Drug Safety-related Labeling Changes (SrLC)

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OPANA ER (NDA-021610)

(OXYMORPHONE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/15/2023 (SUPPL-31)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions underlined)

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OPANA ER

Addiction, Abuse, and Misuse

Because the use of OPANA 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 and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of OPANA ER, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of OPANA ER are essential. Instruct patients to swallow OPANA ER tablets whole; crushing, chewing, or dissolving OPANA ER tablets can cause rapid release and absorption of a potentially fatal dose of oxymorphone [see Dosage and Administration (2.1), Warnings and Precautions (5.2)].

Accidental Ingestion

Accidental ingestion of even one dose of OPANA ER, especially by children, can result in a fatal overdose of oxymorphone [see Warnings and Precautions (5.2)].

Interaction with Alcohol

Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking OPANA ER. The co-ingestion of alcohol with OPANA ER may result in increased plasma levels and a potentially fatal overdose of oxymorphone [see Warnings and Precautions (5.2, 5.3)].

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 OPANA ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. [see Warnings and Precautions (5.3), Drug Interactions (7)].

Neonatal Opioid Withdrawal Syndrome (NOWS)

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)].

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5)].

 

4 Contraindications

(Additions and/or revisions underlined)

OPANA ER is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.7)]

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

  [see Warnings and Precautions (5.7)]

• Hypersensitivity (e.g., anaphylaxis) to oxymorphone, any other ingredients in OPANA ER, [see Warnings and Precautions (5.8) and Adverse Reactions (6)].

• Moderate and severe hepatic impairment [see Warnings and Precautions (5.10) and Clinical Pharmacology (12.3)]

• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)]

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

(Additions and/or revisions underlined)

OPANA ER contains oxymorphone, a Schedule II controlled substance. As an opioid, OPANA ER exposes users to the risks of addiction, abuse, and misuse. Because extended-release products such as OPANA 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 oxymorphone present. As long-acting opioids such as OPANA ER have pharmacological effects over an extended period of time, there is a greater risk for overdose and death [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OPANA 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 OPANA ER, and reassess all patients receiving OPANA ER for the 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 OPANA ER, but use in such patients necessitates intensive counseling about the risks and proper use of OPANA ER along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

Abuse, or misuse of OPANA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the oxymorphone and can result in overdose and death [see Overdosage (10)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing OPANA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. 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 Life-Threatening Respiratory Depression

(Additions and/or revisions underlined)

…

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3), Overdosage (10)].

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(Additions and/or revisions underlined)

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on OPANA ER therapy. The co-ingestion of alcohol with OPANA ER may result in increased plasma oxymorphone levels and a potentially fatal overdose of oxymorphone [see Clinical Pharmacology (12.3)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OPANA ER with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). 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. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose

[see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)]…

5.4 Neonatal Opioid Withdrawal Syndrome

(Additions and/or revisions underlined)

Use of OPANA ER for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

(Newly added subsection)

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.

5.6 Opioid-Induced Hyperalgesia and Allodynia

(Newly added subsection)

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5), Warnings and Precautions (5.15)].

5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

(Additions and/or revisions underlined)

The use of OPANA 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: OPANA 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 OPANA 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)].

Regularly evaluate patients, particularly when initiating and titrating OPANA ER and when OPANA ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of opioids. 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.

…

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology (12)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.6)]

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

(Additions and/or revisions underlined)

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4)]. Available data with OPANA ER in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

…

Fetal/Neonatal adverse reactions

Use of opioid analgesics for an extended period of time 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 [see Warning and Precautions (5.4)].

8.2 Lactation

(Additions and/or revisions underlined)

…

Monitor infants exposed to oxymorphone through breastmilk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the total number of subjects in clinical studies of OPANA ER, 27% were 65 and over, while 9% were 75 and over. No overall differences in effectiveness were observed between these subjects and younger subjects. There were several adverse events that were more frequently observed in subjects 65 and over compared to younger subjects. These adverse events included dizziness, somnolence, confusion, and nausea. On average, age greater than 65 years was associated with an increase in oxymorphone AUC and Cmax. Initiate dosing with OPANA ER in patients 65 years of age and over using the 5 mg dose and frequently reevaluate the patient for signs of respiratory and central nervous system depression when initiating and titrating OPANA ER [see Warnings and Precautions (5.2)]. For patients on prior opioid therapy, start at 50% of the starting dose for a younger patient on prior opioids and titrate slowly…

8.6 Hepatic Impairment

(Additions and/or revisions underlined)

