Oxymorphone Tablets

• Tell all of your health care providers that you take this medicine (oxymorphone tablets). This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Do not take more than what your doctor told you to take. Taking more than you are told may raise your chance of very bad side effects.
• Do not take this medicine (oxymorphone tablets) with other strong pain drugs or if you are using a pain patch without talking to your doctor first.
• If you have been taking this medicine on a regular basis and you stop it all of a sudden, you may have signs of withdrawal. Do not stop taking this medicine (oxymorphone tablets) all of a sudden without calling your doctor. Tell your doctor if you have any bad effects.
• Allergic reactions have happened with this medicine. Rarely, some reactions can be very bad or life-threatening. Talk with the doctor.
• If you have been taking this medicine (oxymorphone tablets) for a long time or at high doses, it may not work as well and you may need higher doses to get the same effect. This is known as tolerance. Call your doctor if this medicine stops working well. Do not take more than ordered.
• Long-term use of an opioid drug like this medicine (oxymorphone tablets) may lead to lower sex hormone levels. This may lead to signs like change in sex ability in men, no menstrual period in women, lowered interest in sex, or fertility problems. Call your doctor if you have any of these signs.
• This medicine may raise the chance of seizures in some people, including people who have had seizures in the past. Talk to your doctor to see if you have a greater chance of seizures while taking this medicine.
• If you are 65 or older, use this medicine (oxymorphone tablets) with care. You could have more side effects.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.

Use this medicine (oxymorphone tablets) as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take on an empty stomach. Take 1 hour before or 2 hours after meals.
• Take by mouth only.
• Do not inject or snort this medicine. Doing any of these things can cause very bad side effects like trouble breathing and death from overdose.

What do I do if I miss a dose?

• If you take this medicine (oxymorphone tablets) on a regular basis, take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• Many times this medicine is taken on an as needed basis. Do not take more often than told by the doctor.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Important Dosage and Administration Instructions

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 24-72 hours of initiating therapy and following dosage increases with Oxymorphone Hydrochloride Tablets and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

Oxymorphone Hydrochloride Tablets should be administered on an empty stomach, at least one hour prior to or two hours after eating [see Clinical Pharmacology (12.3)].

To avoid medication errors, prescribers and pharmacists must be aware that oxymorphone is available as both immediate-release 5 mg and 10 mg tablets and extended-release 5 mg and 10 mg tablets [see Dosage Forms and Strengths (3)].

Initial Dosage

Use of Oxymorphone Hydrochloride Tablets as the first Opioid Analgesic 

Initiate treatment with Oxymorphone Hydrochloride Tablets in a dosing range of 10 to 20 mg every 4 to 6 hours as needed for pain.

Do not initiate treatment with doses higher than 20 mg because of the potential serious adverse reactions [see Clinical Studies (14.1)].

Conversion from Other Opioids to Oxymorphone Hydrochloride Tablets

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Oxymorphone Hydrochloride Tablets. It is safer to underestimate a patient’s 24-hour Oxymorphone Hydrochloride Tablets dosage than to overestimate the 24-hour Oxymorphone Hydrochloride Tablets dosage and manage an adverse reaction due to overdose.

For conversion from other opioids to Oxymorphone Hydrochloride Tablets, 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 Oxymorphone Hydrochloride Tablets therapy by administering half of the calculated total daily dose of Oxymorphone Hydrochloride Tablets in 4 to 6 equally divided doses, every 4-6 hours. The initial dose of Oxymorphone Hydrochloride Tablets can be gradually adjusted until adequate pain relief and acceptable side effects have been achieved.

Conversion from Parenteral Oxymorphone to Oxymorphone Hydrochloride Tablets

Given Oxymorphone Hydrochloride Tablet’s absolute oral bioavailability of approximately 10%, patients receiving parenteral oxymorphone may be converted to Oxymorphone Hydrochloride Tablets by administering 10 times the patient’s total daily parenteral oxymorphone dose as Oxymorphone Hydrochloride Tablets, in four or six equally divided doses (e.g., [IV dose x 10] divided by 4 or 6). For example, approximately 10 mg of Oxymorphone Hydrochloride Tablets four times daily may be required to provide pain relief equivalent to a total daily IM dose of 4 mg oxymorphone.   Due to patient variability with regard to opioid analgesic response, upon conversion patients should be closely monitored to ensure adequate analgesia and to minimize side effects.

Conversion from Oxymorphone Hydrochloride Tablets to Extended-Release Oxymorphone

The relative bioavailability of Oxymorphone Hydrochloride Tablets compared to extended-release oxymorphone is unknown, so conversion to extended-release tablets must be accompanied by close observation for signs of excessive sedation and respiratory depression.

