Oxymorphone global

Overdose

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.

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxymorphone overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on Oxymorphone Global. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Because the duration of reversal would be expected to be less than the duration of action of oxymorphone in Oxymorphone Global, carefully monitor the patient until spontaneous respiration is reliably re-established. Oxymorphone Global will continue to release oxymorphone adding to the oxymorphone load for up to 24 hours after administration, necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product's prescribing information.

In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced 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 begun with care and by titration with smaller than usual doses of the antagonist.

Contraindications

Oxymorphone Global 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 Oxymorphone Global, or to morphine analogs such as codeine.

Undesirable effects

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

• Addiction, Abuse, and Misuse
• Life Threatening Respiratory Depression
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Other CNS Depressants
• Hypotensive Effect
• Gastrointestinal Effects
• Seizures

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 of patients with moderate 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.

Tables 1 and 2 list the most frequently occurring adverse reactions (in at least 5% of patients) from the placebo-controlled trials in patients with low back pain.

Table 1:Treatment-Emergent Adverse Reactions Reported in ≥ 5% of Patients During the Open-Label Titration Period and Double-Blind Treatment Period by Preferred Term —Number (%) of Treated Patients (12-Week Study In Opioid-Naïve Patients with Low Back Pain)

Table 2: Treatment-Emergent Adverse Reactions Reported in ≥ 5% of Patients During the Open-Label Titration Period and Double-Blind Treatment Period by Preferred Term —Number (%) of Treated Patients (12-Week Study In Opioid-Experienced Patients with Low Back Pain)

The following table lists adverse reactions that were reported in at least 2% of patients in placebo-controlled trials (N=5).

Table 3: Adverse Reactions Reported in Placebo-Controlled Clinical Trials with Incidence ≥ 2% in Patients Receiving Oxymorphone Hydrochloride Extended-Release Tablets

The common ( ≥ 1% to < 10%) adverse drug reactions reported at least once by patients treated with oxymorphone hydrochloride extended-release tablets in the clinical trials organized by MedDRA's (Medical Dictionary for Regulatory Activities) System Organ Class and not represented in Table 1 were:

Eye disorders: vision blurred

Gastrointestinal disorders: diarrhea, abdominal pain, dyspepsia

General disorders and administration site conditions: dry mouth, appetite decreased, fatigue, lethargy, weakness, pyrexia, dehydration, weight decreased, edema

Nervous system disorders: insomnia

Psychiatric disorders: anxiety, confusion, disorientation, restlessness, nervousness, depression

Respiratory, thoracic and mediastinal disorders: dyspnea

Vascular disorders: flushing and hypertension

Other less common adverse reactions known with opioid treatment that were seen < 1% in the oxymorphone hydrochloride extended-release tablets trials include the following: Bradycardia, palpitation, syncope, tachycardia, postural hypotension, miosis, abdominal distention, ileus, hot flashes, allergic reactions, hypersensitivity, urticaria, oxygen saturation decreased, central nervous system depression, depressed level of consciousness, agitation, dysphoria, euphoric mood, hallucination, mental status changes, difficult micturition, urinary retention, hypoxia, respiratory depression, respiratory distress, clamminess, dermatitis, hypotension.

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

Therapeutic indications

Oxymorphone Global is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Oxymorphone Global for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Oxymorphone Global is not indicated as an as-needed (prn) analgesic.

Pharmacodynamic properties

The minimum effective plasma concentration of oxymorphone for analgesia varies widely among patients, especially among patients who have been previously treated with agonist opioids. As a result, individually titrate patients to achieve a balance between therapeutic and adverse effects. The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, progression of disease, development of a new pain syndrome and/or potential development of analgesic tolerance.

There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression.

Additive pharmacodynamic effects may be expected when Oxymorphone Global is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

The principal therapeutic action of oxymorphone is analgesia. Oxymorphone causes respiratory depression, in part by a direct effect on the brainstem 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 depresses the cough reflex by direct effect on the cough center in the medulla.

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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Other therapeutic effects of oxymorphone include anxiolysis, euphoria, and feeling of relaxation, drowsiness and changes in mood.

Gastric, biliary and pancreatic secretions are decreased by oxymorphone. Oxymorphone causes a reduction in motility and is associated with an increase in 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 is increased to the point of spasm. The end result is constipation. Oxymorphone can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi, and transient elevations in serum amylase. Oxymorphone may also cause spasm of the sphincter of the urinary bladder.

Oxymorphone produces peripheral vasodilation which may result in orthostatic hypotension. Release of histamine can occur and may contribute to opioid-induced hypotension. Manifestations of histamine release may include orthostatic hypotension, pruritus, flushing, red eyes, and sweating.

Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

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.

Pharmacokinetic properties

The absolute oral bioavailability of oxymorphone is approximately 10%.

Steady-state levels are achieved after three days of multiple dose administration. Under both single-dose and steady-state conditions, dose proportionality has been established for the 5 mg, 10 mg, 20 mg, and 40 mg doses of oxymorphone hydrochloride extended-release tablets, for both peak plasma levels (Cmax) and extent of absorption (AUC) (see Table 4).

Table 4: Mean (±SD) Oxymorphone Hydrochloride Extended-Release Tablets Pharmacokinetic Parameters

Two studies examined the effect of food on the bioavailability of single doses of 20 and 40 mg of oxymorphone hydrochloride extended-release tablets in healthy volunteers. In both studies, after the administration of oxymorphone hydrochloride extended-release tablets, the Cmax was increased by approximately 50% in fed subjects compared to fasted subjects. A similar increase in Cmax was also observed with oxymorphone solution.

The AUC was unchanged in one study and increased by approximately 18% in the other study in fed subjects following the administration of oxymorphone hydrochloride extended-release tablets. Examination of the AUC suggests that most of the difference between fed and fasting conditions occurs in the first four hours after dose administration. After oral dosing with a single dose of 40 mg, a peak oxymorphone plasma level of 2.8 ng/ml is achieved at 1hour in fasted subjects and a peak of 4.25 ng/ml is achieved at 2 hours in fed subjects and that beyond the 12 hour time point, there is very little difference in the curves. As a result, Oxymorphone Global should be dosed at least one hour prior to or two hours after eating.

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%.

Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive metabolites. The two major metabolites of oxymorphone are oxymorphone-3-glucuronide and 6-OHoxymorphone. 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.

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 less than 1% excreted as 6-OHoxymorphone 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Oxymorphone Global contains oxymorphone, a Schedule II controlled substance. As an opioid, Oxymorphone Global exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as Oxymorphone Global 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 Oxymorphone Global 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 Oxymorphone Global, and monitor all patients receiving Oxymorphone Global 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 Oxymorphone Global for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Oxymorphone Global, but use in such patients necessitates intensive counseling about the risks and proper use of Oxymorphone Global along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Oxymorphone Global 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 Oxymorphone Global are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Oxymorphone Global. 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.

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 of Oxymorphone Global, 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 Oxymorphone Global are essential. Overestimating the Oxymorphone Global dose when converting patients from another opioid product can result in fatal overdose with the first dose.

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

Prolonged use of Oxymorphone Global 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.

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Oxymorphone Global therapy. The co-ingestion of alcohol with Oxymorphone Global may result in increased plasma levels and a potentially fatal overdose of oxymorphone.

Hypotension, profound sedation, coma, respiratory depression, and death may result if Oxymorphone Global 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 Oxymorphone Global 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. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin Oxymorphone Global is made, start with Oxymorphone Global 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.

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 Oxymorphone Global is given concomitantly with other drugs that depress respiration.

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 Oxymorphone Global, as in these patients, even usual therapeutic doses of Oxymorphone Global may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

A study of Oxymorphone Global in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function. Oxymorphone Global 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.

Oxymorphone Global 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 Oxymorphone Global. In patients with circulatory shock, Oxymorphone Global may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Oxymorphone Global in patients with circulatory shock.

Monitor patients taking Oxymorphone Global 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 Oxymorphone Global. Oxymorphone Global 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 Oxymorphone Global in patients with impaired consciousness or coma.

There have been post-marketing reports of difficulty in swallowing Oxymorphone Global tablets. These reports included choking, gagging, regurgitation and tablets stuck in the throat. Instruct patients not to pre-soak, lick or otherwise wet Oxymorphone Global 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.

Oxymorphone Global is contraindicated in patients with paralytic ileus. Avoid the use of Oxymorphone Global in patients with other GI obstruction.

The oxymorphone in Oxymorphone Global 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.

The oxymorphone in Oxymorphone Global 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 Oxymorphone Global therapy.

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 Oxymorphone Global. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing Oxymorphone Global, gradually taper the dose. Do not abruptly discontinue Oxymorphone Global.

Oxymorphone Global 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 Oxymorphone Global and know how they will react to the medication.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients that the use of Oxymorphone Global, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death. Instruct patients not to share Oxymorphone Global with others and to take steps to protect Oxymorphone Global from theft or misuse.

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oxymorphone Global or when the dose is increased, and that it can occur even at recommended doses. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death. Instruct patients to take steps to store Oxymorphone Global securely and to dispose of unused Oxymorphone Global by flushing the tablets down the toilet.

