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ARYMO® ER (morphine sulfate) extended-release tablets CII 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.

IMPORTANT SAFETY INFORMATION

WARNING: ADDICTION, ABUSE, and MISUSE; 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

ARYMO 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 ARYMO ER, and monitor all patients regularly for the development of these behaviors or conditions.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of ARYMO ER. Monitor for respiratory depression, especially during initiation of ARYMO ER or following a dose increase. Instruct patients to swallow ARYMO ER tablets whole; crushing, chewing, or dissolving ARYMO ER tablets can cause rapid release and absorption of a potentially fatal dose of morphine.

Accidental Ingestion

Accidental ingestion of even one dose of ARYMO ER, especially by children, can result in a fatal overdose of morphine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of ARYMO 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.

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.

  • Reserve concomitant prescribing of ARYMO 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.

ARYMO ER is:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
  • A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
  • Not for use to treat pain that is not around-the-clock.

Important Information about ARYMO ER:

  • Get emergency help right away if you take too much ARYMO ER (overdose). When you first start taking ARYMO ER, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Taking ARYMO ER with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
  • Never give anyone else your ARYMO ER. They could die from taking it. Store ARYMO ER away from children and in a safe place to prevent stealing or abuse. Selling or giving away ARYMO ER is against the law.

Do not take ARYMO ER if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.

Before taking ARYMO ER, tell your healthcare provider if you have a history of:

  • head injury, seizures
  • problems urinating
  • liver, kidney, thyroid problems
  • pancreas or gallbladder problems
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

  • pregnant or planning to become pregnant. Prolonged use of ARYMO ER during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. Not recommended during treatment with ARYMO ER. It may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking ARYMO ER with certain other medicines can cause serious side effects and could lead to death.

When taking ARYMO ER:

  • Do not change your dose. Take ARYMO ER exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose every 8 to 12 hours, as directed by your healthcare provider. Do not take more than your prescribed dose. If you miss a dose, take your next dose at the usual time.
  • Swallow ARYMO ER whole. Do not cut, break, chew, crush, dissolve, snort, or inject ARYMO ER because this may cause you to overdose and die.
  • ARYMO ER should be taken one tablet at a time. Do not pre-soak, lick, or wet the tablet before placing in your mouth to avoid choking on the tablet.
  • Call your healthcare provider if the dose that you are taking does not control your pain.
  • Do not stop taking ARYMO ER without talking to your healthcare provider.
  • After you stop taking ARYMO ER, flush any unused tablets down the toilet.

While taking ARYMO ER DO NOT:

  • Drive or operate heavy machinery, until you know how ARYMO ER affects you. ARYMO ER can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with ARYMO ER may cause you to overdose and die. 

The possible effects of ARYMO ER are:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

  • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of ARYMO ER. Call your doctor for medical advice about side effects.

Please see Full Prescribing Information, including Boxed Warning and Medication Guide.

To report suspected adverse reactions, contact Egalet US Inc. at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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
ARYMO 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 ARYMO ER, and monitor all patients regularly for the development of these behaviors or conditions.

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. 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 ARYMO ER. Monitor for respiratory depression, especially during initiation of ARYMO ER or following a dose increase. Instruct patients to swallow ARYMO ER capsules whole, or to sprinkle the contents of the capsule on applesauce and swallow immediately without chewing. Crushing, chewing, or dissolving the pellets in ARYMO ER can cause rapid release and absorption of a potentially fatal dose of morphine.

Accidental Ingestion
Accidental ingestion of even one dose of ARYMO ER, especially by children, can result in a fatal overdose of morphine.

Neonatal Opioid Withdrawal Syndrome
Prolonged use of ARYMO 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.

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.

  • Reserve concomitant prescribing of ARYMO 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.

IMPORTANT SAFETY INFORMATION ABOUT ARYMO ER

INDICATIONS AND USAGE

ARYMO 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, reserve ARYMO 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.
  • ARYMO ER is not indicated as an as-needed (prn) analgesic.

