EMBEDA- morphine sulfate and naltrexone hydrochloride capsule, extended release Pfizer Laboratories Div Pfizer Inc
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HIGHLIGHTSOFPRESCRIBINGINFORMATION
ThesehighlightsdonotincludealltheinformationneededtouseEMBEDAsafelyandeffectively.SeefullprescribinginformationforEMBEDA.
EMBEDA®(morphinesulfateandnaltrexonehydrochloride)extended-releasecapsules,fororaluse,CII
InitialU.S.Approval:2009
RECENTMAJORCHANGES
BoxedWarning / 04/2014IndicationsandUsage(1) / 04/2014
DosageandAdministration(2) / 04/2014
WarningsandPrecautions(5) / 04/2014
INDICATIONSANDUSAGE
EMBEDAisacombinationopioidagonist/opioidantagonistproductindicatedforthemanagementofpainsevereenoughtorequiredaily,around-the-clock,long-termopioidtreatmentandforwhichalternativetreatmentoptionsareinadequate.(1)
LimitationsofUse
Foropioid-naïveandopioidnon-tolerantpatients,initiatewith20mg/0.8mgcapsules(morphinesulfate/naltrexonehydrochloride)orallyevery24hours.(2.1)
DonotabruptlydiscontinueEMBEDAinaphysically-dependentpatient.(2.3,5.11)
InstructpatientstoswallowEMBEDAcapsulesintact,ortosprinklethecapsulecontentsonapplesauceandimmediatelyswallowwithoutchewing.(2.4)
Instructpatientsnottocrush,dissolve,orchewthepelletsinthecapsuletoavoidtheriskofreleaseandabsorptionofapotentiallyfataldoseofmorphine,andtoavoidreleaseofsequesterednaltrexonethatcouldprecipitateopioidwithdrawal.(2.4)
DOSAGEFORMSANDSTRENGTHS
Extended-releasecapsules(morphinesulfate/naltrexonehydrochloride):20mg/0.8mg,30mg/1.2mg,50mg/2mg,60mg/2.4
mg,80mg/3.2mg,100mg/4mg(3)
CONTRAINDICATIONS
Significantrespiratorydepression(4)Acuteorseverebronchialasthma(4)Knownorsuspectedparalyticileus(4)
Hypersensitivitytomorphineornaltrexone(4)
WARNINGSANDPRECAUTIONS
InteractionswithCNSdepressants:Concomitantusemaycauseprofoundsedation,respiratorydepression,anddeath.Ifcoadministrationisrequired,considerdosereductionofoneorbothdrugsbecauseofadditivepharmacologicaleffects.(5.4,7.2)Elderly,cachectic,debilitatedpatients,andthosewithchronicpulmonarydisease:Monitorcloselybecauseofincreasedriskforlife-threateningrespiratorydepression.(5.5,5.6)
Hypotensiveeffect:Monitorduringdoseinitiationandtitration.(5.7)
Patientswithheadinjuryorincreasedintracranialpressure:Monitorforsedationandrespiratorydepression.AvoiduseofEMBEDAinpatientswithimpairedconsciousnessorcomasusceptibletointracranialeffectsofCO2retention.(5.8)
ADVERSEREACTIONS
Mostcommonadversereactions(>10%):constipation,nausea,andsomnolence.(6.1)
ToreportSUSPECTEDADVERSEREACTIONS,contactPfizerInc.at1-800-438-1985orFDAat1-800-FDA-1088or
DRUGINTERACTIONS
Mixedagonist/antagonistandpartialagonistopioidanalgesics:AvoidusewithEMBEDAbecausetheymayreduceanalgesiceffectofEMBEDAorprecipitatewithdrawalsymptoms.(5.11,7.3)
Monoamineoxidaseinhibitors(MAOIs):AvoidEMBEDAinpatientstakingMAOIsorwithin14daysofstoppingsuchtreatment.(7.5)
Becauseoftherisksofaddiction,abuse,andmisusewithopioids,USEINSPECIFICPOPULATIONS
evenatrecommendeddoses,andbecauseofthegreaterrisksof
overdoseanddeathwithextended-releaseopioidformulations,reserveEMBEDAforuseinpatientsforwhomalternativetreatmentoptions(e.g.,non-opioidanalgesicsorimmediate-releaseopioids)areineffective,nottolerated,orwouldbeotherwiseinadequatetoprovidesufficientmanagementofpain.(1)EMBEDAisnotindicatedasanas-needed(prn)analgesic.(1)
Pregnancy:Basedonanimaldata,maycausefetalharm.(8.1)Nursingmothers:Morphinehasbeendetectedinhumanmilk.CloselymonitorinfantsofnursingwomenreceivingEMBEDA.(8.3)
See17forPATIENTCOUNSELINGINFORMATIONand
MedicationGuide.
