EMBEDA is to be swallowed whole or the contents of the
capsules sprinkled on apple sauce. The pellets in the capsules are not to be
crushed, dissolved, or chewed. The resulting morphine dose may be fatal,
particularly in opioid-naïve individuals. In opioid-tolerant individuals, the absorption of naltrexone may increase the risk of precipitating withdrawal.
EMBEDA 100 mg/4 mg is for use in opioid-tolerant patients
only. Ingestion of these capsules or of the pellets within the capsules may
cause fatal respiratory depression when administered to patients not already
tolerant to high doses of opioids.
Misuse, Abuse, and Diversion of Opioids
EMBEDA contains morphine, an opioid agonist, and is a
Schedule II controlled substance. Opioid agonists have the potential for being
abused and are sought by drug abusers and people with addiction disorders and
are subject to criminal diversion.
Morphine can be abused in a manner similar to other opioid
agonists, legal or illicit. This should be considered when prescribing or dispensing
EMBEDA in situations where the physician or pharmacist is concerned about an
increased risk of misuse, abuse, or diversion.
Abuse of EMBEDA by crushing, chewing, snorting, or injecting the dissolved
product will result in the uncontrolled delivery of the opioid and pose a significant
risk to the abuser that could result in overdose and death [see Drug
Abuse and Dependence].
Concerns about abuse and addiction should not prevent the
proper management of pain. Healthcare professionals should contact their State
Professional Licensing Board or State Controlled Substances Authority for
information on how to prevent and detect abuse of this product.
Interactions with Alcohol and Drugs of Abuse
EMBEDA may be expected to have additive effects when used in
conjunction with alcohol, other opioids, or illicit drugs that cause central
nervous system depression because respiratory depression, hypotension, and
profound sedation or coma may result.
Patients should not consume alcoholic beverages, prescription or non-prescription
medications containing alcohol while on EMBEDA therapy. The co-ingestion of
alcohol with EMBEDA can result in an increase of morphine plasma levels and
potentially fatal overdose of morphine [see CLINICAL
PHARMACOLOGY].
Impaired Respiration
Respiratory depression is the chief hazard of all morphine
preparations such as EMBEDA. Respiratory depression occurs more frequently and
is more dangerous in elderly and debilitated patients, and those suffering from
conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction
(when even moderate therapeutic doses may significantly decrease pulmonary ventilation).
EMBEDA should be used with extreme caution in patients with
chronic obstructive pulmonary disease or cor pulmonale, and in patients having
a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis),
hypoxia, hypercapnia, or pre-existing respiratory depression. In such
patients, even usual therapeutic doses of morphine may increase airway resistance and decrease respiratory drive to the point of apnea. In these
patients, alternative non-opioid analgesics should be considered, and opioids
should be employed only under careful medical supervision at the lowest
effective dose.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of morphine with carbon
dioxide retention and secondary elevation of cerebrospinal fluid pressure may
be markedly exaggerated in the presence of head injury, other intracranial
lesions, or a pre-existing increase in intracranial pressure. EMBEDA can
produce effects on pupillary response and consciousness, which may obscure
neurologic signs of further increases in pressure in patients with head
injuries. EMBEDA should only be administered under such circumstances when
considered essential and then with extreme care.
Hypotensive Effect
EMBEDA may cause severe hypotension. There is an added risk
to individuals whose ability to maintain blood pressure has already been
compromised by a reduced blood volume or a concurrent administration of drugs
such as phenothiazines or general anesthetics [see DRUG INTERACTIONS].
EMBEDA may produce orthostatic hypotension and syncope in ambulatory patients.
EMBEDA should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce
cardiac output and blood pressure.
Interactions with other CNS Depressants
EMBEDA should be used with caution and in reduced dosage in patients who are
concurrently receiving other central nervous system depressants including sedatives
or hypnotics, general anesthetics, phenothiazines, other tranquilizers, and
alcohol because respiratory depression, hypotension, and profound sedation
or coma may result [see DRUG INTERACTIONS].
Gastrointestinal Effects
EMBEDA should not be given to patients with gastrointestinal obstruction, particularly paralytic ileus, as there is a risk of the product
remaining in the stomach for an extended period and the subsequent release of a
bolus of morphine when normal gut motility is restored. As with other solid
morphine formulations diarrhea may reduce morphine absorption.
The administration of morphine may obscure the diagnosis or
clinical course in patients with acute abdominal condition.
