WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS);LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse, and Misuse
MORPHABOND™ ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Morphabond ER, and monitor all patients regularly for the development of these behaviors and conditions[see Warnings and Precautions (5.1)].
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products[see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to
•complete a REMS-compliant education program,
•counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage,and disposal of these products,
•emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
•consider other tools to improve patient, household, and community safety.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Morphabond ER. Monitor for respiratory depression, especially during initiation of Morphabond ER or following a dose increase. Instruct patients to swallow Morphabond ER tablets whole; crushing, chewing, or dissolving Morphabond ER tablets can cause rapid release and absorption of a potentially fatal dose of morphine[see Warnings and Precautions (5.3)].
Accidental ingestion of even one dose of Morphabond ER, especially by children, can result in a fatal overdose of morphine[see Warnings and Precautions (5.3)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of Morphabond ER 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[see Warnings and Precautions (5.4)].
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death[see Warnings and Precautions (5.5), Drug Interactions (7)].
•Reserve concomitant prescribing of Morphabond ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
•Limit dosages and durations to the minimum required.
•Follow patients for signs and symptoms of respiratory depression and sedation
1 INDICATIONS AND USAGE
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Morphabond ER 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 [see Warnings andPrecautions(5.1)], reserve Morphabond ER 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.
Morphabond ER is not indicated as an as-needed (prn) analgesic.
2 DOSAGE AND ADMINISTRATION
2.1 Important Dosage and Administration Instructions
Morphabond ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
Morphabond ER 100 mg tablets, a single dose greater than 60 mg, or a total daily dose greater than 120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established. 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, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [seeWarnings and Precautions (5)].
Initiate the dosing regimen for each patient individually; taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [seeWarnings and Precautions (5.1)].
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Morphabond ER and adjust the dosage accordingly [seeWarnings and Precautions (5.3)].
Instruct patients to swallow Morphabond ER tablets whole [seePatient Counseling Information (17)]. Crushing, chewing, or dissolving Morphabond ER tablets will result in uncontrolled delivery of morphine and can lead to overdose or death [seeWarnings and Precautions (5.1)].
Morphabond ER is administered orally every 8 or 12 hours.
2.2 Initial Dosage
Use ofMorphabond ERas the First Opioid Analgesic(opioid-naïve patients)
Initiate treatment with Morphabond ER with 15 mg tablets orally every 8 or 12 hours.
Use ofMorphabond ERin Patients who are not Opioid Tolerant(opioidnon-tolerantpatients)
The starting dosage for patients who are not opioid tolerant is Morphabond ER 15 mg orally every 8 or 12 hours.
Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions (5.3)].
Conversion from Other Oral Morphine toMorphabond ER
Patients receiving other oral morphine formulations may be converted to Morphabond ER by administering one-half of the patient’s 24-hour requirement as Morphabond ER on an every-12-hour schedule or by administering one-third of the patient’s daily requirement as Morphabond ER on an every-8-hour schedule.
Conversion from Other Opioids toMorphabond ER
Discontinue all other around-the-clock opioid drugs when Morphabond ER therapy is initiated.
There are no established conversion ratios for conversion from other opioids to Morphabond ER defined by clinical trials. Initiate dosing using Morphabond ER 15 mg orally every 8 to 12 hours.
It is safer to underestimate a patient’s 24-hour oral morphine dosage and provide rescue medication (e.g., immediate-release morphine) than to overestimate the 24-hour oral morphine dosage and manage an adverse reaction due to an overdose. While useful tables of opioid equivalents are readily available, there is inter-patient variability in the relative potency of opioid drugs and formulations.
Close observation and frequent titration are warranted until pain management is stable on the new opioid. Monitor patients for signs and symptoms of opioid withdrawal and for signs of oversedation/toxicity after converting patients to Morphabond ER.
