Buprenorphine chemical structure
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Subutex

Buprenorphine, also colloquially referred to as bupe, is an opioid drug with partial agonist and antagonist actions. Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, yet is now primarily used for the treatment of opioid addiction. It is a Schedule III drug under the Convention on Psychotropic Substances. more...

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Commercial preparations

Britsh firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations, no active additives) and Buprenex (parenteral, no active additives). Two more recent formulations from Reckitt Benckiser have been approved for opioid addiction treatment in the U.S.: Subutex (lemon-lime flavored sublingual, no active additives; in 2mg and 8mg dosages) and Suboxone (orange-tang flavored sublingual, one part naloxone for every four parts buprenorphine; hexagon shaped tablet in 2mg and 8mg dosages). Suboxone contains the opioid antagonist naloxone to deter illicit intravenous preparation of the tablet, this is intended to attenuate the effects of buprenorphine on opioid-naive users should this formulation be injected - however no human studies have been done demonstrating the efficacy of this approach with buprenorphine. It must also be noted that buprenorphine in and of itself will induce a precipitated withdrawal syndrome if ingested by an acutely opioid dependant/intoxicated individual.

Buprenorphine is also delivered transdermally in 25, 50 and 75 mcg/hour. The trade name in the UK is Transtec, and manufactured by Napp. A new 5, 10 and 20 mcg/hour patch marketed as Bu'7rans (Bu-trans), where the 7 indicates its once weekly dosage for pain in osteoarthritis.

Pharmacology and pharmacokinetics

Buprenorphine is a thebaine derivative, and its analgesic effect is due to partial agonist activity at μ-opioid receptors. Buprenorphine is also a κ-opioid receptor antagonist. The partial agonist activity means that opioid receptor antagonists (e.g., an antidote such as naloxone) only partially reverse the effects of buprenorphine.

Buprenorphine hydrochloride is administered by intramuscular injection, intravenous infusion, via a transdermal patch, or as a sublingual tablet. It is not administered orally, due to very high first-pass metabolism. Buprenorphine is metabolised by the liver, via the CYP3A4 isozyme of the cytochrome p450 enzyme system, into norbuprenorphine (by N-dealkylation) and other metabolites. The metabolites are further conjugated with glucuronic acid and eliminated mainly through excretion into the bile. The elimination half-life of buprenorphine is 20.4–72.9 hours (mean 34.6).

Clinical use

Buprenorphine is indicated for the treatment of moderate to severe pain, peri-operative analgesia, and opioid dependence. It has a longer duration of action than morphine, and sublingual tablets offer an analgesic effect for 6 to 8 hours. (Joint Formulary Committee, 2004) Australian guidelines recommend against the use of buprenorphine as an analgesic because: its effect is not reversed by naloxone, it may precipitate withdrawal symptoms in people dependent on other opioids, and it may cause dependence itself and has potential for misuse. (Rossi, 2005) When used for opioid dependence, buprenorphine remains effective in the body for up to 48 hours, curbing withdrawal symptoms and counteracting other opioids that may be administered to the patient (licitly or illicitly).

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US FDA Marketing Approval For Reckitt Benckiser's Subutex(R) & Suboxone(R)
From Market Wire,

Reckitt Benckiser plc announced today that its new treatments for opiate dependence, Suboxone(R) (buprenorphine/naloxone) and Subutex(R) (buprenorphine) 2mg and 8mg tablets have been approved by the US Food and Drug Administration for the treatment of opiate dependence. These products were developed under a Cooperative Research and Development Agreement between Reckitt Benckiser and the National Institutes of Health's National Institute on Drug Abuse in the USA over the past ten years.

Subutex and Suboxone will become useful additions to the available range of pharmacotherapies that can help opiate-dependent patients overcome their addiction. The major benefit of Subutex/Suboxone is that qualified physicians in the US will now be able to treat patients with these products in the privacy of the Doctor's office rather than only from the limited number of existing drug treatment programs.

Subutex first received marketing approval in France and was launched in February 1996 by Schering-Plough under licence from Reckitt Benckiser. Since then the product has been launched in 24 countries. Licence income from these sales forms a modest but growing contribution to Reckitt Benckiser's core Health & Personal Care category.

For further information

For further information on Suboxone, www.suboxone.com

Call 1-877-SUBOXONE

For further information on Reckitt Benckiser plc www.reckittbenckiser.com

Announcement in Detail

FIRST NEW ADDICTION TREATMENT PRODUCTS IN 30 YEARS APPROVED FOR IN-OFFICE TREATMENT

Qualified Physicians Have New Weapon to treat addicted patients With Office-Based, Private Treatment Regimen

Reckitt Benckiser plc (RB.L) announced today that the U.S. Food and Drug Administration (FDA) has granted marketing approval for SUBOXONE(R) (buprenorphine hydrochloride/naloxone hydrochloride) and SUBUTEX(R) (buprenorphine hydrochloride), sublingual tablets for the treatment of opioid dependence.

SUBOXONE and SUBUTEX are the first therapies approved for in-office prescribing under the federal Drug Addiction Treatment Act of 2000 (DATA). The new medications and the new in-office model offer a discreet, effective and convenient new treatment option.

"The approval of SUBOXONE and SUBUTEX is a much anticipated step toward opening up access to treatment for patients with opioid dependence who currently have little or no treatment options," said Herbert D. Kleber, MD, professor of psychiatry and director, Division of Substance Abuse at the College of Physicians and Surgeons of Columbia University and the New York State Psychiatric Institute. "These treatments have potential for tremendous impact in combating opioid dependence, especially in formerly underserved communities."

