FDA Label for Oxymorphone Hydrochloride

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

1 Indications And Usage

Oxymorphone Hydrochloride Extended-Release Tablets are 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.

2 Dosage And Administration

2.1 Important Dosage And Administration Instructions

Oxymorphone Hydrochloride Extended-Release Tablets 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)]. 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 to 72 hours of initiating therapy and following dosage increases with Oxymorphone Hydrochloride Extended-Release Tablets and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Instruct patients to swallow Oxymorphone Hydrochloride Extended-Release Tablets whole [see Patient Counseling Information (17)] . Crushing, chewing, or dissolving Oxymorphone Hydrochloride Extended-Release 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.

Oxymorphone Hydrochloride Extended-Release Tablets are administered orally twice daily (every 12 hours).

2.3 Titration And Maintenance Of Therapy

Individually titrate Oxymorphone Hydrochloride Extended-Release Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxymorphone Hydrochloride Extended-Release Tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, and misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During chronic therapy, periodically reassess the continued need for the use of opioid analgesics.

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

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

When a patient no longer requires therapy with Oxymorphone Hydrochloride Extended-Release Tablets, 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 Oxymorphone Hydrochloride Extended-Release Tablets [see Warnings and Precautions (5.13) , Drug Abuse and Dependence (9.3)].

2.5 Dosage Modifications In Patients With Hepatic Impairment

Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated in patients with moderate or severe hepatic impairment.

In opioid-naïve patients with mild hepatic impairment, initiate treatment with the 5 mg dose. For patients on prior opioid therapy, start Oxymorphone Hydrochloride Extended-Release Tablets 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)].

2.6 Dosage Modifications In Patients With Renal Impairment

In patients with creatinine clearance rates less than 50 mL/min, start Oxymorphone Hydrochloride Extended-Release Tablets in the opioid-naïve patient with the 5 mg dose. For patients on prior opioid therapy, start Oxymorphone Hydrochloride Extended-Release Tablets 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 Modifications In Geriatric Patients

The steady-state plasma concentrations of oxymorphone are higher in elderly subjects than in young subjects. Initiate dosing with Oxymorphone Hydrochloride Extended-Release Tablets in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets at 50% lower than the starting dose for a younger patient on prior opioids and titrate slowly.

3 Dosage Forms And Strengths

The 5 mg dosage form is a purple, round, film-coated extended-release tablet debossed with "G71" on one side and blank on the other side.

The 7.5 mg dosage form is a gray, round, film-coated extended-release tablet debossed with "G75" on one side and blank on the other side.

The 10 mg dosage form is an orange, round, film-coated extended-release tablet debossed with "G72" on one side and blank on the other side.

The 15 mg dosage form is a white, round, film-coated extended-release tablet debossed with "G76" on one side and blank on the other side.

The 20 mg dosage form is a green, round, film-coated extended-release tablet debossed with "G73" on one side and blank on the other side.

The 30 mg dosage form is a brown, round, film-coated extended-release tablet debossed with "G77" on one side and blank on the other side.

The 40 mg dosage form is an orange, round, film-coated extended-release tablet debossed with "G74" on one side and blank on the other side.

4 Contraindications

Oxymorphone Hydrochloride Extended-Release Tablets are 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 (e.g., anaphylaxis) to oxymorphone, any other ingredients in Oxymorphone Hydrochloride Extended-Release Tablets [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)]

5.1 Addiction, Abuse, And Misuse

Oxymorphone Hydrochloride Extended-Release Tablets contain oxymorphone, a Schedule II controlled substance. As an opioid, Oxymorphone Hydrochloride Extended-Release Tablets expose users to the risks of addiction, abuse, and misuse. Because extended-release products such as Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid abuse or addiction, abuse, or misuse prior to prescribing Oxymorphone Hydrochloride Extended-Release Tablets, and monitor all patients receiving Oxymorphone Hydrochloride Extended-Release Tablets for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of Oxymorphone Hydrochloride Extended-Release Tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Oxymorphone Hydrochloride Extended-Release Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Oxymorphone Hydrochloride Extended-Release Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse, or misuse of Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets. 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 Oxymorphone Hydrochloride Extended-Release Tablets, the risk is greatest during the initiation of therapy or following a dose increase. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dose increases of Oxymorphone Hydrochloride Extended-Release Tablets.

