NDC 70518-2216 Buprenorphine Hydrochloride

Buprenorphine Hydrochloride

NDC Product Code 70518-2216

NDC Code: 70518-2216

Proprietary Name: Buprenorphine Hydrochloride What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Buprenorphine Hydrochloride What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325)
Shape: ROUND (C48348)
Size(s):
7 MM
Imprint(s):
2
Score: 1

NDC Code Structure

  • 70518 - Remedyrepack Inc.
    • 70518-2216 - Buprenorphine Hydrochloride

NDC 70518-2216-0

Package Description: 30 TABLET in 1 BLISTER PACK

NDC Product Information

Buprenorphine Hydrochloride with NDC 70518-2216 is a a human prescription drug product labeled by Remedyrepack Inc.. The generic name of Buprenorphine Hydrochloride is buprenorphine hydrochloride. The product's dosage form is tablet and is administered via sublingual form.

Labeler Name: Remedyrepack Inc.

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

DEA Schedule: Schedule III (CIII) Substances What is the Drug Enforcement Administration (DEA) CIII Schedule?
The controlled substances in the CIII schedule have an abuse potential and dependence liability less than those in schedules CI and CII, and have an accepted medical use in the United States. Schedule CIII controlled substances include preparations containing limited quantities of certain narcotic drugs, and other nonnarcotic drugs such as: derivatives of barbituric acid, except those that are listed in another schedule, glutethimide (Doriden), methyprylon (Noludar), nalorphine, benzphetamine, chlorphentermine, clortermine, and phendimetrazine.

Buprenorphine Hydrochloride Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • BUPRENORPHINE HYDROCHLORIDE 2 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • STARCH, CORN (UNII: O8232NY3SJ)
  • SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MANNITOL (UNII: 3OWL53L36A)
  • ANHYDROUS CITRIC ACID (UNII: XF417D3PSL)
  • TRISODIUM CITRATE DIHYDRATE (UNII: B22547B95K)
  • POVIDONE K30 (UNII: U725QWY32X)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Sublingual - Administration beneath the tongue.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Partial Opioid Agonists - [MoA] (Mechanism of Action)
  • Partial Opioid Agonist - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Remedyrepack Inc.
Labeler Code: 70518
FDA Application Number: ANDA090622 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 07-15-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Buprenorphine Sublingual and Buccal (opioid dependence)

Buprenorphine Sublingual and Buccal (opioid dependence) is pronounced as (byoo pre nor' feen)

Why is buprenorphine sublingual and buccal (opioid dependence) medication prescribed?
Buprenorphine and the combination of buprenorphine and naloxone are used to treat opioid dependence (addiction to opioid drugs, including heroin and narcotic painkillers)...
[Read More]

* Please review the disclaimer below.

Buprenorphine Hydrochloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Buprenorphine sublingual tablets is indicated for the treatment of opioid dependence and is preferred for induction. Buprenorphine sublingual tablets should be used as part of a complete treatment plan to include counseling and psychosocial support.

2.2 Important Dosage And Administration Instructions

Buprenorphine sublingual tablets is administered sublingually as a single daily dose.Buprenorphine sublingual tablets does not contain naloxone and is preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets is preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of buprenorphine sublingual tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets; for example, those patients who have been shown to be hypersensitive to naloxone.Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits.

2.3 Induction

Prior to induction, consideration should be given to the type of opioid dependence (i.e. long- or short-acting opioid products), the time since last opioid use, and the degree or level of opioid dependencePatients dependent on heroin or other short-acting opioid products: At treatment initiation, the first dose of buprenorphine sublingual tablets should be administered only when objective and clear signs of moderate opioid withdrawal appear, and not less than 4 hours after the patient last used an opioidIt is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible. The dosing on the initial day of treatment may be given in 2 mg to 4 mg increments if preferred. In some studies, gradual induction over several days led to a high rate of drop-out of buprenorphine patients during the induction period. In a one-month study, patients received 8 mg of buprenorphine sublingual Tablets on Day 1 and 16 mg buprenorphine sublingual tablets on Day 2. From Day 3 onward, patients received either buprenorphine and naloxone sublingual tablet or buprenorphine sublingual tablets at the same buprenorphine dose as Day 2 based on their assigned treatment. Induction in the studies of buprenorphine solution was accomplished over 3 to 4 days, depending on the target dose.Patients dependent on methadone or other long-acting opioid products: Patients dependent upon methadone or other long-acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short-acting opioid products; therefore, the first dose of buprenorphine sublingual tablets should only be administered when objective and clear signs of moderate opioid withdrawal appear, and generally not less than 24 hours after the patient last used a long-acting opioid product.There is little controlled experience with the transfer of methadone-maintained patients to buprenorphine. Available evidence suggests that withdrawal signs and symptoms are possible during induction onto buprenorphine. Withdrawal appears more likely in patients maintained on higher doses of methadone (greater than 30 mg) and when the first buprenorphine dose is administered shortly after the last methadone dose.

