BUPRENORPHINE- buprenorphine patch
Lake Erie Medical DBA Quality Care Products LLC
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BUPRENORPHINE TRANSDERMAL SYSTEM safely and effectively. See full prescribing information for BUPRENORPHINE TRANSDERMAL SYSTEM.
Buprenorphine Transdermal System CIII
Initial U.S. Approval: 1981
WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Buprenorphine Transdermal System is a partial opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. (1)
Limitations of Use
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Transdermal system: 5 mcg/hour, 7.5 mcg/hour, 10 mcg/hour, 15 mcg/hour, and 20 mcg/hour. (3)
WARNINGS AND PRECAUTIONS
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 L.P. at 1-888-827-0616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, and Debilitated Patients
5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness
Buprenorphine transdermal system exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing buprenorphine transdermal system, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1) and Overdosage (10)].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of buprenorphine transdermal system. Monitor for respiratory depression, especially during initiation of buprenorphine transdermal system or following a dose increase. Misuse or abuse of buprenorphine transdermal system by chewing, swallowing, snorting or injecting buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant risk of overdose and death [see Warnings and Precautions (5.2)].
Accidental exposure to even one dose of buprenorphine transdermal system, especially in children, can result in a fatal overdose of buprenorphine [see Warnings and Precautions (5.2)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of buprenorphine transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].
Buprenorphine Transdermal System is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
|Previous Opioid Analgesic Daily Dose
(Oral Morphine Equivalent)
|<30 mg||30-80 mg|
|Recommended Buprenorphine Transdermal System Starting Dose||5 mcg/hour||10 mcg/hour|
Conversion from Methadone to Buprenorphine Transdermal System
Close monitoring 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.
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 (5.7) and 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.
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 (5.10), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
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 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 is contraindicated in patients with:
In rare cases, severe application site skin reactions with signs of marked inflammation including "burn," "discharge," and "vesicles" have occurred. Time of onset varies, ranging from days to months following the initiation of buprenorphine transdermal system treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.
Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of buprenorphine transdermal system.
The following serious adverse reactions are described elsewhere in the labeling:
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:
|Open-Label Titration Period||Double-Blind Treatment Period|
|Buprenorphine Transdermal System||Buprenorphine Transdermal System||Placebo|
|MedDRA Preferred Term||(N = 1024)||(N = 256)||(N = 283)|
|Application site pruritus||8%||4%||7%|
|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)|
|Application site pruritus||9%||13%||5%|
|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.
|MedDRA Preferred Term||Buprenorphine Transdermal System|
(N = 392)
(N = 261)
|Application site pruritus||15%||12%|
|Application site erythema||7%||2%|
|Application site rash||6%||6%|
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.
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 chronic use of opioids [see Clinical Pharmacology (12.2)].
Table 5 Includes clinically significant drug interactions with buprenorphine transdermal system.
|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:||Closely monitor 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.|
|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. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].|
|Examples:||Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.|
|Inhibitors of CYP3A4|
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.
If concomitant use is necessary, consider dosage reduction of buprenorphine transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
|Examples:||Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)|
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.
If concomitant use is necessary, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider buprenorphine transdermal system dosage reduction and monitor for signs of respiratory depression.
|Examples:||Rifampin, carbamazepine, phenytoin|
|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 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), 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) [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|
|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 buprenorphine transdermal system for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine transdermal system and/or the muscle relaxant as necessary.|
|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.|
|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:||Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine transdermal system is used concomitantly with anticholinergic drugs.|
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. 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 estimated 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.
Fetal/neonatal adverse reactions
Prolonged use of opioid analgesics 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 (5.3)].
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.
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 to17). Rabbits were administered four buprenorphine transdermal systems 20 mcg/hour every 3 days (gestation days 6, 9, 12, 15, 18, & 19) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6 to19). 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 associated with toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant rats were administered 1/4 of one buprenorphine transdermal system 5 mcg/hour every 3 days or received daily SC buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from Gestation Day 6 to Lactation Day 21 (weaning). Administration of buprenorphine transdermal system or SC buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the MRHD of one buprenorphine transdermal system 20 mcg/hour. Maternal toxicity was also observed at the no observed adverse effect level (NOAEL) for offspring.
Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with buprenorphine transdermal system.
The safety and efficacy of buprenorphine transdermal system in patients under 18 years of age has not been established.
Of the total number of subjects in the clinical trials (5,415), buprenorphine transdermal system was administered to 1,377 patients aged 65 years and older. Of those, 457 patients were 75 years of age and older. In the clinical program, the incidences of selected buprenorphine transdermal system-related AEs were higher in older subjects. The incidences of application site AEs were slightly higher among subjects < 65 years of age than those ≥ 65 years of age for both buprenorphine transdermal system and placebo treatment groups.
In a single-dose study of healthy elderly and healthy young subjects treated with buprenorphine transdermal system 10 mcg/hour, the pharmacokinetics were similar. In a separate dose-escalation safety study, the pharmacokinetics in the healthy elderly and hypertensive elderly subjects taking thiazide diuretics were similar to those in the healthy young adults. In the elderly groups evaluated, adverse event rates were similar to or lower than rates in healthy young adult subjects, except for constipation and urinary retention, which were more common in the elderly. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use [see Clinical Pharmacology (12.3)]. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of buprenorphine transdermal system slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5)].
In a study utilizing intravenous buprenorphine, peak plasma levels (Cmax) and exposure (AUC) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. Buprenorphine transdermal system has not been evaluated in patients with severe hepatic impairment. As buprenorphine transdermal system is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
Buprenorphine transdermal system contains buprenorphine, a Schedule III controlled substance.
Buprenorphine transdermal system contains buprenorphine, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. Buprenorphine transdermal system can be abused and is subject to misuse, addiction and criminal diversion [see Warnings and Precautions (5.1)]. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.
All patients treated with opioids, including buprenorphine transdermal system, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
"Drug-seeking" behavior is very common to persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Buprenorphine transdermal system, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to reduce abuse of opioid drugs.
Risks Specific to the Abuse of Buprenorphine Transdermal System
Buprenorphine transdermal system is intended for transdermal use only. Abuse of buprenorphine transdermal system poses a risk of overdose and death. This risk is increased with concurrent abuse of buprenorphine transdermal system with alcohol and other substances including other opioids and benzodiazepines [see Warnings and Precautions (5.4) and Drug Interactions (7)]. Intentional compromise of the transdermal delivery system will result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)]. Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by chewing, swallowing, snorting, or injecting buprenorphine extracted from the transdermal system. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Buprenorphine transdermal system should not be abruptly discontinued [see Dosage and Administration (2.4)]. If buprenorphine transdermal system is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. 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, increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)].
Acute overdosage with buprenorphine transdermal system 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, 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 techniques.
Naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10 to 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.
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 C29H41NO4. 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, 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.
|Buprenorphine Delivery Rate (mcg/hour)||Active Surface Area (cm2)||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.
Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappaopioid receptors, an agonist at delta-opioid receptors, and a partial agonist at ORL-1 (nociceptin) receptors. The contributions of these actions to its analgesic profile are unclear.
Effects on the Central Nervous System
Buprenorphine produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.
Buprenorphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Buprenorphine causes a reduction in motility associated with an increase in tone smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid induced effects may include a reduction in biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Buprenorphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Effects on Cardiac Electrophysiology
The effect of buprenorphine transdermal system 10 mcg/hour and 2 × buprenorphine transdermal system 20 mcg/hour on QTc interval, was evaluated in a double-blind (buprenorphine transdermal system vs. placebo), randomized, placebo and active-controlled (moxifloxacin 400 mg, open label), parallel-group, dose-escalating, single-dose study in 132 healthy male and female subjects aged 18 to 55 years. The dose escalation sequence for buprenorphine transdermal system during the titration period was: buprenorphine transdermal system 5 mcg/hour for 3 days, then buprenorphine transdermal system 10 mcg/hour for 3 days, then buprenorphine transdermal system 20 mcg/hour for 3 days, then 2 × buprenorphine transdermal system 20 mcg/hour for 4 days. The QTc evaluation was performed during the third day of buprenorphine transdermal system 10 mcg/hour and the fourth day of 2 × buprenorphine transdermal system 20 mcg/hour when the plasma levels of buprenorphine were at steady state for the corresponding doses [see Warnings and Precautions (5.7)].