Conversion from Parenteral Morphine or Other Opioids (Parenteral or Oral) toMorphabond ER
When converting from parenteral morphine or other non-morphine opioids (parenteral or oral) to Morphabond ER, consider the following general points:
Parenteral to oral morphine ratio: Between 2 to 6 mg of oral morphine may be required to provide analgesia equivalent to 1 mg of parenteral morphine. Typically, a dose of morphine that is approximately three times the previous daily parenteral morphine requirement is sufficient.
Other parenteral or oral non-morphine opioids to oral morphineRatios: Specific recommendations are not available because 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.
Conversion from Methadone toMorphabond ER
Close monitoring is of particular importance when converting 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.
2.3 Titration and Maintenance of Therapy
Individually titrate Morphabond ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Morphabond ER 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 [see Warnings and Precautions (5.1)]. 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 the use of opioid analgesics.
Patients who experience breakthrough pain may require a dosage adjustment of Morphabond ER, 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 Morphabond ER dosage. Because steady-state plasma concentrations are approximated in 1 day, Morphabond ER dosage adjustments may be done every 1 to 2 days.
If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
2.4 Dosage Modifications with Concomitant Use of Central Nervous System Depressants
If the patient is currently taking a central nervous system (CNS) depressant and the decision is made to begin Morphabond ER, start with the lowest possible dose, 15 mg every 12 hours, monitor patients for signs of respiratory depression, sedation, and hypotension, and consider using a lower dosage of the concomitant CNS depressant [see Warnings and Precautions (5.5), Drug Interactions (7)].
2.5 Safe Reduction or Discontinuation of Morphabond ER
Do not abruptly discontinue Morphabond ER in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Morphabond ER, there are a variety of factors that should be considered, including the dose of Morphabond ER the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Morphabond ER who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.13), Drug Abuse and Dependence (9.3)].
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)]
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [seeWarnings and Precautions (5.7)/Drug Interactions (7)]
Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)]
Hypersensitivity (e.g., anaphylaxis) to morphine [see Adverse Reactions (6.2)]
5 WARNINGS AND PRECAUTIONS
5.1 Addiction, Abuse, and Misuse
Morphabond ER contains morphine, a Schedule II controlled substance. As an opioid, Morphabond ER exposes its users to the risks of addiction, abuse, and misuse. Because extended-release products such as Morphabond ER 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 Morphabond ER. 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 Morphabond ER, and monitor all patients receiving Morphabond ER for 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 Morphabond ER, but use in such patients necessitates intensive counseling about the risks of proper use of Morphabond ER along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of Morphabond ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death [see Overdosage (10)].
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Morphabond ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper storage and disposal of unused drug [seePatient 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.
5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
5.3 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 Morphabond ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Morphabond ER.
To reduce the risk of respiratory depression, proper dosing and titration of Morphabond ER are essential [see Dosage and Administration (2)]. Overestimating the Morphabond ER dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of Morphabond ER, especially by children, can result in respiratory depression and death due to an overdose of morphine.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].
5.4 Neonatal Opioid Withdrawal Syndrome
Prolonged use of Morphabond ER 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)].
5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Morphabond ER with benzodiazepines or other CNS system depressants (e.g., non-benzodiazepine sedatives/hypnotics, tranquilizers, muscle relaxants, general anesthetics, anxiolytics, 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 Morphabond ER 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 [seeDrug Interactions (7) andPatient Counseling Information (17)].
5.6 Life -Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of Morphabond ER 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:Morphabond ER-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 Morphabond ER [seeWarnings and Precautions (5.3)].
Elderly, Cachectic, or 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 [seeWarnings and Precautions (5.3)].
Monitor such patients closely, particularly when initiating and titrating Morphabond ER and when Morphabond ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3,5.5)]. Alternatively, consider the use of non-opioid analgesics in these patients.
5.7 Interaction with Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion. Morphabond ER should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
5.8 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.
5.9 Severe Hypotension
Morphabond ER 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 Morphabond ER. In patients with circulatory shock, Morphabond ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Morphabond ER in patients with circulatory shock.
5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Morphabond ER 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 Morphabond ER.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Morphabond ER in patients with impaired consciousness or coma.
