Central Nervous System

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.

Hydromorphone produces respiratory depression by direct action of brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem to increases in carbon dioxide and to electrical stimulation.

Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Hydromorphone causes miosis even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of Palladone™ Capsule overdose (see OVERDOSAGE).

Gastrointestinal System

Hydromorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and in the duodenum. Digestion of food is delayed in the small intestine and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid induced-effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System

Hydromorphone may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Endocrine System

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Absorption

Administration of a single Palladone™ Capsule dose is characterized by biphasic absorption, a relatively rapid rise to an initial peak concentration, followed by a second broader peak with therapeutic plasma concentrations maintained over the 24-hour dosing interval. The absolute bioavailability of hydromorphone from Palladone™ Capsules has not been determined. Under conditions of multiple dosing, the bioavailability of a once-daily dose of Palladone™ Capsules is equivalent to the same total daily dose of immediate-release hydromorphone given in divided doses every 6 hours. Hydromorphone absorption from Palladone Capsules is pH independent but can be significantly increased in the presence of alcohol (see PHARMACOKINETICS: Drug Interactions). Dose proportionality has been established in terms of Cmax and AUC for the 12 mg and 24 mg dosage strengths. Dosage form proportionality on a dose-adjusted basis has been demonstrated for three 12 mg capsules to one 32 mg capsule.

In a study comparing 12 mg Palladone™ Capsules dosed every 24 hours to 3 mg of immediate-release hydromorphone dosed every 6 hours in healthy human subjects, the two treatments were found to be equivalent in terms of extent of absorption (AUC) (see Figure 1). The extended-release characteristics of Palladone™ Capsules resulted in lower steady-state peak levels (Cmax), higher trough levels (Cmin), and an approximately twofold to threefold reduction in the fluctuation seen with the immediate-release hydromorphone tablets.

Steady-state plasma concentrations with Palladone™ Capsules were achieved within 2 to 3 days after initiation of dosing. This is consistent with the mean apparent terminal elimination half-life for Palladone™ of approximately 18.6 hours. This supports the ability to titrate every 2 to 3 days, as necessary. Hydromorphone did not accumulate significantly after multiple dosing with once-daily administration.

Food had no significant effect on the peak (Cmax), AUC or the elimination of hydromorphone from Palladone™ Capsules (See Figure 2.).

Distribution

Following intravenous admininstration of hydromorphone, the reported volume of distribution is 295 L (4 L/kg). Hydromorphone is approximately 20% bound to human plasma proteins.

Metabolism

Hydromorphone is metabolized by direct conjugation, or by 6-keto reduction followed by conjugation. Following absorption, hydromorphone is metabolized to the major metabolites hydromorphone-3-glucuronide, hydromorphone-3-glucoside and dihydroisomorphine-6-glucuronide. Also observed were the less prevalent metabolites, dihydroisomorphine-6-glucoside, dihydromorphine and dihydroisomorphine.

Hydromorphone metabolites have been found in plasma, urine and in human hepatocyte test systems. However, it is not known whether hydromorphone is metabolized by the cytochrome P450 enzyme system. Hydromorphone is a poor inhibitor of human recombinant CYP isoforms including CYP1A2, 2A6, 2C8, 2D6, and 3A4 with an IC50 > 50 µM. Therefore, hydromorphone is not expected to inhibit the metabolism of other drugs metabolized by these CYP isoforms.

Elimination

Full mass balance and recovery studies have not been reported for extended-release hydromorphone products. However, hydromorphone and its metabolites have been recovered in urine following the use of immediate-release hydromorphone. Following intravenous administration of hydromorphone, terminal half-life is approximately 3 hours and clearance is 1.66 L/hr. The apparent terminal half-life with controlled release hydromorphone is about 18.6 hours.

Drug Interactions

Concomitant administration of H2 receptor blockers (cimetidine, famotidine, ranitidine) or proton pump inhibitors (omeprazole, lansoprazole) showed no significant effect on Palladone™ steady-state pharmacokinetics.

