Endo Provides Update On OPANA® ER
DUBLIN, July 6, 2017 /PRNewswire/ -- Endo International plc (NASDAQ: ENDP) continues to believe in the safety, efficacy, and favorable benefit-risk profile of OPANA(®) ER (oxymorphone hydrochloride extended release) when used as intended, and notes that the Company has taken significant steps over the years to combat misuse and abuse. Nevertheless, after careful consideration and consultation with the FDA following the FDA's June 2017 withdrawal request, the Company has decided to voluntarily remove OPANA(®) ER from the market. As a result, the Company expects to incur a pre-tax impairment charge of approximately $20 million in the second quarter of 2017 to write-off the remaining net book value of its OPANA(®) ER intangible asset. Reported net sales of OPANA® ER were $158.9 million for full-year 2016 and $35.7 million for first quarter 2017.
Endo plans to work with FDA to coordinate the orderly removal of OPANA(®) ER in a manner that looks to minimize treatment disruption for patients and allows patients sufficient time to seek guidance from their healthcare professionals. Patients taking OPANA(®) ER should discuss treatment options with their prescribing physician at their next visit.
Endo reiterates that neither the FDA's withdrawal request nor Endo's decision to voluntarily remove OPANA(®) ER from the market reflect a finding that the product is not safe or effective when taken as prescribed. To the contrary, Endo remains confident in the clinical research and other data demonstrating OPANA(®) ER's safety and efficacy, as well as its favorable risk-benefit profile when used as intended in appropriate patients.
INDICATION
OPANA(®) ER is an opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Limitations of Use
-- Because of the risks of addiction, abuse, and misuse with opioids, even
at recommended doses, and because of the greater risks of overdose and
death with extended-release opioid formulations, reserve OPANA(®) ER
for use in patients for whom alternative treatment options (e.g.,
non-opioid analgesics or immediate-release opioids) are ineffective, not
tolerated, or would be otherwise inadequate to provide sufficient
management of pain.
-- OPANA(®) ER is not indicated as an as-needed (prn) analgesic.
IMPORTANT SAFETY INFORMATION ABOUT OPANA(® )ER
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-
THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL
INGESTION; NEONATAL OPIOID WITHDRAWAL
SYNDROME;
INTERACTION WITH ALCOHOL; and RISKS FROM
CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER
CNS DEPRESSANTS
Addiction, Abuse, and Misuse
OPANA(R) ER exposes patients and other users to
the risks of opioid addiction, abuse, and
misuse, which can lead to overdose and death.
Assess each patient's risk prior to
prescribing OPANA(R) ER, and monitor all
patients regularly for the development of
these behaviors and conditions.
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal
respiratory depression may occur with use of
OPANA(R) ER. Monitor for respiratory
depression, especially during initiation of
OPANA(R) ER or following a dose increase.
Instruct patients to swallow OPANA(R) ER
tablets whole; crushing, chewing, or
dissolving OPANA(R) ER tablets can cause rapid
release and absorption of a potentially fatal
dose of oxymorphone.
Accidental Ingestion
Accidental ingestion of even one dose of
OPANA(R) ER, especially by children, can
result in a fatal overdose of oxymorphone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of OPANA(R) ER during pregnancy
can result in neonatal opioid withdrawal
syndrome, which may be life-threatening if
not recognized and treated, and requires
management according to protocols developed by
neonatology experts. If opioid use is required
for a prolonged period in a pregnant woman,
advise the patient of the risk of neonatal
opioid withdrawal syndrome and ensure that
appropriate treatment will be available.
Interaction with Alcohol
Instruct patients not to consume alcoholic
beverages or use prescription or non-
prescription products that contain alcohol
while taking OPANA(R) ER. The co-ingestion of
alcohol with OPANA(R) ER may result in
increased plasma levels and a potentially
fatal overdose of oxymorphone.
Risks from Concomitant Use with Benzodiazepines
or Other CNS Depressants
Concomitant use of opioids with benzodiazepines
or other central nervous system (CNS)
depressants, including alcohol, may result in
profound sedation, respiratory depression,
coma, and death.
-- Reserve concomitant prescribing of
OPANA(R) ER and benzodiazepines or other CNS
depressants for use in patients for whom
alternative treatment options are inadequate.
-- Limit dosages and durations to the minimum
required.
-- Follow patients for signs and symptoms of
respiratory depression and sedation.
