"The U.S. Food and Drug Administration today approved Hysingla ER (hydrocodone bitartrate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternat"...
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]. As modified-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.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed EMBEDA and in those who obtain the drug illicitly. 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 or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of EMBEDA for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations 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]. Misuse or abuse of EMBEDA by these methods may also release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals [see Avoidance of Withdrawal].
Opioid agonists such as EMBEDA 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 INFORMATION]. 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 modified-release opioids, even when used as recommended. Respiratory depression from opioid use, 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]. 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 dose increase. Closely monitor patients for respiratory depression when initiating therapy with EMBEDA and following dose increases.
To reduce the risk of respiratory depression, proper dosing and titration of EMBEDA are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the EMBEDA dose 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 signs 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. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the newborn.
Interactions With Central Nervous System Depressants
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].
Hypotension, profound sedation, coma, respiratory depression, and death may result if EMBEDA is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of EMBEDA in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin EMBEDA is made, start with EMBEDA 20 mg/0.8 mg every 24 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see DRUG INTERACTIONS].
Use in Elderly, Cachectic, And Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating EMBEDA and when EMBEDA is given concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression].
Use In Patients With Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with EMBEDA, as in these patients, even usual therapeutic doses of EMBEDA may decrease respiratory drive to the point of apnea [see Life-Threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in these patients if possible.
EMBEDA may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an 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]. Monitor these patients for signs of hypotension after initiating or titrating the dose 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 Head Injury Or Increased Intracranial Pressure
Monitor patients taking EMBEDA who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with EMBEDA. EMBEDA may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. 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.
Use In Patients With Gastrointestinal Conditions
EMBEDA is contraindicated in patients with paralytic ileus. Avoid the use of EMBEDA in patients with other GI obstruction.
The morphine in EMBEDA may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in serum amylase.
Use In Patients With Convulsive Or Seizure Disorders
The morphine in EMBEDA may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during EMBEDA therapy.
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with 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 and can last for up to 48 hours. Mental status changes can include 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 dose [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue EMBEDA.
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.
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)
Addiction, Abuse, and Misuse
Inform patients that the use of EMBEDA, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share EMBEDA with others and to take steps to protect EMBEDA from theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting EMBEDA or when the dose is increased, and that it can occur even at recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store EMBEDA securely and to dispose of unused EMBEDA by flushing the capsules down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of EMBEDA during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS AND PRECAUTIONS].
Interactions with Alcohol and other CNS Depressants
Instruct patients not to consume alcoholic beverages, or prescription and non-prescription products that contain alcohol, during treatment with EMBEDA. The co-ingestion of alcohol with EMBEDA may result in increased plasma levels and a potentially fatal overdose of morphine [see WARNINGS AND PRECAUTIONS].
Inform patients that potentially serious additive effects may occur if EMBEDA is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a healthcare provider.
Important Administration Instructions
Instruct patients how to properly take EMBEDA, including the following:
- Swallow EMBEDA capsules whole or sprinkle the capsule contents on applesauce and then swallow immediately without chewing
- Do not crush, chew, or dissolve the pellets contained in the capsules due to a risk of fatal morphine overdose or naltrexone
- precipitated withdrawal symptoms in opioid-dependent individuals
- Use EMBEDA exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
- Do not discontinue EMBEDA without first discussing the need for a tapering regimen with the prescriber
Inform patients that EMBEDA may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).
Driving or Operating Heavy Machinery
Inform patients that EMBEDA may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Inform patients that anaphylaxis has been reported with ingredients contained in EMBEDA. Advise patients how to recognize such a reaction and when to seek medical attention.
Advise female patients that EMBEDA can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.
Disposal of Unused EMBEDA
Advise patients to flush the unused capsules down the toilet when EMBEDA is no longer needed.
This product's label may have been updated. For current full prescribing information please visit www.pfizer.com.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Studies in animals to evaluate the carcinogenic potential of morphine have not been conducted.
