerous activity until it is established that they are not adversely affected.
Use During Pregnancy
Instruct females of reproductive potential who become or are planning to become pregnant to consult a physician prior to initiating or continuing therapy with XARTEMIS XR. Advise patients that safe use in pregnancy has not been established.
Information Regarding Nursing
Advise women to not breastfeed as breastfeeding may cause sedation in the infant.
Cessation Of Therapy
If patients have been receiving treatment with XARTEMIS XR for more than a few weeks and cessation of therapy is indicated, counsel them on the possibility of withdrawal and provide medical support for safe discontinuation of the product.
Common Side Effects
Advise patients taking XARTEMIS XR of the potential for severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.
Advise patients of the most common adverse reactions that may occur while taking XARTEMIS XR: nausea, dizziness, headache, vomiting, constipation and somnolence.
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity, mutagenicity, or fertility studies were conducted with the combination of oxycodone and APAP, the components of XARTEMIS XR. The following data are based on findings from studies performed with the individual components.
No animal studies to evaluate the carcinogenic potential of oxycodone have been conducted. Longterm studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 0.7 times or mice at up to 1.2-1.4 times the MHDD, on a body surface area comparison.
Oxycodone hydrochloride was genotoxic in an In vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an In vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations (In vivo mouse bone marrow micronucleus assay).
Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast, acetaminophen tested positive for induction of sister chromatid exchanges and chromosomal aberrations in In vitro assays using Chinese hamster ovary cells. In the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times the MHDD, based on a body surface area comparison), suggesting a threshold effect.
Impairment Of Fertility
No animal studies to evaluate the effect of oxycodone on male or female fertility have been conducted.
In studies conducted by the National Toxicology Program, fertility assessments have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.7 times the MHDD (based on a body surface area comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.
Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies of XARTEMIS XR tablets or oxycodone/acetaminophen in pregnant women. Epidemiological data on oral acetaminophen use in pregnant women show no increased risk of major congenital malformations. The incidence of malformations in human pregnancies has not been established for oxycodone as the data are limited. All pregnancies, regardless of drug exposure, have a background risk of 2 to 4% for major birth defects, and 15 to 20% for pregnancy loss.
No animal reproductive or developmental studies were conducted with the combination of oxycodone and acetaminophen, the components of XARTEMIS XR. The following data are based on findings from studies performed with the individual components. Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen approximately equal to the maximum human daily dose (MHDD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately equal to the MHDD. In mice treated with acetaminophen at doses within the clinical dosing range, a reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation. Reproductive studies in rats and rabbits with doses of oxycodone greater than clinical doses did not show any teratogenic or embryo-fetal toxic effects. XARTEMIS XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Fetal/Neonatal Adverse Reactions
Prolonged maternal use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see WARNINGS AND PRECAUTIONS].
Labor And Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. XARTEMIS XR is not recommended for use in women during or immediately prior to labor. Neonates, whose mothers received opioid analgesics during labor, must be observed closely for signs of respiratory depression. An opioid antagonist such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.
Two large population based studies have evaluated the safety of acetaminophen in pregnant women during the first trimester; neither study showed an increased risk of congenital malformations. Available published data on oxycodone exposure during pregnancy and risk for malformations are limited and do not allow conclusions regarding a possible association.
No reproductive or developmental studies were conducted with the combination of oxycodone and acetaminophen, the components of XARTEMIS XR. The following data are based on findings from studies performed with the individual components.
Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 0.85 times the maximum human daily dose (MHDD = 4 grams/day, based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at doses of 1.2-times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral acetaminophen at doses 0.3-times the MHDD, based on a body surface area comparison. In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.43, 0.87, and 1.7 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. Reproduction studies in Sprague-Dawley rats and New Zealand rabbits revealed that when oxycodone was administered orally at doses up to 16 mg/kg (approximately 2 times the daily oral dose of 90 mg for adults based on a body surface area comparison) and 25 mg/kg (approximately 5 times the daily oral dose of 90 mg based on body surface area comparison), it was non teratogenic or embryo-fetal toxic.
Oxycodone is present in human milk and may result in accumulation and toxicities such as sedation and respiratory depression in some infants. Acetaminophen is present in human milk in small quantities. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to 2% of the maternal dose. There is one well-documented report of a rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. Because of the potential for serious adverse reactions in nursing infants from XARTEMIS XR, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of XARTEMIS XR in pediatric patients under the age of 18 years have not been established.
Of the 607 subjects in the Phase 3 studies treated with XARTEMIS XR, 63 (10.3%) were older than age 65, of which 10 (1.6%) were older than age 75. No untoward or unexpected adverse reactions were seen in the elderly patients who received oxycodone hydrochloride/acetaminophen extendedrelease tablets. However, special precaution should be given when determining the dosing amount and frequency of XARTEMIS XR for geriatric patients, since a greater sensitivity to oxycodone may be observed in this patient population when compared to younger patients.
XARTEMIS XR contains oxycodone and acetaminophen, which are extensively metabolized in the liver. Their clearance may be decreased in patients with hepatic impairment. In patients with hepatic impairment start with one tablet and adjust the dosage as needed. Monitor closely for respiratory depression [see CLINICAL PHARMACOLOGY].
Information from oxycodone HCl indicates that patients with renal impairment (defined as a creatinine clearance < 60 mL/min) had higher plasma concentrations of oxycodone than subjects with normal renal function.
In patients with renal impairment start with one tablet and adjust the dosage as needed. Monitor closely for respiratory depression [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/24/2016
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