2.4 Maintenance

  • Buprenorphine and naloxone is preferred for maintenance treatment.Where buprenorphine is used in maintenance in patients who cannot tolerate the presence of naloxone, the dosage of buprenorphine should be progressively adjusted in increments/decrements of 2 mg or 4 mg buprenorphine to a level that holds the patient in treatment and suppresses opioid withdrawal signs and symptoms.After treatment induction and stabilization, the maintenance dose of buprenorphine is generally in the range of 4 mg to 24 mg buprenorphine per day depending on the individual patient. The recommended target dosage of buprenorphine sublingual tablets is 16 mg as a single daily dose. Dosages higher than24 mg have not been demonstrated to provide any clinical advantage.When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability to manage supplies of take-home medication.There is no maximum recommended duration of maintenance treatment. Patients may require treatment indefinitely and should continue for as long as patients are benefiting and the use of buprenorphine sublingual tablets contributes to the intended treatment goals.

2.5 Method Of Administration

Buprenorphine sublingual tablets must be administrated whole. Do not cut, chew, or swallow buprenorphine sublingual sablets. Advise patients not to eat or drink anything until the tablet is completely dissolved.Buprenorphine sublingual tablets should be placed under the tongue until it is dissolved. For doses requiring the use of more than two tablets, patients are advised to either place all the tablets at once or alternatively (if they cannot fit in more than two tablets comfortably), place two tablets at a time under the tongue. Either way, the patients should continue to hold the tablets under the tongue until they dissolve; swallowing the tablets reduces the bioavailability of the drug. To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.Proper administration technique should be demonstrated to the patient.

2.6 Clinical Supervision

  • Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits. The use of buprenorphine for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone, for example those patients with known hypersensitivity to naloxone. Buprenorphine and naloxone and buprenorphine are both subject to diversion and abuse. When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability of the patient to manage supplies of take-home medication.Ideally, patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient. Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits. Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives. Continuation or modification of pharmacotherapy should be based on the physician’s evaluation of treatment outcomes and objectives such as: Absence of medication toxicity.Absence of medical or behavioral adverse effects.Responsible handling of medications by the patient.Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, psychotherapy, and /or other psychosocial modalities).Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of continuing the current treatment.

2.7 Patients With Severe Hepatic Impairment

Consider reducing the starting and titration incremental dose by half and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

2.8 Unstable Patients

Healthcare providers will need to decide when they cannot appropriately provide further management for particular patients. For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the physician does not feel that he/she has the expertise to manage the patient. In such cases, the physician may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment. Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment..Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.

2.9 Discontinuing Treatment

The decision to discontinue therapy with buprenorphine and naloxone or buprenorphine after a period of maintenance should be made as part of a comprehensive treatment plan. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-assisted treatment. Taper patients to reduce the occurrence of withdrawal signs and symptoms


[See Warnings and Precautions (


5.7)]


.

3 Dosage Forms And Strengths

  • Buprenorphine sublingual tablets is supplied as white, sublingual tablets available in two dosage strengths:buprenorphine 2 mg, andbuprenorphine 8 mg

4 Contraindications

Buprenorphine sublingual tablets is contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported.


[see Warnings and Precautions (


5.9)]


.

5.1 Addiction, Abuse And Misuse

Buprenorphine sublingual tablets contain buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits


[see Drug Abuse and Dependence (


9.2)].

5.2 Risk Of Respiratory And Central Nervous System (Cns) Depression

Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with buprenorphine sublingual tablets.



[see Warnings and Precautions (


5.3), Drug Interactions (


7)].


Use buprenorphine sublingual tablets with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).

5.3 Managing Risks From Concomitant Use Of Benzodiazepines Or Other Cns Depressants

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines


[see Drug
Interactions (


7)].

