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Examiné médicalement par Kovalenko Svetlana Olegovna, Pharmacie Dernière mise à jour le 09.04.2022
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PALLADONE is indicated for the management of pain in opioid-tolerant patients severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Patients considered opioid tolerant are those who are receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid.
Limitations of Use
- Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve PALLADONE for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
- PALLADONE is not indicated as an as-needed (prn) analgesic.
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. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with PALLADONE.
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.
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 |
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.
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.
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.
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.
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.
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.
PALLADONE est contre-indiqué dans :
- Patients opioïdes non tolérants. Une dépression respiratoire fatale peut survenir chez les patients qui ne sont pas tolérants aux opioïdes.
- Patients souffrant de dépression respiratoire importante
- Patients souffrant d'asthme bronchique aigu ou sévère dans un cadre non surveillé ou en l'absence d'équipement réanimation
- Patients atteints d'iléus paralytique connu ou suspecté
- Les patients qui ont subi des interventions chirurgicales et / ou une maladie sous-jacente entraînant un rétrécissement du tractus gastro-intestinal, ou qui ont des «boucles aveugles» du tractus gastro-intestinal ou une obstruction gastro-intestinale.
- Patients présentant une hypersensibilité (par ex., anaphylaxie) aux médicaments contenant de l'hydromorphone ou du sulfite.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Addiction, Abuse, And Misuse
PALLADONE contains hydromorphone, a Schedule II controlled substance. As an opioid, PALLADONE exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as PALLADONE deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydromorphone present.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed PALLADONE and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing PALLADONE, and monitor all patients receiving PALLADONE for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of PALLADONE for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as PALLADONE, but use in such patients necessitates intensive counseling about the risks and proper use of PALLADONE along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of PALLADONE by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death.
Opioid agonists such as PALLADONE are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing PALLADONE. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of PALLADONE, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with PALLADONE and following dose increases.
To reduce the risk of respiratory depression, proper dosing and titration of PALLADONE are essential. Overestimating the PALLADONE dose when converting patients from another opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of PALLADONE, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of PALLADONE during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, 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.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.
Interactions With Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression, and death may result if PALLADONE is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of PALLADONE in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin PALLADONE is made, start with 1/3 to ½ the calculated starting dose of PALLADONE, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.
Use In Ederly, Cachectic, and Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating PALLADONE and when PALLADONE is given concomitantly with other drugs that depress respiration.
Use In Patients With Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with PALLADONE, as in these patients, even usual therapeutic doses of PALLADONE may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.
Hypotensive Effect
PALLADONE may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of PALLADONE.
Use In Patients With Head Injury Or Increased Intracranial Pressure
Monitor patients taking PALLADONE who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with PALLADONE. PALLADONE may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of PALLADONE in patients with impaired consciousness or coma.
Use In Patients with Gastrointestinal Conditions
PALLADONE is contraindicated in patients with paralytic ileus. Avoid the use of PALLADONE in patients with other GI obstruction.
Because the PALLADONE capsule is nondeformable and does not appreciably change in shape in the GI tract, PALLADONE is contraindicated in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.
It is possible that PALLADONE capsules may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.
The hydromorphone in PALLADONE may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
Sulfites
PALLADONE contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Use In Patients With Convulsive Or Seizure Disorders
The hydromorphone in PALLADONE may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during PALLADONE therapy.
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonists (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including PALLADONE. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.
When discontinuing PALLADONE, gradually taper the dose. Do not abruptly discontinue PALLADONE.
Driving And Operating Machinery
PALLADONE may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of PALLADONE and know how they will react to the medication.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addiction, Abuse, and Misuse
Inform patients that the use of PALLADONE, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death. Instruct patients not to share PALLADONE with others and to take steps to protect PALLADONE from theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening of respiratory depression, including information that the risk is greatest when starting PALLADONE or when the dose is increased, and that it can occur even at recommended doses. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Accidental Ingestion
Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death. Instruct patients to take steps to store PALLADONE securely and to dispose of unused PALLADONE by flushing the capsules down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of PALLADONE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
Interactions with Alcohol and other CNS Depressants
Inform patients that potentially serious additive effects may occur if PALLADONE is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider.
