Buprenorfina + Naloxona2

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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HIGHLIGHTS OF PRESCRIBING INFORMATION • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement
These highlights do not include all the information needed to use of corticosteroids, and wean patient off of the opioid. (5.6)
ZUBSOLV® safely and effectively. See full prescribing information for • Chronic administration produces opioid-type physical dependence.
ZUBSOLV. Abrupt discontinuation or rapid dose taper may result in opioid
withdrawal syndrome. (5.7)
ZUBSOLV (buprenorphine and naloxone) sublingual tablets for • Monitor liver function tests prior to initiation and during treatment and
sublingual administration CIII evaluate suspected hepatic events. (5.8)
Initial U.S. Approval: 2002 • Do not administer ZUBSOLV to patients with known hypersensitivity to
buprenorphine or naloxone (5.9).
----------------------------RECENT MAJOR CHANGES------------------------- • An opioid withdrawal syndrome is likely to occur with parenteral misuse
Warnings and Precautions (5.5, 5.6) 12/2016 of ZUBSOLV by individuals physically dependent on full opioid
agonists or by sublingual administration before the agonist effects of
-----------------------------INDICATIONS AND USAGE------------------------- other opioids have subsided. (5.10)
ZUBSOLV contains buprenorphine, a partial opioid agonist, and naloxone, an • ZUBSOLV is not appropriate as an analgesic. There have been reported
opioid antagonist, and is indicated for treatment of opioid dependence. deaths of opioid naïve individuals who received a 2 mg equivalent
Prescription use of this product is limited under the Drug Addiction Treatment sublingual dose of buprenorphine. (5.11)
Act. (1) • Buprenorphine/naloxone products are not recommended in patients with
----------------------DOSAGE AND ADMINISTRATION---------------------- severe hepatic impairment and may not be appropriate for patients with
• To avoid precipitating withdrawal, induction with ZUBSOLV moderate hepatic impairment. (5.12)
sublingual tablet should be undertaken when objective and clear signs • Caution patients about the risk of driving or operating hazardous
of withdrawal are evident and ZUBSOLV should be administered in machinery. (5.13)
divided doses when used as initial treatment. (2.2)
• For patients dependent on short-acting opioid products who are in ------------------------------ADVERSE REACTIONS-----------------------------
opioid withdrawal; on Day 1, administer up to 5.7 mg/1.4 mg of Adverse events commonly observed with administration of
ZUBSOLV sublingual tablet (in divided doses). On Day 2, administer buprenorphine/naloxone sublingual tablets during clinical trials and post-
up to a total dose of 11.4 mg/2.9 mg of ZUBSOLV sublingual tablet as marketing experience are headache, nausea, vomiting, hyperhidrosis,
a single dose. (2.2) constipation, signs and symptoms of withdrawal, insomnia, pain, and
• For patients dependent on methadone or long-acting opioid products, peripheral edema. (6)
induction onto sublingual buprenorphine monotherapy is recommended
on Days 1 and 2 of treatment. (2.2) To report SUSPECTED ADVERSE REACTIONS, contact Orexo at
• The recommended single daily dose of ZUBSOLV for maintenance 1-888-982-7658, or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.
treatment is 11.4 mg/2.9 mg buprenorphine and naloxone. (2.3) ------------------------------DRUG INTERACTIONS-----------------------------
• Place ZUBSOLV sublingual tablet under the tongue until it dissolves. • Monitor patients starting or ending CYP3A4 inhibitors or inducers for
For dosages requiring more than one sublingual tablet, place all tablets potential over or under dosing. (7)
in different places under the tongue at the same time. Advise patients • Patients who are on chronic buprenorphine treatment should have their
not to cut, crush, break, chew, or swallow ZUBSOLV. (2.4) dose monitored if NNRTIs are added to their treatment regimen.
---------------------DOSAGE FORMS AND STRENGTHS---------------------- Monitor patients taking buprenorphine and atazanavir with and without
Sublingual tablet: 0.7 mg buprenorphine with 0.18 mg naloxone, 1.4 mg ritonavir, and reduce dose of buprenorphine if warranted. (7)
buprenorphine with 0.36 mg naloxone, 2.9 mg buprenorphine with 0.71 mg • Use caution in prescribing ZUBSOLV for patients receiving
naloxone, 5.7 mg buprenorphine with 1.4 mg naloxone, 8.6 mg buprenorphine benzodiazepines or other CNS depressants and warn patients against
with 2.1 mg naloxone and 11.4 mg buprenorphine with 2.9 mg naloxone. (3) concomitant self-administration/misuse. (7)
• Serotonergic Drugs: Concomitant use may result in serotonin syndrome.
-------------------------------CONTRAINDICATIONS---------------------------- Discontinue ZUBSOLV if serotonin syndrome is suspected. (7)
Hypersensitivity to buprenorphine or naloxone. (4)
-----------------------USE IN SPECIFIC POPULATIONS----------------------
-----------------------WARNINGS AND PRECAUTIONS----------------------- • Nursing mothers: Caution should be exercised when administered to a
• Buprenorphine can be abused in a similar manner to other opioids. nursing woman. (8.3)
Clinical monitoring appropriate to the patient’s level of stability is • Safety and effectiveness in patients below the age of 16 has not been
essential. Multiple refills should not be prescribed early in treatment or established. (8.4)
without appropriate patient follow-up visits. (5.1) • Administer with caution to elderly or debilitated patients. (8.5)
• Significant respiratory depression and death have occurred in association • Buprenorphine/naloxone products are not recommended in patients with
with buprenorphine, particularly when taken by the intravenous route in severe hepatic impairment and may not be appropriate for patients with
combination with benzodiazepines or other CNS depressants (including moderate hepatic impairment. (8.6)
alcohol). (5.2)
• Consider dose reduction of CNS depressants, ZUBSOLV, or both, in See 17 for PATIENT COUNSELING INFORMATION and Medication
situations of concomitant prescription. (5.3) Guide
• Store safely out of the sight and reach of children. Buprenorphine can Revised: 12/2016
cause severe and fatal respiratory depression in children. (5.4)
• Neonatal opioid withdrawal syndrome (NOWS) is an expected and
treatable outcome of prolonged use of opioids during pregnancy (5.5)
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS* 2.8 Switching between ZUBSOLV Sublingual Tablets and Other
Buprenorphine/Naloxone Combination Products
1 INDICATIONS AND USAGE 3 DOSAGE FORMS AND STRENGTHS
2 DOSAGE AND ADMINISTRATION 4 CONTRAINDICATIONS
2.1 Important Dosage and Administration Information 5 WARNINGS AND PRECAUTIONS
2.2 Induction 5.1 Abuse Potential
2.2 Maintenance 5.2 Respiratory Depression
2.3 Method of Administration 5.3 CNS Depression
2.4 Clinical Supervision 5.4 Unintentional Pediatric Exposure
2.5 Unstable Patients 5.5 Neonatal Opioid Withdrawal Syndrome
2.6 Patients with Hepatic Impairment 5.6 Adrenal Insufficiency
2.7 Stopping Treatment 5.7 Dependence
5.8 Hepatitis, Hepatic Events
Reference ID: 4028807

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5.9 Allergic Reactions 8.6 Hepatic Impairment
5.10 Precipitation of Opioid Withdrawal Signs and Symptoms 8.7 Renal Impairment
5.11 Use in Opioid Naïve Patients 9 DRUG ABUSE AND DEPENDENCE
5.12 Use in Patients With Impaired Hepatic Function 9.1 Controlled Substance
5.13 Impairment of Ability to Drive or Operate Machinery 9.2 Abuse
5.14 Orthostatic Hypotension 9.3 Dependence
5.15 Elevation of Cerebrospinal Fluid Pressure 10 OVERDOSAGE
5.16 Elevation of Intracholedochal Pressure 11 DESCRIPTION
5.17 Effects in Acute Abdominal Conditions 12 CLINICAL PHARMACOLOGY
5.18 General Precautions 12.1 Mechanism of Action
6 ADVERSE REACTIONS 12.2 Pharmacodynamics
6.1 Clinical Trials Experience 12.3 Pharmacokinetics
6.2 Post-marketing Experience 13 NONCLINICAL TOXICOLOGY
7 DRUG INTERACTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
8 USE IN SPECIFIC POPULATIONS 14 CLINICAL STUDIES
8.1 Pregnancy 16 HOW SUPPLIED / STORAGE AND HANDLING
8.2 Lactation 17 PATIENT COUNSELING INFORMATION
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use *Sections or subsections omitted from the full prescribing information are not
8.5 Geriatric Use listed.
FULL PRESCRIBING INFORMATION Buprenorphine/naloxone combination products have not been evaluated in
adequate and well-controlled studies for induction in patients who are
1 INDICATIONS AND USAGE physically dependent on long-acting opioid products and transitioning to
ZUBSOLV sublingual tablet is indicated for treatment of opioid buprenorphine treatment. Buprenorphine/naloxone combination products
dependence and should be used as part of a complete treatment plan to include contain naloxone, which is absorbed in small amounts by the sublingual
counseling and psychosocial support. route and could cause worse precipitated and prolonged withdrawal. For this
reason, buprenorphine monotherapy is recommended in patients taking
Under the Drug Addiction Treatment Act (DATA) codified at 21 long-acting opioids when used according to approved administration
U.S.C. 823(g), prescription use of this product in the treatment of opioid instructions. Following induction, the patient may then be transitioned to
dependence is limited to physicians who meet certain qualifying once-daily ZUBSOLV sublingual tablet.
requirements, and who have notified the Secretary of Health and Human
Services (HHS) of their intent to prescribe this product for the treatment Patients dependent on heroin or other short-acting opioid products
of opioid dependence and have been assigned a unique identification Patients dependent on heroin or other short-acting opioid products
number that must be included on every prescription. may be induced with ZUBSOLV sublingual tablet or with sublingual
buprenorphine monotherapy. At treatment initiation, the dose of ZUBSOLV
2 DOSAGE AND ADMINISTRATION should be administered when moderate objective signs of opioid withdrawal
2.1 Important Dosage and Administration Information appear, not less than (6) hours after the patient last used opioids.
ZUBSOLV sublingual tablet is administered sublingually as a single
daily dose for maintenance treatment or in divided doses for induction 2.3 Maintenance
treatment. ZUBSOLV sublingual tablet is indicated for maintenance treatment.
The difference in bioavailability of ZUBSOLV compared to The recommended target dosage of ZUBSOLV sublingual tablet is 11.4
Suboxone® tablet requires a different tablet strength to be given to the mg/2.9 mg buprenorphine/naloxone/day as a single daily dose.
patient. One ZUBSOLV 5.7 mg/1.4 mg sublingual tablet provides equivalent The dosage of ZUBSOLV sublingual tablet should be progressively
buprenorphine exposure to one Suboxone 8 mg/2 mg sublingual tablet. adjusted in increments/decrements of 2.9 mg/0.71 mg or lower
buprenorphine/naloxone to a level that holds the patient in treatment and
2.2 Induction suppresses opioid withdrawal signs and symptoms.
Prior to induction, consideration should be given to the type of The maintenance dose of ZUBSOLV sublingual tablet is generally in
opioid dependence (i.e., long- or short-acting opioid products; see discussion the range of 2.9 mg/0.71 mg buprenorphine/naloxone to 17.2 mg/4.2 mg
that follows), the time since last opioid use, and the degree or level of opioid buprenorphine/naloxone per day depending on the individual patient. Dosages
dependence. To avoid precipitating an opioid withdrawal syndrome, the first higher than this have not been demonstrated to provide any clinical advantage
dose of buprenorphine/naloxone should be administered only when objective When determining the prescription quantity for unsupervised
and clear signs of moderate withdrawal are evident, and divided doses should administration, consider the patient’s level of stability, the security of his or
be used. It is recommended that an adequate treatment dose, titrated to her home situation, and other factors likely to affect the ability to manage
clinical effectiveness, be achieved as rapidly as possible. supplies of take-home medication.
On Day 1, an induction dosage of up to 5.7 mg/1.4 mg ZUBSOLV
sublingual tablet is recommended. This is administered sublingually in 2.4 Method of Administration
divided doses under supervision. Clinicians should start with an initial dose Do not cut, crush, break, chew, or swallow ZUBSOLV sublingual
of 1.4 mg/0.36 mg ZUBSOLV sublingual tablet. The remainder of the Day 1 tablets. ZUBSOLV sublingual tablet should be placed under the tongue until
dose of up to 4.2 mg/1.08 mg should be divided into doses of 1 to 2 tablets of dissolved. The dissolve time for ZUBSOLV varies between individuals, and
1.4 mg/0.36 mg at 1.5 to 2 hour intervals. Some patients (e.g., those with the median dissolve time observed was 5 minutes. For dosages requiring more
recent exposure to buprenorphine) may tolerate up to 3 x 1.4 mg/0.36 mg than one sublingual tablet, place all tablets in different places under the tongue
ZUBSOLV sublingual tablets as a single, second dose. at the same time. Patients should keep the tablets under the tongue until
On Day 2, a single daily dose of up to 11.4 mg/2.9 mg ZUBSOLV dissolved; swallowing the tablets reduces the bioavailability of the drug.
sublingual tablet is recommended. Advise patients not to eat or drink anything until the tablet is completely
All doses should be based on clinical need to control acute dissolved. To ensure consistency in bioavailability, patients should follow the
withdrawal symptoms and administered under supervision. same manner of dosing with continued use of the product.
Medications should be prescribed in consideration of the frequency If a sequential mode of administration is preferred, patients should
of visits. Provision of multiple refills is not advised early in treatment or follow the same manner of dosing with continued use of the product, to ensure
without appropriate patient follow-up visits. consistency in bioavailability.
Patients dependent on methadone or long-acting opioid products Proper administration technique should be demonstrated to the patient.
Patients dependent on methadone or long-acting opioid products
may be more susceptible to precipitated and prolonged withdrawal during
induction than those on short-acting opioid products.

