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Overview
What is EMBEDA?
EMBEDA Capsules contain pellets of morphine sulfate and
naltrexone hydrochloride at a ratio of 100:4. Morphine sulfate is an agonist and
naltrexone hydrochloride is an antagonist at the mu-opioid receptor.
The chemical name of morphine sulfate is 7,8-didehydro-4,5
α-epoxy-17-methyl-morphinan-3,6 α-diol sulfate (2:1) (salt) pentahydrate. The
empirical formula is (CHNO)●HSO●5HO and its
molecular weight is 758.85.
Morphine sulfate is an odorless, white, crystalline powder with a bitter
taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of
alcohol, but is practically insoluble in chloroform or ether. The octanol: water
partition coefficient of morphine is 1.42 at physiologic pH and the pK is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4).
Its structural formula is:
The chemical name of naltrexone hydrochloride is
(5α)-17-(Cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one
hydrochloride. The empirical formula is CHNO•HCl and its molecular weight is
377.46.
Naltrexone hydrochloride is a white to slightly off-white powder that is
soluble in water. Its structural formula is
Each capsule contains the following inactive ingredients common to all
strengths: talc, ammonio methacrylate copolymer, sugar spheres, ethylcellulose,
sodium chloride, polyethylene glycol, hydroxypropyl cellulose, dibutyl sebacate,
methacrylic acid copolymer, diethyl phthalate, magnesium stearate, sodium lauryl
sulfate, and ascorbic acid. The capsule shells contain gelatin, titanium
dioxide, and grey ink, D and C yellow #10 (EMBEDA 20 mg/0.8 mg), FD and C red
#3, FD and C blue #1 (EMBEDA 30 mg/1.2 mg), D and C red #28, FD and C red #40,
FD and C blue #1 (EMBEDA 50 mg/2 mg), D and C red #28, FD and C red #40,
FD and C blue #1 (EMBEDA 60 mg/2.4 mg), FD and C blue #1, FD and C red #40,
FD and C yellow #6 (EMBEDA 80 mg/3.2 mg), D and C yellow #10, FD and C blue #1
(EMBEDA 100 mg/4 mg).
EMBEDA contains no gluten.
What does EMBEDA look like?
What are the available doses of EMBEDA?
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What should I talk to my health care provider before I take EMBEDA?
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How should I use EMBEDA?
EMBEDA is an extended-release oral formulation of morphine
sulfate and naltrexone hydrochloride 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.
EMBEDA is NOT intended for use as a prn analgesic.
EMBEDA is not indicated for acute/postoperative pain or if the pain is mild
or not expected to persist for an extended period of time. EMBEDA is only
indicated for postoperative use if 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. Physicians should
individualize treatment, moving from parenteral to oral analgesics as
appropriate
Selection of patients for treatment with morphine sulfate should
be governed by the same principles that apply to the use of similar opioid
analgesics. Physicians should individualize treatment in every case, using
non-opioid analgesics, opioids on an as needed basis and/or combination
products, and chronic opioid therapy in a progressive plan of pain management
such as outlined by the World Health Organization and Federation of State
Medical Boards Model Guidelines.
Care should be taken to use low initial doses of EMBEDA in
patients who are not already opioid-tolerant, especially those who are receiving
concurrent treatment with muscle relaxants, sedatives, or other CNS active
medications.
The 100 mg/4 mg capsules are for use only in opioid-tolerant
patients.
EMBEDA is to be swallowed whole or the contents of the capsules sprinkled on
apple sauce and taken by mouth. The pellets in the capsules are not to be
crushed, dissolved, or chewed before swallowing.
It is critical to adjust the dosing regimen for each patient
individually, taking into account the patient's prior analgesic treatment
experience. In the selection of the initial dose of EMBEDA, attention should be
given to:
1) the total daily dose, potency, and kind of opioid the patient has been
taking previously;2) the reliability of the relative potency estimate used
to calculate the equivalent dose of morphine needed (Note: potency estimates may
vary with the route of administration);3) the patient's degree of opioid
experience and opioid tolerance;4) the general condition and medical status
of the patient;5) concurrent medication;6) the type and severity of the
patient's pain.
The following dosing recommendations can be considered approaches to what is
actually a series of clinical decisions over time in the management of the pain
of an individual patient:
Use of EMBEDA as the First Opioid
Analgesic
The lowest dose of EMBEDA should be used as the initial opioid analgesic in
patients with chronic pain. Patients may subsequently be titrated to a once or
twice a day dosage which adequately manages their pain.
