5 WARNINGS AND PRECAUTIONS
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.
5.1 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 (9) ].
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.
5.2 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 ].
5.3 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.
5.4 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.
5.5 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.
5.6 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
(7.1)
].
5.7 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.
5.8 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.
5.9 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.
5.10 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 ].
5.11 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.
5.12 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 ].
5.13 Anaphylaxis
Although extremely rare, cases of anaphylaxis have been reported
with the use of a similar extended release morphine formulation.
5.14 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.
5.15 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.
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