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OPANA
(oxymorphone hydrochloride) Tablets
WARNING
ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
OPANA 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, and monitor all patients regularly for the development of these behaviors and conditions [see WARNINGS AND PRECAUTIONS].
Serious, life-threatening, or fatal respiratory depression may occur with use of OPANA. Monitor for respiratory depression, especially during initiation of OPANA or following a dose increase [see WARNINGS AND PRECAUTIONS].
Accidental ingestion of even one dose of OPANA, especially by children, can result in a fatal overdose of oxymorphone [see WARNINGS AND PRECAUTIONS].
Prolonged use of OPANA during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see WARNINGS AND PRECAUTIONS].
Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking OPANA. The co-ingestion of alcohol with OPANA may result in increased plasma levels and a potentially fatal overdose of oxymorphone [see WARNINGS AND PRECAUTIONS].
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
OPANA (oxymorphone hydrochloride) tablet is an opioid agonist available in 5 mg and 10 mg tablet strengths for oral administration. The chemical name for oxymorphone hydrochloride is 4, 5α-epoxy-3, 14-dihydroxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 337.80. The molecular formula is C17H19NO4. HCl and it has the following chemical structure.
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Oxymorphone hydrochloride is white to off white odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water
The inactive ingredients in OPANA include: lactose monohydrate, magnesium stearate, and pregelatinized starch. In addition, the 5 mg tablets contain FD&C blue No. 2 aluminum lake. The 10 mg tablets contain D&C red No. 30 aluminum lake.
OPANA is indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see WARNINGS AND PRECAUTIONS], reserve OPANA for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS AND PRECAUTIONS].
Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see WARNINGS AND PRECAUTIONS].
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with OPANA and adjust the dosage accordingly [see WARNINGS AND PRECAUTIONS].
OPANA should be administered on an empty stomach, at least one hour prior to or two hours after eating [see CLINICAL PHARMACOLOGY].
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 [see Dosage Forms and Strengths].
Initiate treatment with OPANA in a dosing range of 10 to 20 mg every 4 to 6 hours as needed for pain.
Do not initiate treatment with doses higher than 20 mg because of the potential serious adverse reactions [see Clinical Studies].
There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of OPANA. It is safer to underestimate a patient's 24-hour OPANA dosage than to overestimate the 24-hour OPANA dosage and manage an adverse reaction due to overdose.
For conversion from other opioids to OPANA, physicians and other healthcare professionals are advised to refer to published relative potency information, keeping in mind that conversion ratios are only approximate. In general, it is safest to start OPANA therapy by administering half of the calculated total daily dose of OPANA in 4 to 6 equally divided doses, every 4-6 hours. The initial dose of OPANA can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved.
Given OPANA's absolute oral bioavailability of approximately 10%, patients receiving parenteral oxymorphone may be converted to OPANA by administering 10 times the patient's total daily parenteral oxymorphone dose as OPANA, in four or six equally divided doses (e.g., [IV dose x 10] divided by 4 or 6). For example, approximately 10 mg of OPANA four times daily may be required to provide pain relief equivalent to a total daily IM dose of 4 mg oxymorphone. Due to patient variability with regard to opioid analgesic response, upon conversion patients should be closely monitored to ensure adequate analgesia and to minimize side effects.
The relative bioavailability of OPANA compared to extended-release oxymorphone is unknown, so conversion to extended-release tablets must be accompanied by close observation for signs of excessive sedation and respiratory depression.
OPANA is contraindicated in patients with moderate or severe hepatic impairment. Use OPANA with caution in patients with mild hepatic impairment, starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring for signs of respiratory and central nervous system depression [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Use OPANA with caution in patients with creatinine clearance rates less than 50 mL/min., starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring for signs of respiratory and central nervous system depression [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Exercise caution in the selection of the starting dose of OPANA for an elderly patient by starting with the lowest dose (e.g., 5 mg) and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression [see Use in Specific Populations].
OPANA, like all opioid analgesics, should be started at one-third to one-half of the usual dose in patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, because respiratory depression, hypotension and profound sedation, coma or death may result [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.
