FDA label 9ec90307-c51c-41b2-9ba2-21c20ca8cd37

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL Addiction, Abuse, and Misuse PALLADONE exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing PALLADONE, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) ]. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of PALLADONE. Monitor for respiratory depression, especially during initiation of PALLADONE or following a dose increase. Instruct patients to swallow PALLADONE capsules whole; crushing, chewing, or dissolving PALLADONE capsules can cause rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5.2) ]. Accidental Ingestion Accidental ingestion of even one dose of PALLADONE, especially by children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.2) ]. Neonatal Opioid Withdrawal Syndrome Prolonged use of PALLADONE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3) ]. Interaction with Alcohol Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking PALLADONE. The co-ingestion of alcohol with PALLADONE may result in increased plasma levels and a potentially fatal overdose of hydromorphone [see Warnings and Precautions (5.4) ]. WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning. PALLADONE exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow PALLADONE capsules whole to avoid exposure to a potentially fatal dose of hydromorphone. ( 5.2 ) Accidental ingestion of PALLADONE, especially in children, can result in fatal overdose of hydromorphone. (5.2) Prolonged use of PALLADONE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.3 ) Instruct patients not to consume alcohol or any products containing alcohol while taking PALLADONE because co-ingestion can result in fatal plasma hydromorphone levels. ( 5.4 )

5 WARNINGS AND PRECAUTIONS Interactions with CNS depressants: Concomitant use may cause profound sedation, respiratory depression, and death. If coadministration is required, consider dose reduction of one or both drugs. ( 5.4 ) Elderly, cachectic, debilitated patients, and those with chronic pulmonary disease: Monitor closely because of increased risk for life-threatening respiratory depression. ( 5.5 ) Hypotensive effect: Monitor during dose initiation and titration ( 5.7 ) Patients with head injury or increased intracranial pressure: Monitor for sedation and respiratory depression. Avoid use of PALLADONE in patients with impaired consciousness or coma susceptible to intracranial effects of CO 2 retention. ( 5.8 ) 5.1 Addiction, Abuse, and Misuse PALLADONE contains hydromorphone, a Schedule II controlled substance. As an opioid, PALLADONE exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. As modified-release products such as PALLADONE deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydromorphone present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed PALLADONE and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing PALLADONE, and monitor all patients receiving PALLADONE for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of PALLADONE for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as PALLADONE, but use in such patients necessitates intensive counseling about the risks and proper use of PALLADONE along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse or misuse of PALLADONE by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death [see Overdosage (10) ]. Opioid agonists such as PALLADONE are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing PALLADONE. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17) ]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10) ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of PALLADONE, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with PALLADONE and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of PALLADONE are essential [see Dosage and Administration (2) ]. Overestimating the PALLADONE dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of PALLADONE, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of PALLADONE during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System Depressants Hypotension, profound sedation, coma, respiratory depression, and death may result if PALLADONE is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of PALLADONE in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin PALLADONE is made, start with 1/3 to 1/2 the calculated starting dose of PALLADONE, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)]. 5.5 Use in Ederly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating PALLADONE and when PALLADONE is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2) ]. 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with PALLADONE, as in these patients, even usual therapeutic doses of PALLADONE may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2) ]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Hypotensive Effect PALLADONE may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7.2)]. Monitor these patients for signs of hypotension after initiating or titrating the dose of PALLADONE. 5.8 Use in Patients with Head Injury or Increased Intracranial Pressure Monitor patients taking PALLADONE who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with PALLADONE. PALLADONE may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of PALLADONE in patients with impaired consciousness or coma. 5.9 Use in Patients with Gastrointestinal Conditions PALLADONE is contraindicated in patients with paralytic ileus. Avoid the use of PALLADONE in patients with other GI obstruction. Because the PALLADONE capsule is nondeformable and does not appreciably change in shape in the GI tract, PALLADONE is contraindicated in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations. It is possible that PALLADONE capsules may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. The hydromorphone in PALLADONE may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. 5.10 Sulfites PALLADONE contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 5.11 Use in Patients with Convulsive or Seizure Disorders The hydromorphone in PALLADONE may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during PALLADONE therapy. 5.12 Avoidance of Withdrawal Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonists (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including PALLADONE. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7.3 )]. When discontinuing PALLADONE, gradually taper the dose [see Dosage and Administration (2.3) ]. Do not abruptly discontinue PALLADONE. 5.13 Driving and Operating Machinery PALLADONE may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of PALLADONE and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3) ] Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)] Hypotensive Effect [see Warnings and Precautions (5.7) ] Gastrointestinal Effects [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.11) ] Most common adverse reactions seen on initiation of therapy are: constipation, nausea, vomiting, somnolence, headache, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals L.P. at (1-888-827-0616); or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 (10) ]. 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 _______________________________ 35.1% ______ 49.5% ______ Body as a Whole 15.7% 18.4% Headache 2.1% 4.7% Asthenia 0.5% 3.2% Infection 5.8% 5.3% _______________________________ ______ ______ Digestive System 13.1% 27.9% Constipation 1.0% 15.8% Nausea 6.3% 10.5% Vomiting 1.6% 3.2% _______________________________ ______ ______ Nervous System 13.1% 11.6% Somnolence 1.6% 4.7% _______________________________ ______ ______ Skin 5.2% 4.7% Pruritus 1.0% 2.6% * 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