5.4 Unintentional Pediatric Exposure

Buprenorphine can cause severe, possibly fatal,
respiratory depression in children who are accidentally exposed
to it. Store buprenorphine-containing medications safely out of
the sight and reach of children and destroy any unused
medication appropriately


. [see
Patient Counseling (


17)].

5.5 Neonatal Opioid Withdrawal Syndrome

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [


see Use in Specific Populations (


8.1)].


Advise pregnant women receiving opioid addiction treatment with buprenorphine sublingual tablets of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [


see Use in Specific Populations (


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 associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

5.6 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as
some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.7 Risk Of Opioid Withdrawal With Abrupt Discontinuation

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by 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 Drug Abuse and Dependence (


9.3)].


When discontinuing buprenorphine sublingual tablets, gradually taper the dosage [see Dosage and Administration (


2.7)].

5.8 Risk Of Hepatitis, Hepatic Events

Cases of cytolytic hepatitis and hepatitis with jaundice
have been observed in individuals receiving buprenorphine in
clinical trials and through post-marketing adverse event
reports. The spectrum of abnormalities ranges from transient
asymptomatic elevations in hepatic transaminases to case reports
of death, hepatic failure, hepatic necrosis, hepatorenal
syndrome, and hepatic encephalopathy. In many cases, the
presence of pre-existing liver enzyme abnormalities, infection
with hepatitis B or hepatitis C virus, concomitant usage of
other potentially hepatotoxic drugs, and ongoing injecting drug
use may have played a causative or contributory role. In other
cases, insufficient data were available to determine the
etiology of the abnormality. Withdrawal of buprenorphine has
resulted in amelioration of acute hepatitis in some cases;
however, in other cases no dose reduction was necessary. The
possibility exists that buprenorphine had a causative or
contributory role in the development of the hepatic abnormality
in some cases. Liver function tests, prior to initiation of
treatment is recommended to establish a baseline. Periodic
monitoring of liver function during treatment is also
recommended. A biological and etiological evaluation is
recommended when a hepatic event is suspected. Depending on the
case, buprenorphine sublingual tablets may need to be
carefully discontinued to prevent withdrawal signs and symptoms
and a return by the patient to illicit drug use, and strict
monitoring of the patient should be initiated.

5.9 Hypersensitivity Reactions

Cases of hypersensitivity to buprenorphine products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine is a contraindication to the use of buprenorphine sublingual tablets.

5.10 Precipitation Of Opioid Withdrawal Signs And Symptoms

Because of the partial agonist properties of
buprenorphine, buprenorphine sublingual tablets may
precipitate opioid withdrawal signs and symptoms in individuals
physically dependent on full opioid agonists if administered
sublingually or parenterally before the agonist effects of other
opioids have subsided.

5.11 Risk Of Overdose In Opioid Naïve Patients

There have been reported deaths of opioid naïve
individuals who received a 2 mg dose of buprenorphine as a
sublingual tablet for analgesia. Buprenorphine sublingual tablets are not appropriate as an analgesic.

5.12 Use In Patients With Impaired Hepatic Function

In a pharmacokinetic study, buprenorphine plasma levels
were found to be higher and the half-life was found to be longer
in subjects with moderate and severe hepatic impairment, but not
in subjects with mild hepatic impairment.For patients with severe hepatic impairment, a dose
adjustment is recommended, and patients with moderate or severe
hepatic impairment should be monitored for signs and symptoms of
toxicity or overdose caused by increased levels of
buprenorphine


[see Dosage and
Administration (


2.5) and Use in Specific Populations (


8.6)].

5.13 Impairment Of Ability To Drive Or Operate Machinery

Buprenorphine sublingual tablets may impair the
mental or physical abilities required for the performance of
potentially dangerous tasks such as driving a car or operating
machinery, especially during treatment induction and dose
adjustment. Patients should be cautioned about driving or
operating hazardous machinery until they are reasonably certain
that buprenorphine therapy does not adversely affect his or her
ability to engage in such activities.

5.14 Orthostatic Hypotension

Like other opioids, buprenorphine sublingual tablets
may produce orthostatic hypotension in ambulatory
patients.

5.15 Elevation Of Cerebrospinal Fluid Pressure

Buprenorphine, like other opioids, may elevate
cerebrospinal fluid pressure and should be used with caution in
patients with head injury, intracranial lesions and other
circumstances when cerebrospinal pressure may be increased.
Buprenorphine can produce miosis and changes in the level of
consciousness that may interfere with patient
evaluation.

