BioDelivery Sciences International, Inc. (NASDAQ: BDSI), a
rapidly growing specialty pharmaceutical company dedicated to
patients living with serious and complex chronic conditions, today
presented at the American Academy of Pain Medicine’s (AAPM) 36th
Annual Meeting the results of a study titled, “A Phase I
Placebo-Controlled Trial Comparing the Effect of Buprenorphine
Buccal Film and Oral Oxycodone Hydrochloride on Respiratory Drive”.
In May 2019, in response to significant
challenges chronic pain patients face in obtaining adequate care
and the ongoing opioid crisis, The Pain Management Best Practices
Inter-Agency Task Force report recommended more research activities
directed to better understanding the use of buprenorphine, a
Schedule III opioid. Opioids can cause serious, life-threatening,
or fatal respiratory depression. Respiratory depression is a
breathing disorder characterized by slow and ineffective breathing
and is the leading cause of opioid related deaths. In this clinical
trial, BDSI evaluated the effect of BELBUCA® (buprenorphine buccal
film), a Schedule III opioid, and oral oxycodone HCI, a Schedule II
opioid, on respiratory drive.
Study Design:– Study
subjects (N = 19) were healthy males and females self-identifying
as recreational drug users and determined via naloxone challenge to
not be physically dependent on opioids.
– Effect on respiratory drive was assessed
using a double-blind, double-dummy, 6-treatment, 6-period, placebo
controlled, randomized crossover design.
– Treatments studied included single doses
of: BELBUCA (300 mcg, 600 mcg, and 900 mcg); oral oxycodone
hydrochloride (Oxy 30 mg and 60 mg); and placebo (each separated by
a 7-day washout period).
– Respiratory drive was evaluated by
measuring the ventilatory response to hypercapnia (excess carbon
dioxide in the bloodstream) through assessment of the maximum
change in minute ventilation (Emax), which is the maximum amount
inhaled or exhaled in one minute, after administration of each
study drug. Statistical analyses were performed using a linear
mixed-effects model.
Results:– The least square
mean differences in Emax versus placebo were as follows: Oxy 30 mg
(−828.5, P=0.668); Oxy 60 mg (−5188.6, P=0.008); BELBUCA 300 mcg
(+1206.9, P=0.533); BELBUCA 600 mcg (+245.4, P=0.896); and BELBUCA
900 mcg (+1473.3, P=0.440).
A chart/graphic accompanying this
announcement is available
at:https://www.globenewswire.com/NewsRoom/AttachmentNg/d148dcf8-f359-4b36-ada6-dd34da39f6e6
Conclusion:– BELBUCA effect
on respiratory drive was comparable to placebo at all doses
tested.
– The effect of immediate release oral
oxycodone HCl resulted in a dose-dependent decrease in respiratory
drive compared to placebo.
“This is an important and novel study that shows
the comparative effects of buprenorphine buccal film and oral
oxycodone on respiratory drive,” stated Lynn Webster, M.D., the
principal investigator of the study. Thomas Smith, M.D., Chief
Medical Officer at BDSI, added, “Consistent with the Task Force’s
recommendation, BDSI is providing the medical community with the
results of this safety study to help providers make informed
treatment decisions. This study provides additional scientific
support for the use of BELBUCA as a primary treatment option 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.”
Serious, life-threatening, or fatal respiratory
depression may occur with use of BELBUCA. BELBUCA is
contraindicated in patients with significant respiratory
depression; acute or severe bronchial asthma in an unmonitored
setting or in the absence of resuscitative equipment; known or
suspected gastrointestinal obstruction, including paralytic ileus;
and hypersensitivity (e.g., anaphylaxis) to buprenorphine.
Please see important safety information
about BELBUCA below.
For full Prescribing Information,
including Boxed Warning, visit www.belbuca.com.
The Pain Management Best Practices Inter-Agency
Task Force report is available for viewing online
at https://www.hhs.gov/ash/advisory-committees/pain/index.html.
IMPORTANT SAFETY INFORMATION ABOUT
BELBUCA®
INDICATIONBELBUCA® (buprenorphine buccal
film) 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 long-acting
opioid formulations, reserve BELBUCA 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.
