Enter section text here

Enter section text here

Enter section text here

Enter section text here

Enter section text here

Enter section text here

Enter section text here

Enter section text here

1 INDICATIONS AND USAGE

1 INDICATIONS AND USAGE

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.

Limitations of Usage
OPANA ER is not intended for use as an as needed analgesic.

OPANA ER is not indicated for pain in the immediate 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 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).

2 DOSAGE AND ADMINISTRATION 2.1 Safe Administration Instructions 2.2 Initiating Therapy with OPANA ER 2.3 Patients with Hepatic Impairment 2.4 Patients with Renal Impairment 2.5 Use with Central Nervous System Depressants 2.6 Geriatric Patients 2.7 Maintenance of Therapy 2.8 Cessation of Therapy

2 DOSAGE AND ADMINISTRATION

2.1 Safe Administration Instructions

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.

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 (1)]. Physicians should individualize treatment in every case, using non-opioid analgesics, opioids on an as needed basis, 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].

2.2 Initiating Therapy with OPANA ER It is necessary to adjust the dosing regimen for each patient individually, taking into account the patient’s prior analgesic treatment experience. In the selection of the initial dose of OPANA ER, attention should be given to the following:

- total daily dose, potency and specific characteristics of the opioid the patient has been taking previously;

- relative potency estimate used to calculate the equivalent oxymorphone dose needed;

- patient’s degree of opioid tolerance;

- age, general condition, and medical status of the patient;

- concurrent non-opioid analgesics and other medications;

- type and severity of the patient’s pain;

- balance between pain control and adverse experiences;

- risk factors for abuse or addiction, including a prior history of abuse or addiction.

Once therapy is initiated, frequently assess pain relief and other opioid effects. Base the titration of the total daily OPANA ER dose upon the amount of supplemental opioid utilization, severity of the patient’s pain, and the patient’s ability to tolerate the opioid. Titrate dose 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. Patients who experience breakthrough pain may require dosage adjustment.



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 an immediate-release opioid, or a non-opioid analgesic may be administered. Adjust dosing 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 adequately managed, continue upward titration 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. Advise patients and caregivers/family members of the potential adverse reactions.



The dosing recommendations below, 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.



Titrate dose to adequate pain relief (generally mild or no pain).



Administer OPANA ER on an empty stomach, at least one hour prior to or two hours after eating [see Clinical Pharmacology (12.3)].



Opioid-Naïve Patients

The initial dose for patients who are not opioid-experienced and who are being initiated on chronic around-the-clock opioid therapy with OPANA ER is 5 mg every 12 hours. Thereafter, titrate the dose individually 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.



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.



Conversion from Parenteral Oxymorphone to OPANA ER

Given OPANA ER’s 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] divided by 2). Due to patient variability with regards to opioid analgesic response, upon conversion monitor patients closely to evaluate for adequate analgesia and side effects.



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. Gradually adjust the initial dose of OPANA ER 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. There is substantial patient variation in the relative potency of different opioid drugs and formulations.

	CONVERSION RATIOS TO OPANA ER
	Approximate Equivalent Dose	Oral
Opioid	Oral	Conversion Ratioa
Oxymorphone	10 mg	1
Hydrocodone	20 mg	0.5
Oxycodone	20 mg	0.5
Methadone b	20 mg	0.5
Morphine	30 mg	0.333
aRatio for conversion of oral opioid dose to approximate oxymorphone equivalent dose. 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 of 10 mg every 12 hours every 3-7 days, until adequate pain relief and acceptable side effects have been achieved [see Dosage and Administration (2.1)]. b It is extremely important to monitor all patients closely when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and tends to accumulate in the plasma.

No dose adjustment for CYP 3A4- or 2C9-mediated drug-drug interactions is required [see Clinical Pharmacology (12.3)].



2.3 Patients with Hepatic Impairment

Start patients with mild hepatic impairment with the lowest dose and titrate slowly while carefully monitoring side effects. OPANA ER is contraindicated in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].



2.4 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 (12.3)]. Accordingly, in patients with creatinine clearance rates less than 50 mL/min, start OPANA ER with the lowest dose and titrate slowly while carefully monitoring side effects.



2.5 Use with Central Nervous System Depressants In patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, start OPANA ER at 1/3 to 1/2 of the usual dose because respiratory depression, hypotension, and profound sedation, coma or death may result [see Warnings and Precautions (5.4) and Drug Interactions (7.2)].



Although no specific interaction between oxymorphone and monoamine oxidase inhibitors has been observed, OPANA ER is not recommended for use in patients who have received MAO inhibitors within 14 days [see Drug Interactions (7.6)].



2.6 Geriatrics Patients

The steady-state plasma concentrations of oxymorphone are approximately 40% higher in elderly subjects than in young subjects. Exercise caution in the selection of the starting dose of OPANA ER for an elderly patient by starting at the low end of the dosing range and slowly titrating to adequate analgesia [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.5)].



2.7 Maintenance of Therapy

During chronic therapy with OPANA ER, periodically reassess the continued need for around-the-clock opioid therapy. Continue to assess patients for their clinical risks for opioid abuse, addiction, or diversion particularly with high-dose formulations. If patients need to titrate while on maintenance therapy, follow the same method outlined in Initiating Therapy with OPANA ER.



2.8 Cessation of Therapy

When the patient no longer requires therapy with OPANA ER tablets, gradually taper doses to prevent signs and symptoms of withdrawal in the physically dependent patient.

3 DOSAGE FORMS AND STRENGTHS

3 DOSAGE FORMS AND STRENGTHS

The 5 mg dosage form is a pink, octagon shape, film coated, convex extended-release tablets debossed with “5” on one side and plain on the other.

The 7.5 mg dosage form is a gray, octagon shape, film coated, convex extended-release tablets debossed with “7 ½” on one side and plain on the other.

The 10 mg dosage form is a light orange, octagon shape, film coated, convex extended-release tablets debossed with “10” on one side and plain on the other.

The 15 mg dosage form is a white, octagon shape, film coated, convex extended-release tablets debossed with “15” on one side and plain on the other.

The 20 mg dosage form is a light green, octagon shape, film coated, convex extended-release tablets debossed with “20” on one side and plain on the other.

The 30 mg dosage form is a red, octagon shape, film coated, convex extended-release tablets debossed with “30” on one side and plain on the other.

The 40 mg dosage form is a yellow, octagon shape, film coated, convex extended-release tablets debossed with “40” on one side and plain on the other.

4 CONTRAINDICATIONS

4 CONTRAINDICATIONS

OPANA ER is contraindicated in patients who have:

- significant respiratory depression
- or are suspected of having paralytic ileus
- acute or severe bronchial asthma or hypercarbia
- moderate and severe hepatic impairment [see Clinical Pharmacology (12.3), Warnings and Precautions (5.7),].
- known hypersensitivity to any of its components or the active ingredient, oxymorphone or with known hypersensitivity to morphine analogs such as codeine.

5 WARNINGS AND PRECAUTIONS 5.1 Information Essential for Safe Administration 5.2 Respiratory Depression 5.3 Misuse, Abuse and Diversion of Opioids 5.4 Interactions with Alcohol and other CNS Depressants 5.5 Use in Patients with Head Injury and Increased Intracranial Pressure 5.6 Hypotensive Effect 5.7 Hepatic Impairment 5.8 Special Risk Groups 5.9 Gastrointestinal Effects 5.10 Ambulatory Surgery and Post Operative Use 5.11 Use in Pancreatic/Biliary Tract Disease 5.12 Driving and Operating Machinery

5 WARNINGS AND PRECAUTIONS

5.1 Information Essential for Safe 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 [see Boxed Warning].

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 [see Pharmacokinetics (12.3)].

Instruct patients against use by individuals other than the patient for whom OPANA ER was prescribed, as such inappropriate use may have severe medical consequences, including death.

5.2 Respiratory Depression
Respiratory depression is the chief hazard of OPANA ER. Respiratory depression is a 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.

Administer OPANA ER with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS depression or coma. In these patients, even usual therapeutic doses of oxymorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Consider alternative non-opioid analgesics and use OPANA ER only under careful medical supervision at the lowest effective dose in such patients.

5.3 Misuse, Abuse and Diversion of Opioids
OPANA ER contains oxymorphone, a mu opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Oxymorphone can be abused in a manner similar to other opioid agonists, legal or illicit. This issue should be considered when prescribing or dispensing oxymorphone in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

OPANA 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 Drug Abuse and Dependence (9)].

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, and security requirements for storing and handling of OPANA ER.

Healthcare professionals should advise patients to store OPANA ER in a secure place, preferably locked and out of the reach of children and other non-caregivers.

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

5.4 Interactions with Alcohol and other CNS 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, coma and death [see Drug Interactions (7.2) ]. Avoid concurrent use of alcohol and OPANA ER [see Pharmacokinetics (12.3)].

5.5 Use in Patients with 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 papillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Administer OPANA ER with extreme caution to patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted.

5.6 Hypotensive Effect
OPANA ER may cause severe hypotension in a patient whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents that compromise vasomotor tone. Administer OPANA ER with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

5.7 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 (12)]. Use OPANA ER with caution in patients with mild impairment, starting with the lowest dose and titrating slowly while carefully monitoring for side effects [see Dosage and Administration (2.3)]. OPANA ER is contraindicated in patients with moderate or severe hepatic impairment.

5.8 Special Risk Groups
Use OPANA ER with caution in the following conditions: adrenocortical insufficiency (e.g., Addison's disease), prostatic hypertrophy or urethral stricture, severe impairment of pulmonary or renal function, and toxic psychosis.

Opioids may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings.

5.9 Gastrointestinal Effects
OPANA ER decreases bowel motility. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of OPANA ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. OPANA ER is contraindicated in patients with paralytic ileus.

5.10 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 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.

5.11 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.

5.12 Driving and Operating Machinery
Opioid analgesics impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

6 ADVERSE REACTIONS 6.1 Clinical Trial Experience

6 ADVERSE REACTIONS



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



- Respiratory depression [see Warnings and Precautions (5.2)]

- Misuse and abuse [see Warning and Precautions (5.3) and Drug Abuse and Dependence (9)]

- CNS depressant effects [see Warnings and Precautions (5.4)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.



The safety of OPANA ER was evaluated in a total of 2011 patients in controlled clinical trials. The clinical trials consisted of patients with moderate to severe chronic non-malignant pain, cancer pain, and post surgical pain.



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

Table 1:Treatment-Emergent Adverse Events Reported in greater than or equal to 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)

	Open-Label Titration Period	Double-Blind Treatment Period
	OPANA ER	OPANA ER	Placebo
Preferred Term	(N = 325)	(N = 105)	(N = 100)
Constipation	26%	7%	1%
Somnolence	19%	2%	0%
Nausea	18%	11%	9%
Dizziness	11%	5%	3%
Headache	11%	4%	2%
Pruritus	7%	3%	1%

Table 2. Treatment-Emergent Adverse Events Reported in greater than or equal to 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)

	Open-Label Titration Period	Double-Blind Treatment Period
	OPANA ER	OPANA ER	Placebo
Preferred Term	(N = 250)	(N = 70)	(N = 72)
Nausea	20%	3%	1%
Constipation	12%	6%	1%
Headache	12%	3%	0%
Somnolence	11%	3%	0%
Vomiting	9%	0%	1%
Pruritus	8%	0%	0%
Dizziness	6%	0%	0%

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

Table 3: Adverse Reactions Reported in Placebo-Controlled Clinical Trials with Incidence greater than or equal to 2% in Patients Receiving OPANA ER.