Conversion from Other Oral Morphine
Formulations to EMBEDA
Patients on other oral morphine formulations may be converted to EMBEDA by
administering one-half of the patient's total daily oral morphine dose as EMBEDA
every 12 hours (twice-a-day) or by administering the total daily oral morphine
dose as EMBEDA every 24 hours (once-a-day). EMBEDA should not be given more
frequently than every 12 hours.
Conversion from Oral Opioids,
Parenteral Morphine, or Other Parenteral Opioids to EMBEDA
EMBEDA can be administered to patients previously receiving treatment with
parenteral morphine or other opioids. While there are useful tables of oral and
parenteral equivalents in cancer analgesia, there is substantial inter-patient
variation in the relative potency of different opioid drugs and formulations.
For these reasons, it is better to underestimate the patient's 24-hour oral
morphine requirement and provide rescue medication than to overestimate and
manage an adverse event. The following general points should be considered:
The first dose of EMBEDA may be taken with the last dose of any
immediate-release (short-acting) opioid medication due to the extended-release
characteristics of EMBEDA.
Patients may develop some degree of tolerance, requiring dosage
adjustment until they have achieved their individual balance between effective
analgesia and opioid side effects such as confusion, sedation, and constipation.
During periods of changing analgesic requirements including initial
titration, frequent communication is recommended between physician, other
members of the healthcare team, the patient, and the caregiver/family.
Patients who have difficulty swallowing whole capsules or tablets
may benefit from an alternative method of administration. EMBEDA pellets may be
sprinkled over apple sauce. Other foods have not been tested and should not be
substituted for apple sauce.
Do not administer EMBEDA pellets through a nasogastric or gastric
tubes.
Continual re-evaluation of the patient receiving morphine sulfate
is important, with special attention to the maintenance of pain control and the
relative incidence of side effects associated with therapy. If the level of pain
increases, effort should be made to identify the source of increased pain, while
adjusting the dose as described above to decrease the level of pain. During
chronic therapy, especially for non-cancer-related pain (or pain associated with
other terminal illnesses), the continued need for the use of opioid analgesics
should be re-assessed as appropriate.
In general, EMBEDA should not be abruptly discontinued. However,
EMBEDA, like other opioids, can be safely discontinued without the development
of withdrawal symptoms by slowly tapering the daily dose.
What interacts with EMBEDA?
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What are the warnings of EMBEDA?
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What are the precautions of EMBEDA?
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What are the side effects of EMBEDA?
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What should I look out for while using EMBEDA?
EMBEDA is contraindicated in patients with a known
hypersensitivity to morphine, morphine salts, naltrexone, or in any situation
where opioids are contraindicated.
EMBEDA is contraindicated in patients with significant
respiratory depression in unmonitored settings or the absence of resuscitative
equipment.
EMBEDA is contraindicated in patients with acute or severe bronchial asthma
or hypercapnia in unmonitored settings or the absence of resuscitative equipment
[see ].
EMBEDA is contraindicated in any patient who has or is suspected
of having paralytic ileus.
EMBEDA™ capsules contain morphine, an opioid
agonist and a Schedule II controlled substance with an abuse liability similar
to other opioid agonists. EMBEDA 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.
EMBEDA contains pellets of an extended-release oral
formulation of morphine sulfate, an opioid receptor agonist, surrounding an
inner core of naltrexone hydrochloride, an opioid receptor antagonist 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.
EMBEDA is NOT intended for use as a prn analgesic.
EMBEDA 100 mg/4 mg IS FOR USE IN OPIOID-TOLERANT PATIENTS
ONLY. Ingestion of these capsules or the pellets within the capsules may cause
fatal respiratory depression when administered to patients not already tolerant
to high doses of opioids.
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. 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 due to the risk of rapid
release and absorption of a potentially fatal dose of morphine.
Crushing, chewing, or dissolving EMBEDA will also result in
the release of naltrexone which may precipitate withdrawal in opioid-tolerant
individuals.
What might happen if I take too much EMBEDA?
Acute overdosage with morphine is manifested by respiratory
depression, somnolence progressing to stupor or coma, skeletal muscle
flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary
edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis
may be seen due to severe hypoxia in overdose situations.
