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Impax Laboratories Launches Oxymorphone Hydrochloride Extended-Release Tablets

01/04/2013

HAYWARD, Calif.--(BUSINESS WIRE)-- Impax Laboratories, Inc. (NASDAQ: IPXL) today announced that it is commencing shipment of Oxymorphone Hydrochloride Extended-Release Tablets, through Global Pharmaceuticals, Impax’s generics division.

In June 2010, Impax reached agreement with Endo Pharmaceuticals and Penwest Pharmaceuticals (collectively Endo) to settle U.S. patent litigation with regard to the production and sale of its Oxymorphone Hydrochloride Extended-Release Tablets approved by the U.S. Food and Drug Administration (FDA) as therapeutically equivalent to the original formulation of OPANA® ER. Under the terms of the settlement, Endo agreed to grant Impax a license to sell Impax’s approved product on January 1, 2013.

As a company whose mission is to provide high quality, lower-cost prescription drugs, Impax is actively participating in efforts to support prescriber and patient education of this product through the FDA-approved Risk Evaluation and Mitigation Strategy (REMS).

Oxymorphone Hydrochloride Extended-Release Tablets are indicated for the relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time.

IMPORTANT RISK INFORMATION

Oxymorphone Hydrochloride Extended-Release Tablets, for oral use, CII

BRIEF SUMMARY

WARNING: ABUSE POTENTIAL, LIFE-THREATENING RESPIRATORY DEPRESSION, ACCIDENTAL EXPOSURE, and INTERACTION WITH ALCOHOL

Abuse Potential
Oxymorphone hydrochloride extended-release tablets contains oxymorphone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit [see Warnings and Precautions]. Assess each patient’s risk for opioid abuse or addiction prior to prescribing oxymorphone hydrochloride extended-release tablets. The risk for opioid abuse is 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 depressive disorder). Routinely monitor all patients receiving oxymorphone hydrochloride extended-release tablets for signs of misuse, abuse, and addiction during treatment.

Life-threatening Respiratory Depression
Respiratory depression, including fatal cases, may occur with use of oxymorphone hydrochloride extended-release tablets, even when the drug has been used as recommended and not misused or abused. Proper dosing and titration are essential and oxymorphone hydrochloride extended-release tablets should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain. Monitor for respiratory depression, especially during initiation of oxymorphone hydrochloride extended-release tablets or following a dose increase. Instruct patients to swallow oxymorphone hydrochloride extended-release tablets whole. Crushing, dissolving, or chewing oxymorphone hydrochloride extended-release tablets can cause rapid release and absorption of a potentially fatal dose of oxymorphone.

Accidental Exposure
Accidental ingestion of oxymorphone hydrochloride extended-release tablets, especially in children, can result in a fatal overdose of oxymorphone.

Interaction with Alcohol
The co-ingestion of alcohol with oxymorphone hydrochloride extended-release tablets may result in an increase of plasma levels and potentially fatal overdose of oxymorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while on oxymorphone hydrochloride extended-release tablets.

INDICATIONS AND USAGE
Oxymorphone hydrochloride extended-release tablets are 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
Oxymorphone hydrochloride extended-release tablets are not intended for use:

  • As an as-needed (prn) analgesic
  • For pain that is mild or not expected to persist for an extended period of time
  • For acute pain
  • For postoperative pain unless the patient is already receiving chronic opioid therapy prior to surgery or if the postoperative pain is expected to be moderate to severe and persist for an extended period of time.

CONTRAINDICATIONS
Oxymorphone hydrochloride extended-release tablets are contraindicated in patients with:

  • Significant respiratory depression
  • Acute or severe bronchial asthma or hypercarbia
  • Known or suspected paralytic ileus
  • Moderate and severe hepatic impairment
  • Hypersensitivity (e.g. anaphylaxis) to oxymorphone, any other ingredients in oxymorphone hydrochloride extended-release tablets, or to morphine analogs such as codeine.

WARNINGS AND PRECAUTIONS
Abuse Potential
Oxymorphone hydrochloride extended-release tablets contains oxymorphone, an opioid agonist and a Schedule II controlled substance. Oxymorphone can be abused in a manner similar to other opioid agonists, legal or illicit. Opioid agonists 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 in situations where there is concern about increased risks of misuse, abuse, or diversion. Concerns about abuse, addiction, and diversion should not, however, prevent the proper management of pain.