Individually titrate OPANA to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving OPANA to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see WARNINGS AND PRECAUTIONS]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.
If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the OPANA dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
When a patient who has been taking OPANA regularly and may be physically dependent no longer requires therapy with OPANA, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue OPANA in a physically-dependent patient [see WARNINGS AND PRECAUTIONS, Drug Abuse and Dependence].
Tablets 5 mg: blue, round, convex tablet debossed with E612 over 5 on one side and plain on the other.
Tablets 10 mg: red, round, convex tablet debossed with E613 over 10 on one side and plain on the other.
OPANA (oxymorphone hydrochloride) tablets are supplied as follows:
Blue, round, convex tablets debossed with E612 over 5 on one side and plain on the other.
Bottles of 100 tablets with child-resistant closure NDC
63481-612-70
Unit-Dose package of 100 tablets (5 blister cards of 20 tablets,
not child-resistant, for hospital use only) NDC 63481-612-75
Red, round, convex tablets debossed with E613 over 10 on one side and plain on the other.
Bottles of 100 tablets with child-resistant closure NDC
63481-613-70
Unit-Dose package of 100 tablets (5 blister cards of
20tablets, not child-resistant, for hospital use only) NDC 63481-613-75
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
Dispense in tight container as defined in the USP, with a child-resistant closure (as required).
Distributed by: Endo Pharmaceuticals Inc., Malvern, PA 19355. Revised: Dec 2016
The following serious adverse reactions are described, or described in greater detail, in other sections:
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.
A total of 591 patients were treated with OPANA in controlled clinical trials. The clinical trials consisted of patients with acute post-operative pain (n=557) and cancer pain (n=34) trials.
The following table lists adverse reactions that were reported in at least 2% of patients receiving OPANA in placebo-controlled trials (acute post-operative pain (N=557)).
Table 1: Adverse Reactions Reported in
Placebo-Controlled Trials
| MedDRA Preferred Term | OPANA (N=557) |
Placebo (N=270) |
| Nausea | 19% | 12% |
| Pyrexia | 14% | 8% |
| Somnolence | 9% | 2% |
| Vomiting | 9% | 7% |
| Pruritus | 8% | 4% |
| Headache | 7% | 4% |
| Dizziness (Excluding Vertigo) | 7% | 2% |
| Constipation | 4% | 1% |
| Confusion | 3% | < 1% |
The common ( ≥ 1% - < 10%) adverse drug reactions reported at least once by patients treated with OPANA in the clinical trials organized by MedDRA's (Medical Dictionary for Regulatory Activities) System Organ Class were and not represented in Table 1:
Cardiac disorders: tachycardia
Gastrointestinal disorders: dry mouth, abdominal distention, and flatulence
General disorders and administration site conditions: sweating increased
Nervous system disorders: anxiety and sedation
Respiratory, thoracic and mediastinal disorders: hypoxia
Vascular disorders: hypotension
Other less common adverse reactions known with opioid treatment that were seen < 1% in the OPANA trials includes the following:
Abdominal pain, ileus, diarrhea, agitation, disorientation, restlessness, feeling jittery, hypersensitivity, allergic reactions, bradycardia, central nervous system depression, depressed level of consciousness, lethargy, mental impairment, mental status changes, fatigue, depression, clamminess, flushing, hot flashes, dehydration, dermatitis, dyspepsia, dysphoria, edema, euphoric mood, hallucination, hypertension, insomnia, miosis, nervousness, palpitation, postural hypotension, syncope, dyspnea, respiratory depression, respiratory distress, respiratory rate decreased, oxygen saturation decreased, difficult micturition, urinary retention, urticaria, vision blurred, visual disturbances, weakness, appetite decreased, and weight decreased.
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.
Nervous system disorder: amnesia, convulsion, memory impairment
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
Immune System Disorders: Angioedema, and other hypersensitivity reactions:
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].
Table 2 includes clinically significant drug interactions with OPANA.
