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Embeda (Morphine Sulfate / Naltrexone Hydrochloride) - Description and Clinical Pharmacology



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 (C17H19NO3)2●H2SO4●5H2O 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 pKb 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 C20H23NO4•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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism Of Action

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 [see OVERDOSAGE ].

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.

12.2 Pharmacodynamics

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 Cmax and a higher Cmin 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.

12.3 Pharmacokinetics


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 (Tmax) 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: While concurrent administration of high fat food decreases the rate and extent of morphine absorption from EMBEDA, the total bioavailability is not affected. Co-administration of a high-fat meal with EMBEDA did not compromise sequestration of naltrexone.

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.


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 [see USE IN SPECIFIC POPULATIONS ] and has been found in breast milk [see USE IN SPECIFIC POPULATIONS (8.3) ].


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.


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: Pharmacokinetics of EMBEDA have not been investigated in elderly patients (greater than 65 years) although such patients were included in clinical studies. However, in a long-term open label safety study, the pre-dose plasma morphine concentrations after dose normalization were similar for subjects less than 65 years and those greater than or equal to 65 years of age [see USE IN SPECIFIC POPULATIONS ].

Pediatric: Pharmacokinetics of EMBEDA were not evaluated in pediatric population.

Gender: No meaningful differences were noted between male and female patients in the analysis of pharmacokinetic data of morphine from clinical studies.

Race: Pharmacokinetic differences due to race may exist. Additionally, 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.

Drug Interaction/Alcohol Interaction: As such additive pharmacodynamic effects may be expected when EMBEDA is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Additionally, a pharmacokinetic drug interaction is noted with concomitant administration of 40% alcohol and EMBEDA, where an average 2-fold (range 1.4- to 5-fold increase) higher Cmax of morphine was noted compared to EMBEDA consumed with water

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