Label: BUTRANS- buprenorphine patch, extended release
- Packager: Purdue Pharma LP
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: CIII
- Marketing Status: New Drug Application
Updated December 27, 2016
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- BOXED WARNING(What is this?)
WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OROTHER CNS DEPRESSANTS
- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BUTRANS ® safely and effectively. See full prescribing information for BUTRANS.
BUTRANS ® (buprenorphine) Transdermal System for transdermal administration 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
BUTRANS 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
Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)
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 Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
- Benzodiazepines: May increase buprenorphine-induced respiratory depression. Monitor patients on concurrent therapy closely. (7)
- CYP3A4 Inhibitors/Inducers: Initiating CYP3A4 inhibitors or discontinuing CYP3A4 inducers may result in an increase in buprenorphine plasma concentrations. Closely monitor patients starting CYP3A4 inhibitors or stopping CYP3A4 inducers for respiratory depression. (7)
- Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue BUTRANS if serotonin syndrome is suspected. (7)
- Mixed Agonist/Antagonist Analgesics: Avoid use with BUTRANS because they may reduce analgesic effect of BUTRANS or precipitate withdrawal symptoms. (7)
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 OROTHER CNS DEPRESSANTS
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
- 2 DOSAGE AND ADMINISTRATION
- 3 DOSAGE FORMS AND STRENGTHS
- BUTRANS 5 mcg/hour Transdermal System (dimensions: 45 mm by 45 mm)
- BUTRANS 7.5 mcg/hour Transdermal System (dimensions: 58 mm by 45 mm)
- BUTRANS 10 mcg/hour Transdermal System (dimensions: 45 mm by 68 mm)
- BUTRANS 15 mcg/hour Transdermal System (dimensions: 59 mm by 72 mm)
- BUTRANS 20 mcg/hour Transdermal System (dimensions: 72 mm by 72 mm)
- 4 CONTRAINDICATIONS
- 5 WARNINGS AND PRECAUTIONS
5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness
- 6 ADVERSE REACTIONS
- Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
- Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
- Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4)]
- Adrenal Insufficiency [see Warnings and Precautions (5.6)]
- QTc Prolongation [see Warnings and Precautions (5.7)]
- Severe Hypotension [see Warnings and Precautions (5.8)]
- Hepatotoxicity [see Warnings and Precautions (5.10)]
- Application Site Skin Reactions [see Warnings and Precautions (5.11)]
- Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.12)]
- Gastrointestinal Effects [see Warnings and Precautions (5.15)]
- Seizures [see Warnings and Precautions (5.16)]
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 BUTRANS 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 BUTRANS were: chest pain, abdominal pain, vomiting, dehydration, and hypertension/blood pressure increased.
The most common adverse reactions (≥ 5%) reported by patients in clinical trials comparing BUTRANS 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing BUTRANS 20 mcg/hour to BUTRANS 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
Double-Blind Treatment Period BUTRANS BUTRANS 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
Double-Blind Treatment Period BUTRANS BUTRANS 20 BUTRANS 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% Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/Active-Controlled Clinical Trials with Incidence ≥ 2% MedDRA Preferred Term BUTRANS
(N = 392)
(N = 261)
Nausea 21% 6% Application site pruritus 15% 12% Dizziness 15% 7% Headache 14% 9% Somnolence 13% 4% Constipation 13% 5% Vomiting 9% 1% Application site erythema 7% 2% Application site rash 6% 6% Dry mouth 6% 2% Fatigue 5% 1% Hyperhidrosis 4% 1% Peripheral edema 3% 1% Pruritus 3% 0% Stomach discomfort 2% 0%
The most common adverse reactions (≥ 5%) reported by patients treated with BUTRANS in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.
Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].
- 7 DRUG INTERACTIONS
Table 5: Significant Drug Interactions with BUTRANS 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: Closely monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS 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 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 BUTRANS 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 BUTRANS 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 BUTRANS 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) CYP3A4 Inducers Clinical Impact: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention: If concomitant use is necessary, consider increasing the BUTRANS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider BUTRANS dosage reduction and monitor for signs of respiratory depression.
