Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
EMBEDA contains morphine, a Schedule II controlled
substance. As an opioid, EMBEDA exposes users to the risks of addiction, abuse,
and misuse [see Drug Abuse and Dependence]. As modified-release products
such as EMBEDA deliver the opioid over an extended period of time, there is a
greater risk for overdose and death due to the larger amount of morphine
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed EMBEDA 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 EMBEDA, and monitor all patients receiving
EMBEDA 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 EMBEDA for the proper management of pain in any given patient.
Patients at increased risk may be prescribed modified-release opioid
formulations such as EMBEDA, but use in such patients necessitates intensive
counseling about the risks and proper use of EMBEDA along with intensive
monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of EMBEDA by crushing, chewing, snorting,
or injecting the dissolved product will result in the uncontrolled delivery of
the morphine and can result in overdose and death [see OVERDOSAGE].
Misuse or abuse of EMBEDA by these methods may also release sufficient
naltrexone to precipitate withdrawal in opioid-dependent individuals [see Avoidance of Withdrawal].
Opioid agonists such as EMBEDA are sought by drug abusers
and people with addiction disorders and are subject to criminal diversion.
Consider these risks when prescribing or dispensing EMBEDA. 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 EMBEDA, the risk is greatest
during the initiation of therapy or following a dose increase. Closely monitor
patients for respiratory depression when initiating therapy with EMBEDA and
following dose increases.
To reduce the risk of respiratory depression, proper
dosing and titration of EMBEDA are essential [see DOSAGE AND ADMINISTRATION].
Overestimating the EMBEDA dose when converting patients from another opioid
product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of EMBEDA,
especially by children, can result in respiratory depression and death due to
an overdose of morphine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of EMBEDA 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 drug elimination by the newborn.
Interactions With Central Nervous System Depressants
Patients must not consume alcoholic beverages or
prescription or non-prescription products containing alcohol while on EMBEDA
therapy. The co-ingestion of alcohol with EMBEDA may result in increased plasma
levels and a potentially fatal overdose of morphine. [see CLINICAL
Hypotension, profound sedation, coma, respiratory
depression, and death may result if EMBEDA 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 EMBEDA 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 EMBEDA is made, start
with EMBEDA 20 mg/0.8 mg every 24 hours, 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 Elderly, 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
EMBEDA and when EMBEDA is given concomitantly with other drugs that depress
respiration [see Life-Threatening Respiratory Depression].
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 EMBEDA, as in these patients, even usual therapeutic
doses of EMBEDA may decrease respiratory drive to the point of apnea [see Life-Threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in
these patients if possible.
EMBEDA 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 EMBEDA. In patients with circulatory shock,
EMBEDA may cause vasodilation that can further reduce cardiac output and blood
pressure. Avoid the use of EMBEDA in patients with circulatory shock.
Use In Patients With Head Injury Or Increased
Monitor patients taking EMBEDA 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 EMBEDA.
EMBEDA 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 EMBEDA in patients with impaired
consciousness or coma.
Use In Patients With Gastrointestinal Conditions
EMBEDA is contraindicated in patients with paralytic
ileus. Avoid the use of EMBEDA in patients with other GI obstruction.
The morphine in EMBEDA may cause spasm of the sphincter
of Oddi. Monitor patients with biliary tract disease, including acute
pancreatitis, for worsening symptoms. Opioids may cause increases in serum amylase.
Use In Patients With Convulsive Or Seizure Disorders
The morphine in EMBEDA 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 EMBEDA therapy.
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine)
analgesics in patients who have received or are receiving a course of therapy
with a full opioid agonist analgesic, including EMBEDA. In these patients,
mixed agonists/antagonist and partial agonist analgesics may reduce the
analgesic effect and/or may precipitate withdrawal symptoms.
Consuming EMBEDA capsules that have been altered by
crushing, chewing, or dissolving the pellets can release sufficient naltrexone
to precipitate withdrawal in opioid-dependent individuals. Symptoms of
withdrawal usually appear within five minutes of ingestion of naltrexone and
can last for up to 48 hours. Mental status changes can include restlessness,
lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis.
Significant fluid losses from vomiting and diarrhea can require intravenous
(IV) fluid administration.
When discontinuing EMBEDA, gradually taper the dose [see
DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue EMBEDA.