- BELBUCA is not indicated as an
as-needed (prn) analgesic.
IMPORTANT SAFETY INFORMATION about
BELBUCA®
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK
EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING
RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID
WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT
USE WITH BENZODIAZEPINES AND OTHER CNS
DEPRESSANTSAddiction, Abuse, and Misuse
BELBUCA 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 BELBUCA,
and monitor regularly for these behaviors and
conditions.Risk Evaluation and Mitigation Strategy
(REMS) To ensure that the benefits of opioid
analgesics outweigh the risks of addiction, abuse, and misuse, the
FDA has required a REMS for these products. Under the requirements
of the REMS, drug companies with approved opioid analgesic products
must make REMS-compliant education programs available to healthcare
providers. Healthcare providers are strongly encouraged to
- complete a REMS-compliant education
program,
- counsel patients and/or their caregivers, with every
prescription, on safe use, serious risks, storage, and disposal of
these products,
- emphasize to patients and their caregivers the
importance of reading the Medication Guide every time it is
provided by their pharmacist, and
- consider other tools to improve patient, household, and
community safety.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression
may occur with use of BELBUCA. Monitor for respiratory depression,
especially during initiation of BELBUCA or following a dose
increase. Misuse or abuse of BELBUCA by chewing, swallowing,
snorting, or injecting buprenorphine extracted from the buccal film
will result in the uncontrolled delivery of buprenorphine and poses
a significant risk of overdose and
death.Accidental Exposure
Accidental exposure to even one dose of BELBUCA, especially
in children, can result in a fatal overdose of
buprenorphine.Neonatal Opioid Withdrawal
Syndrome Prolonged use of BELBUCA during
pregnancy can result in neonatal opioid withdrawal syndrome, which
may be life-threatening if not recognized and treated. If prolonged
opioid use is required 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 for use in patients for whom alternative
treatment options are inadequate; limit dosages and durations to
the minimum required; and follow patients for signs and symptoms of
respiratory depression and sedation. |
CONTRAINDICATIONS
BELBUCA is contraindicated in patients with
significant respiratory depression; acute or severe bronchial
asthma in an unmonitored setting or in the absence of resuscitative
equipment; known or suspected gastrointestinal obstruction,
including paralytic ileus; and hypersensitivity (e.g., anaphylaxis)
to buprenorphine.
WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse
- BELBUCA contains
buprenorphine, a Schedule III controlled substance. As an opioid,
BELBUCA exposes users to the risks of addiction, abuse, and
misuse. Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed BELBUCA.
Addiction can occur at recommended dosages and if the drug is
misused or abused.
- Assess each patient’s risk for
opioid addiction, abuse, or misuse prior to prescribing BELBUCA and
monitor all patients receiving BELBUCA 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 the proper management of pain in any given patient.
Patients at increased risk may be prescribed opioids such as
BELBUCA, but use in such patients necessitates intensive counseling
about the risks and proper use of BELBUCA, along with intensive
monitoring for signs of addiction, abuse, or misuse.
- Abuse or misuse of BELBUCA by
swallowing may cause choking, 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
BELBUCA. Strategies to reduce the risk include prescribing the drug
in the smallest appropriate quantity and advising the patient on
the proper disposal of unused drug.
Opioid Analgesic Risk Evaluation and Mitigation
Strategy (REMS)
- To ensure that the benefits of
opioid analgesics outweigh the risks of addiction, abuse, and
misuse, the FDA has required a REMS for these products. Under the
requirements of the REMS, drug companies with approved opioid
analgesic products must make REMS-compliant education programs
available to healthcare providers. To obtain further information on
the REMS and for a list of accredited REMS CME/CE, call
1-800-503-0784, or log on to www.opioidanalgesicrems.com
- Healthcare providers are strongly
encouraged to complete a REMS-compliant education program; to
discuss the safe use, serious risks, and proper storage and
disposal of opioid analgesics with patients or caregivers; to
emphasize to patients and caregivers the importance of reading the
Medication Guide; and to consider using other tools to improve
patient, household, and community safety, such as
patient-prescriber agreements that reinforce patient-prescriber
responsibilities.
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.