Examples: Rifampin, carbamazepine, phenytoin Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BUTRANS 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 BUTRANS 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 BUTRANS and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine Muscle Relaxants Clinical Impact: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients receiving muscle relaxants and BUTRANS for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BUTRANS and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of 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 BUTRANS is used concomitantly with anticholinergic drugs.
- 8 USE IN SPECIFIC POPULATIONS
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. Available data with BUTRANS 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 BUTRANS 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 2-4% and 15-20%, 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. BUTRANS 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 BUTRANS, 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 BUTRANS or subcutaneous (SC) administration of buprenorphine during the period of organogenesis. Rats were administered up to one BUTRANS 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 BUTRANS 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 6-19). No teratogenicity was observed at any dose. AUC values for buprenorphine with BUTRANS application and SC injection were approximately 110 and 140 times, respectively, that of human subjects who received the MRHD of one BUTRANS 20 mcg/hour.
In a pre- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as BUTRANS or SC buprenorphine was associated with toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant rats were administered 1/4 of one BUTRANS 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 BUTRANS 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 BUTRANS 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 BUTRANS.
Monitor infants exposed to BUTRANS through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breast-feeding is stopped.
8.3 Females and Males of Reproductive Potential
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Preclinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
8.5 Geriatric Use
Of the total number of subjects in the clinical trials (5,415), BUTRANS 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 BUTRANS-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 BUTRANS and placebo treatment groups.
In a single-dose study of healthy elderly and healthy young subjects treated with BUTRANS 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 BUTRANS slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5)].
8.6 Hepatic Impairment
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. BUTRANS has not been evaluated in patients with severe hepatic impairment. As BUTRANS is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
- 9 DRUG ABUSE AND DEPENDENCE
BUTRANS contains buprenorphine, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. BUTRANS 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 BUTRANS, 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.
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 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 providers(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.
BUTRANS, 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.
Risks Specific to the Abuse of BUTRANS
BUTRANS is intended for transdermal use only. Abuse of BUTRANS poses a risk of overdose and death. This risk is increased with concurrent abuse of BUTRANS 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 dosage 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.
BUTRANS should not be abruptly discontinued [see Dosage and Administration (2.4)]. If BUTRANS 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, or 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 signs [see Use in Specific Populations (8.1)].
- 10 OVERDOSAGE
Acute overdosage with BUTRANS 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, 10-35 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 BUTRANS immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from BUTRANS, 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 BUTRANS, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10-24 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.Close
- 11 DESCRIPTION
BUTRANS 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 BUTRANS 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.
BUTRANS 5 6.25 5 BUTRANS 7.5 9.375 7.5 BUTRANS 10 12.5 10 BUTRANS 15 18.75 15 BUTRANS 20 25 20
BUTRANS 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.
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid 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 both increases in carbon dioxide tension and 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 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 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 BUTRANS 10 mcg/hour and 2 x BUTRANS 20 mcg/hour on QTc interval was evaluated in a double-blind (BUTRANS 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 BUTRANS during the titration period was: BUTRANS 5 mcg/hour for 3 days, then BUTRANS 10 mcg/hour for 3 days, then BUTRANS 20 mcg/hour for 3 days, then 2 x BUTRANS 20 mcg/hour for 4 days. The QTc evaluation was performed during the third day of BUTRANS 10 mcg/hour and the fourth day of 2 x BUTRANS 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 BUTRANS dose of 10 mcg/hour. A BUTRANS dose of 40 mcg/hour (given as two 20 mcg/hour BUTRANS Transdermal Systems) prolonged mean QTc by a maximum of 9.2 (90% CI: 5.2-13.3) 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)].
BUTRANS 5, 10, and 20 mcg/hour provide dose-proportional total buprenorphine exposures (AUC) following 7-day applications. BUTRANS 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
BUTRANS 5 mcg/hour 12087 (37) 176 (67) BUTRANS 10 mcg/hour 27035 (29) 191 (34) BUTRANS 20 mcg/hour 54294 (36) 471 (49) Multiple 7-day Applications AUCtau,ss
BUTRANS 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 BUTRANS 10 mcg/hour to deliver quantifiable buprenorphine concentrations (≥ 25 pg/mL) was approximately 17 hours.
