ROUNDTABLE DISCUSSION: Reformulating Opioids to Deter Abuse

Pain is a significant public health problem in the United States. It is estimated that over 100 million people in the U.S. live with chronic pain.1 Prescription opioid analgesics are the mainstay of pharmacologic management of pain. They are administered through various routes and are available in many dosage forms. In the past two decades, the use of opioid therapy for the treatment of pain has dramatically increased. Simultaneously, opioid prescription abuse and overdose has markedly increased.2,3 From 1997 to 2007, the milligram-per-person use of prescription opioids in the U.S. increased from 74 to 369 mg, an increase of 402%.2 In addition, in 2000, retail pharmacies dispensed 174 million prescriptions for opioids; by 2009, 257 million prescriptions were dispensed, an increase of 48%.4 National surveys show that opioid misuse has increased dramatically over the past decade and that opioid medications have surpassed cocaine and heroin as the leading drugs of abuse.5,6

Due to the emerging issues of opioid misuse and abuse, the FDA issued a new Risk Evaluation and Mitigation Strategy (REMS) for opioids in July 2012. The REMS program stems from the national prescription drug abuse plan that was announced by the Obama administration in 2011. According to U.S. Pharmacist.com,7 REMS is a risk management plan that exceeds standard drug prescribing information; the FDA selected the ER and LA formulations of opioids because of the inherent risks of using these drugs. These formulations contain greater amounts of drug compared to the short-acting formulations, thus making those medications more dangerous in situations of abuse and misuse. The program focuses on educating providers and patients on the safe use of ER and LA opioids while ensuring that patients who require treatment with opioids have access to them. Manufacturers are responsible for creating educational programs and materials for all Drug Enforcement Administration (DEA)-registered prescribers.

In an effort to further safety precautions with the use of ER/LA opioid analgesics, the FDA has imposed safety labeling changes and post-market study requirements. The labeling changes will include an updated indication emphasizing the use of ER/LA opioids in patients with pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment is inadequate.8

In this exclusive Drug Development & Delivery magazine roundtable discussion, several Specialty Pharmaceutical company executives were asked to share their thoughts about FDA’s labeling requirements, describe their company’s formulation technologies, and explain their vision for where they think the opioid market is headed. Participants are: Ted Andrew, Product Manager-Rx Softgel, Catalent Pharma Solutions; Nasrat A. Hakim, President & Chief Executive Officer, Elite Pharmaceuticals Inc.; Bob Radie, President and CEO, Egalet Ltd.; and Anthony Soscia, President, Atlantic Pharmaceuticals.

Q: The FDA “limitation of use” labeling language suggests that extended-release opioid-containing products should only be used when other alternatives have not been successful. Do you think that this may eventually drive physicians to further prescribe immediate-release opioids and non-opioids as an alternative for chronic analgesic therapy?

Mr. Soscia: The labeling changes for ER/LA opioids were primarily intended to address the Physicians for Responsible Opioid Prescribing (“PROP”) Citizen’s petition filed in July 2012, which requested changes to the approved labeling of all Extended-Release/Long-Acting (ER/LA) opioid analgesics, quantity, and day limits, and that ER/LA dosing be limited when prescribed for non-cancer pain. The current language deletes the reference to moderate pain and adds the requirement that the prescriber has explored other treatment options. This change is intended to encourage prescribing decisions based on an individualized assessment, which is necessary for any patient on ER/LA opioids.

I do not believe it is FDA’s intention to push prescriptions one way or the other but there may be a prescribing shift to immediate-release (IR) opioids and non-opioid treatments as there are certain patients taking ER/LA therapy who may be better served by IR opioids or non-opioid therapy. In addition, there are several side effect trends being observed with the chronic use of opioids in certain populations. These include hyperalgesia and alterations in hormonal production such as testosterone. In certain cases, an acute, immediate-release product may be more appropriate. The FDA will most likely be following these trends very closely.

Mr. Andrew: The FDA has taken a proactive approach to addressing the growing epidemic of prescription drug abuse by narrowing the scope of extended-release labeling to a second level therapy, only after immediate-release, faster-acting opioids and non-opioid treatments are exhausted or not applicable.