5.16 Elevation Of Intracholedochal Pressure

Buprenorphine has been shown to increase intracholedochal
pressure, as do other opioids, and thus should be administered
with caution to patients with dysfunction of the biliary
tract.

5.17 Effects In Acute Abdominal Conditions

As with other opioids, buprenorphine may obscure the
diagnosis or clinical course of patients with acute abdominal
conditions.

6 Adverse Reactions

  • The following serious adverse reactions are described elsewhere in the labelling:Addiction, Abuse, and Misuse [see Warnings and Precautions (
  • 5.1)]
  • Respiratory and CNS Depression [see Warnings and Precautions (
  • 5.2)]
  • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (
  • 5.5)]
  • Adrenal Insufficiency [see Warnings and Precautions (
  • 5.6)]
  • Opioid Withdrawal [see Warnings and Precautions (
  • 5.7,
  • 5.10)]
  • Hepatitis, Hepatic Events [see Warnings and Precautions (
  • 5.8)]
  • Hypersensitivity Reactions [see Warnings and Precautions (
  • 5.9)]
  • Orthostatic Hypotension [see Warnings and Precautions (
  • 5.14)]
  • Elevation of Cerebrospinal Fluid Pressure [see Warnings and Precautions (
  • 5.15)]
  • Elevation of Intracholedochal Pressure [see Warnings and Precautions (
  • 5.16)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practiceThe safety of buprenorphine sublingual tablets was
supported by clinical trials using buprenorphine sublingual tablets, buprenorphine and naloxone sublingual tablets and other
trials using buprenorphine sublingual solutions. In total,
safety data were available from 3214 opioid-dependent subjects
exposed to buprenorphine at doses in the range used in treatment
of opioid addiction.Few differences in adverse event profile were noted
between buprenorphine sublingual tablets or buprenorphine
administered as a sublingual solution.The following adverse events were reported to occur by at
least 5% of patients in a 4-week study (


Table 1).


Table 1: Adverse Events ≥5% by Body System and Treatment Group in a 4-week StudyN(%) N(%) Body
System /Adverse Event (COSTART Terminology)
Buprenorphine


Sublingual Tablets


16 mg/day


N=103



Placebo


N=107


Body as a Whole Asthenia 5 (4.9%) 7 (6.5%) Chills 8 (7.8%) 8 (7.5%) Headache 30 (29.1%) 24 (22.4%) Infection 12 (11.7%) 7 (6.5%) Pain 19 (18.4%) 20 (18.7%) Pain Abdomen 12 (11.7%) 7 (6.5%) Pain Back 8 (7.8%) 12 (11.2%) Withdrawal Syndrome 19 (18.4%) 40 (37.4%)Cardiovascular System Vasodilation 4 (3.9%) 7 (6.5%)Digestive System Constipation 8 (7.8%) 3 (2.8%) Diarrhea 5 (4.9%) 16 (15.0%) Nausea 14 (13.6%) 12 (11.2%) Vomiting 8 (7.8%) 5 (4.7%)Nervous System Insomnia 22 (21.4%) 17 (15.9%)Respiratory System Rhinitis 10 (9.7%) 14 (13.1%)Skin and Appendages Sweating 13 (12.6%) 11 (10.3%)The adverse event profile of buprenorphine was also
characterized in the dose-controlled study of buprenorphine
solution, over a range of doses in four months of treatment.
Table 2 shows adverse events reported by at least 5% of subjects
in any dose group in the dose-controlled study.Table 2: Adverse Events (≥5%) by Body System
and Treatment Group in a 16-week StudyBody System/


Adverse Event (COSTART
Terminology)


Buprenorphine DoseSublingual solution. Doses in this table
cannot necessarily be delivered in tablet form, but for comparison
purposes:
"Very low" dose (1 mg solution) would be less
than a tablet dose of 2 mg.
"Low" dose (4 mg solution)
approximates a 6 mg tablet dose.
"Moderate" dose (8 mg
solution) approximates a 12 mg tablet dose.
"High" dose
(16 mg solution) approximates a 24 mg tablet dose.
Very
Low


(N=184)



Low


(N=180)



Moderate


(N=186)



High


(N=181)



Total


(N=731)