Effects of Application Site
A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by BUTRANS 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 BUTRANS 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 BUTRANS 10 mcg/hour system caused a 26% - 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 BUTRANS system during system wear [see Warnings and Precautions (5.13)].
Fever may increase the permeability of the skin, leading to increased buprenorphine concentrations during BUTRANS treatment. As a result, febrile patients are at increased risk for the possibility of BUTRANS-related reactions during treatment with BUTRANS. 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 BUTRANS 10 mcg/hour wear, the AUC and Cmax were similar despite a physiologic response of mild fever to endotoxin.
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 BUTRANS 20 mcg/hour.
Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. After removal of BUTRANS, mean buprenorphine concentrations decrease approximately 50% within 10-24 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.
Effect of CYP3A4 inhibitors
In a drug-drug interaction study, BUTRANS 10 mcg/hour (single dose x 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 BUTRANS 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 BUTRANS 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 BUTRANS was similar in healthy elderly and healthy young adult subjects, though the elderly subjects showed a trend toward higher plasma concentrations immediately after BUTRANS 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, BUTRANS at a fixed dose-escalation schedule (BUTRANS 5 mcg/hour for 3 days, followed by BUTRANS 10 mcg/hour for 3 days and BUTRANS 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 BUTRANS 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 BUTRANS.
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.
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.
- 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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 BUTRANS 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 BUTRANS 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
BUTRANS (1/4 of a BUTRANS 5 mcg/hour, one BUTRANS 5 mcg/hour, or one BUTRANS 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 BUTRANS 20 mcg/hour, the MRHD.
- 14 CLINICAL STUDIES
The efficacy of BUTRANS 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 BUTRANS 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 BUTRANS 5 mcg/hour. After three days, if adverse events were tolerated, the dose was increased to BUTRANS 10 mcg/hour. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to BUTRANS 20 mcg/hour for an additional 10-12 days. Patients who achieved adequate analgesia and tolerable adverse effects on BUTRANS 10 or 20 mcg/hour were then randomized to remain on their titrated dose of BUTRANS 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 BUTRANS completed the 12-week treatment compared to 70% of the patients treated with placebo. Of the 256 patients randomized to BUTRANS, 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 BUTRANS 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 BUTRANS 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.
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 30-80 mg morphine equivalent) entered an open-label, dose-titration period with BUTRANS for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with BUTRANS 10 mcg/hour for three days. After three days, if the patient tolerated the adverse effects, the dose was increased to BUTRANS 20 mcg/hour for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on BUTRANS 20 mcg/hour were randomized to remain on BUTRANS 20 mcg/hour or were switched to a low-dose control (BUTRANS 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 BUTRANS 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, patientswere 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 BUTRANS 20 mcg/hour and 58% of patients treated with BUTRANS 5 mcg/hour completed the 12-week treatment. Of the 219 patients randomized to BUTRANS 20 mcg/hour, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to BUTRANS 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 BUTRANS 5 mcg/hour and BUTRANS 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 BUTRANS 20 mcg/hour compared to subjects treated with BUTRANS 5 mcg/hour. A higher proportion of BUTRANS 20 mcg/hour patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to BUTRANS 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.
- 16 HOW SUPPLIED/STORAGE AND HANDLING
BUTRANS (buprenorphine) 5 mcg/hour Transdermal Systems are square, beige-colored adhesive patches measuring 45 mm by 45 mm. Each system is printed in blue with the BUTRANS logo and 5 mcg/hr and are supplied in a 4-count carton (NDC 59011-750-04).
BUTRANS (buprenorphine) 7.5 mcg/hour Transdermal Systems are rectangular, beige-colored adhesive patches measuring 58 mm by 45 mm. Each system is printed in blue with the BUTRANS logo and 7.5 mcg/hr and are supplied in a 4-count carton (NDC 59011-757-04).