Assess each patient’s risk for opioid abuse or addiction prior to prescribing oxymorphone hydrochloride extended-release tablets. The risk for opioid abuse is 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). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Routinely monitor all patients receiving opioids for signs of misuse, abuse, and addiction because these drugs carry a risk for addiction even under appropriate medical use.

Misuse or abuse of oxymorphone hydrochloride extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the opioid and pose a significant risk that could result in overdose and death.

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.

Life Threatening Respiratory Depression
Respiratory depression is the primary risk of oxymorphone hydrochloride extended-release tablets. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with a “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.

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. Closely monitor patients for respiratory depression when initiating therapy with oxymorphone hydrochloride extended-release tablets and following dose increases. Instruct patients against use by individuals other than the patient for whom oxymorphone hydrochloride extended-release tablets were prescribed and to keep oxymorphone hydrochloride extended-release tablets out of the reach of children, as such inappropriate use may result in fatal respiratory depression.

To reduce the risk of respiratory depression, proper dosing and titration of oxymorphone hydrochloride extended-release tablets are essential. Overestimating the oxymorphone hydrochloride extended-release tablets dose when converting patients from another opioid product can result in fatal overdose with the first dose. Respiratory depression has also been reported with use of modified-release opioids when used as recommended and not misused or abused.

To further reduce the risk of respiratory depression, consider the following:

  • Proper dosing and titration are essential and oxymorphone hydrochloride extended-release tablets should only be prescribed by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
  • Instruct patients to swallow oxymorphone hydrochloride extended-release tablets intact. The tablets are not to be crushed, dissolved, or chewed. The resulting oxymorphone dose may be fatal, particularly in opioid-naïve individuals.
  • Oxymorphone hydrochloride extended-release tablets are contraindicated in patients with respiratory depression and in patients with conditions that increase the risk of life-threatening respiratory depression.

Accidental Exposure
Accidental consumption of oxymorphone hydrochloride extended-release tablets, especially in children, can result in a fatal overdose of oxymorphone.

Interaction with Alcohol
The co-ingestion of alcohol with oxymorphone hydrochloride extended-release tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on oxymorphone hydrochloride extended-release tablets therapy.

Elderly, Cachectic, and Debilitated Patients
Respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance compared to younger, healthier patients. Therefore, 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.

Use in Patients with Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with oxymorphone hydrochloride extended-release tablets, as in these patients, even usual therapeutic doses of oxymorphone hydrochloride extended-release tablets may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

Interactions with CNS Depressants and Illicit Drugs
Hypotension, profound sedation, coma, or respiratory depression may result if oxymorphone hydrochloride extended-release tablets are used concomitantly with other CNS depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of oxymorphone hydrochloride extended-release tablets in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, consider the patient’s use, if any, of alcohol or illicit drugs that cause CNS depression. If oxymorphone hydrochloride extended-release tablets therapy is to be initiated in a patient taking a CNS depressant, start with a lower oxymorphone hydrochloride extended-release tablets dose than usual and monitor patients for signs of sedation and respiratory depression and consider using a lower dose of the concomitant CNS depressant.

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. 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.

Hypotensive Effect
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). Monitor these patients for signs of hypotension after initiating or titrating the dose 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.

Use in Patients with Head Injury or Increased Intracranial Pressure
Monitor patients taking oxymorphone hydrochloride extended-release tablets who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with oxymorphone hydrochloride extended-release tablets. Oxymorphone hydrochloride extended-release tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. 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.

Use in Patients with Gastrointestinal Conditions
Oxymorphone hydrochloride extended-release tablets are contraindicated in patients with paralytic ileus. Avoid the use of oxymorphone hydrochloride extended-release tablets in patients with other GI obstruction.

The oxymorphone in oxymorphone hydrochloride extended-release tablets may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Opioids may cause increases in the serum amylase.

Use in Patients with Convulsive or Seizure Disorders
The oxymorphone in oxymorphone hydrochloride extended-release tablets may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during oxymorphone hydrochloride extended-release tablets therapy.

Avoidance of Withdrawal
Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received or are receiving a course of therapy with an opioid agonist analgesic, including oxymorphone hydrochloride extended-release tablets. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing oxymorphone hydrochloride extended-release tablets, gradually taper the dose. Do not abruptly discontinue oxymorphone hydrochloride extended-release tablets.

