Palladone

Palladone is part of the drug class:

• Natural opium alkaloids

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Palladone falls into category C. There are no well-controlled studies that have been done in pregnant women. Palladone should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

Take Palladone exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The Palladone dose your doctor recommends will be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• what pain medication you where taking and the dose you were on

• Store Palladone at 25ºC (77ºF).
• Keep this and all medicines out of the reach of children.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; AND NEONATAL OPIOID WITHDRAWAL SYNDROME

Addiction, Abuse, and Misuse

Hydromorphone hydrochloride extended-release tablets expose 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 hydromorphone hydrochloride extended-release tablets, and monitor all patients regularly for the development of these behaviors or conditions.

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of hydromorphone hydrochloride extended-release tablets. Monitor for respiratory depression, especially during initiation of hydromorphone hydrochloride extended-release tablets or following a dose increase. Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole; crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets can cause rapid release and absorption of a potentially fatal dose of hydromorphone.

Accidental Ingestion

Accidental ingestion of even one dose of hydromorphone hydrochloride extended-release tablets, especially by children, can result in a fatal overdose of hydromorphone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of hydromorphone hydrochloride extended-release tablets 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.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Agitation
• bloody, black, or tarry stools
• blurred vision
• changes in behavior
• chest pain or discomfort
• convulsions
• decreased urination
• dry mouth
• fast, pounding, slow or irregular heartbeat
• lightheadedness, dizziness, or fainting
• mood or mental changes
• rapid breathing
• severe stomach pain, cramping, or burning
• stiff neck
• sunken eyes
• thoughts of killing oneself
• trouble breathing
• unusual tiredness
• vomiting of material that looks like coffee grounds, severe and continuing
• wrinkled skin

• Bluish lips or skin
• change in the ability to see colors, especially blue or yellow
• cold, clammy skin
• confusion
• cough
• decrease in frequency of urination or urine amount
• difficulty in passing urine (dribbling)
• dizziness
• fast or weak pulse
• headache
• irregular, fast or slow, or shallow breathing
• loss of appetite
• noisy breathing
• painful urination
• pale or blue lips, fingernails, or skin
• sweating
• tightness in the chest
• trouble sleeping

Get emergency help immediately if any of the following symptoms of overdose occur:

• Cold, clammy skin
• convulsions (seizures)
• drowsiness that is so severe you are not able to answer when spoken to or, if asleep, cannot be awakened
• pinpoint (small) pupils in the eyes
• slow heartbeat
• very slow or troubled breathing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Difficulty having a bowel movement (stool)
• difficulty with moving
• joint pain
• muscle pain or stiffness
• nausea

• Acid or sour stomach
• back pain
• belching
• bloating or swelling of the face, arms, hands, lower legs, or feet
• diarrhea
• discouragement
• feeling sad or empty
• heartburn
• indigestion
• irritability
• loss of interest or pleasure
• muscle spasms
• pain in the arms or legs
• stomach discomfort, upset, or pain
• tingling of the hands or feet
• trouble concentrating
• unusual weight gain or loss

• Being forgetful
• bleeding after defecation
• clumsiness
• continuing ringing or buzzing or other unexplained noise in the ears
• crying
• delusions of persecution, mistrust, suspiciousness, or combativeness
• difficulty with swallowing
• difficulty with walking
• double vision
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• full feeling
• increased appetite
• joint pain, stiffness, or swelling
• loss in sexual ability, desire, drive, or performance
• loss of balance
• low body temperature
• muscle aches
• muscle twitching or jerking
• overactive reflexes
• rhythmic movement of muscles
• runny nose
• seeing, hearing, or feeling things that are not there
• sensation of spinning
• shivering
• slurred speech
• sneezing
• swelling of the feet or lower legs
• trouble with speaking

• Bad, unusual or unpleasant (after) taste
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chills
• constricted, pinpoint, or small pupils (black part of the eye)
• deep or fast breathing with dizziness
• drowsiness
• dry mouth
• false or unusual sense of well-being
• fear or nervousness
• feeling of warmth
• hives or welts
• itching
• muscle stiffness or tightness
• numbness of the feet, hands, and around the mouth
• redness of the face, neck, arms, and occasionally, upper chest
• relaxed and calm feeling
• shaking
• uncontrolled eye movements
• upper stomach pain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

2.1  Initial Dosing 

Palladone should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, Palladone is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning Palladone therapy. As Palladone is only for use in opioid-tolerant patients, do not begin any patient on Palladone as the first opioid.

Patients considered opioid-tolerant are those who are taking at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.

Initiate the dosing regimen for each patient individually; taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Palladone [see Warnings and Precautions (5.2)].

Palladone extended-release capsules must be taken whole. Crushing, chewing, or dissolving Palladone capsules will result in uncontrolled delivery of hydromorphone and can lead to overdose or death [see Warnings and Precautions (5.1)].  

Conversion from Other Oral Opioids to Palladone

Discontinue all other around-the-clock opioid drugs when Palladone therapy is initiated.

While useful tables of opioid equivalents are readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour oral hydromorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone requirements which could result in adverse reaction.

In a Palladone clinical trial with an open-label titration period, patients were converted from their prior opioid to Palladone using the Table 1 as a guide for the initial Palladone dose.  The recommended starting dose of Palladone is 50% of the calculated estimate of daily hydromorphone requirement.  Calculate the estimated daily hydromorphone requirement using Table 1.

