Keeping Up With Clinical Trends — A Closer Look at Fentanyl

Brigette Nelson, PharmD
Senior Vice President, Clinical Management

As part of its August 2018 Provisional Drug Overdose Death Counts update, the Centers for Disease Control and Prevention (CDC) released preliminary data on the drug overdose epidemic. This monthly report, launched in June 2018, contains both actual and estimated data due to delays in reporting and underreporting. Unfortunately, drug overdose death numbers continue to rise, with estimates nearing 72,000 for the 12 months ending on January 31, 2018. The report notes that many deaths also involve multiple drugs, prescription and/or illicit, in combination.1

Although deaths from illegal drugs continue to rise, deaths from prescription opioids, including methadone, oxycodone, hydrocodone and other natural and semi-synthetic forms, appear to have remained relatively steady. Over the last two years, the largest rise in overdose deaths was from synthetic opioids, like fentanyl and tramadol, with approximately 29,000 deaths in 2017. Deaths from cocaine and psychostimulants with abuse potential (like methamphetamine) are also on the rise ̶ accounting for approximately 15,000 and 11,000 deaths, respectively. The heroin death rate appears to have decreased by about 1,000 since this time last year, but it still represents about 15,000 deaths, annually.1 Because of these alarming trends, we are taking a look at opioid use in the latest Q&A with our workers’ comp pharmacy experts, that examine drivers of the continued increases in deaths.

 

Why am I hearing so much about fentanyl in the news?

Fentanyl continues as an emerging threat in the drug overdose epidemic. In understanding why fentanyl is one of the most potent and most highly misused opioids, it’s helpful to look first at its prescription use and to recognize its many different available dosage forms.

We’ll start with the use of transmucosal immediate release fentanyl (TIRF) products like Actiq® (fentanyl citrate oral transmucosal lozenge), Fentora® (fentanyl buccal tablet) and Subsys® (fentanyl sublingual spray), among others and including some generics. Transmucosal fentanyl drugs are indicated only for the management of breakthrough pain for patients who are already receiving opioid therapy for their underlying persistent cancer pain, but who are tolerant to other sources of pain relief.

All TIRF products have FDA-required Risk Evaluation and Management Strategy (REMS) programs.2 The most current information regarding the TIRF REMS program can be found here. The goal of the TIRF REMS program is to mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by:

  • prescribing and dispensing TIRF medications only to appropriate patients, which includes use only in opioid-tolerant patients;
  • preventing inappropriate conversion between TIRF medications;
  • preventing accidental exposure to children and others for whom it was not prescribed and
  • educating prescribers, pharmacists and patients on the potential for misuse, abuse, addiction and overdose.

The REMS program contains various commitments by prescribers and pharmacies prior to dispensing TIRF medications to assure documentation of safe-use conditions (e.g., the dispensing pharmacy and prescriber are enrolled and active in the TIRF REMS program). Healthcare providers who prescribe TIRF medications must pass an educational program before they can enroll in the program. Additionally, TIRF medications can be dispensed only by pharmacies that are specially certified. For prescribers and dispensing pharmacies, re-enrollment in the program is required every two years. Furthermore, manufacturers must ensure that wholesalers and suppliers distributing their TIRF medications are enrolled in TIRF REMS. For outpatient use, the patient must also sign a Prescriber-Patient agreement form with their healthcare provider to review risk versus benefit. On August 3, 2018, the U.S. Food and Drug Administration (FDA) hosted a public advisory committee meeting to review data from the most recent assessment of the REMS with Elements to Assure Safe Use (ETASU) for TIRF products. Members of the FDA’s Drug Safety and Risk Management Advisory Committee and its Anesthetic and Analgesic Drug Products Advisory Committee discussed findings from assessments conducted by manufacturers, as well as additional data about use patterns and adverse events for TIRF. The purpose was to determine whether changes to the REMS might be necessary. The FDA’s press release about the meeting reported that the total number of TIRF prescriptions have declined to only around 5,000 since the introduction of the REMS strategy in December 2011. Serious concerns still exist, however.3

The committee meeting revealed a number of red flags for the TIRF REMS program. Most alarmingly, approximately 42% of prescriptions for TIRF products were to non-opioid tolerant patients, which is a contraindication for prescribing.3 Committee members expressed concern over the number of TIRF prescriptions for conditions other than cancer pain, as well.4 Concerns also were raised over both limited supervision for prescribers and loosened requirements on prescribing for non-opioid tolerant patients. The committees called for greater oversight of the REMS programs and for greater transparency of data collected by the REMS assessments.

As an example of prescribing oversight concerns, Insys Therapeutics provides a timely example. Insys has faced multiple investigations by state and federal agencies over its sales and marketing practices for the fentanyl spray, Subsys. Several former Insys executives were indicted in December 2017 on federal charges that they conspired to bribe doctors to prescribe the drug. On August 8, 2018, Insys announced that it had reached an agreement in principle with the U.S. Department of Justice (DoJ) for a penalty amount of $150 million over five years, in response to the civil and criminal investigations into inappropriate sales and commercial practices.5

 

What does this mean for workers’ compensation?

Due to their limited indication, TIRF products are not included on workers’ compensation formularies. Any use of them for worker’s compensation patients requires specific authorization by the client. Their significant safety risks means that additional clinical strategies also are in place.

For more than a decade, myMatrixx has been reaching out to clinicians who prescribe TIRF products for workers’ compensation patients. Our communications outline the safety risks of using the drugs and ask the prescriber for documentation of appropriate prescribing, including plans to discontinue therapy. To highlight the need for intervention, use of TIRF products are also included in a generated patient safety risk score identified by our Business Analytics product, Clinical Analysis Results Engine (CARE). Additionally, the use of TIRF products is part of a supplemental reporting package for clinical safety alerts that call further attention to individual patients using these medications. Because of our various interactions ̶ from point-of-sale to prescriber outreach to client analytics, the usage of TIRF products in the myMatrixx workers’ compensation book of business is minimal.

Although our programs manage prescription TIRF use well, we don’t stop there. We have similar strategies in place to manage other forms of fentanyl as well. In our next Keeping Up With Clinical Trends, we will address the prescription use of other fentanyl dose forms, like Duragesic® (fentanyl transdermal system). In addition, watch for our upcoming research paper entitled It’s Not Just Heroin Anymore: Evolving Role of Fentanyl in Drug Overdose.

 

 

    1. Ahmad FB, Rossen LM, Spencer MR, Warner M, Sutton P. Vital statistics rapid release. Provisional drug overdose death counts. National Center for Health Statistics.  Last Updated Aug. 15, 2018. Accessed Aug. 17, 2018.
    2. U.S. Food and Drug Administration. Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS).  Most recent modification: December 2014. Accessed 8/17/18.
    3. Statement from FDA Commissioner Scott Gottlieb, M.D., on FDA’s continued, careful oversight of the REMS associated with transmucosal immediate-release fentanyl products [press release]. Silver Spring, MD; U.S. Food and Drug Administration; Aug. 1, 2018. 
    4. Alexander GC, Sharfstein JM. Testimony for the Record Submitted to the U.S. Food and Drug Administration for the Joint Meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee. Aug. 1, 2018.  Accessed 8/17/18
    5. Lord SM, Kerr JS. INSYS Therapeutics reaches settlement in connection with marketing of opioid painkiller. Arnall Golden Gregory, LLP. Legal Insight.  Aug. 15, 2018. Accessed 8/17/18.