Arymo ER

• ARYMO™ ER (morphine sulfate) extended-release tablets 15 mg (blue film coated, capsule shaped tablets debossed with “EGLT 15”)
• ARYMO™ ER (morphine sulfate) extended-release tablets 30 mg (light purple film coated, capsule shaped tablets debossed with “EGLT 30”)
• ARYMO™ ER (morphine sulfate) extended-release tablets 60 mg (light orange film coated, capsule shaped tablets debossed with “EGLT 60”)

Addiction, Abuse, and Misuse

Arymo ER contains morphine, a Schedule II controlled substance. As an opioid, Arymo ER exposes its users to the risks of addiction, abuse, and misuse. As extended-release products such as Arymo 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 Arymo ER and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Arymo ER, and monitor all patients receiving Arymo ER for development of these behaviors or 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 Arymo ER, but use in such patients necessitates intensive counseling about the risks of proper use of Arymo ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Attempts at misuse or abuse of Arymo ER by crushing, snorting, or injecting the dissolved product may compromise some of the extended-release properties resulting in delivery of morphine that could lead to 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 Arymo 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 [see Patient Counseling Information (17)]. Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Arymo 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 with Arymo ER.

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

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

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Arymo 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)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

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

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

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

Advise both patients and caregivers about the risks of respiratory depression and sedation when 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 for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

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 [see Warnings and Precautions (5.2)].

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

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

Interaction with Monoamine Oxidase Inhibitors

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

Adrenal Insufficiency

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

Severe Hypotension

Arymo ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dose 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 Arymo ER in patients with circulatory shock.

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), 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.

Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen

Moistened Arymo ER tablets may become sticky leading to difficulty in swallowing the tablets. Patients could experience choking, gagging, regurgitation and tablets stuck in the throat. Instruct patients not to pre-soak, lick, or otherwise wet Arymo ER tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth.

Tablet stickiness and swelling may also predispose patients to intestinal obstruction and exacerbation of diverticulitis. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen.

Risks of Use in Patients with Gastrointestinal Conditions

Arymo ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The morphine in Arymo 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.

Increased Risk of Seizures in Patients with Seizure Disorders

The morphine in Arymo 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 Arymo ER therapy.

Withdrawal

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

When discontinuing Arymo ER, gradually taper the dose [see Dosage and Administration (2.4)]. Do not abruptly discontinue Arymo ER [see Drug Abuse and Dependence (9.3)].

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 [see Patient Counseling Information (17)].

The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4)]
• Adrenal Insufficiency [see Warnings and Precautions (5.7)]
• Severe Hypotension [see Warnings and Precautions (5.8)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11)]
• Seizures [see Warnings and Precautions (5.12)]
• Withdrawal [see Warnings and Precautions (5.13)]

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.

Arymo 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 formulations 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.

Less Frequently Observed Reactions

Cardiovascular disorders: tachycardia, bradycardia, palpitations

Eye disorders: visual impairment, vision blurred, diplopia, miosis

Gastrointestinal disorders: dry mouth, diarrhea, abdominal pain, constipation, dyspepsia

General disorders and administration site conditions: chills, feeling abnormal, edema, edema peripheral, weakness

Hepatobiliary disorders: biliary colic

Metabolism and nutrition disorders: anorexia

Musculoskeletal and connective tissue disorders: muscle rigidity, muscle twitching

Nervous system disorders: presyncope, syncope, headache, tremor, uncoordinated muscle movements, convulsion, intracranial pressure increased, taste alteration, paresthesia, nystagmus

Psychiatric disorders: agitation, mood altered, anxiety, depression, abnormal dreams, hallucination, disorientation, insomnia

Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effect

Reproductive system and breast disorders: reduced libido and/or potency

Respiratory, thoracic and mediastinal disorders: laryngospasm

Skin and subcutaneous tissue disorders: pruritus, urticaria, rash

Vascular disorders: flushing, hypotension, hypertension

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of morphine sulfate extended-release formulations. 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. These events include: amenorrhea, asthenia, bronchospasm, confusional state, drug hypersensitivity, fatigue, hyperalgesia, hypertonia, ileus, increased hepatic enzymes, intestinal obstruction, lethargy, malaise, pulmonary edema, thinking disturbances, somnolence, and vertigo.

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 Arymo ER.

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

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with Arymo 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 [see Human 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 [see Animal 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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. 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 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 signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

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. Arymo ER is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including Arymo 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.

Data

Human Data

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.

Animal Data

Formal reproductive and developmental toxicology studies for morphine have not been conducted. Exposure margins for the following published study reports are based on 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).

Lactation

Risk Summary

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 Arymo 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 Arymo ER.

Clinical Considerations

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.

Females and Males of Reproductive Potential

Infertility

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 [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

In published animal studies, morphine administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats [see Nonclinical Toxicology (13.1)].