Consider the following when using the information in Table 1:

• This is not a table of equianalgesic doses.
• The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to Palladone.
• The table cannot be used to convert from Palladone to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose. Table 1. Conversion Factors to Palladone*

  Prior Oral Opioid	Approximate Oral Conversion Factor
  Hydromorphone	1.00
  Codeine	0.04
  Hydrocodone	0.22
  Methadone†	0.38
  Morphine	0.12
  Oxycodone	0.25

To calculate the estimated Palladone dose using Table 1:

• For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydromorphone daily dose.
• For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose.
• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.

Always round the dose down, if necessary, to the appropriate Palladone strength(s) available.

Example conversion from a single opioid to Palladone:

Step 1:  Sum the total daily dose of the opioid

• 30 mg of oxycodone 2 times = 60 mg total daily dose of oxycodone

Step 2:  Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1

• 60 mg total daily dose of oxycodone x Conversion Factor of 0.25 = 15 mg of oral hydromorphone daily

Step 3:  Calculate the approximate starting dose of Palladone to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose.  Round down, if necessary, to the appropriate Palladone capsule strengths available.

• 50 % of 15 mg is an initial dose of 6 mg of  Palladone once daily
• Adjust individually for each patient

Close observation and frequent titration are warranted until pain management is stable on the new opioid.  Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Palladone.

Conversion from Transdermal Fentanyl to Palladone

Eighteen hours following the removal of the transdermal fentanyl patch, Palladone treatment can be initiated. To calculate the 24-hour Palladone dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of Palladone.  Then reduce the Palladone dose by 50%.

For example:

Step 1: Identify the dose of transdermal fentanyl.

• 75 mg of transdermal fentanyl

Step 2: Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of Palladone.

• 75 mg of transdermal fentanyl : 36 mg total daily dose of Palladone

Step 3: Calculate the approximate starting dose of Palladone to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate Palladone tablet strengths available.

• 50% of 36 mg results in an initial dose of 18 mg, which would be rounded down to 16 mg of Palladone once daily
• Adjust individually for each patient

Conversion from Methadone to Palladone

Close monitoring is of particular importance when converting from methadone to other opioid agonists.  The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure.  Methadone has a long half-life and can accumulate in the plasma.

2.2 Titration and Maintenance of Therapy 

Individually titrate Palladone to a dose that provides adequate analgesia and minimizes adverse reactions.  Continually reevaluate patients receiving Palladone to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse.  Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.  During chronic therapy, periodically reassess the continued need for opioid analgesics.

Plasma levels of Palladone are sustained for 18 to 24 hours. Dosage adjustments of Palladone may be made in increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia.

Patients who experience breakthrough pain may require a dose increase of Palladone, or may need rescue medication with an appropriate dose of an immediate-release analgesic.  If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the Palladone dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced.  Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.3 Discontinuation of Palladone

When a patient no longer requires therapy with Palladone, taper doses gradually, by 25% to 50% every 2 or 3 days down to a dose of 12 mg before discontinuation of therapy, to prevent signs and symptoms of withdrawal in the opioid-tolerant patient.

To dispose of unused Palladone flush all remaining capsules down the toilet or remit to authorities at a certified drug take-back program.

2.4 Hepatic Impairment

Start patients with moderate hepatic impairment on 25% of the Palladone dose that would be prescribed for patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with Palladone and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

2.5 Renal Impairment

Start patients with moderate renal impairment on 50% and patients with severe renal impairment on 25% of the Palladone dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with Palladone and during dose titration. As Palladone is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Use in Specific Populations (8.7)].

2.6 Administration of Palladone

Instruct patients to swallow Palladone capsules intact. The capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5.1)].

Palladone extended-release capsules are available in 12 mg, 16 mg, 24 mg or 32 mg dosage strengths.

The 12 mg extended-release capsules are cinnamon-colored capsules imprinted with “P-XL” on the cap and “12 mg” on the body.

The 16 mg extended-release capsules are pink, imprinted with "P-XL" on the cap and 16 mg on the body.

The 24 mg extended-release capsules are blue, imprinted with "P-XL" on the cap and 24 mg on the body.

The 32 mg extended-release capsules are white, imprinted with "P-XL" on the cap and 32 mg on the body.

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)]

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.

 * 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

7.1 Alcohol

Concomitant use of alcohol with Palladone can result in an increase of hydromorphone plasma levels and potentially fatal overdose of hydromorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on Palladone therapy [see Clinical Pharmacology (12.3)].

7.2 CNS Depressants

The concomitant use of Palladone with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and Palladone for signs of respiratory depression, sedation and hypotension.

When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)].

7.3 Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Mixed agonist/antagonist (pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of Palladone and/or may precipitate withdrawal symptoms in these patients. Avoid the use of mixed agonist/antagonist analgesics in patients receiving Palladone.

7.4 Monoamine Oxidase Inhibitors (MAOIs)

The effects of opioid analgesics may be potentiated by MAOIs. Palladone is not recommended for use in patients who have received MAOIs within 14 days. If concurrent therapy with an MAOI and Palladone is unavoidable, monitor patients for increased respiratory and central nervous system depression.

7.5 Anticholinergics

Anticholinergics or other medications with anticholinergic activity when used concurrently with Palladone may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when Palladone is used concurrently with anticholinergic drugs.