Primary attention should be given to the re-establishment of a
patent and protected airway and institution of assisted or controlled
ventilation if needed. Other supportive measures (including oxygen,
vasopressors) should be employed in the management of circulatory shock and
pulmonary edema accompanying overdose as indicated. Cardiac arrest or
arrhythmias will require advanced life support techniques.
The pure opioid antagonists, naloxone or nalmefene, are specific antidotes to
respiratory depression which results from opioid overdose. Since the duration of
reversal would be expected to be less than the duration of action of morphine in
EMBEDA, the patient must be carefully monitored until spontaneous respiration is
reliably re-established. EMBEDA will continue to release and add to the morphine
load for up to 24 hours after administration and the management of an overdose
should be monitored accordingly. If the response to opioid antagonists is
suboptimal or not sustained, additional antagonist should be given as directed
by the manufacturer of the product.
Opioid antagonists should not be administered in the absence of clinically
significant respiratory or circulatory depression secondary to morphine
overdose. Such agents should be administered cautiously to persons who are
known, or suspected to be physically dependent on EMBEDA. In such cases, an
abrupt or complete reversal of opioid effects may precipitate an acute
withdrawal syndrome.
The sequestered naltrexone in EMBEDA has no role in the treatment of opioid
overdose.
In an individual physically dependent on opioids, administration of an opioid
receptor antagonist may precipitate an acute withdrawal. The severity of the
withdrawal produced will depend on the degree of physical dependence and the
dose of the antagonist administered. Use of an opioid antagonist should be
reserved for cases where such treatment is clearly needed. If it is necessary to
treat serious respiratory depression in the physically dependent patient,
administration of the antagonist should be begun with care and by titration with
smaller than usual doses of the antagonist
How should I store and handle EMBEDA?
Store bottles of 1000 SINGULAIR 5-mg chewable tablets and 8000 SINGULAIR 10-mg film-coated tablets at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Store in original container. When product container is subdivided, repackage into a well-closed, light resistant container. HOW SUPPLIED/STORAGE AND HANDLINGStore at 25°C (77°F); excursions permitted between 15° and 30°C
(59° and 86°F). Dispense in a sealed, tamper-evident, childproof, light-resistant container.HOW SUPPLIED/STORAGE AND HANDLINGStore at 25°C (77°F); excursions permitted between 15° and 30°C
(59° and 86°F). Dispense in a sealed, tamper-evident, childproof, light-resistant container.HOW SUPPLIED/STORAGE AND HANDLINGStore at 25°C (77°F); excursions permitted between 15° and 30°C
(59° and 86°F). Dispense in a sealed, tamper-evident, childproof, light-resistant container.
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Clinical Information
Chemical Structure
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Clinical Pharmacology
Morphine sulfate, a pure opioid agonist, is relatively selective
for the mu receptor, although it can interact with other opioid receptors at
higher doses. In addition to analgesia, the widely diverse effects of morphine
sulfate include analgesia, dysphoria, euphoria, somnolence, respiratory
depression, diminished gastrointestinal motility, altered circulatory dynamics,
histamine release, physical dependence, and alterations of the endocrine and
autonomic nervous systems.
Morphine produces both its therapeutic and its adverse effects by interaction
with one or more classes of specific opioid receptors located throughout the
body. Morphine acts as a pure agonist, binding with and activating opioid
receptors at sites in the peri-aqueductal and peri-ventricular grey matter, the
ventro-medial medulla and the spinal cord to produce analgesia.
Effects on the Central Nervous
System
The principal actions of therapeutic value of morphine are analgesia and
sedation (i.e., sleepiness and anxiolysis). Specific CNS opiate receptors and
endogenous compounds with morphine-like activity have been identified throughout
the brain and spinal cord and are likely to play a role in the expression of
analgesic effects. In addition, when morphine binds to mu-opioid receptors, it
results in positive subjective effects, such as drug liking, euphoria, and high.
Morphine produces respiratory depression by direct action on brainstem
respiratory centers. The mechanism of respiratory depression involves a
reduction in the responsiveness of the brainstem respiratory centers to
increases in carbon dioxide tension, and to electrical stimulation. Morphine
depresses the cough reflex by direct effect on the cough center in the medulla.
Antitussive effects may occur with doses lower than those usually required for
analgesia. Morphine causes miosis, even in total darkness, and little tolerance
develops to this effect. Pinpoint pupils are a sign of opioid overdose but are
not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may
produce similar findings). Marked mydriasis rather than miosis may be seen with
worsening hypoxia in the setting of EMBEDA overdose .
