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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*
(N=191)
Double-blind %
PALLADONE*
(N=190)
Double-blind %
Total percentage of patients with AEs 35.10% 49.50%
Body as a Whole 15.70% 18.40%
Headache 2.10% 4.70%
Asthenia 0.50% 3.20%
Infection 5.80% 5.30%
Digestive System 13.10% 27.90%
Constipation 1.00% 15.80%
Nausea 6.30% 10.50%
Vomiting 1.60% 3.20%
Nervous System 13.10% 11.60%
Somnolence 1.60% 4.70%
Skin 5.20% 4.70%
Pruritus 1.00% 2.60%
* 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

Body as a Whole: headache, asthenia, pain, abdominal pain, fever, chest pain, infection, chills, malaise, neck pain, carcinoma, accidental injury

Cardiovascular System: vasodilatation, tachycardia, migraine

Digestive System: nausea, constipation, vomiting, diarrhea, dyspepsia, anorexia, dry mouth, nausea and vomiting, dysphagia, flatulence

Hemic and Lymphatic System: anemia, leukopenia

Metabolic and Nutritional Disorders: peripheral edema, dehydration, edema, generalized edema, hypokalemia, weight loss

Musculoskeletal: arthralgia, bone pain, leg cramps, myalgia

Nervous System: somnolence, dizziness, nervousness, confusion, insomnia, anxiety, depression, hypertonia, hypesthesia, paresthesia, tremor, thinking abnormal, hallucinations, speech disorder, agitation, amnesia, tinnitus, abnormal gait

Respiratory System: dyspnea, cough increased, rhinitis, pharyngitis, pneumonia, epistaxis, hiccup, hypoxia, pleural effusion

Skin and Appendages: pruritus, sweating, rash

Special Senses: amblyopia, taste perversion

Urogenital System: dysuria, urinary incontinence

Infrequent Adverse Events

Body as a Whole: face edema, ascites, allergic reaction, cellulitis, overdose, hypothermia, neoplasm, photosensitivity reaction, sepsis, flank pain

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

Hemic and Lymphatic System: ecchymosis, thrombocytopenia, leukocytosis, lymphadenopathy, agranulocytosis, lymphoma like reaction, pancytopenia, petechia

Metabolic and Nutritional Disorders: hyperglycemia, hyponatremia, cachexia, hypercalcemia, hypomagnesemia, cyanosis, diabetes mellitus, gout, respiratory acidosis, elevated liver enzymes, thirst

Musculoskeletal: myasthenia

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

Respiratory System: hypoventilation, apnea, atelectasis, hemoptysis, asthma, hyperventilation, pulmonary embolus, laryngismus

Skin and Appendages: urticaria, maculopapular rash, alopecia

Special Senses: abnormal vision, diplopia, dry eyes, lacrimation disorder, hyperacusis

Urogenital: urinary retention, hematuria, impotence, urinary frequency, urination impaired, dysmenorrhea, creatinine increased, urinary urgency

Additional Adverse Events From Non-U.S. Experience

Addiction, blurred vision, drowsiness, dysphoria, sedation, seizure, physical dependence, biliary spasm, and ileus