DUBLIN, March 14, 2017 /CNW/ -- Endo International
plc (NASDAQ / TSX: ENDP) today announced that the U.S. Food
and Drug Administration's (FDA) Drug Safety Risk Management and
Anesthetic and Analgesic Drug Products Advisory Committees voted 18
to eight, with one abstention, that the benefits of reformulated
OPANA® ER (oxymorphone hydrochloride extended
release) no longer outweigh its risks. While several of the
Advisory Committee members acknowledged the role of
OPANA® ER in clinical practice, others believed its
benefits are now overshadowed by the continuing public health
concerns around the product's misuse, abuse and diversion. During
the Advisory Committee discussion following the vote, a number of
Committee members expressed their preference that OPANA®
ER remain on the market with additional regulatory restrictions to
mitigate the risks.
The FDA convened these Advisory Committees 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 FDA will consider
the Committees' vote, any decision regarding whether to take
regulatory action rests solely with the Agency. Endo believes that
OPANA® ER remains an important clinical choice for
appropriate patients and will evaluate the range of available
options for maintaining access for legitimate use.
"Endo remains confident that the body of evidence established
through clinical research demonstrates that OPANA® ER
has a favorable risk-benefit profile when used as intended in
appropriate patients," said Matthew W.
Davis, M.D., R.Ph., Senior Vice President, Research &
Development, Branded Pharmaceuticals at Endo. "Our top priorities
include patient safety and ensuring that patients with chronic pain
have access to safe and effective therapeutic options. We plan to
work collaboratively with the FDA as the Agency completes its
evaluation of OPANA® ER, while advocating to preserve
the important benefits of the medicine for patients."
Endo's Commitment to Reducing the Abuse and Diversion of
Opioid Medications
As a responsible opioid manufacturer,
Endo is committed to reducing the potential abuse, misuse and
diversion of these products and has taken a number of efforts to
date, including:
- Supporting initiatives with targeted interventions aimed at
understanding IV abuse of opioids, including: parent coaching
trainings; a pilot mobile texting parent support initiative; a
toll-free hotline for families and patients; a media awareness
campaign; increased law enforcement outreach; increased local
treatment center outreach; and increased outreach with local
community leaders;
- Conducting an ethnographic study aimed at better understanding
the causes of IV abuse in the Tennessee region; and
- Implementing a product serialization project aimed at
preventing product counterfeiting, tampering and diversion and
protecting patient safety in compliance with the Federal Drug
Supply Chain Security Act (DSCSA).
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 / TSX: 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, the statements by Dr. Davis. These statements
are based on current expectations of future events. If underlying
assumptions prove inaccurate or unknown risks or uncertainties
materialize, actual results could vary materially
from Endo's expectations and projections. 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;
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. Additional information
about Endo is available on the World Wide Web
at www.endo.com or you can contact the Endo Investor
Relations department by calling (484) 216-0000.
To view the original version on PR Newswire,
visit:http://www.prnewswire.com/news-releases/endo-statement-on-fda-advisory-committees-vote-related-to-opana-er-300423788.html
SOURCE Endo International plc