Table 2: Clinically Significant Drug Interactions with
Opana
| Alcohol | |
| Clinical Impact: | The concomitant use of alcohol with OPANA can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. |
| Intervention: | Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on OPANA therapy [see CLINICAL PHARMACOLOGY]. |
| Benzodiazepines and Other Central Nervous System (CNS) Depressants | |
| Clinical Impact: | Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
| Intervention: | Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [ WARNINGS AND PRECAUTIONS]. |
| Examples: | Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
| Serotonergic Drugs | |
| Clinical Impact: | The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
| Intervention: | If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OPANA if serotonin syndrome is suspected. |
| Examples: | 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), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
| Monoamine Oxidase Inhibitors (MAOIs) | |
| Clinical Impact: | MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS AND PRECAUTIONS]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. |
| Intervention: | The use of OPANA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
| Examples: | phenelzine, tranylcypromine, linezolid |
| Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics | |
| Clinical Impact: | May reduce the analgesic effect of OPANA and/or precipitate withdrawal symptoms. |
| Intervention: | Avoid concomitant use. |
| Examples: | butorphanol, nalbuphine, pentazocine, buprenorphine, |
| Muscle Relaxants | |
| Clinical Impact: | Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
| Intervention: | Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OPANA and/or the muscle relaxant as necessary. |
| Diuretics | |
| Clinical Impact: | Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
| Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs. |
| Anticholinergic Drugs | |
| Clinical Impact: | The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
| Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs. |
| Cimetidine | |
| Clinical Impact: | Cimetidine can potentiate opioid-induced respiratory depression. |
| Intervention: | Monitor patients for respiratory depression when OPANA and cimetidine are used concurrently. |
| Anticholinergic Drugs | |
| Clinical Impact: | The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
| Intervention: | Monitor patients for signs of urinary retention or reduced gastric motility when Opana is used concomitantly with anticholinergic drugs. |
OPANA contains oxymorphone, a Schedule II controlled substance
OPANA contains oxymorphone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone and tapentadol. OPANA can be abused and is subject to misuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].
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 treating 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. Health care 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.
OPANA, 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 limit abuse of opioid drugs.
Risks Specific To Abuse Of OPANA
OPANA is for oral use only. Abuse of OPANA poses a risk of overdose and death. This risk is increased with concurrent abuse of OPANA with alcohol and other central nervous system depressants.
Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
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 dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
OPANA should not be abruptly discontinued in a physically-dependent patient [see DOSAGE AND ADMINISTRATION]. If OPANA 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 WARNINGS AND PRECAUTIONS, Use in Specific Populations].
Included as part of the PRECAUTIONS section.
Respiratory depression is the chief hazard of OPANA. Respiratory depression may occur more frequently in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia, when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.
Administer OPANA with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression, or coma. In these patients, even usual therapeutic doses of oxymorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Consider alternative non-opioid analgesics and use OPANA only under careful medical supervision at the lowest effective dose in such patients.
OPANA contains oxymorphone, a mu opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
Oxymorphone can be abused in a manner similar to other opioid agonists, legal or illicit. This issue should be considered when prescribing or dispensing oxymorphone in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
OPANA tablets may be abused by crushing, chewing, snorting, or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death [see Drug Abuse and Dependence].
OPANA may be targeted for theft and diversion. Healthcare professionals should contact their State Medical Board, State Board of Pharmacy, or State Control Board for information on how to detect or prevent diversion of this product, and security requirements for storing and handling of OPANA.
Healthcare professionals should advise patients to store OPANA in a secure place, preferably locked and out of the reach of children and other non-caregivers.
Concerns about abuse, misuse, diversion and addiction should not prevent the proper management of pain.
The concomitant use of other CNS depressants including other opioids, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, and alcohol with oxymorphone may produce increased depressant effects including hypoventilation, hypotension, profound sedation, coma and death [see DRUG INTERACTIONS].
In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, opioid analgesics can produce effects on papillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.
Administer OPANA with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness.
Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.
OPANA, like all opioid analgesics, may cause severe hypotension in a patient whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents that compromise vasomotor tone. Administer OPANA with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.
