- This head-to-head pharmacodynamic study in healthy
volunteers examined the ability of both OPVEE and intranasal
naloxone to reverse opioid-induced respiratory depression, which is
the shallow and slow breathing associated with an opioid
overdose
- In this model, OPVEE 2.7mg reversed respiratory depression
to 95% of pre-opioid baseline within 5 minutes; a similar reversal
following a 4 mg dose of intranasal naloxone required 20
minutes
RICHMOND, Va., March 11,
2024 /PRNewswire/ -- Indivior PLC (LSE/Nasdaq: INDV)
today announced results from a pharmacodynamic study demonstrating
that OPVEE® rapidly reverses opioid-induced respiratory
depression, which is the major cause of deaths due to opioid
overdose. The study, "Reversal of opioid-induced respiratory
depression in healthy volunteers: comparison of intranasal
nalmefene and intranasal naloxone", was published in the Journal
of Clinical Pharmacology (Reversal of Opioid‐Induced
Respiratory Depression in Healthy Volunteers: Comparison of
Intranasal Nalmefene and Intranasal Naloxone - Ellison - The
Journal of Clinical Pharmacology - Wiley Online Library) and is the
first head-to-head comparison examining the effects of 2.7 mg
intranasal (IN) nalmefene (OPVEE) and 4 mg IN naloxone on
opioid-induced respiratory depression. This study was a part of the
OPVEE development program and reviewed by the FDA as part of the
approval process.
This study met the primary endpoint by demonstrating that OPVEE
reversed the respiratory depression produced by remifentanil, a
potent synthetic opioid related to fentanyl, within the first 5
minutes following administration. Both OPVEE and IN naloxone
produced a time-dependent reversal of the opioid-induced
respiratory depression 2.5 to 20 minutes post administration. Point
estimates favored OPVEE, demonstrating non-inferiority and
superiority to naloxone. After OPVEE administration, subjects'
minute ventilation (a measure of the amount of air that enters the
lungs per minute) reached approximately 95% of the pre-opioid
baseline within 5 minutes and maintained this robust reversal
through the initial 20-minute monitoring period. By contrast,
naloxone required 20 minutes to restore respiration to levels
equaling those observed 5 minutes after OPVEE. There is an
urgent need for rapid acting reversal agents because synthetic
opioids, like fentanyl, impair breathing and reduce oxygen levels
to vital organs like the brain more rapidly than other opioids such
as morphine and heroin.
"This study provides the first head-to-head comparison of IN
OPVEE and IN naloxone in a clinical model of opioid-induced
respiratory depression. While both reverse the effects of
remifentanil induced respiratory depression, this pharmacodynamic
study provides important insights about the time course of reversal
for both drugs," said Christian
Heidbreder, Ph.D. and Chief Scientific Officer of Indivior.
"The first few minutes following an overdose – particularly with
very potent and fast acting synthetic opioids like fentanyl – are
critical for a successful rescue. OPVEE reverses the
respiratory depression rapidly in this model, making it a valuable
tool for combating the synthetic opioid overdose crisis we're
facing as a nation."
Following administration of OPVEE, subjects' minute ventilation
(MV), a measure of how much a person is breathing, increased by an
average of 5.75 L/min at 5 minutes, the study's primary endpoint.
Intranasal naloxone produced a mean increase of 3.01 L/min at 5
minutes post-administration, and 20 minutes was required to produce
an increase in MV similar to that observed 5 minutes after
OPVEE.
Adverse events (AEs) occurred in 91.8% of subjects following
OPVEE and 86.7% of subjects following IN naloxone. The authors
conclude that the AEs observed in this study are most likely
related to remifentanil and hypercapnic experimental conditions
used and not the drugs under investigation. The most common adverse
events were headache (59.0% following OPVEE and 58.3% following
intranasal naloxone), nausea (39.3% and 41.7%), vomiting (11.5% and
23.3%), and dizziness (18.0% and 21.7%). Adverse events were mild
or moderate, with no subjects reporting a serious adverse
event.
In the United States, the
provisional number of reported opioid overdose deaths reached
80,318 in the 12 months ending in September
2023.1 The reported overdose deaths linked to
synthetic opioids, such as fentanyl, during the same period was
73,686, representing more than 90% of all opioid overdose
fatalities.
About the Study
This study was an open-label, head-to-head, randomized,
2-period, 2-treatment crossover noninferiority study designed to
model the pharmacodynamic effects of intranasal OPVEE®
(nalmefene) and intranasal naloxone. A total of 69
opioid-experienced, non -dependent healthy male and female
volunteers were randomized to receive study drugs. Subjects
breathed a hypercapnic gas mixture containing 7% carbon dioxide and
their minute ventilation (MV) was monitored. Minute ventilation is
a measure of how deeply and rapidly a patient is breathing and is
reduced by opioid exposure.2 Previous work has
demonstrated that opioids blunt the increase in MV that normally
occurs with hypercapnia (excessive carbon dioxide in the
bloodstream) and that opioid antagonists can reverse this
effect.3-7 After 10 minutes of breathing the hypercapnic
gas mixture, subjects were administered a loading dose of
remifentanil followed by a continuous infusion of remifentanil to
maintain steady state plasma concentrations. After 25 minutes, the
subjects were administered a single dose of either intranasal OPVEE
2.7 mg or intranasal naloxone 4 mg and MV was monitored. The
primary objectives were to demonstrate noninferiority at the
primary endpoint of 5 minutes after antagonist exposure of IN
nalmefene to reverse remifentanil-induced reductions in MV and to
determine the tolerability of IN nalmefene during remifentanil
infusion. Of the 69 subjects who received a single dose of either
IN nalmefene or IN naloxone, a total of 52 subjects received both
treatments and data was collected at the primary endpoint in 50
subjects.
