General Information

Embeda is an extended-release oral formulation of morphine sulfate and naltrexone hydrochloride. Morphine sulfate is an agonist and naltrexone hydrochloride is an antagonist at the mu-opioid receptor. Morphine provides analgesic and sedative effects while naltrexone hydrochloride reverses the subjective and analgesic effects.

Embeda is specifically 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 supplied as a capsule intended for oral administration. The recommended dosing regimens are as follows:

Initiating therapy with Embeda
The dosing regimen should be calculated individually, taking into account the patient's prior analgesic treatment experience.

Use of Embeda as the First Opioid Analgesic
The lowest dose of Embeda should be used as the initial opioid analgesic. 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.
1) Parenteral to Oral Morphine Ratio: It may take anywhere from 2-6 mg of oral morphine to provide analgesia equivalent to 1 mg of parenteral morphine.
2) Other Oral or Parenteral Opioids to Oral Morphine Sulfate: There is lack of systematic evidence bearing on these types of analgesic substitutions. Therefore, specific recommendations are not possible.

Individualization of Dosage
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.

Embeda should be titrated no more frequently than every-other-day to allow patients to stabilize before escalating the dose.

If breakthrough pain occurs, the dose may be supplemented with a small dose (less than 20% of the total daily dose) of a short-acting analgesic.

Patients who exhibit signs of excessive opioid side effects such as sedation should have their dose reduced.

Patients who experience inadequate analgesia on once-daily dosing should be switched to twice-a-day.

Embeda should not be dosed more frequently than every 12 hours.

Alternative Methods of Administration
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.

Maintenance of Therapy
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.

Cessation of Therapy
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.

Clinical Results

FDA Approval
The FDA approval of Embeda was based on a randomized, double-blind, placebo-controlled clinical trial. This study, ALO-KNT-301, enrolled subjects with moderate to severe osteoarthritic pain of the hip or knee. The subjects started open-label treatment with Embeda and titrated to effect. Once their pain was controlled (Brief Pain Inventory Average 24-hour Pain Intensity AND at least a 2-point drop from screening baseline), they were randomized to either active treatment with Embeda or were tapered off Embeda using a double-dummy design and placed on placebo. Of these, 75.1% of the randomized subjects were opioid naïve and distributed evenly between the 2 groups. The mean change in the weekly diary BPI average pain score from randomization baseline (Visit Y) to the end of study (Visit Y + 12 Weeks/Early Termination) was statistically significantly superior for those treated with Embeda compared to the placebo group.

Ongoing Study Commitments

• King Pharmaceuticals has agreed to conduct a deferred pediatric efficacy, safety, and pharmacokinetic (single- and multiple-dose) study under PREA for the treatment of moderate to severe pain, when a continuous, around-the-clock opioid analgesic is needed for an extended period of time in pediatric patients ages 12 to 17 years.
  Final Protocol Submission Date: November 2009
  Study Completion Date: April 2011
  Final Report Submission: July 2011
• King Pharmaceuticals has agreed to conduct a deferred pediatric efficacy, safety, and pharmacokinetic (single- and multiple-dose) study under PREA for the treatment of moderate to severe pain, when a continuous, around-the-clock opioid analgesic is needed for an extended period of time in pediatric patients ages 2 to <12 years.
  Final Protocol Submission Date: November 2010
  Study Completion Date: November 2011
  Final Report Submission: February 2012

Side Effects

Adverse reactions associated with the use of Embeda may include, but are not limited to, the following:

• Nausea
• Constipation
• Vomiting
• Fatigue
• Dizziness
• Pruritus
• Somnolence

Mechanism of Action

Embeda is an extended-release oral formulation of morphine sulfate and naltrexone hydrochloride. Morphine sulfate is an agonist and naltrexone hydrochloride is an antagonist at the mu-opioid receptor. 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 periaqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia. 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.

Literature References

Hamann S, Sloan P Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: a randomized, double-blind, prospective pilot study. Journal of Opioid Management 2007 May-Jun;3(3):137-44.

Additional Information

For additional information regarding Embeda or moderate to severe pain, please visit the Embeda web page.