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CONTRAINDICATIONS
OPANA(®) ER is contraindicated in patients with:
-- Significant respiratory depression
-- Acute or severe bronchial asthma in an unmonitored setting or in the
absence of resuscitative equipment
-- Hypersensitivity to oxymorphone (e.g., anaphylaxis)
-- Moderate and severe hepatic impairment
-- Known or suspected gastrointestinal obstruction, including paralytic
ileus
WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse
-- OPANA(®) ER contains oxymorphone, a Schedule II controlled substance.
Because extended-release products such as OPANA(®) ER deliver the
opioid over an extended period of time, there is a greater risk for
overdose and death due to the larger amount of oxymorphone present.
-- Although the risk of addiction in any individual is unknown, it can
occur in patients appropriately prescribed OPANA(®) ER. Addiction can
occur at recommended doses and if the drug is misused or abused.
-- Assess each patient's risk for opioid addiction, abuse, or misuse prior
to prescribing OPANA(® )ER, and monitor all patients receiving
OPANA(®) ER for the development of these behaviors and conditions.
Risks are increased in patients with a personal or family history of
substance abuse (including drug or alcohol abuse or addiction) or mental
illness (e.g., major depression). The potential for these risks should
not, however, prevent proper management of pain in any given patient.
Patients at increased risk may be prescribed opioids such as OPANA(®
)ER, but use in such patients necessitates intensive counseling about
the risks and proper use of OPANA(® )ER, along with intensive
monitoring for signs of addiction, abuse, and misuse.
-- Abuse or misuse of OPANA(®) ER by crushing, chewing, snorting, or
injecting the dissolved product will result in the uncontrolled delivery
of the oxymorphone and can result in overdose and death.
-- Opioids are sought by drug abusers and people with addiction disorders
and are subject to criminal diversion. Consider these risks when
prescribing or dispensing OPANA(®) ER. Strategies to reduce these risks
include prescribing the drug in the smallest appropriate quantity and
advising the patient on the proper disposal of unused drug. 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
-- 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. Carbon dioxide (CO2) retention from opioid- induced
respiratory depression can exacerbate the sedating effects of opioids.
-- While serious, life-threatening, or fatal respiratory depression can
occur at any time during the use of OPANA(®) ER, the risk is greatest
during the initiation of therapy or following a dosage increase. Monitor
patients closely for respiratory depression especially within 24-72
hours of initiating therapy with and following dose increases of
OPANA(®) ER.
-- To reduce the risk of respiratory depression, proper dosing and
titration of OPANA(®) ER are essential. Overestimating the OPANA(®) ER
dosage when converting patients from another opioid product can result
in fatal overdose with the first dose.
-- Accidental ingestion of even one dose of OPANA ER, especially by
children, can result in respiratory depression and death due to an
overdose of oxymorphone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of OPANA(®) ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal symptoms 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.
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
-- Patients must not consume alcoholic beverages or prescription or
non-prescription products containing alcohol while on OPANA(®) ER
therapy. The co-ingestion of alcohol with OPANA(®) ER may result in
increased plasma levels and a potentially fatal overdose of oxymorphone.
-- Profound sedation, respiratory depression, coma, and death may result
from the concomitant use of OPANA(®) ER with benzodiazepines or other
CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics,
anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids). 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.
-- If the decision is made to prescribe a benzodiazepine or other CNS
depressant concomitantly with an opioid analgesic, prescribe the lowest
effective dosages and minimum durations of concomitant use. In patients
already receiving an opioid analgesic, prescribe a lower initial dose of
the benzodiazepine or other CNS depressant than indicated in the absence
of an opioid, and titrate based on clinical response. If an opioid
analgesic is initiated in a patient already taking a benzodiazepine or
other CNS depressant, prescribe a lower initial dose of the opioid
analgesic, and titrate based on clinical response. Follow patients
closely for signs and symptoms of respiratory depression and sedation.
-- Advise both patients and caregivers about the risks of respiratory
depression and sedation when OPANA(®) ER is used with 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.
Life-threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, and Debilitated Patients
The use of OPANA(®) ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: OPANA(®) ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive, including apnea, even at recommended dosages of OPANA(®) ER.