No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes. Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the above positive findings, in vitro studies in the literature have also shown that morphine did not induce chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.
Impairment of Fertility
No formal nonclinical studies to assess the potential of morphine to impair fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse effects on male fertility in the rat from exposure to morphine. One study in which male rats were administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects including reduction in total pregnancies, higher incidence of pseudopregnancies, and reduction in implantation sites were seen. Studies from the literature have also reported changes in hormonal levels (i.e., testosterone, LH, serum corticosterone) following treatment with morphine. These changes may be associated with the reported effects on fertility in the rat.
Use In Specific Populations
Fetal/neonatal Adverse Reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see WARNINGS AND PRECAUTIONS].
Teratogenic Effects - Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. EMBEDA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In humans, the frequency of congenital anomalies has been reported to be no greater than expected among the children of 70 women who were treated with morphine during the first four months of pregnancy, or in 448 women treated with morphine anytime during pregnancy. Furthermore, no malformations were observed in the infant of a woman who attempted suicide by taking an overdose of morphine and other medication during the first trimester of pregnancy.
Several literature reports indicate that morphine administered subcutaneously during the early gestational period in mice and hamsters produced neurological, soft tissue and skeletal abnormalities. With one exception, the effects that have been reported occurred following doses that were maternally toxic and the abnormalities noted were characteristic of those observed when maternal toxicity is present. In one study, following subcutaneous infusion of doses greater than or equal to 0.15 mg/kg to mice, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted in the absence of maternal toxicity. In the hamster, morphine sulfate given subcutaneously on gestation day 8 produced exencephaly and cranioschisis. In rats treated with subcutaneous infusions of morphine during the period of organogenesis, no teratogenicity was observed. No maternal toxicity was observed in this study, however, increased mortality and growth retardation were seen in the offspring. In two studies performed in the rabbit, no evidence of teratogenicity was reported at subcutaneous doses up to 100 mg/kg.
Infants born to mothers who have taken opioids chronically may exhibit neonatal withdrawal syndrome [see WARNINGS AND PRECAUTIONS], reversible reduction in brain volume, small size, decreased ventilatory response to CO2 and increased risk of sudden infant death syndrome. Morphine should be used by a pregnant woman only if the need for opioid analgesia clearly outweighs the potential risks to the fetus.
Controlled studies of chronic in utero morphine exposure in pregnant women have not been conducted. Published literature has reported that exposure to morphine during pregnancy in animals is associated with reduction in growth and a host of behavioral abnormalities in the offspring. Morphine treatment during gestational periods of organogenesis in rats, hamsters, guinea pigs and rabbits resulted in the following treatment-related embryotoxicity and neonatal toxicity in one or more studies: decreased litter size, embryo-fetal viability, fetal and neonatal body weights, absolute brain and cerebellar weights, delayed motor and sexual maturation, and increased neonatal mortality, cyanosis and hypothermia. Decreased fertility in female offspring, and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed. Decreased litter size and viability were observed in the offspring of male rats administered morphine (25 mg/kg, IP) for 1 day prior to mating. Behavioral abnormalities resulting from chronic morphine exposure of fetal animals included altered reflex and motor skill development, mild withdrawal, and altered responsiveness to morphine persisting into adulthood.
Labor And Delivery
Opioids cross the placenta and may produce respiratory depression in neonates. EMBEDA is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.
Morphine is excreted in breast milk, with a milk to plasma morphine AUC ratio of approximately 2.5:1. The amount of morphine received by the infant varies depending on the maternal plasma concentration, the amount of milk ingested by the infant, and the extent of first pass metabolism. Closely monitor infants of nursing women receiving EMBEDA.
Withdrawal symptoms can occur in breast-feeding infants when maternal administration of morphine is stopped.
Because of the potential for adverse reactions in nursing infants from EMBEDA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
The safety and efficacy of EMBEDA in patients less than 18 years of age have not been established.
Clinical studies of EMBEDA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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. Limited data are available on the pharmacokinetics of EMBEDA in geriatric patients [see CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/31/2014
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