Results of a Pivotal Phase 3 Efficacy and Safety Study for Butrans® (Buprenorphine) Transdermal System CIII Published in The Journal of Pain
STAMFORD, Conn., Sept. 23, 2011 /PRNewswire/ -- Butrans® (Buprenorphine) Transdermal System CIII 20 mcg/hour provided significantly lower "average pain over the last 24 hours" scores compared to Butrans 5 mcg/hour when used in opioid-experienced patients with moderate-to-severe chronic low back pain, according to a pivotal Phase 3 clinical study published in the online, August issue of The Journal of Pain.
"The publication of this data provides important information to healthcare professionals about the role of Butrans 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," 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 an 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 healthcare providers training, 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
Patients evaluated in this randomized, double-blind, double-dummy active controlled, superiority study had moderate-to-severe low back pain for at least three months and were receiving treatment with opioid analgesics at doses between 30 to 80 mg of morphine sulfate or the equivalent at least four days per week for at least 30 days prior to the screening visit. Sixty-two percent (62%) of patients were taking hydrocodone-containing medications; 21% were taking oxycodone-containing medications; and 12% of patients were taking propoxyphene-containing medications. Prospective patients were excluded if they were currently using the fentanyl transdermal-system, extended-release hydromorphone, or more than 80 mg per day of oral morphine equivalent for pain control upon entry into the study.
The study employed an enriched design – allowing only patients who both tolerated and responded to Butrans during an open label run-in period to enter into the 12-week double-blind phase of the trial, mimicking the treatment of patients in a clinical practice setting.
The efficacy and safety of Butrans 20 mcg/hour was assessed using Butrans 5 mcg/hour as the low-dose control group. All patients wore either active or placebo patches (double-dummy technique). The study was performed at 75 centers in the United States.
Of the 1160 patients that entered the open-label run-in period, 57% 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 (12%) of patients discontinued due to an adverse event and 21% discontinued due to lack of a therapeutic effect during the open-label titration period. A total of 660 patients were randomized to the double-blind phase to receive Butrans 20 mcg/hour, Butrans 5 mcg/hour, or an active control, for 12 weeks. During the double-blind treatment, in the Butrans 20 mcg/hour group, 11% discontinued early due to a lack of therapeutic effect and 13% due to an adverse event; in the Butrans 5 mcg/hour group, 24% discontinued early due to a lack of therapeutic effect and 6% due to an adverse event.
Analysis of the primary efficacy endpoint – "average pain over the last 24 hours" scores – showed that patients treated with Butrans 20 mcg/hour experienced significantly lower pain scores compared to those treated with Butrans 5 mcg/hour. The results of four sensitivity analyses, performed to assess the robustness of the primary efficacy analysis with respect to differing imputation algorithms, were all statistically significant for Butrans 20 mcg/hour compared to Butrans 5 mcg/hour and consistent with the results of the primary efficacy analysis. There were statistically significant differences in pain scores observed between the active comparator and Butrans 5 mcg/hour treatment groups for all sensitivity analyses.
Treatment-related adverse events were primarily classified as gastrointestinal, general disorders and administration site conditions, and nervous system disorders. The adverse events most frequently observed during the double-blind phase (greater than or equal to 10%) for patients treated with Butrans 5 mcg/hour and Butrans 20 mcg/hour, were nausea [8%, and 12%]; application site pruritus (itching) [5% and 13% application site]; application site erythema (redness of the skin) [5%, and 10%]; and headache [5% and 11%].
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 (greater 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.