Elite Pharmaceuticals Inc (ELTP)

[WeeZuhl]

Acetaminophen is a lame abuse-deterrent.


I have struggled to understand the concept of acetaminophen as an abuse-deterrent, which is essentially the FDA’s position regarding the hydrocodone and oxycodone combination products. They do not believe there is significant IV abuse, and they believe acetaminophen is an adequate aversive ADF for nasal abuse. This is specifically relevant to Elite’s development of ELI-202, which is presumed to be immediate-release oxycodone/acetaminophen combination with sequestered naltrexone. According to Nasrat Hakim, it makes no sense to add an expensive naltrexone bead to the capsules if the FDA does not believe your product will do more to deter abuse than inexpensive generic competitors. The latest data and thinking from the FDA on this subject was very recently described during the AdComm for KemPharm’s KP201/APAP. As part of their application, KemPharm asserted that hydrocodone acetaminophen products are regularly abused, and their product will prevent some of that abuse. They cited certain studies in their application, and some FDA lackeys prepared a summary report for the AdComm. It starts on Page 107 of this file:

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM498784.pdf

My opinion is that the data in the report was incongruent with the conclusion of the report. They prove there is a significant amount of parenteral (non-oral) abuse of these products, especially in certain subgroups, but then they go on to conclude that parenteral abuse is inconsequential to the overall health burden in comparison to the rampant oral abuse of the same products.

5 CONCLUSION
The estimated prevalence of intranasal abuse among HCP abusers varies widely—from approximately 6% to more than 70%—depending on the setting and characteristics of the study population, how the questions about ROA are asked, and the referent time frame. The available data suggest that snorting is not an uncommon route of administration in certain populations of HCP abusers, particularly those with more advanced opioid addiction, those with polysubstance abuse, and high-risk adolescents. However, snorting is infrequently identified as the preferred or the exclusive route for abusing HCPs, and limited data suggest that regular (a few times a week or more) intranasal HCP abuse may be uncommon. Parenteral abuse of HCPs is reported very infrequently in all populations studied. Because of the widespread availability and abuse of HCPs, even a relatively low prevalence of intranasal abuse among HCP abusers translates to large absolute numbers of individuals exposed to potential harms associated with this behavior. Unfortunately, population data on harms associated with intranasal HCP abuse are very limited. However, the totality of the available epidemiologic data, interpreted in the context of the known pharmacologic properties of HCPs, suggests that intranasal abuse of HCPs may contribute relatively little to the overall public health burden of morbidity and mortality associated with HCP abuse, misuse, and addiction.

But now let’s drill down into some of the data in the report, which I believe ultimately is very favorable toward ongoing development of ELI-202, including the “expensive” naltrexone bead. I wonder if any company has ever requested an AdComm? I believe Elite should file their 505b2 NDA with the naltrexone ADF, as originally intended, and request an AdComm to discuss the potential for significant, relevant abuse-deterrence with the 2 bead antagonist ADF version of ELI-202. As you look at the following graphs, remember there is no such thing as “single-entity” IR hydrocodone, only combination products with acetaminophen. The IR products are always on the left: hydrocodone combo, oxycodone combo, and oxyIR single entity. The ER/LA products on the right. The ASI-MV data is from adults, and the CHAT network data is from at-risk adolescents. The first graph is from adult data, and very clearly shows that even a small percentage of nasal abuse for the highly-prescribed combo products results in a significant amount of nasal abuse, just as many nasal abuse incidents as oxyIR SE.







The same graph with the adolescent data shows that snorting the combo products is multiple times more common than snorting oxyIR SE, just based on number of incidents.







The above graphs look at total incidents of abuse, and the below graphs look at the same data in a different way: what percentage of abusers have used which routes of abuse in the last 30 days. Each abuser can report multiple forms of abuse. First thing to notice is the high percentage of nasal and IV abuse of Oxy IR SE, for you SequestOx fans. The FDA may not believe there is a lot of IV abuse of IR drugs, but when it comes to oxyIR, the data says otherwise. But also notice that snorting is a common form of abuse of the combo products, even among abusers who also admit to oral abuse. Acetaminophen may be somewhat aversive for nasal abuse, but it is by no means a strong deterrent to nasal abuse.







Below is an especially poignant graph for the adolescent data. They snort everything, especially the ubiquitous combo products. No suggestion whatsoever of an aversive ADF in this data. How could an AdComm look at this graph and not conclude that nasal abuse of combination products is an important step in the pathway to hardcore IV drug abuse among at-risk adolescents?







