2.1. Drug Addiction Treatment Act

Under the Drug Addiction Treatment Act (DATA) codified at 21 United States Code (U.S.C.) 823(g), use of this product in the treatment of opioid dependence is limited to Healthcare Providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe or dispense this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

2.2. Important Dosage and Administration Information

PROBUPHINE implants should be used only in patients who are opioid tolerant.

Each dose consists of four PROBUPHINE implants inserted subdermally in the inner side of the upper arm.

PROBUPHINE subdermal implants are intended to be in place for 6 months of treatment. Remove PROBUPHINE implants by the end of the sixth month.

New implants may be inserted subdermally in an area of the inner side of either upper arm that has not been previously used at the time of removal, if continued treatment is desired. If new implants are not inserted on the same day as the removal of implants, maintain patients on their previous dosage of transmucosal buprenorphine (i.e., the dose from which they were transferred to PROBUPHINE treatment) prior to additional PROBUPHINE treatment.

After one insertion in each arm, most patients should be transitioned back to a transmucosal buprenorphine-containing product for continued treatment. There is no experience with inserting additional implants into other sites in the arm to recommend an approach to a second insertion into a previously-used arm. Neither re-insertion into previously-used administration sites, nor into sites other than the upper arm, has been studied [see Dosage and Administration (2.4, 2.5, and 2.9), Warnings and Precautions (5.1)].

2.3. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with PROBUPHINE. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions (5.4)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine, such as due to an accidental exposure of a household contact to a PROBUPHINE implant that has been expelled. Inform patients to call a Healthcare Provider immediately and follow protrusion or/and expulsion guidelines [see Patient Counseling Information (17)].

Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of PROBUPHINE and its affinity for the mu receptor.

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information (17)].

2.4. Healthcare Provider Training

All Healthcare Providers who intend to prescribe PROBUPHINE must successfully complete a live training program [see Warnings and Precautions (5.2)].

All Healthcare Providers performing insertions and/or removals of PROBUPHINE must successfully complete a live training program, and demonstrate procedural competency prior to inserting or removing the implants.

Information concerning the insertion and removal procedures can be obtained by calling 1-844-859-6341. The basis for successful use and subsequent removal of PROBUPHINE is a correct and carefully-performed subdermal insertion of the four implants in accordance with the instructions. As a prerequisite for participating in the live training program leading to certification, the Healthcare Provider must have performed at least one qualifying surgical procedure in the last 3 months. Qualifying procedures are those performed under local anesthesia using aseptic technique, and include, at a minimum, making skin incisions, or placing sutures [see Warnings and Precautions (5.2)].

2.5. Patient Selection

PROBUPHINE implants are only for use in patients who meet ALL of the following criteria:

• Achieved and sustained prolonged clinical stability on transmucosal buprenorphine
• Are currently on a maintenance dose of 8 mg per day or less of a Subutex or Suboxone sublingual tablet or its transmucosal buprenorphine product equivalent (the dose of transmucosal buprenorphine providing blood levels comparable or lower than the level provided by PROBUPHINE)
  • Patients should not be tapered to a lower dose for the sole purpose of transitioning to PROBUPHINE.
• Stable transmucosal buprenorphine dose (of 8 mg per day or less of a sublingual Subutex tablet or Suboxone sublingual tablet or its transmucosal buprenorphine product equivalent) for three months or longer without any need for supplemental dosing or adjustments

Examples of acceptable doses of transmucosal buprenorphine include:

• Subutex (buprenorphine) sublingual tablet (generic equivalent) 8 mg or less
• Suboxone (buprenorphine and naloxone) sublingual tablet (generic equivalent) 8 mg/2 mg or less
• Bunavail (buprenorphine and naloxone) buccal film 4.2 mg/0.7 mg or less
• Zubsolv (buprenorphine and naloxone) sublingual tablets 5.7 mg/1.4 mg or less

Consider the following factors in determining clinical stability and suitability for PROBUPHINE treatment:

• period free from illicit opioid drug use
• stability of living environment
• participation in a structured activity/job
• consistency in participation in recommended behavioral therapy/peer support program
• consistency in compliance with clinic visit requirements
• minimal to no desire or need to use illicit opioids
• period without episodes of hospitalizations (addiction or mental health issues), emergency room visits, or crisis interventions
• social support system

2.6. Clinical Supervision

Examine the insertion site one week following insertion of PROBUPHINE for signs of infection or any problems with wound healing, including evidence of implant extrusion from the skin.

