OPANA ER (oxymorphone hydrochloride) extended-release, is a semi-synthetic opioid analgesic supplied in 5 mg, 10 mg, 20 mg, and 40 mg tablet strengths for oral administration. The tablet strength describes the amount of oxymorphone hydrochloride per tablet. The tablets contain the following inactive ingredients: hypromellose, iron oxide black, methylparaben, propylene glycol, silicified microcrystalline cellulose, sodium stearyl fumarate, TIMERx® -N, titanium dioxide, and triacetin. The 5 mg, 10 mg and 20 mg tablets also contain macrogol, and polysorbate 80. In addition, the 5 mg tablets contain iron oxide red. The 10 mg tablets contain FD&C yellow No. 6. The 20 mg tablets contain FD&C blue No. 1, FD&C yellow No. 6, and D&C yellow No. 10. The 40 mg tablets contain FD&C yellow No. 6, D&C yellow No. 10, and lactose monohydrate.

Chemically, oxymorphone hydrochloride is 4, 5α -epoxy-3, 14-dihydroxy-17-methylmorphinan-6-one hydrochloride, a white or slightly off-white, odorless powder, which is sparingly soluble in alcohol and ether, but freely soluble in water. The molecular weight of oxymorphone hydrochloride is 337.80. The pK_a1 and pK_a2 of oxymorphone at 37°C are 8.17 and 9.54, respectively. The octanol/aqueous partition coefficient at 37°C and pH 7.4 is 0.98.

The structural formula for oxymorphone hydrochloride is as follows:

The tablet strengths, 5, 10, 20 and 40 mg, describe the amount of oxymorphone hydrochloride per tablet.

OPANA ER is indicated for the relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time.

OPANA ER is not intended for use as a prn analgesic.

OPANA ER is not indicated for pain in the immediate post-operative period (12-24 hours following surgery) for patients not previously taking opioids because of the risk of oversedation and respiratory depression requiring reversal with opioid antagonists.

OPANA ER is not indicated for pain in the post-operative period if the pain is mild or not expected to persist for an extended period of time.

OPANA ER TABLETS are to be swallowed whole and are not to be broken, chewed, dissolved, or crushed. Taking broken, chewed, dissolved, or crushed OPANA ER TABLETS leads to rapid release and absorption of a potentially fatal dose of oxymorphone.

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

OPANA ER is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine and other opioids.

OPANA ER, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.

OPANA ER tablets are to be swallowed whole, and are not to be broken, chewed, crushed or dissolved. Taking broken, chewed, crushed or dissolved OPANA ER tablets leads to the rapid release and absorption of a potentially fatal dose of oxymorphone.

While symmetric (same dose AM and PM), around-the-clock, every 12 hours dosing is appropriate for the majority of patients, some patients may benefit from asymmetric (different dose given in AM than in PM) dosing, tailored to their pain pattern. It is usually appropriate to treat a patient with only one extended-release opioid for around-the-clock therapy.

Selection of patients for treatment with OPANA ER should be governed by the same principles that apply to the use of other extended-release opioid analgesics (see INDICATIONS AND USAGE). As with any opioid drug product, it is necessary to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. Physicians should individualize treatment in every case (see DOSAGE AND ADMINISTRATION), using non-opioid analgesics, prn opioids and/or combination products, and chronic opioid therapy in a progressive plan of pain management such as outlined by the World Health Organization, the American Pain Society and the Federation of State Medical Boards Model Guidelines. Healthcare professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring (see BOXED WARNING).

In the selection of the initial dose of OPANA ER, attention should be given to the following:

1. The total daily dose, potency and specific characteristics of the opioid the patient has been taking previously;
2. The relative potency estimate used to calculate the equivalent oxymorphone dose needed;
3. The patient's degree of opioid tolerance;
4. The age, general condition, and medical status of the patient;
5. Concurrent non-opioid analgesic and other medications;
6. The type and severity of the patient's pain;
7. The balance between pain control and adverse experiences;
8. Risk factors for abuse, addiction or diversion, including a prior history of abuse, addiction or diversion.

The following dosing recommendations, therefore, can only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient.

OPANA ER should be administered on an empty stomach, at least one hour prior to or two hours after eating.

Initiation of Therapy

Opioid-Naïve Patients

It is suggested that patients who are not opioid-experienced being initiated on chronic around-the-clock opioid therapy be started with OPANA ER 5 mg every 12 hours. Thereafter, it is recommended that the dose be individually titrated, preferably at increments of 5-10 mg every 12 hours every 3-7 days, to a level that provides adequate analgesia and minimizes side effects under the close supervision of the prescribing physician (see CLINICAL TRIALS: 12-Week Study in Opioid-Naïve Patients with Low Back Pain).