Patients taking Palladone with other opioid analgesics, general anesthetics, phenothiazines, tricyclic antidepressants or other CNS depressants may experience additional CNS depression and therefore, dose adjustments should be considered. Consuming alcohol while taking Palladone Capsules can cause significant increases in peak hydromorphone concentrations.

Pediatric

The safety and effectiveness of Palladone™ Capsules have not been established in patients below the age of 18.

Geriatric

Age-related increases in exposure in clinical studies were observed between geriatric and younger adult subjects. Greater sensitivity of some older individuals cannot be excluded. Dosages should be adjusted according to the clinical situation.

Gender

Pharmacokinetics of hydromorphone from Palladone™ Capsules are comparable in men and women.

Renal Impairment

In patients with mild to moderate renal impairment, based on calculated creatinine clearance, the concentrations of hydromorphone in plasma were slightly higher than in subjects with normal renal function.

Hepatic Impairment

Palladone™ Capsules were not studied in patients with severe hepatic insufficiency and are not recommended for use in such patients. Care in initial dose selection and careful observation are recommended in patients with evidence of lesser degrees of hepatic impairment.

Race

The pharmacokinetics of hydromorphone in African Americans and Caucasians in the clinical population were comparable.

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.

General

Opioid analgesics have a narrow therapeutic index in certain patient populations, especially when combined with CNS depressant drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known risks of respiratory depression, altered mental state, and postural hypotension.

Use of Palladone™ Capsules is associated with increased potential risks and should be used only with caution in the following conditions: alcoholism, alcohol abuse or alcohol intoxication; drug abuse; history of drug or alcohol abuse; adrenocortical insufficiency (e.g., Addison's disease); CNS depression or coma; debilitated patients; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of hepatic, pulmonary or renal function; and toxic psychosis.

The administration of any opioid agonist, including hydromorphone, may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydromorphone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Use in Pancreatic/Biliary Tract Disease

Hydromorphone may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like hydromorphone may cause increases in the serum amylase concentration.

Tolerance

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical Dependence

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

Information for Patients/Caregivers

The healthcare professional should explain the points listed below to caregivers and patients.

1. Patients should be instructed to read the Medication Guide each time Palladone is dispensed because new information may be available. The complete text of the Medication Guide is reprinted at the end of this document.
2. Patients should be aware that Palladone™ Capsules contain hydromorphone, which is a strong pain medication similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone.
3. Palladone™ Capsules are only to be swallowed whole. To prevent fatal overdose, the capsules and the pellets must not be broken, chewed, crushed, opened, or dissolved. Patients should be instructed not to consume alcohol while taking Palladone Capsules.
4. Patients should talk to their doctor if pain persists or worsens while they are taking Palladone™ Capsules. Patients who have bothersome side effects should also let their doctors know. The amount of medicine the patient takes may have to be changed.
5. Patients should NEVER change the amount of Palladone™ Capsules they take without speaking to their doctor first.
6. Palladone™ Capsules can affect a person’s ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Patients taking Palladone™ Capsules should be warned of these dangers and counseled accordingly.
7. Patients should NOT combine Palladone™ Capsules with alcohol or other pain medications, sleep aids, or tranquilizers except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
8. Women who become pregnant, or who plan to become pregnant, should ask their doctor about the effects that Palladone™ Capsules (or any medicine) may have on them and their unborn children.
9. Patients should be advised that if they have been receiving treatment with Palladone™ Capsules for more than a few weeks and the medicine is no longer needed, they should contact their doctor who will advise them on how to gradually decrease the medication. When Palladone™ Capsules are no longer needed, the unused capsules should be flushed down the toilet.
10. The active ingredient in Palladone™ Capsules is hydromorphone, which is a drug that some people abuse. Palladone™ Capsules should be taken only by the patient it was prescribed for, and it should be protected from theft or misuse in the work or home environment.
11. Patients should be instructed to keep Palladone™ Capsules in a secure place out of the reach of children. Children, especially small children, exposed to Palladone™ Capsules are at high risk of FATAL RESPIRATORY DEPRESSION.

