BUPRENORPHINE

Buprenorphine Transdermal System is a transdermal system providing systemic delivery of buprenorphine, a mu opioid partial agonist analgesic, continuously for 7 days. The chemical name of buprenorphine is 6,14-ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- α-(1,1-dimethylethyl)-4, 5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy-α-methyl-, [5α, 7α, (S)]. The structural formula is: The molecular weight of buprenorphine is 467.6; the empirical formula is C 29 H 41 NO 4 . Buprenorphine occurs as a white or almost white powder and is very slightly soluble in water, freely soluble in acetone, soluble in methanol and ether, and slightly soluble in cyclohexane. The pKa is 8.5 and the melting point is about 217°C. Chemical Structure System Components and Structure Five different strengths of buprenorphine transdermal system are available: 5, 7.5, 10, 15, and 20 mcg/hour (Table 6). The proportion of buprenorphine mixed in the adhesive matrix is the same in each of the five strengths. The amount of buprenorphine released from each system per hour is proportional to the active surface area of the system. The skin is the limiting barrier to diffusion from the system into the bloodstream. Table 6: Buprenorphine Transdermal System Product Specifications Buprenorphine Delivery Rate (mcg/hour) Active Surface Area (cm 2 ) Total Buprenorphine Content (mg) Buprenorphine Transdermal System 5 6.25 5 Buprenorphine Transdermal System 7.5 9.375 7.5 Buprenorphine Transdermal System 10 12.5 10 Buprenorphine Transdermal System 15 18.75 15 Buprenorphine Transdermal System 20 25 20 Buprenorphine transdermal system is a rectangular or square, beige-colored system consisting of a protective liner and functional layers. Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a beige-colored web backing layer; (2) an adhesive rim without buprenorphine; (3) a separating layer over the buprenorphine-containing adhesive matrix; (4) the buprenorphine- containing adhesive matrix; and (5) a peel-off release liner. Before use, the release liner covering the adhesive layer is removed and discarded. Figure 1: Cross-Section Diagram of Buprenorphine Transdermal System (not to scale). The active ingredient in buprenorphine transdermal system is buprenorphine. The inactive ingredients in each system are: levulinic acid, oleyl oleate, povidone, and polyacrylate cross-linked with aluminum. Figure 1