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2.5 Clinical Supervision The differences in bioavailability of ZUBSOLV compared to
Treatment should be initiated with supervised administration, Suboxone tablet require that different tablet strengths be given to the patient.
progressing to unsupervised administration as the patient’s clinical stability One ZUBSOLV 5.7 mg/1.4 mg sublingual tablet provides equivalent
permits. ZUBSOLV sublingual tablet is subject to diversion and abuse. When buprenorphine exposure to one Suboxone 8 mg/2 mg sublingual tablet.
determining the prescription quantity for unsupervised administration, When switching between Suboxone dosage strengths and
consider the patient’s level of stability, the security of his or her home ZUBSOLV dosage strengths the corresponding dosage strengths are:
situation, and other factors likely to affect the ability to manage supplies of
take-home medication. Suboxone sublingual tablets, Corresponding dosage
Ideally patients should be seen at reasonable intervals (e.g., at least including generic equivalents strength of ZUBSOLV
weekly during the first month of treatment) based upon the individual sublingual tablets
circumstances of the patient. Medication should be prescribed in consideration One 2 mg/0.5 mg sublingual One 1.4 mg/0.36 mg
of the frequency of visits. Provision of multiple refills is not advised early in buprenorphine/naloxone tablet ZUBSOLV sublingual
treatment or without appropriate patient follow-up visits. Periodic assessment tablet
is necessary to determine compliance with the dosing regimen, effectiveness
of the treatment plan, and overall patient progress. 4 mg/1 mg buprenorphine/naloxone One 2.9 mg/0.71 mg
Once a stable dosage has been achieved and patient assessment taken as: ZUBSOLV sublingual
(e.g., urine drug screening) does not indicate illicit drug use, less frequent • Two 2 mg/0.5 mg sublingual tablet
follow-up visits may be appropriate. A once-monthly visit schedule may be buprenorphine/naloxone tablets
reasonable for patients on a stable dosage of medication who are making One 8 mg/2 mg sublingual One 5.7 mg/1.4 mg
progress toward their treatment objectives. Continuation or modification of buprenorphine/naloxone tablet ZUBSOLV
pharmacotherapy should be based on the physician’s evaluation of treatment sublingual tablet
outcomes and objectives such as: 12 mg/3 mg One 8.6 mg/2.1 mg
buprenorphine/naloxone, taken as: ZUBSOLV
1. Absence of medication toxicity • One 8 mg/2 mg sublingual sublingual tablet
buprenorphine/naloxone
2. Absence of medical or behavioral adverse effects tablet AND
3. Responsible handling of medications by the patient • Two 2 mg/0.5 mg sublingual
4. Patient’s compliance with all elements of the treatment plan (including tablets
recovery-oriented activities, psychotherapy, and/or other psychosocial 16 mg/4 mg One 11.4 mg/2.9 mg
modalities) buprenorphine/naloxone, taken as: ZUBSOLV
• Two 8 mg/2 mg sublingual sublingual tablet
5. Abstinence from illicit drug use (including problematic alcohol and/or
benzodiazepine use)
tablets
If treatment goals are not being achieved, the physician should re
evaluate the appropriateness of continuing the current treatment.
2.6 Unstable Patients 3 DOSAGE FORMS AND STRENGTHS

Physicians will need to decide when they cannot appropriately ZUBSOLV sublingual tablet is supplied in six dosage strengths:
provide further management for particular patients. For example, some • buprenorphine/naloxone 0.7 mg/0.18 mg, white, oval shape
patients may be abusing or dependent on various drugs, or unresponsive to tablets imprinted with “.7”
psychosocial intervention such that the physician does not feel that he/she has • buprenorphine/naloxone 1.4 mg/0.36 mg, white, triangular
the expertise to manage the patient. In such cases, the physician may want to shape tablets imprinted with “1.4”
assess whether to refer the patient to a specialist or more intensive behavioral • buprenorphine/naloxone 2.9 mg/0.71 mg, white, D shape tablets
treatment environment. Decisions should be based on a treatment plan imprinted with “2.9”
established and agreed upon with the patient at the beginning of treatment. • buprenorphine/naloxone 5.7 mg/1.4 mg, white, round shape
Patients who continue to misuse, abuse, or divert buprenorphine tablets imprinted with “5.7”
products or other opioids should be provided with, or referred to, more • buprenorphine/naloxone 8.6 mg/2.1 mg, white, diamond shape
intensive and structured treatment. tablets imprinted with “8.6”
• buprenorphine/naloxone 11.4 mg/2.9 mg, white, capsule shape
2.7 Patients With Hepatic Impairment tablets imprinted with “11.4”
Severe hepatic impairment results in a reduced clearance of
naloxone to a much greater extent than buprenorphine, and moderate 4 CONTRAINDICATIONS
hepatic impairment also results in a reduced clearance of naloxone to a ZUBSOLV sublingual tablet should not be administered to patients
greater extent than buprenorphine. Because the doses of this fixed who have been shown to be hypersensitive to buprenorphine or naloxone as
combination product cannot be individually titrated, the combination serious adverse reactions, including anaphylactic shock, have been reported
product should generally be avoided in patients with severe hepatic [see Warnings and Precautions (5.9)].
impairment and may not be appropriate for patients with moderate
hepatic impairment [see Warnings and Precautions (5.12)]. 5 WARNINGS AND PRECAUTIONS
2.8 Stopping Treatment 5.1 Abuse Potential
The decision to discontinue therapy with ZUBSOLV sublingual Buprenorphine can be abused in a manner similar to other opioids,
tablets after a period of maintenance should be made as part of a legal or illicit. Prescribe and dispense buprenorphine with appropriate
comprehensive treatment plan. Both gradual and abrupt discontinuation of precautions to minimize risk of misuse, abuse, or diversion, and ensure
buprenorphine has been used, but the data are insufficient to determine the appropriate protection from theft, including in the home. Clinical monitoring
best method of dose taper at the end of treatment. appropriate to the patient’s level of stability is essential. Multiple refills
should not be prescribed early in treatment or without appropriate patient
2.9 Switching between ZUBSOLV Sublingual Tablets and Other follow-up visits [see Drug Abuse and Dependence (9.2)].
Buprenorphine/Naloxone Combination Products
For patients being switched between ZUBSOLV sublingual tablets 5.2 Respiratory Depression
and other buprenorphine/naloxone products dosage adjustments may be Buprenorphine, particularly when taken by the IV route, in
necessary. Patients should be monitored for over-medication as well as combination with benzodiazepines or other CNS depressants (including
withdrawal or other signs of under-dosing. alcohol), has been associated with significant respiratory depression and
death. Many, but not all, post-marketing reports regarding coma and death