Cordotomy
Patients taking EMBEDA who are scheduled for cordotomy or
other interruption of pain transmission pathways should have EMBEDA ceased 24
hours prior to the procedure and the pain controlled by parenteral short-acting
opioids. In addition, the post- procedure titration of analgesics for such
patients should be individualized to avoid either oversedation or withdrawal
syndromes.
Use in Pancreatic/Biliary Tract Disease
EMBEDA may cause spasm of the sphincter of Oddi and should
be used with caution in patients with biliary tract disease, including acute
pancreatitis. Opioids may cause increases in the serum amylase level.
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to
maintain a defined effect such as analgesia (in the absence of disease progression
or other external factors). Physical dependence is manifested by withdrawal
symptoms after abrupt discontinuation of a drug or upon administration of an
antagonist. Physical dependence and tolerance are common during chronic opioid
therapy.
The opioid abstinence or withdrawal syndrome is
characterized by some or all of the following: restlessness, lacrimation,
rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other
symptoms also may develop, including: irritability, anxiety, backache, joint
pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting,
diarrhea, or increased blood pressure, respiratory rate, or heart rate.
EMBEDA should not be abruptly discontinued [see DOSAGE
AND ADMINISTRATION].
Special Risk Groups
EMBEDA should be administered with caution, and in reduced
dosages in elderly or debilitated patients; patients with severe renal or hepatic
insufficiency; patients with Addison's disease; myxedema; hypothyroidism;
prostatic hypertrophy or urethral stricture.
Caution should also be exercised in the administration of
EMBEDA to patients with CNS depression, toxic psychosis, acute alcoholism, and
delirium tremens.
All opioids may aggravate convulsions in patients with
convulsive disorders, and all opioids may induce or aggravate seizures in some clinical
settings.
Driving and Operating Machinery
EMBEDA may impair the mental and/or physical abilities
needed to perform potentially hazardous activities such as driving a car or operating
machinery. Patients must be cautioned accordingly. Patients should also be
warned about the potential combined effects of EMBEDA with other CNS
depressants, including other opioids, phenothiazines, sedative/hypnotics, and
alcohol [see DRUG INTERACTIONS].
Anaphylaxis
Although extremely rare, cases of anaphylaxis have been
reported with the use of a similar extended release morphine formulation.
Accidentally Precipitated Withdrawal
Agonist/antagonist analgesics (i.e., pentazocine,
nalbuphine, butorphanol) should be administered with caution to a patient who
has received or is receiving a course of therapy with EMBEDA. In this
situation, mixed agonist/antagonist analgesics may reduce the analgesic effect
of EMBEDA and/or may precipitate withdrawal symptoms in these patients.
Consuming EMBEDA that have been tampered by crushing,
chewing, or dissolving the extended-release formulation 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 confusion,
somnolence, and visual hallucinations. Significant fluid losses from vomiting
and diarrhea can require intravenous fluid administration. Patients should be
closely monitored and therapy with non-opioid medications tailored to meet
individual requirements.
Laboratory Tests
Naltrexone does not interfere with thin-layer, gas-liquid,
and high pressure 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. Please consult the test manufacturer
for specific details.
Patient Counseling Information
Patients receiving EMBEDA should be given the following
instructions by the physician:
- Patients should be advised that EMBEDA contains morphine and naltrexone
and should be taken only as directed.
- The dose of morphine sulfate should not be adjusted without consulting with
a physician or other healthcare professional. EMBEDA should be swallowed
whole (not crushed, dissolved, or chewed) due to a risk of fatal morphine
overdose or naltrexone precipitated withdrawal symptoms. Alternately, EMBEDA
Capsules may be opened and the entire contents sprinkled on a small amount
of apple sauce immediately prior to ingestion [see DOSAGE AND ADMINISTRATION].
- Patients should not consume alcoholic beverages while on EMBEDA therapy.
Additionally, patients must not use prescription or non-prescription medications
containing alcohol while on EMBEDA therapy. The co-ingestion of alcohol with
EMBEDA may result in an increase of plasma levels and potentially fatal overdose
of morphine.
- Patients should be advised of the most common adverse reactions that may
occur while taking EMBEDA: constipation, nausea, somnolence, vomiting, dizziness,
pruritus, and headache.
- Patients should be advised that EMBEDA may cause drowsiness, dizziness,
or lightheadedness and may impair mental and/or physical ability required
for the performance of potentially hazardous tasks (e.g., driving, operating
machinery). Patients started on EMBEDA or patients whose dose has been adjusted
should refrain from any potentially dangerous activity until it is established
that they are not adversely affected.
