DUBLIN, June 8, 2017 /PRNewswire/ -- Endo
International plc (NASDAQ: ENDP) is aware of today's
announcement by the U.S. Food and Drug Administration (FDA)
requesting that Endo voluntarily withdraw OPANA® ER
(oxymorphone hydrochloride extended release) from the market.
Endo is reviewing the request and is evaluating the full range of
potential options as we determine the appropriate path forward.
While the benefits of opioids in treating and managing pain are
widely recognized, the misuse and abuse of these products have
increased greatly in the U.S. As a pharmaceutical company with a
demonstrated commitment to the improvement of pain management, Endo
feels a strong sense of responsibility to improve the care of pain
for patients while at the same time taking comprehensive steps to
minimize the potential misuse of its products.
Despite the FDA's request to withdraw OPANA® ER from
the market, this request does not indicate uncertainty with the
product's safety or efficacy when taken as prescribed. Endo remains
confident in the body of evidence established through clinical
research demonstrating that OPANA® ER has a favorable
risk-benefit profile when used as intended in appropriate
patients.
FDA Drug Safety Risk Management and Anesthetic and Analgesic
Drug Products Advisory Committees Meeting Outcome
On March 13 and 14, 2017, the U.S.
Food and Drug Administration's (FDA) Drug Safety Risk Management
and Anesthetic and Analgesic Drug Products Advisory Committees were
convened to discuss pre- and post-marketing data about the
abuse of OPANA® ER, the product's overall risk-benefit
profile, as well as the abuse of generic oxymorphone ER and
oxymorphone immediate-release (IR) products.
While the Advisory Committee members voted 18 to eight, with one
abstention, that the benefits of reformulated OPANA® ER
no longer outweigh its risks, more than half expressed their
preference that OPANA® ER remain on the market, but with
additional regulatory restrictions to mitigate the risks of misuse
and abuse.
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® ER exposes patients
and other users to the risks of opioid addiction, abuse, and
misuse, which can lead to overdose and death. Assess each patient's
risk prior to prescribing OPANA® ER, and monitor
all patients regularly for the development of these behaviors and
conditions.
Life-threatening Respiratory Depression
Serious,
life-threatening, or fatal respiratory depression may occur with
use of OPANA® ER. Monitor for respiratory
depression, especially during initiation of OPANA®
ER or following a dose increase. Instruct patients to swallow
OPANA® ER tablets whole; crushing, chewing,
or dissolving OPANA® ER tablets can cause
rapid release and absorption of a potentially fatal dose of
oxymorphone.
Accidental Ingestion
Accidental ingestion of even
one dose of OPANA® ER, especially by
children, can result in a fatal overdose of oxymorphone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use
of OPANA® ER during pregnancy can result in
neonatal opioid withdrawal syndrome, which may be life-threatening
if not recognized and treated, and requires management according to
protocols developed by neonatology experts. If opioid use is
required for a prolonged period in a pregnant woman, advise the
patient of the risk of neonatal opioid withdrawal syndrome and
ensure that appropriate treatment will be available.
Interaction with Alcohol
Instruct patients not to
consume alcoholic beverages or use prescription or non-prescription
products that contain alcohol while taking
OPANA® ER. The co-ingestion of alcohol with
OPANA® ER may result in increased plasma
levels and a potentially fatal overdose of oxymorphone.
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®
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.
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 the FDA's
request to withdraw OPANA® ER, the Company's evaluation of
potential options and the potential impact of such request and
evaluation on the Company's business and expected, estimated or
anticipated future results. Because forecasts are inherently
estimates that cannot be made with precision, the Company's
performance may differ materially from its expectations, estimates
and targets, and the Company often does not know what the actual
results will be until after the end of the applicable reporting
period. Therefore, the Company 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 the Company. All
forward-looking statements in this press release reflect the
Company's current analysis of information and represent the
Company'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 the Company'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, product recalls,
withdrawals 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. The Company 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 the
Company'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.