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associated with the concomitant use of buprenorphine and benzodiazepines post-marketing adverse event reports. The spectrum of abnormalities ranges
involved misuse by self-injection. Deaths have also been reported in from transient asymptomatic elevations in hepatic transaminases to case
association with concomitant administration of buprenorphine with other reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and
depressants such as alcohol or other CNS depressant drugs. Patients should be hepatic encephalopathy. In many cases, the presence of pre-existing liver
warned of the potential danger of self-administration of benzodiazepines or enzyme abnormalities, infection with hepatitis B or hepatitis C virus,
other depressants while under treatment with ZUBSOLV sublingual tablets concomitant usage of other potentially hepatotoxic drugs, and ongoing
[see Drug Interactions (7)]. injecting drug use may have played a causative or contributory role. In other
In the case of overdose, the primary management should be the cases, insufficient data were available to determine the etiology of the
re-establishment of adequate ventilation with mechanical assistance of abnormality. Withdrawal of buprenorphine has resulted in amelioration of
respiration, if required. Naloxone may be of value for the management of acute hepatitis in some cases; however, in other cases no dose reduction was
buprenorphine overdose. Higher than normal doses and repeated necessary. The possibility exists that buprenorphine had a causative or
administration may be necessary. contributory role in the development of the hepatic abnormality in some cases.
ZUBSOLV sublingual tablets should be used with caution in patients Liver function tests, prior to initiation of treatment is recommended to
with compromised respiratory function (e.g., chronic obstructive pulmonary establish a baseline. Periodic monitoring of liver function during treatment is
disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, also recommended. A biological and etiological evaluation is recommended
or pre-existing respiratory depression). when a hepatic event is suspected. Depending on the case, ZUBSOLV
sublingual tablet may need to be carefully discontinued to prevent withdrawal
5.3 CNS Depression signs and symptoms and a return by the patient to illicit drug use, and strict
Patients receiving buprenorphine in the presence of opioid analgesics, monitoring of the patient should be initiated.
general anesthetics, benzodiazepines, phenothiazines, other tranquilizers,
sedative/hypnotics, or other CNS depressants (including alcohol) may exhibit 5.9 Allergic Reactions
increased CNS depression. Consider dose reduction of CNS depressants, Cases of hypersensitivity to buprenorphine and naloxone containing
ZUBSOLV sublingual tablets, or both in situations of concomitant prescribing products have been reported both in clinical trials and in the post-marketing
[see Drug Interactions (7)]. experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic
shock have been reported. The most common signs and symptoms include
5.4 Unintentional Pediatric Exposure rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or
Buprenorphine can cause fatal respiratory depression in children who naloxone is a contraindication to the use of ZUBSOLV sublingual tablet.
are accidentally exposed to it. Store buprenorphine containing medications
safely out of the sight and reach of children and destroy any unused 5.10 Precipitation of Opioid Withdrawal Signs and Symptoms
medication appropriately [see Patient Counseling Information (17)]. Because it contains naloxone, ZUBSOLV sublingual tablet is likely
to produce withdrawal signs and symptoms if misused parenterally by
5.5 Neonatal Opioid Withdrawal Syndrome individuals dependent on full opioid agonists such as heroin, morphine, or
Neonatal opioid withdrawal syndrome (NOWS) is an expected and methadone. Because of the partial agonist properties of buprenorphine,
treatable outcome of prolonged use of opioids during pregnancy, whether that ZUBSOLV sublingual tablet may precipitate opioid withdrawal signs and
use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in symptoms in such persons if administered sublingually before the agonist
adults, NOWS may be life-threatening if not recognized and treated in the effects of the opioid have subsided.
neonate. Healthcare professionals should observe newborns for signs of
NOWS and manage accordingly [see Use in Specific Populations (8.1)]. 5.11 Use in Opioid Naïve Patients
Advise pregnant women receiving opioid addiction treatment with There have been reported deaths of opioid naive individuals who
ZUBSOLV of the risk of neonatal opioid withdrawal syndrome and ensure received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia.
that appropriate treatment will be available [see Use in Specific Populations ZUBSOLV sublingual tablet is not appropriate as an analgesic.
(8.1)]. This risk must be balanced against the risk of untreated opioid
addiction which often results in continued or relapsing illicit opioid use and is 5.12 Use in Patients With Impaired Hepatic Function
associated with poor pregnancy outcomes. Therefore, prescribers should Buprenorphine/naloxone products are not recommended in patients
discuss the importance and benefits of management of opioid addiction with severe hepatic impairment and may not be appropriate for patients with
throughout pregnancy. moderate hepatic impairment. The doses of buprenorphine and naloxone in
this fixed-dose combination product cannot be individually titrated, and
5.6 Adrenal Insufficiency hepatic impairment results in a reduced clearance of naloxone to a much
Cases of adrenal insufficiency have been reported with opioid use, greater extent than buprenorphine. Therefore, patients with severe hepatic
more often following greater than one month of use. Presentation of adrenal impairment will be exposed to substantially higher levels of naloxone than
insufficiency may include non-specific symptoms and signs including nausea, patients with normal hepatic function. This may interfere with
vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If buprenorphine’s efficacy throughout treatment. In patients with moderate
adrenal insufficiency is suspected, confirm the diagnosis with diagnostic hepatic impairment, the differential reduction of naloxone clearance compared
testing as soon as possible. If adrenal insufficiency is diagnosed, treat with to buprenorphine clearance is not as great as in subjects with severe hepatic
physiologic replacement doses of corticosteroids. Wean the patient off of the impairment. Therefore, buprenorphine/naloxone products may be used with
opioid to allow adrenal function to recover and continue corticosteroid caution for maintenance treatment in patients with moderate hepatic
treatment until adrenal function recovers. Other opioids may be tried as some impairment who have initiated treatment on a buprenorphine product without
cases reported use of a different opioid without recurrence of adrenal naloxone. However, patients should be carefully monitored and consideration
insufficiency. The information available does not identify any particular given to the possibility of naloxone interfering with buprenorphine’s efficacy
opioids as being more likely to be associated with adrenal insufficiency. [see Use in Specific Populations (8.6)].
5.7 Dependence 5.13 Impairment of Ability to Drive or Operate Machinery

Buprenorphine is a partial agonist at the mu-opioid receptor and ZUBSOLV sublingual tablet may impair the mental or physical
chronic administration produces physical dependence of the opioid type, abilities required for the performance of potentially dangerous tasks such as
characterized by withdrawal signs and symptoms upon abrupt discontinuation driving a car or operating machinery, especially during treatment induction
or rapid taper. The withdrawal syndrome is typically milder than seen with and dose adjustment. Patients should be cautioned about driving or operating
full agonists and may be delayed in onset. Buprenorphine can be abused in a hazardous machinery until they are reasonably certain that ZUBSOLV
manner similar to other opioids. This should be considered when prescribing sublingual tablet therapy does not adversely affect his or her ability to engage
or dispensing buprenorphine in situations when the clinician is concerned in such activities.
about an increased risk of misuse, abuse, or diversion [see Drug Abuse and
Dependence (9.3)]. 5.14 Orthostatic Hypotension
Like other opioids, ZUBSOLV sublingual tablets may produce
5.8 Hepatitis, Hepatic Events orthostatic hypotension in ambulatory patients.
Cases of cytolytic hepatitis and hepatitis with jaundice have been
observed in individuals receiving buprenorphine in clinical trials and through

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5.15 Elevation of Cerebrospinal Fluid Pressure Body System / Adverse Buprenorphine/ Placebo N=107
Buprenorphine, like other opioids, may elevate cerebrospinal fluid Event (COSTART naloxone
pressure and should be used with caution in patients with head injury, Terminology) 16 mg/day N=107
intracranial lesions, and other circumstances when cerebrospinal pressure may Body as a Whole
be increased. Buprenorphine can produce miosis and changes in the level of
consciousness that may interfere with patient evaluation. Asthenia 7 (7%) 7 (7%)
5.16 Elevation of Intracholedochal Pressure Chills 8 (8%) 8 (8%)

Buprenorphine has been shown to increase intracholedochal pressure, Headache 39 (37%) 24 (22%)
as do other opioids, and thus should be administered with caution to patients
with dysfunction of the biliary tract. Infection 6 (6%) 7 (7%)
Pain 24 (22%) 20 (19%)
5.17 Effects in Acute Abdominal Conditions
As with other opioids, buprenorphine may obscure the diagnosis or Pain Abdomen 12 (11%) 7 (7%)
clinical course of patients with acute abdominal conditions.
Pain Back 4 (4%) 12 (11%)
5.18 General Precautions Withdrawal Syndrome 27 (25%) 40 (37%)
ZUBSOLV sublingual tablet should be administered with caution in
Cardiovascular System
debilitated patients and those with myxedema or hypothyroidism, adrenal
cortical insufficiency (e.g., Addison's disease); CNS depression or coma; toxic Vasodilation 10 (9%) 7 (7%)
psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism;
delirium tremens; or kyphoscoliosis. Digestive System
6 ADVERSE REACTIONS Constipation 13 (12%) 3 (3%)

Diarrhea 4 (4%) 16 (15%)
6.1 Clinical Trials Experience
Nausea 16 (15%) 12 (11%)
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug Vomiting 8 (8%) 5 (5%)
cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice. Nervous System
ZUBSOLV for use as initial treatment was evaluated in two clinical Insomnia 15 (14%) 17 (16%)
trials that had identical, blinded, two-day induction phases, comparing
ZUBSOLV to generic buprenorphine. On the first day, subjects received an Respiratory System
initial dose of ZUBSOLV 1.4 mg/0.36 mg or generic buprenorphine 2 mg,
followed by ZUBSOLV 4.2 mg/1.08 mg or generic buprenorphine 6 mg 1.5 Rhinitis 5 (5%) 14 (13%)
hours later. In total, safety data were available for 538 opioid-dependent
Skin and Appendages
subjects exposed to ZUBSOLV (buprenorphine/naloxone) sublingual tablets
when used for initial treatment. Sweating 15 (14%) 11 (10%)
Table 1. Adverse Reactions in ≥ 5% of Patients During the Induction

The adverse event profile of buprenorphine was also characterized in
Phase by System Organ Class and Preferred Term (Safety Population) the dose-controlled study of buprenorphine solution, over a range of doses in
System Organ Class ZUBSOLV Generic BUP Overall four months of treatment. Table 3 shows adverse events reported by at least
Preferred Term (N=538) (N=530) (N=1068) 5% of subjects in any dose group in the dose-controlled study.
N (%)
Patients with any 139 (26%) 136 (26%) 275 (26%) Table 3. Adverse Events (≥ 5%) by Body System and Treatment Group
in a 16-week Study
Adverse Reactions
Gastrointestinal 64 (12%) 60 (11%) 124 (12%) Body System Buprenorphine dose*
Disorders /Adverse Event
Very Low* Low* Moderate* High* Total*
Nausea 29 (5%) 36 (7%) 65 (6%) (COSTART
(N=184) (N=180) (N=186) (N=181) (N=731)
Terminology)
Vomiting 25 (5%) 26 (5%) 51 (5%) N (%) N (%) N (%) N (%) N (%)
Nervous System 48 (9%) 44 (8%) 92 (9%) *Sublingual solution. Doses in this table cannot necessarily be delivered in tablet
Disorders form, but for comparison purposes:
Headache 36 (7%) 35 (7%) 71 (7%) "Very low" dose (1 mg solution) would be less than a Suboxone tablet dose of 2
mg
BUP = buprenorphine
"Low" dose (4 mg solution) approximates a 6 mg Suboxone tablet dose
ZUBSOLV = buprenorphine/naloxone
"Moderate" dose (8 mg solution) approximates a 12 mg Suboxone tablet dose
"High" dose (16 mg solution) approximates a 24 mg Suboxone tablet dose
The safety of buprenorphine/naloxone for longer-term use (up to 16 Body as a Whole
weeks of treatment) was evaluated in previous studies in 497 opioid-
dependent subjects. The prospective evaluation of buprenorphine/naloxone Abscess 9 (5%) 2 (1%) 3 (2%) 2 (1%) 16 (2%)
was supported by clinical trials using buprenorphine tablets without naloxone Asthenia 26 (14%) 28 (16%) 26 (14%) 24 (13%) 104 (14%)
and other trials using buprenorphine sublingual solutions. In total, safety data
were available from 3214 opioid-dependent subjects exposed to Chills 11 (6%) 12 (7%) 9 (5%) 10 (6%) 42 (6%)
buprenorphine at doses in the range used in treatment of opioid addiction. See
Table 2. Fever 7 (4%) 2 (1%) 2 (1%) 10 (6%) 21 (3%)
Flu Syndrome. 4 (2%) 13 (7%) 19 (10%) 8 (4%) 44 (6%)
Table 2. Adverse Events > 5% by Body System and Treatment Group
in a 4-week Study Headache 51 (28%) 62 (34%) 54 (29%) 53 (29%) 220 (30%)
N (%) N (%) Infection 32 (17%) 39 (22%) 38 (20%) 40 (22%) 149 (20%)