Opioid-Experienced Patients

Conversion from OPANA to OPANA ER

Patients receiving OPANA may be converted to OPANA ER by administering half the patient's total daily oral OPANA dose as OPANA ER, every 12 hours. For example, a patient receiving 40 mg/day OPANA may require 20 mg OPANA ER every 12 hours.

Conversion from Parenteral Oxymorphone to OPANA ER

Given the absolute oral bioavailability of approximately 10%, patients receiving parenteral oxymorphone may be converted to OPANA ER by administering 10 times the patient's total daily parenteral oxymorphone dose as OPANA ER in two equally divided doses (e.g., IV dose x 10/2). For example, approximately 20 mg of OPANA ER, every 12 hours, may be required to provide pain relief equivalent to a total daily dose of 4 mg of parenteral oxymorphone. Due to patient variability with regards to opioid analgesic response, upon conversion patients should be closely monitored to ensure adequate analgesia and to minimize side effects.

Conversion from Other Oral Opioids to OPANA ER

For conversion from other opioids to OPANA ER, 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 the OPANA ER therapy by administering half of the calculated total daily dose of OPANA ER (see conversion ratio table below) in 2 divided doses, every 12 hours. The initial dose of OPANA ER can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved. The following table provides approximate equivalent doses, which may be used as a guideline for conversion. The conversion ratios and approximate equivalent doses in this conversion table are only to be used for the conversion from current opioid therapy to OPANA ER. In a Phase 3 clinical trial with an open-label titration period, patients were converted from their current opioid to OPANA ER using the following table as a guide. In general, patients were able to successfully titrate to a stabilized dose of OPANA ER within 4 weeks (see CLINICAL TRIALS: 12-Week Study in Opioid-Experienced Patients with Low Back Pain). There is substantial patient variation in the relative potency of different opioid drugs and formulations.

CONVERSION RATIOS TO OPANA ER

Individualization of Dose

Once therapy is initiated, pain relief and other opioid effects should be frequently assessed. In clinical practice, titration of the total daily OPANA ER dose should be based upon the amount of supplemental opioid utilization, severity of the patient's pain, and the patient's ability to tolerate the opioid. Patients should be titrated to generally mild or no pain with the regular use of no more than two doses of supplemental analgesia, i.e. “rescue,” per 24 hours.

If signs of excessive opioid-related adverse experiences are observed, the next dose may be reduced. If this adjustment leads to inadequate analgesia, a supplemental dose of OPANA, another immediate-release opioid, or a non-opioid analgesic may be administered. Dose adjustments should be made to obtain an appropriate balance between pain relief and opioid-related adverse experiences. If significant adverse events occur before the therapeutic goal of mild or no pain is achieved, the events should be treated aggressively. Once adverse events are under control, upward titration should continue to an acceptable level of pain control.

During periods of changing analgesic requirements, including initial titration, frequent contact is recommended between physician, other members of the healthcare team, the patient and the caregiver/family. Patients and caregivers/family members should be advised of the potential side effects.

Patients with Hepatic Impairment

Patients with mild hepatic impairment should be started with the lowest dose and titrated slowly while carefully monitoring side effects. OPANA ER is contraindicated in patients with moderate and severe hepatic dysfunction(see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS and PRECAUTIONS).

Patients with Renal Impairment

There are 57% and 65% increases in oxymorphone bioavailability in patients with moderate and severe renal impairment, respectively (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Accordingly, in patients with creatinine clearance rate less than 50 mL/min, OPANA ER should be started with the lowest dose and titrated slowly while carefully monitoring side effects.

Use with CNS Depressants

OPANA ER, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result. No specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate (see PRECAUTIONS: General and PRECAUTIONS: Drug-Drug Interactions).

Geriatrics

The steady-state plasma concentrations of oxymorphone are approximately 40% higher in elderly subjects than in young subjects (see CLINICAL PHARMACOLOGY and PRECAUTIONS). In general, caution should be exercised in the selection of the starting dose of OPANA ER for an elderly patient usually starting at the low end of the dosing range and slowly titrating to adequate analgesia.

Maintenance of Therapy and Supplemental Analgesia

The intent of the titration period is to establish a patient-specific every 12 hours dose that will maintain adequate analgesia with acceptable side effects for as long as pain relief is necessary. During titration and before a stable dose is achieved, OPANA or other immediate-release medications can be used as supplemental analgesia between dosings. Should pain recur, the dose can be incrementally increased to re-establish pain control. The method of therapy adjustment outlined above should be employed to re-establish pain control.

