Embeda

Since morphine and naltrexone is used for pain, you are not likely to miss a dose. Skip any missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Morphine and naltrexone is not for use on an as-needed basis for pain.

• If you have an allergy to morphine, naltrexone, or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Very bad asthma, trouble breathing, recent head injury, growths or tumors in the brain, raised pressure in the brain, or very bad bowel or stomach problems like bowel block.
• If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for Parkinson's disease like selegiline or rasagiline in the last 14 days. Taking Embeda within 14 days of those drugs can cause very bad high blood pressure.
• If you are taking any of these drugs: Linezolid or methylene blue.
• If you are taking any of these drugs: Buprenorphine, butorphanol, nalbuphine, or pentazocine.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with Embeda.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Seizures.
• Very upset stomach or throwing up.
• Very hard stools (constipation).
• Chest pain or pressure or a fast heartbeat.
• Feeling very sleepy.
• Noisy breathing.
• Feeling confused.
• Very bad belly pain.
• Long-term use of an opioid drug like Embeda may lead to lower sex hormone levels. This may lead to signs like change in sex ability in men, no menstrual period in women, lowered interest in sex, or fertility problems. Call your doctor if you have any of these signs.
• A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take this medicine with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
• Taking an opioid drug like Embeda may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about Embeda, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Embeda. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Embeda.

Review Date: October 4, 2017

Extended-release capsules (morphine sulfate/naltrexone hydrochloride): 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, 100 mg/4 mg. Embeda capsules contain creamy white to light tan spheroidal pellets, have an outer opaque capsule with colors as identified below.

Embeda is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.5)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.6)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)]
• Hypersensitivity (e.g., anaphylaxis) to morphine or naltrexone [see Adverse Reactions (6.2)]

Addiction, Abuse, and Misuse

Embeda contains morphine, a Schedule II controlled substance. As an opioid, Embeda exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. Because extended-release products such as Embeda deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of morphine present [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Embeda. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Embeda, and monitor all patients receiving Embeda for the development of these behaviors and conditions. Risks are 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 depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Embeda, but use in such patients necessitates intensive counseling about the risks and proper use of Embeda along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Embeda by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the morphine and can result in overdose and death [see Overdosage (10)]. Misuse or abuse of Embeda by these methods may also release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals [see Warnings and Precautions (5.12)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Embeda. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO2) 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 dosage increase. Monitor patients closely for respiratory depression especially during the first 24–72 hours of initiating therapy with and following dosage increases of Embeda.

To reduce the risk of respiratory depression, proper dosing and titration of Embeda are essential [see Dosage and Administration (2)]. Overestimating the Embeda dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of Embeda, especially by children, can result in respiratory depression and death due to an overdose of morphine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Embeda during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Embeda with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Embeda is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Embeda therapy. The co-ingestion of alcohol with Embeda may result in increased plasma levels and a potentially fatal overdose of morphine [see Clinical Pharmacology (12.3)].

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Embeda in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with chronic pulmonary disease: Embeda-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Embeda [see Warnings and Precautions (5.2)].

Elderly, cachectic, or debilitated patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Monitor such patients closely, particularly when initiating and titrating Embeda and when Embeda is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.4)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Embeda should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension

Embeda may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is 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 (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage 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 in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Embeda may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Embeda.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Embeda in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions

Embeda is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The morphine in Embeda may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders

The morphine in Embeda may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Embeda therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a full opioid agonist analgesic, including Embeda. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Consuming Embeda capsules that have been altered by crushing, chewing, or dissolving the pellets can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals. Symptoms of withdrawal usually appear within five minutes of ingestion of naltrexone, can last for up to 48 hours, and can include mental status changes, restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Significant fluid losses from vomiting and diarrhea can require intravenous (IV) fluid administration.

When discontinuing Embeda, gradually taper the dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue Embeda [see Drug Abuse and Dependence (9.3)].

Risks of 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 [see Patient Counseling Information (17)].

Interference with Laboratory Tests

Naltrexone does not interfere with thin-layer, gas-liquid, and high performance 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. Consult the test manufacturer for specific details.

The following serious adverse reactions described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
• Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.4)]
• Interaction with Monoamine Oxidase Inhibitors [see Warnings and Precautions (5.6)]
• Adrenal Insufficiency [see Warnings and Precautions (5.7)]
• Severe Hypotension [see Warnings and Precautions (5.8)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)]
• Seizures [see Warnings and Precautions (5.11)]
• Withdrawal [see Warnings and Precautions (5.12)]

Clinical Trials Experience

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.

In the randomized study, the most common adverse reactions with Embeda therapy were constipation, nausea, and somnolence. The most common adverse reactions leading to study discontinuation were nausea, constipation (sometimes severe), vomiting, fatigue, dizziness, pruritus, and somnolence.