The “limitation of use” labeling is an effective step that will, at a minimum, serve to educate the patient and physician, which in turn, can foster a more substantive dialog about the risks and other treatment options available. However, ultimately, this is a physician-patient decision so I do not feel like the movement to more immediate-release prescriptions at the expense of extended release will be significant.

Mr. Hakim: I do not believe the “limitation of use” labeling language will drive physicians to switch from extended-release opioids to immediate-release opioids. I believe the vast majority of physicians already understand both the benefits and shortcomings of extended-release and immediate-release opioids and prescribing will continue to be driven by what is best for the patient. Given all considerations, I believe extended-release opioids will continue to be the primary choice for chronic pain.

Q: There are several types of technologies being evaluated for abuse deterrence i.e. physical, aversive, antagonist, and prodrug. How do technologies in the same class differentiate themselves from other technologies and from generics that may pursue competitors’ technologies?

Mr. Andrew: As the public and regulatory pressure for effective abuse-deterrent opioids increase, the technology available continues to expand. The abuse market continues to develop to address new trends in abuse. This creates an environment where an effective abuse-deterrent technology will need to continually evolve and/or be multi-level to be effective in the longer term.

While different abuse-deterrence technologies have strengths and weaknesses, a successful approach needs to balance therapeutic effectiveness, level of abuse deterrence, and cost considerations. For example, while incorporating an aversion or antagonist adds complexity to the formulation to prevent abuse, it could potentially impact patients taking the medicine as directed. Physical deterrence is another method that has shown some initial promise making it more difficult to abuse, however, can be readily abused by adding manipulation steps.

Mr. Hakim: Key factors that will differentiate these products include safety, which includes product attributes such as robustness and stability. For example, within the antagonist category, there was an abuse-deterrent product pulled from the market due to stability issues. Companies developing new products will want to avoid such issues.

Intellectual property is also a differentiator. The area of opioid abuse resistance has the interest of many companies and this has led to a large number of patents for abuse-resistant technologies. To be successful, companies will not only have to develop a product to address the market and regulatory needs, but the product will need to have patent protection. Any company introducing a new abuse-resistant product can expect to be challenged in the courts by competitors.

Finally, with regard to epidemiological data, the FDA would like to see a number of years of epidemiological data to determine what technologies work and, given time, this data will differentiate technologies and products.

Mr. Soscia: Differentiation within and between classes is an important question with regard to establishing the market longevity of the branded products containing abuse-deterrent technologies. The abuse-deterrent product’s market life is a key metric to observe meaningful changes in abuse deterrence before generic penetration. It remains to be seen how the FDA is going to allow generic competition to technologies in the same class. Questions include issues of abuse-deterrent matching or equivalence on the category and tier abuse deterrent labeling. What constitutes abuse-deterrence equivalence? Will a generic have to match an innovator product with Phase 4 studies that may be included on the innovator label?

Other questions and issues arise relative to incremental increases in abuse-deterrence in the same category. For instance, if a new technology exhibits statistically significant improvements in drug extraction resistance or in nasal liking compared to a currently marketed abuse-deterrent platform, will the FDA grant the new entry a branded status and remove the former abuse-deterrent product? How about other classes of drugs that are known to exhibit safety issues if accidentally or intentionally abused? Can those be reformulated and will the FDA force or agree to removal of the reference listed drug? This is certainly only the beginning of myriad of questions that will evolve in this space. The FDA labeling changes should encourage current and future development of these products but not be used in a way to stifle long-term competition or more advanced technologies.

Q: Describe your abuse-deterrent formulation technology and how it works to deter abuse yet maintain patient effectiveness.

Mr. Soscia: Our patented abuse-deterrent drug delivery technology is called SMART/Script™ (SMART/Simple, controllable, resistant, insoluble, physical trap). The Atlantic technology is unique amongst physical technologies in that when a moderate amount of physical force, such as that incurred by chewing or grinding with a coffee mill, is applied to the product, the drug contained is sequestered and reduced from dose dumping. This decrease in release may be permanent depending on the circumstances. When taken intact however, the drug will release as intended. The sequestering action does not require an external solvent to activate (a.k.a. gelling agents). It can be applied to both immediate- and sustained-release drug candidates whereas most platforms take either an immediate-release or sustained-release abuse-deterrent approach.