N (%) N (%) N (%) N (%) N (%)Body as a Whole Abscess 9 (5%) 2 (1%) 3 (2%) 2 (1%) 16 (2%) Asthenia 26 (14%) 28 (16%) 26 (14%) 24 (13%) 104 (14%) Chills 11 (6%) 12 (7%) 9 (5%) 10 (6%) 42 (6%) Fever 7 (4%) 2 (1%) 2 (1%) 10 (6%) 21 (3%) Flu Syndrome 4 (2%) 13 (7%) 19 (10%) 8 (4%) 44 (6%) Headache 51 (28%) 62 (34%) 54 (29%) 53 (29%) 220 (30%) Infection 32 (17%) 39 (22%) 38 (20%) 40 (22%) 149 (20%) Injury Accidental 5 (3%) 10 (6%) 5 (3%) 5 (3%) 25 (3%) Pain 47 (26%) 37 (21%) 49 (26%) 44 (24%) 177 (24%) Pain Back 18 (10%) 29 (16%) 28 (15%) 27 (15%) 102 (14%) Withdrawal Syndrome 45 (24%) 40 (22%) 41 (22%) 36 (20%) 162 (22%)Digestive System Constipation 10 (5%) 23 (13%) 23 (12%) 26 (14%) 82 (11%) Diarrhea 19 (10%) 8 (4%) 9 (5%) 4 (2%) 40 (5%) Dyspepsia 6 (3%) 10 (6%) 4 (2%) 4 (2%) 24 (3%) Nausea 12 (7%) 22 (12%) 23 (12%) 18 (10%) 75 (10%) Vomiting 8 (4%) 6 (3%) 10 (5%) 14 (8%) 38 (5%)Nervous System Anxiety 22 (12%) 24 (13%) 20 (11%) 25 (14%) 91 (12%) Depression 24 (13%) 16 (9%) 25 (13%) 18 (10%) 83 (11%) Dizziness 4 (2%) 9 (5%) 7 (4%) 11 (6%) 31 (4%) Insomnia 42 (23%) 50 (28%) 43 (23%) 51 (28%) 186 (25%) Nervousness 12 (7%) 11 (6%) 10 (5%) 13 (7%) 46 (6%) Somnolence 5 (3%) 13 (7%) 9 (5%) 11 (6%) 38 (5%)Respiratory System Cough Increase 5 (3%) 11 (6%) 6 (3%) 4 (2%) 26 (4%) Pharyngitis 6 (3%) 7 (4%) 6 (3%) 9 (5%) 28 (4%) Rhinitis 27 (15%) 16 (9%) 15 (8%) 21 (12%) 79 (11%)Skin and Appendages Sweat 23 (13%) 21 (12%) 20 (11%) 23 (13%) 87 (12%)Special Senses Runny Eyes 13 (7%) 9 (5%) 6 (3%) 6 (3%) 34 (5%)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.The most frequently reported postmarketing adverse
events with buprenorphine not observed in
clinical trials, excluding drug exposure during pregnancy, was
drug misuse or abuse.Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.


Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.


Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Buprenorphine Sublingual Tablets.


Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids


[see Clinical Pharmacology (


12.2)]


.


Other: glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

7 Drug Interactions

Table 3 includes clinically significant drug interactions with buprenorphine sublingual tablets


Table 3. Clinically Significant Drug InteractionsBenzodiazepines or other Central Nervous System (CNS) DepressantsClinical Impact:Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.Intervention:Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or CNS depressant or decreasing to the lowest effective dose may be appropriate.



Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see Warnings and Precautions (


5.2,


5.3)].


Examples:Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.Inhibitors of CYP3A4Clinical 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 buprenorphine sublingual tablets 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 buprenorphine sublingual tablets 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 buprenorphine sublingual tablets 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 InducersClinical 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 buprenorphine sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.



If a CYP3A4 inducer is discontinued, consider buprenorphine sublingual tablets dosage reduction and monitor for signs of respiratory depression.


Examples:Rifampin, carbamazepine, phenytoinAntiretrovirals: 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 delaviridine 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 buprenorphine sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimenExamples:Efavirenz, nevirapine, etravirine, delavirdineAntiretrovirals: 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 buprenorphine sublingual tablets and atazanavir with and without ritonavir, and reduce dose of buprenorphine sublingual tablets if warranted.Examples:Atazanavir, ritonavirAntiretrovirals: 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:NoneSerotonergic DrugsClinical 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 buprenorphine sublingual tablets 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 affect 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).Intervention:The use of buprenorphine sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.Examples:Phenelzine, tranylcypromine, linezolidMuscle RelaxantsClinical 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 buprenorphine sublingual tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine sublingual tablets and/or the muscle relaxant as necessary.DiureticsClinical 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 DrugsClinical 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 buprenorphine sublingual tablets is used concomitantly with anticholinergic drugs.

