ADVERSE REACTIONS
The safety of Palladone™ Capsules 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™ Capsules 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™ Capsules 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™ Capsules 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 3 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 12mg Palladone™ Capsules than those treated with placebo.drug abuse and dependence (addiction)
TABLE 3. Adverse Events Reported in the Placebo-Controlled Clinical Trials With Incidence ≥ 2% in Patients Receiving Palladone™ Capsules for Nonmalignant Pain | Placebo* (N = 191) | Palladone™* (N = 190) |
Body System/ COSTART Term | Double-blind % | Double-blind % |
* Average exposure was 21 days for Palladoneä and 15 days for placebo. |
Total percentage of patients with AEs | 35.1% | 49.5% |
Body as a Whole | 15.7% | 18.4% |
Headache Asthenia Infection | 2.1% 0.5% 5.8% | 4.7% 3.2% 5.3% |
|
Digestive | 13.1% | 27.9% |
Constipation Nausea Vomiting | 1.0% 6.3% 1.6% | 15.8% 10.5% 3.2% |
|
Nervous | 13.1% | 11.6% |
Somnolence | 1.6% | 4.7% |
|
Skin | 5.2% | 4.7% |
Pruritus | 1.0% | 2.6% |
Adverse Events Observed in Clinical Trials
Palladone™ Capsules have 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™ Capsules. 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™ Capsule 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: vasodilatation, tachycardia, migraine
Digestive: nausea, constipation, vomiting, diarrhea, dyspepsia, anorexia, dry mouth, nausea and vomiting, dysphagia, flatulence
Hematologic and Lymphatic: anemia, leukopenia
Metabolic and Nutritional: peripheral edema, dehydration, edema, generalized edema, hypokalemia, weight loss
Musculoskeletal: arthralgia, bone pain, leg cramps, myalgia
Nervous: somnolence, dizziness, nervousness, confusion, insomnia, anxiety, depression, hypertonia, hypesthesia, paresthesia, tremor, thinking abnormal, hallucinations, speech disorder, agitation, amnesia, tinnitus, abnormal gait
Respiratory: dyspnea, cough increased, rhinitis, pharyngitis, pneumonia, epistaxis, hiccup, hypoxia, pleural effusion
Skin and Appendages: pruritus, sweating, rash
Special Senses: amblyopia, taste perversion
Urogenital: dysuria, urinary incontinence Infrequent Adverse Events
Infrequent Adverse Events
Body as a Whole: face edema, ascites, allergic reaction, cellulitis, overdose, hypothermia, neoplasm, photosensitivity reaction, sepsis, flank pain
Cardiovascular: 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: 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
Hematologic and Lymphatic: ecchymosis, thrombocytopenia, leukocytosis, lymphadenopathy, agranulocytosis, lymphoma like reaction, pancytopenia, petechia
Metabolic and Nutritional: hyperglycemia, hyponatremia, cachexia, hypercalcemia, hypomagnesemia, cyanosis, diabetes mellitus, gout, respiratory acidosis, elevated liver enzymes, thirst
Musculoskeletal: myasthenia
Nervous: 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: 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
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