There was no clinically meaningful effect on mean QTc with a buprenorphine transdermal system dose of 10 mcg/hour. A buprenorphine transdermal system dose of 40 mcg/hour (given as two 20 mcg/hour buprenorphine transdermal systems) prolonged mean QTc by a maximum of 9.2 (90% CI: 5.2 to 13.3) msec across the 13 assessment time points.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2)]
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of buprenorphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1, 2.3)].
Concentration–Adverse Reaction Relationships
There is a relationship between increasing buprenorphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1, 2.2, 2.3)].
Each buprenorphine transdermal system provides delivery of buprenorphine for 7 days. Steady state was achieved during the first application by Day 3 (see Figure 2).
Mean (SD) Buprenorphine Plasma Concentrations Following Three Consecutive Applications of Buprenorphine Transdermal System 10 mcg/hour (N = 36 Healthy Subjects)
Buprenorphine transdermal system 5, 10, and 20 mcg/hour provide dose-proportional total buprenorphine exposures (AUC) following 7-day applications. Buprenorphine transdermal system single 7-day application and steady-state pharmacokinetic parameters are summarized in Table 7. Plasma buprenorphine concentrations after titration showed no further change over the 60-day period studied.
|Single 7-day Application||AUCinf
|Buprenorphine Transdermal System 5 mcg/hour||12087 (37)||176 (67)|
|Buprenorphine Transdermal System 10 mcg/hour||27035 (29)||191 (34)|
|Buprenorphine Transdermal System 20 mcg/hour||54294 (36)||471 (49)|
|Multiple 7-day Applications||AUCtau,ss
|Buprenorphine Transdermal System 10 mcg/hour, steady-state||27543 (33)||224 (35)|
Transdermal delivery studies showed that intact human skin is permeable to buprenorphine. In clinical pharmacology studies, the median time for buprenorphine transdermal system 10 mcg/hour to deliver quantifiable buprenorphine concentrations (≥ 25 pg/mL) was approximately 17 hours.
The absolute bioavailability of buprenorphine transdermal system relative to IV administration, following a 7-day application, is approximately 15% for all doses (buprenorphine transdermal system 5, 10, and 20 mcg/hour).
Effects of Application Site
A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by buprenorphine transdermal system 10 mcg/hour is similar when applied to the upper outer arm, upper chest, upper back, or the side of the chest [see Dosage and Administration (2.6)].
The reapplication of buprenorphine transdermal system 10 mcg/hour after various rest periods to the same application site in healthy subjects showed that the minimum rest period needed to avoid variability in drug absorption is 3 weeks (21 days) [see Dosage and Administration (2.6)].
Effects of Heat
In a study of healthy subjects, application of a heating pad directly on the buprenorphine transdermal system 10 mcg/hour caused a 26% to 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hours after the heat was removed. For this reason, instruct patients not to apply heating pads directly to the buprenorphine transdermal system during system wear [see Warnings and Precautions (5.13)].
Fever may increase the permeability of the skin, leading to increased buprenorphine concentrations during buprenorphine transdermal system treatment. As a result, febrile patients are at increased risk for the possibility of buprenorphine transdermal system-related reactions during treatment with buprenorphine transdermal system. Monitor patients with febrile illness for adverse effects and consider dose adjustment [see Warnings and Precautions (5.14)]. In a crossover study of healthy subjects receiving endotoxin or placebo challenge during buprenorphine transdermal system 10 mcg/hour wear, the AUC and Cmax were similar despite a physiologic response of mild fever to endotoxin.
Buprenorphine is approximately 96% bound to plasma proteins, mainly to alpha- and beta-globulin.
Studies of IV buprenorphine have shown a large volume of distribution (approximately 430 L), implying extensive distribution of buprenorphine.