To reduce the risk of respiratory depression, proper dosing and titration of Oxymorphone Hydrochloride Extended-Release Tablets are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the Oxymorphone Hydrochloride Extended-Release Tablet dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of Oxymorphone Hydrochloride Extended-Release Tablets, 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 Oxymorphone Hydrochloride Extended-Release Tablets during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) , Patient Counseling Information (17)].

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 Oxymorphone Hydrochloride Extended-Release Tablet therapy. The co-ingestion of alcohol with Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets 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 drug-related 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 Oxymorphone Hydrochloride Extended-Release Tablets are used with benzodiazepines 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)].

5.5 Risk Of Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients

The use of Oxymorphone Hydrochloride Extended-Release Tablets 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: Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets [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 Oxymorphone Hydrochloride Extended-Release Tablets and when Oxymorphone Hydrochloride Extended-Release Tablets are 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 Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets immediately, discontinue Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3)]. Oxymorphone Hydrochloride Extended-Release Tablets are 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

Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets. In patients with circulatory shock, Oxymorphone Hydrochloride Extended-Release Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Oxymorphone Hydrochloride Extended-Release Tablets 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), Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Oxymorphone Hydrochloride Extended-Release Tablets in patients with impaired consciousness or coma.

5.11 Risks Of Use In Patients With Gastrointestinal Conditions

Oxymorphone Hydrochloride Extended-Release Tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. 

The oxymorphone in Oxymorphone Hydrochloride Extended-Release Tablets 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.

5.12 Increased Risk Of Seizures In Patients With Seizure Disorders

The oxymorphone in Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets therapy.

5.13 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 Oxymorphone Hydrochloride Extended-Release Tablets. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing Oxymorphone Hydrochloride Extended-Release Tablets, gradually taper the dose [see Dosage and Administration (2.4)]. Do not abruptly discontinue Oxymorphone Hydrochloride Extended-Release Tablets. 

5.14 Risks Of Driving And Operating Machinery

Oxymorphone Hydrochloride Extended-Release Tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Oxymorphone Hydrochloride Extended-Release Tablets and know how they will react to the medication.

6 Adverse Reactions

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

• 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)] 
• Seizures [see Warnings and Precautions (5.12)]
• Withdrawal [see Warnings and Precautions (5.13)]

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 Extended-Release Tablets were chest pain, pneumonia and vomiting.

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

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

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

Eye disorders: vision blurred

Gastrointestinal disorders: diarrhea, abdominal pain, dyspepsia

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

Nervous system disorders: insomnia

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

Respiratory, thoracic and mediastinal disorders: dyspnea

Vascular disorders: flushing and hypertension

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

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 Oxymorphone Hydrochloride Extended-release Tablets.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12)]

7 Drug Interactions

Table 4 includes clinically significant drug interactions with Oxymorphone Hydrochloride Extended-Release Tablets.

8.2 Lactation

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 Oxymorphone Hydrochloride Extended-Release Tablets.

Clinical Considerations

Monitor infants exposed to Oxymorphone Hydrochloride Extended-Release Tablets 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 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 Oxymorphone Hydrochloride Extended-Release Tablets in patients below the age of 18 years have not been established.

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 a 1.4-fold increase in oxymorphone AUC and a 1.5-fold increase in C_max. Initiate dosing with Oxymorphone Hydrochloride Extended-Release Tablets in patients 65 years of age and over using the 5 mg dose and monitor closely for signs of respiratory and central nervous system depression when initiating and titrating Oxymorphone Hydrochloride Extended-Release Tablets. 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 of 1.6-fold. In opioid-naïve patients with mild hepatic impairment, initiate Oxymorphone Hydrochloride Extended-Release Tablets using the 5 mg dose and monitor closely for respiratory and central nervous system depression. Oxymorphone Hydrochloride Extended-Release Tablets are 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 bioavailability compared to the subjects with normal renal function [see Clinical Pharmacology (12.3)]. Start opioid-naïve patients with the 5 mg dose of Oxymorphone Hydrochloride Extended-Release Tablets 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.

9.1 Controlled Substance

Oxymorphone Hydrochloride Extended-Release Tablets contain oxymorphone, a Schedule II controlled substance.

9.2 Abuse

Oxymorphone Hydrochloride Extended-Release Tablets contains oxymorphone a substance with a high potential for abuse similar to other opioids fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and tapentadol. Oxymorphone Hydrochloride Extended-Release Tablets 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, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

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

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance , and sometimes a physical withdrawal.

"Drug seeking" behavior is very common 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 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.