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. Monitor such patients closely, particularly when initiating and titrating OPANA(®) ER and when OPANA(® )ER is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
Anaphylaxis, Angioedema, and Other Hypersensitivity Reactions
Potentially life-threatening hypersensitivity reactions, including anaphylaxis and angioedema, have occurred in patients treated with OPANA(®) ER in the postmarket setting. The most commonly described clinical features in these reports were swelling of the face, eyes, mouth, lips, tongue, hands, and/or throat; dyspnea; hives, pruritus, and/or rash; and nausea/vomiting. If anaphylaxis or other hypersensitivity occurs, stop administration of OPANA(®) ER immediately, discontinue OPANA(® )ER permanently, and do not rechallenge with any formulation of oxymorphone. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction.
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.
Use in Patients with Hepatic Impairment
A study of OPANA(®) ER in patients with hepatic disease indicated greater plasma concentrations than those with normal hepatic function. OPANA(®) ER is contraindicated in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment, reduce the starting dose to the lowest dose and monitor for signs of respiratory and central nervous system depression.
Severe Hypotension
OPANA(®) ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of OPANA(®) ER. In patients with circulatory shock, OPANA(®) ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OPANA(®) ER in patients with circulatory shock.
Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired
Consciousness
-- In patients who may be susceptible to the intracranial effects of CO2
retention (e.g., those with evidence of increased intracranial pressure
or brain tumors), OPANA(®) ER may reduce respiratory drive, and the
resultant CO2 retention can further increase intracranial pressure.
Monitor such patients for signs of sedation and respiratory depression,
particularly when initiating therapy with OPANA(®) ER.
-- Opioids may also obscure the clinical course in a patient with a head
injury. Avoid the use of OPANA(®) ER in patients with impaired
consciousness or coma.
Difficulty in Swallowing and Risk for Obstruction in Patients at Risk for a Small Gastrointestinal Lumen
-- There have been post-marketing reports of difficulty in swallowing
OPANA(® )ER tablets. These reports included choking, gagging,
regurgitation and tablets stuck in the throat. Instruct patients not to
pre-soak, lick or otherwise wet OPANA(®) ER tablets prior to placing in
the mouth, and to take one tablet at a time with enough water to ensure
complete swallowing immediately after placing in the mouth.
-- There have been rare post-marketing reports of cases of intestinal
obstruction, some of which have required medical intervention to remove
the tablet. Patients with underlying GI disorders, such as esophageal
cancer or colon cancer, with a small gastrointestinal lumen are at
greater risk of developing these complications. Consider use of an
alternative analgesic in patients who have difficulty swallowing and
patients at risk for underlying GI disorders resulting in a small
gastrointestinal lumen.
Risks of Use in Patients with Gastrointestinal Conditions
-- OPANA(®) ER is contraindicated in patients with known or suspected
gastrointestinal obstructions, including paralytic ileus.
-- The oxymorphone in OPANA(®) ER may cause spasm of the sphincter of
Oddi. Opioids may cause increases in the serum amylase. Monitor patients
with biliary tract disease, including acute pancreatitis, for worsening
symptoms.
Increased Risk of Seizures in Patients with Seizure Disorders
The oxymorphone in OPANA(®) ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in some other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during OPANA(®) ER therapy.
Withdrawal
-- Avoid the use of mixed agonist/antagonist (i.e., pentazocine,
nalbuphine, and butorphanol) and partial agonist (e.g., buprenorphine)
analgesics in patients who are receiving a full opioid agonist
analgesic, including OPANA(® )ER. In these patients, mixed
agonist/antagonist and partial agonist analgesics may reduce the
analgesic effect and/or may precipitate withdrawal symptoms.
-- When discontinuing OPANA(®) ER, gradually taper the dosage. Do not
abruptly discontinue OPANA(®) ER.
Risks of Driving and Operating Machinery
OPANA(®) ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OPANA(® )ER and know how they will react to the medication.
ADVERSE REACTIONS
Clinical Trial Experience
-- The most common serious adverse events reported in clinical trials with
administration of oxymorphone hydrochloride extended-release tablets
were chest pain, pneumonia and vomiting.
-- Adverse reactions reported at (>=2%) in placebo-controlled trials were:
nausea (33%), constipation (28%), dizziness (18%), somnolence (17%),
vomiting (16%), pruritus (15%), headache (12%), sweating increased (9%),
dry mouth (6%), sedation (6%), diarrhea (4%), insomnia (4%), fatigue
(4%), appetite decreased (3%), and abdominal pain (3%).
-- In clinical trials 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.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
-- OPANA(®) ER contains oxymorphone, a Schedule II controlled substance.