About OPVEE®
OPVEE (nalmefene) nasal spray
INDICATION
OPVEE nasal spray is an opioid antagonist indicated for the
emergency treatment of known or suspected overdose induced by
natural or synthetic opioids in adults and pediatric patients aged
12 years and older, as manifested by respiratory and/or central
nervous system depression.
OPVEE nasal spray is intended for immediate administration as
emergency therapy in settings where opioids may be present.
OPVEE nasal spray is not a substitute for emergency medical
care.
HIGHLIGHTED SAFETY INFORMATION
CONTRAINDICATIONS
Hypersensitivity to nalmefene or to any of the other
ingredients.
WARNINGS AND PRECAUTIONS
Risk of Recurrent Respiratory and Central Nervous System
Depression: While the duration of action of nalmefene is as
long as most opioids, a recurrence of respiratory depression is
possible, therefore, keep patient under continued surveillance and
administer repeat doses of OPVEE using a new nasal spray with each
dose, as necessary, while awaiting emergency medical
assistance.
Limited Efficacy with Partial Agonists or Mixed
Agonist/Antagonists: Reversal of respiratory depression caused by
partial agonists or mixed agonists/antagonists, such as
buprenorphine and pentazocine, may be incomplete. Larger or repeat
doses may be required.
Precipitation of Severe Opioid Withdrawal: Use in patients who
are opioid dependent may precipitate opioid withdrawal. In
neonates, opioid withdrawal may be life-threatening if not
recognized and properly treated. Monitor for the development of
opioid withdrawal.
Risk of Cardiovascular (CV) Effects: Abrupt postoperative
reversal of opioid depression may result in adverse CV effects.
These events have primarily occurred in patients who had
preexisting CV disorders or received other drugs that may have
similar adverse CV effects. Monitor these patients closely in an
appropriate healthcare setting after use of nalmefene
hydrochloride.
Risk of Opioid Overdose from Attempts to Overcome the Blockade:
Attempts to overcome opioid withdrawal symptoms caused by opioid
antagonists with high or repeated doses of exogenous opioids may
lead to opioid intoxication and death.
ADVERSE REACTIONS
Most common adverse reactions (incidence at least 2%) are nasal
discomfort, headache, nausea, dizziness, hot flush, vomiting,
anxiety, fatigue, nasal congestion, throat irritation, rhinalgia,
decreased appetite, dysgeusia, erythema, and hyperhidrosis.
For more information about OPVEE and the full Prescribing
Information visit www.opvee.com.
About Indivior
Indivior is a global pharmaceutical company working to help
change patients' lives by developing medicines to treat substance
use disorders (SUD) and serious mental illnesses. Our vision is
that all patients around the world will have access to
evidence-based treatment for the chronic conditions and
co-occurring disorders of SUD. Indivior is dedicated to
transforming SUD from a global human crisis to a recognized and
treated chronic disease. Building on its global portfolio of opioid
use disorder treatments, Indivior has a pipeline of product
candidates designed to both expand on its heritage in this category
and potentially address other chronic conditions and co-occurring
disorders of SUD, including alcohol use disorder and cannabis use
disorder. Headquartered in the United
States in Richmond, VA,
Indivior employs more than 1,100 individuals globally and its
portfolio of products is available in 37 countries worldwide. Visit
www.indivior.com to learn more. Connect with Indivior on LinkedIn
by visiting www.linkedin.com/company/indivior.
References
- Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional drug
overdose death counts. National Center for Health Statistics.
July 2023. Accessed February 8, 2024, from
https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm
- Palkovic B, Marchenko V, Stuth EA, Stucke AG. Multi-level
regulation of opioid-induced respiratory depression. Physiology.
2020; 35(6):391-404.
- Rawat, D., Modi, P., & Sharma, S. (2023).
Hypercapnea. In StatPearls. StatPearls Publishing. Accessed
February 15, 2024, from
https://pubmed.ncbi.nlm.nih.gov/29763188/
- Gelberg J, Jonmarker C, Stenqvist O, Werner O. Intravenous
boluses of fentanyl, 1 μg kg-1, and remifentanil, 0.5 μg
kg-1, give maximum ventilatory depression in awake
volunteers. Brit. J. Anaes. 2012; 108(6):1028-34.
- Webster L, Hansen E, Stoddard G, Rynders A, Ostler D,
Lennon H. Ventilatory response to hypercapnia as experimental model
to study effects of oxycodone on respiratory depression. Curr. Rev.
Clin. Exper. Pharmacol. 2021; 16:1-9.
- Glass PS, Iselin-Chaves IA, Goodman D, Delong E, Hermann
DJ. Determination of the potency of remifentanil compared with
alfentail using ventilatory depression as the measure of opioid
effect. Anesthesiol. 1999; 90(6):1556-1563.
- Dahan A, Aarts L, Smith T. Incidence, reversal and prevention
of opioid-induced respiratory depression. Anesthes. 2010;
112(1):226-238.
- Glass, P, Jhaveri, R, Smith, L. Comparison of potency and
duration of action of nalmefene and naloxone. Anesth. Analg., 1994;
78(3):536-541.
- Konieczko K, Jones J, Barrowcliffe M, Jordan C, Altman, D.
Antagonism of morphine-induced respiratory depression with
nalmefene. Br. J. Anaesth. 1988; 61(3):318-323.
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