Patients with mild hepatic impairment have an increase in oxymorphone bioavailability compared to the subjects with normal hepatic function. In opioid-naïve patients with mild hepatic impairment, initiate OPANA ER using the 5 mg dose and regularly evaluate patients for respiratory and central nervous system depression. OPANA ER is contraindicated for patients with moderate and severe hepatic impairment [see Dosage and Administration (2.6), Contraindications (4), Warnings and Precautions (5.10), Clinical Pharmacology 12.3)]. For patients on prior opioid therapy, start at the 50% of the dose for that a patient with normal hepatic function on prior opioids and titrate slowly.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label for complete information)

04/28/2022 (SUPPL-30)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

 

Additions underlined

The safety and effectiveness of OPANA ER in patients below the age of 18 years have not been established. Two open-label studies were conducted in a total of 42 pediatric patients between the ages of 7 to 17 years requiring continuous, around the clock opioid treatment. The available safety and efficacy data were inconclusive for chronic use of OPANA ER. Limited data from one of the studies suggested that OPANA ER is not recommended for post- surgical pain.

03/04/2021 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

… Patients at increased risk may be prescribed opioids such as OPANA ER, but use in such patients necessitates intensive counseling about the risks and proper use of OPANA ER along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

5.3 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

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

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

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)].

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with OPANA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.1, 5.5), Patient Counseling Information (17)].

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… 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.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

7 Drug Interactions

Table 5: Clinically Significant Drug Interactions with OPANA ER

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3, 5.5)].

Muscle Relaxants

Under Intervention, the following language is added:

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3, 5.5)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Important information about OPANA ER:

Additions and/or revisions underlined:

• Get emergency help or call 911 right away if you take too much OPANA ER (overdose). When you first start taking OPANA 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. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.

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

• abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.

Tell your healthcare provider if you are:

• living in a household where there are small children or someone who has abused street or prescription drugs

Get emergency medical help or call 911 right away if you have: …

PATIENT COUNSELING INFORMATION

Life-Threatening Respiratory Depression

Newly added information:

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.3)].

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with OPANA ER. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administrations (2.2), Warnings and Precautions (5.3)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose

• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency

• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

10/07/2019 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Life-Threatening Respiratory Depression

Newly added information to end of subsection:

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.

Additions and/or revisions underlined:

5.14 Withdrawal

Do not abruptly discontinue OPANA ER in a patient physically dependent on opioids. When discontinuing OPANA ER in a physically dependent patient, gradually taper the dosage. Rapid tapering of oxymorphone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

Additionally, avoid the use of mixed agonist/antagonist …

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions with OPANA ER

Serotonergic Drugs

Additions and/or revisions underlined:

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect 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).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

Important information about OPANA ER:

• Store OPANA ER securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

When taking OPANA ER:

• Dispose of expired, unwanted, or unused OPANA ER by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

PATIENT COUNSELING INFORMATION

Storage and Disposal:

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store OPANA ER securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving OPANA 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 OPANA 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.

Newly added titled section:

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue OPANA ER without first discussing a tapering plan with the prescriber.

09/18/2018 (SUPPL-26)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

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.

5 Warnings and Precautions

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

(Additions and/or revisions are underlined)

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.

12/16/2016 (SUPPL-22)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS.

Addiction, Abuse, and Misuse

…Assess each patient’s risk prior to prescribing OPANA ER, and monitor all patients regularly for the development of these behaviors and conditions.

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 OPANA 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.

4 Contraindications

(Additions and/or revisions are underlined)

OPANA ER is contraindicated in patients with:

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

(Additions and/or revisions are underlined)

…Because extended-release products such as OPANA 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 oxymorphone present.

Assess each patient’s risk for opioid abuse or addiction, abuse, or misuse prior to prescribing OPANA ER, and monitor all patients receiving OPANA ER for the development of these behaviors and conditions…

5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness

(Revised subsection title)

5.11 Risks of Use in Patients with Gastrointestinal Conditions

(Revised subsection title; Additions and/or revisions are underlined)

OPANA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

5.12 Increased Risk of Seizures in Patients with Convulsive or Seizure Disorders

(Revised subsection title; Additions and/or revisions are underlined)

The oxymorphone in OPANA 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…

5.13 Withdrawal

(Revised subsection title; Additions and/or revisions are underlined)

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) and partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including OPANA ER.

5.14 Risk of Driving and Operating Machinery

(Revised subsection title)

5.2 Life Threatening Respiratory Depression

(Additions and/or revisions are underlined)

…Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dose increases of OPANA ER.

5.3 Neonatal Opioid Withdrawal Syndrome

(Additions and/or revisions are underlined)

…Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly…

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

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…Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OPANA 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

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 OPANA ER is used with benzodiazepine 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.

5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

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The use of OPANA 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: OPANAN 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 OPANA ER.

