WAYNE, Pa., Sept. 8, 2017 /PRNewswire/ -- Egalet Corporation
(Nasdaq: EGLT) ("Egalet"), a fully integrated specialty
pharmaceutical company focused on developing, manufacturing and
commercializing innovative treatments for pain and other
conditions, yesterday presented findings from two studies at
PAINWeek 2017 in Las Vegas. One
study showed that the reduction in abuse potential of
ARYMO® ER (morphine sulfate) extended-release (ER)
tablets, as measured by drug liking and other pharmacodynamic (PD)
endpoints, strongly correlated to the pharmacokinetic (PK) results.
Another study showed the majority of abusers progress to more
dangerous routes of abuse after taking opioids orally.
"An analysis from the clinical abuse deterrence studies for
ARYMO ER demonstrated a correlation between the PK data and the PD
results, supporting its potential to help deter opioid abuse," said
Jeffrey Dayno, MD, chief medical
officer at Egalet. "In addition, another study looked at the
motivation behind individuals progressing from oral abuse, which is
particularly relevant given the ongoing opioid epidemic, and one
for which there is little data. The study showed that the majority
of abusers do progress to more dangerous, non-oral routes of abuse.
This is why we believe ARYMO ER and other abuse-deterrent opioids
could play an important role in deterring opioid abuse."
Misuse/abuse of opioids often involves manipulation (eg.
chewing, crushing or dissolving) of the drug to get it into an
abuseable form for alternative routes of administration (eg.
intranasal or intravenous) and/or to achieve a quicker and more
potent euphoric effect. To make manipulation more difficult,
abuse-deterrent (AD) formulations, such as ARYMO ER, were
developed. ARYMO ER is a U.S. Food and Drug Administration (FDA)
approved AD opioid 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.
In a study led by Ben Vaughn,
principal statistical scientist from Rho Inc., the objective was to
better understand the PK/PD relationship using results from the
oral and intranasal human abuse potential (HAP) studies of ARYMO
ER. Evaluation of the relationship between PK and PD results can
elucidate time points that coincide with the onset, peak and
duration of the effects for intact and manipulated products. Such
PK/PD evaluations may allow for a better understanding of how
barriers to deter abuse affect the PK properties of AD opioids, and
how changes in PK influence the PD outcomes. Highlights from the
study included:
- All PD assessments of opioid abuse potential significantly
correlated with Cmax, Tmax and abuse quotient in the anticipated
directions, reinforcing literature suggesting that rate and degree
of drug absorption influence abuse potential; and
- PK parameters were most effective in predicting Drug Liking
Emax, followed by Overall Drug Liking and Take Drug Again.
"Understanding the PK/PD properties of an opioid is critical
because the rate and degree of drug absorption correlates to the
potential for abuse," said Mr. Vaughn. "The data presented at
PAINWeek illustrate that abuse-deterrent products, such as ARYMO
ER, may provide barriers to misuse or abuse. When prescribing an
opioid, healthcare providers should consider medicines with
abuse-deterrent features."
A second study led by Stacey
McCaffrey, PhD, research scientist at Inflexxion, Inc.,
looked at the motivation for change in route of administration
during the course of opioid abuse. Oral ingestion of intact pills
is the most frequently reported route of misuse and abuse for many
prescription opioids, but alternative routes of administration
(RoA) such as intranasal and intravenous are also common.
Traditionally, the opioid misuse or abuse pathway has been
described as follows: an initial oral opioid exposure in a
genetically susceptible person induces a "high" or euphoric
feeling, which may then trigger a desire to intensify the euphoric
effect through chewing pills, snorting, or injecting the opioid. No
research has evaluated the motivation for these changes in RoA over
the course of opioid abuse. Dr. McCaffrey et. al studied adult
patients entering an opioid abuse treatment center with the purpose
of understanding the natural history of opioid abuse and motivation
for changes in RoA. The data regarding motivations for changing RoA
include:
- 75% of the patients began prescription opioid abuse by
swallowing pills intact, and 80% of those patients progressed to
chewing, snorting, or injecting during the course of their
abuse;
- Euphoria was the most common motive for change in RoA from oral
to more dangerous, non-oral routes;
-
- Nearly all (92.3%) "achieved desired effect" motivation
statements were associated with a progression from swallowing to a
more dangerous RoA;
- Most (80.0%) patients reporting social influences
motivation began their abuse as "recreational abusers" (i.e.,
without a legitimate prescription written for them by a physician);
and
- The majority (83.0%) of "social influences:
pressure/encouragement" motivation statements were associated
with transitioning to a more dangerous RoA.
