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Probuphine

Last reviewed on RxList: 3/24/2021
Probuphine Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Probuphine?

Probuphine (buprenorphine) implant for subdermal administration is a partial opioid agonist 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.

What Are Side Effects of Probuphine?

Common side effects of Probuphine include:

  • implant-site reactions (pain, itching, redness, and swelling)
  • headache
  • depression
  • constipation
  • nausea
  • vomiting
  • abdominal pain
  • gas (flatulence)
  • back pain
  • toothache
  • mouth and throat pain
  • fatigue
  • weakness or lack of energy
  • chest pain
  • fever
  • swelling
  • chills
  • feeling cold
  • skin scratching
  • pain in extremities
  • migraine
  • dizziness
  • drowsiness
  • numbness and tingling
  • cough
  • shortness of breath
  • rash
  • skin lesions

Dosage for Probuphine

Four Probuphine implants are inserted subdermally in the upper arm for 6 months of treatment and are removed by the end of the sixth month.

What Drugs, Substances, or Supplements Interact with Probuphine?

Probuphine may interact with azole antifungals, macrolide antibiotics, HIV protease inhibitors, antiretrovirals, non-nucleoside reverse transcriptase inhibitors (NNRTIs), benzodiazepines, 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), and monoamine oxidase (MAO) inhibitors. Tell your doctor all medications and supplements you use.

Probuphine During Pregnancy and Breastfeeding

Probuphine is not recommended for use during pregnancy; it may harm a fetus. Tell your doctor if you become pregnant while Probuphine implants are inserted. Probuphine passes into breast milk. Consult your doctor before breastfeeding. Withdrawal symptoms may occur if you suddenly have Probuphine removed.

Additional Information

Our Probuphine (buprenorphine) implant for subdermal administration Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Probuphine Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Inserting or removing the implants can cause serious or life-threatening complications, including damage to nerves or blood vessels. Ask your doctor about these risks.

Call your doctor at once if you have:

  • opioid withdrawal symptoms--shivering, goose bumps, increased sweating, feeling hot or cold, runny nose, watery eyes, diarrhea, vomiting;
  • confusion, agitation, or other changes in your mental status;
  • extreme drowsiness, trouble concentrating;
  • a light-headed feeling, like you might pass out;
  • weak or shallow breathing, breathing that stops during sleep;
  • blurred vision, slurred speech, problems with walking, reflexes, or coordination; or
  • low cortisol levels--nausea, vomiting, loss of appetite, dizziness, worsening tiredness or weakness.

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Long-term use of opioid medication may affect fertility (ability to have children) in men or women. It is not known whether opioid effects on fertility are permanent.

Common side effects may include:

  • pain, itching, redness, swelling, bruising, or bleeding where the implants were inserted;
  • headache, depressed mood;
  • nausea, vomiting, constipation;
  • back pain;
  • tooth pain; or
  • sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Probuphine (Buprenorphine Implant)

Probuphine Professional Information

SIDE EFFECTS

The following adverse reactions are discussed in more detail in other sections of the labeling:

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 regularlydosed 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 2: 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.

Table 1: Adverse events (≥ 5% in the PROBUPHINE arm and more than in Placebo/SL BPN) by HLGT and treatment group for phase 3 controlledtrials