A study of extended-release oxymorphone tablets in patients with hepatic disease indicated greater plasma concentrations than in those with normal hepatic function [see CLINICAL PHARMACOLOGY]. Use OPANA with caution in patients with mild impairment, starting with the lowest dose and titrating slowly while carefully monitoring for side effects [see DOSAGE AND ADMINISTRATION]. OPANA is contraindicated in patients with moderate or severe hepatic impairment.
Use OPANA with caution in the following conditions: adrenocortical insufficiency (e.g., Addison's disease), prostatic hypertrophy or urethral stricture, severe impairment of pulmonary or renal function, and toxic psychosis.
Opioids may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings.
Opioids diminish propulsive peristaltic waves in the gastrointestinal tract. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of OPANA may obscure the diagnosis or clinical course in patients with acute abdominal conditions. OPANA is contraindicated in patients with paralytic ileus.
OPANA, like other opioids, may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.
Opioid analgesics impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
Long-term studies have been completed to evaluate the carcinogenic potential of oxymorphone in both Sprague-Dawley rats and CD-1 mice. Oxymorphone was administered to Sprague-Dawley rats (2.5, 5, and 10 mg/kg/day in males and 5, 10, and 25 mg/kg/day in females) for 2 years by oral gavage. The systemic drug exposure (AUC ng•h/mL) at the 10 mg/kg/day dose in male rats was 0.34-fold and at the 25 mg/kg/day dose in female rats was 1.5fold the human exposure at a dose of 260 mg/day. No evidence of carcinogenic potential was observed in rats. Oxymorphone was administered to CD-1 mice (10, 25, 75 and 150 mg/kg/day) for 2 years by oral gavage. The systemic drug exposure (AUC ng•h/mL) at the 150 mg/kg/day dose in mice was 14.5-fold (in males) and 17.3-fold (in females) times the human exposure at a dose of 260 mg/day. No evidence of carcinogenic potential was observed in mice.
Oxymorphone hydrochloride was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test) at concentrations of ≤ 5270 ≤ g/plate, or in an in vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes at concentrations ≤ 5000 ≤ g/ml with or without metabolic activation. Oxymorphone hydrochloride tested positive in both the rat and mouse in vivo micronucleus assays. An increase in micronucleated polychromatic erythrocytes occurred in mice given doses of ≤ 250 mg/kg and in rats given doses of 20 and 40 mg/kg. A subsequent study demonstrated that oxymorphone hydrochloride was not aneugenic in mice following administration of up to 500 mg/kg. Additional studies indicate that the increased incidence of micronucleated polychromatic erythrocytes in rats may be secondary to increased body temperature following oxymorphone administration. Doses associated with increased micronucleated polychromatic erythrocytes also produce a marked, rapid increase in body temperature. Pretreatment of animals with sodium salicylate minimized the increase in body temperature and prevented the increase in micronucleated polychromatic erythrocytes after administration of 40 mg/kg oxymorphone.
Oxymorphone did not affect reproductive function or sperm parameters in male rats at any dose tested ( ≤ 50 mg/kg/day). In female rats, an increase in the length of the estrus cycle and decrease in the mean number of viable embryos, implantation sites and corpora lutea were observed at doses of oxymorphone ≤ 10 mg/kg/day. The dose of oxymorphone associated with reproductive findings in female rats is 0.8 times a total human daily dose of 120 mg based on a body surface area. The dose of oxymorphone that produced no adverse effects on reproductive findings in female rats (i.e., NOAEL) is 0.4-times a total human daily dose of 120 mg based on body surface area.
The safety of using oxymorphone in pregnancy has not been established with regard to possible adverse effects on fetal development. The use of OPANA in pregnancy, in nursing mothers, or in women of child-bearing potential requires that the possible benefits of the drug be weighted against the possible hazards to the mother and the child.
