Dosing and uses of Probuphine (buprenorphine subdermal implant)
Adult dosage forms and strengths
subdermal implant
- 80mg/implant buprenorphine HCl (equivalent to 74.2 mg of buprenorphine)
Opioid Addiction
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 (ie, doses ≤8 mg/day of Subutex or Suboxone sublingual tablet equivalent or generic equivalent)
4 implants (80 mg/implant of buprenorphine HCl) are inserted in the upper arm for 6 months of treatment and removed by the end of the sixth month (see Administration)
Dosing Considerations
Only for patients who are opioid tolerant
Part of a complete treatment program to include counseling and psychosocial support
Not appropriate for new entrant to treatment and patients who have not achieved and sustained prolonged clinical stability while being maintained on buprenorphine ≤8 mg/day
May only be prescribed by physicians who have met 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
All healthcare providers who intend to prescribe and/or perform insertions/removals must successfully complete a live training program and demonstrate procedural competency
Pediatric dosage forms and strengths
<16 years: Safety and efficacy not established
Probuphine (buprenorphine subdermal implant) adverse (side) effects
>10%
Headache (13%)
Implant-site pain (13%)
Implant-site pruritus (12%)
1-10%
Implant-site erythema (10%)
Implant-site hematoma (7%)
Implant-site hemorrhage (7%)
Depression (6%)
Constipation (6%)
Nausea (6%)
Vomiting (6%)
Implant-site edema (5%)
Toothache (5%)
Pain (4%)
Dizziness (4%)
Cough (3%)
Somnolence (3%)
Fatigue (3%)
Pyrexia (3%)
Oropharyngeal pain (5%)
Upper abdominal pain (3%)
Laceration (3%)
Migraine (2%)
Excoriation (2%)
Asthenia (2%)
Chills (2%)
Rash (2%)
Scratch (1%)
Chest pain (1%)
Local swelling (1%)
Flatulence (1%)
Sedation (1%)
Paraesthesia (1%)
Dyspnea (1%)
Skin lesion (1%)
Warnings
Black box warnings
Risk associated with insertion and removaL
- Insertion and removal of the implants 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
- Because of these risks, buprenorphine subdermal implant 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 the implants
- Patients must be monitored to ensure the implant is removed by a healthcare provider certified to perform insertions
Contraindications
Hypersensitivity
Cautions
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 (see Black box warnings)
Buprenorphine can be abused in a manner similar to other opioids; monitor patients
Significant respiratory depression and death have occurred in association with buprenorphine, particularly when taken by the IV route in combination with benzodiazepines or other CNS depressants (including alcohol)
Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy
Adrenal insufficiency may occur; if diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid
Unintentional pediatric exposure; in the event an implant protrudes or comes out, keep the implant away from children; buprenorphine can cause severe, possibly fatal, respiratory depression in children
If treatment is temporarily interrupted or discontinued, monitor for withdrawal and treat appropriately
Monitor liver function tests prior to initiation and during treatment
Verify that patient is clinically stable on transmucosal buprenorphine and not dependent on full agonists before inserting
Treat pain with a nonopioid analgesic whenever possible; if opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect
May impair ability to drive and operate machinery
May cause orthostatic hypotension in ambulatory patients
May elevate CSF pressure; caution in patients with head injury or intracranial lesions
Can produce miosis and changes in level of consciousness that may interfere with evaluating patient for head injury
Increases intracholedochal pressure (as do other opioids); caution with biliary tract dysfunction
May obscure diagnosis or clinical course of patients with acute abdominal conditions Infection may occur at insertion/removal site; excessive palpation shortly after insertion may increase risk of infection
Administer with caution in debilitated patients and those with myxedema or hypothyroidism, adrenal cortical insufficiency, CNS depression or coma, toxic psychoses, prostatic hypertrophy or urethral stricture, acute alcoholism, delirium tremens, or kyphoscoliosis
Caution with history of keloid formation, connective-tissue disease (eg, scleroderma), or recurrent MRSA infections
Drug interaction overview
- Coadministration of opioids with serotonergic drugs may cause serotonin syndrome, a potentially life-threatening condition
- Buprenorphine is metabolized by CYP3A4; caution if CYP3A4 inhibitors or inducers are initiated or discontinued; monitor to ensure plasma buprenorphine levels are adequate and not excessive
- Postmarketing report of coma and death associated with concomitant use of buprenorphine and benzodiazepine; coadministration with other CNS depressants should only occur with cautious medical supervision
Pregnancy
Pregnancy
May cause fetal harm
Neonatal opioid withdrawal syndrome has been reported in the infants of women treated with buprenorphine sublingual tablets during pregnancy
Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes (eg, low birth weight, preterm birth, and fetal death); untreated opioid addiction often results in continued or relapsing illicit opioid use
Lactation
Based on two studies in 13 lactating women, buprenorphine and the metabolite norbuprenorphine are present at low levels in human milk and infant urine
Available data have not shown adverse reactions in breastfed infants
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Probuphine (buprenorphine subdermal implant)
Mechanism of action
Semisynthetic narcotic mixed agonist-antagonist analgesic; exerts partial agonistic effects at the mu opioid receptor in the CNS and antagonistic effects at the kappa opioid receptor
Absorption
Implants deliver circulating drug blood levels comparable to the average plasma concentrations observed following daily doses of ≤8 mg Subutex or Suboxone tablet equivalent
Initial peak plasma concentration observed ~12 hr after insertion, and then concentrations decrease slowly
Steady-state plasma levels observed by ~4 wk
Distribution
Protein bound: 96%, primarily to alpha and beta globulin
Metabolism
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation
N-dealkylation pathway is mediated primarily by the CYP3A4
Norbuprenorphine, the major metabolite, can further undergo glucuronidation
Norbuprenorphine has been found to bind opioid receptors in vitro; however, it has not been studied clinically for opioidlike activity
Elimination
Excretion: 30% urine; 69% (feces) collected up to 11 days after dosing
Administration
Subdermal implantation
Each dose consists of 4 implants inserted subdermally in the inner side of the upper arm
Examine the insertion site 1 week following insertion for signs of infection or other problems
The implants are intended to be in place for 6 months of treatment; remove 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 (ie, the dose from which they were transferred to buprenorphine subdermal treatment) prior to additional buprenorphine subdermal 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 reinsertion into previously used administration sites, nor into sites other than the upper arm, has been studied
Clinical supervision
- Examine insertion site 1 week following insertion for signs of infection and any problems with wound healing, including evidence of implant extrusion from the skin
- 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 buprenorphine subdermal implant is not adequate for stable maintenance; consider use of alternate buprenorphine products for maintenance of treatment
Patient Selection
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 &le:8 mg/day 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 buprenorphine subdermal implant)
- Note: Patients should not be tapered to a lower dose for the sole purpose of transitioning to buprenorphine subdermal implant
- Stable transmucosal buprenorphine dose for ≥3 months without any need for supplemental dosing or adjustments
Examples of acceptable doses of transmucosal buprenorphine
- Subutex SL tablet ≤8 mg
- Suboxone (buprenorphine/naloxone) SL tablet ≤8 mg/2 mg
- Bunavail (buprenorphine/naloxone) buccal film ≤4.2 mg/0.7 mg
- Zubsolv (buprenorphine/naloxone) SL tablet ≤5.7 mg/1.4 mg
- Or generic equivalents of the above examples
Factors to consider in determining clinical stability/suitability
- 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 department visits, or crisis interventions
- Social support system
Storage
Store at controlled room temperature (20-25°C [68-77°F]); excursions permitted at 15-30°C (59-86°F)