Important Administration Instructions
Instruct patients how to properly take PALLADONE, including the following:
- Swallowing PALLADONE whole
- Not crushing, chewing, splitting or dissolving the capsule
- Using PALLADONE exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
- Not discontinuing PALLADONE without first discussing the need for a tapering regimen with the prescriber
Gastrointestinal Blockage
Advise patients that people with certain stomach or intestinal problems such as narrowing of the intestines or previous surgery may be at higher risk of developing a blockage. Symptoms include abdominal distension, abdominal pain, severe constipation, or vomiting. Instruct patients to contact their healthcare provider immediately if they develop these symptoms.
Hypotension
Inform patients that PALLADONE may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
Driving or Operating Heavy Machinery
Inform patients that PALLADONE may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Anaphylaxis
Inform patients that anaphylaxis has been reported with ingredients contained in PALLADONE. Advise patients how to recognize such a reaction and when to seek medical attention.
Pregnancy
Advise female patients that PALLADONE can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.
Disposal
Advise patients to flush the unused capsules down the toilet when PALLADONE is no longer needed.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
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.
Mutagenesis
Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay.
Impairment of Fertility
Hydromorphone given orally to rats during the mating period caused a slight but statistically significant reduction in implantations at 6.25 mg/kg/day (~1.2 times the human exposure following to 32 mg/day).
Use In Specific Populations
Pregnancy
Clinical Considerations
Fetal/neonatal adverse reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.
Teratogenic Effects -Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. PALLADONE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Hydromorphone was not teratogenic in female rats given oral doses up to 10 mg/kg or female rabbits given oral doses up to 50 mg/kg during the major period of organ development. Estimated exposures in the female rat and rabbit were approximately 3-fold and 6-fold higher than a 32 mg human daily oral dose based on exposure (AUC0-24h).
Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 278 mg/kg during organogenesis (gestation days 8 to10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately 3-fold higher and < 1-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.
Nonteratogenic Effect
In a rat pre-and post-natal study, an increase in pup mortality and a decrease in pup body weight which was associated with maternal toxicity was observed at doses of 2 and 5 mg/kg/day. The maternal no effect level for hydromorphone was 0.5 mg/kg/day which is < 1-fold lower than a 32 mg human daily oral dose on a body surface area. Hydromorphone had no effect on pup development or reproduction when given to female rats during the pre-natal and postnatal periods up to a dose of 5 mg/kg which is equivalent to a 32 mg human daily oral dose on a body surface area basis.
Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.
Labor And Delivery
PALLADONE is not for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor.
Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations.
Nursing Mothers
Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving PALLADONE since hydromorphone is excreted in the milk.
Pediatric Use
The safety and effectiveness of PALLADONE in pediatric patients below the age of 18 have not been established.
Geriatric Use
Hepatic Impairment
PALLADONE was 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.
Hydromorphone may impair the ability to drive and use machines. This is particularly likely at the initiation of treatment with hydromorphone, after dose increase or product rotation and if hydromorphone is combined with alcohol or other CNS depressant substances. Patients stabilised on a specific dosage will not necessarily be restricted. Patients should therefore consult with their physician whether driving or the use of machinery is permitted.
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
- The medicine is likely to affect your ability to drive.
- Do not drive until you know how the medicine affects you.
- It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence'). This defence applies when:
o The medicine has been prescribed to treat a medical or dental problem; and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.
- Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).
Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law
The following serious adverse reactions are discussed elsewhere in the labeling:
- Addiction, Abuse, and Misuse
- Life Threatening Respiratory Depression
- Neonatal Opioid Withdrawal Syndrome
- Interactions with Other CNS Depressants
- Hypotensive Effect
- Gastrointestinal Effects
- Seizures
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.