<table width="100%"> <caption>Table 2. Adverse Events Reported in the Placebo-Controlled Clinical Trials with Incidence &#x2265; 2% in Patients Receiving PALLADONE Capsules for Nonmalignant Pain</caption> <thead> <tr styleCode="First Last"> <td> <content styleCode="bold"> Body System / Adverse Event</content> <content styleCode="bold">(COSTART Terminology) </content> </td> <td align="center"> <content styleCode="bold"> Placebo*</content> <content styleCode="bold">(N=191)</content> <content styleCode="bold">Double-blind</content> <content styleCode="bold">% </content> </td> <td align="center"> <content styleCode="bold">PALLADONE*</content> <content styleCode="bold">(N=190)</content> <content styleCode="bold">Double-blind</content> <content styleCode="bold">% </content> </td> </tr> </thead> <tbody> <tr> <td> <paragraph> <content styleCode="bold"> Total percentage of patients with AEs</content> </paragraph> <paragraph> <content styleCode="bold">_______________________________</content> </paragraph> </td> <td align="center"> <content styleCode="bold">35.1% ______ </content> </td> <td align="center"> <content styleCode="bold">49.5% ______ </content> </td> </tr> <tr> <td/> <td/> <td/> </tr> <tr> <td> <content styleCode="bold"> Body as a Whole</content> </td> <td align="center"> <content styleCode="bold"> 15.7%</content> </td> <td align="center"> <content styleCode="bold">18.4%</content> </td> </tr> <tr> <td> Headache</td> <td align="center"> 2.1%</td> <td align="center"> 4.7%</td> </tr> <tr> <td>Asthenia</td> <td align="center"> 0.5%</td> <td align="center"> 3.2%</td> </tr> <tr> <td> Infection</td> <td align="center"> 5.8%</td> <td align="center"> 5.3%</td> </tr> <tr> <td> _______________________________</td> <td align="center"> ______</td> <td align="center"> ______</td> </tr> <tr> <td> <content styleCode="bold"> Digestive System</content> </td> <td align="center"> <content styleCode="bold"> 13.1%</content> </td> <td align="center"> <content styleCode="bold"> 27.9%</content> </td> </tr> <tr> <td> Constipation</td> <td align="center"> 1.0%</td> <td align="center"> 15.8%</td> </tr> <tr> <td> Nausea</td> <td align="center"> 6.3%</td> <td align="center"> 10.5%</td> </tr> <tr> <td> Vomiting</td> <td align="center"> 1.6%</td> <td align="center"> 3.2%</td> </tr> <tr> <td> _______________________________</td> <td align="center"> ______</td> <td align="center"> ______</td> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td align="center"> <content styleCode="bold">13.1%</content> </td> <td align="center"> <content styleCode="bold">11.6%</content> </td> </tr> <tr> <td>Somnolence</td> <td align="center"> 1.6%</td> <td align="center"> 4.7%</td> </tr> <tr> <td> _______________________________</td> <td align="center"> ______</td> <td align="center"> ______</td> </tr> <tr> <td> <content styleCode="bold">Skin</content> </td> <td align="center"> <content styleCode="bold"> 5.2%</content> </td> <td align="center"> <content styleCode="bold"> 4.7%</content> </td> </tr> <tr> <td>Pruritus</td> <td align="center"> 1.0%</td> <td align="center"> 2.6%</td> </tr> <tr> <td/> <td/> <td/> </tr> </tbody> </table>