- While serious, life-threatening or
fatal respiratory depression can occur at any time during the use
of BELBUCA, the risk is greatest during initiation of therapy or
following a dosage increase. Monitor patients closely for
respiratory depression when initiating therapy with
BELBUCA and following dosage increases.
- To reduce the risk of respiratory
depression, proper dosing and titration of BELBUCA are
essential. Overestimating the dose of BELBUCA when converting
patients from another opioid product may result in fatal overdose
with the first dose.
- Accidental exposure to BELBUCA,
especially in children, can result in respiratory depression and
death due to an overdose of buprenorphine.
- Opioids can cause sleep-related
breathing disorders including central sleep apnea (CSA) and
sleep-related hypoxemia. Opioid use increases the risk of CSA in a
dose-dependent fashion. In patients who present with CSA, consider
decreasing the opioid dosage using best practices for opioid
taper.
Neonatal Opioid Withdrawal Syndrome
- Prolonged use of
BELBUCA 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 due to Interactions with Benzodiazepines
or Other Central Nervous System Depressants
- Profound sedation, respiratory
depression, coma, and death may result from the concomitant use of
BELBUCA 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.
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. Follow patients closely for signs and
symptoms of respiratory depression and sedation.
Risk of Life-Threatening Respiratory Depression
in Patients with Chronic Pulmonary Disease or in Elderly,
Cachectic, or Debilitated Patients
- The use of BELBUCA in patients with
acute or severe bronchial asthma in an unmonitored setting or in
the absence of resuscitative equipment is contraindicated.
- BELBUCA-treated patients with
significant chronic obstructive pulmonary disease or cor pulmonale,
and those with 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 BELBUCA.
- Life-threatening respiratory
depression is more likely to occur in elderly, cachectic, or
debilitated patients as they may have altered pharmacokinetics or
altered clearance compared with younger, healthier patients.
- Monitor such patients closely,
particularly when initiating and titrating BELBUCA and when
BELBUCA is given concomitantly with other drugs that depress
respiration.
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.
QTc Prolongation
- BELBUCA has been observed to
prolong the QTc interval in some subjects participating in clinical
trials. Consider these observations in clinical decisions when
prescribing BELBUCA to patients with hypokalemia,
hypomagnesemia, or clinically unstable cardiac disease, including
unstable atrial fibrillation, symptomatic bradycardia, unstable
congestive heart failure, or active myocardial ischemia. Periodic
electrocardiographic (ECG) monitoring is recommended in these
patients. Avoid the use of BELBUCA in patients with a history
of Long QT Syndrome or an immediate family member with this
condition or those taking Class IA antiarrhythmic medications
(e.g., quinidine, procainamide, disopyramide) or Class III
antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide),
or other medications that prolong the QT interval.
Severe Hypotension
- BELBUCA 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 BELBUCA. In patients with circulatory
shock, BELBUCA may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of BELBUCA 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),
BELBUCA 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 BELBUCA.
- Opioids may also obscure the
clinical course in a patient with a head injury. Avoid the use of
BELBUCA in patients with impaired consciousness or coma.
Hepatotoxicity
- Cases of cytolytic hepatitis and
hepatitis with jaundice have been observed in individuals receiving
sublingual formulations of buprenorphine for the treatment of
opioid dependence, both in clinical trials and in post-marketing
adverse events reports. For patients at increased risk of
hepatotoxicity (e.g., patients with a history of excessive alcohol
intake, intravenous drug abuse or liver disease), obtain baseline
liver enzyme levels and monitor periodically during treatment with
BELBUCA.
Risk of Overdose in Patients with Moderate or
Severe Hepatic Impairment
- In a pharmacokinetic study of
subjects dosed with buprenorphine sublingual tablets, buprenorphine
plasma levels were found to be higher and the half-life was found
to be longer in subjects with moderate and severe hepatic
impairment, but not in subjects with mild hepatic impairment. For
patients with severe hepatic impairment, a dose adjustment is
recommended, and patients with moderate or severe hepatic
impairment should be monitored for signs and symptoms of toxicity
or overdose caused by increased levels of buprenorphine.
Anaphylactic/Allergic Reactions
- Cases of acute and chronic
hypersensitivity to buprenorphine have been reported both in
clinical trials and in post-marketing experience. The most common
signs and symptoms include rashes, hives, and pruritus. Cases of
bronchospasm, angioneurotic edema, and anaphylactic shock have been
reported.
