Buprenorphine Transdermal System

BUTRANS 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.

Limitations Of Use

• Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risk of overdose and death with extended-release opioid formulations [see WARNINGS AND PRECAUTIONS], reserve BUTRANS for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• BUTRANS is not indicated as an as-needed (prn) analgesic

The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
• Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
• Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
• Interactions with Benzodiazepines or Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
• Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
• QTc Prolongation [see WARNINGS AND PRECAUTIONS]
• Severe Hypotension [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Application Site Skin Reactions [see WARNINGS AND PRECAUTIONS]
• Anaphylactic/Allergic Reactions [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Effects [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]

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 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 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

MedDRA Preferred Term	Open-Label Titration Period BUTRANS (N = 1024)	Double-Blind BUTRANS (N = 256)	Treatment Period Placebo (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

MedDRA Preferred Term	Open-Label Titration Period BUTRANS (N = 1160)	Double-Blind BUTRANS 20 (N = 219)	Treatment Period BUTRANS 5 (N = 221)
Nausea	14%	11%	6%
Application site pruritus	9%	13%	5%
Headache	9%	8%	3%
Somnolence	6%	4%	2%
Dizziness	5%	4%	2%
Constipation	4%	6%	3%
Application site erythema	3%	10%	5%
Application site rash	3%	8%	6%
Application site irritation	2%	6%	2%

The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials.

Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/Active- Controlled Clinical Trials with Incidence ≥ 2%

MedDRA Preferred Term	BUTRANS (N = 392)	Placebo (N = 261)
Nausea	21%	6%
Application site pruritus	15%	12%
Dizziness	15%	7%
Headache	14%	9%
Somnolence	13%	4%
Constipation	13%	5%
Vomiting	9%	1%
Application site erythema	7%	2%
Application site rash	6%	6%
Dry mouth	6%	2%
Fatigue	5%	1%
Hyperhidrosis	4%	1%
Peripheral edema	3%	1%
Pruritus	3%	0%
Stomach discomfort	2%	0%

The adverse reactions seen in controlled and open-label studies are presented below in the following manner: most common (≥ 5%), common (≥ 1% to < 5%), and less common (< 1%).

The most common adverse reactions (≥ 5%) reported by patients treated with BUTRANS 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 BUTRANS 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 BUTRANS 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin Syndrome

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis

Anaphylaxis has been reported with ingredients contained in BUTRANS.

Androgen Deficiency

Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].

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.

Pharmacodynamics

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].

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]. 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].

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.

Concentration–Efficacy Relationships

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].

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].

Pharmacokinetics

Absorption

Each BUTRANS system provides delivery of buprenorphine for 7 days. Steady state was achieved during the first application by Day 3 (see Figure 2).

Figure 2: Mean (SD) Buprenorphine Plas ma Concentrations Following Three Consecutive Applications of BUTRANS 10 mcg/hour (N = 36 Healthy Subjects )

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.

Table 7: Pharmacokinetic Parameters of BUTRANS in Healthy Subjects, Mean (%CV)

Single 7-day Application	AUCinf (pg•h/mL)	Cmax (pg/mL)
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 (pg•h/mL)	Cmax,ss (pg/mL)
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.

The absolute bioavailability of BUTRANS relative to IV administration, following a 7-day application, is approximately 15% for all doses (BUTRANS 5, 10, and 20 mcg/hour).

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].

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].

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].

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]. 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.

Distribution

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 15-25% of concurrent plasma concentrations.

Elimination

Metabolism

Buprenorphine metabolism in the skin following BUTRANS 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 BUTRANS 20 mcg/hour.

Excretion

Following IV administration, buprenorphine and its metabolites are secreted into bile and excreted in urine.

Following IV 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 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.

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, 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].

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].

Effect Of CYP3A4 Inducers

The interaction between buprenorphine and CYP3A4 inducers has not been studied.

Specific Populations

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].

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].

Sex

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.

Hepatic Impairment

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.

BUTRANS has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment. [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

Renal Impairment

No studies in patients with renal impairment have been performed with BUTRANS.

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 BUTRANS therapy.

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 nonopioid 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 openlabel 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.

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 30-80 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 prerandomization (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.

