Probuphine

PROBUPHINE- buprenorphine hydrochloride implant
Braeburn Pharmaceuticals

WARNING: IMPLANT MIGRATION, PROTRUSION, EXPULSION, and NERVE DAMAGE ASSOCIATED WITH INSERTION and REMOVAL

Risk Associated with Insertion and Removal

Insertion and removal of PROBUPHINE are associated with the risk of implant migration, protrusion, and expulsion resulting from the procedure. 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.

Incomplete insertions or infections may lead to protrusion or expulsion. [see Warnings and Precautions (5.1)] .

Because of the risks associated with insertion and removal, PROBUPHINE is available only through a restricted program called the PROBUPHINE REMS Program. All Healthcare Providers must successfully complete a live training program on the insertion and removal procedures and become certified, prior to performing insertions or prescribing PROBUPHINE implants. Patients must be monitored to ensure that PROBUPHINE is removed by a healthcare provider certified to perform insertions. [see Warnings and Precautions (5.2)].

1. INDICATIONS AND USAGE

PROBUPHINE is indicated for the maintenance treatment of opioid dependence in patients who have achieved and sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (i.e., doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet or generic equivalent).

PROBUPHINE should be used as part of a complete treatment program to include counseling and psychosocial support.

PROBUPHINE is not appropriate for new entrants to treatment and patients who have not achieved and sustained prolonged clinical stability, while being maintained on buprenorphine 8 mg per day or less of a Subutex or Suboxone sublingual tablet equivalent or generic equivalent.

2. DOSAGE AND ADMINISTRATION

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. 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)].

2.4. 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

2.5. 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.

2.6. Insertion of PROBUPHINE

Preparation

Prior to inserting PROBUPHINE, carefully read the insertion instructions as well as the full prescribing information.

Before insertion of PROBUPHINE, confirm that:

  • The patient does not have any contraindications for the use of PROBUPHINE [see Contraindications (4)].
  • The patient has had a medical history and physical examination.
  • The patient understands the benefits and risks of PROBUPHINE.
  • The patient has received a copy of the Medication Guide included in the packaging.
  • The patient does not have allergies to the antiseptic and anesthetic to be used during insertion.

Insert PROBUPHINE Under Aseptic Conditions.

The Following Equipment is Needed for Implant Insertion:

  • An examination table for the patient to lie on
  • Instrument stand, sterile tray

    Figure

  • Adequate lighting (e.g., headlamp)
  • Sterile fenestrated drape
  • Latex and talc-free sterile gloves
  • EtOH prep
  • Surgical marker
  • Antiseptic solution (e.g., chlorhexidine)
  • Local anesthetic (1% lidocaine with epinephrine 1:100,000)
  • 5 mL syringe with 1.5 inch 25g needle
  • Adson single tooth tissue forceps
  • #15 blade scalpel
  • ¼ inch thin adhesive strip (butterfly strip) (e.g., Steri-strip skin closures)
  • 4×4 sterile gauze
  • Adhesive bandages
  • 3-inch pressure bandages
  • Liquid adhesive (e.g., Mastisol)
  • 4 PROBUPHINE implants
  • 1 PROBUPHINE disposable applicator (Figure 1)

The applicator and its parts are shown in Figure 1.

Correctly performed subdermal insertion of the implants will facilitate their removal. Implants should be placed just under the skin to avoid the large blood vessels that lie in the subcutaneous deep tissue. If the implants are placed improperly, resulting in deep tissue placement, the implants will be more difficult to remove.

Figure 1

Figure 1
(click image for full-size original)

Insertion Procedure

Step 1. Have the patient lie on his/her back, with the intended arm flexed at the elbow and externally rotated, so that the hand is positioned next to the head (Figure 2).

Figure 2

Figure 2

Step 2. Identify the insertion site, which is at the inner side of the upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus in the sulcus between the biceps and triceps muscle. Having the patient flex the biceps muscle may facilitate identification of the site (Figure 3).

Figure 3

Figure 3

Step 3. Clean insertion site with alcohol prep pad prior to marking the skin.

Step 4. Mark the insertion site with the surgical marker. The implants will be inserted through a small 2.5 mm-3mm subdermal incision.

Step 5. Using the surgical marker, mark the channel tracks where each implant will be inserted by drawing 4 lines with each line 4 cm in length. The implants will be positioned in a close fan-shaped distribution 4-6 mm apart with the fan opening towards the shoulder (Figure 4). The closer the implants lie to each other at time of insertion, the more easily they can be removed. There should be at least 5 mm between the incision and the implant when the implant is properly positioned.

Figure 4

Figure 4

Step 6. Put on sterile gloves.

Step 7. Using aseptic technique, place the sterile equipment, PROBUPHINE implants and the applicator on the sterile field of the instrument stand. One applicator is used to insert all four implants.