8.1 Pregnancy

Risk SummaryThe data on use of buprenorphine, the active ingredient in buprenorphine sublingual tablets , in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations


[see


Data]


. Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure


[see


Data]


.


Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine. Pre- and post-natal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 times and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see


Data]. Based on animal data, advice pregnant women of the potential risk to a fetus.


The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated maternal and embryo-fetal riskUntreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.Dose Adjustment during Pregnancy and the Postpartum PeriodDosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary.Fetal/neonatal adverse reactionsNeonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with buprenorphine sublingual tablets.Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.


[see Warnings and Precautions (


5.5)]


.


Labor or DeliveryOpioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.


DataHuman DataStudies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. Rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes.In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.Among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group.There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1- minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret. Animal DataThe exposure margins listed below are based on body surface area comparisons (mg/m2) to the human sublingual dose of 16 mg buprenorphine via buprenorphine sublingual tablets.


No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of 16 mg). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.



Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) were not statistically significant.In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-
implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure was approximately
0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). No maternal toxicity was noted at doses causing post-implantation loss in this study.Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Fertility, pre- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily sublingual dose of 16 mg on mg/m2 basis). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m


2 basis).

8.2 Lactation

Risk SummaryBased on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk, and available data have not shown adverse reactions in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.Clinical ConsiderationsAdvise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.DataData were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily doseIn a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.

8.3 Females And Males Of Reproductive Potential

InfertilityChronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (


6.2), Clinical Pharmacology (


12.2), Nonclinical Toxicology (


13.1)].

8.4 Pediatric Use

The safety and effectiveness of buprenorphine
sublingual tablet has not been established in pediatric
patients.

8.5 Geriatric Use

Clinical studies of buprenorphine sublingual tablets, buprenorphine and naloxone sublingual film, or buprenorphine and naloxone sublingual tablet did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine sublingual tablets should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

8.6 Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics
of buprenorphine were evaluated in a pharmacokinetic study.
 Buprenorphine is extensively metabolized in the liver
and buprenorphine plasma levels were found to be higher and the
half-life was found to be longer in subjects with moderate and
severe hepatic impairment, but not in subjects with mild hepatic
impairment.For patients with severe hepatic impairment, a dose
adjustment is recommended, and patients with moderate or severe
hepatic impairment should be monitored for signs and symptoms of
toxicity or overdose caused by increased levels of
buprenorphine


[see Dosage and
Administration (


2.5), Warnings and Precautions (


5.12) and Clinical Pharmacology (


12.3)]


.

8.7 Renal Impairment

No differences in buprenorphine pharmacokinetics were
observed between 9 dialysis-dependent and 6 normal patients
following IV administration of 0.3 mg buprenorphine.

9.1 Controlled Substance

Buprenorphine sublingual tablets contains buprenorphine, a Schedule III controlled substance under the Controlled Substances Act.Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to physicians who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

9.2 Abuse

Buprenorphine, like morphine and other opioids, has the
potential for being abused and is subject to criminal diversion.
This should be considered when prescribing or dispensing
buprenorphine in situations when the clinician is concerned
about an increased risk of misuse, abuse, or diversion.
Healthcare professionals should contact their state professional
licensing board or state controlled substances authority for
information on how to prevent and detect abuse or diversion of
this product.Patients who continue to misuse, abuse, or divert,
buprenorphine products or other opioids should be provided or
referred for more intensive and structured treatment.Abuse of buprenorphine poses a risk of overdose and
death. This risk is increased with the abuse of buprenorphine
and alcohol and other substances, especially benzodiazepines.The healthcare provider may be able to more easily detect misuse or diversion by maintaining records of medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of medication prescribed.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.

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

Clinical Presentation The manifestations of acute overdose include pinpoint pupils,
sedation, hypotension, respiratory depression, and death.Treatment of Overdose In the event of overdose, the respiratory and cardiac status of
the patient should be monitored carefully. When respiratory or cardiac
functions are depressed, primary attention should be given to the
re-establishment of adequate respiratory exchange through provision of a
patent airway and institution of assisted or controlled ventilation.
Oxygen, IV fluids, vasopressors, and other supportive measures should be
employed as indicated.In the case of overdose, the primary
management should be the re-establishment of adequate ventilation
with mechanical assistance of respiration, if required. Naloxone may
be of value for the management of buprenorphine overdose. Higher
than normal doses and repeated administration may be necessary. The
long duration of action of buprenorphine
should be taken into consideration when determining the length of
treatment and medical surveillance needed to reverse the effects of
an overdose. Insufficient duration of monitoring may put patients at
risk.