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Injury Accidental 5 (3%) 10 (6%) 5 (3%) 5 (3%) 25 (3%) Rhinitis 27 (15%) 16 (9%) 15 (8%) 21 (12%) 79 (11%)
Pain 47 (26%) 37 (21%) 49 (26%) 44 (24%) 177 (24%) Skin and
Appendages
Pain Back 18 (10%) 29 (16%) 28 (15%) 27 (15%) 102 (14%)
Sweat 23 (13%) 21 (12%) 20 (11%) 23 (13%) 87 (12%)
Withdrawal
45 (24%) 40 (22%) 41 (22%) 36 (20%) 162 (22%) Special Senses
Syndrome
Digestive System Runny Eyes 13 (7%) 9 (5%) 6 (3%) 6 (3%) 34 (5%)
Constipation 10 (5%) 23 (13%) 23 (12%) 26 (14%) 82 (11%)
6.2 Post-marketing Experience
Diarrhea 19 (10%) 8 (4%) 9 (5%) 4 (2%) 40 (5%) The following adverse reactions have been identified during post-
Dyspepsia 6 (3%) 10 (6%) 4 (2%) 4 (2%) 24 (3%) approval use of buprenorphine and naloxone sublingual tablets. Because
these reactions are reported voluntarily from a population of uncertain size, it
Nausea 12 (7%) 22 (12%) 23 (12%) 18 (10%) 75 (10%) is not always possible to reliably estimate a causal relationship to drug
exposure.
Vomiting 8 (4%) 6 (3%) 10 (5%) 14 (8%) 38 (5%) The most frequently reported post-marketing adverse event not
observed in clinical trials was peripheral edema.
Nervous System
Anxiety 22 (12%) 24 (13%) 20 (11%) 25 (14%) 91 (12%)
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-
Depression 24 (13%) 16 (9%) 25 (13%) 18 (10%) 83 (11%) threatening condition, have been reported during concomitant use of opioids
with serotonergic drugs.
Dizziness 4 (2%) 9 (5%) 7 (4%) 11 (6%) 31 (4%)
Adrenal insufficiency: Cases of adrenal insufficiency have been reported
Insomnia 42 (23%) 50 (28%) 43 (23%) 51 (28%) 186 (25%) with opioid use, more often following greater than one month of use.
Nervousness 12 (7%) 11 (6%) 10 (5%) 13 (7%) 46 (6%) Anaphylaxis: Anaphylaxis has been reported with ingredients contained in
ZUBSOLV.
Somnolence 5 (3%) 13 (7%) 9 (5%) 11 (6%) 38 (5%)
Androgen deficiency: Cases of androgen deficiency have occurred with
Respiratory
chronic use of opioids [see Clinical Pharmacology (12.2)].
System
Cough Increase 5 (3%) 11 (6%) 6 (3%) 4 (2%) 26 (4%)
Pharyngitis 6 (3%) 7 (4%) 6 (3%) 9 (5%) 28 (4%)

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7 DRUG INTERACTIONS
Table 4. Includes clinically significant drug interactions with ZUBSOLV
Benzodiazepines
Clinical Impact: There have been a number of reports regarding coma and death associated with the misuse and abuse of the
combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was
misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination
of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory
depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention: Closely monitor patients with concurrent use of ZUBSOLV and benzodiazepines. Warn patients that it is
extremely dangerous to self-administer benzodiazepines while taking ZUBSOLV, and warn patients to use
benzodiazepines concurrently with ZUBSOLV only as directed by their physician.
Non-Benzodiazepines Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including
alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are
inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of
respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples: Non-benzodiazepines sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, and other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of
buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a
stable dose of ZUBSOLV is achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma
concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid
efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention: If concomitant use is necessary, consider dosage reduction of ZUBSOLV until stable drug effects are achieved.
Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the ZUBSOLV dosage until stable drug effects are
achieved. Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g.,
ritonavir).
CYP3A4 Inducers
Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of
buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a
withdrawal syndrome in patients who have developed physical dependence to buprenorphine.
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration
will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and
adverse reactions and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the ZUBSOLV dosage until stable drug effects are
achieved. Monitor for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider ZUBSOLV dosage reduction and monitor for signs of respiratory
depression.
Examples: Rifampin, carbamazepine, phenytoin.
Antiretrovirals: Non-Nucleoside Reverse Transcriptase inhibitors (NNRTIs)
Clinical Impact: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz,
nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant
pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been
shown in clinical studies, but these pharmacokinetic interactions did not result in any significant
pharmacodynamic effects.
Intervention: Patients who are on chronic ZUBSOLV treatment should have their dose monitored if NNRTIs are added to
their treatment regimen.
Examples: Efavirenz, nevirapine, etravirine, delavirdine.
Antiretrovirals: Protease Inhibitors (PIs)
Clinical Impact: Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir,
lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant
pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir)
resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased
sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving
buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention: Monitor patients taking ZUBSOLV and atazanavir with and without ritonavir, and reduce dose of ZUBSOLV if
warranted.
Examples: Atazanavir, ritonavir.
Antiretrovirals: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Clinical Impact: Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme
pathway, thus no interactions with buprenorphine are expected.
Intervention: None.
Serotonergic Drugs

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Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted
in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose
adjustment. Discontinue ZUBSOLV if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin
neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those
intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory
depression, coma) [see Warnings and Precautions (5.2)]
Intervention: The use of ZUBSOLV is not recommended for patients taking MAOIs or within 14 days of stopping such
treatment.
Examples: Phenelzine, tranylcypromine, linezolid.
Muscle Relaxants
Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an
increased degree of respiratory depression.
Intervention: Monitor patients receiving muscle relaxants and ZUBSOLV for signs of respiratory depression that may be
greater than otherwise expected and decrease the dosage of ZUBSOLV and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the
diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe
constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when ZUBSOLV is used concomitantly
with anticholinergic drugs.

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8 USE IN SPECIFIC POPULATIONS presentation for prenatal care, infection, poor compliance, poor nutrition, and
psychosocial circumstances. Interpretation of data is complicated further by
8.1 Pregnancy the lack of information on untreated opioid-dependent pregnant women, who
Risk Summary would be the most appropriate group for comparison. Rather, women on
The data on use of buprenorphine, the active ingredient in another form of opioid medication-assisted treatment, or women in the general
ZUBSOLV, in pregnancy, are limited; however, these data do not indicate an population are generally used as the comparison group. However, women in
increased risk of major malformations specifically due to buprenorphine these comparison groups may be different from women prescribed
exposure. There are limited data from randomized clinical trials in women buprenorphine-containing products with respect to maternal factors that may
maintained on buprenorphine that were not designed appropriately to assess lead to poor pregnancy outcomes.
the risk of major malformations [see Data]. Observational studies have In a multicenter, double-blind, randomized, controlled trial
reported on congenital malformations among buprenorphine-exposed (“MOTHER”) designed primarily to assess neonatal opioid withdrawal
pregnancies, but were also not designed appropriately to assess the risk of effects, opioid-dependent pregnant women were randomized to buprenorphine
congenital malformations specifically due to buprenorphine exposure [see (n=86) or methadone (n=89) treatment, with enrollment at an average
Data]. The extremely limited data on sublingual naloxone exposure in gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in
pregnancy are not sufficient to evaluate a drug-associated risk. the buprenorphine group (33%) and 16 of the 89 women in the methadone
Reproductive and developmental studies in rats and rabbits identified group (18%) discontinued treatment before the end of pregnancy.
adverse events at clinically relevant and higher doses. Embryofetal death was Among women who remained in treatment until delivery, there was
observed in both rats and rabbits administered buprenorphine during the no difference between buprenorphine-treated and methadone-treated groups in
period of organogenesis at doses approximately 6 and 0.3 times, respectively, the number of neonates requiring NOWS treatment or in the peak severity of
the human sublingual dose of 16 mg/day of buprenorphine. Pre-and postnatal NOWS. Buprenorphine-exposed neonates required less morphine (mean total
development studies in rats demonstrated increased neonatal deaths at 0.3 dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days),
times and above and dystocia at approximately 3 times the human sublingual and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared
dose of 16 mg/day of buprenorphine. No clear teratogenic effects were seen to the methadone-exposed group. There were no differences between groups
when buprenorphine was administered during organogenesis with a range of in other primary outcomes (neonatal head circumference,) or secondary
doses equivalent to or greater than the human sublingual dose of 16 mg/day of outcomes (weight and length at birth, preterm birth, gestational age at
buprenorphine. However, increases in skeletal abnormalities were noted in delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal
rats and rabbits administered buprenorphine daily during organogenesis at or neonatal adverse events. The outcomes among mothers who discontinued
doses approximately 0.6 times and approximately equal to the human treatment before delivery and may have relapsed to illicit opioid use are not
sublingual dose of 16 mg/day of buprenorphine, respectively. In a few studies, known. Because of the imbalance in discontinuation rates between the
some events such as acephalus and omphalocele were also observed but these buprenorphine and methadone groups, the study findings are difficult to
findings were not clearly treatment-related [see Data]. interpret.
The estimated background risk of major birth defects and miscarriage
for the indicated population are unknown. All pregnancies have a background Animal Data
risk of birth defect, loss, or other adverse outcomes In the U.S. general ZUBSOLV has been shown to have differences in bioavailability
population, the estimated background risk of major birth defects and compared to other buprenorphine/naloxone-containing sublingual products.
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, The exposure margins listed below are based on body surface area
respectively. comparisons (mg/m2) to the recommended human sublingual dose of 16 mg
buprenorphine via Suboxone, which is equivalent to a human sublingual dose
of 11.4 mg buprenorphine via ZUBSOLV.
Clinical Considerations
Disease-Associated Maternal and Embryo-fetal Risk Effects on embryo-fetal development were studied in Sprague-
Untreated opioid addiction in pregnancy is associated with adverse Dawley rats and Russian white rabbits following oral (1:1) and intramuscular
obstetrical outcomes such as low birth weight, preterm birth, and fetal death. (IM) (3:2) administration of mixtures of buprenorphine and naloxone during
In addition, untreated opioid addiction often results in continued or relapsing the period of organogenesis. Following oral administration to rats no
illicit opioid use. teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day
(estimated exposure approximately 150 times the human sublingual dose of 16
Dose Adjustment during Pregnancy and the Postpartum Period mg).
Dosage adjustments of buprenorphine may be required during
pregnancy, even if maintained on a stable dose prior to pregnancy. Following oral administration to rabbits, no teratogenic effects were
Withdrawal signs and symptoms should be monitored closely and the dose observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure
adjusted as necessary. approximately 50 times the human sublingual dose of 16 mg). No definitive
drug-related teratogenic effects were observed in rats and rabbits at IM doses
Fetal/neonatal Adverse Reactions up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times,
Neonatal opioid withdrawal syndrome may occur in newborn infants respectively, the human sublingual dose of 16 mg). Acephalus was observed
of mothers who are receiving treatment with ZUBSOLV. in one rabbit fetus from the low-dose group and omphalocele was observed in
Neonatal opioid withdrawal syndrome presents as irritability, two rabbit fetuses from the same litter in the mid-dose group; no findings
hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, were observed in fetuses from the high-dose group. Following oral
diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually administration of buprenorphine to rats, dose-related post-implantation losses,
occur in the first days after birth. The duration and severity of neonatal opioid evidenced by increases in the numbers of early resorptions with consequent
withdrawal syndrome may vary. Observe newborns for signs of neonatal reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day
opioid withdrawal syndrome and manage accordingly [see Warnings and or greater (estimated exposure approximately 6 times the human sublingual
Precautions (5.5)]. dose of 16 mg).
Labor or Delivery In the rabbit, increased post-implantation losses occurred at an oral