Oxymorphone Hydrochloride Extended-Release Tablets, 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 law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.

Risks Specific to Abuse of Oxymorphone Hydrochloride Extended-Release Tablets

Oxymorphone Hydrochloride Extended-Release Tablets are for oral use only. Abuse of Oxymorphone Hydrochloride Extended-Release Tablets poses a risk of overdose and death. This risk is increased with concurrent abuse of Oxymorphone Hydrochloride Extended-Release Tablets with alcohol and other substances. Taking cut, broken, chewed, crushed, or dissolved Oxymorphone Hydrochloride Extended-Release Tablets enhances drug release and increases the risk of over dose and death.

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 dose 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.

Oxymorphone Hydrochloride Extended-Release Tablets should not be abruptly discontinued [see Dosage and Administration (2.4)]. If Oxymorphone Hydrochloride Extended-Release Tablets are 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)].

11 Description

Oxymorphone Hydrochloride Extended-Release Tablets are for oral use and contain oxymorphone, a semi-synthetic opioid analgesic. Oxymorphone Hydrochloride 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: microcrystalline cellulose, lactose monohydrate, hypromellose, xanthan gum, magnesium stearate, polyvinyl alcohol - partially hydrolyzed, macrogol, talc, and titanium dioxide. The 5 mg, 7.5 mg, 10 mg, 20 mg, and 40 mg tablets contain FD&C Yellow No. 6 Aluminum Lake. In addition, the 5 mg tablets contain FD&C Blue No. 2 and D&C Red No. 27. The 7.5 mg tablets contain FD&C Blue No. 2 and FD&C Red No. 40. The 10 mg tablets contain FD&C Red No. 40. The 20 mg tablets contain D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1, and FD&C Blue No. 2. The 30 mg tablets contain Iron Oxide Yellow and Iron Oxide Black. The 40 mg tablets contain D&C Yellow No. 10 Aluminum Lake.

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:

Chemical Structure - oxymorphone hydrochloride extended release tablets 1

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 oxymorphone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when Oxymorphone Hydrochloride Extended-Release Tablets are 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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and on Other Smooth Muscle

Oxymorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone 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 pruritis, flushing, red eyes, sweating, and/or orthostatic hypotension.

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 varies 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 development of analgesic tolerance [see Dosage and Administration (2.1, 2.2, 2.3)].

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)].

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.

16 How Supplied/Storage And Handling

Oxymorphone Hydrochloride Extended-Release Tablets are supplied as follows:

17 Patient Counseling Information

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

Medication Guide

OXYMORPHONE HYDROCHLORIDE (ox” i mor’ fone hy” dro khlor’ ide) Extended-Release Tablets, for oral use, CII

Oxymorphone Hydrochloride Extended-Release Tablets are:

• 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 non-opioid 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 Oxymorphone Hydrochloride Extended-Release Tablets:

• Get emergency help right away if you take too much Oxymorphone Hydrochloride Extended-Release Tablets (overdose). When you first start taking Oxymorphone Hydrochloride Extended-Release Tablets, 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 Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets. They could die from taking it. Store Oxymorphone Hydrochloride Extended-Release Tablets away from children and in a safe place to prevent stealing or abuse. Selling or giving away Oxymorphone Hydrochloride Extended-Release Tablets is against the law.

Do not take Oxymorphone Hydrochloride Extended-Release Tablets if you have:

• severe asthma, trouble breathing, or other lung problems.
• a bowel blockage or have a narrowing of the stomach or intestines.

Before taking Oxymorphone Hydrochloride Extended-Release Tablets, tell your healthcare provider if you have a history of:

head injury, seizures problems urinating abuse of street or prescription drugs, alcohol addiction, or mental health problems

liver, kidney, thyroid problems pancreas or gallbladder problems

Tell your healthcare provider if you are:

• pregnant or planning to become pregnant. Prolonged use of Oxymorphone Hydrochloride Extended-Release Tablets during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
• breast-feeding. Not recommended during treatment with Oxymorphone Hydrochloride Extended-Release Tablets. It may harm your baby.
• taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Oxymorphone Hydrochloride Extended-Release Tablets with certain other medicines can cause serious side effects that could lead to death.