BUTRANS (buprenorphine) 10 mcg/hour Transdermal Systems are rectangular, beige-colored adhesive patches measuring 68 mm by 45 mm. Each system is printed in blue with the BUTRANS logo and 10 mcg/hr and are supplied in a 4-count carton (NDC 59011-751-04).
BUTRANS (buprenorphine) 15 mcg/hour Transdermal Systems are rectangular, beige-colored adhesive patches measuring 72 mm by 59 mm Each system is printed in blue with the BUTRANS logo and 15 mcg/hr and are supplied in a 4-count carton (NDC 59011-758-04).
BUTRANS (buprenorphine) 20 mcg/hour Transdermal Systems are square, beige-colored adhesive patches measuring 72 mm by 72 mm, Each system is printed in blue with the BUTRANS logo and 20mcg/hr and are supplied in a 4-count carton (NDC 59011-752-04).Close
- 17 PATIENT COUNSELING INFORMATION
Addiction, Abuse, and Misuse
Inform patients that the use of BUTRANS, 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 BUTRANS with others and to take steps to protect BUTRANS 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 BUTRANS or when the dosage 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 BUTRANS securely and to dispose of unused BUTRANS 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 BUTRANS 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 BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS 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 BUTRANS while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking BUTRANS [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)].
- To carefully follow instructions for the application, removal, and disposal of BUTRANS. Each week, apply BUTRANS to a different site based on the 8 described skin sites, with a minimum of 3 weeks between applications to a previously used site [see Dosage and Administration (2.6)].
- To apply BUTRANS to a hairless or nearly hairless skin site. If none are available, instruct patients to clip the hair at the site and not to shave the area. Instruct patients not to apply to irritated skin. If the application site must be cleaned, use clear water only. Soaps, alcohol, oils, lotions, or abrasive devices should not be used. Allow the skin to dry before applying BUTRANS [see Dosage and Administration (2.6)].
- To avoid exposing the BUTRANS application site to external heat sources, hot water, or prolonged direct sunlight [see Warnings and Precautions (5.13)].
- Do not discontinue BUTRANS without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration (2.3)].
Inform patients that BUTRANS 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 BUTRANS. 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 BUTRANS 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 BUTRANS 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 BUTRANS [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)].
Inform patients that BUTRANS 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).
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].
Instruct patients to refer to the Instructions for Use for proper disposal of BUTRANS. Patients can dispose of used or unused BUTRANS 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)].Close
- MEDICATION GUIDE
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2016 Medication Guide
BUTRANS® (BYOO-trans) (buprenorphine) Transdermal System, CIII
- A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily, around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
- A long-acting (extended-release) opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
- Not for use to treat pain that is not around-the-clock.
Important information about BUTRANS:
- Get emergency help right away if you take too much BUTRANS (overdose). When you first start taking BUTRANS, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
- Taking BUTRANS with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
- Never give anyone else your BUTRANS. They could die from taking it. Store BUTRANS away from children and in a safe place to prevent stealing or abuse. Selling or giving away BUTRANS is against the law.
Do not use BUTRANS if you have:
- severe asthma, trouble breathing, or other lung problems.
- a bowel blockage or have narrowing of the stomach or intestines.
Before applying BUTRANS, tell your healthcare provider if you have a history of:
- head injury, seizures
- liver, kidney, thyroid problems
- problems urinating
- pancreas or gallbladder problems
- heart rhythm problems (Long QT syndrome)
- abuse of street or prescription drugs, alcohol addiction, or mental health problems.
- have a fever
- are pregnant or planning to become pregnant. Prolonged use of BUTRANS during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
- are breastfeeding. Not recommended during treatment with BUTRANS. It may harm your baby.
- are taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking BUTRANS with certain other medicines can cause serious side effects.
While using BUTRANS:
- Do not change your dose. Apply BUTRANS exactly as prescribed by your healthcare provider. Use the lowest effective dose for the shortest time needed.
- See the detailed Instructions for Use for information about how to apply the BUTRANS patch.
- Do not apply a BUTRANS patch if the pouch seal is broken, or the patch is cut, damaged, or changed in any way.