11 Descriptions

Buprenorphine Sublingual Tablets are uncoated round white
tablets intended for sublingual administration. The tablets contain buprenorphine HCL and are available in two
dosage strengths, 2 mg buprenorphine and 8 mg buprenorphine (as free base).
Each tablet also contains citric acid, cornstarch, lactose monohydrate,
mannitol, povidone K30, sodium citrate anhydrous and sodium stearyl
fumerate. The 2 mg buprenorphine tablet is debossed with a
"2" on one side and an "→"
on the other. The 8 mg buprenorphine tablet is debossed with a
"8" on one side and an "→"
on the other.Chemically, buprenorphine HCl is
(2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-
morphinan-7α-yl]-3,3dimethylbutan-2-ol hydrochloride.It has the following chemical structure:Buprenorphine HCl has the molecular formula
C


29H


41 NO


4 ∙ HCl and the
molecular weight is 504.10. It is a white or off-white crystalline
powder, sparingly soluble in water, freely soluble in methanol, soluble
in alcohol and practically insoluble in cyclohexane.

12.1 Mechanism Of Action

Buprenorphine sublingual tablets contain
buprenorphine. Buprenorphine is a partial agonist at the
mu-opioid receptor and an antagonist at the kappa-opioid
receptor.

14 Clinical Studies

Clinical data on the safety and efficacy of uprenorphine were derived from studies of buprenorphine sublingual
tablet formulations, with and without naloxone, and from studies of
sublingual administration of a more bioavailable ethanolic solution of
buprenorphine.Buprenorphine sublingual tablets were studied in 1834 patients;
buprenorphine and naloxone sublingual tablets in 575 patients, and buprenorphine
sublingual solutions in 2470 patients. A total of 1270 women received
buprenorphine in those clinical trials. Dosing recommendations are based
on data from one trial of both tablet formulations and two trials of the
ethanolic solution. All trials used buprenorphine in conjunction with
psychosocial counseling as part of a comprehensive addiction treatment
program. There were no clinical studies conducted to assess the efficacy
of buprenorphine as the only component of treatment.In a double-blind placebo- and active-controlled study, 326
heroin-addicted subjects were randomly assigned to either buprenorphine
and naloxone sublingual tablets, 16/4 mg per day; buprenorphine sublingual tablets, 16 mg per day; or placebo sublingual tablets. For
subjects randomized to either active treatment, dosing began with one 8
mg buprenorphine on Day 1, followed by 16 mg (two
8 mg tablets) of buprenorphine on Day 2. On Day
3, those randomized to receive buprenorphine and naloxone sublingual
tablets were switched to the combination tablet. Subjects randomized to
placebo received one placebo tablet on Day 1 and two placebo tablets per
day thereafter for four weeks. Subjects were seen daily in the clinic
(Monday through Friday) for dosing and efficacy assessments. Take-home
doses were provided for weekends. Subjects were instructed to hold the
medication under the tongue for approximately 5 to 10 minutes until
completely dissolved. Subjects received counseling regarding HIV
infection and up to one hour of individualized counseling per week. The
primary study comparison was to assess the efficacy of buprenorphine and
naloxone sublingual tablets and buprenorphine sublingual tablets
individually against placebo sublingual tablet. The percentage of
thrice-weekly urine samples that were negative for non-study opioids was
statistically higher for both buprenorphine and naloxone sublingual
tablets and buprenorphine sublingual tablets than for placebo
sublingual tablets.In a double-blind, double-dummy, parallel-group study comparing
buprenorphine ethanolic solution to a full agonist active control, 162
subjects were randomized to receive the ethanolic sublingual solution of
buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose
of 12 mg per day of buprenorphine sublingual tablets), or two
relatively low doses of active control, one of which was low enough to
serve as an alternative to placebo, during a 3 to 10 day induction
phase, a 16-week maintenance phase and a 7-week detoxification phase.
Buprenorphine was titrated to maintenance dose by Day 3; active control
doses were titrated more gradually.Maintenance dosing continued through Week 17, and then
medications were tapered by approximately 20% to 30% per week over Weeks
18 to 24, with placebo dosing for the last two weeks. Subjects received
individual and/or group counseling weekly.Based on retention in treatment and the percentage of
thrice-weekly urine samples negative for non-study opioids,
buprenorphine was more effective than the low dose of the control, in
keeping heroin addicts in treatment and in reducing their use of opioids
while in treatment. The effectiveness of buprenorphine, 8 mg per day was
similar to that of the moderate active control dose, but equivalence was
not demonstrated.In a dose-controlled, double-blind, parallel-group, 16-week
study, 731 subjects were randomized to receive one of four doses of
buprenorphine ethanolic solution: 1 mg, 4 mg, 8 mg, and 16 mg.
Buprenorphine was titrated to maintenance doses over 1 to 4 days and
continued for 16 weeks. Subjects received at least one session of AIDS
education and additional counseling ranging from one hour per month to
one hour per week, depending on site.Based on retention in treatment and the percentage of
thrice-weekly urine samples negative for non-study opioids, the three
highest tested doses were superior to the 1 mg dose. Therefore, this
study showed that a range of buprenorphine doses may be effective. The 1
mg dose of buprenorphine sublingual solution can be considered to be
somewhat lower than a 2 mg tablet dose. The other doses used in the
study encompass a range of tablet doses from approximately 6 mg to
approximately 24 mg.