During chronic therapy with OPANA ER, the continued need for around-the-clock opioid therapy should be reassessed periodically.

Cessation of Therapy

When the patient no longer requires therapy with OPANA ER tablets, doses should be tapered gradually to prevent signs and symptoms of withdrawal in the physically dependent patient (see CLINICAL TRIALS: 12-Week Study in Opioid-Naïve Patients with Low Back Pain and CLINICAL TRIALS: 12-Week Study in Opioid-Experienced Patients with Low Back Pain).

SAFETY AND HANDLING

OPANA ER contains oxymorphone, which is a controlled substance. Oxymorphone is controlled under Schedule II of the Controlled Substances Act. Oxymorphone, like all opioids, is liable to diversion and misuse and should be handled accordingly. Patients and their families should be instructed to flush any OPANA ER tablets that are no longer needed.

OPANA ER 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.

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).

OPANA ER tablets are supplied as follows:

5 mg

Pink, octagon shape, film coated, convex tablets with“E907” over “5” in black print on one side and plain on the other.

Bottles of 100 with child-resistant closure                          NDC 63481-907-70
Unit-Dose package of 100 tablets (5 blister cards of 20 tablets, not child-resistant, for hospital use only)               NDC 63481-907-75

10 mg

Light orange, octagon shape, film coated, convex tablets with “E674” over “10” in black print on one side and plain on the other.

Bottles of 100 with child-resistant closure                          NDC 63481-674-70
Unit-Dose package of 100 tablets (5 blister cards of 20 tablets, not child-resistant, for hospital use only)               NDC 63481-674-75

20 mg

Light green, octagon shape, film coated, convex tablets with “E617” over “20” in black print on one side and plain on the other.

Bottles of 100 with child-resistant closure                          NDC 63481-617-70
Unit-Dose package of 100 tablets (5 blister cards of 20 tablets, not child-resistant, for hospital use only)               NDC 63481-617-75

40 mg

Yellow, octagon shape, film coated, convex tablets with “E693” over “40” in black print on one side and plain on the other.

Bottles of 100 with child-resistant closure                          NDC 63481-693-70
Unit-Dose package of 100 tablets (5 blister cards of 20 tablets, not child-resistant, for hospital use only)               NDC 63481-693-75

CAUTION

DEA Order Form Required.

Manufactured for: Endo Pharmaceuticals Inc. Chadds Ford, Pennsylvania 19317 Manufactured by: Novartis Consumer Health Inc. Lincoln, NE 68517
TIMERx®-N is a registered Trademark of Penwest Pharmaceuticals Co., Danbury, Connecticut and is used herein pursuant to a license agreement between Penwest and Endo Pharmaceuticals. 200218A/June, 2007
FDA rev date: 7/9/2007

Tables 2 and 3 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 2: Treatment-Emergent Adverse Events 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 3. Treatment-Emergent Adverse Events 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)

Adverse Reactions Reported in Placebo-Controlled Trials

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

Table 4: Adverse Reactions Reported in Placebo-Controlled Clinical Trials with Incidence ≥ 2% in Patients Receiving OPANA ER.

Adverse Reactions Reported in All Clinical Trials

A total of 2011 patients were treated with OPANA ER in the Phase 2/3 controlled and open-label clinical trials. The clinical trials consisted of patients with moderate to severe chronic pain and post surgical pain.

The adverse reactions are presented in the following manner: most common, common, and less common adverse reactions.

The most common adverse drug reactions (≥ 10%) reported at least once by patients treated with OPANA ER in the clinical trials were nausea, constipation, dizziness (exc. vertigo), vomiting, pruritus, somnolence, headache, sweating increased, and sedation.

The common (≥ 1% - < 10%) adverse drug reactions reported at least once by patients treated with OPANA ER in the clinical trials organized by MedDRA's (Medical Dictionary for Regulatory Activities) System Organ Class 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 OPANA ER trials include the following in alphabetical order.

Abdominal distention, agitation, allergic reactions, bradycardia, central nervous system depression, clamminess, depressed level of consciousness, dermatitis, difficult micturition, dysphoria, euphoric mood, feeling jittery, hallucination, hot flashes, hypersensitivity, hypotension, hypoxia, ileus, mental impairment, mental status changes, miosis, oxygen saturation decreased, palpitation, postural hypotension, respiratory depression, respiratory distress, respiratory rate decreased, syncope, tachycardia, urinary retention, urticaria, and visual disturbances.

Oxymorphone is highly metabolized principally in the liver and undergoes reduction or conjugation with glucuronic acid to form both active and inactive metabolites (see PHARMACOKINETICS: Metabolism).