DOSAGEANDADMINISTRATION
EMBEDA100mg/4mgcapsulesareonlyforpatientsinwhomtolerancetoanopioidofcomparablepotencyisestablished.
Patientsconsideredopioid-tolerantarethosetaking,foroneweekorlonger,atleast60mgofmorphinedaily,atleast30mgoforaloxycodonedaily,atleast8mgoforalhydromorphonedaily,oranequianalgesicdoseofanotheropioid.(2.1)
Revised:10/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ADDICTION, ABUSE, AND MISUSE;LIFE-THREATENING RESPIRATORYDEPRESSION; ACCIDENTAL INGESTION;NEONATAL OPIOID WITHDRAWALSYNDROME; and INTERACTION WITHALCOHOL
1INDICATIONS AND USAGE
2DOSAGE AND ADMINISTRATION
2.1Initial Dosing
2.2Titration and Maintenance of Therapy
2.3Discontinuation of EMBEDA
2.4Administration of EMBEDA
3DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5WARNINGS AND PRECAUTIONS
5.1Addiction, Abuse, and Misuse
5.2Life-Threatening Respiratory Depression
5.3Neonatal Opioid Withdrawal Syndrome
5.4Interactions with Central Nervous SystemDepressants
5.5Use in Elderly, Cachectic, and Debilitated Patients
5.6Use in Patients with Chronic Pulmonary Disease
5.7Hypotensive Effect
5.8Use in Patients with Head Injury or IncreasedIntracranial Pressure
5.9Use in Patients with Gastrointestinal Conditions
5.10Use in Patients with Convulsive or SeizureDisorders
5.11Avoidance of Withdrawal
7.3Mixed Agonist/Antagonist and Partial AgonistOpioid Analgesics
7.4Muscle Relaxants
7.5Monoamine Oxidase Inhibitors (MAOIs)
7.6Cimetidine
7.7Diuretics
7.8Anticholinergics
7.9P-Glycoprotein (P-gp) Inhibitors
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.2Labor and Delivery
8.3Nursing Mothers
8.4Pediatric Use
8.5Geriatric Use
9DRUG ABUSE AND DEPENDENCE
9.1Controlled Substance
9.2Abuse
9.3Dependence10 OVERDOSAGE11 DESCRIPTION
12CLINICAL PHARMACOLOGY
12.1Mechanism of Action
12.2Pharmacodynamics
12.3Pharmacokinetics
13NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment ofFertility
14CLINICAL STUDIES
16HOW SUPPLIED/STORAGE AND HANDLING
17PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
5.12Driving and Operating Machinery
5.13Interference with Laboratory Tests
6ADVERSE REACTIONS
6.1Clinical Trial Experience
7DRUG INTERACTIONS
7.1Alcohol
7.2CNS Depressants
FULL PRESCRIBING INFORMATION
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME;
and INTERACTION WITH ALCOHOL
Addiction, Abuse, and Misuse
EMBEDA®exposes patients and other usersto the risks of opioidaddiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing EMBEDA, and monitor all patients regularly for the development of these behaviors or conditions [seeWarnings andPrecautions (5.1)].
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of EMBEDA. Monitor for respiratory depression, especially during initiation of EMBEDA or following a dose increase.Instructpatients to swallow EMBEDA capsules whole, or to sprinkle the contents of the capsule on applesauce and swallow immediately without chewing. Crushing, chewing, or dissolving EMBEDA can cause rapid release and absorption of a potentially fatal dose of morphine [seeWarnings and Precautions (5.2)].