CSF buprenorphine concentrations appear to be approximately 15 to 25% of concurrent plasma concentrations.
Buprenorphine metabolism in the skin following buprenorphine transdermal system application is negligible.
Buprenorphine primarily undergoes N-dealkylation by CYP3A4 to norbuprenorphine and glucuronidation by UGT-isoenzymes (mainly UGT1A1 and 2B7) to buprenorphine 3β-O-glucuronide. Norbuprenorphine, the major metabolite, is also glucuronidated (mainly UGT1A3) prior to excretion.
Norbuprenorphine is the only known active metabolite of buprenorphine. It has been shown to be a respiratory depressant in rats, but only at concentrations at least 50-fold greater than those observed following application to humans of buprenorphine transdermal system 20 mcg/hour.
Following IV administration, buprenorphine and its metabolites are secreted into bile and excreted in urine.
Following intramuscular administration of 2 mcg/kg dose of buprenorphine, approximately 70% of the dose was excreted in feces within 7 days. Approximately 27% was excreted in urine.
Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. After removal of buprenorphine transdermal system, mean buprenorphine concentrations decrease approximately 50% within 10 to 24 hours, followed by decline with an apparent terminal half-life of approximately 26 hours.
Since metabolism and excretion of buprenorphine occur mainly via hepatic elimination, reductions in hepatic blood flow induced by some general anesthetics (e.g., halothane) and other drugs may result in a decreased rate of hepatic elimination of the drug, leading to increased plasma concentrations.
The total clearance of buprenorphine is approximately 55 L/hour in postoperative patients.
Drug Interaction Studies
Effect of CYP3A4 inhibitors
In a drug-drug interaction study, buprenorphine transdermal system 10 mcg/hour (single dose × 7 days) was co-administered with 200 mg ketoconazole, a strong CYP3A4 inhibitor or ketoconazole placebo twice daily for 11 days and the pharmacokinetics of buprenorphine and its metabolites were evaluated. Plasma buprenorphine concentrations did not accumulate during co-medication with ketoconazole 200 mg twice daily. Based on the results from this study, metabolism during therapy with buprenorphine transdermal system is not expected to be affected by co-administration of CYP3A4 inhibitors [see Drug Interactions (7)].
Antiretroviral agents have been evaluated for CYP3A4 mediated interactions with sublingual buprenorphine. Nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) do not appear to have clinically significant interactions with buprenorphine. However, certain protease inhibitors (PIs) with CYP3A4 inhibitory activity such as atazanavir and atazanavir/ritonavir resulted in elevated levels of buprenorphine and norbuprenorphine when buprenorphine and naloxone were administered sublingually. Cmax and AUC for buprenorphine increased by up to 1.6 and 1.9 fold, and Cmax and AUC for norbuprenorphine increased by up to 1.6 and 2.0 fold respectively, when sublingual buprenorphine was administered with these PIs. Patients in this study reported increased sedation, and symptoms of opiate excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. It should be noted that atazanavir is both a CYP3A4 and UGT1A1 inhibitor. As such, the drug-drug interaction potential for buprenorphine with CYP3A4 inhibitors is likely to be dependent on the route of administration as well as the specificity of enzyme inhibition [see Drug Interactions (7)].
Age: Geriatric Patients
Following a single application of buprenorphine transdermal system 10 mcg/hour to 12 healthy young adults (mean age 32 years) and 12 healthy elderly subjects (mean age 72 years), the pharmacokinetic profile of buprenorphine transdermal system was similar in healthy elderly and healthy young adult subjects, though the elderly subjects showed a trend toward higher plasma concentrations immediately after buprenorphine transdermal system removal. Both groups eliminated buprenorphine at similar rates after system removal [see Use in Specific Populations (8.5)].
In a study of healthy young subjects, healthy elderly subjects, and elderly subjects treated with thiazide diuretics, buprenorphine transdermal system at a fixed dose-escalation schedule (buprenorphine transdermal system 5 mcg/hour for 3 days, followed by buprenorphine transdermal system 10 mcg/hour for 3 days and buprenorphine transdermal system 20 mcg/hour for 7 days) produced similar mean plasma concentration vs. time profiles for each of the three subject groups. There were no significant differences between groups in buprenorphine Cmax or AUC [see Use in Specific Populations (8.5)].