Pregnancy Category C
There are no adequate and well-controlled studies of oxymorphone in pregnant women. In animal studies, oxymorphone caused decreased fetal and pup weights, an increase in stillbirth, and a decrease in postnatal pup survival at maternal oxymorphone doses equivalent to 0.4 to 4 times the human daily dose of 120 mg (Based on body surface area). OPANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryo-fetal developmental toxicity studies, pregnant rats and rabbits received oxymorphone hydrochloride at doses up to about 2 times (rats) and 8 times (rabbits) total human daily dose of 120 mg (based on body surface area). No malformations occurred, but reduced fetal weights occurred at maternal doses of 0.8 (rat) and 4 (rabbit) times the total human daily dose of 120 mg (based on body surface area). There were no adverse developmental effects in rats that received 0.4 times or rabbits that received less than 4 times the total human dose. There were no effects of oxymorphone hydrochloride on intrauterine survival at doses in rats ≤ 2 times, or in rabbits at ≤ 8 times the human dose (see Non-teratogenic Effects, below). In a study conducted prior to the establishment of Good Laboratory Practices (GLP) and not according to current recommended methodology, a single subcutaneous injection of oxymorphone hydrochloride on gestation day 8 produced malformations in offspring of hamsters that received a dose equivalent to 10 times the total human daily dose of 120 mg (based on body surface area). This dose also produced 83% maternal lethality.
Oxymorphone hydrochloride administration to female rats during gestation in a pre- and postnatal developmental toxicity study reduced mean litter size (18%) at a dose of 25 mg/kg/day, attributed to an increase in the incidence of stillborn pups. An increase in neonatal death occurred at doses ≤ 5 mg/kg/day (0.4 times a total human daily dose of 120 mg, based on body surface area). Low pup birth weight, decreased post-natal weight gain, and reduced post-natal survival of pups occurred following treatment of the dams with 25 mg/kg/day (about 2 times a total human daily dose of 120 mg, based on body surface area).
Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence. Neonatal withdrawal may occur. Symptoms usually appear during the first days of life and may include convulsions, irritability, excessive crying, tremors, hyperactive reflexes, fever, vomiting, diarrhea, sneezing, yawning, and increased respiratory rate.
Opioids cross the placenta and may produce respiratory depression in neonates. OPANA 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. Occasionally, opioid analgesics may prolong labor through actions which 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. Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific opioid antagonist, such as naloxone or nalmefene, should be available for reversal of opioid-induced respiratory depression in the neonate.
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 is administered to a nursing woman. Infants exposed to OPANA through breast milk should be monitored 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.
Safety and effectiveness of OPANA in pediatric patients below the age of 18 years have not been established.
OPANA should be used with caution in elderly patients [see CLINICAL PHARMACOLOGY].
Of the total number of subjects in clinical studies of OPANA, 31% were 65 and over, while 7% 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. In general, dose selection for elderly patients 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
In a study of extended-release oxymorphone tablets, patients with mild hepatic impairment were shown to have an increase in bioavailability of 1.6 fold. OPANA should be used with caution in patients with mild impairment. These patients should be started with the lowest dose and titrated slowly while carefully monitoring for side effects. OPANA is contraindicated for patients with moderate and severe hepatic impairment [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION].
In a study of extended-release oxymorphone tablets, patients with moderate to severe renal impairment were shown to have an increase in bioavailability ranging from 57-65% [see CLINICAL PHARMACOLOGY]. Such patients should be started cautiously with lower doses of OPANA and titrated slowly while monitoring for side effects [see DOSAGE AND ADMINISTRATION].
Acute overdose with OPANA can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see CLINICAL PHARMACOLOGY].
In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxymorphone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxymorphone overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of oxymorphone in OPANA, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
OPANA is contraindicated in patients with:
Oxymorphone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxymorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxymorphone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Oxymorphone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Oxymorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Oxymorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Oxymorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see ADVERSE REACTIONS]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see ADVERSE REACTIONS].
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
The minimum effective analgesic concentration varies widely among patients, especially among patients who have been previously treated with potent agonist opioids The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see DOSAGE AND ADMINISTRATION].
There is a relationship between increasing oxymorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see DOSAGE AND ADMINISTRATION].