Accidental Ingestion
Accidental ingestion of even one dose of EMBEDA, especially by children, can result in a fatal overdose of morphine [seeWarnings and Precautions (5.2)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of EMBEDA during pregnancy can result in neonatal opioid withdrawal syndrome, which 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 [seeWarnings and Precautions (5.3)].
Interaction with Alcohol
Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking EMBEDA. The co-ingestion of alcohol with EMBEDA may result in increased plasma level and a potentially fatal overdose of morphine [seeWarnings and Precautions
1INDICATIONS AND USAGE
EMBEDA is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Limitations of Use
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve EMBEDA for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
EMBEDA is not indicated as an as-needed (prn) analgesic.
2DOSAGE AND ADMINISTRATION
2.1Initial Dosing
EMBEDA should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
EMBEDA 100 mg/4 mg capsules are only for patients in whom tolerance to an opioid of comparable potency is established. Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg of morphine daily, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.
Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse [seeWarnings and Precautions (5.1)]. Monitor patientsclosely for respiratory depression, especially within the first 24–72 hours of initiating therapy with EMBEDA [seeWarnings and Precautions (5.2)].
EMBEDA capsules must be taken whole.Crushing, chewing, or dissolving EMBEDA capsules will result inuncontrolled delivery of morphine and can lead to overdose or death [seeWarnings and Precautions (5.2)]. Patientswho are unable to swallow EMBEDA should be instructed to sprinkle the capsule contents on applesauce and immediately swallow without chewing [seeAdministration of EMBEDA (2.4)].
EMBEDA is administered at a frequency of either once daily (every 24 hours) or twice daily (every 12 hours).
Initiate treatment with EMBEDA with 20 mg/0.8 mg capsule orally every 24 hours.
The starting dose for patients who are not opioid tolerant is EMBEDA 20 mg/0.8 mg orally every 24 hours. Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid.
Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.
There are no established conversion ratios from other opioids to EMBEDA defined by clinical trials. Discontinue all other around-the-clock opioid drugs when EMBEDA therapy is initiated and initiate dosing using EMBEDA 30 mg orally every 24 hours.
While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variation in the relative potency of different opioid drugs and products. As such, it is safer to underestimate a patient's 24-hour oral morphine requirement and provide rescue medication (e.g., immediate-release morphine) than to overestimate and manage an adverse reaction.
Conversion from Other Oral Morphine Formulations to EMBEDA
Patients receiving other oral morphine formulations may be converted to EMBEDA by administering one-half of the patient's total daily oral morphine dose as EMBEDA twice daily, or by administering the total daily oral morphine dose as EMBEDA once daily. There are no data to support the efficacy or safety of prescribing EMBEDA more frequently than every 12 hours.
Conversion from Parenteral Morphine, or Other Opioids, to EMBEDA
When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to EMBEDA, consider the following general points:
Parenteral to Oral Morphine Ratio: Between 2 mg and 6 mg of oral morphine may be required to provideanalgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of oral morphine that is three times the daily parenteral morphine requirement is sufficient.
Other Oral or Parenteral Opioids to Oral Morphine Ratios: Specific recommendations are not availablebecause of a lack of systematic evidence for these types of analgesic substitutions. Published relative potency data are available, but such ratios are approximations. In general, begin with half of the estimated daily morphine requirement as the initial dose, managing inadequate analgesia by supplementation with immediate- release morphine.
Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.
The first dose of EMBEDA may be taken with the last dose of any immediate-release opioid medication due to the extended-release characteristics of the EMBEDA formulation.
2.2Titration and Maintenance of Therapy
Individually titrate EMBEDA to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving EMBEDA to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for opioid analgesics.
If the level of pain increases, attempt to identify the source of increased pain, while adjusting the EMBEDA dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 24 to 36 hours, EMBEDA dose may be adjusted every 1 to 2 days.
Patients who experience breakthrough pain may require a dose increase of EMBEDA, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the EMBEDA dose. In patients experiencing inadequate analgesia with once-daily dosing of EMBEDA, consider a twice-daily regimen.
If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
2.3Discontinuation of EMBEDA
When a patient no longer requires therapy with EMBEDA, use a gradual downward titration of the dose every 2 to 4 days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue EMBEDA.