The following posters were presented yesterday, including the
two discussed above, during the PAINWeek 2017 poster session from
6:30 pm – 8:30
pm PT:
- The Relationship Between the Pharmacokinetics of Morphine
Abuse-Deterrent, Extended-Release, Injection-Molded Tablets and
Pharmacodynamic Outcomes in Oral and Intranasal Human Abuse
Potential Studies. Authors: Ben
Vaughn, MS, Colville Brown,
MD, John Lawler, BS, Karsten Lindhardt, MSc, PhD, DBE, Gwendolyn Niebler, DO, Jeffrey M. Dayno, MD.
- Motivation for Change in Route of Administration during the
Course of Opioid Abuse. Authors: Stacey
McCaffrey, PhD, ; Kelly
Manser, BA, ; Colville Brown,
MD, ; Gwendolyn Nieber, DO.
- A Responders Analysis of Morphine Abuse-Deterrent, Extended
Release, Injection-Molded Tablets in Oral and Intranasal Human
Abuse Potential Studies. Author: Lynn R.
Webster, MD, Michael D.
Smith, PharmD, Ben Vaughn,
MS, Colville Brown, MD, John Lawler, BS, Karsten
Lindhardt, MSc, PhD, DBE, Gwendolyn
Niebler, DO, Jeffrey M.
Dayno, MD.
- A Harm Reduction Model to Quantify Potential Misuse/Abuse
Reduction and Abuse Related Events Avoided from Abuse Deterrent
Opioids. Authors: Alan White, PhD;
Tim Spittle BS; Gwendolyn Niebler,
DO; Jeffrey Dayno, MD; Colville Brown, MD, Nathaniel Katz, MD, MS.
- Bioequivalence of Immediate-Release (IR) Oxycodone with
Aversion Technology Compared with a Non–Abuse-Discouraging
Formulation of IR Oxycodone. Authors: Sean Gill, MA, John
Lawler, BS, Gwendolyn
Niebler, DO, Colville Brown,
MD, Jeffrey M. Dayno, MD.
About ARYMO ER
ARYMO ER was developed 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. ARYMO ER is the first
approved product developed using Egalet's proprietary Guardian™
Technology—a physical and chemical barrier approach to abuse
deterrence without the use of an opioid antagonist—creating tablets
that are difficult to manipulate for the purpose of misuse and
abuse. Results from in vitro testing demonstrated that ARYMO ER
tablets, in comparison to non-abuse-deterrent morphine sulfate
extended-release tablets, have increased resistance to cutting,
crushing, grinding or breaking using a variety of tools. Due to its
physical and chemical properties, ARYMO ER is expected to make
abuse by injection difficult. Abuse of ARYMO ER by injection, as
well as by the oral and nasal routes, is still possible. Please see
important safety information on ARYMO ER below.
About Egalet
Egalet, a fully integrated specialty
pharmaceutical company, is focused on developing, manufacturing and
commercializing innovative treatments for pain and other
conditions. Egalet has three approved products:
ARYMO® ER (morphine sulfate) extended-release
tablets for oral use —CII, developed using Egalets proprietary
Guardian™ Technology, OXAYDO® (oxycodone HCI, USP)
tablets for oral use only –CII and SPRIX® (ketorolac
tromethamine) Nasal Spray. Using Guardian Technology, Egalet is
developing a pipeline of clinical-stage, product candidates
including Egalet-002, an abuse-deterrent, extended-release, oral
oxycodone formulation 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. Guardian
Technology can be applied broadly across different classes of
pharmaceutical products and can be used to develop combination
products that include multiple active pharmaceutical ingredients
with similar or different release profiles. For full prescribing
information on ARYMO ER, including the boxed warning and medication
guide, please visit arymoer.com. For full prescribing information
on SPRIX, including the boxed warning and medication guide, please
visit sprix.com. For full prescribing information on OXAYDO,
including the boxed warning and medication guide, please visit
oxaydo.com.