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.
Table 2: Adverse Events Reported in the Placebo-Controlled Clinical Trials with Incidence ≥ 2% in Patients Receiving PALLADONE Capsules for Nonmalignant Pain
Body System / Adverse Event (COSTART Terminology) | Placebo* (N=191) Double-blind % | PALLADONE* (N=190) Double-blind % |
Total percentage of patients with AEs | 35.10% | 49.50% |
Body as a Whole | 15.70% | 18.40% |
Headache | 2.10% | 4.70% |
Asthenia | 0.50% | 3.20% |
Infection | 5.80% | 5.30% |
Digestive System | 13.10% | 27.90% |
Constipation | 1.00% | 15.80% |
Nausea | 6.30% | 10.50% |
Vomiting | 1.60% | 3.20% |
Nervous System | 13.10% | 11.60% |
Somnolence | 1.60% | 4.70% |
Skin | 5.20% | 4.70% |
Pruritus | 1.00% | 2.60% |
* 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
Présentation clinique
Un surdosage aigu d'opioïdes peut se manifester par une dépression respiratoire, une somnolence évoluant vers la stupeur ou le coma, une flaccidité musculaire squelettique, une peau froide et moite, des pupilles resserrées et parfois un œdème pulmonaire, une bradycardie, une hypotension et la mort. Une mydriase marquée plutôt qu'une myose peut être observée en raison d'une hypoxie sévère dans des situations de surdosage.
Traitement de la surdose
En cas de surdosage, les priorités sont le rétablissement d'un brevet et de voies respiratoires protégées et l'institution d'une ventilation assistée ou contrôlée si nécessaire. Utiliser d'autres mesures de soutien (y compris l'oxygène, les vasopresseurs) dans la gestion des chocs circulatoires et des œdèmes pulmonaires comme indiqué. L'arrêt cardiaque ou les arythmies nécessiteront des techniques avancées de survie.
Les antagonistes des opioïdes, tels que la naloxone et la naltrexone, sont des antidotes spécifiques à la dépression respiratoire résultant d'un surdosage d'opioïdes. Les antagonistes des opioïdes ne doivent pas être administrés en l'absence de dépression respiratoire ou circulatoire cliniquement significative secondaire à un surdosage d'hydromorphone. Ces agents doivent être administrés avec prudence aux patients connus ou soupçonnés d'être physiquement dépendants de PALLADONE. Dans de tels cas, une inversion brutale ou complète des effets des opioïdes peut précipiter un syndrome de sevrage aigu.
Étant donné que la durée de l'inversion devrait être inférieure à la durée d'action de l'hydromorphone dans PALLADONE, surveillez attentivement le patient jusqu'à ce que la respiration spontanée soit rétablie de manière fiable. PALLADONE continuera de libérer l'hydromorphone en ajoutant à la charge hydromorphone jusqu'à 24 heures après l'administration, ce qui nécessite une surveillance prolongée pendant au moins 24 à 48 heures au-delà de la surdose. Si la réponse aux antagonistes des opioïdes est sous-optimale ou non soutenue, un antagoniste supplémentaire doit être indiqué comme indiqué dans les informations de prescription du produit.
Chez un individu physiquement dépendant des opioïdes, l'administration d'un antagoniste des récepteurs des opioïdes peut précipiter un retrait aigu. La gravité du syndrome de sevrage produit dépendra du degré de dépendance physique et de la dose de l'antagoniste administré. Si une décision est prise de traiter une dépression respiratoire grave chez le patient physiquement dépendant, l'administration de l'antagoniste doit être commencée avec soin et par titration avec des doses plus petites que d'habitude de l'antagoniste.
Interaction CNS dépresseur / alcool
Des effets pharmacodynamiques additifs peuvent être attendus lorsque PALLADONE est utilisé en association avec de l'alcool, d'autres opioïdes, des drogues légales ou illicites qui provoquent une dépression du système nerveux central.