Effects on the Gastrointestinal
Tract and Other Smooth Muscle
Gastric, biliary, and pancreatic secretions are decreased by morphine.
Morphine causes a reduction in motility associated with an increase in tone in
the antrum of the stomach and duodenum. Digestion of food in the small intestine
is delayed and propulsive contractions are decreased. Propulsive peristaltic
waves in the colon are decreased, while tone is increased to the point of spasm.
The end result is constipation. Morphine can cause a marked increase in biliary
tract pressure as a result of spasm of the sphincter of Oddi.
Effects on the Cardiovascular
System
Morphine produces peripheral vasodilation which may result in orthostatic
hypotension or syncope. Release of histamine may be induced by morphine and can
contribute to opioid-induced hypotension. Manifestations of histamine release
and/or peripheral vasodilation may include pruritus, flushing, red eyes and
sweating.
Mechanism of Action of
Naltrexone
Naltrexone is a pure, centrally acting mu-opioid antagonist that reverses the
subjective and analgesic effects of mu-opioid receptor agonists by competitively
binding at mu-opioid receptors.
Plasma Level-Analgesia
Relationships
In any particular patient, both analgesic effects and plasma morphine
concentrations are related to the morphine dose.
While plasma morphine-efficacy relationships can be demonstrated in
non-tolerant individuals, they are influenced by a wide variety of factors and
are not generally useful as a guide to the clinical use of morphine. The
effective dose in opioid-tolerant patients may be 10-50 times as great (or
greater) than the appropriate dose for opioid-naïve individuals. Dosages of
morphine should be chosen and must be titrated on the basis of clinical
evaluation of the patient and the balance between therapeutic and adverse
effects.
For any fixed dose and dosing interval, EMBEDA will have, at steady-state, a
lower C and a higher C than
conventional immediate-release morphine.
The pharmacodynamic effect of naltrexone in the setting of crushed EMBEDA was
examined in two clinical trials. In a randomized double-blind, triple-dummy,
four-way cross-over study, 32 non-dependent recreational opioid users received
120 mg of EMBEDA whole and crushed, 120 mg of immediate-release morphine sulfate
and placebo. Overall, 87.5% of subjects had some degree of reduced drug liking
after receiving crushed EMBEDA, while 12.5% had no reduction in drug liking.
There was considerable individual variability in the degree of reduction in drug
liking, ranging between 10 and 50%. Similarly, 69% of subjects showed some
degree of a decrease in euphoria with crushed EMBEDA compared to IR morphine and
31% of subjects did not report a reduction in euphoria. There was similar
individual variability in the degree of reduction in euphoria.
A randomized double-blind, placebo-controlled, three-way cross-over trial in
28 non-dependent recreational opioid-users was performed using 30 mg of IV
morphine alone and 30 mg of IV morphine in combination with 1.2 mg of IV
naltrexone to simulate parenteral use of crushed EMBEDA. The combination of
morphine with naltrexone resulted in 71% of subjects reporting a reduction in
euphoria compared to morphine alone. Note that the intravenous injection of
crushed EMBEDA may result in serious injury and death due to a morphine overdose
or an embolic event. Intravenous injection of crushed EMBEDA may preciptitate a
severe withdrawal syndrome in opioid-dependent patients.
The clinical significance of the degree of reduction in drug liking and
euphoria reported in these studies has not yet been established. There is no
evidence that the naltrexone in EMBEDA reduces the abuse liability of
EMBEDA.
Absorption
EMBEDA Capsules contain extended-release pellets of morphine sulfate that
release morphine slowly compared to an oral morphine solution. Following the
administration of oral morphine solution, approximately 50% of the morphine
absorbed reaches the systemic circulation within 30 minutes. However, following
the administration of an equal amount of EMBEDA to healthy volunteers, this
occurs, on average, after 8 hours. As with most forms of oral morphine, because
of pre-systemic elimination, only about 20 to 40% of the administered dose
reaches the systemic circulation.
EMBEDA is bioequivalent to a similar morphine sulfate extended release
capsules product with regard to rate and extent of plasma morphine absorption.
The median time to peak plasma morphine levels (T) was
shorter for EMBEDA (7.5 hrs) compared to KADIAN (10
hrs). Dose-related increase in steady-state pre-dose plasma concentrations of
morphine were noted following multiple dose administration of EMBEDA in
patients.