Use in Drug and Alcohol Addiction

Palladone™ Capsules are not approved for use in detoxification or maintenance treatment of opioid addiction. However, the history of an addictive disorder does not necessarily preclude the use of this medication for the treatment of chronic pain. These patients will require intensive monitoring for signs of misuse, abuse, or addiction.

CNS Depressants

Hydromorphone should be dosed with caution in patients who are concurrently taking other central nervous system depressants that may cause respiratory depression, hypotension, profound sedation or potentially result in coma. Such agents include barbiturates, other sedatives or hypnotics, general anesthetics, other opioid analgesics, phenothiazines and other neuroleptics, centrally acting anti-emetics, benzodiazepines or other tranquilizers, and alcohol.

Muscle Relaxants

Hydromorphone may interact with skeletal muscle relaxants to enhance neuromuscular blocking action to increase respiratory depression.

Mixed Agonist-Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as hydromorphone. In this situation, significant doses of mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs)

No specific interaction between hydromorphone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate. MAOI therapy should be discontinued for at least two weeks prior to the initiation of therapy with Palladone™ Capsules.

H2 Antagonists/Proton Pump Inhibitors

In the patients enrolled in the clinical trials, Palladone™ exposure and effects on pain were comparable when administered with or without various H2 antagonists/proton pump inhibitors.

Drug/Laboratory Test Interactions

There is no known interference of this drug with laboratory tests.

Food

The bioavailability of Palladone™ Capsules is not significantly affected by food.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted in animals.

Hydromorphone was negative in the in vitro  bacterial reverse mutation assay and in the in vivo  mouse micronucleus assay. Hydromorphone was negative in the mouse lymphoma assay in the absence of metabolic activation, but was positive in the mouse lymphoma assay in the presence of metabolic activation. Morphinone, an impurity, tested as a besylate salt was negative in the in vitro  bacterial reverse mutation assay and negative in the in vivo  mouse micronucleus assay. Morphinone was positive in the Chinese Hamster Ovary Cell Chromosomal Aberration test in the absence and presence of metabolic activation.

Hydromorphone did not affect fertility in rats at oral doses up to 5 mg/kg which is equivalent to a 32 mg human daily oral dose on a body surface area basis.

Pregnancy

Labor and Delivery

Palladone™ Capsules are not recommended to be initiated prior to or during labor or in the immediate post-partum period. Women who are taking opioids during pregnancy should not be withdrawn abruptly during labor and delivery, but maintained on their current dose of medication since abrupt withdrawal can precipitate delivery. Neonates whose mothers have been taking hydromorphone chronically may exhibit respiratory depression and/or withdrawal symptoms, at birth and/or in the post-delivery period.

Neonatal Withdrawal Syndrome

Chronic use of opioids during pregnancy can affect the fetus with subsequent withdrawal symptoms. Neonatal withdrawal syndrome presents as irritability, hyperactivity and loss of sleep pattern, abnormal crying, tremor, vomiting, diarrhea and subsequent weight loss or failure to gain weight and may result in death. The duration and severity of neonatal withdrawal syndrome varies based on the drug used, duration of use, the time and dose of last maternal use, and rate of elimination by the newborn. Use standard care as medically appropriate.

Nursing Mothers

Low concentrations of opioid analgesics have been detected in breast milk with the potential for withdrawal symptoms when administration of opioid analgesics to the mother is stopped. The distribution of hydromorphone has not been studied. It is prudent to assume that hydromorphone would also distribute into breast milk. Ordinarily, nursing should not be undertaken while a patient is receiving Palladone™ Capsules because of the possibility of sedation and/or respiratory depression in the infant.

Pediatric Use

The safety and effectiveness of Palladone™ Capsules have not been established in patients below the age of 18 years.

Geriatric Use

Of the total number of subjects in clinical studies of Palladone™ Capsules, 22% were 65 and over, and 6% were 75 and over. Dosages should be adjusted according to the clinical situation. As with all opioids, the starting dose should be reduced to 1/3 to 1/2 of the usual dosage in debilitated patients. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.

