ParagonRx® | Minimize Risk and Optimize Use

Introduction

The poppy is a stunning flowering plant, with a species of flower (opium poppy) that yields a natural agonist for the μ-opioid receptor.1 This receptor is a G-protein coupled receptor found extensively in the brain and spinal cord, whereby activation causes potent analgesia, with such ancillary effects as sedation, respiratory depression, itching, constipation, nausea and dependence, among others.1-2

Opiates are drugs derived from the opium flower, such as morphine and opium, that serve as agonists at the receptor site.1 The term "opioid" is a more general term that also encompasses synthetic and semi-synthetic opiates, such as fentanyl and butorphanol.1-2 Opioids are used in the treatment of moderate and severe pain, depending on the agent.3 They exist in short, intermediate and long-acting formulations and are primarily administered orally, by injection, transdermally, rectally and via mucosa.2-3

Opioids are some of the most widely used and abused (prescription) drugs in the United States.4 In 2010, approximately 210 million prescriptions were dispensed for opioids in the United States.4 In 2007, the number of overdose deaths involving opioids outnumbered those involving heroin and cocaine combined.4 In 2010, 35 million Americans ages 12 years and older reported nonmedical use of opioids, up from 29 million in 2002.5 Consequently, opioids are tightly regulated as controlled substances in the United States.

FDA and REMS

The Food and Drug Administration is charged, in part, with ensuring safe and effective drug use. Since its inception, the FDA has had a number of tools available to balance and communicate risks of prescription drugs, including directing the package insert, requiring black-box warning and relying on "Dear Doctor" letters. In 2007, the FDA was granted an important additional authority under the Food and Drug Administration Amendments Act, or FDAAA, to impose a risk evaluation and mitigation strategy, or REMS, for select drugs, where additional regulation is deemed critical to ensuring the benefits of a particular drug outweigh the risks.6

There are five major components to REMS: medication guides, communication plans, elements to assure safe use, implementation systems, and assessment.6 Approximately 200 drugs currently involve a REMS. Failure to properly exercise or comply with REMS renders the drug product misbranded. Importantly, the FDAAA authorizes the FDA to require REMS for new drug applications, as well as previously approved drugs.6 Opioids are extremely well-suited for REMS as the products are highly effective yet pose significant risk. Accordingly, the FDA has recently implemented the following REMS for opioids.

Long-acting/extended-release (LA/ER) opioid REMS program

Most pharmacists, and laymen for that matter, appreciate the risks associated with long-acting opioids. The drugs contain larger amounts of opioids than immediate-release formulations, release active medication over a long period of time and are subject to destruction of the delayed-release mechanism, providing a rapid and potent high. Not surprisingly then, in February 2009, the FDA notified a number of manufacturers of long-acting opioids that their products are required to have a REMS.7 After sending these letters, the FDA convened a number of public and private meetings, soliciting input from relevant stakeholders and an advisory committee, regarding the extent and implementation pathway of the program. The products targeted include all long-acting and extended-release branded and generic versions of buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone and tapentadol. Tables 1 and 2 include LA/ER opioids requiring REMS.8

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