Short-Term Randomized Study

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, 344 of 547 subjects were randomized to either an active treatment with Embeda or were tapered off Embeda using a double-dummy design and placed on placebo. The maintenance Period was 12 weeks. Adverse reactions, reported in ≥2% 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 reactions. Adverse reactions reported in ≥2.0% of subjects are presented in Table 2.

Adverse Reactions Observed in the Phase 2/3 Studies

Most common (≥10%): constipation, nausea, somnolence

Common (≥1% to <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

Less common (<1%):
Eye disorders: vision blurred, orthostatic hypotension
Gastrointestinal disorders: abdominal distension, pancreatitis, abdominal discomfort, fecaloma, abdominal pain lower, abdominal tenderness
General disorders and administration site conditions: malaise, asthenia, feeling jittery, drug withdrawal syndrome
Hepatobiliary disorders: cholecystitis
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased
Musculoskeletal and connective tissue disorders: myalgia, muscular weakness
Nervous system disorders: depressed level of consciousness, mental impairment, memory impairment, disturbance in attention, stupor, paresthesia, coordination abnormal
Psychiatric disorders: disorientation, thinking abnormal, mental status changes, confusional state, euphoric mood, hallucination, abnormal dreams, mood swings, nervousness
Renal and urinary disorders: urinary retention, dysuria
Reproductive system and breast disorders: erectile dysfunction
Respiratory, thoracic and mediastinal disorders: dyspnea, rhinorrhea
Skin and subcutaneous tissue disorders: rash, piloerection, cold sweat, night sweats
Vascular disorders: hypotension, flushing

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of morphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Embeda.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Mechanism of Action

Morphine Sulfate

Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Naltrexone Hydrochloride

Naltrexone is an opioid antagonist that reverses the subjective and analgesic effects of mu-opioid receptor agonists by competitively binding at mu-opioid receptors.

Pharmacodynamics

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when Embeda is used in conjunction with alcohol, other opioids, or illicit drugs that cause CNS depression.

Effects on the Central Nervous System

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 both increases in carbon dioxide tension and electrical stimulation.

Morphine causes miosis, even in total darkness. 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 hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

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, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)].

Concentration-Adverse Reaction Relationships

There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

Pharmacokinetics

Absorption

Morphine Sulfate

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, compared to 8 hours with an equal amount of Embeda. Because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.

Embeda is bioequivalent to a similarly formulated 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 the comparator (10 hrs). Dose-related increase in steady-state pre-dose plasma concentrations of morphine were noted following multiple-dose administration of Embeda in patients.

Naltrexone

Following single dose administration of intact Embeda 60/2.4 – 120/4.8 mg, a limited number (~2%) of blood samples had low plasma naltrexone levels (median = 7.74 pg/mL, range 4–132 pg/mL); naltrexone was not detected in the remaining samples. In patients titrated up to 60/2.4–80/3.2 mg Embeda twice daily, naltrexone levels (4–26 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 of morphine administered twice daily for 12 months, 11% of blood samples at pre-dose timepoints at steady-state had detectable plasma naltrexone concentrations ranging from 4 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.

When Embeda is crushed or chewed, up to 100% of the sequestered naltrexone dose could be released, bioequivalent to an immediate-release oral solution of the same dose.

Food Effect

While concurrent administration of high-fat food decreased the rate and extent of morphine absorption from Embeda, the total bioavailability was not affected. Co-administration of a high-fat meal with Embeda did not compromise the sequestration of naltrexone.

Distribution

Morphine

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 (8.1)] and has been found in breast milk [see Use in Specific Populations (8.3)].

Elimination

Metabolism

Morphine:

Major pathways of morphine metabolism include glucuronidation in the liver to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation in the liver to produce 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:

Naltrexone is extensively metabolized into 6-β-naltrexol.

Excretion

Morphine:

Approximately 10% of a morphine dose is excreted unchanged in the urine. Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites M3G and M6G 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 of morphine is about 20 to 30 mL/minute/kg. The effective half-life of morphine after IV administration is reported to be approximately 2 hours. The terminal elimination half-life of morphine following single dose Embeda administration is approximately 29 hours.

Specific Populations

Age: Geriatric Population

The pharmacokinetics of Embeda have not been investigated in elderly patients (>65 years) although such patients were included in clinical studies. In a long-term open label safety study, the pre-dose plasma morphine concentrations after dose normalization were similar for subjects <65 years and those ≥65 years of age.

Sex

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

Race/Ethnicity

Chinese subjects given IV morphine in one study had a higher clearance when compared to Caucasian subjects (1852 ± 116 mL/min vs. 1495 ± 80 mL/min).

Hepatic Impairment

Morphine pharmacokinetics are altered in patient with alcoholic cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. M3G and M6G to morphine plasma AUC ratios also decreased in these patients, indicating a decrease in metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.

Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure. The AUC is increased and clearance is decreased and the metabolites, M3G and M6G, may accumulate several-fold in patients with renal failure compared to healthy subjects. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.

Drug Interaction Studies

Alcohol

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.