Opioid-dependent women on buprenorphine maintenance therapy dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit,
may require additional analgesia during labor. post-implantation losses, as evidenced by decreases in live fetuses and
increases in resorptions, occurred at 30 mg/kg/day.
Data Buprenorphine was not teratogenic in rats or rabbits after IM or
Human Data subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was
Studies have been conducted to evaluate neonatal outcomes in approximately 3 and 6 times, respectively, the human sublingual dose of 16
women exposed to buprenorphine during pregnancy. Limited data from trials, mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was
observational studies, case series, and case reports on buprenorphine use in approximately 0.5 times and equal to, respectively, the human sublingual dose
pregnancy do not indicate an increased risk of major malformations of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure
specifically due to buprenorphine. Several factors may complicate the was approximately 95 times the human sublingual dose of 16 mg) and 25
interpretation of investigations of the children of women who take mg/kg/day in rabbits (estimated exposure was approximately 30 times the
buprenorphine during pregnancy, including maternal use of illicit drugs, late human sublingual dose of 16 mg). Significant increases in skeletal
abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted

455-9
in rats after SC administration of 1 mg/kg/day and up (estimated exposure was 8.4 Pediatric Use
approximately 0.6 times the human sublingual dose of 16 mg), but were not The safety and effectiveness of ZUBSOLV sublingual tablets have
observed at oral doses up to 160 mg/kg/day. not been established in pediatric patients. This product is not appropriate for
Increases in skeletal abnormalities in rabbits after IM administration the treatment of neonatal opioid withdrawal syndrome in neonates, because it
of 5 mg/kg/day (estimated exposure was approximately 6 times the human contains naloxone, an opioid antagonist.
sublingual dose of 16 mg) or oral administration of 1 mg/kg/day or greater
(estimated exposure was approximately equal to the human sublingual dose of 8.5 Geriatric Use
16 mg) were not statistically significant.
Clinical studies of buprenorphine/naloxone sublingual tablets did not
In rabbits, buprenorphine produced statistically significant pre include sufficient numbers of subjects aged 65 and over to determine whether
implantation losses at oral doses of 1 mg/kg/day or greater and post- they responded differently than younger subjects. Other reported clinical
implantation losses that were statistically significant at IV doses of 0.2 experience have not identified differences in responses between the elderly
mg/kg/day or greater (estimated exposure approximately 0.3 times the human and younger patients. In general, dose selection for an elderly patient should
sublingual dose of 16 mg). be cautious, usually starting at the low end of the dosing range, reflecting the
Dystocia was noted in pregnant rats treated intramuscularly with greater frequency of decreased hepatic, renal, or cardiac function, and of
buprenorphine during gestation and lactation at 5 mg/kg/day (approximately 3 concomitant disease or other drug therapy.
times the human sublingual dose of 16 mg). Fertility, pre-, and post-natal
development studies with buprenorphine in rats indicated increases in 8.6 Hepatic Impairment
neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately The effect of hepatic impairment on the pharmacokinetics of
0.5 times the human sublingual dose of 16 mg), after IM doses of 0.5 buprenorphine and naloxone has been evaluated in a pharmacokinetic study.
mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 Both drugs are extensively metabolized in the liver. While no clinically
mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times significant changes have been observed in subjects with mild hepatic
the human sublingual dose of 16 mg). An apparent lack of milk production impairment; the plasma levels have been shown to be higher and half-life
during these studies likely contributed to the decreased pup viability and values have been shown to be longer for both buprenorphine and naloxone in
lactation indices. Delays in the occurrence of righting reflex and startle subjects with moderate and severe hepatic impairment. The magnitude of the
response were noted in rat pups at an oral dose of 80 mg/kg/day effects on naloxone is greater than that on buprenorphine in both moderately
(approximately 50 times the human sublingual dose of 16 mg). and severely impaired subjects. The difference in magnitude of the effects on
naloxone and buprenorphine are greater in subjects with severe hepatic
8.2 Lactation impairment than in subjects with moderate hepatic impairment, and therefore
Risk Summary the clinical impact of these effects is likely to be greater in patients with
Based on two studies in 13 lactating women, maintained on severe hepatic impairment than in patients with moderate hepatic impairment.
buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine Buprenorphine/naloxone products should be avoided in patients with severe
were present in low levels in human milk and infant urine, and available data hepatic impairment and may not be appropriate for patients with moderate
have not shown adverse reactions in breastfed infants. There are no data on hepatic impairment [see Warnings and Precautions (5.12), Clinical
the combination product buprenorphine/naloxone in breastfeeding, however Pharmacology (12.3)].
oral absorption of naloxone is limited. Caution should be exercised when
ZUBSOLV is administered to a nursing woman. The developmental and 8.7 Renal Impairment
health benefits of breastfeeding should be considered along with the mother’s No differences in buprenorphine pharmacokinetics were observed
clinical need for ZUBSOLV and any potential adverse effects on the breastfed between 9 dialysis-dependent and 6 normal patients following IV
child from the drug or from the underlying maternal condition. administration of 0.3 mg buprenorphine. The effects of renal failure on
naloxone pharmacokinetics are unknown [see Clinical Pharmacology (12.3)].
Clinical Considerations
Advise the breastfeeding women taking buprenorphine products to 9 DRUG ABUSE AND DEPENDENCE
monitor the infant for increased drowsiness and breathing difficulties.
9.1 Controlled Substance
Data
Buprenorphine is a Schedule III narcotic under the Controlled
Data were consistent from two studies (N=13) of breastfeeding
Substances Act.
infants whose mothers were maintained on sublingual doses of buprenorphine
Under the Drug Addiction Treatment Act (DATA) codified at 21
ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less
U.S.C. 823(g), prescription use of this product in the treatment of opioid
than 1% of the maternal daily dose.
dependence is limited to physicians who meet certain qualifying
In a study of six lactating women who were taking a median
requirements, and who have notified the Secretary of Health and Human
sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery,
Services (HHS) of their intent to prescribe this product for the treatment
breast milk provided a median infant dose of 0.42 mcg/kg/day of
of opioid dependence and have been assigned a unique identification
buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and
number that must be included on every prescription.
0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg
(%) of norbuprenorphine was calculated from the assumption that
9.2 Abuse
buprenorphine and norbuprenorphine are equipotent).
Data from a study of seven lactating women who were taking a Buprenorphine, like morphine and other opioids, has the potential to
median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months be abused and is subject to criminal diversion. This should be considered
after delivery indicated that, the mean milk concentrations (Cavg) of when prescribing or dispensing buprenorphine in situations when the clinician
buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L is concerned about an increased risk of misuse, abuse, or diversion. Healthcare
respectively. Based on the study data, and assuming milk consumption of 150 professionals should contact their state professional licensing board or state
mL/kg/day, an exclusively breastfed infant would receive an estimated mean controlled substances authority for information on how to prevent and detect
absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 abuse or diversion of this product.
mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of Patients who continue to misuse, abuse, or divert buprenorphine
0.38% and 0.18%, respectively, of the maternal weight-adjusted dose. products or other opioids should be provided with, or referred to, more
intensive and structured treatment.
8.3 Females and Males of Reproductive Potential Abuse of buprenorphine poses a risk of overdose and death. This risk
is increased with the abuse of buprenorphine and alcohol and other
Infertility
substances, especially benzodiazepines.
Chronic use of opioids may cause reduced fertility in females and
The physician may be able to more easily detect misuse or diversion
males of reproductive potential. It is not known whether these effects on
by maintaining records of medication prescribed including date, dose,
fertility are reversible [see Adverse Reactions (6.2), Nonclinical Toxicology
quantity, frequency of refills, and renewal requests of medication prescribed.
(13.1)].
Proper assessment of the patient, proper prescribing practices,
periodic re-evaluation of therapy, and proper handling and storage of the
medication are appropriate measures that help to limit abuse of opioid drugs.

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9.3 Dependence
Buprenorphine is a partial agonist at the mu-opioid receptor and
chronic administration produces physical dependence of the opioid type,
characterized by moderate withdrawal signs and symptoms upon abrupt
discontinuation or rapid taper. The withdrawal syndrome is typically milder
than seen with full agonists and may be delayed in onset [see Warnings and
Precautions (5.7)].
Neonatal opioid withdrawal syndrome (NOWS) is an expected and