Pediatric Use

The safety and effectiveness in pediatric patients below the age of 18 have not been established.

Geriatric Use

The pharmacokinetics of Arymo ER have not been studied in elderly patients. Clinical studies of morphine sulfate extended-release formulations 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, dose 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 Arymo ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5)].

This drug 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.

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

Controlled Substance

Arymo ER contains morphine, a Schedule II controlled substance.

Abuse

Arymo ER contains morphine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, oxymorphone, and tapentadol. Arymo 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 misuse and abuse.

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.

Arymo 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 to reduce abuse of opioid drugs.

Risks Specific to Abuse of Arymo ER

Arymo ER is for oral use only. Abuse of Arymo ER poses a risk of overdose and death. This risk is increased with concurrent abuse of Arymo ER with alcohol and other central nervous system depressant. Attempting to cut, break, chew, crush, or dissolve Arymo ER tablets may compromise some of the extended-release properties, resulting in delivery of morphine that could lead to overdose and death.

Parenteral abuse of Arymo 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

Arymo ER is formulated with inactive ingredients that make the tablet more difficult to manipulate for misuse and abuse.

To evaluate the ability of Arymo ER to reduce the potential for misuse and abuse, a series of abuse-deterrent in vitro laboratory physical manipulation, chemical extraction, and syringeability studies was conducted. An oral pharmacokinetic study and an oral clinical abuse potential study were also conducted.

In Vitro Testing

In vitro physical and chemical manipulation studies were performed to evaluate the ability of different methods to defeat the extended-release properties. The results of this testing demonstrated that Arymo ER tablets, in comparison to morphine sulfate extended-release tablets, have increased resistance to cutting, crushing, grinding or breaking using a variety of tools. When subjected to a liquid environment, the manipulated Arymo ER tablets form a viscous hydrogel (i.e., a gelatinous mass) that resists passage through a hypodermic needle.

Oral Pharmacokinetic Study

The pharmacokinetic profile of manipulated Arymo ER was characterized following oral administration. The study was conducted in a randomized cross-over design. The pharmacokinetic profile of manipulated and intact Arymo ER compared to crushed morphine sulfate extended-release was evaluated in 38 subjects after oral administration. The results are summarized in Table 2 and demonstrate that oral ingestion of manipulated Arymo ER resulted in a higher Cmax, but similar AUC, when compared to intact Arymo ER. In addition, manipulated Arymo ER had a lower Cmax and longer Tmax than crushed morphine sulfate extended-release tablets.

Oral Clinical Abuse Potential Study

An oral abuse potential study was conducted in 39 subjects who were non-dependent recreational opioid users; 38 subjects completed the study. Treatment arms included manipulated Arymo ER 60 mg tablets (taken with juice), intact Arymo ER 60 mg tablets (taken with juice), crushed 60 mg morphine sulfate extended-release tablets (mixed in juice), and placebo.

The study demonstrated that the oral administration of manipulated Arymo ER resulted in a statistically lower mean drug liking score than the oral administration of crushed morphine sulfate extended-release tablets. However, the difference between manipulated Arymo ER and crushed morphine sulfate extended-release tablets for Take Drug Again was not statistically significant, indicating that the difference in drug liking scores was not clinically meaningful.

These results are summarized in Table 3.

Summary

The in vitro data demonstrate that Arymo ER has physical and chemical properties expected to make abuse by injection difficult.

Although the results of the oral human abuse potential study showed a difference in the Drug Liking endpoint, there was no statistically significant reduction in the response to Take Drug Again. Therefore, it cannot be concluded that Arymo ER has physical and chemical properties that are expected to reduce abuse via the oral route.

Abuse of Arymo ER by injection, as well as by the oral and nasal routes, is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of Arymo ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

Dependence

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 results in withdrawal symptoms after abrupt discontinuation or a significant dose 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.

Arymo ER should not be abruptly discontinued [see Dosage and Administration (2.4)]. If Arymo ER is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: 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.

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)].

ARYMO™ 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: polyethylene oxide 400,000, butylated hydroxytoluene, polyvinyl alcohol, polyethylene glycol 3350, talc, and titanium dioxide.

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. 2 and ferric oxide yellow.

The 30 mg tablets also contain: ferric oxide red, FD&C Blue No. 2, and ferrosoferric oxide.

The 60 mg tablets also contain: ferric oxide yellow, and ferric oxide red.