The absolute oral bioavailability of oxymorphone is approximately 10%. Studies in healthy volunteers reveal predictable relationships between OPANA dosage and plasma oxymorphone concentrations.
Steady-state levels were achieved after three days of multiple dose administration. Under both singledose and steady-state conditions, dose proportionality has been established for 5 mg, 10 mg and 20 mg doses of OPANA, for both peak plasma levels (Cmax) and extent of absorption (AUC) (see Table 3).
Table 3: Mean (±SD) OPANA Pharmacokinetic Parameters
| Regimen | Dosage | Cmax (ng/mL) | AUC (ng•hr/mL) | T½ (hr) |
| Single Dose | 5 mg | 1.10±0.55 | 4.48±2.07 | 7.25±4.40 |
| 10 mg | 1.93±0.75 | 9.10±3.40 | 7.78±3.58 | |
| 20 mg | 4.39±1.72 | 20.07±5.80 | 9.43±3.36 | |
| Multiple Dose a | 5 mg | 1.73±0.62 | 4.63±1.49 | NA |
| 10 mg | 3.51±0.91 | 10.19±3.34 | NA | |
| 20 mg | 7.33±2.93 | 21.10±7.59 | NA | |
| NA = not applicable a Results after 5 days of every 6 hours dosing. |
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After oral dosing with 40 mg of OPANA in healthy volunteers under fasting conditions or with a high-fat meal, the Cmax and AUC were increased by approximately 38% in fed subjects relative to fasted subjects. As a result, OPANA should be dosed at least one hour prior to or two hours after eating [see DOSAGE AND ADMINISTRATION].
Formal studies on the distribution of oxymorphone in various tissues have not been conducted. Oxymorphone is not extensively bound to human plasma proteins; binding is in the range of 10% to 12%.
Opana half-life ranges from approximately 9-11 hours after a single oral dose (5-40 mg).
Metabolism
Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive products. The two major metabolites of oxymorphone are oxymorphone-3-glucuronide and 6-OH-oxymorphone. The mean plasma AUC for oxymorphone-3- glucuronide is approximately 90-fold higher than the parent compound. The pharmacologic activity of the glucuronide metabolite has not been evaluated. 6-OH-oxymorphone has been shown in animal studies to have analgesic bioactivity. The mean plasma 6-OH-oxymorphone AUC is approximately 70% of the oxymorphone AUC following single oral doses but is essentially equivalent to the parent compound at steady-state.
Excretion
Because oxymorphone is extensively metabolized, < 1% of the administered dose is excreted unchanged in the urine. On average, 33% to 38% of the administered dose is excreted in the urine as oxymorphone- 3-glucuronide and 0.25% to 0.62% is excreted as 6-OH-oxymorphone in subjects with normal hepatic and renal function. In animals given radiolabeled oxymorphone, approximately 90% of the administered radioactivity was recovered within 5 days of dosing. The majority of oxymorphone-derived radioactivity was found in the urine and feces.
The plasma levels of oxymorphone administered as an extended-release tablet were about 40% higher in elderly ( ≥ 65 years of age) than in younger subjects [see Use in Specific Populations].
The effect of sex on the pharmacokinetics of OPANA has not been studied. In a study with an extendedrelease formulation of oxymorphone, there was a consistent tendency for female subjects to have slightly higher AUCss and Cmax values than male subjects. However, sex differences were not observed when AUCss and Cmax were adjusted by body weight.
The liver plays an important role in the pre-systemic clearance of orally administered oxymorphone. Accordingly, the bioavailability of orally administered oxymorphone may be markedly increased in patients with moderate to severe liver disease. The effect of hepatic impairment on the pharmacokinetics of OPANA has not been studied. However, in a study with an extended-release formulation of oxymorphone, the disposition of oxymorphone was compared in 6 patients with mild, 5 patients with moderate, and one patient with severe hepatic impairment, and 12 subjects with normal hepatic function. The bioavailability of oxymorphone was increased by 1.6-fold in patients with mild hepatic impairment and by 3.7-fold in patients with moderate hepatic impairment. In one patient with severe hepatic impairment, the bioavailability was increased by 12.2-fold. The half-life of oxymorphone was not significantly affected by hepatic impairment.