MedDRA Preferred Term	OPANA ER (N=1259)	Placebo (N=461)
Nausea	33%	13%
Constipation	28%	13%
Dizziness (Excl Vertigo)	18%	8%
Somnolence	17%	2%
Vomiting	16%	4%
Pruritus	15%	8%
Headache	12%	6%
Sweating increased	9%	9%
Dry mouth	6%	less than 1%
Sedation	6%	8%
Diarrhea	4%	6%
Insomnia	4%	2%
Fatigue	4%	1%
Appetite decreased	3%	less than 1%
Abdominal pain	3%	2%

The common (greater than or equal to 1% to 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 and not represented in Table 1 were:



Eye disorders: vision blurred

Gastrointestinal disorders: diarrhea, abdominal pain, dyspepsia

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

Nervous system disorders: insomnia

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

Respiratory, thoracic and mediastinal disorders: dyspnea

Vascular disorders: flushing and hypertension



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

7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions 7.2 Use in CNS Depressants 7.3 Interactions with Mixed Agonist/Antagonist Opioid Analgesics 7.4 Cimetidine 7.5 Anticholinergics 7.6 MAO Inhibitors

7 DRUG INTERACTIONS

7.1 Drug-Drug Interactions
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 (12.3)]). 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 [see Clinical Pharmacology (12.3)].

7.2 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 should be started at 1/3 to 1/2 of the usual dose in patients who are concurrently receiving other central nervous system depressants because respiratory depression, hypotension, and profound sedation, coma and death may result, and titrated slowly as necessary for adequate pain relief.

When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Dosage and Administration (2.5) and Warnings and Precautions (5.4)].

7.3 Interactions with Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or 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.

7.4 Cimetidine
CNS side effects have been reported (e.g., confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; a causal relationship has not been established.

7.5 Anticholinergics
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.

7.6 MAO Inhibitors
OPANA ER is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. No specific interaction between oxymorphone and MAO inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

The safety of using oxymorphone in pregnancy has not been established with regard to possible adverse effects on fetal development. The use of OPANA ER in pregnancy, in nursing mothers, or in women of child-bearing potential requires that the possible benefits of the drug be weighed against the possible hazards to the mother and the child.

Prolonged use of opioid analgesics during pregnancy may cause fetal-neonatal physical dependence.

Teratogenic Effects
Pregnancy Category C
There are no adequate and well-controlled studies of oxymorphone in pregnant women. OPANA ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].

Oxymorphone hydrochloride administration did not cause malformations at any doses evaluated during developmental toxicity studies in rats (less than or equal to 25 mg/kg/day) or rabbits (less than or equal to 50 mg/kg/day). These doses are 3-fold and 12-fold the human dose of 40 mg every 12 hours, based on body surface area. There were no developmental effects in rats treated with 5 mg/kg/day or rabbits treated with 25 mg/kg/day. Fetal weights were reduced in rats and rabbits given doses of greater than or equal to 10 mg/kg/day and 50 mg/kg/day, respectively. These doses are 1.2-fold and 12-fold the human dose of 40 mg every 12 hours based on body surface area, respectively. There were no effects of oxymorphone hydrochloride on intrauterine survival in rats at doses less than or equal to 25 mg/kg/day, or rabbits at less than or equal to 50 mg/kg/day in these studies (see Non-teratogenic Effects, below). In a study that was conducted prior to the establishment of Good Laboratory Practices (GLP) and not according to current recommended methodology, a single subcutaneous injection of oxymorphone hydrochloride on gestation day 8 was reported to produce malformations in offspring of hamsters that received 15.5-fold the human dose of 40 mg every 12 hours based on body surface area. This dose also produced 20% maternal lethality.

Non-teratogenic Effects
Oxymorphone hydrochloride administration to female rats during gestation in a pre- and postnatal developmental toxicity study reduced mean litter size (18%) at a dose of 25 mg/kg/day, attributed to an increased incidence of stillborn pups. An increase in neonatal death occurred at greater than or equal to 5 mg/kg/day. Post-natal survival of the pups was reduced throughout weaning following treatment of the dams with 25 mg/kg/day. Low pup birth weight and decreased postnatal weight gain occurred in pups born to oxymorphone-treated pregnant rats given a dose of 25 mg/kg/day. This dose is ~ 3-fold higher than the human dose of 40 mg every 12 hours on a body surface area basis.

8.2 Labor and Delivery

8.2 Labor and Delivery

Opioids cross the placenta and may produce respiratory depression in neonates. OPANA ER 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.

Upon delivery from a mother who received opioids for a long period of time, 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.

8.3 Nursing Mothers

8.3 Nursing Mothers

It is not known whether oxymorphone is excreted in human milk. Because many drugs, including some opioids, are excreted in human milk, caution should be exercised when OPANA ER is administered to a nursing woman. Infants exposed to OPANA ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.4 Pediatric Use

8.4 Pediatric Use

Safety and effectiveness of OPANA ER in pediatric patients below the age of 18 years have not been established.

8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment

8.5 Geriatric Use
OPANA ER should be used with caution in elderly patients [see Clinical Pharmacology 12.3)].

Of the total number of subjects in clinical studies of OPANA ER, 27% were 65 and over, while 9% were 75 and over. No overall differences in effectiveness were observed between these subjects and younger subjects. There were several adverse events that were more frequently observed in subjects 65 and over compared to younger subjects. These adverse events included dizziness, somnolence, confusion, and nausea.

8.6 Hepatic Impairment
In a PK study of OPANA ER, patients with mild hepatic impairment were shown to have an increase in bioavailability of 1.6 fold. Use OPANA ER with caution in patients with mild impairment. Start these patients on the lowest dose and titrate slowly while carefully monitoring for side effects. OPANA ER is contraindicated for patients with moderate and severe hepatic impairment [see Contraindications (4), Warnings and Precautions (5.7), and Dosage and Administration (2.3)].

8.7 Renal Impairment
In a PK 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 (12.3)]. Start these patients with the lowest dose of OPANA ER and titrate slowly while monitored for side effects [see Dosage and Administration (2.4)].

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

OPANA ER contains oxymorphone, a mu opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine and other opioids. Oxymorphone can be abused and is subject to criminal diversion [see Warning and Precautions (5.3)].

9.2 Abuse

9.2 Abuse

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Addiction is characterized by one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, and continued use despite harm. Drug addiction is a treatable disease, 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 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.

OPANA ER is intended for oral use only. Abuse of OPANA ER poses a risk of overdose and death. This risk is increased with concurrent abuse of OPANA ER with alcohol and other substances. 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.

9.3 Dependence

9.3 Dependence

Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an opioid antagonist or mixed opioid agonist/antagonist agent. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

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.

OPANA ER should not be abruptly discontinued [see Dosage and Administration (2.8)]. 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.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

10 OVERDOSAGE 10.1 Symptoms 10.2 Treatment

10 OVERDOSAGE

10.1 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 some cases, 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 (12.2)].

10.2 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.

The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression that may result from overdosage or unusual sensitivity to opioids including OPANA ER. 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, keep the patient under continued surveillance and administer repeated doses of the antagonist 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. Administer opioid antagonists 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.

11 DESCRIPTION

11 DESCRIPTION

OPANA ER (oxymorphone hydrochloride) extended-release is a semi-synthetic opioid analgesic supplied in 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 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, methylparaben, silicified microcrystalline cellulose, sodium stearyl fumarate, TIMERx-N, titanium dioxide, and triacetin. The 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets also contain macrogol, and polysorbate 80. In addition, the 5 mg, 7.5 mg and 30 mg tablets contain iron oxide red. The 7.5 mg tablets contain iron oxide black, and iron oxide yellow. The 10 mg tablets contain FDandC yellow No. 6. The 20 mg tablets contain FDandC blue No. 1, FDandC yellow No. 6, and DandC yellow No. 10. The 40 mg tablets contain FDandC yellow No. 6, DandC yellow No. 10, and lactose monohydrate.

Chemically, oxymorphone hydrochloride is 4, 5-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:

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Oxymorphone, a pure opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses.

The precise mechanism of analgesia, the principal therapeutic action of oxymorphone, is unknown. Specific central nervous system (CNS) opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression and perception of analgesic effects. In addition, opioid receptors have also been identified within the peripheral nervous system (PNS). The role that these receptors play in these drugs’ analgesic effects is unknown.

12.2 Pharmacodynamics

12.2 Pharmacodynamics

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

Concentration-Adverse Experience Relationships
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 of OPANA ER must be individualized [see Dosage and Administration (2.1)]. The effective analgesic dose for some patients will be too high to be tolerated by other patients.

Effects on the Central Nervous System (CNS)
The principal therapeutic action of oxymorphone is analgesia. In common with other opioids, oxymorphone causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Opioids depress the cough reflex by direct effect on the cough center in the medulla.

Oxymorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage (10.1)]. Other therapeutic effects of oxymorphone include anxiolysis, euphoria and feeling of relaxation.

In addition to analgesia, the widely diverse effects of oxymorphone include drowsiness, changes in mood, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system [see Clinical Pharmacology (12.1)].

Effects on the Gastrointestinal Tract and on Other Smooth Muscle
Gastric, biliary and pancreatic secretions are decreased by oxymorphone. Oxymorphone causes a reduction in motility and is associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result may be constipation. Oxymorphone can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi, and transient elevations in serum amylase. Oxymorphone may also cause spasm of the sphincter of the urinary bladder.

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

12.3 Pharmacokinetics

12.3 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 doses of OPANA ER, for both peak plasma levels (Cmax) and extent of absorption (AUC) (see Table 4).

Table 4: Mean (±SD) OPANA ER Pharmacokinetic Parameters

Regimen	Dosage	Cmax (ng/mL)	AUC (ng·hr/mL)	T ½ (hr)
Single Dose	5 mg 10 mg 20 mg 40 mg	0.27±0.13 0.65±0.29 1.21±0.77 2.59±1.65	4.54±2.04 8.94±4.16 17.81±7.22 37.90±16.20	11.30+10.81 9.83+5.68 9.89+3.21 9.35+2.94
Multiple Dosea	5 mg 10 mg 20 mg 40 mg	0.70±0.55 1.24±0.56 2.54±1.35 4.47±1.91	5.60±3.87 9.77±3.52 19.28±8.32 36.98±13.53	NA NA NA NA
NA = not applicable a Results after 5 days of q12h dosing.

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 1hour in fasted subjects and a peak of 4.25 ng/ml is achieved at 2 hours in fed subjects and that beyond the 12 hour time point, there is very little difference in the curves. As a result, OPANA ER should be dosed at least one hour prior to or two hours after eating [see Dosage and Administration (2.2)].