Food effect
When taken as directed, the sequestered naltrexone in EMBEDA is not
consistently absorbed into systemic circulation following single dose
administration. In some subjects, a limited number (~2%) of blood samples had
low and highly variable plasma naltrexone levels (median = 7.74 pg/mL, range
4.05-132 pg/mL) following single dose administration of 60 – 120 mg EMBEDA
compared to oral naltrexone solution. In patients titrated up to 60 – 80 mg BID
EMBEDA, naltrexone levels (4-25.5 pg/mL) were detected in 13 out of 67 patients
at steady-state. In a long-term safety study where an average dose of EMBEDA was
up to 860 mg administered twice a day for 12 months, 11.0% of blood samples at
pre-dose timepoints at steady-state had detectable plasma naltrexone
concentrations ranging from 4.03 to 145 pg/mL.
Compared to 2.4 mg naltrexone oral solution, which produced mean (SD)
naltrexone plasma levels of 689 ( 429 pg/mL) and
mean (SD) 6β-naltrexol plasma levels of 3920 (
1350 pg/mL), administration of intact 60 mg EMBEDA produced no naltrexone plasma
levels and mean (SD) 6β-naltrexol plasma levels of 16.7 ( 13.5 pg/mL). Trough levels of plasma naltrexone and
6-β-naltrexol did not accumulate upon repeated administration of EMBEDA.
Tampering with the EMBEDA formulation by crushing or chewing the pellets,
results in the rapid release and absorption of both morphine and naltrexone
comparable to an oral solution. This has not been shown to reduce the abuse
liability of EMBEDA.
Distribution
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver,
intestinal tract, lungs, spleen, and brain. The volume of distribution of
morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35% reversibly bound to
plasma proteins. Although the primary site of action of morphine is in the CNS,
only small quantities pass the blood brain barrier. Morphine also crosses the
placental membranes and has been found in breast milk .
Metabolism
Major pathways of morphine metabolism include glucuronidation and sulfation
in the liver to produce including morphine-3-glucuronide, M3G (about 50%) and
morphine-6-glucuronide, M6G (about 5 to 15%) or morphine-3-etheral sulfate. A
small fraction (less than 5%) of morphine is demethylated. M3G has no
significant contribution to the analgesic activity. Although M6G does not
readily cross the blood-brain barrier, it has been shown to have opioid agonist
and analgesic activity in humans.
Naltrexone is extensively metabolized into 6-β-naltrexol.
Excretion
Approximately 10% of morphine dose is excreted unchanged in the urine.
Elimination of morphine is primarily via hepatic metabolism to glucuronide
metabolites M3G and M6G (55 to 65%) which are then renally excreted. A small
amount of the glucuronide metabolites is excreted in the bile and there is some
minor enterohepatic cycling.
The mean adult plasma clearance is about 20-30 mL/minute/kg. The effective
half-life of morphine after IV administration is reported to be approximately
2.0 hours. The terminal elimination half-life of morphine following single dose
EMBEDA administration is approximately 29 hours.
Special Populations
Geriatric
[see ].
Pediatric
Gender
Race:
+
+
Hepatic Failure
Renal Insufficiency:
Drug Interaction/Alcohol Interaction:
Non-Clinical Toxicology
EMBEDA is contraindicated in patients with a known
hypersensitivity to morphine, morphine salts, naltrexone, or in any situation
where opioids are contraindicated.
EMBEDA is contraindicated in patients with significant
respiratory depression in unmonitored settings or the absence of resuscitative
equipment.
EMBEDA is contraindicated in patients with acute or severe bronchial asthma
or hypercapnia in unmonitored settings or the absence of resuscitative equipment
[see ].
EMBEDA is contraindicated in any patient who has or is suspected
of having paralytic ileus.
EMBEDA™ capsules contain morphine, an opioid
agonist and a Schedule II controlled substance with an abuse liability similar
to other opioid agonists. EMBEDA 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.
EMBEDA contains pellets of an extended-release oral
formulation of morphine sulfate, an opioid receptor agonist, surrounding an
inner core of naltrexone hydrochloride, an opioid receptor antagonist 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.
EMBEDA is NOT intended for use as a prn analgesic.