Driving And Operating Machinery
EMBEDA may impair the mental 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 EMBEDA and know how they will react to the
Interference With Laboratory Tests
Naltrexone does not interfere with thin-layer,
gas-liquid, and high performance liquid chromatographic methods which may be
used for the separation and detection of morphine, methadone, or quinine in the
urine. Naltrexone may or may not interfere with enzymatic methods for the
detection of opioids depending on the specificity of the test. Consult the test
manufacturer for specific details.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide and Instructions for Use)
Addiction, Abuse, and Misuse
Inform patients that the use of
EMBEDA, 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
EMBEDA with others and to take steps to protect EMBEDA from theft or misuse.
Inform patients of the risk of
life-threatening respiratory depression, including information that the risk is
greatest when starting EMBEDA 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 EMBEDA securely and to dispose of
unused EMBEDA by flushing the capsules down the toilet.
Neonatal Opioid Withdrawal
Inform female patients of
reproductive potential that prolonged use of EMBEDA 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
Instruct patients not to consume
alcoholic beverages, or prescription and non-prescription products that contain
alcohol, during treatment with EMBEDA. The co-ingestion of alcohol with EMBEDA
may result in increased plasma levels and a potentially fatal overdose of
morphine [see WARNINGS AND PRECAUTIONS].
Inform patients that
potentially serious additive effects may occur if EMBEDA is used with alcohol
or other CNS depressants, and not to use such drugs unless supervised by a
Important Administration Instructions
Instruct patients how to properly take EMBEDA, including
- Swallow EMBEDA capsules whole or sprinkle the capsule
contents on applesauce and then swallow immediately without chewing
- Do not crush, chew, or dissolve the pellets contained in
the capsules due to a risk of fatal morphine overdose or naltrexone
- precipitated withdrawal
symptoms in opioid-dependent individuals
- Use EMBEDA exactly as
prescribed to reduce the risk of life-threatening
adverse reactions (e.g., respiratory depression)
- Do not discontinue EMBEDA
without first discussing the need for a tapering regimen with the prescriber
Inform patients that EMBEDA 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
Inform patients that EMBEDA 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 EMBEDA. Advise
patients how to recognize such a reaction and when to seek medical attention.
Advise female patients that
EMBEDA can cause fetal harm and to inform the prescriber if they are pregnant
or plan to become pregnant.
Disposal of Unused EMBEDA
Advise patients to flush the unused
capsules down the toilet when EMBEDA is no longer needed.
This product's label may have
been updated. For current full prescribing information please visit www.pfizer.com.
Impairment Of Fertility
Studies in animals to evaluate
the carcinogenic potential of morphine have not been conducted.
No formal studies to assess the
mutagenic potential of morphine have been conducted. In the published
literature, morphine was found to be mutagenic in vitro increasing DNA
fragmentation in human T-cells. Morphine was reported to be mutagenic in the in
vivo mouse micronucleus assay and positive for the induction of chromosomal
aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies
suggest that the in vivo clastogenic effects reported with morphine in mice may
be related to increases in glucocorticoid levels produced by morphine in this
species. In contrast to the above positive findings, in vitro studies in the
literature have also shown that morphine did not induce chromosomal aberrations
in human leukocytes or translocations or lethal mutations in Drosophila.
Impairment of Fertility
No formal nonclinical studies
to assess the potential of morphine to impair fertility have been conducted.
Several nonclinical studies from the literature have demonstrated adverse
effects on male fertility in the rat from exposure to morphine. One study in
which male rats were administered morphine sulfate subcutaneously prior to
mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily)
with untreated females, a number of adverse reproductive effects including
reduction in total pregnancies, higher incidence of pseudopregnancies, and
reduction in implantation sites were seen. Studies from the literature have
also reported changes in hormonal levels (i.e., testosterone, LH, serum
corticosterone) following treatment with morphine. These changes may be
associated with the reported effects on fertility in the rat.
Use In Specific Populations
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
Teratogenic Effects - Pregnancy Category C
There are no adequate and
well-controlled studies in pregnant women. EMBEDA should be used during
pregnancy only if the potential benefit justifies the potential risk to the
In humans, the frequency of
congenital anomalies has been reported to be no greater than expected among the
children of 70 women who were treated with morphine during the first four
months of pregnancy, or in 448 women treated with morphine anytime during pregnancy.