In a pooled data analysis utilizing data from several studies that administered buprenorphine transdermal system 10 mcg/hour to healthy subjects, no differences in buprenorphine Cmax and AUC or body-weight normalized Cmax and AUC were observed between males and females treated with buprenorphine transdermal system.
The pharmacokinetics of buprenorphine following an IV infusion of 0.3 mg of buprenorphine were compared in 8 patients with mild impairment (Child-Pugh A), 4 patients with moderate impairment (Child-Pugh B) and 12 subjects with normal hepatic function. Buprenorphine and norbuprenorphine exposure did not increase in the mild and moderate hepatic impairment patients.
No studies in patients with renal impairment have been performed with buprenorphine transdermal system.
In an independent study, the effect of impaired renal function on buprenorphine pharmacokinetics after IV bolus and after continuous IV infusion administrations was evaluated. It was found that plasma buprenorphine concentrations were similar in patients with normal renal function and in patients with impaired renal function or renal failure. In a separate investigation of the effect of intermittent hemodialysis on buprenorphine plasma concentrations in chronic pain patients with end-stage renal disease who were treated with a transdermal buprenorphine product (marketed outside the US) up to 70 mcg/hour, no significant differences in buprenorphine plasma concentrations before or after hemodialysis were observed.
No notable relationship was observed between estimated creatinine clearance rates and steady-state buprenorphine concentrations among patients during buprenorphine transdermal system therapy.
Buprenorphine administered daily by skin painting to Sprague Dawley rats for 100 weeks at dosages (20, 60, or 200 mg/kg) produced systemic exposures (based on AUC) that ranged from approximately 130 to 350 times that of human subjects administered the maximum recommended human dose (MRHD) of buprenorphine transdermal system 20 mcg/hour. An increased incidence of benign testicular interstitial cell tumors, considered buprenorphine treatment-related, was observed in male rats compared with concurrent controls. The tumor incidence was also above the highest incidence in the historical control database of the testing facility. These tumors were noted at 60 mg/kg/day and higher at approximately 220 times the proposed MRHD based on AUC. The no observed effect level (NOEL) was 20 mg/kg/day (approximately 140 times the proposed MRHD based on AUC). The mechanism leading to the tumor findings and the relevance to humans is unknown.
Buprenorphine was administered by skin painting to hemizygous Tg.AC mice over a 6-month study period. At the dosages administered daily (18.75, 37.5, 150, or 600 mg/kg/day), buprenorphine was not carcinogenic or tumorigenic at systemic exposure to buprenorphine, based on AUC, of up to approximately 1000 times that of human subjects administered buprenorphine transdermal system 20 mcg/hour, the MRHD.
Buprenorphine was not genotoxic in three in vitro genetic toxicology studies (bacterial mutagenicity test, mouse lymphoma assay, chromosomal aberration assay in human peripheral blood lymphocytes), and in one in vivo mouse micronucleus test.
Impairment of Fertility
Buprenorphine transdermal system (1/4 of a buprenorphine transdermal system 5 mcg/hour, one buprenorphine transdermal system 5 mcg/hour, or one buprenorphine transdermal system 20 mcg/hour every 3 days in males for 4 weeks prior to mating for a total of 10 weeks and in females for 2 weeks prior to mating through Gestation Day 7) had no effect on fertility or general reproductive performance of rats at AUC-based exposure levels as high as approximately 65 times (females) and 100 times (males) that for human subjects who received buprenorphine transdermal system 20 mcg/hour, the MRHD.
The efficacy of buprenorphine transdermal system has been evaluated in four 12-week double-blind, controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate to severe chronic low back pain or osteoarthritis using pain scores as the primary efficacy variable. Two of these studies, described below, demonstrated efficacy in patients with low back pain. One study in low back pain and one study in osteoarthritis did not show a statistically significant pain reduction for either buprenorphine transdermal system or the respective active comparators.
