FDA label f832eeaa-faaf-bbdc-64e7-86ef908223a5

WARNING: Palladone™ (hydromorphone hydrochloride extended-release) Capsules are indicated for the management of persistent, moderate to severe pain in patients requiring continuous, around-the-clock analgesia with a high potency opioid for an extended period of time (weeks to months) or longer. Palladone™ Capsules should only be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a minimum total daily dose of opiate medication equivalent to 12 mg of oral hydromorphone. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, or at least 30 mg of oral oxycodone/day, or at least 8 mg oral hydromorphone/day, or an equianalgesic dose of another opioid, for a week or longer. Palladone™ Capsules should be administered once every 24 hours. Appropriate patients for treatment with Palladone Capsules include patients who require high doses of potent opioids on an around-the-clock basis to improve pain control and patients who have difficulty attaining adequate analgesia with immediate-release opioid formulations. Palladone Capsules are contraindicated for use on an as needed basis (i.e., prn). Palladone™ Capsules are NOT intended to be used as the first opioid product prescribed for a patient, or in patients who require opioid analgesia for a short period of time. Palladone™ Capsules are for use in OPIOID-TOLERANT patients ONLY. Use in non-opioid-tolerant patients may lead to FATAL RESPIRATORY DEPRESSION. Overestimating the Palladone dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean apparent 18-hour elimination half-life of Palladone, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 18 hours. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects. Palladone™ Capsules contain the potent Schedule II opioid agonist, hydromorphone. Schedule II opioid agonists (which include hydromorphone, fentanyl, methadone, morphine, oxycodone, and oxymorphone), have the highest risk of fatal overdoses due to respiratory depression, as well as the highest potential for abuse. Palladone can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing Palladone in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Palladone capsules are to be swallowed whole and are not to be broken, chewed, opened, dissolved or crushed. Consuming alcohol while taking palladone™ capsules or taking broken, chewed, dissolved, or crushed palladone™ capsules or its contents can lead to the rapid release and absorption of a potentially fatal dose of hydromorphone. Overestimating the palladone dose when converting the patient from another opioid medication can result in fatal overdose with the first dose. With the long half-life of palladone (18 hours), patients who receive the wrong dose will require an extended period of monitoring and treatment that may go beyond 18 hours. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

WARNINGS Palladone Capsules are to be swallowed WHOLE and are not to be broken, chewed, OPENED, DISSOLVED OR CRUSHED. Consuming alcohol while taking Palladone Capsules or taking broken, chewed, dissolved, or crushed Palladone™ Capsules or capsule contents can lead to the rapid release and absorption of a potentially fatal dose of hydromorphone. Palladone™ Capsules are for use in OPIOID-TOLERANT patients ONLY. Use in non-opioid-tolerant patients may lead to fatal respiratory depression. Misuse, Abuse and Diversion of Opioids Hydromorphone is an opioid agonist of the morphine type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Like other opioid agonists, legal or illicit, hydromorphone can be abused. This should be considered when prescribing or dispensing Palladone™ Capsules in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion (see WARNINGS: Drug Abuse and Addiction ). Breaking, crushing, chewing, or dissolving the contents of a Palladone™ Capsule or consuming alcohol while taking Palladone Capsules can result in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death (see Boxed WARNING ). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. 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. Interactions with Alcohol and Drugs of Abuse Hydromorphone may be expected to have additive effects, when used in conjunction with alcohol, other opioids, or drugs, whether legal or illicit, which cause central nervous system depression. Additionally, consuming alcohol while taking Palladone Capsules can cause significant increases in peak hydromorphone concentrations. Drug Abuse and Addiction Palladone™ Capsules contain an opioid agonist (i.e., hydromorphone), that is a Schedule II controlled substance with high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. Hydromorphone can be abused and is subject to criminal diversion. The high drug content in the extended-release formulation may add to the risk of adverse outcomes from abuse. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in 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 “loss” of prescriptions, tampering with, forging or counterfeiting prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell. 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 addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since Palladone™ Capsules may be diverted for non-medical use, 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. Palladone™ Capsules are intended for oral use only. Consumption of alcohol while taking Palladone Capsules or the use of the broken, crushed, chewed, opened, or dissolved capsule contents poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse can reasonably be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. In addition, parenteral abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Respiratory Depression Respiratory depression is the chief hazard of opioid agonists, including hydromorphone, the active ingredient in Palladone™ Capsules. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. Hydromorphone should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of hydromorphone may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. Head Injury The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in the presence of head injury, intracranial lesions, or other sources of pre-existing increased intracranial pressure. Hydromorphone produces effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Hypotensive Effect Palladone™ Capsules may cause severe hypotension. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume or who are concurrently taking drugs such as phenothiazines or other agents which compromise vasomotor tone. Hydromorphone may produce orthostatic hypotension in ambulatory patients. Hydromorphone, like all opioid analgesics of the morphine-type, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

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

<table ID="table3" width="85%"> <caption>TABLE 3. Adverse Events Reported in the Placebo-Controlled Clinical Trials With Incidence &#x2265; 2% in Patients Receiving Palladone&#x2122; Capsules for Nonmalignant Pain</caption> <col width="29%"/> <col width="28%"/> <col width="28%"/> <thead> <tr> <th> </th> <th align="center">Placebo* (N = 191)</th> <th align="center">Palladone&#x2122;* (N = 190)</th> </tr> <tr> <th align="left">Body System/ COSTART Term</th> <th align="center"> <content styleCode="bold">Double-blind</content> %</th> <th align="center"> <content styleCode="bold">Double-blind</content> %</th> </tr> </thead> <tfoot> <tr> <td colspan="3">* Average exposure was 21 days for Palladone&#xE4; and 15 days for placebo.</td> </tr> </tfoot> <tbody> <tr styleCode="Botrule"> <td align="left">Total percentage of patients with AEs</td> <td align="center">35.1%</td> <td align="center">49.5%</td> </tr> <tr> <td align="left">Body as a Whole</td> <td align="center">15.7%</td> <td align="center">18.4%</td> </tr> <tr styleCode="Botrule"> <td align="left"> Headache Asthenia Infection</td> <td align="center"> 2.1% 0.5% 5.8%</td> <td align="center">4.7% 3.2% 5.3%</td> </tr> <tr styleCode="Botrule"> <td colspan="3"> </td> </tr> <tr> <td align="left">Digestive</td> <td align="center">13.1%</td> <td align="center">27.9%</td> </tr> <tr styleCode="Botrule"> <td align="left"> Constipation Nausea Vomiting</td> <td align="center"> 1.0% 6.3% 1.6%</td> <td align="center">15.8% 10.5% 3.2%</td> </tr> <tr styleCode="Botrule"> <td colspan="3"> </td> </tr> <tr> <td align="left">Nervous</td> <td align="center">13.1%</td> <td align="center">11.6%</td> </tr> <tr styleCode="Botrule"> <td align="left"> Somnolence</td> <td align="center"> 1.6%</td> <td align="center">4.7%</td> </tr> <tr styleCode="Botrule"> <td colspan="3"> </td> </tr> <tr styleCode="Botrule"> <td align="left">Skin </td> <td align="center">5.2%</td> <td align="center">4.7%</td> </tr> <tr> <td align="left"> Pruritus</td> <td align="center"> 1.0%</td> <td align="center">2.6%</td> </tr> </tbody> </table>