Furthermore, no malformations were observed in the infant of a woman who
attempted suicide by taking an overdose of morphine and other medication during
the first trimester of pregnancy.
Several literature reports
indicate that morphine administered subcutaneously during the early gestational
period in mice and hamsters produced neurological, soft tissue and skeletal
abnormalities. With one exception, the effects that have been reported occurred
following doses that were maternally toxic and the abnormalities noted were
characteristic of those observed when maternal toxicity is present. In one
study, following subcutaneous infusion of doses greater than or equal to 0.15
mg/kg to mice, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital,
malformed sternebrae, and malformed xiphoid were noted in the absence of
maternal toxicity. In the hamster, morphine sulfate given subcutaneously on
gestation day 8 produced exencephaly and cranioschisis. In rats treated with
subcutaneous infusions of morphine during the period of organogenesis, no
teratogenicity was observed. No maternal toxicity was observed in this study,
however, increased mortality and growth retardation were seen in the offspring.
In two studies performed in the rabbit, no evidence of teratogenicity was
reported at subcutaneous doses up to 100 mg/kg.
Infants born to mothers who
have taken opioids chronically may exhibit neonatal withdrawal syndrome [see WARNINGS
AND PRECAUTIONS], reversible reduction in brain
volume, small size, decreased ventilatory response to CO2 and increased risk of
sudden infant death syndrome. Morphine should be used by a pregnant woman only
if the need for opioid analgesia clearly outweighs the potential risks to the
Controlled studies of chronic
in utero morphine exposure in pregnant women have not been conducted. Published
literature has reported that exposure to morphine during pregnancy in animals
is associated with reduction in growth and a host of behavioral abnormalities
in the offspring. Morphine treatment during gestational periods of
organogenesis in rats, hamsters, guinea pigs and rabbits resulted in the
following treatment-related embryotoxicity and neonatal toxicity in one or more
studies: decreased litter size, embryo-fetal viability, fetal and neonatal body
weights, absolute brain and cerebellar weights, delayed motor and sexual
maturation, and increased neonatal mortality, cyanosis and hypothermia.
Decreased fertility in female offspring, and decreased plasma and testicular
levels of luteinizing hormone and testosterone, decreased testes weights,
seminiferous tubule shrinkage, germinal cell aplasia, and decreased
spermatogenesis in male offspring were also observed. Decreased litter size and
viability were observed in the offspring of male rats administered morphine (25
mg/kg, IP) for 1 day prior to mating. Behavioral abnormalities resulting from
chronic morphine exposure of fetal animals included altered reflex and motor
skill development, mild withdrawal, and altered responsiveness to morphine
persisting into adulthood.
Labor And Delivery
Opioids cross the placenta and
may produce respiratory depression in neonates. EMBEDA is not for use in women
during and immediately prior to labor, when shorter acting analgesics or other
analgesic techniques are more appropriate. Opioid analgesics can prolong labor
through actions that temporarily reduce the strength, duration, and frequency
of uterine contractions. However this effect is not consistent and may be
offset by an increased rate of cervical dilatation, which tends to shorten
Morphine is excreted in breast
milk, with a milk to plasma morphine AUC ratio of approximately 2.5:1. The
amount of morphine received by the infant varies depending on the maternal
plasma concentration, the amount of milk ingested by the infant, and the extent
of first pass metabolism. Closely monitor infants of nursing women receiving
Withdrawal symptoms can occur
in breast-feeding infants when maternal administration of morphine is stopped.
Because of the potential for
adverse reactions in nursing infants from EMBEDA, a decision should be made
whether to discontinue nursing or discontinue the drug, taking into account the
importance of the drug to the mother.
The safety and efficacy of
EMBEDA in patients less than 18 years of age have not been established.
Clinical studies of EMBEDA did
not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. The pharmacokinetics of
EMBEDA have not been investigated in elderly patients ( > 65 years) although
such patients were included in clinical studies. In a long-term open-label
safety study, the pre-dose plasma morphine concentrations after dose
normalization were similar for subjects < 65 years and those ≥ 65 years
of age. Limited data are available on the pharmacokinetics of EMBEDA in
geriatric patients [see CLINICAL PHARMACOLOGY].