16 How Supplied/Storage And Handling

Buprenorphine sublingual tablets are supplied in white HDPE
bottles.2 mg - White, round, biconvex uncoated tablets with
"2" debossed on one side and a dart
"→" debossed on the other sideNDC 50383-924-93 30 tablets per bottle8 mg - White, round, biconvex uncoated tablets with
"8" debossed on one side and a dart
"→" debossed on the other sideNDC 50383-930-93 30 tablets per bottle

17 Patient Counseling Information

  • Advise patients to read the FDA-approved patient labeling (
  • Medication Guide)
  • Safe Use
  • Before initiating treatment with buprenorphine sublingual tablets, explain the points listed below to
  • Caregivers and patients. Instruct patients to read the Medication
  • Guide each time buprenorphine sublingual tablets are dispensed
  • Because new information may be available.
  • Inform patients and caregivers that potentially fatal additive effects may occur if buprenorphine sublingual tablets are used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a health care provider
  • [see Warnings and
  • Precautions (
  • 5.2,
  • 5.3), Drug Interactions (
  • 7)].
  • Advise patients that buprenorphine sublingual tablets contains an opioid that can be a target for people who abuse prescription medications or street drugs, to keep their tablets in a safe place, and to protect them from theft.Instruct patients to keep buprenorphine sublingual tablets in a secure place, out of the sight and reach of children. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Advise patients to seek medical attention immediately if a child is exposed to buprenorphine sublingual tablets.
  • Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of 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 healthcare providers if they are taking, or plan to take serotonergic medications [
  • See Drug Interactions (
  • 7)].
  • Inform patients that opioids 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)].
  • Advise patients to never give buprenorphine sublingual tablets to anyone else, even if he or she has the same signs and symptoms. It may cause harm or death..Advise patients that selling or giving away this medication is against the law.Caution patients that buprenorphine sublingual tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous 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)].
  • Advise patients not to change the dosage of buprenorphine sublingual tablets without consulting their healthcare providersAdvise patients that if they miss a dose of buprenorphine sublingual tablets, 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.Advise patients to take buprenorphine sublingual tablets once a day.Inform patients that buprenorphine sublingual tablets can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.Advise patients seeking to discontinue treatment with buprenorphine for opioid dependence to work closely with their healthcare providers on a tapering schedule and inform them of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.Advise patients that, like other opioids, buprenorphine sublingual tablets may produce orthostatic hypotension in ambulatory individuals.
  • [see Warnings and Precautions (
  • 5.14)].
  • Advise patients to inform their healthcare providers 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 buprenorphine sublingual tablets, the baby may have signs of withdrawal at birth and that withdrawal is treatable [
  • See Warnings and Precautions (
  • 5.5), Specific Populations (
  • 8.1)
  • ].
  • Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing
  • [see
  • Specific Populations (
  • 8.2)].
  • Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible
  • [see
  • Specific Populations (
  • 8.3)].
  • Advise patients to inform their family members that, in the event of emergency, the treating healthcare providers or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with buprenorphine sublingual tablets.Disposal of Unused Buprenorphine HCL Sublingual tabletsUnused buprenorphine sublingual tablets should be
  • Disposed of as soon as they are no longer needed. Flush unused tablets
  • Down the toilet.

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