Label: OPANA ER- oxymorphone hydrochloride tablet, film coated, extended release

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 and C yellow No. 6. The 20 mg tablets contain FD and C blue No. 1, FD and C yellow No. 6, and D and C yellow No. 10. The 40 mg tablets contain FD and C yellow No. 6, D and 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 pKa1 and pKa2 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.

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.

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

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 is contraindicated in patients with a known hypersensitivity to oxymorphone hydrochloride or to any of the other ingredients in OPANA ER, or with known hypersensitivity to morphine analogs such as codeine.

OPANA ER is not indicated for pain in the immediate post-operative period (the first 12-24 hours following surgery), or if the pain is mild, or not expected to persist for an extended period of time. OPANA ER is only indicated for post-operative use if the patient is already receiving the drug prior to surgery or if the post-operative pain is expected to be moderate or severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (See American Pain Society guidelines).

OPANA ER is contraindicated in any situation where opioids are contraindicated such as: patients with respiratory depression (in the absence of resuscitative equipment or in unmonitored settings), and in patients with acute or severe bronchial asthma or hypercarbia.

OPANA ER, like all opioids, is contraindicated in any patient who has or is suspected of having paralytic ileus.

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

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 could lead to the 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.

Misuse, Abuse and Diversion of Opioids

OPANA ER contains oxymorphone, an opioid agonist similar to morphine, and is 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 OPANA ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

OPANA ER tablets may be abused by crushing, chewing, snorting or injecting the product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and 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.

Interactions with Alcohol and Drugs of Abuse

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. 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 240mL 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 by 7% on average and as much as 110% for individual subjects.

Drug Abuse and Addiction

Controlled Substance

OPANA ER contains oxymorphone, an opioid with an abuse liability similar to morphine and other opioid agonists and is a Schedule II controlled substance. OPANA ER and other opioids used in analgesia, can be abused and are 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 multi-disciplinary 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 ER, 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 ER poses a risk of overdose and death. This risk is increased with concurrent abuse of OPANA ER with alcohol and other substances. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease 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: Usage in Pregnancy and PRECAUTIONS: Labor and Delivery).

Respiratory Depression

Respiratory depression is the chief hazard of OPANA ER. 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 ER 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.

Interactions with Other Central Nervous System Depressants

Patients receiving other opioid analgesics, general anesthetics, phenothiazines or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with oxymorphone may experience respiratory depression, hypotension, profound sedation, or coma (see PRECAUTIONS: Drug-Drug Interactions).

Head Injury and Increased Intracranial Pressure

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.

Hypotensive Effect

OPANA ER, 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 ER, 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.

Hepatic Impairment

A study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function (see CLINICAL PHARMACOLOGY). OPANA ER 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 ER is contraindicated for patients with moderate and severe hepatic impairment (see CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION).

General

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 ER 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 ER should be used with caution in the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's 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 oxymorphone may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Oxymorphone may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

OPANA ER is intended for use in patients who require more than several days continuous treatment with an opioid analgesic.

Ambulatory Surgery and Post-Operative Use

OPANA ER is not indicated for pre-emptive analgesia (administration pre-operatively for the management of post-operative pain).

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 is only indicated for postoperative use in the patient if the patient is already receiving the drug prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate (see American Pain Society guidelines).

Patients who are already receiving OPANA ER as part of ongoing analgesic therapy may be safely continued on the drug if appropriate dosage adjustments are made considering the procedure, other drugs given, and the temporary changes in physiology caused by the surgical intervention (see DOSAGE AND ADMINISTRATION).

OPANA ER, 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.

Use in Pancreatic/Biliary Tract Disease

OPANA ER, 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 and Tolerance

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 tolerance is not unusual during chronic opioid therapy.

If OPANA ER 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 ER should not be abruptly discontinued. However, OPANA ER, like other opioids, can be safely discontinued without the development of withdrawal symptoms by slowly tapering the daily dose (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

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.

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)

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% - less than 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

Psychiatricdisorders: 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 less than 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.

Signs and Symptoms

Acute overdosage with OPANA ER 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 ER 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).

Treatment

In the treatment of OPANA ER overdosage, primary attention should be given to the re-establishment 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 ER. 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 ER 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 ER, opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to OPANA ER overdose. They should be administered cautiously to persons who are known, or suspected to be, physically dependent on any opioid agonist including OPANA ER. 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 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 progressiveplan 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 PatientsConversion 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
                                        Approximate Equivalent Dose

a - Ratio for conversion of oral opioid dose to approximate oxymorphone equivalent does. Select opioid and multiply
     the dose by the conversion ratio to calculate the approximate oral oxymorphone equivalent.

• 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.
• Sum the total daily dose for the opioid and multiply by the conversion ratio to calculate the oxymorphone total daily dose.
• For patients on a regimen of mixed opioids, calculate the approximate oral oxymorphone dose for each opioid and sum the totals to estimate the total daily oxymorphone dose.
• The dose of OPANA ER can be gradually adjusted, preferably at increments if 10 mg every 12 hours every 3-7 days, until adequate pain relief and acceptable side effects have achieved (see individualization of Dose).
  