2.4Administration of EMBEDA
Instruct patients to swallow EMBEDA capsules intact. The capsules contain pellets that consist of morphine and sequestered naltrexone. 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 [seeWarnings and Precautions (5.2)].
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 [seeWarnings and Precautions(5.12)].
Alternatively, the contents of the EMBEDA capsules (pellets) may be sprinkled over applesauce and then swallowed. This method is appropriate only for patients able to reliably swallow the applesauce without chewing. Other foods have not been tested and should not be substituted for applesauce. Instruct the patient to:
Sprinkle the pellets onto a small amount of applesauce and consume immediately without chewing. Rinse the mouth to ensure all pellets have been swallowed.
Discard any unused portion of the EMBEDA capsules after the contents have been sprinkled on applesauce.
Do not administer EMBEDA pellets through a nasogastric or gastric tube.
3DOSAGE FORMS AND STRENGTHS
EMBEDA capsules contain creamy white to light tan spheroidal pellets, have an outer opaque capsule with colors as identified below and are available in six dosage strengths.
Each 20 mg/0.8 mg extended-release capsule contains 20 mg of morphine sulfate and 0.8 mg of naltrexone hydrochloride in a two-toned yellow opaque capsule with "EMBEDA" printed in grey ink on the darker-toned cap and a single grey band around ¾ of the circumference. The lighter-toned body has "20" reverse-printed in a grey circle.
Each 30 mg/1.2 mg extended-release capsule contains 30 mg of morphine sulfate and 1.2 mg of naltrexone hydrochloride in a two-toned blue-violet opaque capsule with "EMBEDA" printed in grey ink on the darker-toned cap and a single grey band around ¾ of the circumference. The lighter-toned body has "30" reverse-printed in a grey circle.
Each 50 mg/2 mg extended-release capsule contains 50 mg of morphine sulfate and 2 mg of naltrexone hydrochloride in a two-toned blue opaque capsule with "EMBEDA" printed in grey ink on the darker-toned cap and a single grey band around ¾ of the circumference. The lighter-toned body has "50" reverse-printed in a grey circle.
Each 60 mg/2.4 mg extended-release capsule contains 60 mg of morphine sulfate and 2.4 mg of naltrexone hydrochloride in a two-toned pink opaque capsule with "EMBEDA" printed in grey ink on the darker-toned cap and a single grey band around ¾ of the circumference. The lighter-toned body has "60" reverse-printed in a grey circle.
Each 80 mg/3.2 mg extended-release capsule contains 80 mg of morphine sulfate and 3.2 mg of naltrexone hydrochloride in a two-toned light peach opaque elongated capsule with "EMBEDA" printed in grey ink on the darker-toned cap and a single grey band around ¾ of the circumference. The lighter-toned body has "80" reverse- printed in a grey circle.
Each 100 mg/4 mg extended-release capsule contains 100 mg of morphine sulfate and 4 mg of naltrexone hydrochloride in a two-toned green opaque capsule with "EMBEDA" printed in grey ink on the darker-toned cap and a single grey band around ¾ of the circumference. The lighter-toned body has "100" reverse-printed in a grey circle.
4CONTRAINDICATIONS
EMBEDA is contraindicated in patients with: Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment Known or suspected paralytic ileus
Hypersensitivity (e.g., anaphylaxis) to morphine or naltrexone [seeAdverse Reactions (6.1)]
5WARNINGS AND PRECAUTIONS
5.1Addiction, 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 [seeDrug Abuse and Dependence (9)]. As modified-release products such asEMBEDA 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 [seeOverdosage (10)]. Misuse or abuseof EMBEDA by these methods may also release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals [seeWarnings and Precautions (5.11)].
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 [seePatient Counseling Information (17)]. Contact local state professional licensing board or statecontrolled substances authority for information on how to prevent and detect abuse or diversion of this product.
5.2Life-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 [seeOverdosage (10)]. Carbon dioxide (CO2) retention fromopioid-induced respiratory depression can exacerbate thesedating 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 [seeDosage andAdministration (2)]. Overestimating the EMBEDA dose when converting patients from another opioid product canresult 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.