Approved August 13, 2009

MORPHINE SULFATE/NALTREXONE HYDROCHLORIDE
(FDA Category 4S)

EMBEDA(R) (King Pharmaceuticals) is an extended-release oral capsule containing pellets of morphine sulfate, an opioid receptor agonist, surrounding an inner core of naltrexone hydrochloride, an opioid receptor antagonist, at a ratio of 100:4.

DOSING INFORMATION: It is critical to adjust the dosing regimen for each patient individually. Morphine sulfate/naltrexone hydrochloride extended-release capsules are available in the following strengths: 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, and 80 mg/3.2 mg. There is a 100 mg/4 mg strength, which should be reserved for opioid-tolerant patients. Morphine sulfate/naltrexone hydrochloride should not be given more frequently than every 12 hr. Patients who have difficulty swallowing may open the capsules and sprinkle the pellets onto a small amount of apple sauce, however, 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. In opioid-tolerant patients, the absorption of naltrexone may precipitate withdrawal.

PHARMACOKINETICS: As with most forms of oral morphine, only about 20% to 40% of the administered morphine dose reaches systemic circulation due to pre-systemic elimination. Median time to peak morphine levels is 7.5 hr. Following oral administration of morphine sulfate/naltrexone hydrochloride, the sequestered naloxone is not consistently absorbed, and when absorbed levels were low and highly variable. Tampering with the formulation by crushing or chewing the pellets, results in rapid release and absorption of both morphine and naltrexone. The Vd of morphine is approximately 3 to 4 L/kg and 30% to 35% of morphine is reversibly bound to plasma proteins. Morphine sulfate/naltrexone hydrochloride is extensively metabolized in the liver; morphine via glucuronidation and sulfation to active metabolites which are then renally excreted, and naltrexone to 6-beta-naltrexol, The terminal elimination half-life of morphine sulfate/naltrexone hydrochloride is approximately 29 hr.

CAUTIONS: Morphine sulfate/naltrexone hydrochloride is for use in opioid-tolerant patients only. It is contraindicated in patients who have or a suspected of having paralytic ileus. Use with caution in patients with chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve (eg, severe kyphoscoliosis), and preexisting respiratory depression, hypoxia, or hypercapnia as it may decrease respiratory drive. Morphine sulfate/naltrexone hydrochloride has additive CNS effects in patients who are taking alcohol, other opioids, or illicit drugs; additionally, addiction or abuse may occur. It is also associated with risk of increased cerebrospinal fluid pressure in patients with head injury or increased intracranial pressure, and seizures in patients with a history of seizures. The most common adverse reactions include constipation, nausea, and somnolence.

FDA APPROVED INDICATIONS: Morphine sulfate/naltrexone hydrochloride 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.