Use with CNS Depressants

The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol may produce additive CNS depressant effects. OPANA ER, like all opioid analgesics, should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol because respiratory depression, hypotension, and profound sedation or coma may result, and titrated slowly as necessary for adequate pain relief.

Additive effects resulting in respiratory depression, hypotension, profound sedation or coma may result if these drugs are taken in combination with the usual doses of OPANA ER. No specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate.

When combined therapy with any of the above medications is contemplated, the dose of one or both agents should be reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).

Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, such as OPANA ER. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of OPANA ER and/or may precipitate withdrawal symptoms.

Other

Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

In addition, CNS side effects have been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established.

Respiratory depression is the chief hazard of OPANA. Respiratory depression is a particular potential problem 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.

OPANA should be administered 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. Alternative non-opioid analgesics should be considered, and oxymorphone should be employed only under careful medical supervision at the lowest effective dose in such patients.

OPANA contains oxymorphone, an opioid agonist with an abuse liability similar to morphine and a Schedule II controlled substance. Opioid agonists have the potential for being abused and 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 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 WARNINGS: Drug Abuse and Addiction).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Oxymorphone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation or coma may result.

OPANA contains oxymorphone, an opioid with an abuse liability similar to morphine and other opioids and is a Schedule II controlled substance. Oxymorphone, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion (see WARNINGS: Misuse, Abuse and Diversion of Opioids).

Drug addiction is characterized by a preoccupation with the procurement, hoarding, and abuse of drugs for non-medicinal purposes. Drug addiction is treatable, utilizing a multidisciplinary approach, but relapse is common.

"Drug seeking" behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating physician(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. Physicians 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 and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. OPANA, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Abuse of OPANA poses a risk of overdose and death. This risk is increased with concurrent abuse of OPANA with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see PRECAUTIONS: Pregnancy and PRECAUTIONS: Labor and Delivery).

Patients receiving other opioid analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with oxymorphone may exhibit an additive CNS depression (see PRECAUTIONS: Drug-Drug Interactions). Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dose of OPANA.

In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible 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 pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

OPANA, like all opioid analgesics, may cause severe hypotension in an individual 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 which compromise vasomotor tone. OPANA, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

A study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function (see CLINICAL PHARMACOLOGY). 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 DOSAGE AND ADMINISTRATION).

Opioid analgesics should be used with caution, especially when combined with other drugs, and should be reserved for cases where the benefits of opioid analgesia outweigh the known potential risks of respiratory depression, altered mental state and postural hypotension. OPANA should be used with caution in elderly and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease.

OPANA should be used with caution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addisons disease); CNS depression or coma; delirium tremens; kyphoscoliosis associated with respiratory depression; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; severe impairment of pulmonary or renal function; moderate impairment of hepatic function; and toxic psychosis.

The administration of all opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions. All opioids may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as oxymorphone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxymorphone and/or may precipitate withdrawal symptoms in these patients.

OPANA, like other opioids, decreases bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative patients receiving opioids. Standard supportive therapy should be implemented.

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.

Physical dependence is the occurrence of withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an opioid antagonist or mixed opioid agonist/antagonist agent. 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). The development of physical dependence and/or tolerance is not unusual during chronic opioid therapy.

If OPANA is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other 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.

In general, OPANA should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

OPANA is not approved for use in detoxification or maintenance treatment of opioid addiction. However, the history of an addictive disorder does not necessarily preclude the use of this medication for the treatment of chronic pain. These patients will require intensive monitoring for signs of misuse, abuse, or addiction.

Carcinogenesis: 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 dose 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 HCl 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.

Mutagenesis: Oxymorphone hydrochloride was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test) at concentrations of £ 5270 mg/plate, or in an in vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes at concentrations £ 5000 mg/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.

Impairment of fertility: Oxymorphone hydrochloride 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 (see PRECAUTIONS).

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 ~2 times and 8 times a total human daily dose of 120 mg, 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 ~0.8 and 4 times respectively a total human daily dose of 120 mg, based on body surface area. There were no effects of oxymorphone hydrochloride on intrauterine survival at doses £ 25 mg/kg/day in rats, or £ 50 mg/kg/day in rabbits (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 10 times a total human daily dose of 120 mg based on body surface area. This dose also produced 83% maternal lethality.

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

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. 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 female rats given a dose of 25 mg/kg/day. This dose is ~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 and psycho-physiologic effects 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. Ordinarily, nursing should not be undertaken while a patient is receiving oxymorphone because of the possibility of sedation and/or respiratory depression in the infant.

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. The plasma levels of oxymorphone are about 40% higher in elderly (≥65 years of age) than in younger subjects (see CLINICAL PHARMACOLOGY).

