Probuphine - Drug Monograph

Introduction

Probuphine is a novel implantable formulation of buprenorphine designed for the maintenance treatment of opioid use disorder (OUD). This innovative delivery system provides continuous, low-level buprenorphine administration over six months, offering a unique approach to medication-assisted treatment that may improve adherence and reduce diversion potential compared to sublingual formulations.

Mechanism of Action

Probuphine contains buprenorphine hydrochloride, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. As a partial agonist, it binds strongly to opioid receptors but produces less euphoria and respiratory depression than full agonists like heroin or methadone. The implant formulation provides sustained release of buprenorphine, maintaining stable plasma concentrations that suppress withdrawal symptoms and cravings while blocking the effects of additional opioid use.

Indications

Probuphine is FDA-approved 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 (generally 8 mg/day or less). It is intended for use as part of a comprehensive treatment program that includes counseling and psychosocial support.

Dosage and Administration

• Dosage: Four implants inserted subdermally in the inner aspect of the upper arm
• Duration: Provides continuous buprenorphine delivery for six months
• Administration: Must be inserted and removed by healthcare providers trained in the procedure
• Special populations: Not recommended for patients with severe hepatic impairment
• Transition: Patients should be stabilized on transmucosal buprenorphine (≤8 mg/day) before implantation

Pharmacokinetics

• Absorption: Slow, sustained release from ethylene vinyl acetate (EVA) polymer matrix
• Distribution: Extensive tissue distribution; 96% protein-bound
• Metabolism: Primarily hepatic via CYP3A4 and CYP2C8
• Elimination: Primarily fecal (≈70%) with some renal elimination
• Half-life: Effective half-life correlates with implant duration (≈6 months)
• Steady-state: Achieved within 24 hours after insertion and maintained throughout treatment

Contraindications

• Hypersensitivity to buprenorphine or any implant components
• Patients without established opioid tolerance
• Acute or severe bronchial asthma in an unmonitored setting
• Known or suspected gastrointestinal obstruction
• Concomitant use with benzodiazepines or other CNS depressants without careful medical supervision

Warnings and Precautions

• Risk of implant migration: Rare instances of implant movement requiring surgical removal
• Local complications: Infection, extrusion, or nerve damage at insertion site
• Addiction potential: Although reduced compared to full agonists, abuse potential exists
• Respiratory depression: Particularly when combined with other CNS depressants
• Hepatic impairment: Use with caution in moderate impairment; contraindicated in severe impairment
• QT prolongation: Monitor patients with congenital long QT syndrome or taking QT-prolonging medications
• Neonatal withdrawal: Use during pregnancy may result in neonatal withdrawal syndrome

Drug Interactions

• CNS depressants: Enhanced sedation and respiratory depression with alcohol, benzodiazepines, and other depressants
• CYP3A4 inhibitors/inducers: Ketoconazole, rifampin, and other modulators may affect buprenorphine levels
• Opioid antagonists: May precipitate withdrawal (naloxone, naltrexone)
• Serotonergic drugs: Risk of serotonin syndrome when combined with other serotonergic agents
• MAO inhibitors: Potential for enhanced opioid effects

Adverse Effects

• Implant site pain, itching, redness, or bruising
• Headache
• Depression
• Constipation
• Nausea
• vomiting
• Fatigue

• Implant migration or extrusion
• Local infection or nerve damage
• Respiratory depression
• Severe hypersensitivity reactions
• Adrenal insufficiency
• Androgen deficiency with chronic use

Monitoring Parameters

• Treatment effectiveness: Regular assessment of craving reduction, withdrawal symptoms, and functional improvement
• Safety monitoring: Insertion site evaluation for signs of infection, migration, or extrusion
• Drug misuse: Assessment for potential diversion or inappropriate use
• Psychiatric status: Monitoring for depression or suicidal ideation
• Liver function: Periodic LFT monitoring, especially in patients with hepatic impairment
• Renal function: Assessment in patients with renal impairment

Patient Education

• The implants provide continuous medication for six months and must be removed after this period
• Report any signs of infection at the insertion site (redness, swelling, pain, drainage)
• Avoid activities that might excessive strain on the implantation arm for several weeks
• Understand that additional opioids may have reduced effect due to receptor blockade
• Never attempt to remove the implants yourself
• Inform all healthcare providers about the implants, especially before MRI or other procedures
• Continue participating in counseling and support programs
• Seek immediate medical attention for respiratory difficulties, severe allergic reactions, or implant extrusion
• Do not drink alcohol or take sedatives without medical supervision

References

1. FDA Prescribing Information: Probuphine (buprenorphine) implant 2. Rosenthal RN, Lofwall MR, Kim S, et al. Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: a randomized clinical trial. JAMA. 2016;316(3):282-290. 3. White J, Bell J, Saunders JB, et al. Open-label dose-finding study of buprenorphine implants for opioid dependence. Drug Alcohol Depend. 2009;99(1-3):120-127. 4. Ling W, Casadonte P, Bigelow G, et al. Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial. JAMA. 2010;304(14):1576-1583. 5. Substance Abuse and Mental Health Services Administration. Clinical Guidance for Treating Pregnant and Parenting Women With Opioid Use Disorder and Their Infants. HHS Publication No. (SMA) 18-5054. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2018.