EMBEDA 100 mg/4 mg IS FOR USE IN OPIOID-TOLERANT PATIENTS
ONLY. Ingestion of these capsules or the pellets within the capsules may cause
fatal respiratory depression when administered to patients not already tolerant
to high doses of opioids.
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. 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 due to the risk of rapid
release and absorption of a potentially fatal dose of morphine.
Crushing, chewing, or dissolving EMBEDA will also result in
the release of naltrexone which may precipitate withdrawal in opioid-tolerant
individuals.
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See .) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. (See for concurrent administration of these agents with ciprofloxacin.)
Histamine H-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies.
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.
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 .
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.
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 .
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.
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.
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 . 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.
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 .
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.
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.
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 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 .
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.
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 .
Although extremely rare, cases of anaphylaxis have been reported
with the use of a similar extended release morphine formulation.
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.
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.
Serious adverse reactions that may be associated with EMBEDA
therapy in clinical use include: respiratory depression, respiratory arrest,
apnea, circulatory depression, cardiac arrest, hypotension, and/or shock .
The common adverse events seen on initiation of therapy with EMBEDA are dose
dependent, and their frequency depends on the clinical setting, the patient's
level of opioid tolerance, and host factors specific to the individual. They
should be expected and managed as a part of opioid analgesia. The most frequent
of these include drowsiness, dizziness, constipation, and nausea.
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared with rates in the clinical trials of another drug
and may not reflect the rates observed in practice.
There were 1251 subjects exposed to at least one dose of EMBEDA in the
clinical program. During late phase clinical development, 618 subjects received
EMBEDA in two randomized, controlled, double-blind studies in subjects with
osteoarthritis of the hip or knee. An additional 465 subjects received EMBEDA in
an open-label, year-long safety study of subjects with chronic, non-cancer pain,
208 subjects for at least six months and 124 for 12 months. The remaining 168
subjects were exposed to a single dose of EMBEDA in early PK/PD studies.
Short-Term (12-Week) Randomized
Study
Adverse reactions observed in at least 2% of subjects
treated with EMBEDA
This study utilized an enriched enrollment with a randomized withdrawal
design in which subjects were titrated to effect on open-label EMBEDA for up to
45 days. Once their pain was controlled, subjects were randomized to either
active treatment with EMBEDA or were tapered off EMBEDA using a double-dummy
design and placed on placebo. The Maintenance Period was 12 weeks. The most
common adverse reactions leading to study discontinuation were nausea,
constipation, vomiting, fatigue, dizziness, pruritus, and somnolence. Adverse
reactions, defined as treatment-related adverse events assessed by the
investigators, reported by greater than or equal to 2.0% of subjects in either the titration or
maintenance phase of the 12-week study are presented in Table 1.
Long-Term Open-Label Safety
Study
In the long-term open-label safety study, 465 patients with chronic
non-malignant pain were enrolled and 124 patients were treated for up to 1 year.
The distributions of adverse events were similar to that of the randomized,
controlled studies, and were consistent with the most common opioid related
adverse events. Adverse reactions, defined as treatment-related adverse events
assessed by the investigators, reported by greater than or equal to
2.0% of subjects are presented in Table 2.
Adverse Reactions Observed in the
Phase 2/3 Studies
Most common (greater than 10%): constipation, nausea, somnolence
Common (greater than or equal to 1% to less than 10%): vomiting, headache, dizziness, pruritus, dry mouth,
diarrhea, fatigue, insomnia, hyperhidrosis, anxiety, chills, abdominal pain,
lethargy, edema peripheral, dyspepsia, anorexia, muscle spasms, depression,
flatulence, restlessness, decreased appetite, irritability, stomach discomfort,
tremor, arthralgia, hot flush, sedation
Adverse Reactions Observed in the
Phase 2/3 Studies
Most common (greater than or equal to 10%):
Gastrointestinal disorders
Nervous system disorders
Common (greater than or equal to 1% to less than 10%):
Gastrointestinal disorders
General disorders and administration site
conditions
Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Nervous system disorders
Psychiatric disorders
Skin and subcutaneous tissue disorders
Vascular disorders
Less Common (less than 1%):
Eye disorders
Gastrointestinal disorders
General disorders and administration site
conditions
Hepatobiliary disorders
Investigations
Musculoskeletal and connective tissue disorders
Nervous system disorders
Psychiatric disorders
Renal and urinary disorders
Reproductive system and breast disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Vascular disorders