Of the total number of subjects in clinical studies of OPANA, 31 percent were 65 and over, while 7 percent 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.

A study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function (see CLINICAL PHARMACOLOGY). 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 DOSAGE AND ADMINISTRATION).

In a study of OPANA ER, patients with moderate to severe renal impairment were shown to have an increase in bioavailability ranging from 57-65% (see CLINICAL PHARMACOLOGY). These patients should be started cautiously with lower doses of OPANA and titrated slowly while carefully monitoring for side effects (see DOSAGE AND ADMINISTRATION).

In clinical trials with OPANA, the overall incidence rates for one or more adverse events were similar among females and male subjects receiving OPANA and placebo.

Acute overdosage with OPANA is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest, and death may occur.

OPANA may cause 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 (see CLINICAL PHARMACOLOGY: Central Nervous System).

In the treatment of OPANA overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Elimination or evacuation of gastric contents may be necessary in order to eliminate unabsorbed drug. Before attempting treatment by gastric emptying or activated charcoal, care should be taken to secure the airway.

The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression, which may result from overdosage or unusual sensitivity to opioids including OPANA. Therefore, an appropriate dose of naloxone hydrochloride should be administered (usual initial adult dose 0.4 mg-2 mg) preferably by the intravenous route and simultaneously with efforts at respiratory resuscitation. Nalmefene is an alternative pure opioid antagonist, which may be administered as a specific antidote to respiratory depression resulting from opioid overdose. Since the duration of action of OPANA may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered according to the antagonist labeling as needed to maintain adequate respiration.

In patients receiving OPANA, opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression. They should be administered cautiously to persons who are known, or suspected to be, physically dependent on any opioid agonist including OPANA. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If respiratory depression is associated with muscular rigidity, administration of a neuromuscular blocking agent may be necessary to facilitate assisted or controlled ventilation. Muscular rigidity may also respond to opioid antagonist therapy.

OPANA should not be administered to patients with a known hypersensitivity to oxymorphone hydrochloride or to any of the other ingredients in OPANA, or with known hypersensitivity to morphine analogs such as codeine.

OPANA is contraindicated in patients with respiratory depression except in monitored settings and in the presence of resuscitative equipment and in patients with acute or severe bronchial asthma or hypercarbia. OPANA is contraindicated in any patient who has or is suspected of having paralytic ileus.

OPANA is contraindicated in patients with moderate and severe hepatic impairment (see CLINICAL PHARMACOLOGY, PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Oxymorphone is an opioid agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, hydromorphone, fentanyl, codeine, hydrocodone, and tramadol. In addition to analgesia, other pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression. Like all pure opioid agonist analgesics, with increasing doses there is increasing analgesia, unlike with mixed agonist/antagonists or non-opioid analgesics, where there is a limit to the analgesic effect with increasing doses. With pure opioid agonist analgesics, there is no defined maximum dose; the ceiling to analgesic effectiveness is imposed only by side effects, the more serious of which may include somnolence and respiratory depression.

Central Nervous System

The precise mechanism of the analgesic action is unknown. However, specific CNS (central nervous system) opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. In addition, opioid receptors have also been identified within the PNS (peripheral nervous system). The role that these receptors play in these drugs' analgesic effects is unknown.

Opioids produce respiratory depression likely 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.

Opioids depress the cough reflex by direct effect on the cough center in the medulla oblongata. Antitussive effects may occur with doses lower than those usually required for analgesia. Opioids cause 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 (see OVERDOSAGE: Signs and Symptoms).

Gastrointestinal Tract and Other Smooth Muscle

Opioids cause 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 gastric, biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System

Opioids produce 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. Animal studies have shown that oxymorphone has a lower propensity to cause histamine release than other opioids.

Endocrine System

Opioids 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 in humans and other species, rats and dogs. Thyroid stimulating hormone (TSH) has been shown to be both inhibited and stimulated by opioids.

Immune System

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.

Pharmacodynamics

Concentration-Efficacy Relationships

Studies in healthy volunteers reveal predictable relationships between OPANA ER dosage and plasma oxymorphone concentrations.

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, patients need to be individually titrated 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.

Concentration-Adverse Experience Relationships

OPANA ER is associated with typical opioid-related adverse experiences. 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.

As with all opioids, the dose must be individualized (see DOSAGE AND ADMINISTRATION). The effective analgesic dose for some patients will be too high to be tolerated by other patients.

Pharmacokinetics

Absorption

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 tablet strengths for both peak plasma levels (Cmax) and extent of absorption (AUC) (Table 1).