Dosage Modifications in Patients with Mild Hepatic Impairment

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

Use Oxymorphone Hydrochloride Tablets with caution in patients with mild hepatic impairment, starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring for signs of respiratory and central nervous system depression [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Dosage Modifications in Patients with Renal Impairment

Use Oxymorphone Hydrochloride Tablets with caution in patients with creatinine clearance rates less than 50 mL/min., starting with the lowest dose (e.g., 5 mg) and titrating slowly while carefully monitoring for signs of respiratory and central nervous system depression [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Dosage Modifications in Geriatric Patients

Exercise caution in the selection of the starting dose of Oxymorphone Hydrochloride Tablets for an elderly patient by starting with the lowest dose (e.g., 5 mg) and titrate slowly while carefully monitoring for signs of respiratory and central nervous system depression [see Use in Specific Populations (8.5)].

Dosage Modifications with Concomitant Use with Central Nervous System Depressants

Oxymorphone Hydrochloride Tablets, like all opioid analgesics, should be started at one-third to one-half of the usual dose in patients who are concurrently receiving other central nervous system (CNS) depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, and alcohol, because respiratory depression, hypotension and profound sedation, coma or death may result [see Warnings and Precautions (5.4) and Drug Interactions (7)]. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.

Titration and Maintenance of Therapy

Individually titrate Oxymorphone Hydrochloride Tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxymorphone Hydrochloride 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, or misuse [see Warnings and Precautions (5.1)]. 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.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Oxymorphone Hydrochloride Tablets dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation of Oxymorphone Hydrochloride Tablets

When a patient who has been taking Oxymorphone Hydrochloride Tablets regularly and may be physically dependent no longer requires therapy with Oxymorphone Hydrochloride 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 Tablets in a physically-dependent patient [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.2, 9.3)].

Oxymorphone Hydrochloride 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)]

• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)]

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

• Moderate or severe hepatic impairment [see Warnings and Precautions (5.14)].

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions5.1)]

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

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

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

• Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions [see Warnings and Precautions (5.6 )]

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

• Severe Hypotension [see Warnings and Precautions (5.8)]

• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10 )]

• Seizures [see Warnings and Precautions (5.11 )]

• Withdrawal [see Warnings and Precautions (5.12)] 

Clinical Trials 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 practice.

A total of 591 patients were treated with Oxymorphone Hydrochloride Tablets in controlled clinical trials. The clinical trials consisted of patients with acute post-operative pain (n=557) and cancer pain (n=34) trials.

The following table lists adverse reactions that were reported in at least 2% of patients receiving Oxymorphone Hydrochloride Tablets in placebo-controlled trials (acute post-operative pain (N=557)).

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

Cardiac disorders: tachycardia

Gastrointestinal disorders: dry mouth, abdominal distention, and flatulence

General disorders and administration site conditions: sweating increased

Nervous system disorders: anxiety and sedation

Respiratory, thoracic and mediastinal disorders: hypoxia

Vascular disorders: hypotension

Other less common adverse reactions known with opioid treatment that were seen <1% in the Oxymorphone Hydrochloride Tablets trials includes the following:

Abdominal pain, ileus, diarrhea, agitation, disorientation, restlessness, feeling jittery, hypersensitivity, allergic reactions, bradycardia, central nervous system depression, depressed level of consciousness, lethargy, mental impairment, mental status changes, fatigue, depression, clamminess, flushing, hot flashes, dehydration, dermatitis, dyspepsia, dysphoria, edema, euphoric mood, hallucination, hypertension, insomnia, miosis, nervousness, palpitation, postural hypotension, syncope, dyspnea, respiratory depression, respiratory distress, respiratory rate decreased, oxygen saturation decreased, difficult micturition, urinary retention, urticaria, vision blurred, visual disturbances, weakness, appetite decreased, and weight decreased.

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 Tablets

Immune System Disorders: Angioedema, and other hypersensitivity reactions:

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

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.

Pharmacodynamics

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 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 may be 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. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and 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 analgesic concentration varies widely among patients, especially among patients who have been previously treated with potent agonist opioids The minimum effective analgesic concentration of oxymorphone for any individual patient may increase over time due to an increase in pain, the 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, 2.6)].

Pharmacokinetics

Absorption

The absolute oral bioavailability of oxymorphone is approximately 10%. Studies in healthy volunteers reveal predictable relationships between Oxymorphone Hydrochloride Tablets dosage and plasma oxymorphone concentrations.

Steady-state levels were achieved after three days of multiple dose administration. Under both single- dose and steady-state conditions, dose proportionality has been established for 5 mg, 10 mg and 20 mg doses of Oxymorphone Hydrochloride Tablets, for both peak plasma levels (Cmax) and extent of absorption (AUC) (see Table 3).