5.6 Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions

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Potentially life-threatening hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with OPANA ER in the postmarket setting. The most commonly described clinical features in these reports were swelling of the face, eyes, mouth, lips, tongue, hands, and/or throat; dyspnea; hives, pruritus, and/or rash; and nausea/vomiting. If anaphylaxis or other hypersensitivity occurs, stop administration of OPANA ER immediately, discontinue OPANA ER permanently, and do not rechallenge with any formulation of oxymorphone. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction.

5.7 Adrenal Insufficiency

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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

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6 Adverse Reactions

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

• Interactions with Benzodiazepines or Other CNS Depressants
• Anaphylaxis and Angioedema
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Withdrawal

6.2 Post-marketing Experience

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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 OPANA ER

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids

7 Drug Interactions

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Table 4 includes clinically significant drug interactions with OPANA ER. (Table has been added; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

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Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with OPANA ER in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, reduced postnatal survival of pups and an increased incidence of stillborn pups were observed following oral treatment of pregnant rats with oxymorphone during gestation and through lactation at doses 2.4 and 12 times the human daily dose of 20 mg/day (HDD), respectively. Reduced fetal weights were observed with oral administration of oxymorphone to pregnant rats and rabbits during organogenesis at exposures up to 4.9 and 48.8 times the HDD, respectively. 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 clinical recognized pregnancies is 2-4% and 14-20%, respectively.

 

Clinical Considerations

Fetal/Neonatal adverse reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes may cause fetal-neonatal physical dependence and neonatal withdrawal syndrome shortly after birth…

 

Labor or delivery

Opioids cross the placenta and may produce respiratory depression and pyscho-physiologic effects in neonates. An opioid antagonist, such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. OPANA 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 OPANA ER, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions…Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

 

Data

Animal data

Pregnant rats were treated with oxymorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 5, 10, or 25 mg/kg/day (2.4, 4.9, or 12.2 times the HDD based on body surface area, respectively). Reduced mean fetal weights were observed at 4.9 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups and mortality in the high dose group).

Pregnant rabbits were treated with oxymorphone hydrochloride from Gestation Day 7 to 20 via oral gavage doses of 10, 25, or 50 mg/kg/day (9.8, 24.4, or 48.8 times the HDD based on body surface area, respectively). Decreased mean fetal weights were noted at 48.8 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights).

Pregnant rats were treated with oxymorphone hydrochloride from Gestation Day 6 to Lactation Day 20 via oral gavage doses of 1, 5, 10, or 25 mg/kg/day (0.5, 2.4, 4.9, or 12.2 times the HDD based on body surface area, respectively). Increased neonatal death (postnatal day 0-1) was noted at 2.4 times the HDD. Decreased pup survival over the first week of life, reduced pup birth weight, and reduced postnatal weight gain were noted at 4.9 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups and mortality in the 10 and 25 mg/kg/day groups).

In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of 153 mg/kg oxymorphone hydrochloride (62.2 times the HDD) on Gestation Day 8 to pregnant hamsters. This dose also produced significant maternal toxicity (20% maternal deaths).

8.2 Lactation

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Risk Summary

There is no information regarding the presence of oxymorphone in human milk, the effects on the breastfed infant, or the effects on milk production. 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 OPANA ER.

8.3 Females and Males of Reproductive Potential

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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.

8.5 Geriatric Use

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…Oxymorphone 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 the 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

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Patients with mild hepatic impairment have an increase in oxymorphone bioavailability compared to the subjects with normal hepatic function.

8.7 Renal Impairment

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Patients with moderate to severe renal impairment were shown to have an increase in oxymorphone bioavailability compared to the subjects with normal renal function.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

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Interactions with Benzodiazepines and other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if OPANA ER is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.

Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions

Inform patients that anaphylaxis and other hypersensitivity reactions have been reported with ingredients contained in OPANA ER…

Serotonin Syndrome

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.

MAOI Interaction

Inform patients to avoid taking OPANA ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking OXYMORPHONE.

Adrenal Insufficiency

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.

Important Administration Instructions

Instruct patients how to properly take OPANA ER, including the following:

• OPANA ER is designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved OPANA ER tablets can result in a fatal overdose

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of OPANA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

 

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that OPANA ER can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise patients that breastfeeding is not recommended during treatment with OPANA ER.

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Medication Guide

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Important information about OPANA ER:

• Taking OPANA 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.

Tell your healthcare provider if you are:

• breastfeeding. Not recommended during treatment with OPANA ER…
• … Taking OPANA ER with certain other medicines can cause serious side effects that could lead to death.

When taking OPANA ER:

• Do not change your dose. Take OPANA ER exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.

Get emergency medical help if you have:

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

 

Distributed by: Endo Pharmaceuticals Inc. Malvern, PA 19355, www.endo.com or call 1-800-462-3636