WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION;
ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTION WITH ALCOHOL
Addiction, Abuse, and Misuse
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 OPANA® ER, and monitor all patients regularly for the development of these behaviors or conditions.
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of OPANA® ER. Monitor for respiratory depression, especially during initiation of OPANA® ER or following a dose increase. 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.
Accidental ingestion of even one dose of OPANA® ER, especially by children, can result in a fatal overdose of oxymorphone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of OPANA® ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Interaction with Alcohol
Instruct patients not to consume alcoholic beverages or use prescription or non-prescription 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.
OPANA® ER is contraindicated in patients with:
- Significant respiratory depression
- Acute or severe bronchial asthma or hypercarbia
- Known or suspected paralytic ileus and gastrointestinal obstruction
- Moderate and severe hepatic impairment
- Hypersensitivity (e.g. anaphylaxis) to oxymorphone, any other ingredients in OPANA® ER, or to morphine analogs such as codeine
WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse
- OPANA® ER contains oxymorphone, a Schedule II controlled substance with an abuse liability similar to other opioids including fentanyl, hydromorphone, methadone, morphine, oxycodone and tapentadol. As an opioid, OPANA® ER exposes users to the risks of addiction, abuse, and misuse. As modified-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.
- Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OPANA® 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 abuse or addiction, abuse, or misuse prior to prescribing OPANA® ER, and monitor all patients receiving OPANA® ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of OPANA® ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations 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.
- An FDA approved patient counseling document for healthcare providers containing important safety information regarding the safe use, storage, and disposal of extended-release opioids can be obtained or downloaded for no cost at www.er-la-opioidREMS.com or by calling 1-800-503-0784.
- 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.
- Opioid agonists such as OPANA® ER are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. 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 the 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. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests as required by state 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 OPANA® ER
- OPANA® ER is for oral use only. Abuse of OPANA® ER poses a risk of overdose and death. This risk is increased with concurrent abuse of OPANA® ER with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved OPANA® ER enhances drug release and increases the risk of overdose and death.
- With parenteral abuse, cases of thrombotic microangiopathy (a condition characterized clinically by thrombocytopenia and microangiopathic hemolytic anemia) have been reported; many cases resulted in hospitalization and treatment with plasmapheresis. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Life-threatening Respiratory Depression
- Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. 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 ofOPANA® ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with OPANA® ER and following dose increases.
- To reduce the risk of respiratory depression, proper dosing and titration of OPANA® ER are essential. Overestimating the OPANA® ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.
- 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.
Neonatal Opioid Withdrawal Syndrome
- Prolonged use of OPANA® ER during pregnancy can result in withdrawal signs 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. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
- 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.
Interactions with Central Nervous System Depressants
- 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 levels and a potentially fatal overdose of oxymorphone.
- Hypotension, profound sedation, coma, respiratory depression, and death may result if OPANA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
- When considering the use of OPANA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Monitor patients receiving CNS depressants and OPANA® ER for signs of respiratory depression, sedation and hypotension. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA® ER therapy. If the decision to begin OPANA® ER is made, start with OPANA® ER 5 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.
Use in Elderly, Cachectic, and Debilitated Patients
Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating OPANA® ER and when OPANA® ER is given concomitantly with other drugs that depress respiration.
Use in Patients with Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with OPANA® ER, as in these patients, even usual therapeutic doses of OPANA® ER may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.
Use in Patients with Hepatic Impairment
A study of OPANA® ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function. OPANA® ER is contraindicated in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment reduce the starting dose to the lowest dose and monitor for signs of respiratory and central nervous system depression.
OPANA® 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). Monitor these patients for signs of hypotension after initiating or titrating the dose of OPANA® ER. OPANA® ER should be avoided in patients with circulatory shock, because OPANA® ER may cause vasodilation that can further reduce cardiac output and blood pressure.
Use in Patients with Head Injury or Increased Intracranial Pressure
Monitor patients taking OPANA® ER who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with OPANA® ER. OPANA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OPANA® ER in patients with impaired consciousness or coma.
Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen
- There have been post-marketing reports of difficulty in swallowing OPANA® ER tablets. These reports included choking, gagging, regurgitation and tablets stuck in the throat. Instruct patients not to pre-soak, lick or otherwise wet OPANA® 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.
- There have been rare post-marketing reports of cases of intestinal obstruction, some of which have required medical intervention to remove the tablet. 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.
Use in Patients with Gastrointestinal Conditions
- OPANA® ER is contraindicated in patients with paralytic ileus. Avoid the use of OPANA® ER in patients with other GI obstruction.
- The oxymorphone in OPANA® ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.
Use in Patients with Convulsive or Seizure Disorders
The oxymorphone in OPANA® ER may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during OPANA® ER therapy.
Avoidance of Withdrawal
- Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with an opioid agonist analgesic, including OPANA® ER. In these patients, the analgesic effect may be reduced and/or withdrawal symptoms may be precipitated.
- When discontinuing OPANA® ER, gradually taper the dose. Do not abruptly discontinue OPANA® ER.
Driving and Operating Machinery
OPANA® 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 OPANA® ER and know how they will react to the medication.