Withdrawal
- Do not abruptly discontinue BELBUCA
in a patient physically dependent on opioids. When discontinuing
BELBUCA in a physically dependent patient, gradually taper the
dosage. Rapid tapering of buprenorphine in a patient physically
dependent on opioids may lead to a withdrawal syndrome and return
of pain.
- Additionally, the use of BELBUCA, a
partial agonist opioid analgesic, in patients who are receiving a
full opioid agonist analgesic may reduce the analgesic effect
and/or precipitate withdrawal symptoms. Avoid concomitant use of
BELBUCA with a full opioid agonist analgesic.
Risk of Use in Patients with Gastrointestinal
Conditions
- BELBUCA is contraindicated in
patients with known or suspected gastrointestinal obstruction,
including paralytic ileus.
- BELBUCA 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 buprenorphine in BELBUCA 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
BELBUCA therapy.
Risks of Use in Cancer Patients with Oral
Mucositis
- Cancer patients with oral mucositis
may absorb buprenorphine more rapidly than intended and are likely
to experience higher plasma levels of the opioid. For patients with
known or suspected mucositis, a dose reduction is recommended.
Monitor these patients carefully for signs and symptoms of toxicity
or overdose caused by increased levels of buprenorphine.
Risks of Driving and Operating Machinery
- BELBUCA may impair the mental
and 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 side effects of BELBUCA and know how they will
react to the medication.
ADVERSE REACTIONS
- The most common adverse reactions
(≥5%) reported by patients treated with BELBUCA in the
clinical trials were nausea, constipation, headache, vomiting,
fatigue, dizziness, and somnolence.
Please see full
Prescribing Information, including Boxed Warning
and Medication Guide, for BELBUCA.
To report SUSPECTED ADVERSE REACTIONS, contact
BioDelivery Sciences International, Inc.
at 1-800-469-0261 or FDA at 1-800-FDA-1088 or
www.fda.gov/safety/medwatch.
Intended for healthcare professionals of the
United States of America only.
About BioDelivery Sciences
International, Inc.BioDelivery Sciences International,
Inc. (NASDAQ: BDSI) is a commercial-stage specialty pharmaceutical
company dedicated to patients living with chronic conditions. BDSI
has built a portfolio of products that includes utilizing its novel
and proprietary BioErodible MucoAdhesive (BEMA®) technology to
develop and commercialize, either on its own or in partnership with
third parties, new applications of proven therapies aimed at
addressing important unmet medical needs. BDSI's marketed products
address serious and debilitating conditions, including chronic
pain, opioid dependence, and opioid-induced constipation.
Cautionary Note on Forward-Looking
StatementsThis press release and any statements of
employees, representatives, and partners of BDSI related thereto
contain, or may contain, among other things, certain
“forward-looking statements” within the meaning of the Private
Securities Litigation Reform Act of 1995. Such forward-looking
statements involve significant risks and uncertainties. Such
statements may include, without limitation, statements with respect
to the BDSI’s plans, objectives, projections, expectations and
intentions and other statements identified by words such as
“projects,” “may,” “will,” “could,” “would,” “should,” “believes,”
“expects,” “anticipates,” “estimates,” “intends,” “plans,”
“potential” or similar expressions. These statements are based upon
the current beliefs and expectations of the BDSI’s management and
are subject to significant risks and uncertainties, including those
detailed in the BDSI’s filings with the Securities and Exchange
Commission. Actual results may differ materially from those set
forth or implied in the forward-looking statements. These
forward-looking statements involve certain risks and uncertainties
that are subject to change based on various factors (many of which
are beyond the BDSI’s control) including those set forth in our
2018 annual report on Form 10-K filed with the US Securities and
Exchange Commission and subsequent filings. BDSI undertakes no
obligation to publicly update any forward-looking statements,
whether as a result of new information, future presentations or
otherwise, except as required by applicable law.
© 2020 BioDelivery Sciences International, Inc.
All rights reserved.
Contact:Tirth T. PatelDirector
of Investor Relationstpatel@bdsi.com(919) 582-0294
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