Package Insert and Label Information: Palladone
PALLADONE- hydromorphone hydrochloride capsule, extended release
Purdue Pharma L.P.
FOR USE IN OPIOID-TOLERANT PATIENTS ONLY
WARNING:
Palladone™ (hydromorphone hydrochloride 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. 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 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.
DESCRIPTION
Palladone™ (hydromorphone hydrochloride extended-release) Capsules are an opioid analgesic supplied in 12 mg, 16 mg, 24 mg, and 32 mg capsule strengths for oral administration. The pellet formulation is the same for all capsule strengths. The strength designation of each capsule indicates the amount of hydromorphone hydrochloride salt. The structural formula, molecular description, and molecular weight are shown below:
Hydromorphone, a fine, white (or nearly white), crystalline powder, is a semi-synthetic congener of morphine. The inactive ingredients in the pellets are ammonio methacrylate copolymer type B, ethylcellulose, and stearyl alcohol. The inactive ingredients in the capsules and the inks used to imprint them are FD&C blue #2 (24 mg strength capsule only), gelatin, red iron oxide (12 mg and 16 mg strength capsules only), synthetic black iron oxide, and titanium dioxide.
Palladone™ Capsules are based on a controlled-release melt extrusion technology in which pellets containing hydromorphone HCl and co-melted excipients release the active ingredient significantly more slowly and for a longer period than an immediate-release product. Palladone™ Capsules are designed to provide controlled delivery of hydromorphone over 24 hours. The 12 mg, 16 mg, 24 mg, and 32 mg capsules are filled with identical pellets using different fill weights to achieve different strengths.
Palladone™ Capsules are for use in opioid-tolerant patients only. Use in non-opioid-tolerant patients may lead to fatal respiratory depression.
CLINICAL PHARMACOLOGY
Hydromorphone is a pure opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, fentanyl, codeine, and hydrocodone. Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, cough suppression, and analgesia. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.
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.
PHARMACOKINETICS
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.
SPECIAL POPULATIONS
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.
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.
Palladone 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.