Figure 4: Percent Reduction in Pain Intensity

BUTRANS®
(BYOO-trans)
(buprenorphine) Transdermal System

BUTRANS is :

• 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.

Tell your healthcare provider if you:

• 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-Dispos al 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.

These are not all the possible side effects of BUTRANS. 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

Instructions for Use

BUTRANS®
(BYOO-trans ) CIII (buprenorphine)

Transdermal System

Be sure that you read, understand, and follow these Instructions for Use before you use BUTRANS. Talk to your healthcare provider or pharmacist if you have any questions.

Before Applying BUTRANS:

• 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.

Where to apply BUTRANS:

• 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.

Figure A

• 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.

Figure B

• 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. Us e 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.

Figure C

• The skin site should be free of cuts and irritation (rashes, swelling, redness, or other skin problems).

When to apply a new patch:

• 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.

How to apply BUTRANS:

• 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.

Figure D

• 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.

Figure E

Figure F

• 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”).

Figure G

• 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).

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.

Figure I

• 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 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 BUTRANS 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 s hould not be re-applied. They must be thrown away correctly.

Short-term exposure of the BUTRANS patch to water, such as when bathing or showering, is permitted.

If the edges of the BUTRANS patch start to loosen:

• 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).

Disposing of BUTRANS Patch:

BUTRANS patches should be disposed of by using the Patch-Dispos al Unit. Alternatively, the patches can be flus hed down the toilet.

To dispose of BUTRANS patches in household trash using the Patch-Dispos al Unit:

Remove your patch and follow the directions printed on the Patch-Disposal Unit (See Figure J) or see complete instructions below. Us e one Patch-Dis pos al Unit for each patch.

Figure J

1. Peel back the disposal unit liner to show the sticky surface (See Figure K).

Figure K

2. Place the sticky side of the used or unused patch to the indicated area on the disposal unit (See Figure L).

Figure L

3. Close the disposal unit by folding the sticky sides together (See Figure M). Press firmly and smoothly over the entire disposal unit so that the patch is sealed within.

Figure M

4. The closed disposal unit, with the patch sealed inside may be thrown away in the trash (See Figure N).

Figure N

Do not put unused patches in household trash without first sealing them in the Patch-Dispos al 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 BUTRANS patches down the toilet:

Remove your BUTRANS patch, fold the sticky sides of a used patch together and flush it down the toilet right away (See Figure O).

Figure O

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.

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 BUTRANS patches in the trash without first sealing them in the Patch-Dispos al Unit.

This “Instructions for Use” has been approved by the U.S. Food and Drug Administration.

You should not use buprenorphine if you are allergic to it, or if you have:

• asthma or severe breathing disorder; or
• a bowel obstruction called paralytic ileus.

Do not use buprenorphine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. Serious, life threatening side effects can occur if you use buprenorphine before the MAO inhibitor has cleared from your body.

To make sure you can safely use buprenorphine, tell your doctor if you have any of these other conditions:

• COPD (chronic obstructive pulmonary disease), sleep apnea, or other breathing disorders;
• a personal or family history of Long QT syndrome:
• hepatitis B or C;
• liver or kidney disease;
• a thyroid disorder;
• gallbladder disease;
• curvature of the spine;
• a history of head injury or brain tumor;
• epilepsy or other seizure disorder;
• Addison's disease or other adrenal gland disorders;
• enlarged prostate, urination problems;
• depression or other mental illness; or
• a history of drug or alcohol addiction.

Buprenorphine may be habit-forming and should be used only by the person it was prescribed for. Never share buprenorphine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

FDA pregnancy category C. It is not known whether buprenorphine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Buprenorphine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using buprenorphine.

Your dose needs may be different if you have recently used an opioid pain medicine and your body is tolerant to it. Opioids include Tylenol #3, Lortab, Vicodin, Exalgo, OxyContin, Percocet, Actiq, Duragesic, Methadose, Dolophine, Kadian, MS Contin, Oramorph, Opana, and many others. Talk with your doctor if you are not sure you are opioid-tolerant.

Your pharmacist can provide more information about buprenorphine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 2.02. Revision date: 3/15/2012.

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