- Patients should not combine EMBEDA with central nervous system depressants
(sleep aids, tranquilizers) except by the orders of the prescribing physician
because dangerous additive effects may occur resulting in serious injury or
death.
- Patients should be advised that EMBEDA is a potential drug of abuse. They
should protect it from theft.
- Special care must be taken to avoid accidental ingestion or use by individuals
(including children) other than the patient for whom it was originally prescribed,
as such unsupervised use may have severe, even fatal, consequences [see WARNINGS
AND PRECAUTIONS].
- Patients should be advised that EMBEDA 100 mg/4 mg is for use only in opioid-tolerant
patients.
- Women of childbearing potential who become or are planning to become pregnant
should consult a physician prior to initiating or continuing therapy with
EMBEDA.
- Safe use in pregnancy has not been established. Prolonged use of opioid
analgesics during pregnancy may cause fetal neonatal physical dependence,
and neonatal withdrawal may occur.
- As with other opioids, patients taking EMBEDA should be advised of the potential
for severe constipation; appropriate laxatives and/or stool softeners as
well as other appropriate treatments should be initiated from the onset of
opioid therapy.
- Patients should be advised to seek medical attention immediately if signs
of a serious allergic reaction occur, such as swelling of the face, throat,
or tongue, trouble breathing, feeling dizzy or faint, pounding heart beat,
chest pain or feeling of doom. [see WARNINGS AND PRECAUTIONS].
Breakthrough Pain/Adverse Experiences
Patients should be advised to report episodes of
breakthrough pain and adverse experiences occurring during therapy. Individualization
of dosage is essential to make optimal use of this medication.
Mental and/or Physical Ability
Patients should be advised that EMBEDA may impair mental
and/or physical ability required for the performance of potentially hazardous
tasks (e.g., driving, operating machinery). Patients started on EMBEDA or whose
dose has been changed should refrain from dangerous activity until it is
established that they are not adversely affected [see WARNINGS AND
PRECAUTIONS].
Avoidance of Alcohol or Other CNS Depressants
Patients should be advised that EMBEDA should not be taken
with alcohol, prescription or non-prescription medications containing alcohol,
or other CNS depressants (sleeping medication, tranquilizers) except by the
orders of the prescribing healthcare provider because dangerous additive
effects may occur resulting in serious injury or death [see WARNINGS AND
PRECAUTIONS].
Pregnancy
Women of childbearing potential who become or are planning to become pregnant,
should consult their prescribing healthcare provider prior to initiating or
continuing therapy with EMBEDA [see Use in Specific Populations].
Cessation of Therapy
Patients should be advised that if they have been receiving
treatment with EMBEDA for more than a few weeks and cessation of therapy is
indicated, it may be appropriate to taper the EMBEDA dose, rather than abruptly
discontinue it, due to the risk of precipitating withdrawal symptoms. Their
prescribing healthcare provider should provide a dose schedule to accomplish a
gradual discontinuation of the medication.
Drug of Abuse
Patients should be advised that EMBEDA is a potential drug
of abuse. They should protect it from theft, and it should never be given to
anyone other than the individual for whom it was prescribed [see WARNINGS
AND PRECAUTIONS].
Constipation
Patients should be advised that severe constipation could
occur as a result of taking EMBEDA and appropriate laxatives, stool softeners
and other appropriate treatments should be initiated from the beginning of
opioid therapy.
Storage/Destruction of Unused EMBEDA
Patients should be instructed to keep EMBEDA in a secure
place out of the reach of children. When EMBEDA is no longer needed, the unused
capsules should be destroyed by flushing down the toilet.
FDA-Approved Patient Labeling
[See PATIENT INFORMATION section.]
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Studies in animals to evaluate the carcinogenic potential of
morphine have not been conducted.
Mutagenesis
No formal studies to assess the mutagenic potential of
morphine have been conducted. In the published literature, in vitro
studies have reported that morphine is non-mutagenic in Drosophila (no
lethal mutation induction), in the Ames test with Salmonella, and
induces chromosomal aberrations in human leukocytes. Morphine was found to be
mutagenic in vitro in human T- cells, increasing the DNA fragmentation.
In vivo, morphine was mutagenic in the mouse micronucleus test and
induced chromosomal aberrations in spermatids and murine lymphocytes. Chronic
opioid abusers (e.g., heroin abusers) and their offspring display higher rates
of chromosomal damage. However, the rates of chromosomal abnormalities were
similar in nonexposed individuals and in heroin users enrolled in long term
opioid maintenance programs.