Buprenorphine transdermal system is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. Buprenorphine transdermal system is a partial opioid agonist indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate. ( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, and because of the greater risks of overdose and death with extended-release/long-acting opioid formulations, reserve buprenorphine transdermal system for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) 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. Limitations of Use Because of the risks of addiction, abuse and misuse with opioids, which can occur at any dosage or duration, and because of the greater risk of overdose and death with extended-release/long-acting opioid formulations [see Warnings and Precautions (5.1) ] , reserve buprenorphine transdermal system for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) 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 should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. ( 2.1 ) Buprenorphine transdermal system doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of buprenorphine transdermal system for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with buprenorphine transdermal system. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2 , 5 ) Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with buprenorphine transdermal system. Consider prescribing naloxone based on the patient's risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.3 , 10 ) For opioid-naïve patients, initiate treatment with a 5 mcg/hour patch. ( 2.1 ) Instruct patients to wear buprenorphine transdermal system for 7 days and to wait a minimum of 3 weeks before applying to the same site. ( 2.1 ) Do not abruptly discontinue buprenorphine transdermal system in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 ) 2.1 Important Dosage and Administration Information Buprenorphine transdermal system should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. Buprenorphine transdermal system doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid-experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equianalgesic dose of another opioid. Use the lowest effective dosage for the shortest duration of time consistent with individual patient's treatment goals [see Warnings and Precautions (5) ] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of buprenorphine transdermal system for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks . Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1) ] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with buprenorphine transdermal system. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5.2) ] . Instruct patients not to use buprenorphine transdermal system if the pouch seal is broken or the patch is cut, damaged, or changed in any way and not to cut buprenorphine transdermal system. Instruct patients to avoid exposing buprenorphine transdermal system to external heat sources, hot water, or prolonged direct sunlight [see Warnings and Precautions (5.6) ] . Buprenorphine transdermal system is for transdermal use (on intact skin) only. Each buprenorphine transdermal system patch is intended to be worn for 7 days. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with buprenorphine transdermal system [see Warnings and Precautions (5.2) ]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1 , 5.2 , 5.3) , Overdosage (10) ]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose . 2.3 Initial Dosage Use of Buprenorphine Transdermal System as the First Opioid Analgesic (opioid-naive patients) Initiate treatment with buprenorphine transdermal system with a 5 mcg/hour patch. Conversion from Other Opioids to Buprenorphine Transdermal System When buprenorphine transdermal system therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate. There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids. Prior Total Daily Dose of Opioid Less than 30 mg of Oral Morphine Equivalents per Day : Initiate treatment with buprenorphine transdermal system 5 mcg/hour at the next dosing interval (see Table 1 below, middle column). Prior Total Daily Dose of Opioid Between 30 mg to 80 mg of Oral Morphine Equivalents per Day: Taper the patient's current around-the-clock opioids for up to 7 days to no more than 30 mg of morphine or equivalent per day before beginning treatment with buprenorphine transdermal system. Then initiate treatment with buprenorphine transdermal system 10 mcg/hour at the next dosing interval (see Table 1 below, right column). Patients may use short-acting analgesics as needed until analgesic efficacy with buprenorphine transdermal system is attained. Prior Total Daily Dose of Opioid Greater than 80 mg of Oral Morphine Equivalents per Day : Buprenorphine transdermal system 20 mcg/hour may not provide adequate analgesia for patients requiring greater than 80 mg/day oral morphine equivalents. Consider the use of an alternate analgesic. Table 1: Initial Buprenorphine Transdermal System Dose Previous Opioid Analgesic Daily Dose (Oral Morphine Equivalent) <30 mg 30 to 80 mg ⇩ ⇩ Recommended Buprenorphine Transdermal System Starting Dose 5 mcg/hour 10 mcg/hour Conversion from Methadone to Buprenorphine Transdermal System Regular evaluation is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma. 2.4 Titration and Maintenance of Therapy Individually titrate buprenorphine transdermal system to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving buprenorphine transdermal system to assess the maintenance of pain control, signs and symptoms of opioid withdrawal and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1 , 5.19) ] . Frequent communication is important among the prescriber, other members of healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics. The minimum buprenorphine transdermal system titration interval is 72 hours, based on the pharmacokinetic profile and time to reach steady state levels [see Clinical Pharmacology (12.3) ] . The maximum buprenorphine transdermal system dose is 20 mcg/hour. Do not exceed a dose of one 20 mcg/hour buprenorphine transdermal system due to the risk of QTc interval prolongation. In a clinical trial, buprenorphine transdermal system 40 mcg/hour (given as two buprenorphine transdermal system 20 mcg/hour systems) resulted in prolongation of the QTc interval [see Warnings and Precautions (5.17) , Clinical Pharmacology (12.2) ]. Patients who experience breakthrough pain may require dosage adjustment increase of buprenorphine transdermal system, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the buprenorphine transdermal system dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase) consider reducing the dosage [see Warnings and Precautions (5) ]. Adjust the dosage to obtain an appropriate balance between the management of pain and opioid-related adverse reactions. Because steady-state plasma concentrations are achieved within 72 hours, buprenorphine transdermal system dosage may be adjusted every 3 days. Dose adjustments may be made in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than two patches of the 5 mcg/hour, or 7.5 mcg/hour, or 10 mcg/hour system(s). The total dose from both patches should not exceed 20 mcg/hour. For the use of two patches, instruct patients to remove their current patch, and apply the two new patches at the same time, adjacent to one another at a different application site [see Dosage and Administration (2.7) ]. 2.5 Safe Reduction or Discontinuation of Buprenorphine Transdermal System Do not abruptly discontinue buprenorphine transdermal system in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking buprenorphine transdermal system, there are a variety of factors that should be considered, including the total daily dose of opioid (including buprenorphine transdermal system) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on buprenorphine transdermal system who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.19) , Drug Abuse and Dependence (9.3) ] . 2.6 Patients with Hepatic Impairment Buprenorphine transdermal system has not been evaluated in patients with severe hepatic impairment. As buprenorphine transdermal system is only intended for 7-day application, consider use of an alternate analgesic that may permit more flexibility with the dosing in patients with severe hepatic impairment [see Warnings and Precautions (5.14) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. 2.7 Administration of Buprenorphine Transdermal System Instruct patients to apply immediately after removal from the individually sealed pouch. Instruct patients not to use buprenorphine transdermal system if the pouch seal is broken or the patch is cut, damaged, or changed in any way. See the Instructions for Use for step-by-step instructions for applying buprenorphine transdermal system. Apply buprenorphine transdermal system to the upper outer arm, upper chest, upper back or the side of the chest. These 4 sites (each present on both sides of the body) provide 8 possible application sites. Rotate buprenorphine transdermal system among the 8 described skin sites. After buprenorphine transdermal system removal, wait a minimum of 21 days before reapplying to the same skin site [see Clinical Pharmacology (12.3) ]. Apply buprenorphine transdermal system to a hairless or nearly hairless skin site. If none are available, the hair at the site should be clipped, not shaven. Do not apply buprenorphine transdermal system to irritated skin. If the application site must be cleaned, clean the site with water only. Do not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before applying buprenorphine transdermal system. Incidental exposure of the buprenorphine transdermal system patch to water, such as while bathing or showering is acceptable based on experience during clinical studies. If problems with adhesion of buprenorphine transdermal system occur, the edges may be taped with first aid tape. If problems with lack of adhesion continue, the patch may be covered with waterproof or semipermeable adhesive dressings suitable for 7 days of wear. If buprenorphine transdermal system falls off during the 7-day dosing interval, dispose of the transdermal system properly and place a new buprenorphine transdermal system patch on at a different skin site. When changing the system, instruct patients to remove buprenorphine transdermal system and dispose of it properly [see Dosage and Administration (2.8) ] . If the buprenorphine-containing adhesive matrix accidentally contacts the skin, instruct patients or caregivers to wash the area with water and not to use soap, alcohol, or other solvents to remove the adhesive because they may enhance the absorption of the drug. 2.8 Disposal Instructions Patients should refer to the Instructions for Use for proper disposal of buprenorphine transdermal system. Dispose of used and unused patches by following the instructions on the Patch-Disposal Unit that is packaged with the buprenorphine transdermal system patches. Alternatively, patients can dispose of used patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet. Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed.