Effets sur le système nerveux central
L'hydromorphone produit une dépression respiratoire liée à la dose par action directe sur les centres respiratoires du tronc cérébral. La dépression respiratoire implique une réduction de la réactivité des centres respiratoires du tronc cérébral à l'augmentation de la tension du dioxyde de carbone et à la stimulation électrique.
L'hydromorphone déprime le réflexe contre la toux par effet direct sur le centre contre la toux de la médullaire.
L'hydromorphone provoque une myose, même dans l'obscurité totale. Les pupilles ponctuelles sont un signe de surdosage d'opioïdes mais ne sont pas pathognomiques. Une mydriase marquée, plutôt qu'une myose, peut être observée en raison d'une hypoxie sévère dans des situations de surdosage.
Effets sur le tract gastro-intestinal et les autres muscles lisses
Les sécrétions gastriques, biliaires et pancréatiques sont diminuées par l'hydromorphone. L'hydromorphone entraîne une réduction de la motilité associée à une augmentation du tonus dans l'antre de l'estomac et du duodénum. La digestion des aliments dans l'intestin grêle est retardée et les contractions propulsives diminuent. Les ondes péristaltiques propulsives dans le côlon sont diminuées, tandis que le ton peut être augmenté au point de spasme. Le résultat final est la constipation. L'hydromorphone peut également entraîner une augmentation de la pression des voies biliaires en raison du spasme du sphincter d'Oddi.
Effets sur le système cardiovasculaire
L'hydromorphone produit une vasodilatation périphérique qui peut entraîner une hypotension orthostatique ou une syncope. La libération d'histamine peut être induite par l'hydromorphone et peut contribuer à l'hypotension induite par les opioïdes.
Les manifestations de libération d'histamine ou de vasodilatation périphérique peuvent inclure le prurit, les bouffées vasomotrices, les yeux rouges et la transpiration.
Effets sur le système endocrinien
Les opioïdes inhibent la sécrétion d'ACTH, de cortisol et d'hormone lutéinisante (LH) chez l'homme. Ils stimulent également la prolactine, la sécrétion d'hormone de croissance (GH) et la sécrétion pancréatique d'insuline et de glucagon.
Effets sur le système immunitaire
Il a été démontré que les opioïdes ont divers effets sur les composants du système immunitaire in vitro et modèles animaux. La signification clinique de ces résultats est inconnue. Dans l'ensemble, les effets des opioïdes semblent être modestement immunosuppresseurs.
Absorption
PALLADONE est une formulation à libération prolongée d'hydromorphone. L'administration d'une dose unique de PALLADONE se caractérise par une absorption biphasique, une augmentation relativement rapide à une concentration de pic initiale, suivie d'un deuxième pic plus large avec des concentrations plasmatiques thérapeutiques maintenues pendant l'intervalle posologique de 24 heures. La biodisponibilité absolue de l'hydromorphone de PALLADONE n'a pas été déterminée. Dans des conditions de dosage multiple, la biodisponibilité d'une dose une fois par jour de PALLADONE équivaut à la même dose quotidienne totale d'hydromorphone à libération immédiate administrée en doses fractionnées toutes les 6 heures. La proportionnalité de la dose a été établie en termes de Cmax et d'ASC pour les dosages de 12 mg et 24 mg. La proportionnalité de la forme posologique sur une base ajustée en fonction de la dose a été démontrée pour trois gélules de 12 mg à une gélule de 32 mg.
Dans une étude comparant 12 mg de PALLADONE dosés toutes les 24 heures à 3 mg d'hydromorphone à libération immédiate dosé toutes les 6 heures chez des sujets humains en bonne santé, les deux traitements se sont révélés équivalents en termes de degré d'absorption (ASC) (voir figure 1) . Les caractéristiques de libération prolongée de PALLADONE ont entraîné une baisse des niveaux de pic à l'état d'équilibre (Cmax), des niveaux résiduels plus élevés (Cmin) et une réduction d'environ deux à trois fois de la fluctuation observée avec les comprimés d'hydromorphone à libération immédiate.