The recommended visit schedule for most patients is a frequency of no less than once-monthly for continued counseling and psychosocial support.

Although some patients may require occasional supplemental dosing with buprenorphine, patients should not be provided with prescriptions for transmucosal buprenorphine-containing products for as-needed use. Instead, patients who feel the need for supplemental dosing should be seen and evaluated promptly. Ongoing use of supplemental dosing with transmucosal buprenorphine indicates that the amount of buprenorphine delivered by PROBUPHINE is not adequate for stable maintenance. Consider use of alternate buprenorphine products for maintenance of treatment.

2.7. Insertion of PROBUPHINE

2.8. PROBUPHINE Removal Procedure

Before initiating the removal procedure, read the instructions for removal.

Identify the location of the implants by consulting the PATIENT IDENTIFICATION CARD and/or THE PATIENT CHART STICKER. The exact location of all implants in the arm (patients will have four implants) should be verified by palpation.

If all of the implants are not palpable, use other methods to confirm the presence of the implant(s). Non-palpable implants should always be located prior to attempted removal. Suitable methods to locate implants are: Ultrasound with a high frequency linear array transducer (10 MHz or greater) or Magnetic Resonance Imaging (MRI). Note that PROBUPHINE implants are not radiopaque and cannot be seen by X-ray or CT scan.

Report any event of failure to locate non-palpable implants using MRI or ultrasound, by calling 1-844-859-6341 for company surveillance purposes.

After localization of a non-palpable implant, removal should be performed under ultrasound guidance. Exploratory surgery without knowledge of the exact location of all implants is strongly discouraged.

There is a greater risk of injury to neural and vascular structures during removal of implants located deeper than the subdermal space. As the anatomical location of these structures must be taken into consideration during the removal of deeply inserted implants, the procedure should only be attempted by Healthcare Providers familiar with this anatomy. A surgical specialist consulted to assist with a difficult removal does not need to be certified in the REMS program.

2.9. Spontaneous Expulsion

If spontaneous expulsion of the implant occurs after insertion, the following steps should be taken:

• Schedule two appointments for the patient to return to the office of the inserting Healthcare Provider as soon as possible and to the office of the prescribing Healthcare Provider.
• Instruct the patient to place the implant in a plastic bag, store it safely out of reach of children, and to bring it to the Healthcare Provider office to determine whether the full implant has been expelled.
• If the patient returns the expelled implant, measure it to ensure that the entire implant was expelled (26 mm).
• Dispose of the removed implant in keeping with local, state, and federal regulations governing the disposal of pharmaceutical biohazardous waste, after measuring.
• Examine incision site for infection. If infected, treat appropriately and determine if remaining implants need to be removed.
• If the expelled implant is not intact, palpate the insertion location to identify the location of any remaining partial implant. Remove the remaining partial implant using the techniques described above.
• Call 1-844-859-6341 to obtain a new kit that will include four implants and return instructions for any unused implants.
• The prescribing Healthcare Provider must carefully monitor patient until the implant is replaced to evaluate for withdrawal or other clinical indicators that supplemental transmucosal buprenorphine may be needed.
• Schedule an appointment to insert replacement implant(s).
• Insert the replacement implant(s) in same arm either medially or laterally to in situ implants. Alternatively, replacement implant(s) may be inserted in the contralateral arm.
• Record the new serial number on the PROBUPHINE REMS Insertion/Removal Log Form.

2.10. Continuation of Therapy: Subsequent Insertion of PROBUPHINE in the Contralateral Arm

There is no clinical experience with insertion of PROBUPHINE beyond a single insertion in each arm. If continued treatment is desired at the end of the first six-month treatment cycle, PROBUPHINE implants may be replaced by new implants at the time of removal in the contralateral arm, following the insertion steps above to locate the appropriate insertion site.

If new implants are not inserted on the same day as the removal, patients should be maintained on their previous dose of transmucosal buprenorphine (i.e., the dose from which they were transferred to PROBUPHINE treatment) prior to additional PROBUPHINE treatment [see Dosage and Administration (2.6), Warnings and Precautions (5.1)].