Table 1: Mean (±SD) OPANA ER Pharmacokinetic Parameters

Food Effect

Two studies examined the effect of food on the bioavailability of single doses of 20 and 40 mg of OPANA ER in healthy volunteers. In both studies, after the administration of OPANA ER, 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 OPANA ER. 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 1 hour 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, OPANA ER should be dosed at least one hour prior to or two hours after eating (see DOSAGE AND ADMINISTRATION).

Ethanol Effect

In Vivo OPANA ER Formulation-Alcohol Interaction

Although in vitro studies have demonstrated that OPANA ER does not release oxymorphone more rapidly in 500 mL of 0.1N HCl solutions containing ethanol (4%, 20%, and 40%), there is an in vivo interaction with alcohol. An in vivo study examined the effect of alcohol (40%, 20%, 4% and 0%) on the bioavailability of a single dose of 40 mg of OPANA ER in healthy, fasted volunteers. The results showed that the oxymorphone mean AUC was 13% higher (not statistically significant) after co-administration of 240 mL of 40% alcohol. The AUC was essentially unaffected in subjects following the co-administration of OPANA ER and ethanol (240 mL of 20% or 4% ethanol).

There was a highly variable effect on Cmax with concomitant administration of alcohol and OPANA ER. The change in Cmax ranged from a decrease of 50% to an increase of 270% across all conditions studied. 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. Following the concomitant administration of 240 mL of 4 % ethanol, the Cmax increased 7% on average and by as much as 110% for individual subjects. After oral dosing with a single dose of 40 mg in fasted subjects, the mean peak oxymorphone plasma level is 2.4 ng/mL and the median Tmax is 2 hours. Following co-administration of OPANA ER and alcohol (240 mL of 40% ethanol) in fasted subjects, the mean peak oxymorphone level is 3.9 ng/mL and the median Tmax is 1.5 hours (range 0.75 — 6 hours).

Co-administration of oxymorphone and ethanol must be avoided.

Oxymorphone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression because respiratory depression, hypotension, and profound sedation, coma, or death may result.

Distribution

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%.

Metabolism

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-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-oymorphone 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% 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.

Special Populations

Elderly

The steady-state plasma concentrations of oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide are approximately 40% higher in elderly subjects (≥ 65 years of age) than in young subjects (18 to 40 years of age). 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. This observation does not appear related to a difference in body weight, metabolism, or excretion of oxymorphone (see PRECAUTIONS: Geriatric Use).

Gender

The effect of gender was evaluated following single- and multiple-doses of OPANA ER in male and female adult volunteers. There was a consistent tendency for female subjects to have slightly higher AUC_ss and Cmax values than male subjects; however, gender differences were not observed when AUC_ss and Cmax were adjusted by body weight.

Hepatic Impairment

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 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 (see DOSAGE AND ADMINISTRATION: Patients with Hepatic Impairment).

Renal Impairment

Data from a pharmacokinetic study involving 24 patients with renal dysfunction show an increase of 26%, 57%, and 65% in oxymorphone bioavailability 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.

Drug-Drug Interactions

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 CYP3A4 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.

Clinical Trials

The efficacy and safety of OPANA ER have been evaluated in double-blind, controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate to severe pain including low back pain.

12-Week Study in Opioid-Naïve Patients with Low Back Pain

Patients with chronic low back pain who were suboptimally responsive to their current non-opioid therapy entered a 4-week, open-label dose titration phase. Patients initiated therapy with two days of treatment with OPANA ER 5 mg, every 12 hours. Thereafter, patients were titrated to a stabilized dose, at increments of 5-10 mg every 12 hours every 3-7 days. Of the patients who were able to stabilize within the Open-Label Titration Period, the mean±SD VAS score at Screening was 69.4±11.8 mm and at Baseline (beginning of Double-Blind Period) were 18.5±11.2 mm and 19.3±11.3 mm for the oxymorphone ER and placebo groups, respectively. Sixty three percent of the patients enrolled were able to titrate to a tolerable dose and were randomized into a 12-week double-blind treatment phase with placebo or their stabilized dose of OPANA ER. The mean±SD stabilized doses were 39.2±26.4 mg and 40.9±25.3 mg for the OPANA ER and placebo groups, respectively; total daily doses ranged from 10-140 mg. During the first 4 days of double-blind treatment patients were allowed an unlimited number of OPANA, an immediate-release (IR) formulation of oxymorphone, 5 mg tablets, every 4-6 hours as supplemental analgesia; thereafter the number of OPANA was limited to two tablets per day. This served as a tapering method to minimize opioid withdrawal symptoms in placebo patients. Sixty-eight percent of patients treated with OPANA ER completed the 12-week treatment compared to forty seven percent of patients treated with placebo. OPANA ER provided superior analgesia compared to placebo. The analgesic effect of OPANA ER was maintained throughout the double-blind treatment period in 89% of patients who completed the study. These patients reported a decrease, no change, or a ≤ 10 mm increase in VAS score from Day 7 until the end of the study.