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, less than 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.

Pharmacokinetics in 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 Use in Specific Populations (8.5)].

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 AUCss and Cmax values than male subjects; however, gender differences were not observed when AUCss 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.

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 less than 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 less than or equal to  50 µM. An inhibition of CYP3A4 activity occurred at oxymorphone concentrations greater than or equal to 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 in male rats was 0.34-fold and at the 25 mg/kg/day dose in female rats was 1.5-fold the human exposure at a dose of 260 mg/day. No evidence of carcinogenic potential was observed in rats. Oxymorphone was administered to CD-1 mice (10, 25, 75 and 150 mg/kg/day) for 2 years by oral gavage. The systemic drug exposure (AUC ng•h/mL) at the 150 mg/kg/day dose in mice was 14.5-fold (in males) and 17.3-fold (in females) times the human exposure at a dose of 260 mg/day. No evidence of carcinogenic potential was observed in mice.

Mutagenesis
Oxymorphone hydrochloride was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test) at concentrations of less than or equal to 5270 g/plate, or in an in vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes at concentrations less than or equal to 5000 g/ml with or without metabolic activation. Oxymorphone hydrochloride tested positive in both the rat and mouse in vivo micronucleus assays. An increase in micronucleated polychromatic erythrocytes occurred in mice given doses greater than or equal to 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 (less than or equal to 50 mg/kg/day). The highest dose tested is ~6-fold the human dose of 40 mg every 12 hours, based on body surface area. In female rats, an increase in the length of the estrus cycle and decrease in the mean number of viable embryos, implantation sites and corpora lutea were observed at doses of oxymorphone greater than or equal to 10 mg/kg/day. The dose of oxymorphone associated with reproductive findings in female rats is 1.2-fold the human dose of 40 mg every 12 hours based on a body surface area. The dose of oxymorphone that produced no adverse effects on reproductive findings in female rats is 0.6-fold the human dose of 40 mg every 12 hours on a body surface area basis.

14 CLINICAL STUDIES 14.1 12-Week Study in Opioid-Naïve Patients with Low Back Pain 14.2 12-Week Study in Opioid-Experienced Patients with Low Back Pain

14 CLINICAL STUDIES
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.

14.1 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 less than or equal to 10 mm increase in VAS score from Day 7 until the end of the study.

The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 1. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not complete the study were assigned 0% improvement.

14.2 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 less than or equal to 10 mm increase in VAS score from Day 7 until the end of the study.

The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not complete the study were assigned 0% improvement.

16 HOW SUPPLIED/STORAGE AND HANDLING

16 HOW SUPPLIED/STORAGE AND HANDLING

OPANA ER tablets are supplied as follows:

5 mg Pink, octagon shape, film coated, convex extended-release tablets debossed with “5” 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

7.5 mg
Gray, octagon shape, film coated, convex extended-release tablets debossed with “7 ½” on one side and plain on the other.

Bottles of 100 with child-resistant closure NDC 63481-522-70

Unit-Dose package of 100 tablets
(5 blister cards of 20 tablets, not child-resistant, for hospital use only) NDC 63481-522-75

10 mg
Light orange, octagon shape, film coated, convex extended-release tablets debossed with “10” 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

15 mg
White, octagon shape, film coated, convex extended-release tablets debossed with “15” on one side and plain on the other.

Bottles of 100 with child-resistant closure NDC 63481-553-70

Unit-Dose package of 100 tablets (5 blister cards of 20 tablets, not child-resistant, for hospital use only)                               NDC 63481-553-75

20 mg
Light green, octagon shape, film coated, convex extended-release tablets debossed with “20” 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

30 mg
Red, octagon shape, film coated, convex extended-release tablets debossed with “30” on one side and plain on the other.

Bottles of 100 with child-resistant closure NDC 63481-571-70

Unit-Dose package of 100 tablets (5 blister cards of 20 tablets, not child-resistant, for hospital use only)                               NDC 63481-571-75

40 mg
Yellow, octagon shape, film coated, convex extended-release tablets debossed with “40” 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

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.

Healthcare professionals should advise patients to store OPANA ER in a secure place, preferably locked and out of the reach of children and other non-caregivers.

Manufactured for:
Endo Pharmaceuticals Inc., Chadds Ford, PA 19317

Manufactured by:
Novartis Consumer Health Inc., Lincoln, NE 68517

Store at 25C (77F); excursions permitted to 15-30C (59-86F). [See USP Controlled Room Temperature].

Dispense in tight container as defined in the USP, with a child-resistant closure (as required).

Advise patients to dispose of any unused tablets from a prescription by flushing them down the toilet as soon as they are no longer needed [see Patient Counseling Information (17)].

17 PATIENT COUNSELING INFORMATION

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

- Advise patients that OPANA ER contains oxymorphone, a morphine-like pain reliever, and should be taken only as directed.

- Advise patients that OPANA ER is designed to work properly only if swallowed whole. The extended-release tablets may release all their contents at once if broken, chewed or crushed, resulting in a risk of fatal overdose 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.

- Appropriate pain management requires changes in the dose to maintain best pain control. Advise patients of the need to contact their physician if pain control is inadequate, but not to change the dose of OPANA ER without consulting their physician.

- Advise patients 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.

- Caution patients that OPANA ER 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.

- Instruct patients not to combine OPANA ER with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur, resulting in serious injury or death.

- Advise patients taking OPANA ER of the potential for severe constipation. Appropriate laxatives and/or stool softeners and other therapeutic approaches may be considered for use with the initiation of OPANA ER therapy.

- Advise patients not to adjust the dose of OPANA ER without consulting the prescribing professional.

- Advise patients that OPANA ER 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.

- Advise women of childbearing potential who become, or are planning to become pregnant to consult their physician regarding the effects of opioid analgesics and other drug use during pregnancy on themselves and their unborn child.

- If patients have been receiving treatment with OPANA ER for more than a few days to weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. Provide patients with a dose schedule to accomplish a gradual discontinuation of the medication.

- As with any potent opioid, misuse of OPANA ER may result in serious adverse events. Instruct patients to keep OPANA ER in a secure place out of the reach of children and pets. Accidental consumption especially in children can result in overdose or death. When OPANA ER is no longer needed, instruct patients to destroy unused tablets by flushing them down the toilet.

FDA – Approved Patient Labeling

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

OPANA ER Tablets, 5 mg
OPANA ER Tablets, 7.5 mg
OPANA ER Tablets, 10 mg
OPANA ER Tablets, 15 mg
OPANA ER Tablets, 20 mg
OPANA ER Tablets, 30 mg
OPANA ER Tablets, 40 mg

IMPORTANT: Keep OPANA ER in a safe place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally takes OPANA ER, get emergency help right away.

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.

- Do not consume alcoholic beverages, or prescription or non-prescription medications containing alcohol, while taking OPANA ER.

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 problems

- 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 86F (15to 30C).

- 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.

What are the ingredients in OPANA ER?
Active Ingredient: oxymorphone hydrochloride

Inactive Ingredients: hypromellose, methylparaben, silicified microcrystalline cellulose, sodium stearyl fumarate, TIMERx®-N, titanium dioxide, and triacetin. The 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets also contain macrogol, and polysorbate 80. In addition, the 5 mg, 7.5 mg, and 30 mg tablets contain iron oxide red. The 7.5 mg tablets contain iron oxide black, and iron oxide yellow. The 10 mg tablets contain FDandC yellow No. 6. The 20 mg tablets contain FDandC blue No. 1, FDandC yellow No. 6, and DandC yellow No. 10. The 40 mg tablets contain FDandC yellow No. 6, DandC yellow No.10, and lactose monohydrate.

CAUTION: Federal law prohibits dispensing without prescription.

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.

© 2010 Endo Pharmaceuticals

2005648 / September 2010

1

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

OPANA® ER safely and effectively. See full prescribing information for

OPANA® ER.

OPANA® ER (oxymorphone hydrochloride) extended-release tablets,

for oral use, CII

Initial U.S. Approval: 1959

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING

RESPIRATORY DEPRESSION; ACCIDENTAL

INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME;

INTERACTION WITH ALCOHOL; and RISKS FROM

CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER

CNS DEPRESSANTS

See full prescribing information for complete boxed warning.

• OPANA ER exposes users to risks of addiction, abuse, and

misuse, which can lead to overdose and death. Assess patient’s

risk before prescribing and monitor regularly for these behaviors

and conditions. (5.1)

• Serious, life-threatening, or fatal respiratory depression may

occur. Monitor closely, especially upon initiation or following a

dose increase. Instruct patients to swallow OPANA ER tablets

whole to avoid exposure to a potentially fatal dose of

oxymorphone. (5.2)

• Accidental ingestion of OPANA ER, especially by children, can

result in fatal overdose of oxymorphone. (5.2)

• Prolonged use of OPANA ER during pregnancy can result in

neonatal opioid withdrawal syndrome, which may be lifethreatening

if not recognized and treated. If opioid use is

required for a prolonged period in a pregnant woman, advise the

patient of the risk of neonatal opioid withdrawal syndrome and

ensure that appropriate treatment will be available (5.3).

• Instruct patients not to consume alcohol or any product

containing alcohol while taking OPANA ER because co-ingestion

can result in fatal plasma oxymorphone levels. (5.4)

• Concomitant use of opioids with benzodiazepines or other central

nervous system (CNS) depressants, including alcohol, may result

in profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing for use in patients for whom

alternative treatment options are inadequate; limit dosages and

durations to the minimum required; and follow patients for signs

and symptoms of respiratory depression and sedation. (5.4, 7)

-----------------------------RECENT MAJOR CHANGES--------------------

Boxed Warning 12/2016

Dosage and Administration (2) 12/2016

Contraindications (4) 12/2016

Warnings and Precautions (5) 12/2016

----------------------------INDICATIONS AND USAGE--------------------------

OPANA ER is an opioid agonist indicated for the management of pain

severe enough to require daily, around-the-clock, long-term opioid treatment

and for which alternative treatment options are inadequate. (1)

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids,

even at recommended doses, and because of the greater risks of

overdose and death with extended-release opioid formulations,

reserve OPANA ER for use in patients for whom alternative treatment

options (e.g., non-opioid analgesics or immediate-release opioids) are

ineffective, not tolerated, or would be otherwise inadequate to provide

sufficient management of pain. (1)

• OPANA ER is not indicated as an as-needed (prn) analgesic. (1)

---------------------DOSAGE AND ADMINISTRATION--------------------

• To be prescribed only by healthcare providers knowledgeable in use of

potent opioids for management of chronic pain. (2.1)

• Use the lowest effective dosage for the shortest duration consistent with

individual patient treatment goals (2.1).

• Individualize dosing based on the severity of pain, patient response, prior

analgesic experience, and risk factors for addiction, abuse, and misuse.