Step 8. Check applicator function by removing the obturator from the cannula and relocking it.

Step 9. Clean the insertion site with an antiseptic solution (e.g., chlorhexidine) using gentle repeated back-and-forth strokes for 30 seconds. When using triple swab stick applicators, use each swab stick sequentially within the 30 seconds. Allow the area to air dry for approximately 30 seconds and do not blot or wipe away.

Step 10. Apply the sterile drape to the arm of the patient.

Step 11. Anesthetize the insertion area at the incision site and just under the skin along the planned insertion channels using local anesthetic (for example, by injecting 5 mL lidocaine 1% with epinephrine 1:100,000).

Step 12. After determining that anesthesia is adequate and effective, make a shallow incision that is 2.5-3 mm in length.

Step 13. Lift the edge of the incision opening with a toothed forceps. While applying counter- traction to the skin, insert only the tip of the applicator at a slight angle (no greater than 20 degrees), into the subdermal space (depth of 3-4 mm below the skin), with the bevel-up stop marking on the cannula facing upwards and visible with the obturator locked fully into the cannula (Figure 5).

Figure 5 Figure 6

Figure 5

Figure 6

Figure 7

Figure 7

Step 14. Lower the applicator to a horizontal position, lift the skin up with the tip of the applicator but keep the cannula in the subdermal connective tissue (Figure 6). While tenting (lifting), gently advance the applicator subdermally along the channel marking on the skin until the proximal marking on the cannula just disappears into the incision (Figure 7).

Step 15. While holding the cannula in place, unlock the obturator and remove the obturator.

Step 16. Insert one implant into the cannula (Figure 8), re-insert the obturator, and gently push the obturator forward (mild resistance should be felt) until the obturator stop line is level with the bevel-up stop marking, which indicates the implant is positioned at the tip of the cannula (Figure 9). Do not force the implant beyond the end of the cannula with the obturator. There should be at least 5 mm between the incision and the implant when the implant is properly positioned.

Figure 8 Figure 9

Figure 8
(click image for full-size original)

Figure 9
(click image for full-size original)

Step 17. While holding the obturator fixed in place on the arm, retract the cannula along the obturator, leaving the implant in place (Figure 10). Note: do not push the obturator. By holding the obturator fixed in place on the arm and by retracting the cannula, the implant will be left in its correct subdermal position.

Figure 10

Figure 10
(click image for full-size original)

Step 18. Withdraw the cannula until the hub is flush with the obturator, and then twist the obturator clockwise to lock onto the cannula (Figure 11). Retract the applicator, bevel up, until the distal marking of the cannula is visualized at the incision opening (the sharp tip remaining in the subcutaneous space).

Figure 11

Figure 11
(click image for full-size original)

Step 19. Redirect the applicator to the next channel marking while stabilizing the previously inserted implant, with your index finger, away from the sharp tip (Figure 12). Follow steps 13 through 16 for the insertion of the three remaining implants through the same incision, placing implants in a close fan-shaped distribution 4-6 mm apart at the top of the implant. The applicator can now be removed.

Figure 12

Figure 12
(click image for full-size original)

Step 20. Always verify the presence of each implant by palpation of the patient’s arm immediately after the insertion. By palpating both ends of the implant, you should be able to confirm the presence of the 26 mm implant (Figure 13). If you cannot feel each of the four implants, or are in doubt of their presence, use other methods to confirm the presence of the implant. Suitable methods to locate are: Ultrasound with a high frequency linear array transducer (10 MHz or greater) or Magnetic Resonance Imaging (MRI). Please note that the PROBUPHINE implants are not radiopaque and cannot be seen by X-ray or CT scan. If ultrasound and MRI fail, call 1-844-859- 6341.

Figure 13

Figure 13
(click image for full-size original)

Step 21. Apply pressure to the incision site for approximately five minutes if necessary.

Step 22. Clean the incision site. Apply liquid adhesive to the skin margins and allow to dry before closing the incision with the ¼ inch thin adhesive strip (butterfly strip) (for example Steri-strip skin closures).

Step 23. Place a small adhesive bandage over the insertion site.

Step 24. Apply a pressure bandage with sterile gauze to minimize bruising. The pressure bandage can be removed in 24 hours and the adhesive bandage can be removed in three to five days.

Step 25. Complete the PATIENT IDENTIFICATION CARD and give it to the patient to keep. Also, complete the PATIENT CHART STICKER and affix it to the patient medical record or scan or input into electronic medical record. Provide the patient with the Medication Guide and explain proper care of the insertion site.

Step 26. The applicator is for single use only. Dispose of the applicator in accordance with the Centers for Disease Control and Prevention guidelines for hazardous waste.

Step 27. Instruct the patient to apply an ice pack on his/her arm for 40 minutes every two hours for first 24 hours and as needed.

Step 28. Complete the PROBUPHINE REMS Insertion/Removal Log Form.

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