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.

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

  • Respiratory Depression
  • Chronic Pulmonary Disease
  • Head Injuries and Increased Intracranial Pressure
  • Interactions with Other CNS Depressants
  • Hypotensive Effect
  • Gastrointestinal Effects
  • Seizures

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 were 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.

 

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 HCl ER
Tablets

     

Oxymorphone HCl ER
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 HCl ER
Tablets

     

Oxymorphone HCl ER
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 HCl ER Tablets.

MedDRA Preferred Term      

Oxymorphone HCl ER
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%
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 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.

Post-marketing Experience
The following adverse reactions have been identified during post approval use of oxymorphone hydrochloride extended-release tablets. 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

DRUG INTERACTIONS
Alcohol
Concomitant use of alcohol with oxymorphone hydrochloride extended-release tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on oxymorphone hydrochloride extended-release tablet therapy.

CNS Depressants
Concurrent use of oxymorphone hydrochloride extended-release tablets and other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, hypotension, profound sedation, or coma. Monitor patients receiving CNS depressants and oxymorphone hydrochloride extended-release tablets for signs of respiratory depression and hypotension. When such combined therapy is contemplated, reduce the initial dose of one or both agents.

Mixed Agonist/Antagonist Opioid Analgesics
Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) may reduce the analgesic effect of oxymorphone hydrochloride extended-release tablets or may precipitate withdrawal symptoms in these patients. Avoid the use of mixed agonist/antagonist analgesics in patients receiving oxymorphone hydrochloride extended-release tablets.

Cimetidine
Cimetidine can potentiate opioid-induced respiratory depression. Monitor patients for respiratory depression when oxymorphone hydrochloride extended-release tablets and cimetidine are used concurrently.

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. Monitor patients for signs of respiratory and central nervous system depression when oxymorphone hydrochloride extended-release tablets are used concurrently with anticholinergic drugs.

USE IN SPECIFIC POPULATIONS
Pregnancy
The safety of using oxymorphone in pregnancy has not been established with regard to possible adverse effects on fetal development. The use of oxymorphone hydrochloride extended-release tablets 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. Oxymorphone hydrochloride extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oxymorphone hydrochloride administration did not cause malformations at any doses evaluated during developmental toxicity studies in rats (=25 mg/kg/day) or rabbits (=50 mg/kg/day). These doses are ~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 =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 =25 mg/kg/day, or rabbits at =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 =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.

Labor and Delivery
Oxymorphone hydrochloride extended-release tablets are not for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through by temporarily reducing the strength, duration, and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor.

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations.

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 oxymorphone hydrochloride extended-release tablets are administered to a nursing woman. Monitor infants who may be exposed to oxymorphone hydrochloride extended-release tablets through breast milk 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.

Pediatric Use
The safety and effectiveness of oxymorphone hydrochloride extended-release tablets in patients below the age of 18 years have not been established.

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 Cmax. 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.

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. 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.

Renal Impairment
Patients with moderate to severe renal impairment were shown to have an increase in oxymorphone bioavailability ranging from 57-65%. 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. 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.

Neonatal Opioid Withdrawal Syndrome
Chronic maternal use of oxymorphone during pregnancy can affect the fetus with subsequent withdrawal signs. Neonatal 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 withdrawal syndrome vary based on the drug used, duration of use, the dose of last maternal use, and rate of elimination of the drug by the newborn. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening and should be treated according to protocols developed by neonatology experts.

DRUG ABUSE AND DEPENDENCE
Controlled Substance
Oxymorphone hydrochloride extended-release tablets contains oxymorphone, a mu opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioids including fentanyl, hydromorphone, methadone, morphine, oxycodone and tapentadol. Oxymorphone hydrochloride extended-release tablets can be abused and is subject to criminal diversion.

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

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.

Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the counter drug to get ”high”, or the use of steroids for performance enhancement and muscle build up.

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

Oxymorphone hydrochloride extended-release tablets, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping 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 reevaluation 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.

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, 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

Oxymorphone hydrochloride extended-release tablets should not be abruptly discontinued. If oxymorphone hydrochloride extended-release tablets are 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 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 symptoms.

OVERDOSAGE
Clinical Presentation
Acute overdosage with oxymorphone is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.

