Pfizer Inc. (NYSE: PFE) announced today that the U.S. Food and Drug
Administration (FDA) has approved a Prior Approval Supplement for EMBEDA
(morphine sulfate and naltrexone hydrochloride) Extended Release
The Prior Approval Supplement included an update to the EMBEDA
manufacturing process that addressed the pre-specified stability
requirement that led to the voluntary recall of EMBEDA from the market
in March 2011. Pfizer anticipates product availability in the second
quarter of 2014.
EMBEDA is indicated for the management of moderate to severe pain when a
continuous, around-the-clock opioid analgesic is needed for an extended
period of time.
Limitations of Use
IMPORTANT SAFETY INFORMATION
ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL
EXPOSURE, and INTERACTION WITH ALCOHOL
EMBEDA contains pellets of morphine sulfate, an opioid agonist, with
a sequestered core of naltrexone hydrochloride, an opioid receptor
Morphine sulfate is a Schedule II controlled
substance with an abuse liability similar to other opioid agonists,
legal or illicit. Assess each patient’s risk for opioid abuse or
addiction prior to prescribing EMBEDA. The risk for opioid abuse is
increased in patients with a personal or family history of substance
abuse (including drug or alcohol abuse or addiction) or mental illness
(e.g., major depressive disorder). Routinely monitor all patients
receiving EMBEDA for signs of misuse, abuse, and addiction during
Life-threatening Respiratory Depression
Respiratory depression, including fatal cases, may occur with use of
EMBEDA, even when the drug has been used as recommended and not misused
or abused. Proper dosing and titration are essential and EMBEDA should
only be prescribed by healthcare professionals who are knowledgeable in
the use of potent opioids for the management of chronic pain. Monitor
for respiratory depression, especially during initiation of EMBEDA or
following a dose increase
. Instruct patients to swallow EMBEDA
capsules whole or to sprinkle the contents of the capsule on applesauce
and swallow immediately without chewing. Crushing, dissolving, or
chewing the pellets within the capsule can cause rapid release and
absorption of a potentially fatal dose of morphine.
Accidental ingestion of EMBEDA, especially in children, can result in
a fatal overdose of morphine.
Interaction with Alcohol
The co-ingestion of alcohol with EMBEDA may result in an increase of
plasma levels and potentially fatal overdose of morphine. Instruct
patients not to consume alcoholic beverages or use prescription or
non-prescription products that contain alcohol while on EMBEDA therapy.
EMBEDA is not for use as an as-needed (prn) analgesic, for pain that
is mild or not expected to persist for an extended period of time, for
acute pain, for postoperative pain, unless the patient is already
receiving chronic opioid therapy prior to surgery, or if the
postoperative pain is expected to be moderate to severe and persist
for an extended period of time
EMBEDA 100mg/4mg capsules are only for patients in whom tolerance to
an opioid of comparable potency is established.
EMBEDA is contraindicated in patients with
significant respiratory depression, acute or severe bronchial asthma in
an unmonitored setting or in the absence of resuscitative equipment,
known or suspected paralytic ileus, or hypersensitivity (e.g.,
anaphylaxis) to morphine or naltrexone.
EMBEDA contains morphine, an opioid agonist and a
Schedule II controlled substance. Morphine can be abused in a manner
similar to other opioid agonists, legal or illicit. Such opioid agonists
are sought by drug abusers and people with addiction disorders and are
subject to criminal diversion. Consider these risks when prescribing or
dispensing EMBEDA where there is concern about increased risks of
misuse, abuse, or diversion. Misuse or 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 that
could result in overdose and death, and may also result in release of
sufficient naltrexone to precipitate withdrawal in opioid-dependent
Life Threatening Respiratory Depression
Respiratory depression is
the primary risk of EMBEDA and may lead to respiratory arrest and death.
Respiratory depression from opioids is manifested by a reduced urge to
breathe and a decreased rate of respiration, often associated with a
“sighing” pattern of breathing. Carbon dioxide (CO
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 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. Instruct
patients against use by individuals other than the patient for whom
EMBEDA was prescribed and to keep EMBEDA out of the reach of children,
as such inappropriate use may result in fatal respiratory depression.