12-Week Study in Opioid-Naïve Patients with Chronic Low Back Pain
A total of 1,024 patients with chronic low back pain who were suboptimally responsive to their non-opioid therapy entered an open-label, dose-titration period for up to four weeks. Patients initiated therapy with three days of treatment with buprenorphine transdermal system 5 mcg/hour. After three days, if adverse events were tolerated, the dose was increased to buprenorphine transdermal system 10 mcg/hour. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to buprenorphine transdermal system 20 mcg/hour for an additional 10 to 12 days. Patients who achieved adequate analgesia and tolerable adverse effects on buprenorphine transdermal system, 10 or 20 mcg/hour, were then randomized to remain on their titrated dose of buprenorphine transdermal system or matching placebo. Fifty-three percent of the patients who entered the open-label titration period, were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Twenty-three percent of patients discontinued due to an adverse event from the open-label titration period and 14% discontinued due to lack of a therapeutic effect. The remaining 10% of patients were dropped due to various administrative reasons.
During the first seven days of double-blind treatment patients were allowed up to two tablets per day of immediate-release oxycodone 5 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to either acetaminophen 500 mg or ibuprofen 200 mg at a maximum of four tablets per day. Sixty-six percent of the patients treated with buprenorphine transdermal system completed the 12-week treatment compared to 70% of the patients treated with placebo. Of the 256 patients randomized to buprenorphine transdermal system, 9% discontinued due to lack of efficacy and 16% due to adverse events. Of the 283 patients randomized to placebo, 13% discontinued due to lack of efficacy and 7% due to adverse events.
Of the patients who were randomized, the mean pain (SE) NRS scores were 7.2 (0.08) and 7.2 (0.07) at screening and 2.6 (0.08) and 2.6 (0.07) at pre-randomization (beginning of double-blind phase) for the buprenorphine transdermal system and placebo groups, respectively.
The score for average pain over the last 24 hours at the end of the study (Week 12/Early Termination) was statistically significantly lower for patients treated with buprenorphine transdermal system compared with patients treated with placebo. The proportion of patients with various degrees of improvement, from screening to study endpoint, is shown in Figure 3 below.
Figure 3: Percent Reduction in Pain Intensity
12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain
One thousand one hundred and sixty (1,160) patients on chronic opioid therapy (total daily dose 30 to 80 mg morphine equivalent) entered an open-label, dose-titration period with buprenorphine transdermal system for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with buprenorphine transdermal system 10 mcg/hour for three days. After three days, if the patient tolerated the adverse effects, the dose was increased to buprenorphine transdermal system 20 mcg/hour for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on buprenorphine transdermal system 20 mcg/hour were randomized to remain on buprenorphine transdermal system 20 mcg/hour or were switched to a low-dose control (buprenorphine transdermal system 5 mcg/hour) or an active control. Fifty-seven percent of the patients who entered the open-label titration period were able to titrate to and tolerate the adverse effects of buprenorphine transdermal system 20 mcg/hour and were randomized into a 12-week double-blind treatment phase. Twelve percent of patients discontinued due to an adverse event and 21% discontinued due to lack of a therapeutic effect during the open-label titration period.
During the double-blind period, patients were permitted to take ibuprofen (200 mg tablets) or acetaminophen (500 mg tablets) every 4 hours as needed for supplemental analgesia (up to 3200 mg of ibuprofen and 4 grams of acetaminophen daily). Sixty-seven percent of patients treated with buprenorphine transdermal system 20 mcg/hour and 58% of patients treated with buprenorphine transdermal system 5 mcg/hour completed the 12-week treatment. Of the 219 patients randomized to buprenorphine transdermal system 20 mcg/hour, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to buprenorphine transdermal system 5 mcg/hour, 24% discontinued due to lack of efficacy and 6% due to adverse events.
Of the patients who were able to be randomized in the double-blind period, the mean pain (SE) NRS scores were 6.4 (0.08) and 6.5 (0.08) at screening and were 2.8 (0.08) and 2.9 (0.08) at pre-randomization (beginning of Double-Blind Period) for the buprenorphine transdermal system 5 mcg/hour and buprenorphine transdermal system 20 mcg/hour, respectively.