When taking Oxymorphone Hydrochloride Extended-Release Tablets:

• Do not change your dose. Take Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets whole. Do not cut, break, chew, crush, dissolve, snort, or inject Oxymorphone Hydrochloride Extended-Release Tablets because this may cause you to overdose and die.
• Call your healthcare provider if the dose you are taking does not control your pain.
• Do not stop taking Oxymorphone Hydrochloride Extended-Release Tablets without talking to your healthcare provider.
• After you stop taking Oxymorphone Hydrochloride Extended-Release Tablets, flush any unused tablets down the toilet.

While taking Oxymorphone Hydrochloride Extended-Release Tablets DO NOT:

• Drive or operate heavy machinery, until you know how Oxymorphone Hydrochloride Extended-Release Tablets affect you. Oxymorphone Hydrochloride Extended-Release Tablets 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 Oxymorphone Hydrochloride Extended-Release Tablets may cause you to overdose and die.

The possible side effects of Oxymorphone Hydrochloride Extended-Release Tablets:

• 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, 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 Oxymorphone Hydrochloride Extended-Release Tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov. For more information about Oxymorphone Hydrochloride Extended-Release Tablets, call Impax Laboratories, Inc. at 1-800-934-6729.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Dist. by:
Impax Generics
Hayward, CA 94544

779-14
Rev. 01/2017

Principal Display Panel - 5 Mg Tablet Bottle Label

NDC 0115-1231-01

Twice-A-Day (every 12 hours)
Oxymorphone
Hydrochloride
Extended-Release Tablets
CII

5 mg

PHARMACIST: Dispense
the Medication Guide
provided separately to
each patient.

Rx only
100 Tablets

Impax Generics

PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label - oxymorphone hydrochloride extended release tablets 4

Principal Display Panel - 7.5 Mg Tablet Bottle Label

NDC 0115-1315-01

Twice-A-Day (every 12 hours)
Oxymorphone
Hydrochloride
Extended-Release Tablets
CII

7.5 mg

PHARMACIST: Dispense
the Medication Guide
provided separately to
each patient.

Rx only
100 Tablets

 Impax Generics

PRINCIPAL DISPLAY PANEL - 7.5 mg Tablet Bottle Label - oxymorphone hydrochloride extended release tablets 5

Principal Display Panel - 10 Mg Tablet Bottle Label

NDC 0115-1232-01

Twice-A-Day (every 12 hours)
Oxymorphone
Hydrochloride
Extended-Release Tablets
CII

10 mg

PHARMACIST: Dispense
the Medication Guide
provided separately to
each patient.

Rx only
100 Tablets

Impax Generics

PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Label - oxymorphone hydrochloride extended release tablets 6

Principal Display Panel - 15 Mg Tablet Bottle Label

NDC 0115-1316-01

Twice-A-Day (every 12 hours)
Oxymorphone
Hydrochloride
Extended-Release Tablets
CII

15 mg

PHARMACIST: Dispense
the Medication Guide
provided separately to
each patient.

Rx only
100 Tablets

Impax Generics

PRINCIPAL DISPLAY PANEL - 15 mg Tablet Bottle Label - oxymorphone hydrochloride extended release tablets 7

Principal Display Panel - 20 Mg Tablet Bottle Label

NDC 0115-1233-01

Twice-A-Day (every 12 hours)
Oxymorphone
Hydrochloride
Extended-Release Tablets
CII

20 mg

PHARMACIST: Dispense
the Medication Guide
provided separately to
each patient.

Rx only
100 Tablets

Impax Generics

PRINCIPAL DISPLAY PANEL - 20 mg Tablet Bottle Label - oxymorphone hydrochloride extended release tablets 8

Principal Display Panel - 30 Mg Tablet Bottle Label

NDC 0115-1317-01

Twice-A-Day (every 12 hours)
Oxymorphone
Hydrochloride
Extended-Release Tablets
CII

30 mg

PHARMACIST: Dispense
the Medication Guide
provided separately to
each patient.

Rx only
100 Tablets

Impax Generics

PRINCIPAL DISPLAY PANEL - 30 mg Tablet Bottle Label - oxymorphone hydrochloride extended release tablets 9

Principal Display Panel - 40 Mg Tablet Bottle Label

NDC 0115-1234-01

Twice-A-Day (every 12 hours)
Oxymorphone
Hydrochloride
Extended-Release Tablets
CII

40 mg 

PHARMACIST: Dispense
the Medication Guide
provided separately to
each patient.

Rx only
100 Tablets

Impax Generics

PRINCIPAL DISPLAY PANEL - 40 mg Tablet Bottle Label - oxymorphone hydrochloride extended release tablets 10