buprenorphine transdermal system

1 INDICATIONS AND USAGE 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. 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 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.

2 DOSAGE AND ADMINISTRATION 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 mcg/hour, 10 mcg/hour, 15 mcg/hour, 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 mcg/hour, 10 mcg/hour, 15 mcg/hour, 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 bupren …

3 DOSAGE FORMS AND STRENGTHS Buprenorphine transdermal system is a rectangular or square, beige-colored system consisting of a protective liner and functional layers. Buprenorphine transdermal system is available in five strengths: Buprenorphine transdermal system 5 mcg/hour (dimensions: 6.25 cm 2 ) Buprenorphine transdermal system 7.5 mcg/hour (dimensions: 9.375 cm 2 ) Buprenorphine transdermal system 10 mcg/hour (dimensions: 12.5 cm 2 ) Buprenorphine transdermal system 15 mcg/hour (dimensions: 18.75 cm 2 ) Buprenorphine transdermal system 20 mcg/hour (dimensions: 25 cm 2 ) Transdermal system: 5 mcg/hour, 7.5 mcg/hour, 10 mcg/hour, 15 mcg/hour, and 20 mcg/hour. ( 3 )

4 CONTRAINDICATIONS 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 )

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 Alvogen, Inc. at 1-866-770-3024 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 mcg/hour 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 …

7 DRUG INTERACTIONS 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 …

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. ( 8.1 ) Lactation : Not recommended. ( 8.2 ) Severe Hepatic Impairment : Consider use of an alternate analgesic that may permit more flexibility in dosing. ( 8.6 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with buprenorphine transdermal system in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one buprenorphine transdermal system 20 mcg/hour, the maximum recommended human dose (MRHD) [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/neonatal adverse reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )]. Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates. An opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. Buprenorphine transdermal system is not recommended for use in women immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including buprenorphine transdermal system, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Data Animal Data Studies in rats and rabbits demonstrated no evidence of teratogenicity following buprenorphine transdermal system or subcutaneous (SC) administration of buprenorphine during the period of organogenesis. Rats were administered up to one buprenorphine transdermal system 20 mcg/hour every 3 days (Gestation Days 6, 9, 12, & 15) or received daily SC buprenorphine up to 5 mg/kg (Gestation Days 6 to 17). Rabbits were administered four buprenorphine transdermal system 20 mcg/hour every 3 days (Gestation Days 6, 9, 12, 15, 18, and 19) or received daily SC buprenorphine up to 5 mg/kg (Gestation Days 6 to 19). No teratogenicity was observed at any dose. AUC values for buprenorphine with buprenorphine transdermal system application and SC injection were approximately 110 and 140 times, respectively, that of human subjects who received the MRHD of one buprenorphine transdermal system 20 mcg/hour. In a pre- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as buprenorphine transdermal system or SC buprenorphine was …

11 DESCRIPTION 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. System Components and Structure Five different strengths of buprenorphine transdermal system are available: 5 mcg/hour, 7.5 mcg/hour, 10 mcg/hour, 15 mcg/hour, 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: cross-linked polyacrylate, levulinic acid, oleyl oleate, and kollidon 90F.

10 OVERDOSAGE Clinical Presentation Acute overdosage with buprenorphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. However, naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used. Remove buprenorphine transdermal system immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from buprenorphine transdermal system, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of buprenorphine transdermal system, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10 to 24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

16 HOW SUPPLIED/STORAGE AND HANDLING Buprenorphine transdermal system is supplied in cartons containing 4 individually packaged systems and a pouch containing 4 Patch-Disposal Units. Buprenorphine transdermal system 5 mcg/hour are square, beige-colored adhesive patches (dimensions: 6.25 cm 2 ). Each system is printed with the text “Buprenorphine Transdermal System CIII 5 mcg/hr” in black ink and is supplied in a 4-count carton ( NDC 47781-406-04 ) Buprenorphine transdermal system 7.5 mcg/hour are rectangular, beige-colored adhesive patches (dimensions: 9.375 cm 2 ). Each system is printed with the text “Buprenorphine Transdermal System CIII 7.5 mcg/hr” in black ink and is supplied in a 4-count carton ( NDC 47781-561-04 ) Buprenorphine transdermal system 10 mcg/hour are square, beige-colored adhesive patches (dimensions: 12.5 cm 2 ). Each system is printed with the text “Buprenorphine Transdermal System CIII 10 mcg/hr” in black ink and is supplied in a 4-count carton ( NDC 47781-407-04 ) Buprenorphine transdermal system 15 mcg/hour are rectangular, beige-colored adhesive patches (dimensions: 18.75 cm 2 ). Each system is printed with the text “Buprenorphine Transdermal System CIII 15 mcg/hr” in black ink and is supplied in a 4-count carton ( NDC 47781-419-04 ) Buprenorphine transdermal system 20 mcg/hour are square, beige-colored adhesive patches (dimensions: 25 cm 2 ). Each system is printed with the text “Buprenorphine Transdermal System CIII 20 mcg/hr” in black ink and is supplied in a 4-count carton ( NDC 47781-408-04 ) Store buprenorphine transdermal system securely and dispose of properly [see Patient Counseling Information ( 17 )] . Store at 25oC (77oF); excursions permitted between 15o to 30oC (59o to 86oF) [See USP Controlled Room Temperature].