- Do not apply more than 1 patch at the same time unless your healthcare provider tells you to.
- You should wear 1 BUTRANS patch continuously for 7 days.
- Call your healthcare provider if the dose you are using does not control your pain.
- Do not stop using BUTRANS without talking to your healthcare provider.
- To properly dispose of used and unused patches, use the Patch-Disposal Unit or fold in half and flush down the toilet. See the detailed Instructions for Use.
When using BUTRANS DO NOT:
- Take hot baths or sunbathe, use hot tubs, saunas, heating pads, electric blankets, heated waterbeds, or tanning lamps. These can cause an overdose that can lead to death.
- Drive or operate heavy machinery, until you know how BUTRANS affects you. BUTRANS can make you sleepy, dizzy, or lightheaded.
- Drink alcohol or use prescription or over-the-counter medicines containing alcohol. Using products containing alcohol during treatment with BUTRANS may cause you to overdose and die.
The possible side effects of BUTRANS are:
- constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, itching, redness or rash where the patch is applied. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
- trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue or throat, extreme drowsiness, light-headedness when changing positions feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431, www.purduepharma.com or call 1-888-726-7535
- Do not use soap, alcohol, lotions, oils, or other products to remove any leftover adhesive from a patch because this may cause more BUTRANS to pass through the skin.
- Each patch is sealed in its own protective pouch. Do not remove a patch from the pouch until you are ready to use it.
- Do not use a patch if the seal on the protective pouch is broken or if the patch is cut, damaged or changed in any way.
- BUTRANS patches are available in different strengths and patch sizes. Make sure you have the right strength patch that has been prescribed for you.
- BUTRANS 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 BUTRANS application 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 prescribed, 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 BUTRANS each week, making sure that at least 3 weeks (21 days) pass before you re-use the same skin site.
- Apply BUTRANS to a hairless or nearly hairless skin site. If needed, you can clip the hair at the skin site (See Figure C). Do not shave the area. The skin site should not be irritated. Use only water to clean the application site. You should not use soaps, alcohol, oils, lotions, or abrasive devices. Allow the skin to dry before you apply the patch.
- The skin site should be free of cuts and irritation (rashes, swelling, redness, or other skin problems).
- When you apply a new patch, write down the date and time that the patch is applied. Use this to remember when the patch should be removed.
- Change the patch at the same time of day, one week (exactly 7 days) after you apply it.
- After removing and disposing of the patch, write down the time it was removed and how it was disposed.
- If you are wearing a patch, remember to remove it before applying a new one.
- Each patch is sealed in its own protective pouch.
- If you are using two patches, remember to apply them at the same site right next to each other. Always apply and remove the two patches together at the same time.
- Use scissors to cut open the pouch along the dotted line (See Figure D) and remove the patch. Do not remove the patch from the pouch until you are ready to use it. Do not use patches that have been cut or damaged in any way.
- Hold the patch with the protective liner facing you.
- Gently bend the patch (See Figures E and F) along the faint line and slowly peel the larger portion of the liner, which covers the sticky surface of the patch.
- Do not touch the sticky side of the patch with your fingers.
- Using the smaller portion of the protective liner as a handle (See Figure G), apply the sticky side of the patch to one of the 8 body locations described above (See “Where to apply BUTRANS”).
- While still holding the sticky side down, gently fold back the smaller portion of the patch. Grasp an edge of the remaining protective liner and slowly peel it off (See Figure H).
- Press the entire patch firmly into place with the palm (See Figure I) of your hand over the patch, for about 15 seconds. Do not rub the patch.
- Make sure that the patch firmly sticks to the skin.
- Go over the edges with your fingers to assure good contact around the patch.
- If you are using two patches, follow the steps in this section to apply them right next to each other.
- Always wash your hands after applying or handling a patch.
- After the patch is applied, write down the date and time that the patch is applied. Use this to remember when the patch should be removed.
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.
- Apply first aid tape only to the edges of the patch.