The final graph is maybe the most important. It shows two important facts. While 96% of abusers have swallowed whole tabs in their lifetime, 40% of those abusers would prefer to tamper with pills in ways that are deterred by ELI-202 but not generic combination products. It also shows that there are multiple methods of “oral abuse,” and all of them except swallowing whole tabs are preventable by use of ELTP 2 bead antagonist ADF’s. Even though they are already immediate-release, abusers will crush the drugs prior to ingestion in order to increase the rate of absorption and intensity of high. Chewing, buccal & sublingual absorption, parachuting, and drinking in solution are all methods of “oral abuse” for IR opioids, and all of these forms of oral abuse are prevented by ELI-202 but not by generic combo products, which would be easily proven in a HAL study designed to look at these forms of oral abuse.







Back in 2009, FDA convened an AdComm to discuss the problem of acetaminophen toxicity. One of the options they gave the committee to discuss was a complete removal of prescription acetaminophen combination products. Below is the info they gave to committee members to consider, and as you can see, their biggest concerns were that there was no single entity hydrocodone, and single-entity opioids are more easily abused. They hilariously say: “these are often desirable targets for misuse and abuse because abusers know they can take multiples of these without worrying about exposure to acetaminophen,” as if the standard abuser is calculating their daily allowable acetaminophen dose before swallowing those extra pills. Unconscionable thinking, and I doubt it would pass muster today. The other concern in 2009 was that moving hydrocodone to Schedule III would burden old people, but that has subsequently been done. Now hydrocodone requires the same 30 day hand-signed paper prescription as the rest of the opioids. The 2009 AdComm voted in favor of removal of every acetaminophen combination prescription products.


http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf

Option 5b: Eliminate combination Rx acetaminophen products

Current Situation Many Rx products contain acetaminophen in combination with other active ingredients. Consumers are not always aware when acetaminophen is present in Rx combination products and may take both OTC and Rx medicines containing acetaminophen at the same time, possibly resulting in overdose.

Option Eliminate combination Rx acetaminophen products.

Intended Effect This option could help prevent overdose by reducing the number of Rx products containing acetaminophen.

Considerations Related to Incidence of Hepatotoxicity (liver injury)
• Data from the 2005 Toxic Exposure Surveillance System show that 54% (1,470/2,698) of poison center calls involving acetaminophen-containing products that resulted in major injury involved Rx combination-products. (It is not clear how many of these injuries resulted from overdose of acetaminophen versus the narcotic component of the combination product.)
• A 275-patient study of acetaminophen-induced acute liver failure found that 63% of unintentionally overdosed consumers, and 18% of intentionally overdosed consumers had taken acetaminophen-containing narcotic products prior to injury.
• In the absence of combination hydrocodone–acetaminophen products, Rx NSAIDs are an alternative therapy. However, it is likely that many consumers receiving hydrocodone– acetaminophen products have already failed or are intolerant of NSAIDs for pain management. Other patients, who are getting ready to have surgery or recently had surgery, may not be able to use an NSAID when the risk of bleeding is a concern. The NSAID GI risk alone28 results in greater overall morbidity and mortality than the risk of serious hepatotoxicity with acetaminophen. The other alternative therapies are single ingredient Schedule II opioids, such as oxycodone, morphine, hydromorphone and oxymorphone. However, these are often desirable targets for misuse and abuse because abusers know they can take multiples of these without worrying about exposure to acetaminophen. Also, as these are Schedule II products, patients are required to fill prescriptions monthly to comply with the restrictions imposed by the Controlled Substances Act, rather than being able to obtain a three-month supply with one visit to the pharmacy. This could represent a substantial burden for elderly patients and others with limited mobility as well as for patients who live at a distance from a pharmacy.

Considerations Related to Implementation
• Hydrocodone–acetaminophen combination products are the most frequently prescribed analgesic and the most frequently dispensed Rx drug product in the United States.
• There are currently no approved single-agent hydrocodone products available in the United States. More than 240 NDA/ANDA combination applications would be affected by this option.
• For development of hydrocodone single-agent formulations, implementation would include:
– Submission of NDAs and ANDAs for single-ingredient hydrocodone products, which may also require clinical studies for demonstration of efficacy.
– Reformulation costs

ELI-202 with sequestered naltrexone would make a far superior abuse-deterrent product compared with generic oxycodone/acetaminophen combination. The FDA’s own report shows the combination products are regularly abused by parenteral routes, especially snorting, and especially among at-risk adolescents and hardcore abusers. Likewise, there are multiple forms of oral abuse besides swallowing whole pills, such as chewing and parachuting, that are commonly preferred routes of abuse. All of these routes can be prevented by ELTP 2 bead antagonist ADF technology.

I will never understand the hypocrisy of the FDA to allow the use of acetaminophen as an abuse deterrent when they know a majority of abusers will frequently swallow multiple whole tabs, often in combination with alcohol. There is major risk of liver toxicity due to acute or chronic acetaminophen overdose, which is why the FDA AdComm recommended removal all prescription acetaminophen combination products in 2009. ELI-202 with naltrexone will prevent snorting, IV abuse, and multiple types of oral abuse that generic products do not prevent. Elite needs to make their case to the FDA.