A significantly higher proportion of OPANA ER patients (81.4%) had at least a 30% reduction in pain score from screening to study endpoint compared to placebo patients (51.7%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 1.

Figure 1: Percent Reduction in Average Pain Intensity from Screening to Final Visit

12-Week Study in Opioid-Experienced Patients with Low Back Pain

Patients currently on chronic opioid therapy entered a 4-week, open-label titration phase with OPANA ER dosed every 12 hours at an approximated equianalgesic dose of their pre-study opioid medication. Of the patients who were able to stabilize within the Open-Label Titration Period, the mean±SD VAS score at Screening was 69.5±17.0 mm and at Baseline (beginning of Double-Blind Period) were 23.9±12.1 mm and 22.2±10.8 mm for the oxymorphone ER and placebo groups, respectively. Stabilized patients entered a 12-week double-blind treatment phase with placebo or their stabilized dose of OPANA ER. The mean±SD stabilized doses were 80.9±59.3 mg and 93.3±61.3 mg for the OPANA ER and placebo groups, respectively; total daily doses ranged from 20-260 mg. During the first 4 days of double-blind treatment, patients were allowed an unlimited number of OPANA 5 mg tablets, every 4-6 hours as supplemental analgesia; thereafter the number of OPANA was limited to two tablets per day. This served as a tapering method to minimize opioid withdrawal symptoms in placebo patients. Fifty seven percent of patients were titrated to a stabilized dose within approximately 4 weeks of OPANA ER dose titration. Seventy percent of patients treated with OPANA ER and 26% of patients treated with placebo completed the 12-week treatment. OPANA ER provided superior analgesia compared to placebo . The analgesic effect of OPANA ER was maintained throughout the double-blind treatment period in 80 % of patients who completed the study. These patients reported a decrease, no change, or a ≤ 10 mm increase in VAS score from Day 7 until the end of the study.

A significantly higher proportion of OPANA ER patients (79.7%) had at least a 30% reduction in pain score from screening to study endpoint compared to placebo patients (34.8%). Proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2.

Figure 2: Percent Reduction in Average Pain Intensity from Screening to Final Visit

1. Patients should be advised that OPANA contains oxymorphone, which is a morphine-like pain reliever, and should be taken only as directed.

2. Patients should be advised to report episodes of breakthrough pain and adverse experiences occurring during therapy to their doctor. Individualization of dosage is essential to make optimal use of this medication.

3. Patients should be advised not to adjust the dose of OPANA without consulting the prescribing professional.

4. Patients should be cautioned that OPANA may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car, operating machinery, etc.

5. OPANA will add to the effect of alcohol and other CNS depressants (such as antihistamines, sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and monoamine oxidase [MAO] inhibitors).

6. Patients should not combine OPANA with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.

7. Patients taking OPANA should be advised of the potential for severe constipation. Appropriate laxatives and/or stool softeners and other therapeutic approaches should be considered for use with the initiation of OPANA therapy.

8. Women of childbearing potential who become or are planning to become pregnant should be advised to consult their physician regarding the effects of opioid analgesics and other drug use during pregnancy on themselves and their unborn child.

9. Safe use in pregnancy has not been established. Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence, and neonatal withdrawal may occur.

10. Patients should be advised that if they have been receiving treatment with OPANA for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the OPANA dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.

11. Patients should be advised that OPANA is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

12. Patients should be instructed to keep OPANA in a secure place out of the reach of children and pets. Accidental consumption especially in children may result in overdose or death. When OPANA is no longer needed, the unused tablets should be destroyed by flushing down the toilet.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

OXYMORPHONE - ORAL

(ox-ee-MORE-fown)

COMMON BRAND NAME(S): Opana

USES: This medication is used to treat moderate-to-severe pain. It acts on certain centers in the brain to give you pain relief. This medication is a narcotic pain reliever (opiate-type).

HOW TO USE: Take this medication by mouth without food (1 hour before or 2 hours after eating), usually every 4 to 6 hours or as directed by your doctor. If you have nausea and take this drug with food, your body may absorb more of the drug and increase the risk of side effects. Consult your doctor or pharmacist about other ways to decrease nausea (e.g., antihistamines, lying down for 1-2 hours with as little head movement as possible).

The dosage is based on your medical condition and response to therapy. Pain medications work best if they are used as the first signs of pain occur. If you wait until the pain has worsened, the medication may not work as well.