5.11 Risks of Use in Patients with Gastrointestinal Conditions
Morphabond ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The morphine in Morphabond ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
5.12 Increased Risk of Seizures in Patients with Seizure Disorders
The morphine in Morphabond ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Morphabond ER therapy.
Do not abruptly discontinue Morphabond ER in a patient physically dependent on opioids. When discontinuing Morphabond ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of morphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)].
Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Morphabond ER. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7)].
5.14 Risks of Driving and Operating Machinery
Morphabond ER 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 Morphabond ER and know how they will react to the medication [see Patient Counseling Information (17)].
6 ADVERSE REACTIONS
The following serious adverse reactions are 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 (5.3)]
Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
Interactions with Benzodiazepine or Other CNS Depressants [see Warnings and Precautions (5.5)]
Adrenal Insufficiency [see Warnings and Precautions (5.8)]
Severe Hypotension [see Warnings and Precautions (5.9)]
Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)]
Seizures [see Warnings and Precautions (5.12)]
Withdrawal [see Warnings and Precautions (5.13)]
6.1 Clinical Trial 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Morphabond ER may increase the risk of serious adverse reactions such as those observed with other opioid analgesics, including respiratory depression, apnea, respiratory arrest, circulatory depression, hypotension, or shock [see Overdosage (10)].
Most Frequently Observed Reactions
In clinical trials, the most common adverse reactions with morphine sulfate extended-release were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood.
Some of these effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.
The following adverse reactions have been identified during post-approval use of morphine sulfate. 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 Morphabond ER.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].
7 DRUG INTERACTIONS
Table 1 includes clinically significant drug interactions with Morphabond ER.
Table 1: Clinically Significant Drug Interactions with Morphabond ER
Benzodiazepines and otherCentral Nervous System (CNS) Depressants
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increase the risk of respiratory depression, profound sedation, coma, and death.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions(5.5)].
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphabond ER if serotonin syndrome is suspected.
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings andPrecautions(5.7)].
Do not use Morphabond ER in patients taking MAOIs or within 14 days of stopping such treatment.
phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
May reduce the analgesic effect of Morphabond ER and/or precipitate withdrawal symptoms.
Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphabond ER and/or the muscle relaxant as necessary.
The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphabond ER and/or cimetidine as necessary.
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Monitor patients for signs of urinary retention or reduced gastric motility when Morphabond ER is used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
The concomitant use of P-gp-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphabond ER and/or the P-gp-inhibitor as necessary.
8 USE IN SPECIFIC POPULATIONS
Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [seeWarnings and Precautions (5.4)]. There are no available data with Morphabond ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects [seeHuman Data]. In published animal reproduction studies, morphine administered subcutaneously during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5 and 16 times the human daily dose of 60 mg based on body surface area (HDD) in hamsters and mice, respectively, lower fetal body weight and increased incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at 6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16 times the HDD in the mouse. Administration of morphine sulfate to pregnant rats during organogenesis and through lactation resulted in cyanosis, hypothermia, decreased brain weights, pup mortality, decreased pup body weights, and adverse effects on reproductive tissues at 3-4 times the HDD; and long-term neurochemical changes in the brain of offspring which correlate with altered behavioral responses that persist through adulthood at exposures comparable to and less than the HDD [seeAnimal Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
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. 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 elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [seeWarnings and Precautions (5.4)].
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Morphabond ER is not recommended for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Morphabond ER, 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. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
The results from a population-based prospective cohort, including 70 women exposed to morphine during the first trimester of pregnancy and 448 women exposed to morphine at any time during pregnancy, indicate no increased risk for congenital malformations. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and non-randomized study design.
Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on a human daily dose of 60 mg morphine using a body surface area comparison (HDD).
Neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of morphine sulfate (35-322 mg/kg) on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no adverse effect level was not defined in this study and the findings cannot be clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial skeletal fusions, and cryptorchidism were reported following a single subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500 mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects were noted following 100 mg/kg morphine in this model (8 times the HDD). In one study, following continuous subcutaneous infusion of doses greater than or equal to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted. The effects were reduced with increasing daily dose; possibly due to rapid induction of tolerance under these infusion conditions. The clinical significance of this report is not clear.
Decreased fetal weights were observed in pregnant rats treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation Day 7 to 9. There was no evidence of malformations despite maternal toxicity (10% mortality). In a second rat study, decreased fetal weight and increased incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD) and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD) when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate via continuous infusion from Gestation Day 5 to 20. There was no evidence of fetal malformations or maternal toxicity.
An increased incidence of abortion was noted in a study in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a second study, decreased fetal body weights were reported following treatment of pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation period. No overt malformations were reported in either publication; although only limited endpoints were evaluated.
In published studies in rats, exposure to morphine during gestation and/or lactation periods is associated with: decreased pup viability at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at 15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased absolute brain and cerebellar weights, cyanosis, and hypothermia at 20 mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play, social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1 mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2 times the HDD); and a host of behavioral abnormalities in the offspring of rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the HDD) or greater.
Fetal and/or postnatal exposure to morphine in mice and rats has been shown to result in morphological changes in fetal and neonatal brain and neuronal cell loss, alteration of a number of neurotransmitter and neuromodulator systems, including opioid and non-opioid systems, and impairment in various learning and memory tests that appear to persist into adulthood. These studies were conducted with morphine treatment usually in the range of 4 to 20 mg/kg/day (0.7 to 3.2 times the HDD).
Additionally, delayed sexual maturation and decreased sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), 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 at 20 mg/kg/day (3.2 times the HDD). Decreased litter size and viability were observed in the offspring of male rats that were intraperitoneally administered morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD) and mated to untreated females. Decreased viability and body weight and/or movement deficits in both first and second generation offspring were reported when male mice were treated for 5 days with escalating doses of 120 to 240 mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the HDD) followed by a 5-day treatment-free recovery period prior to mating. Similar multigenerational findings were also seen in female rats pre-gestationally treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the HDD).
Morphine is present in breast milk. Published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study. However, there is insufficient information to determine the effects of morphine on the breastfed infant and the effects of morphine on milk production. Lactation studies have not been conducted with extended-release morphine, including Morphabond ER. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Morphabond ER.
Monitor infants exposed to Morphabond ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.
8.3 Females and Males of Reproductive Potential
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [seeAdverse Reactions(6.2), Clinical Pharmacology (12.2)].
In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [seeNonclinical Toxicology (13)].
8.4 Pediatric Use
The safety and effectiveness in pediatric patients below the age of 18 have not been established.
8.5 Geriatric Use
The pharmacokinetics of Morphabond ER have not been studied in elderly patients. Clinical studies of morphine sulfate extended-release did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Morphabond ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [seeWarnings and Precautions (5.6)].
Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
8.6 Hepatic Impairment
Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Start these patients with a lower than usual dosage of Morphabond ER and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [seeClinical Pharmacology (12.3)].
8.7 Renal Impairment
Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of Morphabond ER and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension [seeClinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Morphabond ER contains morphine, a Schedule II controlled substance.
Morphabond ER contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Morphabond ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].
The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.
All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Morphabond ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help limit abuse of opioid drugs.
Risks Specific to Abuse ofMorphabond ER
Morphabond ER is for oral use only. Abuse of Morphabond ER poses a risk of overdose and death. This risk is increased with concurrent abuse of Morphabond ER with alcohol and other central nervous system depressants. Taking cut, broken, chewed, crushed, or dissolved Morphabond ER enhances drug release and increases the risk of overdose and death.