IMPORTANT SAFETY INFORMATION ABOUT ARYMO ER
WARNING: ADDICTION,
ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION;
ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND
RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS
DEPRESSANTS
Addiction, Abuse,
and Misuse
ARYMO® 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 ARYMO ER, and monitor all patients regularly
for the development of these behaviors or
conditions
Life-Threatening
Respiratory Depression
Serious,
life-threatening, or fatal respiratory depression may occur with
use of ARYMO ER. Monitor for respiratory depression,
especially during initiation of ARYMO ER or following a dose
increase. Instruct patients to swallow ARYMO ER tablets whole;
crushing, chewing, or dissolving ARYMO ER tablets can cause rapid
release and absorption of a potentially fatal dose of
morphine
Accidental
Ingestion
Accidental
ingestion of even one dose of ARYMO ER, especially by children, can
result in a fatal overdose of morphine.
Neonatal Opioid
Withdrawal Syndrome
Prolonged use of
ARYMO 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.
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 ARYMO 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.
|
Indications
ARYMO ER is 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 ARYMO 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.
- ARYMO ER is not indicated as an as-needed (prn) analgesic.
Contraindications
ARYMO 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;
concurrent use of monoamine oxidase inhibitors (MAOIs) or use
within the last 14 days, known or suspected gastrointestinal
obstruction, including paralytic ileus; hypersensitivity (e.g.,
anaphylaxis) to morphine.
Warnings and Precautions
Addiction, Abuse, and Misuse: ARYMO ER contains morphine, a
Schedule II controlled substance. As an opioid, ARYMO ER exposes
its users to the risks of addiction, abuse, and misuse. As
extended-release products such as ARYMO 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 morphine present.
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, 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 ARYMO ER, the risk is
greatest during the initiation of therapy or following a dosage
increase. Monitor patients closely for respiratory depression,
especially within the first 24-72 hours of initiating therapy with
and following dosage increases with ARYMO ER.
To reduce the risk of respiratory depression, proper dosing and
titration of ARYMO ER are essential. Overestimating the ARYMO ER
dose when converting patients from another opioid product can
result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of ARYMO ER, especially by
children, can result in respiratory depression and death due to an
overdose of morphine.
Neonatal Opioid Withdrawal Syndrome: Prolonged use of ARYMO 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
syndrome 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: Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of ARYMO ER with
benzodiazepines or other CNS depressants (e.g., non-benzodiazepine
sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants,
general anesthetics, antipsychotics, other opioids, alcohol).
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.
Life-Threatening Respiratory Depression in Patients with Chronic
Pulmonary Disease or in Elderly, Cachectic, or Debilitated
Patients: The use of ARYMO 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: ARYMO 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 ARYMO 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 ARYMO ER and when ARYMO ER is given concomitantly with
other drugs that depress respiration. Alternatively, consider the
use of non-opioid analgesics in these patients.
Interaction with Monoamine Oxidase Inhibitors: Monoamine oxidase
inhibitors (MAOIs) may potentiate the effects of morphine,
including respiratory depression, coma, and confusion. ARYMO ER
should not be used in patients taking MAOIs or within 14 days of
stopping such treatment.
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.
Severe Hypotension: ARYMO 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
dose of ARYMO ER. In patients with circulatory shock, ARYMO ER may
cause vasodilation that can further reduce cardiac output and blood
pressure. Avoid the use ARYMO 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), ARYMO 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 ARYMO ER.
Opioids may also obscure the clinical course in a patient with a
head injury. Avoid the use of ARYMO ER in patients with
impaired consciousness or coma.
Difficulty in Swallowing and Risk for Obstruction in Patients at
Risk for a Small Gastrointestinal Lumen: Moistened ARYMO ER tablets
may become sticky leading to difficulty in swallowing the tablets.
Patients could experience choking, gagging, regurgitation and
tablets stuck in the throat. Instruct patients not to pre-soak,
lick, or otherwise wet ARYMO 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.
Tablet stickiness and swelling may also predispose patients to
intestinal obstruction and exacerbation of diverticulitis. 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: ARYMO
ER is contraindicated in patients with gastrointestinal
obstruction, including paralytic ileus. The morphine in ARYMO 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 morphine in ARYMO ER may increase the frequency of seizures in
patients with seizure disorders, and may increase the risk of
seizures occurring in other clinical settings associated with
seizures. Monitor patients with a history of seizure disorders for
worsened seizure control during ARYMO ER therapy.
