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FDA Approves Palladone (hydromorphone HCl extended-release) Capsules (CII) For The Management Of Persistent, Moderate To Severe Pain

Stamford, Conn., September 24, 2004 – The U.S. Food and Drug Administration (FDA) has approved Palladone™ (hydromorphone HCl extended-release) Capsules (CII) for the management of persistent, moderate to severe pain in patients requiring continuous, around-the-clock analgesia with a high potency opioid for an extended period of time (weeks to months) or longer. The painful conditions may arise from either cancer or non-cancer conditions. While long-acting (q12h) hydromorphone formulations are available in Canada, the United Kingdom, and Germany, Palladone is the first long-acting hydromorphone formulation available in the U.S. The product offers the convenience of once-daily (q24h) dosing and will be available in 12 mg, 16 mg, 24 mg, and 32 mg dosage strengths. Palladone Capsules are expected to be available in retail pharmacies in the first half of 2005.

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 opioid medication equivalent to 12 mg of oral hydromorphone. Palladone Capsules should be administered once every 24 hours. Palladone Capsules should not be used as the first opioid product prescribed for a patient, or in patients who require opioid analgesia for a short period of time. Palladone Capsules are for use in opioid-tolerant patients only. 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. Use in non-opioid-tolerant patients may lead to FATAL RESPIRATORY DEPRESSION.

“This may be a useful therapy for patients taking short-acting opioids whose pain is not well controlled or who may benefit from once-daily dosing,” said Sharon Weinstein, MD, a lead clinical investigator and Associate Professor of Anesthesiology, Neurology and Oncology at the University of Utah in Salt Lake City, Utah.

When prescribing any opioid medication, patients should be assessed for their clinical risks for opioid abuse or addiction and should be closely monitored for signs of misuse, abuse, and addiction throughout the course of therapy.

Palladone Capsules utilize the patented ATC™ delivery system and contain individual controlled-release pellets containing the active ingredient hydromorphone. Upon oral administration, the pellets release the hydromorphone more slowly and for a longer period of time than an immediate-release product. Palladone Capsules are to be swallowed WHOLE and are not to be broken, chewed, opened, dissolved, or crushed. 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.

Palladone Capsules contain the potent Schedule II opioid agonist, hydromorphone. Schedule II opioid agonists have the highest risk of fatal overdoses due to respiratory depression, as well as the highest potential for abuse. Purdue Pharma has designed a comprehensive Risk Management Program (RMP) that is intended to facilitate proper patient selection, reduce abuse, minimize diversion, and avoid pediatric exposure, and other improper uses of Palladone Capsules. The RMP includes extensive medical education, detailed prescribing information, surveillance of medication use and drug diversion, and appropriate interventions when merited.

“Prescribers need an array of pain medicines so that they can select the most appropriate therapy for their patients. Palladone is an important new tool for healthcare professionals treating patients with persistent, moderate to severe pain,” said J. David Haddox, DDS, MD, Vice President of Risk Management & Health Policy at Purdue. “Appropriate patient selection for Palladone is essential. The labeling and medical education components of our Risk Management Program are designed to help prescribers assess and select appropriate patients for Palladone, while the anti-diversion elements of the RMP are intended to help keep this and other strong pain medications out of the hands of people who should not use them.”

For the first 18 months following the launch of Palladone, the company will market the product to a limited number of medical practitioners experienced in prescribing opioid analgesics. During this 18-month period, the company will monitor and collect data on medication use and drug diversion, and report these data to the FDA.

Clinical Trial Results

The efficacy of Palladone Capsules was established in a double-blind, randomized, parallel group, multicenter, placebo-controlled, four-week trial of patients aged 18 and over with pain that was present for at least one month. The majority of these patients were suffering from 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 persistent 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 for control of their pain. Patients randomized to Palladone Capsules maintained adequate analgesia for a significantly longer period of time (P<0.0001) than patients randomized to placebo.

Contraindications and Adverse Reactions

Palladone Capsules are contraindicated for use on an as needed basis (i.e., prn); in situations of significant respiratory depression, especially in unmonitored settings where there is a lack of resuscitative equipment; in patients who have acute or severe bronchial asthma; in patients who have or are suspected of having paralytic ileus; in patients with known hypersensitivity to any of its components or the active ingredient, hydromorphone.

The most common adverse events reported in clinical trials with Palladone Capsules include constipation, nausea, infection, headache, and somnolence. Serious adverse reactions which may be associated with Palladone Capsules therapy in clinical use are similar to those of other opioid analgesics, including respiratory depression, apnea, respiratory arrest, and to a lesser degree, circulatory depression, hypotension, shock, or cardiac arrest. Acute overdosage with hydromorphone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death. Patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 18 hours.

The professional prescribing information for Palladone Capsules contains the following boxed warning:

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

WARNING:

Palladone™ (hydromorphone HCl extended-release) Capsules are indicated for the management of persistent, moderate to severe pain in patients requiring continuous, around-the-clock analgesia with a high potency opioid for an extended period of time (weeks to months) or longer. Palladone™ Capsules should only be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a minimum total daily dose of opiate medication equivalent to 12 mg of oral hydromorphone. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, or at least 30 mg of oral oxycodone/day, or at least 8 mg oral hydromorphone/day, or an equianalgesic dose of another opioid, for a week or longer. Palladone™ Capsules should be administered once every 24 hours.

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

Palladone Capsules are contraindicated for use on an as needed basis (i.e., prn).

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

Palladone™ Capsules are for use in OPIOID-TOLERANT patients ONLY. Use in non-opioid-tolerant patients may lead to FATAL RESPIRATORY DEPRESSION. Overestimating the Palladone dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean apparent 18-hour elimination half-life of Palladone, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 18 hours. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Palladone™ Capsules contain the potent Schedule II opioid agonist, hydromorphone. Schedule II opioid agonists (which include hydromorphone, fentanyl, methadone, morphine, oxycodone, and oxymorphone), have the highest risk of fatal overdoses due to respiratory depression, as well as the highest potential for abuse. Palladone can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing Palladone in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion.

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

Palladone Capsules are to be swallowed WHOLE and are not to be broken, chewed, opened, dissolved or crushed. Taking broken, chewed, dissolved, or crushed Palladone™ Capsules or its contents can lead to the rapid release and absorption of a potentially fatal dose of hydromorphone. Overestimating the Palladone dose when converting the patient from another opioid medication can result in fatal overdose with the first dose. With the long half-life of Palladone (18 hours), patients who receive the wrong dose will require an extended period of monitoring and treatment that may go beyond 18 hours. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Full prescribing information for Palladone Capsules is available at http://www.purduepharma.com/PI/Prescription/Palladone.pdf.


About Purdue Pharma L.P.

Purdue Pharma L.P. and its associated U.S. companies are privately held pharmaceutical companies known for pioneering research on persistent pain. Headquartered in Stamford, CT, Purdue is engaged in the research, development, production, and distribution of both prescription and over-the-counter medicines and hospital products. Additional information about Purdue can be found at www.purduepharma.com.

Source: Purdue Pharma L.P.

Posted: September 2004

Palladone (hydromorphone hydrochloride) FDA Approval History

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