treatable outcome of prolonged use of opioids during pregnancy [see
Warnings and Precautions (5.5)].
10 OVERDOSAGE
The manifestations of acute overdose include pinpoint pupils,
sedation, hypotension, respiratory depression, and death. Naloxone HCl dihydrate has the molecular formula C19H21NO4 • HCl
In the event of overdose, the respiratory and cardiac status of the • 2H20 and the molecular weight is 399.87. It is a white to slightly off-white
patient should be monitored carefully. When respiratory or cardiac functions powder and is freely soluble in water, soluble in alcohol, and practically
are depressed, primary attention should be given to the re-establishment of insoluble in toluene and ether.
adequate respiratory exchange through provision of a patent airway and
institution of assisted or controlled ventilation. Oxygen, IV fluids, 12 CLINICAL PHARMACOLOGY
vasopressors, and other supportive measures should be employed as indicated.
In the case of overdose, the primary management should be the 12.1 Mechanism of Action
re-establishment of adequate ventilation with mechanical assistance of ZUBSOLV sublingual tablet contains buprenorphine and naloxone.
respiration, if required. Naloxone may be of value for the management of Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist
buprenorphine overdose. Higher than normal doses and repeated at the kappa-opioid receptor. Naloxone is a potent antagonist at mu-opioid
administration may be necessary. The long duration of action of receptors and produces opioid withdrawal signs and symptoms, if
ZUBSOLV should be taken into consideration when determining the administered parenterally, in individuals physically dependent on full opioid
length of treatment and medical surveillance needed to reverse the effects agonists.
of an overdose. Insufficient duration of monitoring may put patients at
risk. 12.2 Pharmacodynamics
11 DESCRIPTION ZUBSOLV has been shown to have different bioavailability
compared to Suboxone tablet. One ZUBSOLV 5.7 mg/1.4 mg tablet provides
ZUBSOLV (buprenorphine and naloxone) sublingual tablets are equivalent buprenorphine exposure and 12% lower naloxone exposure to one
white menthol-flavored tablets in an oval shape for the dosage strength 0.7 Suboxone 8 mg/2 mg tablet. The pharmacodynamic information of other
mg/0.18 mg, a triangular shape for the dosage strength 1.4 mg /0.36 mg, a D currently marketed buprenorphine/naloxone-containing sublingual products is
shape for the dosage strength 2.9 mg/0.71 mg, a round shape for the dosage not directly comparable on a mg basis to ZUBSOLV [see Dosage and
strength 5.7 mg/1.4 mg, a diamond shape for the dosage strength 8.6 mg/2.1 Administration (2.9)].
mg and a capsule shape for the dosage strength 11.4 mg/2.9 mg. They are
debossed with the respective dosage strength of buprenorphine. They contain Subjective Effects
buprenorphine HCl, an opioid partial agonist and naloxone HCl dihydrate, an Comparisons of buprenorphine to full opioid agonists such as
opioid antagonist, at a ratio of 4:1 (ratio of free bases). ZUBSOLV is intended methadone and hydromorphone suggest that sublingual buprenorphine
for sublingual administration and is available in six dosage strengths, 0.7 mg produces typical opioid agonist effects which are limited by a ceiling effect.
buprenorphine with 0.18 mg naloxone, 1.4 mg buprenorphine with 0.36 mg In opioid-experienced subjects who were not physically dependent,
naloxone, 2.9 mg buprenorphine with 0.71 mg naloxone, 5.7 mg acute sublingual doses of Suboxone tablets produced opioid agonist effects
buprenorphine with 1.4 mg naloxone, 8.6 mg buprenorphine with 2.1 mg which reached a maximum between doses of 8 mg/2 mg and 16 mg/4 mg
naloxone and 11.4 mg buprenorphine with 2.9 mg naloxone. Each sublingual buprenorphine/naloxone.
tablet also contains mannitol, citric acid, sodium citrate, microcrystalline Opioid agonist ceiling-effects were also observed in a double-blind,
cellulose, croscarmellose sodium, sucralose, menthol, silicon dioxide and parallel group, dose-ranging comparison of single doses of buprenorphine
sodium stearyl fumarate and menthol flavor. sublingual solution (1 mg, 2 mg, 4 mg, 8 mg, 16 mg, or 32 mg), placebo and a
Chemically, buprenorphine HCl is (2S)-2-[17-(cyclopropylmethyl) full agonist control at various doses. The treatments were given in ascending
4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3 dose order at intervals of at least one week to 16 opioid-experienced subjects
dimethylbutan-2-ol hydrochloride. It has the following chemical structure: who were not physically dependent. Both active drugs produced typical opioid
agonist effects. For all measures for which the drugs produced an effect,
buprenorphine produced a dose-related response. However, in each case, there
was a dose that produced no further effect. In contrast, the highest dose of the
full agonist control always produced the greatest effects. Agonist objective
rating scores remained elevated for the higher doses of buprenorphine (8 mg
32 mg) longer than for the lower doses and did not return to baseline until 48
hours after drug administration. The onset of effects appeared more rapidly
with buprenorphine than with the full agonist control, with most doses nearing
peak effect after 100 minutes for buprenorphine compared to 150 minutes for
the full agonist control.
Physiologic Effects
Buprenorphine in IV (2 mg, 4 mg, 8 mg, 12 mg and 16 mg) and
sublingual (12 mg) doses has been administered to opioid-experienced
subjects who were not physically dependent to examine cardiovascular,
respiratory, and subjective effects at doses comparable to those used for
Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl
treatment of opioid dependence. Compared to placebo, there were no
and the molecular weight is 504.10. It is a white or off-white crystalline
statistically significant differences among any of the treatment conditions for
powder, sparingly soluble in water, freely soluble in methanol, soluble in
blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature
alcohol, and practically insoluble in cyclohexane.
across time. Systolic BP was higher in the 8 mg group than placebo (3-hour
Chemically, naloxone HCl dihydrate is 17-Allyl-4,5α-epoxy-3,14
AUC values). Minimum and maximum effects were similar across all
dihydroxymorphinan-6-one hydrochloride dihydrate. It has the following
treatments. Subjects remained responsive to low voice and responded to
chemical structure:

455-9
computer prompts. Some subjects showed irritability, but no other changes CYP3A4. Norbuprenorphine, the major metabolite, can further undergo
were observed. glucuronidation. Norbuprenorphine has been found to bind opioid receptors
The respiratory effects of sublingual buprenorphine were compared in-vitro; however, it has not been studied clinically for opioid-like activity.
with the effects of methadone in a double-blind, parallel group, dose ranging Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well
comparison of single doses of buprenorphine sublingual solution (1 mg, 2 mg, as N-dealkylation, and reduction of the 6-oxo group.
4 mg, 8 mg, 16 mg, or 32 mg) and oral methadone (15 mg, 30 mg, 45 mg, or
60 mg) in non-dependent, opioid-experienced volunteers. In this study, Excretion
hypoventilation not requiring medical intervention was reported more A mass balance study of buprenorphine showed complete recovery of
frequently after buprenorphine doses of 4 mg and higher than after radiolabel in urine (30%) and feces (69%) collected up to 11 days after
methadone. Both drugs decreased O2 saturation to the same degree. dosing. Almost all of the dose was accounted for in terms of buprenorphine,
norbuprenorphine, and two unidentified buprenorphine metabolites. In urine,
Androgen Deficiency most of buprenorphine and norbuprenorphine was conjugated (buprenorphine,
Chronic use of opioids may influence the hypothalamic-pituitary 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11%
gonadal axis, leading to androgen deficiency that may manifest as low libido, conjugated). In feces, almost all of the buprenorphine and norbuprenorphine
impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine,
opioids in the clinical syndrome of hypogonadism is unknown because the 21% free and 2% conjugated).
various medical, physical, lifestyle, and psychological stressors that may
influence gonadal hormone levels have not been adequately controlled for in Drug Interaction Studies
studies conducted to date. Patients presenting with symptoms of androgen CYP3A4 Inhibitors and Inducers
deficiency should undergo laboratory evaluation. [see Adverse Reactions Subjects receiving ZUBSOLV sublingual tablet should be monitored
(6.2)]. if inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole),
macrolide antibiotics (e.g., erythromycin) or HIV protease inhibitors and may
Effect of Naloxone require dose-reduction of one or both agents. The interaction of buprenorphine
Physiologic and subjective effects following acute sublingual with all CYP3A4 inducers has not been studied, therefore it is recommended
administration of buprenorphine tablets and Suboxone tablets were similar at that patients receiving ZUBSOLV sublingual tablet be monitored for signs
equivalent dose levels of buprenorphine. Naloxone had no clinically and symptoms of opioid withdrawal if inducers of CYP3A4 (e.g.,
significant effect when administered by the sublingual route, although blood phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered
levels of the drug were measurable. Buprenorphine/naloxone, when [see Drug Interactions (7)].
administered sublingually to an opioid-dependent cohort, was recognized as Buprenorphine has been found to be a CYP2D6 and CYP3A4
an opioid agonist, whereas when administered intramuscularly, combinations inhibitor and its major metabolite, norbuprenorphine, has been found to be a
of buprenorphine with naloxone produced opioid antagonist actions similar to moderate CYP2D6 inhibitor in in-vitro studies employing human liver
naloxone. This finding suggests that the naloxone in buprenorphine/naloxone microsomes. However, the relatively low plasma concentrations of
tablets may deter injection of buprenorphine/naloxone tablets by persons with buprenorphine and norbuprenorphine resulting from therapeutic doses are not
active substantial heroin or other full mu-opioid dependence. However, expected to raise significant drug-drug interaction concerns.
clinicians should be aware that some opioid-dependent persons, particularly
those with a low level of full mu-opioid physical dependence or those whose Specific Populations
opioid physical dependence is predominantly to buprenorphine, abuse Hepatic Impairment
buprenorphine/naloxone combinations by the intravenous or intranasal route. In a pharmacokinetic study, the disposition of buprenorphine and
In methadone-maintained patients and heroin-dependent subjects, IV naloxone were determined after administering a Suboxone 2.0 mg/0.5 mg
administration of buprenorphine/naloxone combinations precipitated opioid (buprenorphine/naloxone) sublingual tablet in subjects with varied degrees of
withdrawal signs and symptoms and was perceived as unpleasant and hepatic impairment as indicated by Child-Pugh criteria. The disposition of
dysphoric. In morphine-stabilized subjects, intravenously administered buprenorphine and naloxone in patients with hepatic impairment were
combinations of buprenorphine with naloxone produced opioid antagonist and compared to disposition in subjects with normal hepatic function.
withdrawal signs and symptoms that were ratio-dependent; the most intense
withdrawal signs and symptoms were produced by 2:1 and 4:1 ratios, less In subjects with mild hepatic impairment, the changes in mean Cmax,
intense by an 8:1 ratio. AUC0-last, and half-life values of both buprenorphine and naloxone were not
clinically significant. No dosing adjustment is needed in patients with mild
hepatic impairment.
12.3 Pharmacokinetics For subjects with moderate and severe hepatic impairment, mean
Absorption Cmax, AUC0-last, and half-life values of both buprenorphine and naloxone were
Plasma levels of buprenorphine and naloxone increased with the increased; the effects on naloxone are greater than that on buprenorphine
sublingual dose of ZUBSOLV sublingual tablet. There was wide inter-patient (Table 5).
variability in the sublingual absorption of buprenorphine and naloxone, but
within subjects the variability was low. Both Cmax and AUC of buprenorphine Table 5. Changes in Pharmacokinetic Parameters in Subjects With
increased with the increase in dose (in the range of 1.4 mg to 11.4 mg), Moderate and Severe Hepatic Impairment
although the increase was not directly dose-proportional. Naloxone did not Increase in Increase in
Hepatic PK Parameters buprenorphine naloxone
affect the pharmacokinetics of buprenorphine. Impairment compared to healthy compared to
ZUBSOLV has been shown to have different bioavailability subjects healthy subjects
compared to Suboxone tablet. One ZUBSOLV 5.7 mg/1.4 mg tablet provides Moderate Cmax 8% 170%
equivalent buprenorphine exposure and 12% lower naloxone exposure to one AUC0-last 64% 218%
Suboxone 8 mg/2 mg tablet. Half-life 35% 165%
Severe Cmax 72% 1030%
Distribution AUC0-last 181% 1302%
Buprenorphine is approximately 96% protein bound, primarily to Half-life 57% 122%
alpha and beta globulin.
Naloxone is approximately 45% protein bound, primarily to albumin. The difference in magnitude of the effects on naloxone and
buprenorphine are greater in subjects with severe hepatic impairment than
Elimination subjects with moderate hepatic impairment, and therefore the clinical impact
Buprenorphine has a mean elimination half-life from plasma ranging of these effects is likely to be greater in patients with severe hepatic
from 24 to 42 hours and naloxone has a mean elimination half-life from impairment than in patients with moderate hepatic impairment.
plasma ranging from 2 to 12 hours. Buprenorphine/naloxone products should be avoided in patients with severe
hepatic impairment and may not be appropriate for patients with moderate
Metabolism hepatic impairment [see Warnings and Precautions (5.12) and Use in Specific
Buprenorphine undergoes both N-dealkylation to norbuprenorphine Populations (8.6)].
and glucuronidation. The N-dealkylation pathway is mediated primarily by the
HCV infection