Parenteral abuse of Morphabond ER can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Abuse Deterrence Studies
Morphabond ER is formulated with inactive ingredients that make the tablet more difficult to adulterate for misuse and abuse while maintaining extended-release characteristics even if the tablet is subjected to physical manipulation, and/or chemical extraction. To evaluate the ability of the abuse-deterrent technology to reduce the potential for abuse of Morphabond ER, a series of in vitro laboratory manipulation, extraction, and syringeability, studies was conducted. An in vivo clinical abuse potential study was also conducted. The results of these studies are summarized below. Overall, the results indicate that Morphabond ER has properties that are expected to reduce abuse or misuse via injection or insufflation; however, abuse by these routes is still possible.
In Vitro Testing
Morphabond ER has been tested in vitro using methods of manipulation that drug abusers commonly use for preparation of extended-release opioids for administration by various routes, including oral consumption, intranasal insufflation, injection, and smoking.
Abusers may manipulate extended-release opioids in order to prepare the tablets for oral, intranasal, or intravenous administration. The laboratory test data demonstrated that, relative to morphine sulfate extended-release tablet, Morphabond ER has increased resistance to cutting, crushing, or breaking using a variety of tools. When subjected to a liquid environment the manipulated Morphabond ER formulation forms a viscous material that resists passage through a needle.
A randomized, double-blind, double-dummy, placebo-controlled, single-dose four-way crossover study in 25 non-dependent recreational opioid users with a history of intranasal drug abuse was performed to determine the relative bioavailability and abuse potential of crushed intranasal Morphabond ER 60 mg tablets compared with crushed intranasal morphine sulfate extended-release tablet 60 mg tablets, and intact orally administered Morphabond ER 60 mg tablets. The intact oral tablets were included as a reference for evaluating abuse potential after manipulation and administration via an unintended route.
Drug liking was measured on a 100 mm bipolar visual analog scale (VAS) where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar scale of 0 to 100 where 50 represents a neutral response, 0 represents the strongest negative response (‘definitely would not take drug again’) and 100 represents the strongest positive response (‘definitely would take drug again’).
Intranasal administration of crushed Morphabond ER was associated with statistically significantly lower drug liking (Emax) scores (P < 0.0001), and significantly lower willingness to take the drug again (Emax) scores (P = 0.034), compared to crushed extended-release morphine (Table 2). Drug liking and take drug again scores for crushed intranasal Morphabond ER were not significantly different from those of Morphabond ER taken orally intact. These data are consistent with the similar relative bioavailability after crushed intranasal and intact oral administration of Morphabond ER that support retention of its extended release properties when manipulated compared to morphine sulfate extended-release tablets [seeClinical Pharmacology (12.3)].
Table 2.Summary of Maximum Drug Liking (Emax) and Take Drug Again (Emax) Following Administration of Morphabond ER, morphine sulfate extended-release tablet, and Placebo in Recreational Opioid Users (n=25)
Crushed Intranasalmorphine sulfate extended-release tabletvs. Crushed IntranasalMorphabond ERDifference of LS Means (95% CI)
Drug Liking (Emax)
13.65 (7.80, 19.51)
Take Drug Again (Emax)
Figure 1 demonstrates a comparison of peak drug liking scores for crushed Morphabond ER compared to crushed extended-release morphine in subjects who received both treatments intranasally. Seventy-six percent of subjects (n = 19) experienced some reduction in Emax of Drug Liking VAS with crushed Morphabond ER compared with crushed extended-release morphine, 48%; (n = 12) experienced at least a 30% reduction in Emax and 32% (n = 8) experienced at least a 50% reduction in Emax of drug liking.
Figure1. Percent ReductionProfiles for Emax ofDrug Liking forMorphabond ERvs.Morphine SulfateERTablets(n=25), Following Intranasal Administration
The in vitro data demonstrate that Morphabond ER has physiochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from in vitro data, also indicate that Morphabond ER has physicochemical properties that are expected to reduce abuse by the intranasal route of administration. However, abuse by intranasal, intravenous, and oral routes is still possible.
Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of Morphabond ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Do not abruptly discontinue Morphabond ER in a patient physically dependent on opioids. Rapid tapering of Morphabond ER in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.
When discontinuing Morphabond ER, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Morphabond ER the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.13)].