(2.1)

• Administer on an empty stomach, at least 1 hour prior to or 2 hours

after eating. (2.1)

• OPANA ER tablets should be taken one tablet at a time, with

enough water to ensure complete swallowing immediately after

placing in the mouth. (2.1, 17)

• For opioid-naïve and opioid non-tolerant patients, initiate treatment with

5 mg tablets orally every 12 hours. (2.2)

• To convert to OPANA ER from another opioid, use available conversion

factors to obtain estimated dose. (2.2)

• Dose can be increased every 3 to 7 days, using increments of 5 to 10 mg

every 12 hours (i.e., 10 to 20 mg per day). (2.3)

• Do not abruptly discontinue OPANA ER in a physically dependent

patient. (2.4, 5.14)

• Mild Hepatic Impairment: For opioid-naïve patients, initiate treatment

with 5 mg and titrate slowly. For patients on prior opioid therapy,

reduce starting dose by 50% and titrate slowly. Monitor for signs of

respiratory and central nervous system depression. (2.5)

• Renal Impairment: For opioid-naïve patients, initiate treatment with 5

mg and titrate slowly. For patients on prior opioid therapy, reduce

starting dose by 50% and titrate slowly. Monitor for signs of respiratory

and central nervous system depression. (2.6)

• Geriatric Patients: Initiate dosing with 5 mg, titrate slowly, and monitor

for signs of respiratory and central nervous system depression. (2.7)

---------------------DOSAGE FORMS AND STRENGTHS-------------------

Extended-release tablets: 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and

40 mg

------------------------------CONTRAINDICATIONS---------------------------

• Significant respiratory depression (4)

• Acute or severe bronchial asthma in an unmonitored setting or in

absence of resuscitative equipment (4)

• Hypersensitivity to oxymorphone (4)

• Moderate or severe hepatic impairment (4)

• Known or suspected gastrointestinal obstruction, including paralytic

ileus (4)

------------------------WARNINGS AND PRECAUTIONS--------------------

• Life-Threatening Respiratory Depression in Patients with Chronic

Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:

Monitor closely, particularly during initiation and titration. (5.5, 5.6)

• Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions: If

symptoms occur, stop administration immediately, discontinue

permanently, and do not rechallenge with any oxymorphone

formulation. (5.6)

• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement

of corticosteroids, and wean patient off of the opioid. (5.7)

• Severe Hypotension: Monitor during dose initiation and titration. Avoid

use of OPANA ER in patients with circulatory shock. (5.9)

• Risks of Use in Patients with Increased Intracranial Pressure, Brain

Tumors, Head Injury or Impaired Consciousness: Monitor for sedation

and respiratory depression. Avoid use of OPANA ER in patients with

impaired consciousness or coma. (5.10)

• Difficulty in Swallowing: Use with caution in patients who have

difficulty in swallowing or have underlying GI disorders that may

predispose them to obstruction. (5.11)

-----------------------------ADVERSE REACTIONS-----------------------------

Adverse reactions in ≥2% of patients in placebo-controlled trials: nausea,

constipation, dizziness, somnolence, vomiting, pruritus, headache, sweating

increased, dry mouth, sedation, diarrhea, insomnia, fatigue, appetite

decreased, and abdominal pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Endo

Pharmaceuticals Inc. at class="baec5a81-e4d6-4674-97f3-e9220f0136c1" ="white-space: nowrap;">1-800-462-3636 or FDA at 1-800 FDA-1088 or

www.fda.gov/medwatch.

------------------------------DRUG INTERACTIONS----------------------------

• Serotonergic Drugs: Concomitant use may result in serotonin syndrome.

Discontinue OPANA ER if serotonin syndrome is suspected. (7)

• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics:

Avoid use with OPANA ER because they may reduce analgesic effect of

OPANA ER or precipitate withdrawal symptoms. (7)

• Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of

oxymorphone. Avoid concomitant use in patients receiving MAOIs or

within 14 days of stopping treatment with an MAOI. (7)

------------------------USE IN SPECIFIC POPULATIONS--------------------

• Pregnancy: May cause fetal harm. (8.1)

• Lactation: Not Recommended. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and

Medication Guide

Revised: 12/2016

________________________________________________________________________________________________________________________________________

Reference ID: 4028719

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING

RESPIRATORY DEPRESSION; ACCIDENTAL

INGESTION; NEONATAL OPIOID WITHDRAWAL

SYNDROME; INTERACTION WITH ALCOHOL; and

RISKS FROM CONCOMITANT USE WITH

BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

2.2 Initial Dosing

2.3 Titration and Maintenance of Therapy

2.4 Discontinuation of OPANA ER

2.5 Dosage Modifications in Patients with Hepatic Impairment

2.6 Dosage Modifications in Patients with Renal Impairment

2.7 Dosage Modifications in Geriatric Patients

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse Potential

5.2 Life Threatening Respiratory Depression

5.3 Neonatal Opioid Withdrawal Syndrome

5.4 Risks from Concomitant Use with Benzodiazepines or Other

CNS Depressants

5.5 Risk of Life-Threatening Respiratory Depression in Patients

with Chronic Pulmonary Disease or in Elderly, Cachectic, or

Debilitated Patients

5.6 Anaphylaxis, Angioedema, and Other Hypersensitivity

Reactions

5.7 Adrenal Insufficiency

5.8 Use in Patients with Hepatic Impairment

5.9 Sever Hypotension

5.10 Risks of Use in Patients with Increased Intracranial Pressure,

Brain Tumors, Head Injury, or Impaired Consciousness

5.11 Difficulty in Swallowing and Risk for Obstruction in Patients

at Risk for a Small Gastrointestinal Lumen

5.12 Risks of Use in Patients with Gastrointestinal Conditions

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

5.14 Withdrawal

5.15 Risks of Driving and Operating Machinery

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Post-marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing

information are not listed.

_________________________________________________________________________________________________________________________________

Reference ID: 4028719

FULL PRESCRIBING INFORMATION

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION;

ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME;

INTERACTION WITH ALCOHOL; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR

OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

OPANA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to

overdose and death. Assess each patient’s risk prior to prescribing OPANA ER, and monitor all patients regularly

for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of OPANA ER. Monitor for respiratory

depression, especially during initiation of OPANA ER or following a dose increase. Instruct patients to swallow

OPANA ER tablets whole; crushing, chewing, or dissolving OPANA ER tablets can cause rapid release and

absorption of a potentially fatal dose of oxymorphone [see Warnings and Precautions (5.2)].

Accidental Ingestion

Accidental ingestion of even one dose of OPANA ER, especially by children, can result in a fatal overdose of

oxymorphone [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome

Prolonged use of OPANA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be

life-threatening if not recognized and treated, and requires management according to protocols developed by

neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the

risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings

and Precautions (5.3)].

Interaction with Alcohol

Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain

alcohol while taking OPANA ER. The co-ingestion of alcohol with OPANA ER may result in increased plasma levels

and a potentially fatal overdose of oxymorphone [see Warnings and Precautions (5.4)

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including

alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions

(5.4), Drug Interactions (7)].

• Reserve concomitant prescribing of OPANA ER and benzodiazepines or other CNS depressants for use in patients

for whom alternative treatment options are inadequate.

• Limit dosages and durations to the minimum required.

• Follow patients for signs and symptoms of respiratory depression and sedation.

1 INDICATIONS AND USAGE

OPANA ER is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and

for which alternative treatment options are inadequate.

Limitations of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks

of overdose and death with extended-release opioid formulations [see Warnings and Precautions (5.1)], reserve OPANA ER

for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are

ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• OPANA ER is not indicated as an as-needed (prn) analgesic.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

OPANA ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the

management of chronic pain.

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and

Precautions (5.1)].

Reference ID: 4028719

• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response,

prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].

• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following

dosage increases with OPANA ER and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Instruct patients to swallow OPANA ER tablets whole, one tablet at a time, with enough water to ensure complete swallowing

immediately after placing in the mouth [see Patient Counseling Information (17)]. Crushing, chewing, or dissolving OPANA ER

tablets will result in uncontrolled delivery of oxymorphone and can lead to overdose or death [see Warnings and Precautions (5.2)].

Administer on an empty stomach, at least 1 hour prior to or 2 hours after eating.

OPANA ER is administered orally every 12 hours.

2.2 Initial Dosage

Use of OPANA ER as the First Opioid Analgesic

Initiate treatment with OPANA ER with the 5 mg tablet orally every 12-hours.

Use of OPANA ER in Patients who are not Opioid Tolerant

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

Patients considered opioid tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal

fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral

hydrocodone per day, or an equianalgesic dose of another opioid.

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

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.

Conversion from Parenteral Oxymorphone to OPANA ER

The absolute oral bioavailability of OPANA ER is approximately 10%. Convert patients receiving parenteral oxymorphone 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] divided by 2). Due to patient variability with regards to opioid analgesic response, upon conversion

monitor patients closely to evaluate for adequate analgesia and side effects.

Conversion from Other Oral Opioids to OPANA ER

Discontinue all other around-the-clock opioid drugs when OPANA ER therapy is initiated.

While there are useful tables of opioid equivalents readily available, there is substantial inter- patient variability in the relative

potency of different opioid drugs and products. As such, it is preferable to underestimate a patient’s 24-hour oral oxymorphone

requirements and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral oxymorphone

requirements which could result in adverse reactions. In an OPANA ER clinical trial with an open-label titration period, patients

were converted from their prior opioid to OPANA ER using Table 1 as a guide for the initial OPANA ER dose.

Consider the following when using the information in Table 1:

• This is not a table of equianalgesic doses.

• The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to OPANA ER.

• This table cannot be used to convert from OPANA ER to another opioid. Doing so will result in an overestimation of the dose of

the new opioid and may result in fatal overdose.

CONVERSION FACTORS TO OPANA ER

Prior Oral Opioid Approximate Oral

Conversion Factor

Oxymorphone 1

Hydrocodone 0.5

Oxycodone 0.5

Methadone 0.5

Morphine 0.333

Reference ID: 4028719

To calculate the estimated OPANA ER dose using Table 1:

• For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the

conversion factor to calculate the approximate oral oxymorphone daily dose.

• For patients on a regimen of more than one opioid, calculate the approximate oral oxymorphone dose for each opioid and sum the

totals to obtain the approximate total oxymorphone daily dose.

• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in

the conversion

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

Example conversion from a single opioid to OPANA ER:

Step 1: Sum the total daily dose of the opioid oxycodone 20 mg BID

20 mg former opioid 2 times daily = 40 mg total daily dose of former opioid

Step 2: Calculate the approximate equivalent dose of oral oxymorphone based on the total daily dose of the current opioid using

Table 1

40 mg total daily dose of former opioid x 0.5 mg Conversion Factor = 20 mg of oral oxymorphone daily

Step 3: Calculate the approximate starting dose of OPANA ER to be given every 12 hours. Round down, if necessary, to the

appropriate OPANA ER TABLETS strengths available.

10 mg OPANA ER every 12 hours

Conversion from Methadone to OPANA ER

Close monitoring is of particular importance when converting from methadone to other opioid agonists. The ratio between

methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and

can accumulate in the plasma.