Mr. Hakim: Elite’s proprietary abuse-deterrence technology uses an antagonist approach and is a multi-particulate formulation in a capsule. It uses a two-bead system consisting of the opioid agonist and the opioid antagonist, naltrexone. Both bead populations are the same size, shape, weight, density, etc., so the bead population cannot be differentiated between the two. When our product is taken as intended, the opioid will release and the opioid antagonist will pass through the body unreleased, giving the patient the desired therapeutic effect. If the product is tampered with, the naltrexone will preferentially bind to the same receptors in the brain that the opioid would target, rendering the opioid useless.

Mr. Radie: Egalet has created two drug delivery systems, each with abuse-deterrent features and the ability to control the release profile of the active pharmaceutical ingredient. Our one-component system is used to produce tablets, such as Egalet-001, that consist of a hard matrix that is difficult to crush, grind or dissolve and that also controls the release of the API. The matrix, which contains the API as well as inactive agents, erodes over time in the GI tract, releasing the API.

Our two-component system is used to produce tablets, such as Egalet-002, that consist of a matrix similar to the matrix that is a part of our one-component system, but that is surrounded by a water-impermeable, non-eroding, hard shell made of polylactic acid that creates a cylinder, with the API-containing matrix exposed at both ends. The shell serves to limit the portion of the matrix’s surface area that is exposed to the GI tract, which allows us to tailor the release rate of the API and makes it even more difficult to crush or grind the tablet, thereby enhancing its abuse-deterrent properties. We use an injection molding technology to create the matrix and shell.

Mr. Andrew: Catalent OptiGel Lock™ technology incorporates multi-level abuse deterrence in a softgel dose form. First, because it is in a softgel form, it cannot be ground, grated or blended to create microparticles for both inhalation and further diversion. Second, numerous formulations can potentially be developed that may reduce the syringeability and render the remaining API unavailable for misuse. In addition, the same technology serves as a barrier to heat and solvent extraction and concentration of the formulated opioid.

Q: How does your technology satisfy the FDA’s proposed abuse-deterrent labeling requirements and still promote patient safety?

Mr. Radie: Using our proprietary technology platform, we have developed a pipeline of clinical-stage, opioid-based product candidates in tablet form that are specifically designed to deter abuse by physical and chemical manipulation while also providing the ability to tailor the release of the API. In addition to our planned clinical trials for Egalet-001 and Egalet-002, we are currently conducting abuse-deterrence studies with both product candidates in accordance with the FDA draft guidance, with the goal of obtaining abuse-deterrent claims in our product labels.

We believe that our systems offer several advantages. For example, with regard to abuse deterrence, abusers often seek to accelerate the absorption of opioids into the bloodstream by crushing in order to swallow, snort or smoke, or dissolving in order to inject the drug. Tablets produced using our systems have physical and chemical barriers intended to deter these common methods of abuse.

Additionally, we can tailor the release. In our tablets, the API is integrated into the matrix, which makes it difficult for abusers to extract quickly. However, when the tablet is exposed to GI fluids, the matrix erodes, thereby releasing the API. Using our technology, we can change the amount and composition of the polymer used to create the matrix formulation and can vary the surface area of the matrix exposed to the GI
tract. By varying the matrix composition and surface area, we can control the rate of erosion of the matrix and the rate of release of the API, which allows us to develop products with immediate-release, extended-release, and sustained-release profiles.

Mr. Soscia: A product formulated with SMART/Script™ will satisfy the premarketing Tiers and Categories in the recently released FDA guideline regarding abuse-deterrent labeling. If the Smart/Script product is taken as directed, the drug will release in the same manner as the currently marketed products.

Mr. Hakim: Our formulations, when intact and taken as intended, provide the delivery of the drug in the same manner as the current extended-release formulations. The products will have the same safety and efficacy profile as current products on the market. If the drug is crushed, then our technology will release an antagonist, which will reduce the euphoria level achievable through whichever route of administration the abuser might want to use.