There is no experience with inserting additional implants into other sites in the arm to recommend an approach to a second insertion into a previously-used arm. Neither re-insertion into previously used administration sites, nor into sites other than the upper arm, have been studied. It is important to avoid previously-implanted sites because the effect of scarring and fibrosis in previously-used insertion sites on either the effectiveness of PROBUPHINE or the safety of insertion have not been evaluated. After one insertion in each arm, additional cycles of treatment should only be considered if the potential benefits of continuing PROBUPHINE outweigh the potential risks of additional insertion and removal procedures, taking into account the experience of the Healthcare Provider with PROBUPHINE procedures and related procedures, and the clinical need of the patient for ongoing treatment with subdermal medication. In most cases, patients should be transitioned back to a transmucosal buprenorphine-containing product for continued treatment.

5.1. Serious Complications From Insertion and Removal of PROBUPHINE

Rare but serious complications including nerve damage and migration resulting in embolism and death may result from improper insertion of drug implants inserted in the upper arm. Additional complications may include local migration, protrusion, and expulsion.

Insert PROBUPHINE in accordance with the instructions [see Indications and Usage (1), Dosage and Administration (2.2, 2.6)]. It is essential to insert PROBUPHINE subdermally so that each implant is palpable after insertion. It is also essential to confirm proper placement by palpation immediately after insertion. If PROBUPHINE is inserted too deeply (intramuscular or in the fascia), neural or vascular injury may occur.

Incomplete insertions or infections may lead to protrusion or expulsion [see Dosage and Administration (2.8)]. Accidental exposures to PROBUPHINE can result from protrusion or expulsion of the implants [see Warnings and Precautions (5.8)].

Improper insertion may lead to complicated removal if the implant is inserted too deeply, is not palpable, or has migrated. Deep insertions may lead to difficulty localizing the implant; additional surgical procedures may be required in order to remove the implant [see Dosage and Administration (2.6, 2.7)]. Injury to deeper neural or vascular structures in the arm may occur when removing deeply inserted implants.

All Healthcare Providers must successfully complete a live training program on the insertion and removal procedures and become certified in the PROBUPHINE REMS program, prior to performing insertions or prescribing PROBUPHINE implants. There are additional requirements and prerequisites that must be met to become certified to insert PROBUPHINE implants. Only Healthcare Providers who have performed a surgical procedure in the last 3 months and demonstrate competency in the PROBUPHINE procedures at the live training can become certified to perform insertions. Patients must be monitored to ensure that PROBUPHINE is removed by a Healthcare Provider certified to insert PROBUPHINE implants [see Warnings and Precautions (5.2)].

5.2. PROBUPHINE REMS Program

PROBUPHINE is available only through a restricted program under a REMS, called the PROBUPHINE REMS Program, because of the risk of complications of migration, protrusion and expulsion, and nerve damage associated with the insertion and removal of PROBUPHINE [see Warnings and Precautions (5.1)].

Notable requirements of the PROBUPHINE REMS Program include the following:

• Healthcare Providers who prescribe PROBUPHINE must be certified with the program by enrolling and completing live training
• Healthcare Providers who insert PROBUPHINE must
  • meet the prerequisite requirements [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)]
  • be certified with the program by enrolling and completing live training, including demonstrating competency in PROBUPHINE procedures
• Patients must be monitored to ensure that PROBUPHINE is removed by a Healthcare Provider certified to insert PROBUPHINE implants
• PROBUPHINE will only be distributed to certified prescribers through a restricted distribution program

Further information is available at www.PROBUPHINEREMS.com or 1-844-859-6341.

5.3. Addiction, Abuse, and Misuse

PROBUPHINE contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorders and is subject to criminal diversion. Consider these risks and the patient's stability in treatment for opioid dependence when determining whether PROBUPHINE is appropriate for the patient. Monitor all patients receiving PROBUPHINE for conditions indicative of diversion or progression of opioid dependence and addictive behaviors.

5.4. Risk of Life-Threatening 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 buprenorphine and 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 PROBUPHINE [see Warnings and Precautions (5.5), Drug Interactions (7), Patient Counseling Information (17)].

Use PROBUPHINE 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).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, removal of PROBUPHINE may be required.

5.5. Managing Risks From Concomitant Use of Benzodiazepines or Other CNS Depressants With Buprenorphine

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 benzodiazepines 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.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.4)].

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)].

5.6. 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 PROBUPHINE 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.

5.7. 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.

5.8. Unintentional Pediatric Exposure

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it. Instruct patients to keep the expelled implant(s) away from others, especially children.

