STAMFORD, Conn., Oct. 26, 2011 /PRNewswire/ -- A pivotal Phase 3 study of Butrans® (buprenorphine) Transdermal System CIII in opioid-naive patients with moderate-to-severe chronic low back pain demonstrated significantly lower "average pain over the last 24 hours" scores compared to placebo at the end of a 12-week, randomized, double-blind phase, in a study published in the online version of the September issue of the Journal of Pain and Symptom Management.
"These data are important in understanding the role of Butrans for opioid-naive patients with moderate-to-severe chronic pain requiring a continuous, around-the-clock opioid analgesic for an extended period of time," said Deborah Steiner, MD, MS, medical director at Purdue Pharma L.P.
The Butrans Transdermal System, approved by the U.S. Food and Drug Administration (FDA) in June 2010, is indicated for the management of moderate-to-severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time. Butrans is the first transdermal system approved in the United States that delivers continuous release of the active ingredient, buprenorphine, for seven days.
Butrans is a Schedule III opioid prescription medication and can be abused in a manner similar to other opioid agonists, legal or illicit. Working with the FDA, Purdue Pharma L.P. has developed a Risk Evaluation and Mitigation Strategy (REMS) for Butrans that includes a Medication Guide, Elements to Assure Safe Use, such as a healthcare provider training guide, and a timetable for submitting assessments of the REMS. This information is available at www.Butransrems.com.
Butrans is contraindicated in patients who have significant respiratory depression, severe bronchial asthma, who have or are suspected of having paralytic ileus or known hypersensitivity to any of its components or the active ingredient, buprenorphine, as well as those who require opioid analgesia for a short period of time, for the management of post-operative pain, including use after out-patient or day surgeries, the management of mild pain, and the management of intermittent pain (e.g., use on an as needed basis).
The Full Prescribing Information for Butrans contains the following Boxed Warning:
WARNING: IMPORTANCE OF PROPER PATIENT SELECTION, POTENTIAL FOR ABUSE, AND LIMITATIONS OF USE
Proper Patient Selection
Butrans is a transdermal formulation of buprenorphine indicated for the management of moderate-to-severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time.
Potential for Abuse
Butrans contains buprenorphine which is a mu opioid partial agonist and a Schedule III controlled substance. Butrans can be abused in a manner similar to other opioid agonists, legal or illicit. Consider the abuse potential when prescribing or dispensing Butrans in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Assess patients for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Routinely monitor all patients receiving opioids for signs of misuse, abuse and addiction.
Limitations of Use
Do not exceed a dose of one 20 mcg/hour Butrans system due to the risk of QTc interval prolongation.
Avoid exposing the Butrans application site and surrounding area to direct external heat sources. Temperature-dependent increases in buprenorphine release from the system may result in overdose and death.
Summary of Clinical Study
This multi-center, randomized, double-blind, placebo-controlled, parallel-group study employed an enriched design which included a run-in phase of up to 27 days in which 1,024 opioid-naive patients with moderate-to-severe chronic low back pain who were suboptimally responsive to their non-opioid therapy received open-label treatment with Butrans.
Opioid-naive patients were defined as patients who were receiving less than 5 mg of oxycodone or the equivalent in the 14 days prior to screening, and who did not have a history of daily opioid use of greater than or equal to 5 mg of oxycodone or the equivalent for three months prior to screening, and who, in the opinion of the investigator, were not opioid dependent at time of entry to the study, had not benefitted from or had not tolerated non-opioid therapy, and were deemed to be appropriate candidates for an around-the-clock opioid analgesic regimen.
Of the 1,024 patients who entered the open-label, dose-titration period, 53% were able to titrate to a tolerable and effective dose of Butrans and were randomized into a 12-week, double-blind treatment period. Twenty-three percent (23%) of patients discontinued due to an adverse event from the open-label titration period and 14% discontinued due to lack of a therapeutic effect. Of the patients who were randomized, the mean (SE) Numerical Rating Scale pain 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.
A total of 541 patients were randomized to receive Butrans (10 or 20 mcg/hour, N=257) or placebo (N=284) in a double-blinded fashion, based on tolerability and analgesic response at the end of the open-label titration period. 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. Of the 257 patients randomized to Butrans, 9% discontinued due to lack of efficacy and 16% due to adverse events. Of the 284 patients randomized to placebo, 13% discontinued due to lack of efficacy and 7% due to adverse events.
Results were based on two study arms, Butrans (10 and 20 mcg/hour) and placebo, respectively. The primary efficacy variable "average pain over the last 24 hours" score at Week 12 was statistically significantly lower for patients randomized to Butrans than for those randomized to placebo. Sensitivity analyses of the primary efficacy variable and results of analyses of secondary efficacy variables supported the efficacy of Butrans relative to placebo.
In the Butrans group, gastrointestinal disorders, general disorders and administration site conditions, and nervous system disorders were the organ system classifications with the most commonly reported adverse events during the double-blind phase. Adverse events reported in greater than or equal to 5% of patients during the open-label titration period and double-blind phase were nausea, dizziness, headache, application site pruritus, somnolence, vomiting, and constipation.
Warnings and Precautions
- Respiratory Depression: Respiratory depression is the chief hazard with Butrans. Use with extreme caution in patients at risk of respiratory depression.
- CNS Depression: Butrans may cause somnolence, dizziness, alterations in judgment and alterations in levels of consciousness, including coma. Use with caution in patients who are receiving other central nervous system (CNS) depressants. Additive CNS effects are expected when used with alcohol, benzodiazepines, other opioids, or illicit drugs.
- QTc Prolongation: Avoid in patients with Long QT Syndrome, family history of Long QT Syndrome, or those taking Class IA or Class III antiarrhythmic medications.
- Head Injury: Butrans may worsen increased intracranial pressure and obscure its signs, such as level of consciousness or pupillary signs.
- Hypotensive Effects: Butrans may cause severe hypotension. Use with caution in patients at increased risk of hypotension and in patients in circulatory shock.
- Application Site Skin Reactions: In rare cases, severe application site skin reactions with signs of marked inflammation including "burn," "discharge," and "vesicles" have occurred.
- Anaphylactic/Allergic Reactions: Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience.
- Use in Pancreatic/Biliary Tract Disease and Other Gastrointestinal Conditions: Use with caution in patients with biliary tract disease, including acute pancreatitis. Ileus may occur. Monitor for decreased bowel motility.
Adverse Event Information
The most common adverse events (less than or equal to 5%) reported by patients treated with Butrans in clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash. The most frequently occurring application site skin reactions were application site pruritus, erythema, rash and irritation. In rare cases, severe application site skin reactions with signs of marked inflammation including "burn," "discharge," and "vesicles" have occurred.
Butrans Transdermal System Dosages
Three strengths of Butrans are commercially available by prescription in retail pharmacies nationwide: 5 mcg/hour (NDC code 59011-750-04); 10 mcg/hour (NDC code 59011-751-04); and 20 mcg/hour (NDC code 59011-752-04). The maximum dose of Butrans is 20 mcg/hour.
The Full Prescribing Information for Butrans, including the Medication Guide and Boxed Warning is available at www.purduepharma.com/PI/prescription/ButransPI.pdf and at www.Butrans.com.
About Purdue Pharma L.P.
Purdue Pharma L.P. and its associated U.S. companies are privately-held pharmaceutical companies known for pioneering research on persistent pain. Headquartered in Stamford, CT, Purdue Pharma is engaged in the research, development, production, and distribution of both prescription and over-the-counter medicines and hospital products. Additional information about Purdue can be found at www.purduepharma.com.
SOURCE Purdue Pharma L.P.