      

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

Rx Only

CAUTION
DEA Order Form Required.

OPANA® ER (Ō-pan-a)
(Oxymorphone Hydrochloride) Extended-Release Tablets
CII
Rx Only

OPANA ER Tablets, 5 mg
OPANA ER Tablets, 10 mg
OPANA ER Tablets, 20 mg
OPANA ER Tablets, 40 mg

Read the Patient Information that comes with OPANA ER before you start taking it and each time you get a new prescription. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. Share the important information in this leaflet with members of your household.

What Is the Most Important Information I Should Know About OPANA ER?

• OPANA ER can cause trouble breathing (hypoventilation), which can lead to death, if used differently than the way you were told to use it by your healthcare provider (see “What are the possible side effects of OPANA ER?”).
  
  
• Swallow OPANA ER tablets whole. Do not break, crush, dissolve, or chew OPANA ER tablets before swallowing. If a tablet is broken, crushed, dissolved, or chewed, the full 12 hour dose can be taken into your body all at once. This is very dangerous. You could die from an overdose of the medicine. Use OPANA ER exactly the way your healthcare provider prescribes. If you cannot swallow tablets whole, tell your healthcare provider. You may need a different medicine.

What is OPANA ER?

• OPANA ER is a prescription medicine that contains the opioid (narcotic pain medicine) oxymorphone. OPANA ER is used to treat adults with constant pain (around the clock) that is moderate to severe and is expected to last for an extended period of time. OPANA ER is not for occasional (“as needed”) use.
  
  
• OPANA ER can cause physical dependence. Do not stop taking OPANA ER all of a sudden if you have been taking it for more than a few days. You could become sick with uncomfortable withdrawal symptoms because your body has become use to the medicine. Talk to your healthcare provider about slowly stopping OPANA ER to avoid getting sick with withdrawal symptoms. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.
  
  
• OPANA ER is a controlled substance (CII) because it contains a narcotic painkiller that can be a target for people who abuse prescription medicines or street drugs. Keep your tablets in a safe place to protect them from being stolen. Never give your tablets to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others, even causing death, and is against the law.

Who Should Not Take OPANA ER?
Do not take OPANA ER if:

• You had surgery within the past day (24 hours) and you were not taking OPANA ER before your surgery.
  
  
• Your pain is mild or will go away in a few days.
  
  
• Your pain can be controlled by the occasional use of other pain medicines.
  
  
• You are having an asthma attack or have severe asthma, trouble breathing, or lung problems.
  
  
• You have liver problems.
  
  
• You are allergic to OPANA ER or anything in it. See the end of this leaflet for a complete list of ingredients in OPANA ER.

You have had severe allergic reactions to other narcotic pain medicines (such as morphine or codeine medicines). A severe allergic reaction includes a severe rash, hives, breathing problems, or dizziness.

OPANA ER is not for children under 18 years of age.

What Should I Tell My Healthcare Provider Before Starting OPANA ER?
Tell your healthcare provider about all of your medical problems, especially if you:

• have trouble breathing or lung problems
  
  
• have a head injury or brain problem
  
  
• have liver or kidney problems
  
  
• have adrenal gland problems, such as Addison’s disease
  
  
• have convulsions or seizures
  
  
• have thyroid problems
  
  
• have problems urinating or prostate problems
  
  
• have pancreas problems
  
  
• have a drinking problem or alcoholism
  
  
• have severe mental problems or hallucinations (see or hear things that are not really there)
  
  
• have past or present drug abuse or drug addiction problems
  
  
• are pregnant or plan to become pregnant. OPANA ER may harm your unborn baby.
  
  
• are breastfeeding. OPANA ER may pass through your milk and may harm your baby. You should not breastfeed while taking OPANA ER.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may cause serious problems when taken with OPANA ER, especially if they cause sleepiness (like sleeping pills, anxiety medicines, antihistamines, or tranquilizers).

Do not take any new medicines while using OPANA ER until you have talked to your healthcare provider or pharmacist and they have told you it is safe.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist.

How Should I Take OPANA ER?

• Follow your healthcare provider’s directions exactly. Your healthcare provider may change your dose based on your reactions to the medicine. Do not change your dose unless your healthcare provider tells you to change it. Do not take OPANA ER more often than prescribed.
  
  
• Swallow OPANA ER tablets whole. Do not break, crush, dissolve, or chew OPANA ER tablets before swallowing. If a tablet is broken, crushed, dissolved, or chewed, the full 12 hour dose can be taken into your body all at once. This is very dangerous. You could die from an overdose of the medicine. If you cannot swallow tablets whole, tell your healthcare provider. You may need a different medicine.
  