The score for average pain over the last 24 hours at Week 12 was statistically significantly lower for subjects treated with buprenorphine transdermal system 20 mcg/hour compared to subjects treated with buprenorphine transdermal system 5 mcg/hour. A higher proportion of buprenorphine transdermal system 20 mcg/hour patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to buprenorphine transdermal system 5 mcg/hour patients (33%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 4 below.
Figure 4: Percent Reduction in Pain Intensity
Buprenorphine Transdermal System is supplied in cartons containing 4 individually-packaged systems, and a pouch containing 4 Patch-Disposal Units. The systems are supplied in the strengths below:
5 mcg/hour: square, beige-colored adhesive patches measuring 45 mm by 45 mm. Each system is printed in blue with "Buprenorphine Transdermal System" and 5 mcg/hr.
7.5 mcg/hour: rectangular, beige-colored adhesive patches measuring 58 mm by 45 mm. Each system is printed in blue with the "Buprenorphine Transdermal System" and 7.5 mcg/hr.
10 mcg/hour: rectangular, beige-colored adhesive patches measuring 68 mm by 45 mm. Each system is printed in blue with the "Buprenorphine Transdermal System" and 10 mcg/hr.
15 mcg/hour: rectangular, beige-colored adhesive patches measuring 72 mm by 59 mm. Each system is printed in blue with the "Buprenorphine Transdermal System" and 15 mcg/hr.
20 mcg/hour: square, beige-colored adhesive patches measuring 72 mm by 72 mm. Each system is printed in blue with the "Buprenorphine Transdermal System" and 20mcg/hr.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Addiction, Abuse, and Misuse
Inform patients that the use of buprenorphine transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which could lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share buprenorphine transdermal system with others and to take steps to protect buprenorphine transdermal system from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting buprenorphine transdermal system or when the dose is increased, and that it can occur even at recommended doses [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store buprenorphine transdermal system securely and to dispose of unused buprenorphine transdermal system by folding the patch in half and flushing it down the toilet [see Dosage and Administration (2.7).
Interaction with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if buprenorphine transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4)].
Interaction with 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 [see Drug Interactions (7)].
Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions 7].
Inform patients to avoid taking buprenorphine transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking buprenorphine transdermal system [see Drug Interactions (7)].
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.6)].
Important Administration Instructions
Instruct patients how to properly use buprenorphine transdermal system, including the following:
Inform patients that buprenorphine transdermal system may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.8)].
Inform patients that anaphylaxis has been reported with ingredients contained in buprenorphine transdermal system. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions (5.12), Contraindications (4), Adverse Reactions (6)].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of buprenorphine transdermal system during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3)], Use in Specific Populations (8.1).
Inform female patients of reproductive potential that buprenorphine transdermal system can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].
Advise patients that breastfeeding is not recommended during treatment with buprenorphine transdermal system [see Use in Specific Populations (8.2)]
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [Use in Specific Populations (8.3)].
Driving or Operating Heavy Machinery
Inform patients that buprenorphine transdermal system may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17).
Instruct patients to refer to the Instructions for Use for proper disposal of buprenorphine transdermal system. Patients can dispose of used or unused buprenorphine transdermal system patches in the trash by sealing them in the Patch-Disposal Unit, following the instructions on the unit.
Alternatively, instruct patients to 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.
Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed [see Dosage and Administration (2.7)].
Healthcare professionals can telephone Rhodes Pharmaceuticals L.P. (1-888-827-0616) for information on this product.