-- The high drug content in extended-release formulations adds to the risk
of adverse outcomes from abuse and misuse.
Abuse
-- OPANA(®) ER contains oxymorphone, a substance with a high potential for
abuse similar to other opioids including fentanyl, hydrocodone,
hydromorphone, methadone, morphine, oxycodone, and tapentadol. OPANA(®)
ER can be abused and is subject to misuse, addiction, and criminal
diversion.
-- 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.
-- OPANA(®) ER, like other opioids, can be diverted for non-medical use
into illicit channels of distribution.
-- Careful record keeping of prescribing information, including quantity,
frequency, and renewal requests as required by state 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 OPANA(®) ER
-- OPANA(®) ER is for oral use only. Abuse of OPANA(®) ER poses a risk of
overdose and death. This risk is increased with concurrent abuse of
OPANA(®) ER with alcohol and other substances. Taking cut, broken,
chewed, crushed, or dissolved OPANA(®) ER enhances drug release and
increases the risk of overdose and death.
-- With parenteral abuse, cases of thrombotic microangiopathy (a condition
characterized clinically by thrombocytopenia and microangiopathic
hemolytic anemia) have been reported; many cases resulted in
hospitalization and treatment with plasmapheresis. Parenteral drug abuse
is commonly associated with transmission of infectious diseases such as
hepatitis and HIV.
Dependence
-- Both tolerance and physical dependence can develop during chronic opioid
therapy.
-- Physical dependence results in withdrawal symptoms after abrupt
discontinuation or a significant dosage reduction of a drug. Withdrawal
also may be precipitated through the administration of drugs with opioid
antagonist activity, (e.g., naloxone, nalmefene), mixed
agonist/antagonist analgesics (e.g., pentazocine, butorphanol,
nalbuphine), or partial agonists (e.g., buprenorphine). Physical
dependence may not occur to a clinically significant degree until after
several days to weeks of continued opioid usage.
-- OPANA(®) ER should not be abruptly discontinued. If OPANA(®) ER is
abruptly discontinued in a physically dependent patient, a withdrawal
syndrome may occur.
-- Infants born to mothers physically dependent on opioids will also be
physically dependent and may exhibit respiratory difficulties and
withdrawal signs.
Please see accompanying full Prescribing Information, including Boxed WARNING and Medication Guide.
About Endo International plc
Endo International plc (NASDAQ: ENDP) is a highly focused generics and specialty branded pharmaceutical company delivering quality medicines to patients in need through excellence in development, manufacturing and commercialization. Endo has global headquarters in Dublin, Ireland, and U.S. headquarters in Malvern, PA. Learn more at www.endo.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains "forward-looking statements," including, but not limited to, statements regarding Endo's voluntary withdrawal of OPANA(®) ER, Endo's intent to coordinate with the FDA, the manner in which OPANA(®) ER will be withdrawn and the potential impact of such withdrawal on the patients, the market and Endo's business and expected, estimated or anticipated future results. Because forecasts are inherently estimates that cannot be made with precision, Endo's performance may differ materially from its expectations, estimates and targets, and Endo often does not know what the actual results will be until after the end of the applicable reporting period. Therefore, Endo will not report or comment on its progress during a current quarter except through public announcement. Any statement made by others with respect to progress during a current quarter cannot be attributed to Endo. All forward-looking statements in this press release reflect Endo's current analysis of information and represent Endo's judgment only as of the date of this press release. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from Endo's expectations. Risks and uncertainties include, among other things, general industry and market conditions; technological advances and patents attained by competitors; challenges inherent in the research and development and regulatory processes, including regulatory decisions and other unusual items; challenges related to product marketing, such as the unpredictability of market acceptance for new products and/or the acceptance of new indications for such products; inconsistency of treatment results among patients; potential difficulties in manufacturing; the outcome of litigation, settlement discussions or other adverse proceedings; general economic conditions; and governmental laws and regulations affecting domestic and foreign operations. Endo expressly disclaims any intent or obligation to update these forward-looking statements except as required by law. Additional information concerning these and other risk factors can be found in Endo's periodic reports filed with the U.S. Securities and Exchange Commission and in Canada on the System for Electronic Data Analysis and Retrieval ("SEDAR"), including current reports on Form 8-K, quarterly reports on Form 10-Q and annual reports on Form 10-K.
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SOURCE Endo International plc