2.3 Titration and Maintenance of Therapy

Individually titrate OPANA ER to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate

patients receiving OPANA ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as

monitoring for the development of addiction, abuse, and misuse. Frequent communication is important among the prescriber, other

members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including

initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

If the level of pain increases, attempt to identify the source of increased pain, while adjusting the OPANA ER dose to decrease the

level of pain. Because steady-state plasma concentrations are approximated within 3 days, OPANA ER dosage adjustments, preferably

at increments of 5-10 mg every 12 hours, may be done every 3 to 7 days.

Patients who experience breakthrough pain may require a dose increase of OPANA ER, or may need rescue medication with an

appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source

of increased pain before increasing OPANA ER dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent dose may be reduced. Adjust the dose to obtain an

appropriate balance between management of pain and opioid-related adverse reactions.

2.4 Discontinuation of OPANA ER

When a patient no longer requires therapy with OPANA ER, taper the dose gradually, by 25% to 50% every 2 to 4 days, while

monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the

previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or

both. Do not abruptly discontinue OPANA ER [see Warnings and Precautions (5.14), Drug Abuse and Dependence (9.3)].

2.5 Dosage Modification in Patients with Mild Hepatic Impairment

OPANA ER is contraindicated in patients with moderate or severe hepatic impairment.

In opioid-naïve patients with mild hepatic impairment, initiate treatment with the 5 mg dose. For patients on prior opioid therapy, start

OPANA ER at 50% lower than the starting dose for a patient with normal hepatic function on prior opioids and titrate slowly.

Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and Precautions (5.2), Use in

Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Reference ID: 4028719

2.6 Dosage Modification in Patients with Renal Impairment

In patients with creatinine clearance rates less than 50 mL/min, start OPANA ER in the opioid-naïve patient with the 5 mg dose. For

patients on prior opioid therapy, start OPANA ER at 50% lower than the starting dose for a patient with normal renal function on prior

opioids and titrate slowly. Monitor patients closely for signs of respiratory or central nervous system depression [see Warnings and

Precautions (5.2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.7 Dosage Modification in Geriatric Patients

The steady-state plasma concentrations of oxymorphone are higher in elderly subjects than in young subjects. Initiate dosing with

OPANA ER in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous

system depression when initiating and titrating OPANA ER to adequate analgesia [see Warnings and Precautions (5.2), Use in

Specific Populations (8.5) and Clinical Pharmacology (12.3)]. For patients on prior opioid therapy, start OPANA ER at 50% lower

than the starting dose for a younger patient on prior opioids and titrate slowly.

3 DOSAGE FORMS AND STRENGTHS

Extended Release Tablets 5 mg: pink, round, film-coated, biconcave extended-release tablet debossed with an “E” on one side and a

“5” on the other side.

Extended Release Tablets 7.5 mg: gray, round, film-coated, biconcave extended-release tablet debossed with an “E” on one side and a

“7 ½” on the other side.

Extended Release Tablets 10 mg: light orange, round, film-coated, biconcave extended-release tablet debossed with an “E” on one

side and a “10” on the other side.

Extended Release Tablets 15 mg: white, round, film-coated, biconcave extended-release tablet debossed with an “E” on one side and a

“15” on the other side.

Extended Release Tablets 20 mg: light green, round, film-coated, biconcave extended-release tablet debossed with an “E” on one side

and a “20” on the other side.

Extended Release Tablets 30 mg: red, round, film-coated, biconcave extended-release tablet debossed with an “E” on one side and a

“30” on the other side.

Extended Release Tablets 40 mg: light yellow to pale yellow, round, film-coated, biconcave extended-release tablet debossed with an

“E” on one side and a “40” on the other side.

4 CONTRAINDICATIONS

OPANA ER is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings

and Precautions (5.5)]

• Hypersensitivity to oxymorphone, (e.g. anaphylaxis) [see Warnings and Precautions (5.6), Adverse Reactions (6)]

• Moderate and severe hepatic impairment [see Warnings and Precautions (5.8,) Clinical Pharmacology (12.3)]

• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11)]

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

OPANA ER contains oxymorphone, a Schedule II controlled substance. As an opioid, OPANA ER exposes users to the risks of

addiction, abuse, and misuse. Because extended-release products such as OPANA ER deliver the opioid over an extended period of

time, there is a greater risk for overdose and death due to the larger amount of oxymorphone present [see Drug Abuse and Dependence

(9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OPANA ER. Addiction

can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid r addiction, abuse, or misuse prior to prescribing OPANA ER, and monitor all patients receiving

OPANA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of

substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks

should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed

opioids such as OPANA ER, but use in such patients necessitates intensive counseling about the risks and proper use of OPANA ER

along with intensive monitoring for signs of addiction, abuse, and misuse.

Reference ID: 4028719

Abuse or misuse of OPANA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled

delivery of the oxymorphone and can result in overdose and death [see Overdosage (10)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks

when prescribing or dispensing OPANA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate

quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state

professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of

this product.

5.2 Life Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.

Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death.

Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending

on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can

exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of OPANA ER, the risk is greatest

during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within

24-72 hours of initiating therapy with and following dose increases of OPANA ER.

To reduce the risk of respiratory depression, proper dosing and titration of OPANA ER are essential [see Dosage and Administration

(2)]. Overestimating the OPANA ER dosage when converting patients from another opioid product can result in fatal overdose with

the first dose.

Accidental ingestion of even one dose of OPANA ER, especially by children, can result in respiratory depression and death due to an

overdose of oxymorphone.

5.3 Neonatal Opioid Withdrawal Syndrome

Prolonged use of OPANA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike

opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to

protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage

accordingly. Advise pregnant women using opioids for a prolonged period t of the risk of neonatal opioid withdrawal syndrome and

ensure that appropriate treatment will be available.

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on OPANA ER

therapy. The co-ingestion of alcohol with OPANA ER may result in increased plasma levels and a potentially fatal overdose of

oxymorphone [see Clinical Pharmacology (12.3)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OPANA ER with

benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle

relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of

these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drugrelated

mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to

expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the

lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a

lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on

clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a

lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of

respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when OPANA ER is used with

benzodiazepine or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy

machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients

for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated

with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling

Information (17)].

Reference ID: 4028719

5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or

Debilitated Patients

The use of OPANA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative

equipment is contraindicated.

Patients with Chronic Pulmonary Disease: OPANA ER-treated patients with significant chronic obstructive pulmonary disease or cor

pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression

are at increased risk of decreased respiratory drive, including apnea even at recommended dosages of OPANA ER [see Warnings and

Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or

debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see

Warnings and Precautions (5.2)].

Monitor such patients closely, particularly when initiating and titrating OPANA ER and when OPANA ER is given concomitantly

with other drugs that depress respiration [see Warnings and Precautions (5.2]. Alternatively, consider the use of non-opioid

analgesics in these patients.

5.6 Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions

Potentially life-threatening hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with

OPANA ER in the postmarket setting. The most commonly described clinical features in these reports were swelling of the face, eyes,

mouth, lips, tongue, hands, and/or throat; dyspnea; hives, pruritus, and/or rash; and nausea/vomiting. If anaphylaxis or other

hypersensitivity occurs, stop administration of OPANA ER immediately, discontinue OPANA ER permanently, and do not

rechallenge with any formulation of oxymorphone. Advise patients to seek immediate medical attention if they experience any

symptoms of a hypersensitivity reaction [see Patient Counseling Information (17)].

5.7 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation

of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness,

dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as

possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the

opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be

tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not

identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.8 Use in Patients with Hepatic Impairment

A study of OPANA ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic

function [see Clinical Pharmacology (12.3)]. OPANA ER is contraindicated in patients with moderate or severe hepatic impairment.

In patients with mild hepatic impairment reduce the starting dose to the lowest dose and monitor for signs of respiratory and central

nervous system depression [see Dosage and Administration (2.5)].

5.9 Severe Hypotension

OPANA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an

increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or

concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics) [see Drug Interactions (7)].

Monitor these patients for signs of hypotension after initiating or titrating the dosage of OPANA ER. In patients with circulatory

shock, OPANA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OPANA ER in

patients with circulatory shock.

5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial

pressure or brain tumors), OPANA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial

pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OPANA ER.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OPANA ER in patients with impaired

consciousness or coma.

5.11 Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen

There have been post-marketing reports of difficulty in swallowing OPANA ER tablets. These reports included choking, gagging,

regurgitation and tablets stuck in the throat. Instruct patients not to pre-soak, lick or otherwise wet OPANA ER tablets prior to placing

Reference ID: 4028719

in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the

mouth.

There have been rare post-marketing reports of cases of intestinal obstruction, some of which have required medical intervention to

remove the tablet. Patients with underlying GI disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen

are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty

swallowing and patients at risk for underlying GI disorders resulting in a small gastrointestinal lumen.

5.12 Risks of Use in Patients with Gastrointestinal Conditions

OPANA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The oxymorphone in OPANA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor

patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.13 Increased Risk of Seizures in Patients with Seizure Disorders

The oxymorphone in OPANA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk

of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for

worsened seizure control during OPANA ER therapy.

5.14 Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) and partial agonist (e.g., buprenorphine)

analgesics in patients who are receiving a full opioid agonist analgesic, including OPANA ER. In these patients, mixed

agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing OPANA ER, gradually taper the dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue

OPANA ER.

5.15 Risks of Driving and Operating Machinery

OPANA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or

operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OPANA ER

and know how they will react to the medication.

6 ADVERSE REACTIONS

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]

• Life Threatening Respiratory Depression [see Warnings and Precautions (5.2)]

• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]

• Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4)]

• Anaphylaxis and angioedema [see Warnings and Precautions (5.6)]

• Adrenal Insufficiency [see Warnings and Precautions (5.7)]

• Severe Hypotension [see Warnings and Precautions (5.9)]

• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11, 5.12)]

• Seizures [see Warnings and Precautions (5.13)]

• Withdrawal [see Warnings and Precautions (5.14)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug

cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of oxymorphone hydrochloride extended-release tablets was evaluated in a total of 2011 patients in open-label and

controlled clinical trials. The clinical trials enrolled of patients with moderate to severe chronic non-malignant pain, cancer pain, and

post surgical pain. The most common serious adverse events reported with administration of oxymorphone hydrochloride extendedrelease

tablets were chest pain, pneumonia and vomiting.

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

patients with low back pain.