Buprenorphine transdermal system is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.10) ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.15) ] Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.18) , Adverse Reactions (6) ] Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Hypersensitivity to buprenorphine ( 4 )

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 Rhodes Pharmaceuticals at 1-888-827-0616 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: Opioid-Naïve Patients Open-Label Titration Period Double-Blind Treatment Period Buprenorphine Transdermal System Buprenorphine Transdermal System 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 Double-Blind Treatment Period Buprenorphine Transdermal System Buprenorphine Transdermal System 20 Buprenorphine Transdermal System 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 Transdermal System (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).

Table 5 Includes clinically significant drug interactions with buprenorphine transdermal system. Table 5: Significant Drug Interactions with Buprenorphine Transdermal System Benzodiazepines Clinical Impact: There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. Intervention: Regularly evaluate patients with concurrent use of buprenorphine transdermal system and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine transdermal system, and warn patients to use benzodiazepines concurrently with buprenorphine transdermal system only as directed by their physician. Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3) ] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine transdermal system is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. Intervention: If concomitant use is necessary, consider dosage reduction of buprenorphine transdermal system until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3) ] , potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine transdermal system dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin 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, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine transdermal system 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 affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase 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) [see Warnings and Precautions (5.2) ] Intervention: The use of buprenorphine transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of buprenorphine transdermal system and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of buprenorphine transdermal system and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.3) ]. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate 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 opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when buprenorphine transdermal system is used concomitantly with anticholinergic drugs. Benzodiazepines : May increase buprenorphine-induced respiratory depression. Frequently evaluate patients on concurrent therapy closely. ( 7 ) CYP3A4 Inhibitors/Inducers : Initiating CYP3A4 inhibitors or discontinuing CYP3A4 inducers may result in an increase in buprenorphine plasma concentrations. Evaluate patients starting CYP3A4 inhibitors or stopping CYP3A4 inducers at frequent intervals for respiratory depression. ( 7 ) Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue buprenorphine transdermal system if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist Analgesics : Avoid use with buprenorphine transdermal system because they may reduce analgesic effect of buprenorphine transdermal system or precipitate withdrawal symptoms. ( 7 )

Store buprenorphine transdermal system securely and dispose of properly [see Patient Counseling Information (17) ] . Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).