Withdrawal: Avoid the use of mixed agonist/antagonist (i.e.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g.,
buprenorphine) analgesics in patients who have received or are
receiving a course of therapy with a full opioid agonist analgesic,
including ARYMO ER. In these patients, mixed agonists/antagonist
and partial agonist analgesics may reduce the analgesic effect
and/or may precipitate withdrawal symptoms.
When discontinuing ARYMO ER, gradually taper the dose. Do not
abruptly discontinue ARYMO ER.
Risks of Driving and Operating Machinery: ARYMO 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 ARYMO ER and know how they
will react to the medication.
Adverse Reactions
In clinical trials, the most common adverse reactions with
morphine sulfate extended-release formulations were constipation,
dizziness, sedation, nausea, vomiting, sweating, dysphoria, and
euphoric mood.
Additional Drug Interactions
Serotonergic Drugs: The concomitant use of opioids with other
drugs that affect the serotonergic neurotransmitter system has
resulted in serotonin syndrome.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics:
May reduce the analgesic effect of ARYMO ER and/or precipitate
withdrawal symptoms; avoid concomitant use.
Muscle Relaxants: Morphine may enhance the neuromuscular
blocking action of skeletal muscle relaxants and produce an
increased degree of respiratory depression.
Cimetidine: The concomitant use of cimetidine can potentiate
morphine effects and increase risk of hypotension, respiratory
depression, profound sedation, coma, and death.
Diuretics: Opioids can reduce the efficacy of diuretics by
inducing the release of antidiuretic hormone.
Anticholinergic Drugs: The concomitant use of anticholinergic
drugs may increase risk of urinary retention and/or severe
constipation, which may lead to paralytic ileus.
P-Glycoprotein (P-gp) Inhibitors: The concomitant use of P-gp
inhibitors can increase the exposure to morphine by about two-fold
and can increase risk of hypotension, respiratory depression,
profound sedation, coma, and death.
Use in Specific Populations
Pediatrics: The safety and effectiveness in pediatric patients
below the age of 18 have not been established.
Geriatrics: The pharmacokinetics of ARYMO ER have not been
studied in elderly patients. Elderly patients (aged 65 years or
older) may have increased sensitivity to morphine.
Hepatic Impairment: Morphine pharmacokinetics have been reported
to be significantly altered in patients with cirrhosis. Start these
patients with a lower than usual dosage of ARYMO ER and titrate
slowly while monitoring for signs of respiratory depression,
sedation, and hypotension.
Renal Impairment: Morphine pharmacokinetics are altered in
patients with renal failure. Start these patients with a lower than
usual dosage of ARYMO ER and titrate slowly while monitoring for
signs of respiratory depression, sedation, and hypotension.
Overdosage
Acute overdosage with morphine can be manifested by respiratory
depression, somnolence progressing to stupor or coma, skeletal
muscle flaccidity, cold and clammy skin, constricted pupils, and,
in some cases, pulmonary edema, bradycardia, hypotension, partial
or complete airway obstruction, atypical snoring, and death. Marked
mydriasis rather than miosis may be seen due to severe hypoxia in
overdose situations.
Safe Harbor
Statements included in this press release
(including but not limited to upcoming milestones) that are not
historical in nature are "forward-looking statements" within the
meaning of the Private Securities Litigation Reform Act of 1995.
These forward-looking statements are based on management's current
expectations, and are subject to known and unknown uncertainties
and risks. Actual results could differ materially from those
discussed due to a number of factors, including, but not limited
to: the success of Egalet's clinical trials, including the timely
recruitment of trial subjects and meeting the timelines therefor;
Egalet's ability to obtain and maintain regulatory approval of
Egalet's products and product candidates and any regulatory
action involving Egalet's products; Egalet's ability to maintain
the intellectual property position of Egalet's products and product
candidates; Egalet's ability to identify and reliance upon
qualified third parties to manufacture its products; Egalet's
ability to service its debt obligations; Egalet's ability to find
and hire qualified sales professionals; the receptivity in the
marketplace and among physicians to Egalet's products; the success
of products which compete with Egalet's that are or become
available; general market conditions; and other risk factors
described in Egalet's filings with the United States Securities and
Exchange Commission. Egalet assumes no obligation to update or
revise any forward-looking-statements contained in this press
release whether as a result of new information or future events,
except as may be required by law.
Investor and Media Contact:
E. Blair Clark-Schoeb
Senior Vice President, Communications
Email: bcs@egalet.com
Tel: 484-259-7370
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