Morphine sulfate is an odorless, white crystalline solid with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol, and practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (mostly ionized at pH 7.4). Its structural formula is:

Applies to morphine: oral capsule, oral capsule delayed release, oral capsule extended release, oral capsule extended release 24 hr, oral powder for suspension extended release, oral solution, oral syrup, oral tablet, oral tablet extended release

Other dosage forms:

• epidural suspension extended release
• injection injectable, injection solution

Along with its needed effects, morphine (the active ingredient contained in Arymo ER) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

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

• Abdominal or stomach pain
• blurred vision
• bulging soft spot on the head of an infant
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in the ability to see colors, especially blue or yellow
• chest pain or discomfort
• confusion
• cough
• decreased urination
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, pounding, or irregular heartbeat or pulse
• headache
• hives, itching, or skin rash
• increased sweating
• loss of appetite
• nausea or vomiting
• nervousness
• pounding in the ears
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• severe constipation
• severe vomiting
• shakiness in the legs, arms, hands, or feet
• slow heartbeat
• sweating or chills

• Black, tarry stools
• cold, clammy skin
• feeling of warmth or heat
• flushing or redness of the skin, especially on the face and neck
• irregular, fast or slow, or shallow breathing
• lightheadedness
• loss of consciousness
• low blood pressure or pulse
• painful urination
• pale or blue lips, fingernails, or skin
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• shakiness and unsteady walk
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual bleeding or bruising
• very slow heartbeat

Get emergency help immediately if any of the following symptoms of overdose occur while taking morphine:

• Constricted, pinpoint, or small pupils (black part of the eye)
• decreased awareness or responsiveness
• extreme drowsiness
• fever
• increased blood pressure
• increased thirst
• lower back or side pain
• muscle cramps or spasms
• muscle pain or stiffness
• no muscle tone or movement
• severe sleepiness
• swelling of the face, fingers, or lower legs
• weight gain

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

• Cramps
• difficulty having a bowel movement (stool)
• drowsiness
• false or unusual sense of well-being
• relaxed and calm feeling
• sleepiness or unusual drowsiness
• weight loss

• Absent, missed, or irregular menstrual periods
• agitation
• bad, unusual, or unpleasant (after) taste
• change in vision
• depression
• dry mouth
• face is warm or hot to touch
• floating feeling
• halos around lights
• heartburn or indigestion
• loss in sexual ability, desire, drive, or performance
• muscle stiffness or tightness
• night blindness
• overbright appearance of lights
• problems with muscle control
• redness of the skin
• skin rash
• stomach discomfort or upset
• trouble sleeping
• uncontrolled eye movements

• Abnormal dreams
• change in walking and balance
• change or problem with discharge of semen
• clumsiness or unsteadiness
• confusion as to time, place, or person
• delusions
• dementia
• feeling of constant movement of self or surroundings
• general feeling of discomfort or illness
• holding false beliefs that cannot be changed by fact
• problems with memory
• seeing, hearing, or feeling things that are not there
• sensation of spinning
• unusual excitement, nervousness, or restlessness

Substance Name

Morphine

CAS Registry Number

57-27-2

Drug Class

Analgesics, Opioid

Narcotics

• Tell all of your health care providers that you take Arymo ER (morphine long-acting tablets). This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how Arymo ER (morphine long-acting tablets) affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Do not take Arymo ER (morphine long-acting tablets) with other strong pain drugs or if you are using a pain patch without talking to your doctor first.
• Have your blood work checked if you are on Arymo ER (morphine long-acting tablets) for a long time. Talk with your doctor.
• Do not take more than what your doctor told you to take. Taking more than you are told may raise your chance of very bad side effects.
• If you have been taking Arymo ER (morphine long-acting tablets) for a long time or at high doses, it may not work as well and you may need higher doses to get the same effect. This is known as tolerance. Call your doctor if Arymo ER (morphine long-acting tablets) stops working well. Do not take more than ordered.
• Do not stop taking Arymo ER (morphine long-acting tablets) all of a sudden without calling your doctor. You may have a greater risk of signs of withdrawal. If you need to stop Arymo ER (morphine long-acting tablets), you will want to slowly stop it as ordered by your doctor.
• For some brands, you may see the tablet shell in your stool. For these brands, this is normal and not a cause for concern. If you have questions, talk with your doctor.
• Some products may cause choking, gagging, or trouble swallowing. These products must be taken with a full glass of water. Ask your pharmacist if you need to take your product with a full glass of water.
• Long-term use of an opioid drug like Arymo ER (morphine long-acting tablets) may lead to lower sex hormone levels. This may lead to signs like change in sex ability in men, no menstrual period in women, lowered interest in sex, or fertility problems. Call your doctor if you have any of these signs.
• This medicine may raise the chance of seizures in some people, including people who have had seizures in the past. Talk to your doctor to see if you have a greater chance of seizures while taking Arymo ER (morphine long-acting tablets).
• If you are 65 or older, use Arymo ER (morphine long-acting tablets) with care. You could have more side effects.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking Arymo ER (morphine long-acting tablets), call your doctor right away.