5.9. Risk of Opioid Withdrawal With Abrupt Discontinuation of PROBUPHINE Treatment

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 milder than that seen with full agonists, and may be delayed in onset [see Drug Abuse and Dependence (9.2, 9.3)]. If PROBUPHINE implants are not to be immediately replaced upon removal, maintain patients on their previous dosage of sublingual buprenorphine until PROBUPHINE treatment is resumed [see Dosage and Administration (2.2)]. Patients who elect to discontinue PROBUPHINE treatment should be monitored for withdrawal with consideration given to use of a tapering dose of transmucosal buprenorphine.

5.10. Risk of Hepatitis, Hepatic Events

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both 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 injection drug abuse may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests are recommended prior to initiation of treatment 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. Monitor patients with declining hepatic function for side effects resulting from increased exposure to buprenorphine. Patients may require removal of PROBUPHINE implants.

5.11. Hypersensitivity Reactions

Allergic reactions to buprenorphine and/or EVA are possible. Cases of hypersensitivity to sublingual buprenorphine 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 or EVA is a contraindication to PROBUPHINE use.

5.12. Precipitation of Opioid Withdrawal in Patients Dependent on Full Agonist Opioids

Because of the partial opioid agonist properties of buprenorphine, buprenorphine may precipitate opioid withdrawal signs and symptoms in persons who are currently physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. Verify that patients are clinically stable on transmucosal buprenorphine and not dependent on full agonists before inserting PROBUPHINE.

5.13. Risks Associated With Treatment of Emergent Acute Pain

While on PROBUPHINE, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving PROBUPHINE with a non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. If opioid therapy is required as part of anesthesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy must be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.

5.14. Use in Patients With Impaired Hepatic Function

In a pharmacokinetic study with sublingual buprenorphine, 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. The effect of hepatic impairment on the pharmacokinetics of implanted buprenorphine, such as PROBUPHINE, has not been studied.

Because PROBUPHINE cannot be titrated, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with PROBUPHINE. Patients who develop moderate to severe hepatic impairment while being treated with PROBUPHINE should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine, and patients may require removal of PROBUPHINE implants [see Use in Specific Populations (8.6), Clinical Pharmacology (12)].

5.15. Impairment of Ability to Drive and Operate Machinery

PROBUPHINE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially for the first 24-48 hours following initial insertion. Caution patients about driving or operating hazardous machinery until they are reasonably certain that PROBUPHINE does not adversely affect their ability to engage in such activities.

5.16. Orthostatic Hypotension

PROBUPHINE may produce orthostatic hypotension in ambulatory patients.

5.17. Elevation of Cerebrospinal Fluid Pressure

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

5.18. 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.

5.19. Effects in Acute Abdominal Conditions

Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

5.20. Infection at Implant Site

Infection may occur at the site of the insertion or removal. Excessive palpation shortly after insertion of the implants may increase the chance of infection. Improper removal carries risk of implant-site infection.

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 practice.

The safety of PROBUPHINE is supported by clinical trials using PROBUPHINE, and other trials using buprenorphine tablets and buprenorphine sublingual solutions. The safety of PROBUPHINE was evaluated in 349 opioid-dependent subjects across three double-blind trials (n=309) and two open-label extension studies (n=40). In these studies, there were a total of 258 subjects exposed to PROBUPHINE for at least 24 weeks and 82 subjects exposed for 48 weeks. The safety of the PROBUPHINE insertion and removal procedures has been evaluated in 568 unique subjects across the entire development program who received PROBUPHINE implants or placebo implants, with 507 subjects across the three double-blind trials, 40 subjects from two open-label extension trials, and 21 subjects from two phase 2 pharmacokinetic studies.

In total, safety data from clinical studies are available from over 3000 opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of opioid dependence.

Table 1 shows the non-implant-site related adverse events for PROBUPHINE and comparator groups in the three 6-month, double-blind, PROBUPHINE Phase 3 studies. Patients in the PROBUPHINE arm were treated with 4–5 implants and may have received supplemental sublingual buprenorphine. Patients in the Placebo/SL BPN comparator group had either regularly dosed or as-needed sublingual buprenorphine; some had placebo implants. Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 17).

In Table 1, MedDRA High Level Group Terms (HLGT) reported in at least 5% of patients in the PROBUPHINE group and more commonly than in the comparator group, are listed at the Higher Level Group Term (HLGT) level along with subordinate Preferred Terms (PT) reported in ≥1% of PROBUPHINE patients (and at least 0.5% more frequent than comparator). Events involving the implant site, or insertion or removal procedures or complications are not included in the table below, but are shown in Table 2.

