Included as part of the PRECAUTIONS section.
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 [see Drug Abuse and Dependence]. 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 [see OVERDOSAGE].
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 [see PATIENT INFORMATION]. 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 [see OVERDOSAGE]. Carbon dioxide (CO2) retention from
opioid-induced respiratory depression can exacerbate the sedating effects of
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 [see DOSAGE AND
ADMINISTRATION]. 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 [see DRUG INTERACTIONS].
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
the use of alternative non-opioid analgesics in these patients if possible.
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) [see DRUG
INTERACTIONS]. Monitor these patients for signs of hypotension after
initiating or titrating the dose of PALLADONE.
Use In Patients With Head Injury Or Increased
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.
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 [see DRUG
When discontinuing PALLADONE, gradually taper the dose [see
DOSAGE AND ADMINISTRATION]. 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 [see WARNINGS AND
PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS].
Advise patients how to recognize respiratory depression and to seek medical
attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially in
children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS].
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
- 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
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
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
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.
Advise patients of the potential for severe constipation,
including management instructions and when to seek medical attention.
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.
Advise female patients that PALLADONE can cause fetal
harm and to inform the prescriber if they are pregnant or plan to become
Advise patients to flush the unused capsules down the
toilet when PALLADONE is no longer needed.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity studies have been conducted in
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
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.
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
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 [see
WARNINGS AND PRECAUTIONS].
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.
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
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 [see INDICATIONS AND USAGE]. 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
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.
The safety and effectiveness of PALLADONE in pediatric
patients below the age of 18 have not been established.
Elderly patients have been shown to be more sensitive to
the adverse effects of opioids compared to the younger population. Of the total
number of subjects in clinical studies of Palladone, 22% were 65 and over, and
6% were 75 and over. Dosages should be adjusted according to the clinical
situation. As with all opioids, the starting dose should be reduced to 1/3 to
½ of the usual dosage in debilitated patients. Respiratory depression is the
chief hazard in elderly or debilitated patients, usually following large
initial doses in non-tolerant patients, or when opioids are given in
conjunction with other agents that depress respiration. Therefore, closely
monitor elderly patients for respiratory and central nervous system depression
when prescribing PALLADONE, particularly during initiation and titration.
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.
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.