Laboratory Monitoring

Due to the broad range of plasma concentrations that are associated with individual daily dose requirements to achieve adequate pain relief, the varying degrees of pain, and the development of tolerance seen in patient populations, plasma hydromorphone measurements are usually not helpful in clinical management.

Hepatic Impairment

Palladone™ Capsules were not studied in patients with severe hepatic impairment and are not recommended for use in such patients. Care in initial dose selection and careful observation are recommended in patients with evidence of mild to moderate hepatic impairment.

Renal Impairment

In patients with mild to moderate renal impairment, based on calculated creatinine clearance, the concentrations of hydromorphone in plasma were slightly higher than in subjects with normal renal function. Dosages should always be adjusted according to the clinical situation.

Gender

There were no male/female differences detected for efficacy, pharmacokinetic metrics or adverse events in clinical trials.

Race

Analgesia and adverse events were similar in the various ethnic groups included in the clinical program.

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)

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

Special Precautions

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 from respiratory depression, as well as the highest potential for abuse. Hydromorphone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.

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 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 are for use in OPIOID-TOLERANT patients only. Use in non-opioid-tolerant patients may lead to FATAL RESPIRATORY DEPRESSION.

General Principles

Palladone™ 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, generally 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 oral oxycodone/day, or at least 8 mg oral hydromorphone/day, or an equianalgesic dose of another opioid, for a week or longer. It is usually appropriate to treat a patient with only one opioid for around-the-clock therapy.

Palladone™ Capsules are not intended to be used on an as needed basis or as the first opioid product prescribed for a patient, or in patients who require opioid analgesia for a short period of time.

The extended-release nature of the formulation allows it to be administered once every 24 hours (see CLINICAL PHARMACOLOGY).

Physicians should individualize treatment using a progressive plan of pain management such as outlined by the World Health Organization, the American Pain Society and the Federation of State Medical Boards Model Policy. Healthcare professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring (see BOXED WARNING).

Initiation of Therapy

Palladone™ Capsules are for use in opioid-tolerant patients ONLY.

It is critical to initiate the dosing regimen individually for each patient, taking into account the patient’s prior opioid treatment. 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.

Attention should be given to:

• the patient’s medical condition, past medical history, co-morbid conditions and concurrent medications;
• risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion;
• the intensity, pattern, quality and expected duration of pain;
• the daily dose, potency and kind of opioid the patient has been taking;
• whether adjustments should be made to any non-opioid analgesic(s) the patient has been taking;
• the clinical variability of any conversion estimate used to calculate the dose of hydromorphone; and
• the balance between an adequate level of pain control and adverse experiences.

The total daily (24-hour) dose of the patient’s previous opioid should be determined.

1. Using standard conversion ratio estimates (see Table 4 below), multiply the milligrams per day of the previous opioids by the appropriate conversion factors to obtain the equivalent total daily dose of oral hydromorphone. The conversion ratios represent a reasonable starting point, although they have not been verified in well-controlled, multiple-dose trials.

   
   

2. Modify the dose if indicated, based primarily on considerations outlined in the 7 bulleted items listed above.

3. Round off to a dose which is appropriate for the capsule strengths available (12 mg, 16 mg, 24 mg, and 32 mg capsules).

4. Discontinue all other around-the-clock opioid analgesics when Palladone™ Capsules are initiated.

No fixed conversion ratio is likely to be satisfactory in all patients, especially patients receiving large opioid doses. The recommended doses are only a starting point, and close observation and frequent titration is indicated until a satisfactory dose is obtained on the new therapy.

Most patients given around-the-clock therapy with controlled-release opioids may need to have immediate-release medication available for exacerbations of pain or to treat or prevent pain that occurs predictably during certain patient activities (incident pain).

Palladone™ Capsules can be safely used concomitantly with usual doses of non-opioid analgesics and analgesic adjuvants, provided care is taken to select a proper initial dose (see PRECAUTIONS).

