1 INDICATIONS AND USAGE Buprenorphine transdermal system is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate release opioids.

Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including buprenorphine transdermal system, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Buprenorphine transdermal system is not indicated as an as-needed (prn) analgesic Buprenorphine transdermal system is a partial opioid agonist indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including buprenorphine transdermal system, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

( 1 , 5.1 ) Buprenorphine transdermal system is not indicated as an as-needed (prn) analgesic.

( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Application Site Skin Reactions [see Warnings and Precautions ( 5.8 )] Opioid induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )] Severe Hypotension [see Warnings and Precautions ( 5.12 )] Hepatotoxicity [see Warnings and Precautions ( 5.14 )] Gastrointestinal Effects [see Warnings and Precautions ( 5.15 )] Seizures [see Warnings and Precautions ( 5.16 )] QTc Prolongation [see Warnings and Precautions ( 5.17 )] Anaphylactic/Allergic Reactions [see Warnings and Precautions ( 5.18 ) ] Most common adverse reactions (≥5%) include: nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial 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.

A total of 5,415 patients were treated with buprenorphine transdermal system in controlled and open-label chronic pain clinical trials.

Nine hundred twenty-four subjects were treated for approximately six months and 183 subjects were treated for approximately one year.

The clinical trial population consisted of patients with persistent moderate to severe pain.

The most common serious adverse drug reactions (all <0.1%) occurring during clinical trials with buprenorphine transdermal system were: chest pain, abdominal pain, vomiting, dehydration, and hypertension/blood pressure increased.

The most common adverse events (≥2%) leading to discontinuation were: nausea, dizziness, vomiting, headache, and somnolence.

The most common adverse reactions (≥5%) reported by patients in clinical trials comparing buprenorphine transdermal system 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing buprenorphine transdermal system 20 mcg/hour to buprenorphine transdermal system 5 mcg/hour are shown in Table 3 below: Table 2: Adverse Reactions Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Patients who were not Opioid Tolerant Open-Label Titration Period Buprenorphine Double-Blind Treatment Period Buprenorphine Placebo MedDRA Preferred Term (N = 1024) (N = 256) (N = 283) Nausea 23% 13% 10% Dizziness 10% 4% 1% Headache 9% 5% 5% Application site pruritus 8% 4% 7% Somnolence 8% 2% 2% Vomiting 7% 4% 1% Constipation 6% 4% 1% Table 3: Adverse Reactions Reported in ≥5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients Open-Label Titration Period Buprenorphine Double-Blind Treatment Period Buprenorphine 20 Buprenorphine 5 MedDRA Preferred Term (N = 1160) (N = 219) (N = 221) Nausea 14% 11% 6% Application site pruritus 9% 13% 5% Headache 9% 8% 3% Somnolence 6% 4% 2% Dizziness 5% 4% 2% Constipation 4% 6% 3% Application site erythema 3% 10% 5% Application site rash 3% 8% 6% Application site irritation 2% 6% 2% The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials.

Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/Active-Controlled Clinical Trials with Incidence ≥2% MedDRA Preferred Term Buprenorphine (N = 392) Placebo (N = 261) Nausea 21% 6% Application site pruritus 15% 12% Dizziness 15% 7% Headache 14% 9% Somnolence 13% 4% Constipation 13% 5% Vomiting 9% 1% Application site erythema 7% 2% Application site rash 6% 6% Dry mouth 6% 2% Fatigue 5% 1% Hyperhidrosis 4% 1% Peripheral edema 3% 1% Pruritus 3% 0% Stomach discomfort 2% 0% The adverse reactions seen in controlled and open-label studies are presented below in the following manner: most common (≥5%), common (≥1% to <5%), and less common (<1%).

The most common adverse reactions (≥5%) reported by patients treated with buprenorphine transdermal system in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

The common (≥1% to <5%) adverse reactions reported by patients treated with buprenorphine transdermal system in the clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were: Gastrointestinal disorders : diarrhea, dyspepsia, and upper abdominal pain General disorders and administration site conditions : fatigue, peripheral edema, application site irritation, pain, pyrexia, chest pain, and asthenia Infections and infestations : urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis Injury, poisoning and procedural complications : fall Metabolism and nutrition disorders : anorexia Musculoskeletal and connective tissue disorders : back pain, arthralgia, pain in extremity, muscle spasms, musculoskeletal pain, joint swelling, neck pain, and myalgia Nervous system disorders : hypoesthesia, tremor, migraine, and paresthesia Psychiatric disorders : insomnia, anxiety, and depression Respiratory, thoracic and mediastinal disorders : dyspnea, pharyngolaryngeal pain, and cough Skin and subcutaneous tissue disorders : pruritus, hyperhidrosis, rash, and generalized pruritus Vascular disorders : hypertension Other less common adverse reactions, including those known to occur with opioid treatment, that were seen in <1% of the patients in the buprenorphine transdermal system trials include the following in alphabetical order: Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of buprenorphine.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 buprenorphine transdermal system.

Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] .

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.9 )] .

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids.

Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.15 )].

Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.

Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244).

Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid- involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249).

Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months.

New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months.

Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry.

Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.

Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal.

Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.

Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.