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. Studies from the literature have also reported
changes in hormonal levels (i.e. testosterone, luteinizing hormone, serum corticosterone)
following treatment with morphine. These changes may be associated with the
reported effects on fertility in the rat.
Use In Specific Populations
Pregnancy
Teratogenic Effects
Pregnancy Category C: Teratogenic effects of morphine have
been reported in the animal literature. High parental doses during the second
trimester were teratogenic in neurological, soft and skeletal tissue. The
abnormalities included encephalopathy and axial skeletal fusions. These doses
were often maternally toxic and were 0.3 to 3-fold the maximum recommended
human dose (MRHD) on a mg/m² basis. The relative contribution of
morphine-induced maternal hypoxia and malnutrition, each of which can be
teratogenic, has not been clearly defined. Treatment of male rats with
approximately 3-fold the MRHD for 10 days prior to mating decreased litter size
and viability.
Nonteratogenic Effects
Morphine given subcutaneously, at non-maternally toxic
doses, to rats during the third trimester with approximately 0.15-fold the MRHD
caused reversible reductions in brain and spinal cord volume, and testes size
and body weight in the offspring, and decreased fertility in female offspring.
The offspring of rats and hamsters treated orally or intraperitoneally
throughout pregnancy with 0.04-to 0.3-fold the MRHD of morphine have
demonstrated delayed growth, motor and sexual maturation, and decreased male
fertility. Chronic morphine exposure of fetal animals resulted in mild
withdrawal, altered reflex and motor skill development, and altered responsiveness
to morphine that persisted into adulthood.
There are no well-controlled studies of chronic in utero
exposure to morphine sulfate in human subjects. However, uncontrolled
retrospective studies of human neonates chronically exposed to other opioids in
utero, demonstrated reduced brain volume which normalized over the first
month of life. Infants born to opioid-abusing mothers are more often small for
gestational age, have a decreased ventilatory response to CO2, and
increased risk of sudden infant death syndrome.
There are no adequate and well-controlled studies of
naltrexone in pregnant women.
EMBEDA should only be used during pregnancy if the need for
strong opioid analgesia justifies the potential risk to the fetus.
Labor and Delivery
EMBEDA is not recommended 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 through actions which 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 labor. Neonates whose mothers received opioid analgesics during labor should
be observed closely for signs of respiratory depression. A specific opioid
antagonist, such as naloxone or nalmefene, should be available for reversal of
opioid-induced respiratory depression in the neonate.
Nursing Mothers
Morphine is excreted in the maternal milk, and the milk to
plasma morphine AUC ratio is about 2.5:1. The amount of morphine received by
the infant depends on the maternal plasma concentration, amount of milk
ingested by the infant, and the extent of first pass metabolism.
Withdrawal symptoms can occur in breast-feeding infants when
maternal administration of morphine sulfate 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.
Pediatric Use
The safety and efficacy of EMBEDA in individuals less than
18 years of age have not been established.
Geriatric Use
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. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
Neonatal Withdrawal Syndrome
Chronic maternal use of opiates or opioids during pregnancy
coexposes the fetus. The newborn may experience subsequent neonatal withdrawal
syndrome (NWS). Manifestations of NWS include irritability, hyperactivity,
abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight
loss, and failure to gain weight. The onset, duration, and severity of the
disorder differ based on such factors as the addictive drug used, time and
amount of mother's wborn. last dose, Approaches to the treatment of this
syndrome have included supportive care and, when indicated, drugs such as
paregoric or phenobarbital.
Race
Pharmacokinetic differences due to race may exist. Chinese
subjects given intravenous morphine in one study had a higher clearance when
compared to Caucasian subjects (1852 ± 116 mL/min versus 1495 ± 80 mL/min).
Hepatic Failure
The pharmacokinetics of morphine was found to be
significantly altered in individuals with alcoholic cirrhosis. The clearance
was found to decrease with a corresponding increase in half-life. The
morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) to morphine
plasma AUC ratios also decreased in these patients indicating a decrease in
metabolic activity.
Renal Insufficiency
The pharmacokinetics of morphine is altered in renal failure
patients. AUC is increased and clearance is decreased. The metabolites, M3G
and M6G, accumulate several fold in renal failure patients compared with
healthy subjects.
Adequate studies of naltrexone in patients with severe
hepatic or renal impairment have not been conducted.
Last updated on RxList: 8/27/2009