The following implant site-related adverse events were reported to occur by at least 2% of patients who received either PROBUPHINE or placebo implants in the pooled double-blind, PROBUPHINE Phase 3 studies:

The adverse event profile of buprenorphine in a transmucosal form (i.e., sublingual) was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. The table below shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study.

6.2. Postmarketing Experience

No post-marketing data exist at this time for PROBUPHINE. The most frequently reported post-marketing adverse event observed with sublingual buprenorphine was drug misuse or abuse. The most frequently reported post-marketing adverse event with buprenorphine/naloxone sublingual tablets was peripheral edema.

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 PROBUPHINE.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

8.1. Pregnancy

8.2. Lactation

8.3. Females and Males of Reproductive Potential

8.4. Pediatric Use

The safety and effectiveness of PROBUPHINE have not been established in children or adolescents younger than 16 years of age.

8.5. Geriatric Use

Clinical studies of PROBUPHINE did not include subjects over the age of 65. Other reported clinical experience with buprenorphine has not identified differences in responses between the geriatric 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 PROBUPHINE 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 effect of hepatic impairment on the pharmacokinetics of sublingual buprenorphine has been evaluated in a pharmacokinetic study. While no clinically significant changes have been observed in subjects with mild hepatic impairment, the plasma levels have been shown to be higher and half-life values have been shown to be longer for buprenorphine in subjects with moderate and severe hepatic impairment.

The effect of hepatic impairment on the pharmacokinetics of implanted buprenorphine, such as PROBUPHINE, has not been studied. Since the drug is extensively metabolized, the plasma levels can be expected to be higher in patients with moderate and severe hepatic impairment. Because PROBUPHINE cannot be titrated, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with PROBUPHINE. Monitor patients who develop moderate or severe hepatic impairment while being treated with PROBUPHINE for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. If signs and symptoms of toxicity or overdose are observed, removal of PROBUPHINE implants may be required [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

8.7. Renal Impairment

Clinical studies of PROBUPHINE did not include subjects with 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

PROBUPHINE contains buprenorphine, a Schedule III controlled substance under the Controlled Substances Act.

Under the Drug Addiction Treatment Act (DATA) codified at 21 United States Code (U.S.C.) 823(g), use of this product in the treatment of opioid dependence is limited to Healthcare Providers who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe or dispense 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. Each PROBUPHINE implant contains 74.2 mg of buprenorphine and can come out or protrude, resulting in the potential for accidental exposure or intentional misuse, abuse, and diversion. Healthcare Providers should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect misuse, abuse, and diversion of buprenorphine.

Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the concomitant abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.

Proper assessment of the patient, periodic re-evaluation of therapy, and proper handling and storage of PROBUPHINE are appropriate measures that help to limit misuse, abuse, and diversion of opioid drugs.

Monitor all patients receiving PROBUPHINE and provide or refer patients who have conditions indicative of diversion or progression of opioid dependence and addictive behaviors to more intensive and structured treatment for substance use.

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.

Patients treated with PROBUPHINE who experience a delay between removal of implants and insertion of new implants should be maintained on their previous dose of sublingual buprenorphine. Patients who elect to discontinue PROBUPHINE treatment without continuing on other buprenorphine treatment should be monitored for withdrawal. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate [see Warnings and Precautions (5.9)].

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.6)].

Clinical Presentation

The manifestations of acute buprenorphine overdose include pinpoint pupils, sedation, hypotension, respiratory depression, and death.

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonist naloxone is a specific antidote to respiratory depression resulting from opioid overdose. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.

Clinicians should consider the potential role and contribution of buprenorphine, other CNS depressant drugs, and other opioids in a patient's clinical presentation, in determining whether the implants should be removed. In an emergency situation, the removal procedure can be performed by a surgeon who is not certified in the REMS.

12.1. Mechanism of Action

PROBUPHINE implants contain buprenorphine HCl. Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

12.2. Pharmacodynamics

Four PROBUPHINE implants deliver circulating drug blood levels comparable to the average plasma concentrations observed following daily doses of: 8 mg Subutex or Suboxone tablet equivalent.

12.3. Pharmacokinetics

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

Store PROBUPHINE at 20 to 25°C (68 to 77°F); excursions permitted at 15 to 30°C (59-86°F) [see USP Controlled Room Temperature].

