"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 serious adverse reactions are discussed elsewhere in the labeling:
- Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
- Life Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
- Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
- Interactions with Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
- Hypotensive Effect [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS]
- Seizures [see WARNINGS AND PRECAUTIONS]
Clinical Trial Experience
The safety of PALLADONE was evaluated in double-blind clinical trials involving 612 patients with moderate to severe pain. An open-label extension study involving 143 patients with cancer pain was conducted to evaluate the safety of PALLADONE when used for longer periods of time in higher doses than in the controlled trials. Patients were treated with doses averaging 40 to 50 mg of PALLADONE per day (ranging between 12 and 500 mg/day) for several months (range 1 to ≥ 52 weeks).
Serious adverse reactions which may be associated with PALLADONE therapy in clinical use are similar to those of other opioid analgesics, including respiratory depression, apnea, respiratory arrest, and to a lesser degree, circulatory depression, hypotension, shock or cardiac arrest [see OVERDOSAGE].
Adverse Events Reported in Controlled Trials
Table 2 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in the placebo-controlled trials for which the rate of occurrence was greater for those treated with PALLADONE 12 mg capsules than those treated with placebo.
Table 2: Adverse Events Reported in the
Placebo-Controlled Clinical Trials with Incidence ≥ 2% in Patients Receiving
PALLADONE Capsules for Nonmalignant Pain
|Body System / Adverse Event (COSTART Terminology)||Placebo*
|Total percentage of patients with AEs||35.10%||49.50%|
|Body as a Whole||15.70%||18.40%|
|* Average exposure was 21 days for PALLADONE and 15 days for placebo.|
Adverse Events Observed in Clinical Trials
PALLADONE has been administered to 785 individuals during completed clinical trials. The conditions and duration of exposure to PALLADONE varied greatly, and included open-label and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing.
These categories are used in the listing below. The frequencies represent the proportion of 785 patients from these trials who experienced that event while receiving PALLADONE. All adverse events included in this tabulation occurred in at least one patient. Events are classified by body system and listed using the following definitions: frequent adverse events -those occurring in at least 1/100 patients; adverse events occurring with an incidence less than 1% are considered infrequent. These adverse events are not necessarily related to PALLADONE treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
Frequent Adverse Events
Metabolic and Nutritional Disorders: peripheral edema, dehydration, edema, generalized edema, hypokalemia, weight loss
Nervous System: somnolence, dizziness, nervousness, confusion, insomnia, anxiety, depression, hypertonia, hypesthesia, paresthesia, tremor, thinking abnormal, hallucinations, speech disorder, agitation, amnesia, tinnitus, abnormal gait
Skin and Appendages: pruritus, sweating, rash
Special Senses: amblyopia, taste perversion
Infrequent Adverse Events
Cardiovascular System: hypertension, hypotension, syncope, deep thrombophlebitis, arrhythmia, postural hypotension, atrial fibrillation, pallor, bradycardia, electrocardiogram abnormal, myocardial infarction, palpitation, angina pectoris, congestive heart failure, QT interval prolonged, supraventricular tachycardia, thrombosis, cardiomegaly, hemorrhage
Digestive System: fecal impaction, intestinal obstruction, abnormal stools, fecal incontinence, hepatic failure, increased appetite, cholangitis, cholecystitis, colitis, enterocolitis, hepatomegaly, jaundice, liver function tests abnormal, biliary spasm, ileus, eructation, rectal hemorrhage, esophagitis, glossitis, melena, mouth ulceration, gastrointestinal hemorrhage, tongue edema
Endocrine: adrenal cortex insufficiency
Nervous System: abnormal dreams, emotional lability, paranoid reaction, sleep disorder euphoria, incoordination, stupor, ataxia, convulsion, hallucination, hostility, myoclonus, psychosis, vertigo, withdrawal syndrome, apathy, delirium, dementia, drug dependence, nystagmus, twitching, depersonalization, aphasia, cerebrovascular accident, circumoral parasthesia, seizure, hyperkinesia, hypotonia, increased salivation, neuralgia
Additional Adverse Events From Non-U.S. Experience
Addiction, blurred vision, drowsiness, dysphoria, sedation, seizure, physical dependence, biliary spasm, and ileus
Read the Palladone (hydromorphone hydrochloride extended-release capsules) Side Effects Center for a complete guide to possible side effects
Concomitant use of alcohol with PALLADONE can result in an increase of hydromorphone plasma levels and potentially fatal overdose of hydromorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on PALLADONE therapy [see CLINICAL PHARMACOLOGY].
The concomitant use of PALLADONE 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 PALLADONE for signs of respiratory depression, sedation and hypotension.
Mixed Agonist/Antagonist And Partial Agonist Opioid Analgesics
Mixed agonist/antagonist (pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of PALLADONE and/or may precipitate withdrawal symptoms in these patients. Avoid the use of mixed agonist/antagonist analgesics in patients receiving PALLADONE.
Monoamine Oxidase Inhibitors (MAOIs)
The effects of opioid analgesics may be potentiated by MAOIs. PALLADONE is not recommended for use in patients who have received MAOIs within 14 days. If concurrent therapy with an MAOI and PALLADONE is unavoidable, monitor patients for increased respiratory and central nervous system depression.
Anticholinergics or other medications with anticholinergic activity when used concurrently with PALLADONE may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when PALLADONE is used concurrently with anticholinergic drugs.
Drug Abuse And Dependence
PALLADONE contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. PALLADONE can be abused and 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 to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
PALLADONE, 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, as required by law, 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 Abuse of PALLADONE
PALLADONE is intended for oral use only. Abuse of PALLADONE poses a risk of overdose and death. This risk is increased with concurrent abuse of PALLADONE with alcohol and other substances.
Taking cut, broken, chewed, crushed, or dissolved PALLADONE poses a hazard of overdose and death.
With intravenous abuse, the capsule excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV.
Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Both tolerance and physical dependence can develop during chronic opioid therapy. 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, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine) or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
PALLADONE should not be abruptly discontinued [see DOSAGE AND ADMINISTRATION]. If PALLADONE is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.
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: 5/1/2014
Additional Palladone Information
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