Reference ID: 4028719

Table 1:Treatment-Emergent Adverse Reactions Reported in ≥5% of Patients

During the Open-Label Titration Period and Double-Blind Treatment Period by Preferred

Term—Number (%) of Treated Patients (12-Week Study In Opioid-Naïve Patients with Low

Back Pain)

Open-Label Titration

Period

Double-Blind Treatment Period

Oxymorphone

Hydrochloride Extended-

Release Tablets

Oxymorphone

Hydrochloride

Extended-Release

Tablets

Placebo

Preferred Term (N = 325) (N = 105) (N = 100)

Constipation 26% 7% 1%

Somnolence 19% 2% 0%

Nausea 18% 11% 9%

Dizziness 11% 5% 3%

Headache 11% 4% 2%

Pruritus 7% 3% 1%

Table 2: Treatment-Emergent Adverse Reactions Reported in ≥5% of Patients

During the Open-Label Titration Period and Double-Blind Treatment Period by Preferred

Term—Number (%) of Treated Patients (12-Week Study In Opioid-Experienced Patients with

Low Back Pain)

Open-Label Titration

Period

Double-Blind Treatment Period

Oxymorphone

Hydrochloride Extended-

Release Tablets

Oxymorphone

Hydrochloride

Extended-Release

Tablets

Placebo

Preferred Term (N = 250) (N = 70) (N = 72)

Nausea 20% 3% 1%

Constipation 12% 6% 1%

Headache 12% 3% 0%

Somnolence 11% 3% 0%

Vomiting 9% 0% 1%

Pruritus 8% 0% 0%

Dizziness 6% 0% 0%

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

Table 3: Adverse Reactions Reported in Placebo-Controlled Clinical Trials with

Incidence ≥2% in Patients Receiving Oxymorphone Hydrochloride Extended-

Release Tablets

MedDRA Preferred Term Oxymorphone

Hydrochloride

Extended-Release

Tablets (N=1259)

Placebo (N=461)

Nausea 33% 13%

Constipation 28% 13%

Dizziness (Excl Vertigo) 18% 8%

Somnolence 17% 2%

Vomiting 16% 4%

Pruritus 15% 8%

Headache 12% 6%

Sweating increased 9% 9%

Dry mouth 6% <1%

Reference ID: 4028719

Sedation 6% 8%

Diarrhea 4% 6%

Insomnia 4% 2%

Fatigue 4% 1%

Appetite decreased 3% <1%

Abdominal pain 3% 2%

The common (≥1% to <10%) adverse drug reactions reported at least once by patients treated with oxymorphone hydrochloride

extended-release tablets in the clinical trials organized by MedDRA’s (Medical Dictionary for Regulatory Activities) System Organ

Class and not represented in Table 1 were:

Eye disorders: vision blurred

Gastrointestinal disorders: diarrhea, abdominal pain, dyspepsia

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

weight decreased, edema

Nervous system disorders: insomnia

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

Respiratory, thoracic and mediastinal disorders: dyspnea

Vascular disorders: flushing and hypertension

Other less common adverse reactions known with opioid treatment that were seen <1% in the oxymorphone hydrochloride extendedrelease

tablets trials include the following: Bradycardia, palpitation, syncope, tachycardia, postural hypotension, miosis, abdominal

distention, ileus, hot flashes, allergic reactions, hypersensitivity, urticaria, oxygen saturation decreased, central nervous system

depression, depressed level of consciousness, agitation, dysphoria, euphoric mood, hallucination, mental status changes, difficult

micturition, urinary retention, hypoxia, respiratory depression, respiratory distress, clamminess, dermatitis, hypotension.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post approval use of opioids. Because these reactions are reported

voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal

relationship to drug exposure.

Nervous system disorder: amnesia, convulsion, memory impairment

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use

of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one

month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in OPANA ER

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

7 DRUG INTERACTIONS

Table 4 includes clinically significant drug interactions with OPANA ER

Table 4: Clinically Significant Drug Interactions with OPANA ER

Alcohol

Clinical Impact: The concomitant use of alcohol with OPANA ER can result in an increase of oxymorphone plasma levels and

potentially fatal overdose of oxymorphone.

Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products

containing alcohol while on OPANA ER therapy [see Clinical Pharmacology (12.3)].

Benzodiazepines and other Central Nervous System (CNS) Depressants

Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants

including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and

death.

Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are

inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of

respiratory depression and sedation [see Warnings and Precautions (5.4)].

Reference ID: 4028719

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general

anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs

Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has

resulted in serotonin syndrome.

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and

dose adjustment. Discontinue OPANA ER if serotonin syndrome is suspected.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs),

tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin

neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors

(those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene

blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory

depression, coma) [see Warnings and Precautions (5.2)].

Intervention: The use of OPANA ER is not recommended for patients taking MAOIs or within 14 days of stopping such

treatment.

Examples: phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Clinical Impact: May reduce the analgesic effect of OPANA ER and/or precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Clinical Impact: Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an

increased degree of respiratory depression.

Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease

the dosage of OPANA ER and/or the muscle relaxant as necessary.

Diuretics

Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of

the diuretic as needed.

Anticholinergic Drugs

Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe

constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OPANA ER is used

concomitantly with anticholinergic drugs.

Cimetidine

Clinical Impact: Cimetidine can potentiate opioid-induced respiratory depression.

Intervention: Monitor patients for respiratory depression when OPANA ER and cimetidine are used concurrently.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions

(5.3)]. Available data with OPANA ER in pregnant women are insufficient to inform a drug-associated risk for major birth defects

and miscarriage. In animal reproduction studies, reduced postnatal survival of pups and an increased incidence of stillborn pups were

observed following oral treatment of pregnant rats with oxymorphone during gestation and through lactation at doses 2.4 and 12 times

the human daily dose of 20 mg/day (HDD), respectively. Reduced fetal weights were observed with oral administration of

oxymorphone to pregnant rats and rabbits during organogenesis at exposures up to 4.9 and 48.8 times the HDD, respectively [see

Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a

background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of

major birth defects and miscarriage in clinical recognized pregnancies is 2-4% and 14-20%, respectively.

Reference ID: 4028719

Clinical Considerations

Fetal/Neonatal adverse reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes may cause fetal-neonatal physical

dependence and neonatal withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as

irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of

use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for

symptoms of neonatal opioid withdrawal syndrome, including poor feeding, diarrhea, irritability, tremor, rigidity, and

seizures, and manage accordingly [see Warning and Precautions (5.3)].

Labor or delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid

antagonist, such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. OPANA

ER 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. Opioid analgesics, including OPANA ER, can 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. Monitor neonates exposed to

opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal data

Pregnant rats were treated with oxymorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 5, 10, or 25

mg/kg/day (2.4, 4.9, or 12.2 times the HDD based on body surface area, respectively). Reduced mean fetal weights were

observed at 4.9 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights

in all groups and mortality in the high dose group).

Pregnant rabbits were treated with oxymorphone hydrochloride from Gestation Day 7 to 20 via oral gavage doses of 10, 25, or 50

mg/kg/day (9.8, 24.4, or 48.8 times the HDD based on body surface area, respectively). Decreased mean fetal weights were noted

at 48.8 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights).

Pregnant rats were treated with oxymorphone hydrochloride from Gestation Day 6 to Lactation Day 20 via oral gavage doses of 1,

5, 10, or 25 mg/kg/day (0.5, 2.4, 4.9, or 12.2 times the HDD based on body surface area, respectively). Increased neonatal death

(postnatal day 0-1) was noted at 2.4 times the HDD. Decreased pup survival over the first week of life, reduced pup birth weight,

and reduced postnatal weight gain were noted at 4.9 times the HDD. Maternal toxicity was noted in all treatment groups (reduced

food consumption and body weights in all groups and mortality in the 10 and 25 mg/kg/day groups).

8.2 Lactation

In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of 153

mg/kg oxymorphone hydrochloride (62.2 times the HDD) on Gestation Day 8 to pregnant hamsters. This dose also produced

significant maternal toxicity (20% maternal deaths).

Risk Summary

There is no information regarding the presence of oxymorphone in human milk, the effects on the breastfed infant, or the effects on

milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a

breastfed infant, advise patients that breastfeeding is not recommended during treatment with OPANA ER.

Clinical Considerations

Monitor infants exposed to OPANA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms

can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these

effects on fertility are reversible [Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of OPANA ER in patients below the age of 18 years have not been established.

Reference ID: 4028719

8.5 Geriatric Use

Of the total number of subjects in clinical studies of oxymorphone hydrochloride extended-release tablets, 27% were 65 and over,

while 9% were 75 and over. No overall differences in effectiveness were observed between these subjects and younger subjects.

There were several adverse events that were more frequently observed in subjects 65 and over compared to younger subjects. These

adverse events included dizziness, somnolence, confusion, and nausea. On average, age greater than 65 years was associated with an

increase in oxymorphone AUC and Cmax. Initiate dosing with OPANA ER in patients 65 years of age and over using the 5 mg dose

and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating OPANA ER. For

patients on prior opioid therapy, start at 50% of the starting dose for a younger patient on prior opioids and titrate slowly.

Oxymorphone is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in

patients with impaired renal function. Because the elderly patients are more likely to have decreased renal function, care should be

taken in dose selection, and it may be useful to monitor renal function.

8.6 Hepatic Impairment

Patients with mild hepatic impairment have an increase in oxymorphone bioavailability compared to the subjects with normal hepatic

function. In opioid-naïve patients with mild hepatic impairment, initiate OPANA ER using the 5 mg dose and monitor closely for

respiratory and central nervous system depression. OPANA ER is contraindicated for patients with moderate and severe hepatic

impairment [see Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.8), and, Clinical

Pharmacology (12.3)]. For patients on prior opioid therapy, start at the 50% of the dose for that a patient with normal hepatic function

on prior opioids and titrate slowly.

8.7 Renal Impairment

Patients with moderate to severe renal impairment were shown to have an increase in oxymorphone compared to the subjects with

normal renal function [see Clinical Pharmacology (12.3)]. Start opioid-naïve patients with the 5 mg dose of OPANA ER and titrate

slowly while closely monitoring for respiratory and central nervous system depression [see Dosage and Administration (2.6)]. For

patients on prior opioid therapy, start at 50% of the dose for a patient with normal renal function on prior opioids and titrate slowly.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

OPANA ER contains oxymorphone, a Schedule II controlled substance.

The high drug content in extended release formulations adds to the risk of adverse outcomes from abuse and misuse.

9.2 Abuse

OPANA ER contains oxymorphone, a substance with a high potential for abuse similar to other opioids including fentanyl,

hydrocodone, hydromorphone, methadone, morphine, oxycodone, and tapentadol. OPANA ER can be abused and is subject to misuse,

addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products

carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of prescription drug, even once, for its rewarding psychological or

physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and

includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher

priority given to drug use than to other activities and obligations, increased tolerance , and sometimes a physical withdrawal.

"Drug seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or

visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions,

tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare

provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and

people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient

with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that

addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of

opioids can occur in the absence of true addiction.

OPANA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of

prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised.

Reference ID: 4028719

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are

appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of OPANA ER

OPANA ER is for oral use only. Abuse of OPANA ER poses a risk of overdose and death. This risk is increased with concurrent

abuse of OPANA ER with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved OPANA ER enhances

drug release and increases the risk of over dose and death.

With parenteral abuse, cases of thrombotic microangiopathy (a condition characterized clinically by thrombocytopenia and

microangiopathic hemolytic anemia) have been reported; many cases resulted in hospitalization and treatment with plasmapheresis.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of

opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may

occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug.

Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, (e.g., naloxone, nalmefene),

mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical

dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage

OPANA ER should not be abruptly discontinued [see Dosage and Administration (2.3)]. If OPANA ER is abruptly discontinued in a

physically-dependent patient, withdrawal syndrome may occur. Some or all of the following can characterize this syndrome:

restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may

develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting,

diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and

withdrawal signs [see Use in Specific Populations (8.2)].

10 OVERDOSAGE

Clinical Presentation

Acute overdosage with OPANA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal

muscle flaccidity, cold and clammy skin, constricted pupils, and, some cases, pulmonary edema, bradycardia, hypotension, partial or

complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in

overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled

ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock

and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose.

For clinically significant respiratory or circulatory depression secondary to oxymorphone overdose, administer an opioid antagonist.

Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary

to oxymorphone overdose.

Because the duration of opioid reversal is expected to be less than the duration of action of oxymorphone in OPANA ER, carefully

monitor the patient until spontaneous respiration is reliably reestablished. OPANA ER will continue to release oxymorphone and add

to the oxymorphone load for 24 hour to 48 hours or longer following ingestion, , necessitating prolonged monitoring. If the response

to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed in the product’s prescribing

information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate

an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical

dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically

dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the

antagonist.

Reference ID: 4028719

11 DESCRIPTION

OPANA ER extended-release tablets are for oral use and contain oxymorphone, an opioid agonist. OPANA ER extended-release

tablets are supplied in 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 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, polyethylene oxide, polyethylene glycol, α-tocopherol, citric

acid, polyvinyl alcohol, titanium dioxide, macrogol and talc.

In addition, the 5 mg, 7.5 mg and 30 mg tablets contain iron oxide red. The 7.5 mg tablets contain iron oxide black, and iron oxide

yellow. 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, and D&C yellow No. 10.

The chemical name of 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:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Oxymorphone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid

receptors at higher doses. The principal therapeutic action of oxymorphone is analgesia. Like all full opioid agonists, there is no

ceiling effect for analgesia with oxycodoneoxymorphone [editorial change]. Clinically, dosage is titrated to provide adequate

analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of analgesia, the principal therapeutic action of oxymorphone, is unknown. However, specific CNS opioid

receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are

thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when OPANA ER is used in conjunction with alcohol, other opioids, or illicit

drugs that cause central nervous system depression.

Effects on the Central Nervous System

Oxymorphone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves

a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical

stimulation. Oxymorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not

pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than

miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and on Other Smooth Muscle

Oxymorphone causes a reduction in motility and is associated with an increase in tone in the antrum of the stomach and duodenum.

Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon

are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a

reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Oxymorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine can

occur and may contribute to opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may

include, pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Reference ID: 4028719

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse

Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as

low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of

hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal

hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)].

Effects on the 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. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective plasma concentration of oxymorphone will varyies [editorial change] widely among patients, especially

among patients who have been previously treated with agonist opioids. The minimum effective analgesic concentration of

oxymorphone for any individual patient may increase over time due to an increase in pain, development of a new pain syndrome,

and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.2)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing oxymorphone plasma concentration and increasing frequency of dose-related opioid

adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be

altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

12.3 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 doses of oxymorphone hydrochloride extendedrelease

tablets, for both peak plasma levels (Cmax) and extent of absorption (AUC) (see Table 4).

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

Pharmacokinetic Parameters

Regimen Dosage Cmax

(ng/mL)

AUC0-12h

(ng·hr/mL)

T ½

(hr)

Single Dose 5 mg

10 mg

20 mg

40 mg

0.27±0.13

0.65±0.29

1.21±0.77

2.59±1.65

4.54±2.04

8.94±4.16

17.81±7.22

37.90±16.20

11.30±10.81

9.83±5.68

9.89±3.21

9.35±2.94

Multiple Dosea 5 mg

10 mg

20 mg

40 mg

0.70±0.55

1.24±0.56

2.54±1.35

4.47±1.91

5.60±3.87

9.77±3.52

19.28±8.32

36.98±13.53

NA

NA

NA

NA

NA = not applicable

a Results after 5 days of q12h dosing.

Food Effect

Two studies examined the effect of food on the bioavailability of single doses of 20 and 40 mg of oxymorphone hydrochloride

extended-release tablets in healthy volunteers. In both studies, after the administration of oxymorphone hydrochloride extendedrelease

tablets, the Cmax was increased by approximately 50% in fed subjects compared to fasted subjects. A similar increase in Cmax

was also observed with oxymorphone solution.

The AUC was unchanged in one study and increased by approximately 18% in the other study in fed subjects following the

administration of oxymorphone hydrochloride extended-release tablets. Examination of the AUC suggests that most of the difference

between fed and fasting conditions occurs in the first four hours after dose administration. After oral dosing with a single dose of 40

mg, a peak oxymorphone plasma level of 2.8 ng/ml is achieved at 1hour in fasted subjects and a peak of 4.25 ng/ml is achieved at 2

hours in fed subjects and that beyond the 12 hour time point, there is very little difference in the curves. As a result, OPANA ER

should be dosed at least one hour prior to or two hours after eating [see Dosage and Administration (2.1, 2.2)].

Reference ID: 4028719

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%.

Elimination

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-oxymorphone AUC is approximately 70% of

the oxymorphone AUC following single oral doses, but is essentially equivalent to the parent compound at steady-state.

Excretion

Because oxymorphone is extensively metabolized, <1% of the administered dose is excreted unchanged in the urine. On

average, 33% to 38% of the administered dose is excreted in the urine as oxymorphone-3-glucuronide and less than 1%

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.

Specific Populations

Geriatric Patients

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 Use in Specific Populations (8.5)].

Sex

The effect of sex was evaluated following single- and multiple-doses of oxymorphone hydrochloride extended-release tablets in male

and female adult volunteers. There was a consistent tendency for female subjects to have slightly higher AUCss and Cmax values than

male subjects; however, sex differences were not observed when AUCss and Cmax were adjusted by body weight.

Hepatic Impairment

The bioavailability of orally administered oxymorphone is markedly increased in patients with moderate to severe liver disease. The

disposition of oxymorphone was compared in six patients with mild, five 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.

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 Interaction Studies

Alcohol Interaction

An in vivo study of the effect of alcohol (40%, 20%, 4% and 0%) on the bioavailability of a single dose of 40 mg of oxymorphone

hydrochloride extended-release tablets in healthy, fasted volunteers demonstrated a highly variable effect on Cmax with concomitant

administration of alcohol and oxymorphone hydrochloride extended-release tablets. The change in Cmax ranged from a decrease of

50% to an increase of 270% across all conditions studied. Following 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 coadministration

of oxymorphone hydrochloride extended-release tablets 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). The oxymorphone mean AUC

was 13% higher after co-administration of 240 mL of 40% alcohol. The AUC was essentially unaffected in subjects following the coadministration

of oxymorphone hydrochloride extended-release tablets and ethanol (240 mL of 20% or 4% ethanol).

Reference ID: 4028719

In vitro studies have demonstrated that oxymorphone hydrochloride extended-release tablets does not release oxymorphone more

rapidly in 500 mL of 0.1N HCl solutions containing ethanol (4%, 20%, and 40%),

Instruct patients to avoid use of alcohol when taking OPANA ER.

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 ≤15.1 μg/mL. An inhibition of CYP3A4 activity occurred at oxymorphone concentrations ≥45.3 μg/mL.

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 oxymorphone hydrochloride extended-release tablets 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No evidence of carcinogenic potential was observed in long-term animal studies in mice and rats. Oxymorphone hydrochloride 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. Systemic drug exposure (AUC) at the highest doses tested in male and female rats was 4.8 times and 21.2 times the human

exposure at a dose of 20 mg/day, respectively. Oxymorphone hydrochloride was administered to male and female CD-1 mice (10, 25,

75 and 150 mg/kg/day) for 2 years by oral gavage. Systemic drug exposure (AUC) at 150 mg/kg/day in male and female mice was

205 times and 243 times the human exposure at a dose of 20 mg/day, respectively.

Mutagenesis

Oxymorphone hydrochloride was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test), or in an in

vitro mammalian cell chromosome aberration assay performed with human peripheral blood lymphocytes. Oxymorphone

hydrochloride tested positive in both the rat and mouse in vivo micronucleus assays. An increase in micronucleated polychromatic

erythrocytes occurred in mice given doses ≥250 mg/kg and in rats given doses of 20 and 40 mg/kg. A subsequent study demonstrated

that oxymorphone hydrochloride was not aneugenic in mice following administration of up to 500 mg/kg. Additional studies indicate

that the increased incidence of micronucleated polychromatic erythrocytes in rats may be secondary to increased body temperature

following oxymorphone administration. Doses associated with increased micronucleated polychromatic erythrocytes also produce a

marked, rapid increase in body temperature. Pretreatment of animals with sodium salicylate minimized the increase in body

temperature and prevented the increase in micronucleated polychromatic erythrocytes after administration of 40 mg/kg oxymorphone.

Impairment of Fertility

Female rats were treated with oxymorphone hydrochloride beginning 14 days prior to mating through Gestation Day 7 via oral gavage

doses of 5, 10, or 25 mg/kg/day (2.4, 4.9, or 12.2 times the human daily dose of 20 mg/day based on body surface area, respectively).

Male rats were treated via oral gavage with the same oxymorphone hydrochloride doses beginning 28 days prior to and throughout

mating. 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 4.9 times the human dose of 20 mg/day. No adverse effects of oxymorphone on male

reproductive function or sperm parameters were observed.

14 CLINICAL STUDIES

The efficacy and safety of oxymorphone hydrochloride extended-release tablets 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 non-opioid therapy entered a 4-week, open-label dose

titration phase. Patients initiated therapy with two days of treatment with oxymorphone hydrochloride extended-release tablets 5 mg,

every 12 hours. Thereafter, patients were titrated to a stabilized dose, at increments of 5 to 10 mg every 12 hours every 3 to 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 oxymorphone hydrochloride extended-release tablets.

The mean±SD stabilized doses were 39.2±26.4 mg and 40.9±25.3 mg for the oxymorphone hydrochloride extended-release tablets and

placebo groups, respectively; total daily doses ranged from 10 to 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 oxymorphone hydrochloride

Reference ID: 4028719

extended-release tablets completed the 12-week treatment compared to 47% of patients treated with placebo. Oxymorphone

hydrochloride extended-release tablets provided superior analgesia compared to placebo. The analgesic effect of oxymorphone

hydrochloride extended-release tablets 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.

The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 1. The figure is

cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below

30%. Patients who did not complete the study were assigned 0% improvement.

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 on chronic opioid therapy entered a 4-week, open-label titration phase with oxymorphone hydrochloride extended-release

tablets 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

oxymorphone hydrochloride extended-release tablets. The mean±SD stabilized doses were 80.9±59.3 mg and 93.3±61.3 mg for the

oxymorphone hydrochloride extended-release tablets 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 oxymorphone hydrochloride extended-release tablets dose titration. Seventy percent of patients treated with

oxymorphone hydrochloride extended-release tablets and 26% of patients treated with placebo completed the 12-week treatment.