Embeda® (im-bed-a)
(morphine sulfate and naltrexone hydrochloride) extended-release Capsules, CII

• If you cannot swallow Embeda® capsules, tell your healthcare provider. There may be another way to take Embeda® that may be right for you. If your healthcare provider tells you that you can take Embeda® using this other way, follow these steps:   Embeda® can be opened and the pellets inside the capsule can be sprinkled over applesauce, as follows:

  		Open the Embeda® capsule and sprinkle the pellets over approximately one tablespoon of applesauce (See Figure 1).
  	Figure 1
  		Swallow all of the applesauce and pellets right away. Do not save any of the applesauce and pellets for another dose (See Figure 2).
  	Figure 2
  		Rinse your mouth to make sure you have swallowed all of the pellets. Do not chew the pellets (See Figure 3).
  	Figure 3
  		Flush the empty capsule down the toilet right away (See Figure 4).
  	Figure 4

• You should not receive Embeda® through a nasogastric tube or gastric tube (stomach tube).

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for: Pfizer Inc, New York, NY 10017
by: Actavis Elizabeth LLC, 200 Elmora Avenue, Elizabeth, NJ 07207

LAB-0631-2.0

April 2014

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 60793-437-20

Pfizer

Embeda®
(morphine sulfate and
naltrexone hydrochloride)
Extended Release Capsules

CII

100 mg/4 mg

THE PELLETS SHOULD NOT BE CHEWED, CRUSHED, OR DISSOLVED.

For use in opioid-tolerant patients only

30 Capsules
Rx only

Do not use Embeda if you have used a MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

You should not use Embeda if you have ever had an allergic reaction to a narcotic medicine, or if you have:

• severe asthma or breathing problems; or

• a bowel obstruction called paralytic ileus.

To make sure Embeda is safe for you, tell your doctor if you have ever had:

• any type of breathing problem or lung disease;

• a head injury, brain tumor, or seizures;

• drug or alcohol addiction, or mental illness;

• enlarged prostate, urination problems;

• liver or kidney disease;

• abnormal curvature of the spine that affects your breathing;

• problems with your gallbladder, pancreas, thyroid, or adrenal gland; or

• if you use a sedative like Valium (diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others).

Some medicines can interact with morphine and naltrexone and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take stimulant medicine, opioid medicine, herbal products, or medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

Tell your doctor if you are pregnant. If you use Embeda while you are pregnant, your baby could become dependent on morphine. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks.

Morphine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using Embeda.

Narcotic (opioid) medication can interact with many other drugs and cause dangerous side effects or death. Be sure your doctor knows if you also use:

• other narcotic medications - opioid pain medicine or prescription cough medicine;

• drugs that make you sleepy or slow your breathing - a sleeping pill, muscle relaxer, sedative, tranquilizer, or antipsychotic medicine; or

• drugs that affect serotonin levels in your body - medicine for depression, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting.

This list is not complete. Other drugs may interact with morphine and naltrexone, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to morphine / naltrexone: oral capsule extended release

Along with its needed effects, morphine / naltrexone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking morphine / naltrexone:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• chills
• confusion
• constipation
• drowsiness
• feeling of warmth
• irritability
• mental depression
• rapid weight gain
• redness of the face, neck, arms, and occasionally, upper chest
• relaxed and calm feeling
• restlessness
• sleepiness
• sudden sweating
• tingling of the hands or feet
• trembling or shaking of the hands or feet
• unusual weight gain or loss

• Abnormal dreams
• being forgetful
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• clumsiness or unsteadiness
• confusion about identity, place, and time
• darkened urine
• decrease in frequency or volume of urination
• decreased awareness or responsiveness
• delusions
• dementia
• difficult or labored breathing
• difficult or painful urination
• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly
• fast heartbeat
• feeling of warmth
• fever
• indigestion
• loss of appetite
• nausea
• nervousness
• pains in the stomach, side, or abdomen, possibly radiating to the back
• redness of the face, neck, arms, and occasionally, upper chest
• seeing, hearing, or feeling things that are not there
• severe nausea or vomiting
• severe sleepiness
• sweating
• tightness in the chest
• unusual tiredness or weakness
• vomiting
• yellow eyes or skin

Some side effects of morphine / naltrexone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• anxiety
• belching
• decreased appetite
• diarrhea
• difficulty with moving
• excess air or gas in the stomach or intestines
• full feeling
• heartburn
• itching skin
• muscle pain or stiffness
• muscle spasm
• pain in the joints
• sleepiness or unusual drowsiness
• stomach discomfort or upset
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• weight loss

• Cold sweats
• dizziness
• dry mouth
• general feeling of discomfort or illness
• headache
• inability to have or keep an erection
• increased sweating
• lack or loss of strength
• loss in sexual ability, desire, drive, or performance
• night sweats
• pressure in the stomach
• rash
• stomach tenderness
• swelling of the stomach area
• trouble sleeping
• upper abdominal or stomach pain