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].
Acute overdosage with Morphabond ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2)].
Treatment of Overdose
In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to morphine overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.
Because the duration of reversal would be expected to be less than the duration of action of morphine in Morphabond ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. Morphabond ER will continue to release morphine and add to the morphine load for 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
Morphabond ER (morphine sulfate) extended-release tablets are for oral use and contain morphine sulfate, an opioid agonist.
Each tablet contains the following inactive ingredients common to all strengths: hypromellose, xanthan gum, microcrystalline cellulose, sodium alginate, alginic acid, mannitol, colloidal silicon dioxide, magnesium stearate, ethyl acrylate and methyl methacrylate copolymer dispersion, lactose monohydrate, polysorbate 80, titanium dioxide, polyethylene glycol, shellac in ethanol, isopropyl alcohol, iron oxide black, n-butyl alcohol, propylene glycol, and ammonium hydroxide.
The tablet strengths describe the amount of morphine per tablet as the pentahydrated sulfate salt (morphine sulfate).
The 15 mg tablets also contain: FD&C Blue No. 1, FD&C Red No. 40 and FD&C Yellow No. 6
The 30 mg tablets also contain: FD&C Blue No. 2 and FD&C Red No. 40
The 60 mg tablets also contain: FD&C Yellow No. 6 and FD&C Red No. 40
The 100 mg tablets also contain: FD&C Blue No. 2, FD&C Yellow No. 6 and FD&C Red No. 40
Morphine sulfate is an odorless, white, crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, but is practically insoluble in chloroform or ether. The octanol: water partition coefficient of morphine is 1.42 at physiologic pH and the pKb is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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.
CNS Depressant/Alcohol Interaction
Additive pharmacodynamic effects may be expected when Morphabond ER is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Effects on the Central Nervous System
The principal actions of therapeutic value of morphine are analgesia and sedation. Specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression of analgesic effects.
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 narcotic 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 smooth muscle tone in the antrum of the stomach and in the 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 may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of the 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 and/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.
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 [seeDosage 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 [seeDosage and Administration (2.1,2.2,2.3)].
The dose of Morphabond ER must be individualized because the effective analgesic dose for some patients will be too high to be tolerated by other patients [seeDosage and Administration (2.1)].
Morphabond ER is an extended-release tablet containing morphine sulfate. Morphine is released from Morphabond ER somewhat more slowly than from immediate-release oral preparations. Following oral administration of a given dose of morphine, the amount ultimately absorbed is essentially the same whether the source is Morphabond ER or an immediate-release formulation. Because of pre-systemic elimination (i.e., metabolism in the gut wall and liver) only about 40% of the administered dose reaches the central compartment.
The oral bioavailability of morphine is approximately 20 to 40%. When Morphabond ER is given on a fixed dosing regimen, steady-state is achieved in about a day.
The effect of food upon the systemic bioavailability of Morphabond ER has not been systematically evaluated for all strengths. Administration of a single dose of Morphabond ER with a standardized high-fat meal resulted in a 33% increase in morphine peak plasma concentration and no change in AUC compared to fasted state.
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. Morphine also crosses placental membranes and has been found in breast milk. The volume of distribution (Vd) for morphine is approximately 3 to 4 liters per kilogram and morphine is 30 to 35% reversibly bound to plasma proteins.
The major pathways of morphine metabolism include glucuronidation 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. M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.
The elimination of morphine occurs primarily as renal excretion of M3G and its effective half-life after intravenous administration is normally 2 to 4 hours. Approximately 10% of the dose is excreted unchanged in urine. In some studies involving longer periods of plasma sampling, a longer terminal half-life of about 15 hours was reported. A small amount of the glucuronide conjugate is excreted in the bile, and there is some minor enterohepatic recycling.
An analysis of pharmacokinetic data from healthy subjects taking morphine sulfate extended-release indicated that morphine concentrations were similar in males and females.
Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/- 116 mL/min compared to 1495 +/- 80 mL/min).