Store PROBUPHINE in accordance with Federal and State controlled substance laws and regulations. Contact state controlled substances authority for information on how to store and prevent diversion of this product.

The PROBUPHINE implant is a Schedule III drug product. Handle with adequate security and accountability. Expired implants should be properly disposed, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

NDC code for set of four implants is 52440-0100-14.

Risks Relating to the Insertion and Removal Procedure [see Warnings and Precautions (5.1)], Accidental Overdose, Misuse and Abuse if an Implant Comes Out or Protrudes from the Skin [see Warnings and Precautions (5.3)].

• Inform patients that there are risks associated with the insertion and removal of PROBUPHINE, including:

  –

  Migration with potential for embolism or nerve damage

  –

  Expulsion or protrusion

  –

  Injury to nerves or blood vessels

  –

  Infection at the insertion or removal site

  –

  Removal complications

  • Implants may be difficult to locate if they were inserted too deeply, or if patients manipulate them, or have gained significant weight since insertion.
  • Special procedures, tests, or a referral to a specialist may be needed to remove the implants if they are difficult to locate.

• Inform patients that there is a risk to others of accidental overdose, misuse, and abuse if the implant comes out of the arm.
• Inform patients that appropriate care of their incision is important to reduce the risk of complications associated with the insertion of PROBUPHINE.
• Inform patients to call a Healthcare Provider immediately if they experience any of the following:

  –

  The implant protrudes or is expelled.

  –

  Bleeding or symptoms of infection, such as excessive or worsening itching, pain, irritation or redness, or swelling at the insertion site.

  –

  Symptoms suggesting the implant has migrated, such as numbness or weakness, or shortness of breath.

  –

  Symptoms of numbness or weakness in the arm after insertion or removal procedure.

• Inform patients that if the PROBUPHINE implants protrude or are expelled, they should:

  –

  Wash their hands if they have touched the PROBUPHINE implants.

  –

  Cover the area where the implants were inserted with a clean bandage.

  –

  Not allow others to touch or use the PROBUPHINE implants, since this could be very dangerous.

  –

  Put the implants in a plastic bag and take the implants to a Healthcare Provider right away.

  –

  Keep the implants away from others, especially children.

  –

  Protect the implants from theft until they can take them to their doctor.

• Inform patients that improper removal by a non-Healthcare Provider carries the risk of implant-site infection and premature removal may induce opioid withdrawal symptoms.
• Inform patients that there are risks associated with minor surgical procedures, such as:

  –

  Itching, pain, irritation or redness, swelling, bleeding, or bruising at the insertion or removal site.

  –

  Scarring around the incision site.

Life-Threatening Respiratory Depression

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.4)].

Interaction with Benzodiazepines and other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if PROBUPHINE is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.5), Drug Interactions (7)].

Serotonin Syndrome

Inform patients that PROBUPHINE 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 physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions 7].

Adrenal Insufficiency

Inform patients that PROBUPHINE 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 (5.7)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in PROBUPHINE. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions (5.11)].

Driving or Operating Heavy Machinery

Caution patients that PROBUPHINE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous machinery.

Instruct patients not to drive or operate hazardous machinery until they are reasonably certain that PROBUPHINE therapy does not adversely affect their ability to engage in such activities [see Warnings and Precautions (5.15)].

Dependence and Withdrawal

Inform patients that PROBUPHINE can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued [see Warnings and Precautions (5.9)].

Orthostatic Hypotension

Inform patients that, like other opioids, PROBUPHINE may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.16)].

Drug Interactions

Instruct patients to inform their Healthcare Providers of any other prescription medications, over-the-counter medications, or herbal preparations that are prescribed or currently being used [see Drug Interactions (7)].

Pregnancy

Lactation

Warn patients that buprenorphine passes into breast milk. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties. [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

Emergency Analgesia

Advise patients to instruct their family members to, in the event of emergency, inform the treating physician or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with PROBUPHINE [see Warnings and Precautions (5.13)].

PROBUPHINE REMS Program

PROBUPHINE is available only through a restricted program called the PROBUPHINE REMS Program [see Warnings and Precautions (5.2)]. Inform the patient of the following notable requirements:

• PROBUPHINE is not available in retail pharmacies.
• PROBUPHINE must be inserted or removed only in the facility of a certified prescriber.