- If problems with the patch not sticking continue, cover the patch with special see-through adhesive dressings (for example Bioclusive or Tegaderm).
- Remove the backing from the transparent adhesive dressing and place it carefully and completely over the BUTRANS patch, smoothing it over the patch and your skin.
- Never cover a BUTRANS patch with any other bandage or tape. It should only be covered with a special see-through adhesive dressing. Talk to your healthcare provider or pharmacist about the kinds of dressing that should be used.
If your patch falls off later, but before 1 week (7 days) of use, throw it away properly (See “Disposing of a BUTRANS 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).
To dispose of BUTRANS 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.
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.
When disposing of unused BUTRANS 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.
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- PRINCIPAL DISPLAY PANEL
- INGREDIENTS AND APPEARANCE
buprenorphine patch, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-751 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength buprenorphine (UNII: 40D3SCR4GZ) (buprenorphine - UNII:40D3SCR4GZ) buprenorphine 10 ug in 1 h Inactive Ingredients Ingredient Name Strength ETHYL LEVULINATE (UNII: 7BU24CSS2G) OLEYL OLEATE (UNII: 3X3L452Y85) POVIDONE (UNII: FZ989GH94E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-751-04 4 in 1 CARTON 02/14/2011 1 1 in 1 POUCH 1 168 h in 1 PATCH; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021306 02/14/2011 BUTRANS
buprenorphine patch, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-758 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength buprenorphine (UNII: 40D3SCR4GZ) (buprenorphine - UNII:40D3SCR4GZ) buprenorphine 15 ug in 1 h Inactive Ingredients Ingredient Name Strength ETHYL LEVULINATE (UNII: 7BU24CSS2G) OLEYL OLEATE (UNII: 3X3L452Y85) POVIDONE (UNII: FZ989GH94E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-758-04 4 in 1 CARTON 02/14/2011 1 1 in 1 POUCH 1 168 h in 1 PATCH; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021306 02/14/2011 BUTRANS
buprenorphine patch, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-752 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength buprenorphine (UNII: 40D3SCR4GZ) (buprenorphine - UNII:40D3SCR4GZ) buprenorphine 20 ug in 1 h Inactive Ingredients Ingredient Name Strength ETHYL LEVULINATE (UNII: 7BU24CSS2G) OLEYL OLEATE (UNII: 3X3L452Y85) POVIDONE (UNII: FZ989GH94E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-752-04 4 in 1 CARTON 02/14/2011 1 1 in 1 POUCH 1 168 h in 1 PATCH; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021306 02/14/2011 BUTRANS
buprenorphine patch, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-750 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength buprenorphine (UNII: 40D3SCR4GZ) (buprenorphine - UNII:40D3SCR4GZ) buprenorphine 5 ug in 1 h Inactive Ingredients Ingredient Name Strength ETHYL LEVULINATE (UNII: 7BU24CSS2G) OLEYL OLEATE (UNII: 3X3L452Y85) POVIDONE (UNII: FZ989GH94E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-750-04 4 in 1 CARTON 02/14/2011 1 1 in 1 POUCH 1 168 h in 1 PATCH; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021306 02/14/2011 BUTRANS
buprenorphine patch, extended release
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:59011-757 Route of Administration TRANSDERMAL DEA Schedule CIII Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength buprenorphine (UNII: 40D3SCR4GZ) (buprenorphine - UNII:40D3SCR4GZ) buprenorphine 7.5 ug in 1 h Inactive Ingredients Ingredient Name Strength ETHYL LEVULINATE (UNII: 7BU24CSS2G) OLEYL OLEATE (UNII: 3X3L452Y85) POVIDONE (UNII: FZ989GH94E) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59011-757-04 4 in 1 CARTON 02/14/2011 1 1 in 1 POUCH 1 168 h in 1 PATCH; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021306 02/14/2011 Labeler - Purdue Pharma LP (932323652) Registrant - Purdue Pharma LP (932323652) Establishment Name Address ID/FEI Business Operations Lohman Therapie System 787660513 MANUFACTURE(59011-752, 59011-758, 59011-757, 59011-751, 59011-750)