Morphine pharmacokinetics are altered in individuals with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these subjects, indicating diminished metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.
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 to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term 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 and higher incidence of pseudopregnancies at 20 mg/kg/day (3.2 times the HDD) were reported. Studies from the literature have also reported changes in hormonal levels in male rats (i.e. testosterone, luteinizing hormone) following treatment with morphine at 10 mg/kg/day or greater (1.6 times the HDD).
Female rats that were administered morphine sulfate intraperitoneally prior to mating exhibited prolonged estrous cycles at 10 mg/kg/day (1.6 times the HDD).
Exposure of adolescent male rats to morphine has been associated with delayed sexual maturation and following mating to untreated females, smaller litters, increased pup mortality, and/or changes in reproductive endocrine status in adult male offspring have been reported (estimated 5 times the plasma levels at the HDD).
16 HOW SUPPLIED/STORAGE AND HANDLING
MORPHABOND™ ER (morphine sulfate) extended-release tablets 15 mg are round, blue-colored, coated tablets ink-printed with IDT/M15 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-301-10).
MORPHABOND™ ER (morphine sulfate) extended-release tablets 30 mg are round, purple-colored, coated tablets ink-printed with IDT/M30 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-302-10).
MORPHABOND™ ER (morphine sulfate) extended-release tablets 60 mg are round, orange-colored, coated tablets ink-printed with IDT/M60 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-303-10).
MORPHABOND™ ER (morphine sulfate) extended-release tablets 100 mg are round, gray-colored, coated tablets ink-printed with IDT/M100 on one side; and plain on the other. They are supplied as opaque plastic bottles containing 100 tablets (NDC 65597-304-10).
Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F)[see USP Controlled Room Temperature].
Dispense in a tight, light-resistant container.
Store Morphabond ER securely and dispose of properly [see Patient Counseling Information (17)].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Storage and Disposal
Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Morphabond ER securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.3, 5.13), Drug Abuse and Dependence (9.2)]. Inform patients that leaving Morphabond ER unsecured can pose a deadly risk to others in the home.
Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Morphabond ER should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.
Addiction, Abuse, and Misuse
Inform patients that the use of Morphabond ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share Morphabond ER with others and to take steps to protect Morphabond ER 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 Morphabond ER or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].
Interactions withBenzodiazepinesand other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if Morphabond ER is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.5),Drug Interactions (7)].
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions(7)].
Inform patients not to take Morphabond ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Morphabond ER [see Warnings and Precautions (5.7), Drug Interactions (7)].
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [seeWarnings and Precautions (5.8)].
Important Administration Instructions[see Dosage and Administration(2.1,2.5), Warnings and Precautions (5.3)]
Instruct patients how to properly take Morphabond ER, including the following:
Swallowing Morphabond ER tablets whole [see Dosage and Administration (2.1)]
Not crushing, chewing, or dissolving the tablets [see Dosage and Administration (2.1)]
When taking Morphabond ER, the medicine is absorbed by the body and the part of the tablet that contains inactive ingredients is eliminated from the body; patients may notice something that looks like a tablet in their stool.
Using Morphabond ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.3)].
Important Discontinuation Instructions
In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Morphabond ER without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)].
Inform patients that Morphabond ER 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) [see Warnings and Precautions (5.9)].
Inform patients that anaphylaxis has been reported with ingredients contained in Morphabond ER. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of Morphabond ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [seeWarnings and Precautions (5.4),Use in Specific Populations (8.1)].
Inform female patients of reproductive potential that Morphabond ER can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [seeUse in Specific Populations (8.1)].
Advise patients that breastfeeding is not recommended during treatment with Morphabond ER [seeUse in Specific Populations (8.2)].
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [seeUse in Specific Populations (8.3)].
Driving or Operating Heavy Machinery
Inform patients that Morphabond ER 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 [see Warnings and Precautions (5.14)].
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].
Healthcare professionals can telephone Daiichi Sankyo, Inc. (1-877-437-7763) for information on this product.