455-9
In subjects with HCV infection but no sign of hepatic impairment, first study, 758 patients were randomized. In the second study, 310 patients
the changes in the mean Cmax, AUC0-last, and half-life values of buprenorphine were randomized.
and naloxone were not clinically significant in comparison to healthy subjects
without HCV infection. No dosing adjustment is needed in patients with HCV Both protocols stipulated that first Day 1 dose would be given under
infection. supervision, with an initial dose of buprenorphine 2 mg or ZUBSOLV 1.4 mg.
Subsequently, investigators were provided an option to give buprenorphine 6
13 NONCLINICAL TOXICOLOGY mg or ZUBSOLV 4.2 mg as a single dose 1.5 hours after the second dose, or
to divide the second dose of study medication into 3 separate dosing occasions
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility of ZUBSOLV 1.4 mg/0.36 mg or generic buprenorphine 2 mg each, 1 to 2
ZUBSOLV has been shown to have differences in bioavailability hours between doses, if there was precipitated withdrawal after the first dose,
compared to other buprenorphine/naloxone-containing sublingual products. as assessed by the investigator. The option to divide the second dose was used
The exposure margins listed below are based on body surface area at the discretion of the investigators only rarely in Study 2 (5%), compared to
comparisons (mg/m2) to the recommended human sublingual dose of 16 mg more frequent use in Study 1 (22%).
buprenorphine via Suboxone, which is equivalent to a human sublingual dose
of 11.4 mg buprenorphine via ZUBSOLV. Results for Day 3 retention rate from each study are presented in
Table 6. The lower rate of retention on Day 3 observed for ZUBSOLV in
comparison to generic buprenorphine in Study 2 may be attributable to the
Carcinogenicity infrequent use of divided dosing.
A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the
free bases) was performed in Alderley Park rats. Buprenorphine/naloxone was Table 6. Retention at Day 3 (full analysis set)
administered in the diet at doses of approximately 7 mg/kg/day, 31
mg/kg/day, and 123 mg/kg/day for 104 weeks (estimated exposure was Study 1
approximately 4, 18, and 44 times the recommended human sublingual dose
based on buprenorphine AUC comparisons). A statistically significant Number in ZUBSOLV Generic BUP Overall
increase in Leydig cell adenomas was observed in all dose groups. No other population (N=383) (N=375) (N=758)
drug-related tumors were noted.
Retention at
Carcinogenicity studies of buprenorphine were conducted in
Day 3 357 (93%) 344 (92%) 701 (93%)
Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the
diet to rats at doses of 0.6 mg/kg/day, 5.5 mg/kg/day, and 56 mg/kg/day Study 2
(estimated exposure was approximately 0.4, 3, and 35 times the recommended
human sublingual dose) for 27 months. As in the buprenorphine/naloxone Number in ZUBSOLV Generic BUP Overall
carcinogenicity study in rat, statistically significant dose-related increases in population (N=155) (N=155) (N=310)
Leydig cell tumors occurred. In an 86-week study in CD-1 mice,
Retention at
buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day 132 (85%) 147 (95%) 279 (90%)
Day 3
(estimated exposure was approximately 30 times the recommended human
sublingual dose).
Mutagenicity 16 HOW SUPPLIED / STORAGE AND HANDLING

The 4:1 combination of buprenorphine and naloxone was not ZUBSOLV sublingual tablets are menthol-flavored white tablets
mutagenic in a bacterial mutation assay (Ames test) using four strains of S. supplied in aluminum/aluminum child resistant unit dose blister packages.
typhimurium and two strains of E. coli. The combination was not clastogenic ZUBSOLV is available in six dosage strengths imprinted in their respective
in an in vitro cytogenetic assay in human lymphocytes or in an IV buprenorphine strength:
micronucleus test in the rat. • buprenorphine/naloxone 0.7 mg/0.18 mg, oval shape, imprinted with
Buprenorphine was studied in a series of tests utilizing gene, “.7”
chromosome, and DNA interactions in both prokaryotic and eukaryotic • buprenorphine/naloxone 1.4 mg/0.36 mg, triangular shape, imprinted
systems. Results were negative in yeast (S. cerevisiae) for recombinant, gene with “1.4”
convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, • buprenorphine/naloxone 2.9 mg/0.71mg, D shape, imprinted with
negative for clastogenicity in CHO cells, Chinese hamster bone marrow and
“2.9”
spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.
• buprenorphine/naloxone 5.7 mg/1.4 mg, round shape, imprinted with
Results were equivocal in the Ames test: negative in studies in two
“5.7”
laboratories, but positive for frame shift mutation at a high dose (5 mg/plate)
• buprenorphine/naloxone 8.6 mg/2.1 mg, diamond shape, imprinted
in a third study. Results were positive in the Green-Tweets (E. coli) survival
with “8.6”
test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue
from mice, for both in vivo and in vitro incorporation of [3H]thymidine, and • buprenorphine/naloxone 11.4 mg/2.9 mg, capsule shape, imprinted
positive in unscheduled DNA synthesis (UDS) test using testicular cells from with “11.4”
mice.
• NDC 54123-907-30 (buprenorphine/naloxone 0.7 mg /0.18 mg)
Impairment of Fertility
sublingual tablet – 3x10 tablets per carton
Dietary administration of buprenorphine in the rat at dose levels of
500 ppm or greater (equivalent to approximately 47 mg/kg/day or greater; • NDC 54123-914-30 (buprenorphine/naloxone 1.4 mg /0.36 mg)
estimated exposure approximately 28 times the recommended human sublingual tablet – 3x10 tablets per carton
sublingual dose) produced a reduction in fertility demonstrated by reduced • NDC 54123-929-30 (buprenorphine/naloxone 2.9 mg/0.71 mg
female conception rates. A dietary dose of 100 ppm (equivalent to sublingual tablet – 3x10 tablets per carton
approximately 10 mg/kg/day; estimated exposure approximately 6 times the • NDC 54123-957-30 (buprenorphine/naloxone 5.7 mg/1.4 mg)
recommended human sublingual dose) had no adverse effect on fertility. sublingual tablet– 3x10 tablets per carton
• NDC 54123-986-30 (buprenorphine/naloxone 8.6 mg/2.1 mg)
14 CLINICAL STUDIES sublingual tablet– 3x10 tablets per carton
• NDC 54123-114-30 (buprenorphine/naloxone 11.4 mg/2.9 mg)
The induction of buprenorphine therapy with ZUBSOLV was sublingual tablet– 3x10 tablets per carton
evaluated in two blinded randomized, non-inferiority studies. The identical
blinded induction phase component of the studies was designed to assess the Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59
tolerability of ZUBSOLV versus generic buprenorphine tablets when used as 86°F) [see USP Controlled Room Temperature]
initial treatment, as measured by retention in treatment. The studies included Patients should be advised to store buprenorphine-containing
opioid dependent (DSM-IV criteria) male and female patients 18 to 65 years medications safely and out of sight and reach of children. Destroy any
of age. Induction doses for generic buprenorphine tablets were 8 mg for day 1 unused medication appropriately [see Patient Counseling Information (17)].
and 8 mg or 16 mg for day 2. The induction doses for ZUBSOLV were 5.7
mg/1.4 mg for day 1 and 5.7 mg/1.4 mg or 11.4 mg/2.8 mg for day 2. In the 17 PATIENT COUNSELING INFORMATION

455-9
See FDA-approved patient labeling. (Medication Guide) • Inform patients that chronic use of opioids may cause reduced
fertility. It is not known whether these effects on fertility are reversible [see
Safe Use Adverse Reactions (6.2)].
Before initiating treatment with ZUBSOLV sublingual tablets, • Patients should inform their family members that, in the event of
explain the points listed below to caregivers and patients. Instruct emergency, the treating physician or emergency room staff should be
patients to read the Medication Guide each time ZUBSOLV is dispensed informed that the patient is physically dependent on an opioid and that the
because new information may be available. patient is being treated with ZUBSOLV sublingual tablets.
• Refer to the Medication Guide for additional information regarding
• Patients should be warned that it is extremely dangerous to self- the counseling information.
administer non-prescribed benzodiazepines or other CNS depressants
(including alcohol) while taking ZUBSOLV sublingual tablets. Patients
prescribed benzodiazepines or other CNS depressants should be cautioned to Disposal of Unused ZUBSOLV Sublingual Tablets
use them only as directed by their physician [see Warnings and Precautions Unused ZUBSOLV sublingual tablets should be disposed of as soon
(5.2), Drug Interactions (7)]. as they are no longer needed. Unused tablets should be flushed down the
• Patients should be advised that ZUBSOLV sublingual tablets toilet.
contain an opioid that can be a target for people who abuse prescription
medications or street drugs. Patients should be cautioned to keep their tablets
in a safe place, and to protect them from theft.
• Patients should be instructed to keep ZUBSOLV sublingual tablets
in a secure place, out of the sight and reach of children. Accidental or Manufactured for and distributed by Orexo US, Inc.
deliberate ingestion by a child may cause respiratory depression that can result Morristown, NJ 07960 USA
in death. Patients should be advised that if a child is exposed to ZUBSOLV
sublingual tablets, medical attention should be sought immediately. ZUBSOLV is a licensed trademark of Orexo US, Inc.
• Inform patients that ZUBSOLV could cause a rare but potentially © 2016 Orexo US, Inc. All rights reserved.
life-threatening condition resulting from concomitant administration of Suboxone® is a registered trademark of Indivior UK Limited
serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and
to seek medical attention right away if symptoms develop. Instruct patients to
inform their physicians if they are taking, or plan to take serotonergic
medications [see Drug Interactions (7)].
• Inform patients that ZUBSOLV could cause adrenal insufficiency,
a potentially life-threatening condition. Adrenal insufficiency may present
with non-specific symptoms and signs such as nausea, vomiting, anorexia,
fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek
medical attention if they experience a constellation of these symptoms [see
Warnings and Precautions (5.6)].
• Patients should be advised never to give ZUBSOLV sublingual
tablets to anyone else, even if he or she has the same signs and symptoms. It
may cause harm or death.
• Patients should be advised that selling or giving away this
medication is against the law.
• Patients should be cautioned that ZUBSOLV sublingual tablets
may impair the mental or physical abilities required for the performance of
potentially dangerous tasks such as driving or operating machinery. Caution
should be taken especially during drug induction and dose adjustment and
until individuals are reasonably certain that buprenorphine therapy does not
adversely affect their ability to engage in such activities [see Warnings and
Precautions (5.13)].
• Patients should be advised not to change the dosage of ZUBSOLV
sublingual tablets without consulting their physician.
• Patients should be advised to take ZUBSOLV sublingual tablets
once a day, after induction.
• Patients should be advised that if they miss a dose of ZUBSOLV
they should take it as soon as they remember. If it is almost time for the next
dose, they should skip the missed dose and take the next dose at the regular
time.
• Patients should be informed that ZUBSOLV sublingual tablets can
cause drug dependence and that withdrawal signs and symptoms may occur
when the medication is discontinued.
• Patients seeking to discontinue treatment with buprenorphine for
opioid dependence should be advised to work closely with their physician on a
tapering schedule and should be apprised of the potential to relapse to illicit
drug use associated with discontinuation of opioid agonist/partial agonist
medication-assisted treatment.
• Patients should be cautioned that, like other opioids, ZUBSOLV
sublingual tablets may produce orthostatic hypotension in ambulatory
individuals [see Warnings and Precautions. (5.14)].
• Patients should inform their physician if any other prescription
medications, over-the-counter medications, or herbal preparations are
prescribed or currently being used [see Drug Interactions (7)].
• Advise women that if they are pregnant while being treated with
ZUBSOLV, the baby may have signs of withdrawal at birth and that
withdrawal is treatable [see Warnings and Precautions (5.5), Use in Specific
Populations (8.1)].
• Advise women who are breastfeeding to monitor the infant for
drowsiness and difficulty breathing [see Use in Specific Populations (8.3)].

