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Palladone (Hydromorphone Hydrochloride) - Indications and Dosage

 
 



CLINICAL TRIALS

The efficacy of Palladone™ Capsules was established in a double-blind, randomized, parallel group, multicenter, placebo-controlled, four-week trial of patients with pain that was present for at least one month. The majority of these patients experienced moderate to severe pain due to musculoskeletal disorders while maintained on one or more opioid analgesics, often in addition to non-opioid analgesics. Two hundred twenty-one patients with chronic moderate to severe pain were randomized to receive once daily 12 mg Palladone™ Capsules or placebo after they had demonstrated that they needed approximately 12 mg of immediate-release hydromorphone (in addition to non-opioid medication) around-the-clock to improve their pain control. Patients randomized to Palladone™ Capsules maintained adequate analgesia for a significantly longer period of time (P<0.0001) than patients randomized to placebo.

INDICATIONS AND USAGE

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, 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. Appropriate patients for treatment with Palladone include patients who require high doses of potent opioids on an around-the-clock basis to improve pain control, and patients who have difficulty attaining adequate analgesia with immediate-release opioid formulations.

Palladone™ Capsules are NOT intended to be used:

  • as the first opioid product prescribed for a patient.
  • in patients who require opioid analgesia for a short period of time.
  • on an as needed basis (i.e., prn).

An evaluation of the appropriateness and adequacy of immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction.

DOSAGE AND ADMINISTRATION

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.

  • 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.


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

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

  • 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.

TABLE 4. Multiplication Factors for Converting the Daily Dose of Prior Opioids to the Daily Dose of Oral Hydromorphone* (MG/Day Prior Opioid x Factor = MG/Day Oral Hydromorphone)
Factor
PRIOR OPIOID
ORALPARENTERAL
* To be used only for conversion TO oral hydromorphone. For patients receiving high-dose parenteral opioids, a more conservative conversion is warranted. For example, for high dose parenteral morphine, use 0.38 instead of 0.75 as a multiplication factor, i.e., halve the multiplication factor.
Codeine0.04
Hydrocodone0.22
Hydromorphone1.005.00
Levorphanol1.883.75
Meperidine0.020.10
Methadone0.38 0.75
Morphine0.120.75
Oxycodone 0.25

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.

SPECIAL HANDLING AND STORAGE CONDITIONS

Palladone™ Capsules are solid dosage forms that contain hydromorphone which is a controlled substance. Like fentanyl, methadone, morphine, oxycodone, and oxymorphone, hydromorphone is controlled under Schedule II of the Federal Controlled Substances Act.

Palladone™ Capsules may be targeted for theft and diversion by criminals.

Healthcare professionals can telephone Purdue Pharma's Medical Services Department (1-888-726-7535) for information on this product.

HOW SUPPLIED

Palladone™ (hydromorphone hydrochloride extended-release) Capsules 12 mg are cinnamon-colored capsules imprinted with P-XL on the cap and 12 mg on the body. They are available in multiple-use containers, not intended for dispensing directly to the patient. They are supplied as follows:

NDC 59011-312-60: opaque plastic bottles of 60 capsules
NDC 59011-312-20: Unit dose packaging with 20 capsules; 10 individually numbered blister units per card: two cards per carton

Palladone™ (hydromorphone hydrochloride extended-release) Capsules 16 mg are pink capsules imprinted with P-XL on the cap and 16 mg on the body. They are available in multiple-use containers, not intended for dispensing directly to the patient. They are supplied as follows:

NDC 59011-313-60: opaque plastic bottles of 60 capsules
NDC 59011-313-20: Unit dose packaging with 20 capsules; 10 individually numbered blister units per card; two cards per carton

Palladone™ (hydromorphone hydrochloride extended-release) Capsules 24 mg are blue capsules imprinted with P-XL on the cap and 24 mg on the body. They are available in multiple-use containers, not intended for dispensing directly to the patient. They are supplied as follows:

NDC 59011-314-60: opaque plastic bottles of 60 capsules
NDC 59011-314-20: Unit dose packaging with 20 capsules; 10 individually numbered blister units per card; two cards per carton

Palladone™ (hydromorphone hydrochloride extended-release) Capsules 32 mg are white capsules imprinted with P-XL on the cap and 32 mg on the body. They are available in multiple-use containers, not intended for dispensing directly to the patient. They are -supplied as follows:

NDC 59011-315-60: opaque plastic bottles of 60 capsules
NDC 59011-315-20: Unit dose packaging with 20 capsules; 10 individually numbered blister units per card; two cards per carton

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].

Avoid temperatures above 40°C (104°F) [See USP Excessive Heat]

Dispense in a tight, light-resistant container.

CAUTION

DEA ORDER FORM REQUIRED.

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