The effect of renal impairment on the pharmacokinetics of OPANA has not been studied. However, in a study with an extended-release formulation of oxymorphone, an increase of 26%, 57%, and 65% in oxymorphone bioavailability was observed in mild (creatinine clearance 51-80 mL/min; n=8), moderate (creatinine clearance 30-50 mL/min; n=8), and severe (creatinine clearance < 30 mL/min; n=8) patients, respectively, compared to healthy controls.
In vitro studies revealed little to no biotransformation of oxymorphone to 6-OH-oxymorphone by any of the major cytochrome P450 (CYP P450) isoforms at therapeutically relevant oxymorphone plasma concentrations.
No inhibition of any of the major CYP P450 isoforms was observed when oxymorphone was incubated with human liver microsomes at concentrations of ≤ 50 μM. An inhibition of CYP 3A4 activity occurred at oxymorphone concentrations ≥ 150 μM. Therefore, it is not expected that oxymorphone, or its metabolites will act as inhibitors of any of the major CYP P450 enzymes in vivo.
Increases in the activity of the CYP 2C9 and CYP 3A4 isoforms occurred when oxymorphone was incubated with human hepatocytes. However, clinical drug interaction studies with OPANA ER showed no induction of CYP450 3A4 or 2C9 enzyme activity, indicating that no dose adjustment for CYP 3A4- or 2C9-mediated drug-drug interactions is required.
The effect of co-ingestion of alcohol with OPANA has not been evaluated. However, an in vivo study was performed to evaluate the effect of alcohol (40%, 20%, 4% and 0%) on the bioavailability of a single dose of 40 mg of extended-release oxymorphone tablets in healthy, fasted volunteers. Following concomitant administration of 240 mL of 40% ethanol the Cmax increased on average by 70% and up to 270% in individual subjects. Following the concomitant administration of 240 mL of 20% ethanol, the Cmax increased on average by 31% and up to 260% in individual subjects. In some individuals there was also a decrease in oxymorphone peak plasma concentrations. No effect on the release of oxymorphone from the extended-release tablet was noted in an in vitro alcohol interaction study. The mechanism of the in vivo interaction is unknown. Therefore, avoid co-administration of oxymorphone and ethanol.
The analgesic efficacy of OPANA has been evaluated in acute pain following orthopedic and abdominal surgeries.
Two double-blind, placebo-controlled, dose-ranging studies in patients with acute moderate to severe pain following orthopedic surgery evaluated the doses of OPANA 10 mg and 20 mg, and 30 mg was included in one study. Both studies demonstrated that OPANA 20 mg provided greater analgesia as measured by total pain relief based on a weighted analysis over 8 hours using a 0-4 categorical, compared to placebo. OPANA 10 mg provided greater analgesia as compared to placebo in one of the two studies. There was no evidence of superiority of the 30 mg dose over the 20 mg dose. However, there was a high rate of naloxone use in patients receiving the OPANA 30 mg dose in the post-operative period [see DOSAGE AND ADMINISTRATION].
In a randomized, double-blind, placebo-controlled, multiple-dose study, the efficacy of OPANA 10 mg and 20 mg was assessed in patients with moderate to severe acute pain following abdominal surgery. In this study, patients were dosed every 4 to 6 hours over a 48-hour treatment period. OPANA 10 and 20mg provided greater analgesia, as measured by the mean average pain intensity on a 0-100 mm visual analog scale, over 48 hours, compared to placebo [see DOSAGE AND ADMINISTRATION].
OPANA®
(O-pan-a)
(oxymorphone hydrochloride) Extended-release Tablets, for Oral use
OPANA is:
Important information about OPANA:
Do not take OPANA if you have:
Before taking OPANA, tell your healthcare provider if you have a history of:
Tell your healthcare provider if you are:
When taking OPANA:
While taking OPANA DO NOT:
The possible side effects of OPANA:
Get emergency medical help if you have:
These are not all the possible side effects of OPANA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov