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

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with Oxymorphone Global. The co-ingestion of alcohol with Oxymorphone Global may result in increased plasma levels and a potentially fatal overdose of oxymorphone.

Inform patients that potentially serious additive effects may occur if Oxymorphone Global is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider.

Instruct patients how to properly take Oxymorphone Global, including the following:

• Swallowing Oxymorphone Global tablets whole
• Not crushing, chewing, or dissolving the tablets
• Occasionally, the inactive ingredients of Oxymorphone Global may be eliminated as a soft mass in the stool that may resemble the original tablet. Patients should be informed that the active medication has already been absorbed by the time the patient sees the soft mass.
• Using Oxymorphone Global exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
• Not discontinuing Oxymorphone Global without first discussing the need for a tapering regimen with the prescriber
• Do not pre-soak, lick or otherwise wet the tablet prior to placing in the mouth.
• To take each tablet with enough water to ensure complete swallowing immediately after placing in mouth.

Inform patients that Oxymorphone Global may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Inform patients that Oxymorphone Global may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Inform patients that anaphylaxis has been reported with ingredients contained in Oxymorphone Global. Advise patients how to recognize such a reaction and when to seek medical attention.

Advise female patients that Oxymorphone Global can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Advise patients to flush the unused tablets down the toilet when Oxymorphone Global is no longer needed.

Long-term studies have been completed to evaluate the carcinogenic potential of oxymorphone in both Sprague-Dawley rats and CD-1 mice. Oxymorphone HCl 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 in male rats was 0.34-fold and at the 25 mg/kg/day dose in female rats was 1.5-fold 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 μg/plate, or in an in vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes at concentrations ≤ 5000 μg/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 ≥ 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 hydrochloride did not affect reproductive function or sperm parameters in male rats at any dose tested ( ≤ 50 mg/kg/day). The highest dose tested is ≤ 6-fold the human dose of 40 mg every 12 hours, based on body surface area. 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 1.2-fold the human dose of 40 mg every 12 hours based on a body surface area. The dose of oxymorphone that produced no adverse effects on reproductive findings in female rats is 0.6-fold the human dose of 40 mg every 12 hours on a body surface area basis.

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.

There are no adequate and well-controlled studies in pregnant women. Oxymorphone Global should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oxymorphone hydrochloride administration did not cause malformations at any doses evaluated during developmental toxicity studies in rats ( ≤ 25 mg/kg/day) or rabbits ( ≤ 50 mg/kg/day). These doses are ≤ 3-fold and ≤ 12-fold the human dose of 40 mg every 12 hours, based on body surface area. There were no developmental effects in rats treated with 5 mg/kg/day or rabbits treated with 25 mg/kg/day. Fetal weights were reduced in rats and rabbits given doses of ≥ 10 mg/kg/day and 50 mg/kg/day, respectively. These doses are ≤ 1.2-fold and ≤ 12-fold the human dose of 40 mg every 12 hours based on body surface area, respectively. There were no effects of oxymorphone hydrochloride on intrauterine survival in rats at doses ≤ 25 mg/kg/day, or rabbits at ≤ 50 mg/kg/day in these studies (see Non-teratogenic Effects, below). In a study that was 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 was reported to produce malformations in offspring of hamsters that received 15.5-fold the human dose of 40 mg every 12 hours based on body surface area. This dose also produced 20% 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 increased incidence of stillborn pups. An increase in neonatal death occurred at ≥ 5 mg/kg/day. Post-natal survival of the pups was reduced throughout weaning following treatment of the dams with 25 mg/kg/day. Low pup birth weight and decreased postnatal weight gain occurred in pups born to oxymorphone-treated pregnant rats given a dose of 25 mg/kg/day. This dose is ≤ 3-fold higher than the human dose of 40 mg every 12 hours on a body surface area basis.

Opioids cross the placenta and may produce respiratory depression in neonates. Oxymorphone Global 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 Oxymorphone Global is administered to a nursing woman. Monitor infants who may be exposed to Oxymorphone Global 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 Oxymorphone Global 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 Oxymorphone Global 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 Oxymorphone Global. 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 Oxymorphone Global using the 5 mg dose and monitor closely for respiratory and central nervous system depression. Oxymorphone Global is contraindicated for patients with moderate and severe hepatic impairment. 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.

Patients with moderate to severe renal impairment were shown to have an increase in oxymorphone bioavailability ranging from 5765%. Start opioid-naïve patients with the 5 mg dose of Oxymorphone Global 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.

Dosage (Posology) and method of 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.