Q: What do you see as the pros and cons of immediate-release vs. extended-release opioid formulations as they relate to abuse deterrence?

Mr. Hakim: The objective of the industry is to create abuse-resistant technologies that are effective for both immediate-release and extended-release products. The technologies that work for each type of product may be different or maybe not, but the key is simply that they are effective. If the industry can achieve that, then the choice of using IR or ER will be driven by the patient needs and not by any external factors. This is where I believe the market is heading.

Mr. Andrew: Immediate-release products tend to be over prescribed for acute pain and give a more euphoric feeling compared to extended-release products. Thus, there is a view that immediate-release formulations may more readily lead to addiction.

While extended-release products potentially offer pain management with a lower potential for addiction, the danger occurs when these products are manipulated through crushing or extraction to convert to an immediate-release form. Having a higher concentration of active ingredient than the immediate-release version, the risk of overdose is greater.

Abuse-deterrence technology, in order to be effective, should be applicable across formulations. While the mechanism of abuse can vary, the overall top line methods should be addressed: oral (dose dumping with alcohol), nasal (crushing), injection (extraction), rectal, and smoking.

Mr. Soscia: I believe abuse-deterrent formulations need to be applied to the entire category otherwise you just push abuse to another non-abuse deterrent product (i.e. the pushing down on one side of a balloon to see the other side rise). That theory has been borne out with the reformulation and removal of the previously marketed form of OxyContin. While the epidemiological data is still being collected and analyzed, there was an early observed shift in abuse from the newly reformulated “hardened” OxyContin to other molecules, primarily to immediate release oxycodone products. Empirically this makes sense, as abuse would be driven to the molecule that can be most easily acquired and manipulated. Currently, the number of prescriptions in the U.S. dispensed for immediate-release opioid greatly outnumbers those for extended or long-acting formulations and I believe that trend will continue. In addition, as a 30-mg IR oxycodone contains the same amount of API as an ER 30-mg oxycodone product there should be a matching abuse-deterrent immediate-release dosage form to compliment the latter. The majority of abuse-deterrent technologies are focused on the extended-release market while the immediate-release market has very few technologies. I believe it is possible to rebrand the generic immediate-release space using Atlantic’s technology and further focus on branded products such as an immediate-release, single-ingredient hydrocodone. This product in particular is a priority due to the hepatoxicity, ototoxicity and high abuse rates of hydrcodone:acetaminophen IR combinations.

Q: Is there anything you’d like to add or comment on that is not discussed above?

Mr. Hakim: The barriers to abuse are very different between physical versus pharmacological approaches. While no approach is perfect, we believe the barrier to prevent abuse is higher with the pharmacological approach. In other words, the difficulty in using either crushing or extraction to convert the opioid product into an abusable form is greater with a pharmacological approach, and we believe prescribers will understand this as more products become available.

References

1. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies of Science; 2011. www.iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-fortransforming-Prevention-Care-Education-Research.aspx. Accessed June 19, 2013.
2. Manchikanti L, Fellows B, Ailinani H, et al. Therapeutic use, abuse, and non-medical use of opioids: a ten-year perspective. Pain Physician. 2010;13:401-435.
3. Toblin RL, Paulozzi LJ, Logan JE, et al. Mental illness and psychotropic drug use among prescription drug overdose deaths: a medical examiner chart review. J Clin Psychiatry. 2010;71:491-496.
4. Joint meeting of the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioid analgesics. July 22-23, 2010.www.fda.gov/downloads/AdvisoryCommit tees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/UCM217510.pdf.
5. Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf. 2006;15:618-627.
6. Kuehn BM. Opioid prescriptions soar:increase in legitimate use as well as abuse. JAMA. 2007;297:249-251.
7. Ng Kimberly Erin, et. al. PharmDLegislative Initiatives and Review of Abuse-Deterrent Opioid Formulations. US Pharm. 2013;38(10):21-26. Oct. 18,2013. http://www.uspharmacist.com/content/c/44472/.
8. FDA announces safety labeling changes and post market study requirements for extended-release and long-acting opioid analgesics. FDA news release. September 10, 2013. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ ucm367726.htm. Accessed September 23, 2013.