Probuphine

SIDE EFFECTS

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

• Serious Complications from Insertion and Removal of PROBUPHINE [see WARNINGS AND PRECAUTIONS]
• Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
• Respiratory and CNS Depression [see WARNINGS AND PRECAUTIONS]
• Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
• Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
• Opioid Withdrawal [see WARNINGS AND PRECAUTIONS]
• Hepatitis, Hepatic Events [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Elevation of Cerebrospinal Fluid Pressure [see WARNINGS AND PRECAUTIONS]
• Elevation of Intracholedochal Pressure [see WARNINGS AND PRECAUTIONS]
• Infection [see WARNINGS AND PRECAUTIONS]

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.

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

System Organ Class High Level Group Term MedDRA Preferred Term	PROBUPHINE (N=309) n (%) *	Placebo / SL BPN † (N=317)n (%) *
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 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%. † 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.

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 dose-controlled study

Body System /Adverse Event (COSTART Terminology)	Buprenorphine Dose *
	Very Low * (N=184) N (%)	Low * (N=180) N (%)	Moderate * (N=186) N (%)	High * (N=181) N (%)	Total * (N=731) 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%)
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 (4 mg solution) approximates a 6 mg tablet dose “Moderate” dose (8 mg 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 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].

DRUG INTERACTIONS

Table 4 includes clinically significant drug interactions with PROBUPHINE.

Table 4: Clinically Significant Drug Interactions

Benzodiazepine and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effects, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	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. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments [see WARNINGS AND PRECAUTIONS]. If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see WARNINGS AND PRECAUTIONS].
Examples:	Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:	The effects of coadministered CYP3A4 inhibitors on buprenorphine exposure in subjects treated with PROBUPHINE have not been studied and the effects may be dependent on the route of administration; however, such interactions have been established in studies using transmucosal buprenorphine. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when PROBUPHINE is given concurrently with agents that affect CYP3A4 activity. The concomitant use of sublingual buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects.
Intervention:	Patients who transfer to PROBUPHINE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inhibitors [e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors (e.g., ritonavir, indinavir, and saquinavir)] should be monitored to ensure that the plasma buprenorphine level provided by PROBUPHINE is adequate. If patients already on PROBUPHINE require newly-initiated treatment with CYP3A4 inhibitors, the patients should be monitored for signs and symptoms of overmedication. If the concomitant medication cannot be reduced or discontinued, it may be necessary to remove the PROBUPHINE implants and treat the patient with a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on PROBUPHINE in the setting of concomitant medication that is a CYP3A4 inhibitor, and the concomitant medication is discontinued, the patient should be monitored for withdrawal. If the dose of PROBUPHINE is not adequate in the absence of the concomitant medication, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments [see CLINICAL PHARMACOLOGY].
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The effects of coadministered CYP3A4 inducers on buprenorphine exposure in subjects treated with PROBUPHINE have not been studied and the effects may be dependent on the route of administration; however, such interactions have been established in studies using transmucosal buprenorphine. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when PROBUPHINE is given concurrently with agents that affect CYP3A4 activity. CYP3A4 inducers may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome.
Intervention:	Patients who transfer to PROBUPHINE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level provided by PROBUPHINE is not excessive. If patients already on PROBUPHINE require newly-initiated treatment with CYP3A4 inducers, the patients should be monitored for withdrawal. If the dose of PROBUPHINE is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on PROBUPHINE in the setting of concomitant medication that is a CYP3A4 inducer, and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of overmedication. If the dose provided by PROBUPHINE is excessive in the absence of the concomitant inducer, it may be necessary to remove the PROBUPHINE implants and treat the patient with a formulation of buprenorphine that permits dose adjustments [see CLINICAL PHARMACOLOGY].
Examples:	Rifampin, carbamazepine, phenytoin, phenobarbital
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on PROBUPHINE treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	Efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with PROBUPHINE, the patient should be monitored for signs and symptoms of over-medication. It may be necessary to remove the PROBUPHINE implants and treat the patient with a formulation of buprenorphine that permits dose adjustments.
Examples:	Atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue PROBUPHINE if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of PROBUPHINE is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	Phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and PROBUPHINE for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of PROBUPHINE and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when PROBUPHINE is used concomitantly with anticholinergic drugs.

Drug Abuse And Dependence

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.

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.

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].

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see WARNINGS AND PRECAUTIONS].

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