Figure 1: Courbes de temps de concentration en hydromorphone plasma à l'état d'équilibre
Les concentrations plasmatiques à l'état d'équilibre avec PALLADONE ont été atteintes dans les 2 à 3 jours suivant le début de l'administration. Ceci est cohérent avec la demi-vie d'élimination terminale apparente moyenne de PALLADONE d'environ 18,6 heures. L'hydromorphone ne s'est pas accumulé de manière significative après plusieurs doses avec une administration une fois par jour.
Les aliments n'ont eu aucun effet significatif sur le pic (Cmax), l'ASC ou l'élimination de l'hydromorphone de PALLADONE (voir figure 2).
Figure 2: Profils pharmacocinétiques Palladone ™ à dose unique
Effet alimentaire
La pharmacocinétique de PALLADONE n'est pas affectée par les aliments, comme indiqué par la bioéquivalence lorsqu'elle est administrée dans des conditions d'alimentation et de jeûne. Par conséquent, PALLADONE peut être administré sans égard aux repas.
Distribution
Après administration intraveineuse d'hydromorphone, le volume de distribution déclaré est de 295 L (4 L / kg). L'hydromorphone est lié à environ 20% aux protéines plasmatiques humaines.
Métabolisme
L'hydromorphone est métabolisé par conjugaison directe ou par réduction de 6 cétos suivie d'une conjugaison. Après absorption, l'hydromorphone est métabolisé en principaux métabolites hydromorphone-3glucuronide, hydromorphone-3-glucoside et dihydroisomorphine-6-glucuronide. Les métabolites les moins répandus, la dihydroisomorphine-6-glucoside, la dihydromorphine et la dihydroisomorphine ont également été observés.
Des métabolites hydromorphoniques ont été trouvés dans le plasma, l'urine et dans les systèmes de test des hépatocytes humains. Cependant, on ne sait pas si l'hydromorphone est métabolisé par le système enzymatique du cytochrome P450. L'hydromorphone est un mauvais inhibiteur des isoformes CYP recombinants humains, y compris les CYP1A2, 2A6, 2C8, 2D6 et 3A4 avec un IC50> 50 μM. Par conséquent, l'hydromorphone ne devrait pas inhiber le métabolisme d'autres médicaments métabolisés par ces isoformes CYP.
Les données non cliniques issues des études conventionnelles de pharmacologie de sécurité, de toxicité à doses répétées et de génotoxicité n'ont pas révélé de risque particulier pour l'homme.
Aucun effet sur la fertilité masculine ou féminine ou les paramètres des spermatozoïdes n'a été observé chez le rat à des doses orales d'hydromorphone de 5 mg / kg / jour (30 mg / m2/ jour, qui est 1,4 fois plus élevé que la dose humaine attendue sur la surface corporelle).
L'hydromorphone n'était pas tératogène chez le rat et le lapin à des doses qui ont provoqué une toxicité maternelle. Un développement fœtal réduit a été trouvé chez le lapin à des doses de 50 mg / kg (le niveau sans effet sur le plan du développement a été établi à une dose de 25 mg / kg ou 380 mg / m2 à une exposition à une substance active (ASC) presque quatre fois supérieure à celle attendue chez l'homme). Aucun signe de toxicité fœtale n'a été observé chez les rats traités avec des doses orales d'hydromorphone pouvant atteindre 10 mg / kg (308 mg / m2 avec une AUC environ 1,8 fois supérieure à celle attendue chez l'homme).
La mortalité des petits de périnatum et de rat post-partum (F1) a augmenté à des doses de 2 et 5 mg / kg / jour et les poids corporels ont été réduits pendant la période de lactation.
Aucune étude de cancérogénicité à long terme n'a été réalisée.
Le lactate de cyclizine s'est révélé précipité en présence de Palladone injection sauf si la solution est suffisamment diluée avec de l'eau pour injection. Il est recommandé d'utiliser de l'eau pour injection comme diluant car la cyclizine s'est révélée précipiter en présence de 0,9% de solution saline.
Le lactate de cyclizine s'est révélé précipité en présence de Jurnista injection sauf si la solution est suffisamment diluée avec de l'eau pour injection. Il est recommandé d'utiliser de l'eau pour injection comme diluant car la cyclizine s'est révélée précipiter en présence de 0,9% de solution saline.
Aucun signe d'incompatibilité n'a été observé entre les deux Palladone injection et marques représentatives des formes injectables des médicaments suivants, lorsqu'ils sont stockés dans des combinaisons à haute et faible dose dans des seringues en polypropylène sur une période de 24 heures à température ambiante (25 ° C).
Butylbromure d'hyoscine
Hydrobromure d'hyoscine
Phosphate de sodium de Dexaméthasone
Halopéridol
Chlorhydrate de midazolam
Chlorhydrate de métoclopramide
Chlorhydrate de lévomépromazine
Bromure de glycopyrronium
Chlorhydrate de kétamine
Aucun signe d'incompatibilité n'a été observé entre les deux Palladone injection, non diluée ou diluée avec une solution de chlorure de sodium à 9 mg / ml (0,9%) pour perfusion, une solution de glucose à 50 mg / ml (5%) pour perfusion ou de l'eau pour préparations injectables, et des marques représentatives de seringues en polypropylène, de tubes en polyéthylène et PVC et sacs de perfusion en PVC ou EVA.
Des incompatibilités ont été observées avec des solutions diluées de 50 mg / ml lorsqu'elles étaient stockées dans des seringues en polycarbonate au-delà de 24 heures à 25 ° C. Alors qu'aucun signe d'incompatibilité n'a été trouvé lorsque les mêmes préparations ont été stockées à 4 ° C jusqu'à 7 jours.
Une manipulation inappropriée de la solution non diluée après ouverture de l'ampoule d'origine ou des solutions diluées peut compromettre la stérilité du produit.
Tout médicament non utilisé ou déchet doit être éliminé conformément aux exigences locales.
Aucun signe d'incompatibilité n'a été observé entre les deux Jurnista injection et marques représentatives des formes injectables des médicaments suivants, lorsqu'ils sont stockés dans des combinaisons à haute et faible dose dans des seringues en polypropylène sur une période de 24 heures à température ambiante (25 ° C).
Butylbromure d'hyoscine
Hydrobromure d'hyoscine
Phosphate de sodium de Dexaméthasone
Halopéridol
Chlorhydrate de midazolam
Chlorhydrate de métoclopramide
Chlorhydrate de lévomépromazine
Bromure de glycopyrronium
Chlorhydrate de kétamine
Aucun signe d'incompatibilité n'a été observé entre les deux Jurnista injection, non diluée ou diluée avec une solution de chlorure de sodium à 9 mg / ml (0,9%) pour perfusion, une solution de glucose à 50 mg / ml (5%) pour perfusion ou de l'eau pour préparations injectables, et des marques représentatives de seringues en polypropylène, de tubes en polyéthylène et PVC et sacs de perfusion en PVC ou EVA.
Des incompatibilités ont été observées avec des solutions diluées de 50 mg / ml lorsqu'elles étaient stockées dans des seringues en polycarbonate au-delà de 24 heures à 25 ° C. Alors qu'aucun signe d'incompatibilité n'a été trouvé lorsque les mêmes préparations ont été stockées à 4 ° C jusqu'à 7 jours.
Une manipulation inappropriée de la solution non diluée après ouverture de l'ampoule d'origine ou des solutions diluées peut compromettre la stérilité du produit.
Tout médicament non utilisé ou déchet doit être éliminé conformément aux exigences locales.