Conversion from Transdermal Fentanyl to Palladone™ Capsules

Eighteen hours following the removal of the transdermal fentanyl patch, Palladone™ Capsule treatment can be initiated. A conservative hydromorphone dose, approximately 12 mg once a day of Palladone™, should be initially substituted for each 50 µg/hr of transdermal fentanyl. The patient should be observed closely for early titration as there is very limited clinical experience with this conversion.

Conversion from Opioid Combination Drugs

Patients currently receiving around-the-clock fixed-combination-opioid analgesics, and greater than or equal to a daily dose of 45 mg of oxycodone or hydrocodone equivalents or 300 mg daily dose of codeine equivalents, may be started on 12 mg of Palladone™ Capsules once daily. The non-opioid component of the combination product may be continued as a separate drug. Alternatively, a different non-opioid analgesic may be selected.

Supplemental (Rescue) Analgesics

Most patients given around-the-clock therapy with controlled-release opioids may need to have immediate-release medication available for exacerbations of pain or to treat or prevent pain that occurs predictably during certain patient activities (incident pain).

Individualization of Dosage

Once therapy is initiated, pain relief and other opioid effects should be assessed frequently. Palladone™ Capsules should be titrated to adequate effect (generally mild or less pain with the regular use of no more than two doses of supplemental analgesics per 24 hours). Rescue medication should be available (see Supplemental [Rescue] Analgesics). Because steady-state plasma concentrations are achieved within approximately 2 to 3 days of therapy with Palladone™, dosage adjustment can be carried out as frequently as every two days, when clinically necessary. If more than two doses of rescue medication are needed within a 24 hour period for two consecutive days, the dose of Palladone™ should usually be titrated upward. This formulation should be administered once every 24 hours. As a guideline, the total daily hydromorphone dose (including rescue) usually can be increased by 25% to 50% of the current dose at each upward titration.

If signs of excessive opioid-related adverse experiences are observed, the dose may be reduced. If this adjustment leads to inadequate analgesia, a supplemental dose of immediate-release opioid analgesic may be given. Alternatively, non-opioid analgesic adjuvants may be administered. Dose adjustments should be made to obtain an appropriate balance between pain relief and opioid-related adverse experiences.

If common opioid-related adverse events occur before the therapeutic goal of pain relief is achieved, the events should be effectively treated prior to continuing upward titration of Palladone™ Capsules. Once adverse events are under control, upward titration should continue to an acceptable level of pain control.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient and the caregiver/family.

Managing Expected Opioid Adverse Reactions

Many patients receiving opioids will experience adverse reactions. Frequently the adverse reactions from Palladone™ Capsules are transient, but often they require evaluation and management. Certain opioid adverse reactions such as constipation should be anticipated and effectively and prophylactically treated with a stimulant laxative and/or stool softener. Patients do not usually become tolerant to the constipating effects of opioids.

Other opioid-related adverse reactions such as sedation and nausea are usually self-limited and often do not persist beyond the first few days. If nausea persists and is unacceptable to the patient, treatment with antiemetics or other modalities may relieve these symptoms and should be considered.

Continuation of Therapy

The intent of the titration period is to establish a patient-specific daily dose that will provide adequate analgesia with acceptable side effects and minimal rescue doses (2 or less) for as long as pain relief is necessary. Should pain recur, the dose can be increased to re-establish pain control. The method of therapy adjustment outlined above should be employed to regain pain control.

During chronic around-the-clock opioid therapy, patients should be followed closely and their pain should be reassessed as clinically indicated. Patients should continue to be assessed for their clinical risks for opioid abuse or addiction, particularly with high-dose formulations.

Cessation of Therapy

When the patient no longer requires therapy with Palladone™ Capsules, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient. Proper disposal of unused capsules should be ensured by flushing them down the toilet.

Conversion from Palladone™ Capsules to Parenteral Opioids

To avoid overdose, conservative dose conversion ratios should be followed.