Subutex/Suboxone Prescriber Registration Efforts Ramping Up After Approval

The Substance Abuse & Mental Health Services Administration is working to register physicians to prescribe Schering-Plough/Reckitt Benckiser's opioid addiction treatment therapies Subutex and Suboxone in advance of the products' launch.

FDA approved Subutex (buprenorphine) and Suboxone (buprenorphine/naloxone) sublingual tablets Oct. 8 for "treatment of opioid dependence." FDA said it expects the product to be in pharmacies by the end of the year.

Subutex and Suboxone are the first opioid dependence therapies approved under the Drug Addiction Treatment Act (DATA) of 2000, which allows physicians to prescribe Schedule III, IV and V anti-addiction drugs for dispensing at a retail pharmacy (¹ (Also see "Reckitt Suboxone To Be First Anti-Addiction Narcotic Filled In Pharmacy" - Pink Sheet, 30 Oct, 2000.), p. 28).

The buprenorphine products are Schedule III. The other therapies for opioid addiction, methadone and LAAM (levo-alpha-acetyl-methadol), are Schedule II and can be dispensed only by approved opioid substitution therapy facilities.

Physicians must apply to SAMHSA for a waiver to prescribe narcotic products for addiction therapy. Qualifying physicians must have authorized training in treatment of opioid-dependent patients, have the capacity to provide or refer patients for necessary ancillary services and agree to treat no more than 30 patients at a time.

SAMHSA Center for Substance Abuse Treatment Director Westley Clark, MD, told an Oct. 9 Capitol Hill press briefing on the Subutex/Suboxone approval that "it is important for us to make sure that there are enough practitioners" enrolled to prescribe the products, but added that it has been difficult to get physicians to apply for the waiver because of the absence of products.

About 700 physicians have applied for the waiver since DATA was implemented, he said. The National Institutes of Health said 2,000 physicians have received the training necessary to qualify for the waiver.

SAMHSA will set up a nationwide registry of physicians with the waiver to help healthcare workers and patients find qualified treatment professionals.

SAMHSA also will roll out an information campaign in major cities in December. "The objective is to make sure that physicians in practice understand that the drug is here and that barriers to their getting trained to prescribe the drug are minimal," Clark said.

SAMHSA has set up a website and a toll-free telephone number with information on applying for the waiver. Subutex/Suboxone labeling includes special information sections for patients, physicians and pharmacists and an ² FDA buprenorphine web page provides additional information on the drug.

To prevent abuse, Subutex will be administered under a physician's supervision during an induction period before a prescription for Suboxone is given to the patient as maintenance therapy.

Pharmacies will stock Subutex for physicians who do not want to maintain a supply in the office.

Physicians should arrange for a pharmacy to deliver Subutex as needed. If that is not possible, physicians will be provided with coupons for patients to bring to the pharmacy with the prescription; patients will be instructed to return to the office with the drug.

Suboxone can be taken without supervision because its potential for abuse is considered low. The naloxone component produces unpleasant withdrawal symptoms if taken intravenously, thus discouraging abuse. When taken sublingually, the naloxone has "no clinically significant effect," labeling notes.

The complexity of adding naloxone to buprenorphine was the main reason for the lengthy approval time, FDA Anesthetic, Critical Care & Addiction Drug Products Director Cynthia McCormick, MD, told an Oct. 9 teleconference. The Subutex NDA (20-732) was submitted in March 1997 and the Suboxone NDA (20-733) was submitted in June 1999.

FDA felt it was important to add naloxone because there has been evidence of abuse of Subutex in France, where the drug has been available since 1996, McCormick explained.

However, "the development of that formulation was a significant challenge. It was very complex and it was not an easy thing chemically....There were some false starts," because "the addition of naloxone was not as easy as it was thought."

Naloxone was previously added to another opioid product, Sanofi's Talwin Nx (pentazocine/naloxone), to prevent abuse. Purdue was also considering adding naloxone to OxyContin (controlled-release oxycodone) to prevent abuse, but found the combination would not work (³ (Also see "Purdue OxyContin Abuse-Resistant Pill Will Need 4-5 Years To Complete Trials" - Pink Sheet, 24 Jun, 2002.), p. 27).

Supervised dosing and physician registration are part of a risk management program designed to prevent abuse and diversion, which also includes Schedule III control, child-resistant packaging and education.

All buprenorphine products were moved from Schedule V to III in advance of the Subutex/Suboxone approval (⁴ 'The Pink Sheet' March 25, In Brief).

Reckitt Benckiser also manufactures the injectable buprenorphine product Buprenex , which is indicated for pain management but should not be used for treating opioid addiction.

Active surveillance "will hopefully detect any pockets of abuse and diversion," McCormick said.

Active surveillance will include conducting interviews with drug abusers when they enter treatment "to determine if buprenorphine is being seen on the street....There will be street surveillance by what are called street ethnographers; there will be media surveillance of newspapers, websites and chat rooms."

Distribution channels "will be monitored for appropriate increases in demand, looking at such things as the proportion of Subutex vs. Suboxone that is provided and to look for any sudden increases in prescribing that may be a red flag that physicians may be exceeding their quota of 30 patients and so on," McCormick added.

Passive surveillance will determine if Subutex or Suboxone are implicated in abuse or fatalities by examining data collection sources at SAMHSA's Drug Abuse Warning Network, the Community Epidemiology Working Group and the National Institute of Drug Abuse.

An "expert advisory group" will evaluate surveillance reports, McCormick said, and FDA will receive quarterly reports. FDA has requested information on primary addiction to buprenorphine (abuse of the drug by people who have not previously abused opioids), overdose and neonatal withdrawal.

The reports "will enable FDA to identify untoward effects from the availability of buprenorphine and, if indicated, to take appropriate actions to protect the public health," an FDA "Talk Paper" says.

Suboxone tablets have been studied in 575 patients, Subutex tablets in 1,834 patients, labeling says.

A four-week study randomized 326 heroin-addicted subjects to Suboxone 16 mg daily, Subutex 16 mg daily or placebo. Patients on active treatment received 8 mg on day one and 16 mg on day two. On day three, those randomized to Suboxone were switched to the combination tablet.

"The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both Subutex and Suboxone than for placebo," labeling states.

Labeling recommends a target dose of 16 mg/day, although "doses as low as 12 mg may be effective in some patients." Subutex/Suboxone will be available in 2 mg and 8 mg tablets.

Labeling warns of the possibility of respiratory depression associated with buprenorphine, especially if taken intravenously. Deaths have been reported when buprenorphine is taken intravenously with benzodiazepenes or with other depressants.

FDA's "Talk Paper" says, however, that "clinical data indicate that the risk of serious diminished breathing may be less with buprenorphine than other opioids when used in high doses or in overdose situations." Labeling also notes that buprenorphine's opioid agonist effects "are limited by a ceiling effect."

Reckitt Benckiser had originally developed a buprenorphine sublingual solution, but switched to the tablets because the solution was found to be unstable. The buprenorphine sublingual solution was studied in 2,470 patients, labeling states.

Buprenorphine, like LAAM, was developed under a Cooperative Research & Development Agreement with NIDA. Reckitt Benckiser will manufacturer the products, but Schering-Plough has marketing rights.