Oxymorphone Global should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with Oxymorphone Global.

Oxymorphone Global tablets must be taken whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth. Crushing, chewing, or dissolving Oxymorphone Global tablets will result in uncontrolled delivery of oxymorphone and can lead to overdose or death.

Oxymorphone Global 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.

Initiate treatment with Oxymorphone Global with the 5 mg tablet orally every 12-hours.

The starting dose for patients who are not opioid tolerant is Oxymorphone Global 5 mg orally every 12 hours. 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.

Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression.

Patients receiving OPANA may be converted to Oxymorphone Global by administering half the patient's total daily oral OPANA dose as Oxymorphone Global, every 12 hours.

The absolute oral bioavailability of Oxymorphone Global is approximately 10%. Convert patients receiving parenteral oxymorphone to OPANA ER by administering 10 times the patient's total daily parenteral oxymorphone dose as Oxymorphone Global in two equally divided doses (e.g., [IV dose x 10] divided by 2). Due to patient variability with regards to opioid analgesic response, upon conversion monitor patients closely to evaluate for adequate analgesia and side effects.

Discontinue all other around-the-clock opioid drugs when Oxymorphone Global therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter-patient variability in the relative potency of different opioid drugs and products. As such, it is preferable to underestimate a patient's 24-hour oral oxymorphone requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxymorphone requirements which could result in adverse reactions. In an Oxymorphone Global clinical trial with an open-label titration period, patients were converted from their prior opioid to Oxymorphone Global using Table 1 as a guide for the initial Oxymorphone Global dose.

Consider the following when using the information in Table 1:

• This is not a table of equianalgesic doses.
• The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to Oxymorphone Global.
• This table cannot be used to convert from Oxymorphone Global to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.

CONVERSION FACTORS TO Oxymorphone Global

To calculate the estimated Oxymorphone Global dose using Table 1:

• For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral (active opioid) daily dose.
• For patients on a regimen of more than one opioid, calculate the approximate oral (active opioid) dose for each opioid and sum the totals to obtain the approximate total (active opioid) daily dose.
• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion

Always round the dose down, if necessary, to the appropriate Oxymorphone Global strength(s) available.

Example conversion from a single opioid to Oxymorphone Global:

Step 1: Sum the total daily dose of the opioid oxycodone 20 mg BID 20 mg former opioid 2 times daily = 40 mg total daily dose of former opioid

Step 2: Calculate the approximate equivalent dose of oral (active opioid) based on the total daily dose of the current opioid using Table 1 40 mg total daily dose of former opioid x 0.5 mg Conversion Factor = 20 mg of oral (active opioid) daily

Step 3: Calculate the approximate starting dose of OPANA ER to be given every 12 hours. Round down, if necessary, to the appropriate Oxymorphone Global TABLETS strengths available. 10 mg Oxymorphone Global every 12 hours

Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Individually titrate Oxymorphone Global to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxymorphone Global 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. 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. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the Oxymorphone Global dose to decrease the level of pain. Because steady-state plasma concentrations are approximated within 3 days, Oxymorphone Global dosage adjustments, preferably at increments of 5-10 mg every 12 hours, may be done every 3 to 7 days.

Patients who experience breakthrough pain may require a dose increase of Oxymorphone Global, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing Oxymorphone Global dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

When a patient no longer requires therapy with Oxymorphone Global, 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 Oxymorphone Global.

Instruct patients to swallow Oxymorphone Global 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. Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.

Oxymorphone Global is contraindicated in patients with moderate or severe hepatic impairment.

In opioid-naïve patients with mild hepatic impairment, initiate treatment with the 5 mg dose. For patients on prior opioid therapy, start Oxymorphone Global at 50% lower than the starting dose for a patient with normal hepatic function on prior opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression.

In patients with creatinine clearance rates less than 50 mL/min, start Oxymorphone Global in the opioid-naïve patient with the 5 mg dose. For patients on prior opioid therapy, start Oxymorphone Global at 50% lower than the starting dose for a patient with normal renal function on prior opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression.

The steady-state plasma concentrations of oxymorphone are approximately 40% higher in elderly subjects than in young subjects. Initiate dosing with Oxymorphone Global 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 Oxymorphone Global to adequate analgesia. For patients on prior opioid therapy, start Oxymorphone Global at 50% lower than the starting dose for a younger patient on prior opioids and titrate slowly.

Manufactured for: Endo Pharmaceuticals Inc., Malvern, PA 19355, www.endo.com or call 1-800-462-3636 OPANA® is a registered trademark of Endo Pharmaceuticals Inc. Revised: April 2014