Oxymorphone hydrochloride extended-release tablets provided superior analgesia compared to placebo. The analgesic effect of

oxymorphone hydrochloride extended-release tablets 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.

The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 2. The figure is

cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below

30%. Patients who did not complete the study were assigned 0% improvement.

Reference ID: 4028719

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

16 HOW SUPPLIED/STORAGE AND HANDLING

OPANA ER extended-release tablets are supplied as follows:

5 mg

Pink, round, film-coated, biconcave extended-release tablets debossed with an “E” on one side and a “5” on the other side.

Bottles of 60 with child-resistant closure NDC 63481-812-60

Bottles of 100 with child-resistant closure NDC 63481-812-70

Unit-Dose package of 20 tablets

(2 blister cards of 10 tablets, not child-resistant,

for hospital use only) NDC 63481-812-20

7.5 mg

Gray, round, film coated, biconcave extended-release tablets debossed with an “E” on one side and a “7 ½” on the other side.

Bottles of 60 with child-resistant closure NDC 63481-813-60

Bottles of 100 with child-resistant closure NDC 63481-813-70

Unit-Dose package of 20 tablets

(2 blister cards of 10 tablets, not child-resistant,

for hospital use only) NDC 63481-813-20

10 mg

Light orange, round, film-coated, biconcave extended-release tablets debossed with an “E” on one side and a “10” on the other side.

Bottles of 60 with child-resistant closure NDC 63481-814-60

Bottles of 100 with child-resistant closure NDC 63481-814-70

Unit-Dose package of 20 tablets

(2 blister cards of 10 tablets, not child-resistant,

for hospital use only) NDC 63481-814-20

15 mg

White, round, film-coated, biconcave extended-release tablets debossed with an “E” on one side and a “15” on the other side.

Bottles of 60 with child-resistant closure NDC 63481-815-60

Bottles of 100 with child-resistant closure NDC 63481-815-70

Unit-Dose package of 20 tablets

(2 blister cards of 10 tablets, not child-resistant,

for hospital use only) NDC 63481-815-20

Reference ID: 4028719

20 mg

Light green, round, film-coated, biconcave extended-release tablets debossed with an “E” on one side and a “20” on the other side.

Bottles of 60 with child-resistant closure NDC 63481-816-60

Bottles of 100 with child-resistant closure NDC 63481-816-70

Unit-Dose package of 20 tablets

(2 blister cards of 10 tablets, not child-resistant,

for hospital use only) NDC 63481-816-20

30 mg

Red, round, film-coated, biconcave extended-release tablets debossed with an “E” on one side and a “30” on the other side.

Bottles of 60 with child-resistant closure NDC 63481-817-60

Bottles of 100 with child-resistant closure NDC 63481-817-70

Unit-Dose package of 20 tablets

(2 blister cards of 10 tablets, not child-resistant,

for hospital use only) NDC 63481-817-20

40 mg

Light yellow to pale yellow, round, film-coated, biconcave extended-release tablets debossed with an “E” on one side and a “40” on

the other side.

Bottles of 60 with child-resistant closure NDC 63481-818-60

Bottles of 100 with child-resistant closure NDC 63481-818-70

Unit-Dose package of 20 tablets

(2 blister cards of 10 tablets, not child-resistant,

for hospital use only) NDC 63481-818-20

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).

17 PATIENT COUNSELING INFORMATION

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

Addiction, Abuse, and Misuse

Inform patients that the use of OPANA ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can

lead to overdose or death [see Warnings and Precautions (5.1)]. Instruct patients not to share OPANA ER with others and to take

steps to protect OPANA ER from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting

OPANA ER or when the dosage is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)].

Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and

Precautions (5.2)]. Instruct patients to take steps to store OPANA ER securely and to dispose of unused OPANA ER by flushing the

tablets down the toilet.

Interactions with Benzodiazepines and other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if OPANA ER is used with benzodiazepines or other

CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and

Precautions (5.4), Drug Interactions (7)].

Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during

treatment with OPANA ER. The co-ingestion of alcohol with OPANA ER may result in increased plasma levels and a potentially

fatal overdose of oxymorphone [see Warnings and Precautions (5.4)].

Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions

Inform patients that anaphylaxis and other hypersensitivity reactions have been reported with ingredients contained in OPANA ER.

Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Warnings and

Precautions (5.6), Adverse Reactions (6)].

Reference ID: 4028719

Serotonin Syndrome

Inform patients that OPANA ER could cause a rare but potentially life-threatening condition resulting from concomitant

administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away

if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications

[see Drug Interactions (7)].

MAOI Interaction

Inform patients to avoid taking OPANA ER while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs

while taking OPANA ER [see Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may

present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood

pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and

Precautions (5.7)].

Important Administration Instructions

Instruct patients how to properly take OPANA ER, including the following:

• OPANA ER is designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved OPANA

ER tablets can result in a fatal overdose [see Dosage and Administration (2.1)].

• OPANA ER tablets should be taken one tablet at a time [see Dosage and Administration (2.1)].

• Do not pre-soak, lick or otherwise wet the tablet prior to placing in the mouth [see Dosage and Administration (2.1)].

• Take each tablet with enough water to ensure complete swallowing immediately after placing in the mouth [see Dosage and

Administration (2.1)].

• Occasionally, the inactive ingredients of OPANA ER may be eliminated as a soft mass in the stool that may resemble the original

tablet. Inform patients that the active medication has already been absorbed by the time the patient sees the soft mass.

• Use OPANA ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see

Dosage and Administration (2), Warnings and Precautions (2.1)].

• Do not discontinue OPANA ER without first discussing the need for a tapering regimen with the prescriber [see Dosage and

Administration (2.4), Warnings and Precautions (5.14)].

Hypotension

Inform patients that OPANA ER may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low

blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from

a sitting or lying position).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in OPANA ER. Advise patients how to recognize such a

reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of OPANA ER during pregnancy can result in neonatal

opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions

(5.3), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that OPANA ER can cause fetal harm and to inform their healthcare

provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with OPANA ER [see Use in Specific Populations (8.2)]

Reference ID: 4028719

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible

[see Adverse Reactions (6.2), Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that OPANA ER may impair the ability to perform potentially hazardous activities such as driving a car or operating

heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and

Precautions (5.15)].

Constipation

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

Adverse Reactions (6), Clinical Pharmacology (12.2)].

Disposal of Unused OPANA ER

Advise patients to flush the unused tablets down the toilet when OPANA ER is no longer needed.

Distributed by:

Endo Pharmaceuticals Inc.

Malvern, PA 19355

Manufactured by:

Pharmaceuticals Manufacturing Research Services Inc.

Horsham, PA 19044

INTAC® is a registered trademark of the Grünenthal Group

© 2016 Endo Pharmaceuticals Inc. All rights reserved.

117835

Reference ID: 4028719

Medication Guide

OPANA®ER (Ō-pan-a) (oxymorphone hydrochloride) extended-release tablets, for oral use, CII

OPANA ER is:

• A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough

to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as nonopioid

pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot

tolerate them.

• A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if

you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead

to death.

• Not for use to treat pain that is not around-the-clock.

Important information about OPANA ER:

• Get emergency help right away if you take too much OPANA ER (overdose). When you first start taking

OPANA ER, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing

problems that can lead to death may occur.

• Taking OPANA ER with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants

(including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

• Never give anyone your OPANA ER. They could die from taking it. Store OPANA ER away from children and in a safe

place to prevent stealing or abuse. Selling or giving away OPANA ER is against the law.

Do not take OPANA ER if you have:

• severe asthma, trouble breathing, or other lung problems.

• a bowel blockage or have narrowing of the stomach or intestines.

Before taking OPANA ER, tell your healthcare provider if you have a history of:

• head injury, seizures ● liver, kidney, thyroid problems

• problems urinating ● pancreas or gallbladder problems

• abuse of street or prescription drugs, alcohol addiction, or mental health problems.

Tell your healthcare provider if you are:

• pregnant or planning to become pregnant. Prolonged use of OPANA ER during pregnancy can cause withdrawal

symptoms in your newborn baby that could be life-threatening if not recognized and treated.

• breastfeeding. Not recommended during treatment with OPANA ER. It may harm your baby.

• taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking OPANA ER with certain

other medicines can cause serious side effects that could lead to death.

When taking OPANA ER:

• Do not change your dose. Take OPANA ER exactly as prescribed by your healthcare provider. Use the lowest dose

possible for the shortest time needed.

• Take your prescribed dose every 12 hours at the same time every day on an empty stomach, at least 1 hour

before or 2 hours after meals. Do not take more than your prescribed dose in 24 hours. If you miss a dose, take

your next dose at your usual time.

• Swallow OPANA ER whole. Do not cut, break, chew, crush, dissolve, snort, or inject OPANA ER because this may

cause you to overdose and die.

• To avoid choking on the tablet OPANA ER should be taken 1 tablet at a time. Do not pre-soak, lick, or wet the

tablet before placing in your mouth.

• Call your healthcare provider if the dose you are taking does not control your pain.

• Do not stop taking OPANA ER without talking to your healthcare provider.

• After you stop taking OPANA ER, flush any unused tablets down the toilet.

While taking OPANA ER DO NOT:

• Drive or operate heavy machinery, until you know how OPANA ER affects you. OPANA ER can make you sleepy,

dizzy, or lightheaded.

• Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing

alcohol during treatment with OPANA ER may cause you to overdose and die.

The possible side effects of OPANA ER:

• constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare

provider if you have any of these symptoms and they are severe.

Get emergency medical help if you have:

trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, or hands,

hives, itching, rash, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body

temperature, trouble walking, stiff muscles, or mental changes such as confusion.

These are not all the possible side effects of OPANA ER. Call your doctor for medical advice about side effects. You

may report side effects to FDA at class="baec5a81-e4d6-4674-97f3-e9220f0136c1" ="white-space: nowrap;">1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov

Distributed by: Endo Pharmaceuticals Inc., Malvern, PA 19355, www.endo.com or call class="baec5a81-e4d6-4674-97f3-e9220f0136c1" ="white-space: nowrap;">1-800-462-3636

OPANA® is a registered trademark of Endo Pharmaceuticals Inc.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: December 2016

117836

Reference ID: 4028719

NDC 60760-617-60 CII

OPANA

Extended-Release Tablets

(Oxymorphone HCI)

20 mg

QTY: 60

LOT# XXXXXXX

EXP XX-XX

RX# 0000000

MANUFACTURED BY:

Novartis

Lincoln, NE 68501

60760-617-60

OPANA

Extended-Release Tablets

(Oxymorphone HCI)

20mg

QTY: 60

RX# 0000000

NDC 60760-617-60

LOT# XXXXXXX

EXP XX-XX

St. mary's mpp

PACKAGED BY:

St. Mary's

10860 MAVINEE DR.

ORO VALLEY,AZ 85737

MANAGED PHARMACY PROGRAMS

TAKE AS DIRECTED

Rx only STORE AT CONTROLLED ROOM TEMPERATURE 15 degree - 30 degree C (59 degree -86 degree F).