DOSAGE AND ADMINISTRATION
- To avoid medication errors, prescribers and pharmacists must be aware that oxymorphone is available as both immediate-release 5 mg and 10 mg tablets and extended-release 5 mg and 10 mg tablets.
- OPANA® ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Education and training programs that meet FDA requirements are offered by accredited CME/CE providers, and are available to prescribers of extended-release opioids at no or nominal cost. A list of these programs can be found at www.er-la-opioidREMS.com.
Use of OPANA® ER in Patients who are Opioid-naïve and not Opioid Tolerant
The starting dose for patients who are opioid-naïve or not opioid tolerant is OPANA® ER 5 mg orally every 12 hours. Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.
Use of OPANA® ER in Patients who are Opioid Tolerant
Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, or an equianalgesic dose of another opioid. Discontinue all other around-the-clock opioid drugs when OPANA® ER therapy is initiated.
Titration and Maintenance of Therapy
Individually titrate OPANA® ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving OPANA® ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, and misuse.
Discontinuation of OPANA® ER
When a patient no longer requires therapy with OPANA® ER, use a gradual downward titration of the dose every two to four days, to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue OPANA® ER.
Administration of OPANA® ER
Instruct patients to swallow OPANA® ER tablets intact. The tablets are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of oxymorphone. OPANA® ER is administered at a frequency of twice daily (every 12 hours). Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.
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 clinical practice.
- The safety of oxymorphone hydrochloride extended-release tablets was evaluated in a total of 2011 patients in open-label and controlled clinical trials. The clinical trials enrolled patients with to severe chronic non-malignant pain, cancer pain, and post-surgical pain. The most common serious adverse events reported with administration of oxymorphone hydrochloride extended-release tablets were chest pain, pneumonia and vomiting.
- Adverse reactions reported at (≥2%) in placebo-controlled trials were: nausea (33%), constipation (28%), dizziness (18%), somnolence (17%), vomiting (16%), pruritus (15%), headache (12%), sweating increased (9%), dry mouth (6%), sedation (6%), diarrhea (4%), insomnia (4%), fatigue (4%), appetite decreased (3%), and abdominal pain (3%).
- In clinical trials 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.
Amnesia, convulsion, and memory impairment have been identified during post approval use of OPANA® ER. 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.
Concomitant use of alcohol with OPANA® ER can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA® ER therapy.
- The concomitant use of OPANA® ER with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and OPANA® ER for signs of respiratory depression, sedation and hypotension.
- When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.
Interactions with Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonists (buprenorphine) may reduce the analgesic effect of OPANA® ER or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving OPANA® ER.
Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and OPANA® ER for signs of respiratory depression that may be greater than otherwise expected.
Cimetidine can potentiate opioid-induced respiratory depression. Monitor patients for respiratory depression when OPANA® ER and cimetidine are used concurrently.
Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of respiratory and central nervous system depression when OPANA® ER is used concurrently with anticholinergic drugs.
USE IN SPECIFIC POPULATIONS
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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. OPANA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
Opioids cross the placenta and may produce respiratory depression in neonates. OPANA® ER is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics 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.
It is not known whether oxymorphone is excreted in human milk. Because many drugs, including some opioids, are excreted in human milk, caution should be exercised when OPANA® ER is administered to a nursing woman. Monitor infants who may be exposed to OPANA® ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
The safety and effectiveness of OPANA® ER in patients below the age of 18 years have not been established.
Of the total number of subjects in clinical studies of oxymorphone hydrochloride extended-release tablets, 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 a 1.4-fold increase in oxymorphone AUC and a 1.5-fold increase in Cmax. Initiate dosing with OPANA® ER in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating OPANA® ER. For patients on prior opioid therapy, start at 50% of the starting dose for a younger patient on prior opioids and titrate slowly.
Patients with mild hepatic impairment have an increase in oxymorphone bioavailability of 1.6-fold. In opioid-naïve patients with mild hepatic impairment, initiate OPANA® ER using the 5 mg dose and monitor closely for respiratory and central nervous system depression. OPANA® ER is contraindicated for patients with moderate and severe hepatic impairment. For patients on prior opioid therapy, start at 50% of the dose for a patient with normal hepatic function on prior opioids and titrate slowly.
Patients with severe renal impairment were shown to have an increase in oxymorphone bioavailability ranging from 57-65%. Start opioid-naïve patients with the 5 mg dose of OPANA® ER and titrate slowly while closely monitoring for respiratory and central nervous system depression. For patients on prior opioid therapy, start at 50% of the dose for a patient with normal renal function on prior opioids and titrate slowly.
DRUG ABUSE AND DEPENDENCE
- All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
- OPANA® ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution.
- Both tolerance and physical dependence can develop during chronic opioid therapy.
- OPANA® ER should not be abruptly discontinued. If OPANA® ER is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur.
- Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.
- Acute overdosage with oxymorphone is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.
Please see full Prescribing Information, including boxed WARNING and Medication Guide for OPANA® ER.
Oxymorphone is also available in immediate-release tablets and injectable form. For more information, please see full Prescribing Information for OPANA® ER and OPANA® Injection.