"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.
The following treatment-emergent adverse reactions are discussed in more detail in other sections of the labeling:
- Respiratory Depression [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and OVERDOSAGE]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Use With Other Acetaminophen-containing Products [see WARNINGS AND PRECAUTIONS]
- Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
In safety data from two Phase 3 (one placebo-controlled, one open-label) trials where multiple doses of XARTEMIS XR were administered for up to 42 days, the most common adverse reactions (reported by ≥ 10% in any XARTEMIS XR dose group) were: nausea, dizziness and vomiting. The most common reasons for discontinuation due to AEs in these 2 studies (reported by ≥ 1% in any XARTEMIS XR dose group) were vomiting (4.8%) and nausea (4.1%); there were no reports of these adverse reactions in the placebo-treated patients.
A total of 1028 subjects in 14 clinical studies were treated with XARTEMIS XR during the clinical development program, including 892 subjects treated with 15 mg oxycodone and 650 mg acetaminophen. This dosage regimen of XARTEMIS XR was administered to 607 patients in two Phase 3 studies (one placebo-controlled and one open-label).
In a placebo-controlled post-bunionectomy acute pain trial, 329 patients were dosed with 15 mg oxycodone and 650 mg acetaminophen XARTEMIS XR or placebo orally every 12 hours, for approximately 48 hours (blinded period) [see Clinical Studies]. Table 1 lists the adverse reactions reported by ≥ 1% of XARTEMIS XR-treated patients and more frequently in XARTEMIS XRtreated patients compared with placebo.
Table 1: Treatment-Emergent Adverse Reactions*
Reported by ≥ 1% of XARTEMIS XR-Treated Patients and More Frequently than
Placebo in XARTEMIS XR-Treated Patients with Postoperative Bunionectomy Pain
|Preferred Term||XARTEMIS XR
(N = 166)%
(N = 163)%
|Hot flush||1||< 1|
|*A treatment-emergent adverse reaction refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.|
Other Adverse Reactions Observed During The Premarketing Evaluation Of XARTEMIS XR
The following adverse drug reactions not listed above occurred in ≥ 1% of XARTEMIS XR-treated patients in the pooled safety data from two Phase 3 studies (including a placebo-controlled and an open-label non-controlled safety study) where multiple-doses of XARTEMIS XR were administered every 12 hours for up to 42 days:
General disorders and administration site conditions: fatigue
Investigations: hepatic enzyme increased
Psychiatric disorders: insomnia
Respiratory, thoracic and mediastinal disorders: cough
The following adverse drug reactions occurred in < 1% of XARTEMIS XR-treated patients in the pooled safety data from the two Phase 3 studies described above:
Cardiac disorders: palpitations
Eye and ear disorders: tinnitus, vision blurred
Gastrointestinal disorders: abdominal discomfort, abdominal pain, esophageal spasm
Immune system disorders: hypersensitivity
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood lactate dehydrogenase increased, blood pressure increased, gamma-glutamyltransferase increased, liver functional test abnormal
Metabolic and nutritional: decreased appetite
Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal stiffness
Psychiatric disorders: anxiety, confusional state, disorientation, euphoric mood, mood altered, sleep disorder, withdrawal syndrome
Renal and urinary disorders: urine flow decreased
Vascular disorders: flushing, hypertension
Read the Xartemis XR (oxycodone hydrochloride and acetaminophen extended-release) Side Effects Center for a complete guide to possible side effects
The concomitant use of XARTEMIS XR with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and XARTEMIS XR for signs of respiratory depression, sedation and hypotension.
Neuromuscular Blocking Agents
Monoamine Oxidase Inhibitors
Monoamine Oxidase Inhibitors (MAOIs) have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion, and significant depression of respiration or coma. The use of XARTEMIS XR is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Agents Affecting Cytochrome P450 Enzymes
Because the CYP3A4 isoenzyme plays a major role in the metabolism of oxycodone, drugs that inhibit CYP3A4 activity may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP2D6 and 3A4 inhibitors. If coadministration with XARTEMIS XR is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved [see CLINICAL PHARMACOLOGY].
CYP450 3A4 inducers 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, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. If co-administration with XARTEMIS XR is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see CLINICAL PHARMACOLOGY].
Oxycodone is metabolized in part to oxymorphone via the Cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs, including amiodarone and quinidine, and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. However, clinicians should be aware of this possible interaction [see CLINICAL PHARMACOLOGY].
Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with an opioid agonist analgesic such as XARTEMIS XR. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of XARTEMIS XR and/or may precipitate withdrawal symptoms in these patients.
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Drug Abuse And Dependence
XARTEMIS XR contains oxycodone, a mu-opioid agonist of the morphine type and is a Schedule II controlled substance. XARTEMIS XR is subject to misuse, abuse, addiction and criminal diversion [see WARNINGS AND PRECAUTIONS].
All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build-up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in persons with substance abuse disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction.
XARTEMIS XR, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific To The Abuse Of XARTEMIS XR
XARTEMIS XR is intended for oral use only. Abuse of XARTEMIS XR poses a risk of overdose and death. Abuse may occur by taking intact tablets in quantities greater than prescribed or without legitimate purpose, by crushing and chewing, or snorting the crushed formulation, or by injecting a solution made from the crushed formulation. The risk of overdose and death is increased with concurrent abuse of alcohol or other central nervous system depressants.
With intravenous abuse, the inactive ingredients in XARTEMIS XR can result in death, local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Patients may exhibit tolerance to some of the effects of oxycodone. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In patients suspected of having significant physical dependence, withdrawal symptoms may be reduced by tapering therapy.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use In Specific Populations].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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