Treatment of Overdose
In case of overdose, priorities are the reestablishment 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. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxymorphone overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on oxymorphone hydrochloride extended-release tablets. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Because the duration of reversal would be expected to be less than the duration of action of oxymorphone in oxymorphone hydrochloride extended-release tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. Oxymorphone hydrochloride extended-release tablets will continue to release oxymorphone adding to the oxymorphone load for up to 24 hours after administration, necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product’s prescribing information.

In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal produced 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 begun with care and by titration with smaller than usual doses of the antagonist.

Manufactured by:
Impax Laboratories, Inc.
Hayward, CA 94544 USA

Distributed by:
Global Pharmaceuticals
Division of Impax Laboratories, Inc.
Philadelphia, PA 19124 USA

SEE FULL PRESCRIBING INFORMATION, INCLUDING ADDITIONAL IMPORTANT RISK INFORMATION ABOUT OXYMORPHONE HYDROCHLORIDE EXTENDED-RELEASE TABLETS, AT: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=557e9610-62d7-42bf-90c1-44215bd8c1f8

About Impax Laboratories, Inc.
Impax Laboratories, Inc. (Impax) is a technology based specialty pharmaceutical company applying its formulation expertise and drug delivery technology to the development of controlled-release and specialty generics in addition to the development of branded products. Impax markets its generic products through its Global Pharmaceuticals Division and markets third-party branded products through the Impax Pharmaceuticals Division. Additionally, where strategically appropriate, Impax has developed marketing partnerships to fully leverage its technology platform. Impax Laboratories is headquartered in Hayward, California, and has a full range of capabilities in its Hayward, Philadelphia and Taiwan facilities. For more information, please visit the Company's Web site at: www.impaxlabs.com.

"Safe Harbor" statement under the Private Securities Litigation Reform Act of 1995:
To the extent any statements made in this news release contain information that is not historical, these statements are forward-looking in nature and express the beliefs and expectations of management. Such statements are based on current expectations and involve a number of known and unknown risks and uncertainties that could cause the Company’s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Such risks and uncertainties include, but are not limited to, the effect of current economic conditions on the Company’s industry, business, financial position and results of operations, fluctuations in the Company’s revenues and operating income, the Company’s ability to successfully develop and commercialize pharmaceutical products, reductions or loss of business with any significant customer, the impact of consolidation of the Company’s customer base, the impact of competition, the Company’s ability to sustain profitability and positive cash flows, any delays or unanticipated expenses in connection with the operation of the Company’s Taiwan facility, the effect of foreign economic, political, legal and other risks on the Company’s operations abroad, the uncertainty of patent litigation, increased government scrutiny on the Company’s agreements with brand pharmaceutical companies, consumer acceptance and demand for new pharmaceutical products, the difficulty of predicting Food and Drug Administration filings and approvals, the Company’s inexperience in conducting clinical trials and submitting new drug applications, the Company’s ability to successfully conduct clinical trials, the Company’s reliance on third parties to conduct clinical trials and testing, the availability of raw materials and impact of interruptions in the Company’s supply chain, the use of controlled substances in the Company’s products, disruptions or failures in the Company’s information technology systems and network infrastructure, the Company’s reliance on alliance and collaboration agreements, the Company’s dependence on certain employees, the Company’s ability to comply with legal and regulatory requirements governing the healthcare industry, the regulatory environment, the Company’s ability to protect the Company’s intellectual property, exposure to product liability claims, changes in tax regulations, the Company’s ability to manage the Company’s growth, including through potential acquisitions, the restrictions imposed by the Company’s credit facility, uncertainties involved in the preparation of the Company’s financial statements, the Company’s ability to maintain an effective system of internal control over financial reporting, any manufacturing difficulties or delays, the effect of terrorist attacks on the Company’s business, the location of the Company’s manufacturing and research and development facilities near earthquake fault lines and other risks described in the Company’s periodic reports filed with the Securities and Exchange Commission. Forward-looking statements speak only as to the date on which they are made, and Impax undertakes no obligation to update publicly or revise any forward-looking statement, regardless of whether new information becomes available, future developments occur or otherwise.

Source: Impax Laboratories, Inc.

Impax Laboratories, Inc.

Mark Donohue, 215-558-4526

Sr. Director, Investor Relations and Corporate Communications

www.impaxlabs.com

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