Accidental ingestion of EMBEDA, especially in
children, can result in a fatal overdose of morphine.
Interaction with Alcohol
The co-ingestion of alcohol with EMBEDA
can result in an increase of morphine plasma levels and potentially
fatal overdose of morphine. Instruct patients not to consume alcoholic
beverages or use prescription or non-prescription products containing
alcohol while on EMBEDA therapy.
Elderly, Cachectic, and Debilitated Patients
depression is more likely to occur in elderly, cachectic, or debilitated
patients as they may have altered pharmacokinetics due to poor fat
stores, muscle wasting, or altered clearance compared to younger,
healthier patients. Therefore, monitor such patients closely,
particularly when initiating and titrating EMBEDA and when EMBEDA is
given concomitantly with other drugs that depress respiration.
Use 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, as in these patients, even usual therapeutic doses of EMBEDA
may decrease respiratory drive to the point of apnea. 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. 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 with Head Injury or Increased Intracranial Pressure
patients taking EMBEDA who may be susceptible to the intracranial
effects of CO
retention for signs of sedation and
respiratory depression as EMBEDA may reduce respiratory drive and the
retention can further increase intracranial
Avoid the use of EMBEDA in patients with impaired
consciousness or coma.
Use 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 the serum amylase.
Use 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.
Avoidance of Withdrawal
Avoid the use of mixed agonist/antagonist
analgesics in patients who have received or are receiving a course of
therapy with an opioid agonist analgesic. Mixed agonists/antagonists
analgesics may reduce the analgesic effect and/or may precipitate
withdrawal symptoms. Consuming crushed, chewed or dissolved EMBEDA
capsules can release sufficient naltrexone to precipitate withdrawal in
opioid–dependent individuals, which usually appear within 5 minutes and
can last up to 48 hours. When discontinuing EMBEDA, gradually taper the
dose and do not abruptly discontinue.
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 medication.
Most common adverse reactions (>10%)are
constipation, nausea, and somnolence.
Individualize dosing based on
patient’s prior analgesic treatment experience, and titrate as needed to
provide adequate analgesia and minimize adverse reactions. When EMBEDA
is the first opioid analgesic, initiate EMBEDA therapy with the 20
mg/0.8 mg capsule. Instruct patients to swallow EMBEDA capsules intact,
or to sprinkle the capsule contents on applesauce and immediately
swallow without chewing.
For EMBEDA Full Prescribing Information please visit
Pfizer Inc.: Working together for a healthier world™
Concomitant use of alcohol with EMBEDA can result in an increase of
morphine plasma levels and potentially fatal overdose of morphine.
Concurrent use of EMBEDA and other central nervous system depressants
(e.g. sedatives, hypnotics, general anesthetics, antiemetics,
phenothiazines, other tranquilizers, and alcohol) can increase the
risk of respiratory depression, hypotension, and profound sedation or
Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine,
butorphanol) may reduce the analgesic effect of EMBEDA and/or may
precipitate withdrawal symptoms in these patients. Avoid the use of
agonist/antagonist analgesics in patients receiving EMBEDA.
Opioids may enhance the neuromuscular blocking action of skeletal
relaxants and produce an increased degree of respiratory depression.
The effects of morphine may be potentiated by MAOIs. MAOIs have been
reported to potentiate the effects of morphine anxiety, confusion, and
significant depression of respiration or coma. EMBEDA should not be
used in patients taking MAOIs or within 14 days of stopping such
Cimetidine can potentiate morphine-induced respiratory depression.
There is a report of confusion and severe respiratory depression when
a patient undergoing hemodialysis was concurrently administered
morphine and cimetidine.
Morphine can reduce the efficacy of diuretics by inducing the release
of antidiuretic hormone. Morphine may also lead to acute retention of
urine by causing spasm of the sphincter of the bladder, particularly
in men with enlarged prostates.
Anticholinergics or other drugs with anticholinergic activity when
used concurrently with opioid analgesics may result in increased risk
of urinary retention and/or severe constipation, which may lead to
PGP inhibitors (e.g. quinidine) may increase the absorption/exposure
of morphine by about two-fold.
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