Advise both patients and caregivers about the risks of respiratory depression and sedation when ARYMO 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 of overdose and death associated with the use of additional CNS depressants, including alcohol and illicit drugs.

CONTRAINDICATIONS
ARYMO ER is contraindicated in patients with:

  • Significant respiratory depression
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Hypersensitivity (eg, anaphylaxis) to morphine or naltrexone

WARNINGS AND PRECAUTIONS
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.

Life-threatening Respiratory Depression in Patients With Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
The use of ARYMO 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: ARYMO 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 ARYMO ER.

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely, particularly when initiating and titrating ARYMO ER and when ARYMO ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

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

Severe Hypotension
ARYMO 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 (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of ARYMO ER. In patients with circulatory shock, ARYMO ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of ARYMO ER in patients with circulatory shock.

Use in Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
In patients susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), ARYMO 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 ARYMO ER.

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

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

Increased Risk of Seizures in Patients With Seizure Disorders
The morphine in ARYMO ERmay increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ARYMO ER therapy.

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

When discontinuing ARYMO ER, gradually taper the dosage.

Risks of Driving and Operating Machinery
ARYMO 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 ARYMO ER and know how they will react to the medication.

ADVERSE REACTIONS
The following serious adverse reactions can occur:

  • Addiction, Abuse, and Misuse
  • Life-threatening Respiratory Depression
  • Neonatal Opioid Withdrawal Syndrome
  • Interactions With Benzodiazepines or Other CNS Depressants
  • Adrenal Insufficiency
  • Severe Hypotension
  • Gastrointestinal Adverse Reactions
  • Seizures
  • Withdrawal

Most common adverse reactions in clinical studies were constipation, dizziness, sedation, nausea, vomiting, sweating, dysphoria, and euphoric mood.

DRUG INTERACTIONS
Serotonergic Drugs 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 ARYMO ER if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs) MAOI interactions with opioids may manifest as serotonin syndrome or may potentiate effects of morphine toxicity (eg, respiratory depression, coma, and confusion). Do not use ARYMO ER in patients taking MAOIs or within 14 days of stopping such treatment. 

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics These may reduce the analgesic effect of ARYMO ER and/or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who have received or are receiving a full opioid agonist analgesic, including ARYMO ER.

Muscle Relaxants Opioids 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 ARYMO ER and/or muscle relaxant as necessary.

Cimetidine The concomitant use of cimetidine can potentiate morphine effects and increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients for respiratory depression that may be greater than otherwise expected and decrease the dosage of ARYMO ER and/or cimetidine as necessary.

Diuretics 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.

Anticholinergic Drugs 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 ARYMO ER is used concomitantly with anticholinergic drugs.

P-Glycoprotein (PGP) Inhibitors The concomitant use of PGP inhibitors can increase the exposure of morphine by about two-fold and can increase the 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 ARYMO ER and/or the PGP inhibitor as necessary.

USE IN SPECIFIC POPULATIONS
Pregnancy Prolonged use of opioid analgesics, including ARYMO ER, can cause neonatal opioid withdrawal syndrome. There are no available data with ARYMO ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

Labor or Delivery 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. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Lactation 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 ARYMO ER. Morphine is present in breast milk. Monitor infants exposed to ARYMO 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.

Pediatric and Geriatric Patients Safety and efficacy in patients less than 18 years of age or more than 65 years of age have not been established.

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 ARYMO ER and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.

Renal Impairment: Morphine pharmacokinetics are altered in patients with renal failure. Start these patients with a lower than usual dosage of ARYMO ER and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension.

OVERDOSAGE
Acute overdosage with morphine 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 due to severe hypoxia in overdose situations.

Please see Full Prescribing Information, including BOXED WARNING and MEDICATION GUIDE.

To report SUSPECTED ADVERSE REACTIONS, contact Egalet US Inc. at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.