454-7 (Insert) and 457-7 (Pad)

MEDICATION GUIDE
®
ZUBSOLV (Zub-solve)
(buprenorphine and naloxone)
Sublingual Tablet (CIII)
IMPORTANT:
Keep ZUBSOLV in a secure place away from children. Accidental use by a child is a medical emergency and can result in
death. If a child accidentally uses ZUBSOLV, get emergency help right away.
Read this Medication Guide before you start taking ZUBSOLV and each time you get a refill. There may be new
information. This Medication Guide does not take the place of talking to your doctor. Talk to your doctor or pharmacist if
you have questions about ZUBSOLV.
Share the important information in this Medication Guide with members of your household.
What is the most important information I should know about ZUBSOLV?
• ZUBSOLV can cause serious and life-threatening breathing problems. Call your doctor right away or get emergency
help if:
o You feel faint, dizzy, or confused.
o Your breathing gets much slower than is normal for you.
These can be signs of an overdose or other serious problems.
• Do not switch from ZUBSOLV to other medicines that contain buprenorphine without talking with your doctor. The
amount of buprenorphine in a dose of ZUBSOLV is not the same as the amount of buprenorphine in other medicines
that contain buprenorphine. Your doctor will prescribe a starting dose of buprenorphine that may be different than
other buprenorphine containing medicines you may have been taking.
• ZUBSOLV contains an opioid that can cause physical dependence.
o Do not stop taking ZUBSOLV without talking to your doctor. You could become sick with uncomfortable
withdrawal signs and symptoms because your body has become used to this medicine.
o Physical dependence is not the same as drug addiction.
o ZUBSOLV is not for occasional or “as needed” use.
• An overdose, and even death, can happen if you take benzodiazepines, sedatives, tranquilizers, or alcohol while
using ZUBSOLV. Ask your doctor what you should do if you are taking one of these.
• Call a doctor or get emergency help right away if you:
o Feel sleepy and uncoordinated.
o Have blurred vision.
o Have slurred speech.
o Cannot think well or clearly.
o Have slowed reflexes and breathing.
• Do not inject (“shoot-up”) ZUBSOLV.
o Injecting ZUBSOLV may cause life-threatening infections and other serious health problems.
o Injecting ZUBSOLV may cause serious withdrawal symptoms such as pain, cramps, vomiting, diarrhea, anxiety,
sleep problems, and cravings.
• In an emergency, have family members tell the emergency department staff that you are physically dependent on an
opioid and are being treated with ZUBSOLV.
What is ZUBSOLV?
• ZUBSOLV is a prescription medicine used to treat adults who are addicted to opioid drugs (either prescription or
illegal); as part of a complete treatment program that also includes counseling and behavioral therapy.
ZUBSOLV is a controlled substance (CIII) because it contains buprenorphine, which can be a target for people who abuse
prescription medicines or street drugs. Keep your ZUBSOLV in a safe place to protect it from theft. Never give your
ZUBSOLV to anyone else; it can cause death or harm them. Selling or giving away this medicine is against the law.
• It is not known if ZUBSOLV is safe or effective in children.
Who should not take ZUBSOLV?
Do not take ZUBSOLV if you are allergic to buprenorphine or naloxone.
What should I tell my doctor before taking ZUBSOLV?
ZUBSOLV may not be right for you. Before taking ZUBSOLV, tell your doctor if you:


• Have trouble breathing or lung problems.
• Have an enlarged prostate gland (men).
• Have a head injury or brain problem.
• Have problems urinating.
• Have a curve in your spine that affects your breathing.
• Have liver or kidney problems.
• Have gallbladder problems.
• Have adrenal gland problems.
• Have Addison’s disease.
• Have low thyroid (hypothyroidism).
• Have a history of alcoholism.
• Have mental problems such as hallucinations (seeing or hearing things that are not there).
• Have any other medical condition.
• Are pregnant or plan to become pregnant. If you take ZUBSOLV while pregnant, your baby may have symptoms of
opioid withdrawal or respiratory depression at birth. Talk to your doctor if you are pregnant or plan to become
pregnant.
• Are breastfeeding or plan to breastfeed. ZUBSOLV can pass into your breast milk and may harm your baby. Talk to
your doctor about the best way to feed your baby if you take ZUBSOLV. Monitor your baby for increased sleepiness
and breathing problems.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and
herbal supplements. ZUBSOLV may affect the way other medicines work and other medicines may affect how ZUBSOLV
works. Some medicines may cause serious or life-threatening medical problems when taken with ZUBSOLV.
Sometimes the doses of certain medicines and ZUBSOLV may need to be changed if used together. Do not take any
medicine while using ZUBSOLV until you have talked with your doctor. Your doctor will tell you if it is safe to take other
medicines while you are using ZUBSOLV.
Be especially careful about taking other medicines that may make you sleepy, such as pain medicines, tranquilizers,
sleeping pills, anxiety medicines, or antihistamines.
Know the medicines you take. Keep a list of them to show your doctor or pharmacist each time you get a new medicine.
How should I take ZUBSOLV?
• Always take ZUBSOLV exactly as your doctor tells you. Your doctor may change your dose after seeing how it affects
you. Do not change your dose unless your doctor tells you to change it.
• Do not take ZUBSOLV more often than prescribed by your doctor.
• You may be prescribed a dose of 2 or more ZUBSOLV sublingual tablets at the same time.
• After induction (your first day of dosing), take ZUBSOLV 1 time a day.
• Do not cut, crush, break, chew or swallow the tablet. Your doctor should show you how to take ZUBSOLV the right
way.
• Follow the same instructions every time you take a dose of ZUBSOLV.
• ZUBSOLV comes in a blister pack with 10 blister units. Each blister unit contains a ZUBSOLV tablet.
• Take the dose prescribed by your doctor as follows:
o Pull apart 1 of the blister units from the blister pack by tearing along the dotted lines (perforations) until it is fully
separated (See Figure A).

o When the blister unit is fully separated, fold the single unit down at dotted line toward the blister (See Figure B).
o Slowly tear down at notch to open the blister unit (See Figure C).
o Do not push ZUBSOLV tablets through the foil. This could cause the tablet to break.
o As soon as you remove your prescribed dose of ZUBSOLV from the blister pack place the tablet under your
tongue (See Figures D, E, and F). If more than 1 tablet is required, place the tablets in different places under your
tongue at the same time.


o Let the tablet dissolve completely. ZUBSOLV usually dissolves in your mouth within 5 minutes. If your mouth is
dry, take a sip of water to moisten it. Spit out or swallow the water and dry your hands if they are wet before you
place the ZUBSOLV tablet under your tongue.
• While ZUBSOLV is dissolving, do not chew or swallow the tablet because the medicine will not work as well.
• Do not eat or drink anything until the ZUBSOLV tablet has completely dissolved.
• Talking while the tablet is dissolving can affect how well the medicine in ZUBSOLV is absorbed.
• If you miss a dose of ZUBSOLV, take your medicine when you remember. If it is almost time for your next dose, skip
the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your doctor
tells you to. If you are not sure about your dosing, call your doctor.
• Do not stop taking ZUBSOLV suddenly. You could become sick and have withdrawal symptoms because your body
has become used to the medicine. Physical dependence is not the same as drug addiction. Your doctor can tell you
more about the differences between physical dependence and drug addiction. To have fewer withdrawal symptoms,
ask your doctor how to stop using ZUBSOLV the right way.
• If you take too much ZUBSOLV go to the nearest hospital emergency room right away.
What should I avoid while taking ZUBSOLV?
• Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how this
medication affects you. Buprenorphine can cause drowsiness and slow reaction times. This may happen more often
in the first few weeks of treatment when your dose is being changed, but can also happen if you drink alcohol or take
other sedative drugs when you take ZUBSOLV.
You should not drink alcohol while taking ZUBSOLV, as this can lead to loss of consciousness or even death.
What are the possible side effects of ZUBSOLV?
ZUBSOLV can cause serious side effects, including:
• See “What is the most important information I should know about ZUBSOLV?”
• Respiratory problems. You have a higher risk of death and coma if you take ZUBSOLV with other medicines, such
as benzodiazepines.
• Sleepiness, dizziness, and problems with coordination.
• Dependency or abuse.
• Liver problems. Call your doctor right away if you notice any of these signs of liver problems: Your skin or the white
part of your eyes turning yellow (jaundice), urine turning dark, stools turning light in color, you have less of an
appetite, or you have stomach (abdominal) pain or nausea. Your doctor should do tests before you start taking and
while you take ZUBSOLV.
• Allergic reaction. You may have a rash, hives, swelling of your face, wheezing, or loss of blood pressure and
consciousness. Call a doctor or get emergency help right away.
• Opioid withdrawal. This can include: shaking, sweating more than normal, feeling hot or cold more than normal,
runny nose, watery eyes, goose bumps, diarrhea, vomiting and muscle aches. Tell your doctor if you develop any of
these symptoms.
• Decrease in blood pressure. You may feel dizzy if you get up too fast from sitting or lying down.
The most common side effects of ZUBSOLV include:
• Headache • Increased sweating • Decrease in sleep (insomnia)
• Nausea • Constipation • Pain
• Vomiting • Drug withdrawal syndrome • Swelling of the extremities
Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side
effects of ZUBSOLV. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
How should I store ZUBSOLV?
• Store ZUBSOLV at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep ZUBSOLV in a safe place, out of the sight and reach of children.
How should I dispose of unused ZUBSOLV?
• Dispose of unused ZUBSOLV sublingual tablets as soon as you no longer need them.
• Flush unused tablets down the toilet.


General information about the safe and effective use of ZUBSOLV.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZUBSOLV for
a condition for which it was not prescribed. Do not give ZUBSOLV to other people, even if they have the same symptoms
you have. It may harm them and it is against the law.
This Medication Guide summarizes the most important information about ZUBSOLV. If you would like more information,
talk to your doctor or pharmacist. You can ask your doctor or pharmacist for information that is written for health
professionals.
For more information, call 1-888-ZUBSOLV (1-888-982-7658).
What are the ingredients in ZUBSOLV?
Active Ingredients: buprenorphine and naloxone.
Inactive Ingredients: mannitol, citric acid, sodium citrate, microcrystalline cellulose, croscarmellose sodium, sucralose,
silicon dioxide, sodium stearyl fumarate, and menthol flavor.
Manufactured for and distributed by Orexo US, Inc. Morristown, NJ 07960 USA
ZUBSOLV is a licensed trademark of Orexo US, Inc.© 2016 Orexo US, Inc. All rights reserved.
Printed in USA
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2016

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This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

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2.6 Unstable Patients 3 DOSAGE FORMS AND STRENGTHS

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5.16 Elevation of Intracholedochal Pressure Chills 8 (8%) 8 (8%)

6 ADVERSE REACTIONS Constipation 13 (12%) 3 (3%)

Table 1. Adverse Reactions in ≥ 5% of Patients During the Induction

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Labor or Delivery In the rabbit, increased post-implantation losses occurred at an oral

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Neonatal opioid withdrawal syndrome (NOWS) is an expected and

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Mutagenicity 16 HOW SUPPLIED / STORAGE AND HANDLING

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