  
• Take OPANA ER every 12 hours or as instructed by your healthcare provider. OPANA ER should be taken on an empty stomach, at least one hour before or two hours after meals. Talk to your healthcare provider if you feel sick taking OPANA ER on an empty stomach.
  
  
• If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once unless your healthcare provider tells you to. If you are not sure about your dosing call your healthcare provider.
  
  
• If you take too much OPANA ER or overdose, call your local emergency number or poison control center right away.
  
  
• Talk to your healthcare provider often about your pain. Your healthcare provider can decide if you still need OPANA ER.
  
  
• If you have side effects that bother you or if you continue to have pain, call your healthcare provider.
  
  
• Stopping OPANA ER. If your healthcare provider decides you no longer need OPANA ER, ask how to slowly reduce the dose of your medicine so you don’t get uncomfortable (withdrawal) symptoms such as nausea, sweating, and pain. You should not stop taking OPANA ER all at once if you have been taking it for more than a few days without talking to your healthcare provider. OPANA ER can cause physical dependence. You can get sick with withdrawal symptoms if you stop OPANA ER all at once, because your body has become use to it.

After you stop taking OPANA ER, flush the unused tablets down the toilet. Safely dispose of OPANA ER out of the reach of children and pets.

What Should I Avoid While Taking OPANA ER?

• Do not drive, operate heavy machinery, or participate in any other possibly dangerous activities until you know how you react to this medicine. OPANA ER can make you sleepy. Ask your healthcare provider to tell you when it is okay to do these activities.
  
  
• Do not drink alcohol while using OPANA ER. It may increase the chance of having dangerous side effects including overdose and death.

What are the Possible Side Effects of OPANA ER?
OPANA ER can cause trouble breathing.
Call your healthcare provider or get medical help right away if:

• your breathing slows down
  
  
• you have shallow breathing (little chest movement with breathing)
  
  
• you feel faint, dizzy, confused, or have any other unusual symptoms

These can be signs that you have taken too much OPANA ER (overdose) or the dose is too high for you, which can be dangerous and lead to death if not treated.

OPANA ER can cause your blood pressure to drop. This can make you feel dizzy if you get up too fast from sitting or lying down. Low blood pressure is also more likely to happen if you are taking other medicines that can also lower your blood pressure.

OPANA ER can cause physical dependence. Your body will get used to OPANA ER if you take it more than a few days. You can get sick with withdrawal symptoms if you stop taking OPANA ER all at once. You can avoid getting sick with withdrawal symptoms by stopping OPANA ER slowly. Your healthcare provider will tell you how to do this.

There is a chance of abuse or addiction with OPANA ER. Abuse or addiction is different than a physical dependence. If you have abused prescription medicines, street drugs or alcohol in the past, you may have a higher chance of developing abuse or addiction again while using OPANA ER. If you have more concerns, talk to your healthcare provider for more information about abuse and addiction.

The most common side effects of OPANA ER are nausea, constipation, dizziness, vomiting, itching, sleepiness, headache, increased sweating, and sedation. Some of these side effects may decrease with continued use. Talk to your healthcare provider if you continue to have these side effects.

These are not all the possible side effects of OPANA ER. For a complete list, ask your healthcare provider or pharmacist.

Constipation (decrease in the usual number of hard bowel movements) is a common side effect of opioid medicines, including OPANA ER. Talk to your healthcare provider or pharmacist about the use of laxatives (medicines to treat constipation) and stool softeners to prevent or treat constipation while taking OPANA ER.

How should I store OPANA ER?

• Store OPANA ER at room temperature between 59° to 86°F (15° to 30°C).
  
  
• Keep OPANA ER in a childproof container and store in a safe place to protect it from being stolen.
  
  
• Keep OPANA ER out of the reach of children. Accidental overdose in children is an emergency and can result in death.

General Information about OPANA ER

• Do not use OPANA ER for conditions for which it was not prescribed.
  
  
• Do not give OPANA ER to other people, even if they have the same symptoms you have. It may harm them, even causing death, and it is against the law.

This leaflet summarizes the most important information about OPANA ER. If you would like more information, talk with your healthcare provider. Also, you can ask your pharmacist or healthcare provider for information about OPANA ER that is written for healthcare professionals.

For additional information, please go to www.Endo.com or www.opana.com

What are the ingredients in OPANA ER?
Active Ingredient: oxymorphone hydrochloride
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 and C yellow No. 6. The 20 mg tablets contain FD and C blue No. 1, FD and C yellow No. 6, and D and C yellow No. 10. The 40 mg tablets contain FD and C yellow No. 6, D and C yellow No.10, and lactose monohydrate.

CAUTION: Federal law prohibits dispensing without prescription.

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.

                                                                 Copyright © Endo Pharmaceuticals Inc. 2006

                                                                                                                               413442/June, 2006

OPANA ER   C-II   5 MG  TABLETS

OPANA ER   C-II   10 MG   TABLETS

OPANA ER   C-II   40 MG   TABLETS