Distributed by: Rhodes Pharmaceuticals L.P., Coventry, RI 02816
Manufactured by: LTS Lohmann Therapy Systems Corp., West Caldwell, NJ 07006
U.S. Patent Numbers 5681413; 5804215; 6264980; 6315854; 6344211; RE41408; RE41489; RE41571.
|This Medication Guide has been approved by the U.S. Food and Drug Administration.||Issued: 12/2016|
Buprenorphine (byü-prǝ-ˈnȯr-ˌfēn) Transdermal System, CIII
Buprenorphine transdermal system is:
Important information about buprenorphine transdermal system:
Do not use buprenorphine transdermal system if you have:
Before applying buprenorphine transdermal system, tell your healthcare provider if you have a history of:
Tell your healthcare provider if you:
When using buprenorphine transdermal system:
While using buprenorphine transdermal system DO NOT:
The possible side effects of buprenorphine transdermal system are:
Get emergency medical help if you have:
These are not all the possible side effects of buprenorphine transdermal system. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information, go to dailymed.nlm.nih.gov
Distributed by: Rhodes Pharmaceuticals L.P. Coventry, RI 02816, www.rhodespharma.com or call 1-888-827-0616
Be sure that you read, understand, and follow these Instructions for Use before you use buprenorphine transdermal system. Talk to your healthcare provider or pharmacist if you have any questions.
Before applying buprenorphine transdermal system:
Buprenorphine transdermal system should be applied to the upper outer arm, upper chest, upper back, or the side of the chest (See Figure A). These 4 sites (located on both sides of the body) provide 8 possible buprenorphine transdermal system applicaiton sites.
Do not apply more than 1 patch at the same time unless your doctor tells you to. However, if your healthcare provider tells you to do so, you may use 2 patches as prescdribed, applied at the same site (See Figure A for application sites) right next to each other (See Figure B for an example of patch position when applying 2 patches).
Always apply and remove the two patches together at the same time.
You should change the skin site where you apply buprenorphine transdermal system each week, making sure that at least 3 weeks (21 days) pass before you re-use the same skin site.
When to apply a new patch:
How to apply buprenorphine transdermal system:
If the patch falls off right away after applying, throw it away and put a new one on at a different skin site (See "Disposing of Buprenorphine Transdermal System Patch").
If a patch falls off, do not touch the sticky side of the patch with your fingers. A new patch should be applied to a different site. Patches that fall off should not be re-applied. They must be thrown away correctly.
Short-term exposure of the buprenorphine transdermal system patch to water, such as when bathing or showering, is permitted.
If the edges of the buprenorphine transdermal system patch start to loosen:
If your patch falls off later, but before 1 week (7 days) of use, throw it away properly (See "Disposing of a Buprenorphine Transdermal System Patch") and apply a new patch at a different skin site. Be sure to let your healthcare provider know that this has happened. Do not replace the new patch until 1 week (7 days) after you put it on (or as directed by your healthcare provider).
Buprenorphine transdermal system patches should be disposed of by using the Patch-Disposal Unit. Alternatively, the patches can be flushed down the toilet.
To dispose of buprenorphine transdermal system patches in household trash using the Patch-Disposal Unit:
Remove your patch and follow the directions printed on the Patch-Disposal Unit (See Figure J) or see complete instructions below. Use one Patch-Disposal Unit for each patch.
Do not put unused patches in household trash without first sealing them in the Patch-Disposal Unit.
Always remove the leftover patches from their protective pouch and remove the protective liner. The pouch and liner can be disposed of separately in the trash and should not be sealed in the Patch-Disposal Unit.
To flush your buprenorphine transdermal system patches down the toilet:
Remove your buprenorphine transdermal system patch, fold the sticky sides of a used patch together and flush it down the toilet right away (See Figure O).
When disposing of unused buprenorphine transdermal system patches you no longer need, remove the leftover patches from their protective pouch and remove the protective liner. Fold the patches in half with the sticky sides together, and flush the patches down the toilet.
Do not flush the pouch or the protective liner down the toilet. These items can be thrown away in the trash.
If you prefer not to flush the used patch down the toilet, you must use the Patch-Disposal Unit provided to you to discard the patch.
Never put used buprenorphine transdermal system patches in the trash without first sealing them in the Patch-Disposal Unit.
This "Instructions for Use" has been approved by the U.S. Food and Drug Administration.
Distributed by: Rhodes Pharmaceuticals L.P., Coventry, RI 02816
Bioclusive is a trademark of Systagenix Wound Management (US), Inc.
Tegaderm is a trademark of 3M.
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