After oral dosing with 40 mg of Oxymorphone Hydrochloride Tablets in healthy volunteers under fasting conditions or with a high-fat meal, the Cmax and AUC were increased by approximately 38% in fed subjects relative to fasted subjects. As a result, Oxymorphone Hydrochloride Tablets should be dosed at least one hour prior to or two hours after eating [see Dosage and Administration (2.2)].

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

Oxymorphone Hydrochloride Tablets half-life ranges from approximately 9-11 hours after a single oral dose (5-40 mg).

Metabolism

Oxymorphone is highly metabolized, principally in the liver, and undergoes reduction or conjugation with glucuronic acid to form both active and inactive products.  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 0.25% to 0.62% is 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

Age: Geriatric Population

The plasma levels of oxymorphone administered as an extended-release tablet were about 40% higher in elderly (≥65 years of age) than in younger subjects [see Use in Specific Populations (8.5)].

Sex:

The effect of sex on the pharmacokinetics of Oxymorphone Hydrochloride Tablets has not been studied. In a study with an extended- release formulation of oxymorphone, 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 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 effect of hepatic impairment on the pharmacokinetics of Oxymorphone Hydrochloride Tablets has not been studied. However, in a study with an extended-release formulation of oxymorphone, 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

The effect of renal impairment on the pharmacokinetics of Oxymorphone Hydrochloride Tablets has not been studied. However, in a study with an extended-release formulation of oxymorphone, an increase of 26%, 57%, and 65% in oxymorphone bioavailability was observed 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 Interactions Studies

In vitro studies revealed little to no biotransformation of oxymorphone to 6-OH-oxymorphone by any of the major cytochrome P450 (CYP P450) isoforms at therapeutically relevant oxymorphone plasma concentrations.

No inhibition of any of the major CYP P450 isoforms was observed when oxymorphone was incubated with human liver microsomes at concentrations of ≤50 µM. An inhibition of CYP 3A4 activity occurred at oxymorphone concentrations ≥150 µM. Therefore, it is not expected that oxymorphone, or its metabolites will act as inhibitors of any of the major CYP P450 enzymes in vivo.

Increases in the activity of the CYP 2C9 and CYP 3A4 isoforms occurred when oxymorphone was incubated with human hepatocytes. However, clinical drug interaction studies with Oxymorphone Hydrochloride Tablets 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.

Alcohol Interaction

The effect of co-ingestion of alcohol with Oxymorphone Hydrochloride Tablets has not been evaluated.  However, an in vivo study was performed to evaluate the effect of alcohol (40%, 20%, 4% and 0%) on the bioavailability of a single dose of 40 mg of extended-release Oxymorphone Tablets in healthy, fasted volunteers. 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. In some individuals there was also a decrease in oxymorphone peak plasma concentrations. No effect on the release of oxymorphone from the extended-release tablet was noted in an in vitro alcohol interaction study. The mechanism of the in vivo interaction is unknown.  Therefore, avoid co-administration of oxymorphone and ethanol.

The analgesic efficacy of Oxymorphone Hydrochloride Tablets has been evaluated in acute pain following orthopedic and abdominal surgeries.

Orthopedic Surgery

Two double-blind, placebo-controlled, dose-ranging studies in patients with acute moderate to severe pain following orthopedic surgery evaluated the doses of Oxymorphone Hydrochloride Tablets 10 mg and 20 mg, and 30 mg was included in one study. Both studies demonstrated that Oxymorphone Hydrochloride Tablets 20 mg provided greater analgesia as measured by total pain relief based on a weighted analysis over 8 hours using a 0-4 categorical, compared to placebo. Oxymorphone Hydrochloride Tablets 10 mg provided greater analgesia as compared to placebo in one of the two studies. There was no evidence of superiority of the 30 mg dose over the 20 mg dose. However, there was a high rate of naloxone use in patients receiving the Oxymorphone Hydrochloride Tablets 30 mg dose in the post-operative period [see Dosage and Administration (2.2)].

Abdominal Surgery

In a randomized, double-blind, placebo-controlled, multiple-dose study, the efficacy of Oxymorphone Hydrochloride Tablets 10 mg and 20 mg was assessed in patients with moderate to severe acute pain following abdominal surgery. In this study, patients were dosed every 4 to 6 hours over a 48-hour treatment period. Oxymorphone Hydrochloride Tablets 10 and 20 mg provided greater analgesia, as measured by the mean average pain intensity on a 0-100 mm visual analog scale, over 48 hours, compared to placebo [see Dosage and Administration (2.2)].