You may also take long-acting narcotic medications or use narcotic patches for ongoing pain if so directed by your doctor. In that case, this medication might be used for sudden (breakthrough) pain only as needed. Also follow your doctor's or pharmacist's instructions for safely using non-narcotic pain relievers (e.g., naproxen, ibuprofen). Ask your doctor or pharmacist if you have any questions.

This medication may cause dependence, especially if it has been used regularly for an extended time or if it has been used in high doses. In such cases, withdrawal reactions (e.g., restlessness, irritability, tearing, runny nose, sweating, diarrhea) may occur if you suddenly stop this drug. To prevent withdrawal reactions when stopping extended, regular treatment with this drug, gradually reduce the dosage as directed. Consult your doctor or pharmacist for more details, and report any withdrawal reactions immediately.

Though very unlikely, abnormal drug-seeking behavior (addiction) is possible with this medication. To lessen the risk of becoming addicted, do not increase your dose, take it more frequently, or take it for a longer time than prescribed. Properly stop the medication when so directed.

When used for an extended period, this medication may not work as well and may require different dosing. Talk with your doctor if this medication stops working well.

Inform your doctor if your pain persists or worsens.

SIDE EFFECTS: Nausea, vomiting, fever, constipation, increased sweating, lightheadedness, dizziness, or drowsiness may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

To prevent constipation, maintain a diet adequate in fiber, drink plenty of water, and exercise. If you become constipated while using this drug, consult your pharmacist for help in selecting a laxative (e.g., stimulant-type with stool softener).

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: slow/shallow breathing, mental/mood changes, fainting, vision changes, slow/fast heartbeat, difficulty urinating.

Tell your doctor immediately if any of these rare but very serious side effects occur: severe stomach/abdominal pain, change in the amount of urine, seizures.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking oxymorphone, tell your doctor or pharmacist if you are allergic to it; or to other narcotic pain medications (e.g., codeine, morphine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe breathing problems (e.g., respiratory depression, hypercarbia, severe asthma), certain bowel diseases (e.g., paralytic ileus, infectious diarrhea), intoxication with medications that depress the nervous system or your breathing (CNS/respiratory depressants such as alcohol or tranquilizers/sedatives), moderate/severe liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: brain disorders (e.g., seizures, head injury, tumor, increased intracranial pressure), heart problems (e.g., irregular heartbeat), lung diseases (e.g., chronic obstructive pulmonary disease-COPD, mild asthma, hypoxia, hypercapnia), disease of the pancreas (e.g., pancreatitis), mental/mood disorders (e.g., toxic psychosis), a certain spinal problem (kyphoscoliosis), gallbladder disease, personal or family history of regular use/abuse of drugs/alcohol, kidney disease, mild liver disease, adrenal gland problem (e.g., Addison's disease), difficulty urinating (e.g., due to enlarged prostate or urethral stricture), severe obesity, underactive thyroid (hypothyroidism), intestinal diseases (e.g., colitis), recent bowel/abdominal surgery.

Before having surgery, tell your doctor or dentist that you are using this medication.

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or taking part in any other activity that requires alertness. Avoid alcoholic beverages because they may increase the risk of side effects.

To lower your risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Caution is advised when using this drug in the elderly because they may be more sensitive to its effects, especially slow/shallow breathing and drowsiness.

During pregnancy, this medication should be used only when clearly needed. Using it for long periods or in high doses near the expected delivery date is not recommended because of possible harm to the unborn baby. Discuss the risks and benefits with your doctor. Infants born to mothers who have used this medication for an extended time may have withdrawal symptoms such as irritability, abnormal/persistent crying, vomiting, or diarrhea. Tell your doctor immediately if you notice any of these symptoms in your newborn.

It is not known whether this drug passes into breast milk. Because of the potential risk to the infant, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your health care professionals may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: naltrexone.

If you are currently using this medication listed above, tell your doctor or pharmacist before starting oxymorphone.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anticholinergic medications (e.g., scopolamine), cimetidine, drugs that lower blood pressure (e.g., "water pills"/diuretics such as hydrochlorothiazide, furosemide), other medications for pain (e.g., pentazocine, nalbuphine), MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine).

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, phenothiazines (e.g., prochlorperazine, chlorpromazine), psychiatric medicines (e.g., risperidone, amitriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about using those products safely.

This medication may interfere with certain laboratory tests (including amylase and lipase levels), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center. Symptoms of overdose may include: slow breathing, slow heartbeat, loss of consciousness, very small pupils.

NOTES: Do not share this medication with others. It is against the law.

This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in that case.

MISSED DOSE: If you take this medication regularly and you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.