System Organ Class
High Level Group Term
MedDRA Preferred Term
PROBUPHINE
(N=309)
n (%) [b]
Placebo/ SL BPN[a]
(N=317)
n (%) [b]
GASTROINTESTINAL DISORDERS
  GASTROINTESTINAL SIGNS AND SYMPTOMS 42 (14) 39 (12)
    Nausea 20 (6) 15 (5)
    Vomiting 17 (6) 11 (3)
    Abdominal pain upper 10 (3) 7 (2)
    Flatulence 2 (1) 1 (0.3)
  GASTROINTESTINAL MOTILITY AND DEFAECATION CONDITIONS 27 (9) 23 (7)
    Constipation 20 (6) 9 (3)
  DENTAL AND GINGIVAL CONDITIONS 16 (5) 12 (4)
    Toothache 14 (5) 10 (3)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
  GENERAL SYSTEM DISORDERS NEC 38 (12) 26 (8)
    Pain 12 (4) 9 (3)
    Fatigue 9 (3) 4 (1)
    Asthenia 5 (2) 1 (0.3)
    Chest pain 2 (1) 0
    Local swelling 2 (1) 0
  BODY TEMPERATURE CONDITIONS 14 (5) 6 (2)
    Pyrexia 8 (3) 4 (1)
    Chills 5 (2) 2 (1)
    Feeling cold 2 (1) 0
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
  INJURIES NEC 25 (8) 23 (7)
    Laceration 8 (3) 4 (1)
    Excoriation 6 (2) 2 (1)
    Scratch 2 (1) 0
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
  MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS NEC 26 (8) 23 (7)
    Back pain 18 (6) 15 (5)
    Pain in extremity 8 (3) 3 (1)
NERVOUS SYSTEM DISORDERS
  HEADACHES 42 (14) 35 (11)
    Headache 39 (13) 32 (10)
    Migraine 5 (2) 3 (1)
  NEUROLOGICAL DISORDERS NEC 25 (8) 16 (5)
    Dizziness 11 (4) 7 (2)
    Somnolence 9 (3) 1 (0.3)
    Sedation 3 (1) 0
    Paresthesia 2 (1) 0
PSYCHIATRIC DISORDERS
  DEPRESSED MOOD DISORDERS AND DISTURBANCES 20 (6) 13 (4)
    Depression 20 (6) 10 (3)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
  RESPIRATORY DISORDERS NEC 31 (10) 19 (6)
    Oropharyngeal pain 14 (5) 10 (3)
    Cough 10 (3) 4 (1)
    Dyspnoea 3 (1) 1 (0.3)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
  EPIDERMAL AND DERMAL CONDITIONS 16 (5) 6 (2)
    Rash 5 (2) 2 (1)
    Skin lesion 2 (1) 0
[a] ‘SL BPN’ =Denotes subjects assigned to Daily Sublingual Buprenorphine Arm in PRO-806 and PRO-814 studies. All subjects in all studies took SL BPN before study treatment period was initiated and had the option of taking SL BPN as supplemental medication during treatment.
[b] A subject reporting more than one adverse event for a particular MedDRA Higher Level Group Term or Preferred Term is counted only once for that MedDRA Higher Level Group Term or Preferred Term. Percentages are rounded to the nearest whole number, and to the nearest decimal when < 0.5%.

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:

Table 2: Implant site adverse events reported by ≥ 2% of subjects in the Phase 3 Controlled Trials

MedDRA Preferred Term PROBUPHINE
N=309
n (%)
Placebo implant
N=198
n (%)
Total
N=507
n (%)
Any Implant Site TEAE 115 (37) 54 (27) 169 (33)
Individual Implant Site AE      
  Implant site pain 39 (13) 18 (9) 57 (11)
  Implant site pruritus 38 (12) 15 (8) 53 (11)
  Implant site erythema 32 (10) 13 (7) 45 (9)
  Implant site hematoma 20 (7) 15 (8) 35 (7)
  Implant site hemorrhage 23 (7) 10 (5) 33 (7)
  Implant site edema 16 (5) 5 (3) 21 (4)

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.

Table 3: Adverse events reported by at least 5% of subjects in any dose group in the dosecontrolled study

Body System /Adverse Event (COSTART Terminology) Buprenorphine 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%)
Body as a Whole
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%)
*Sublingual 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 (4mg solution) approximates a 6 mg tablet dose
"Moderate" dose (8mg solution) approximates a 12 mg tablet dose
"High" dose (16 mg solution) approximates a 24 mg tablet dose

Postmarketing Experience

No post-marketing data exist at this time for PROBUPHINE. The most frequently reported postmarketing 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].

Read the entire FDA prescribing information for Probuphine (Buprenorphine Implant)

Related Resources for Probuphine

Related Health

© Probuphine Patient Information is supplied by Cerner Multum, Inc. and Probuphine Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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