There are up to one million opioid-addicted patients in the U.S., including those who are addicted to heroin and prescription pain medications. The estimated annual cost to society of opioid addiction is more than $20 billion.

The problem affects people in a variety of communities. Only about 15 percent of these heroin-dependent individuals are in treatment, partly because of limited access to treatment centers, which, until now, were among the only places to offer treatment. In addition to lack of access and privacy, current options for treating opioid dependence often have a high rate of relapse and can be fraught with other problems.

"People addicted to opioids like heroin and prescription pain medications are faced with a number of obstacles to getting effective treatment," said Dr. Kleber. "We need to change the way we think about addiction. Science has shown that opioid addiction is a chronic, relapsing brain disease, not a character flaw, failure of will or lack of self-control. So we need to stop talking about 'addicts' and start referring to them as 'patients' - people who have a disease that medication can relieve."

SUBOXONE and SUBUTEX

SUBOXONE is a combination of two proven medications, buprenorphine and naloxone. Buprenorphine, a partial opioid agonist, reduces withdrawal symptoms and blocks the effects of subsequently administered opioids, which suggests that it may help reduce illicit opioid use. Because it contains naloxone, SUBOXONE is highly likely to produce intense withdrawal symptoms if misused intravenously by opioid-addicted individuals, however, when used as prescribed naloxone has no effect.

SUBOXONE has demonstrated a low treatment dropout rate in clinical trials. Since SUBOXONE is a partial agonist, withdrawal upon discontinuation is milder than with full agonists. SUBOXONE also exhibits a "ceiling effect" on respiratory depression, which provides a margin of safety in comparison to other opioids. This "ceiling effect" decreases the danger of overdose. Unlike SUBOXONE, SUBUTEX contains no naloxone; patients may be prescribed SUBUTEX during a short induction period, which will be closely supervised by their physician, before being switched to SUBOXONE.

Physician Certification

DATA enables physicians who meet certain qualifying criteria to prescribe Schedules III, IV, or V narcotic drugs in the privacy of their offices. Under the DATA, qualified physicians can manage a total of 30 patients at one time. Further announcements regarding availability will be provided later.

SUBOXONE Clinical Studies

In a comparative study, adverse event profiles were similar for subjects treated with 16 mg SUBOXONE or 16 mg SUBUTEX. The following adverse events were reported to occur by at least 5% of patients in a 4-week study.

The most common adverse events associated with SUBOXONE and placebo were respectively: headache (36 percent vs. 22 percent); withdrawal syndrome (25 percent vs. 37 percent); pain (23 percent vs. 19 percent); nausea (15 percent vs. 11 percent); and sweating (14 percent vs. 10 percent).

As with other opioid agonists, there is a risk of respiratory depression. Patients should be warned of the potential danger of not using SUBOXONE or SUBUTEX according to product information labeling and physician instructions.

SUBOXONE and SUBUTEX were developed by Reckitt Benckiser plc, U.K., and Richmond, VA.

For Financial / Investor and General Corporate Queries
Tom Corran        Reckitt Benckiser plc     +44 1753 217 800
For Medical, Physician and US queries
Kevin Sangsland   Hill & Knowlton           + 1 212 885 0507

For more information about SUBOXONE and SUBUTEX, please see full product information and visit www.suboxone.com or call 1-877-SUBOXONE

For more information on Reckitt Benckiser please visit www.reckittbenckiser.com.

Editor's Note:

Under the Drug Addiction Treatment Act (DATA) of 2000, a physician is qualified to prescribe Schedules III, IV, or V narcotic drugs that are FDA-approved for the treatment of opioid dependence by meeting one or more of the following criteria:

     - Has been an investigator in one or more clinical trials 
       leading to the approval of a Schedule III, IV, or V narcotic 
       drug indicated for the treatment of opioid dependence
     - Has been subspecialty board-certified in addiction psychiatry 
       by the American Board of Medical Specialties
       
     - Has been subspecialty board-certified in addiction medicine by 
       the American Osteopathic Association
     - Holds addiction certification from the American Society of 
       Addiction Medicine
     - Has completed no fewer than 8 hours of approved medical 
       society training in the treatment and management of opioid 
       dependence
     - Has other such training/experience as the State Medical-
       licensing Board or Secretary of Health and Human Services 
       deems appropriate

Reckitt Benckiser plc

Reckitt Benckiser Healthcare's involvement in prescription drugs is a legacy of Reckitt & Colman's involvement in basic new chemical entity research in the 1960's and 1970's. Reckitt Benckiser Healthcare now focuses mainly on Over-the-Counter medicines such as Gaviscon, Lemsip, Disprin, Senokot and Fybogel.

Reckitt Benckiser plc is the world's largest household cleaning product company (excluding laundry detergent) with net revenues in 2001 of 3.4bn pounds stirling ($5.25bn) and net income of 340m pounds stirling ($525m). The Company has many world leading positions including in disinfecting cleaning (Lysol, Dettol), Automatic Dishwashing (Finish, Electrasol, Jet Dry), Fabric Treatment (Vanish, Spray 'n Wash), Fine Fabric (Woolite) and Depilatories (Veet) and is a major player in Air Care (Air Wick, Wizard). Reckitt Benckiser operates in some 60 countries, has sales in some 180 countries and is headquartered in the UK. Reckitt Benckiser plc is listed on the London Stock Exchange.

For more information on Suboxone/Subutex Prescription Information please go to: media.internetwire.com/attachments/200210/146940_APLabel100802.doc

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