Vol. 76 Monday, No. 238 December 12, 2011

Part II

Department of Justice

Drug Enforcement Administration 21 CFR Part 1308 Schedules of Controlled Substances: Placement of Carisoprodol Into Schedule IV; Final Rule

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DEPARTMENT OF JUSTICE (1) [The drug’s] actual or relative that the then-available data did not potential for abuse. support controlling carisoprodol. Id. Drug Enforcement Administration (2) Scientific evidence of its Thereafter, at the direction of the pharmacological effect, if known. National Institute on Drug Abuse 21 CFR Part 1308 (3) The state of current scientific (NIDA) and the College of Problems of knowledge regarding the drug or other Drug Dependence (CPDD), additional [Docket No. DEA–333] substance. pharmacological studies of (4) Its history and current pattern of carisoprodol’s abuse liability were Schedules of Controlled Substances: abuse. conducted. In the meantime, DEA Placement of Carisoprodol Into (5) The scope, duration, and gathered additional new data on actual Schedule IV significance of abuse. abuse and law enforcement encounters (6) What, if any, risk there is to the involving the drug, as well as other AGENCY: Drug Enforcement information, which it sent to HHS on Administration, Department of Justice. public health. (7) Its psychic or physiological November 14, 2005. FDA also acquired ACTION: Final rule. dependence liability. new data from the Drug Abuse Warning Network (DAWN), the National Survey SUMMARY: With the issuance of this final (8) Whether the substance is an rule, the Administrator of the Drug immediate precursor of a substance on Drug Use and Health (NSDUH), Enforcement Administration (DEA) already controlled under this Florida Medical Examiners Commission places the substance carisoprodol, subchapter. reports, FDA’s Adverse Event Reporting including its salts, isomers, and salts of 21 U.S.C. 811(c). System, as well as other information isomers, whenever the existence of such However, ‘‘before initiating from a variety of sources. On October 6, 2009, HHS concluded salts, isomers, and salts of isomers is proceedings * * * to control a drug its review of the evidence pertaining to possible, into Schedule IV of the * * * and after gathering the necessary the eight factors set forth in 21 U.S.C. Controlled Substances Act (CSA). This data,’’ the Attorney General is required 811 and recommended that carisoprodol action is pursuant to the CSA which to ‘‘request from the Secretary a be placed in schedule IV. GX 6, at 1. requires that such actions be made on scientific and medical evaluation, and Thereafter, on November 17, 2009, DEA the record after opportunity for a his recommendations, as to whether issued a Notice of Proposed hearing. The decision of the such drug * * * should be controlled.’’ Rulemaking, which proposed placing Administrator is reprinted in its entirety Id. 811(b). The statute further provides carisoprodol in schedule IV. ALJ Ex., at below. that ‘‘[i]n making such evaluation and 1 (74 FR 59108). Therein, DEA invited recommendations, the Secretary shall DATES: Effective Date: January 11, 2012. all persons to submit written comments consider the Factors listed in paragraphs FOR FURTHER INFORMATION CONTACT: or objections to the proposed rule; DEA (2), (3), (6), (7), and (8) of subsection (c) Rhea D. Moore, Drug Enforcement also notified ‘‘interested persons’’ of * * * and any scientific or medical Administration, 8701 Morrissette Drive, their right to request a hearing. Id. at 2 considerations involved in paragraphs Springfield, Virginia 22152; Telephone (citing 5 U.S.C. 556 and 557). (202) 307–5268. (1), (4), and (5) of such subsection. The DEA received seventeen comments on recommendations of the Secretary shall SUPPLEMENTARY INFORMATION: the proposed rule; sixteen of the include recommendations with respect commenters (which included law ALJ Docket No. 10–46 to the appropriate schedule, if any, enforcement officials, medical under which such drug * * * should be Background professionals and state regulators) listed.’’ Id. supported the proposed rulemaking.1 This is a proceeding under 21 U.S.C. Finally, ‘‘[t]he recommendations of One entity, Meda Pharmaceuticals, Inc. 811(a) for the issuance of a rule placing the Secretary to the Attorney General (Meda), which manufactures the carisoprodol in schedule IV of the shall be binding as to such scientific branded drug Soma, objected to the Controlled Substances Act (CSA). Under and medical matters, and if the proposed rule on the ground that the this provision, ‘‘the Attorney General Secretary recommends that a drug ‘‘the administrative record does not may, by rule,’’ add a ‘‘drug or other * * * not be controlled, the Attorney include substantial and reliable substance’’ to one of the five schedules General shall not control the drug evidence of potential for abuse of controlled substances, ‘‘if he * * * * * *. If the Attorney General sufficient to warrant scheduling finds that such drug or other substance determines that these facts and all other carisoprodol and because the proposal has a potential for abuse, and * * * relevant data constitute substantial gives inadequate weight to the negative makes with respect to such drug or evidence of potential for abuse such as impact on patient care of scheduling other substance the findings prescribed to warrant control * * * he shall carisoprodol.’’ ALJ Ex. 2, at 3. Meda also by [21 U.S.C. 812(b)] for the schedule in initiate proceedings for control * * * requested a hearing. Id. at 1. On March which such drug is to be placed.’’ 21 under subsection (a) of this section.’’ Id. 21, 2010, I granted Meda’s request and U.S.C. 811(a). However, a rule made assigned the matter to the Agency’s under this provision ‘‘shall be made on Procedural History Office of Administrative Law Judges the record after opportunity for a Pursuant to section 811(b), in March (ALJ). ALJ Ex. 3, at 2. 1996, the Drug Enforcement hearing pursuant to the rulemaking Following pre-hearing procedures, an Administration (DEA) requested from procedures prescribed by subchapter II ALJ conducted a hearing on July 6, 8, of chapter 5 of Title 5.’’ Id. the Department of Health and Human ‘‘[W]ith respect to each drug * * * Services (HHS) a scientific and medical 1 None of the commenters raised any issue as to proposed to be controlled,’’ the CSA evaluation of carisoprodol, and a the various Regulatory Certifications contained in requires that the Attorney General recommendation as to whether it should the Notice of Proposed Rulemaking. See 74 FR at consider eight factors in making the be controlled. ALJ Ex 1, at 3. In 59111. One commenter, which represents wholesale distributors, requested that if the proposed rule is findings required under both February 1997, however, the U.S. Food finalized, its effective date be set at 120 days from subsections 811(a) and 812(b). These and Drug Administration’s (FDA) Drug the date of publication to provide adequate time to are: Abuse Advisory Committee concluded comply with various regulations.

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and 9, as well as on August 3–6, 2010. center, that he could not recall a single The ALJ then discussed three At the hearing, both the Government case of a person being treated at his different human studies. With respect to and Meda elicited the testimony of center for dependence on carisoprodol the Fraser study,2 the ALJ noted that witnesses and introduced various and his opinion that ‘‘the data and Meda’s Expert interpreted the results as documents into evidence. Thereafter, information presented by the FDA and showing that ‘‘ingestions ‘did not both the Government and Meda filed DEA do not establish that carisoprodol induce a characteristic barbiturate briefs containing their proposed has a potential for abuse similar’’ to intoxication pattern * * *, nor did the findings of fact and conclusions of law. schedule IV controlled substances. Id. abrupt withdrawal of carisoprodol reveal any signs of barbiturate-like The ALJ’s Recommended Decision However, the ALJ found ‘‘more compelling’’ data compiled by Meda abstinence’ behavior.’’ Id. at 85. On December 8, 2010, the ALJ issued and the predecessor holders of the New However, the ALJ then noted that ‘‘the her recommended decision. Therein, Drug Application for carisoprodol FDA and the DEA found that the prior to discussing the eight ‘‘factors which had been submitted to the FDA’s subjective and objective effects were determinative of control,’’ 21 U.S.C. Adverse Events Reporting System similar to those of barbiturates or 811(c), the ALJ discussed the weight to (AERS). Id. at 82. This data, which alcohol and different from those of be given the FDA’s findings as to includes reports from consumers and opiates’’ and that the drug ‘‘has scientific and medical matters. ALJ at 6; healthcare practitioners, showed that sedative-like effects.’’ Id. Here again, the see also 21 U.S.C. 811(b). As explained between January 1979 and May 1, 2010, ALJ found FDA’s findings binding on more fully below, the ALJ adopted the there had been ‘‘731 spontaneous the proceeding. Id. Government’s argument that the statute adverse event’’ reports of which eighty- Next, the ALJ discussed the studies ‘‘limits the scope of the administrative three used such terms as abuse, Meda had conducted to obtain FDA hearing to those issues outside of the dependency or withdrawal. Id. at 82–83. approval to market a smaller-strength medical and scientific fact-findings of The ALJ further noted that in 2009, dose. While these studies, which the FDA,’’ ALJ at 11, and concluded that FDA required that Meda re-write the involved 4,000 patients, showed no ‘‘the plain language and legislative drug’s label to note the effects of chronic evidence of diversion, misuse, or abuse, history of § 811(b), federal case law, and and none of the patients experienced use, that there are ‘‘published case [HHS’s] process for conducting its withdrawal following discontinuation of reports of human carisoprodol administrative review, make clear that the drug, the ALJ noted that the studies’ dependence,’’ and that various animal Congress intended that the Secretary’s subjects received only therapeutic doses studies indicate the drug has ‘‘effects scientific and medical fact-findings bind and did so only ‘‘for a period of one to similar to the use of barbital, the DEA during the hearing and the two weeks.’’ Id. The ALJ thus concluded meprobamate, and chlordiazepoxide,’’ subsequent scheduling determination.’’ that these trials ‘‘did not test the effects all of which are controlled substances. Id. at 18. of prolonged use of carisoprodol at Id. at 83. The ALJ also noted that Meda However, the ALJ then noted that ingestion levels above the levels for eventually accepted the labeling change. ‘‘not all of the conclusions that the FDA therapeutic use.’’ Id. made in its review are scientific and Id. at n.42. Based on the AERS data and The ALJ then discussed a case study medical’’ in nature and that the FDA’s the drug’s label, the ALJ concluded that by doctors from the Mayo Clinic of a 51- conclusions based on data obtained carisoprodol’s ‘‘abuse potential is year old man who had taken up to six from the Drug Abuse Warning Network recognized,’’ and that ‘‘the record times the maximum recommended daily (DAWN), the National Survey on Drug contains substance evidence of a dose, which concluded that the case Use and Health (NSDUH), and the potential for abuse when carisoprodol is ‘‘demonstrates adverse effects of both Florida Medical Examiners/Coroners chronically used.’’ carisoprodol toxicity and withdrawal.’’ Reports ‘‘could equally fall under the With respect to Factors Two and Id. at 85–86. More specifically, the ALJ umbrella of law enforcement or science Three—the scientific evidence of noted the study’s findings that ‘‘abrupt and medicine.’’ Id. at 19–20. The ALJ carisoprodol’s pharmacological effect discontinuation of high-dose ultimately concluded that ‘‘the data and the state of current scientific carisoprodol may result in withdrawal gathered by these sources [was] knowledge regarding the drug—the ALJ symptoms including anxiety, psychosis, primarily statistical, and not medical, noted that ‘‘[b]oth the DEA and the FDA tremors, myoclonus, ataxia and and [is] therefore capable of review by relied on animal studies of self- seizures,’’ and that ‘‘[t]his withdrawal this agency.’’ Id. at 20. The ALJ thus administration, drug discrimination, syndrome is likely underrecognized.’’ concluded that FDA’s conclusions based and physical dependence to support Id. at 86. on this data are ‘‘not binding.’’ Id. their position that carisoprodol should Finally, the ALJ noted the FDA’s Moreover, notwithstanding her be classified as a schedule IV drug.’’ Id. findings that ‘‘carisoprodol possesses statement as to the scope of the hearing, at 84. The ALJ then noted the testimony sedative properties which may underlie the ALJ allowed Meda to introduce of Meda’s Expert that ‘‘while the its therapeutic usefulness and its extensive evidence including expert animals reflected behavior patterns with potential for abuse,’’ that ‘‘[r]ecent in testimony as to the various scientific respect to carisoprodol that suggest vitro studies demonstrated that and medical matters considered by the patterns similar to barbiturates, the carisoprodol ‘possesses barbiturate-like FDA. limitations of animal studies ‘do not effects,’ ’’ that the drug ‘‘has positive The ALJ then made extensive findings provide an adequate basis to make reinforcing effects and [that] its as to each of the eight section 811(c) decisions concerning abuse potential in discriminative stimulus effects are factors. With respect to Factor One—the humans,’ ’’ and that ‘‘ ‘certain drugs will similar to other schedule IV drugs such actual or relative potential for abuse— substitute for drugs of abuse without as barbital, meprobamate and the ALJ first explained that ‘‘abuse is themselves being subject to any chlordiazepoxide.’’ Id. While the ALJ using a drug for nonmedical purposes significant drug abuse.’ ’’ Id. The ALJ, for [its] positive psychoactive effects.’’ however, then held that ‘‘the FDA’s 2 While both parties and the ALJ cited this study Id. at 82. The ALJ then noted the conclusions regarding carisoprodol’s as if it was an exhibit in the case, it was not included in the record forwarded to this Office and testimony of one of Meda’s expert pharmacology and withdrawal patterns there is no indication that it was entered into witnesses, who runs a drug treatment [were] binding on this proceeding.’’ Id. evidence.

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noted that Meda’s Expert had However, the ALJ then noted the poison center, ‘it [is] impossible to challenged the FDA’s reliance on an in credited testimony of another of Meda’s conclude that a mentioned drug was vitro study, she held again that the expert witnesses that there is a ‘‘lack of causally implicated in the exposure.’ ’’ FDA’s ‘‘conclusion is binding on this transparency in the methods used to Id. However, the ALJ also noted the proceeding.’’ Id. Based on ‘‘the totality collect * * * and statistically testimony of Meda’s Expert that the of the record,’’ the ALJ thus concluded extrapolate’’ the data, that without ‘‘ ‘poison center data have some use, but that ‘‘the record demonstrates that ‘‘understanding the nature and extent of must be interpreted with caution.’ ’’ Id. excessive carisoprodol use creates the changes in case findings(s) during The ALJ further found that while the similar toxicity and withdrawal the last several years, it is impossible to ‘‘the intentional exposure data’’ for the symptoms to other schedule IV drugs.’’ conclusively say what proportion of the years 2006 and 2007 show that the Id. increases in DAWN ED national number of deaths attributable to ‘‘single With respect to Factors Four and estimates is attributable to changes in exposure cases’’ had remained at one Five—the history and current pattern of methodology versus changes in the per year, the number of cases with abuse, and the scope, duration, and actual number of DAWN cases ‘‘major effects went from 105 to 122,’’ significance of abuse—the ALJ began by associated with a particular drug,’’ and and the number of cases with ‘‘moderate noting the testimony of several law that ‘‘[t]his hinders any effort to effects went from 688 to 720.’’ Id. at 91– enforcement officials including the head interpret’’ the trends over time. Id. The 92. The ALJ thus concluded that the of the DEA Office of Diversion Control, ALJ thus agreed with Meda’s expert that increases in the major and moderate the Executive Director of the Ohio State DAWN ED data ‘‘may not be the best effects cases support the ‘‘conclusion Board of Pharmacy, and a Special Agent evidence in this record for concluding that ‘individuals are taking carisoprodol in Charge with the Tennessee Bureau of that the abuse of carisoprodol is in amounts sufficient to cause hazard to Investigation, each of whom testified increasing over time.’’ Id. their health.’ ’’ Id. at 92. that carisoprodol was being obtained for As for the DAWN Medical Examiner Finally, the ALJ observed that the other than a legitimate medical purpose data, the ALJ noted that the ‘‘reporting FDA had ‘‘found that data from ‘2002– and being either abused or sold on the [of] a drug in this reporting system 2006 indicate that more than 25 percent street. means that the drug need only be of patients used the drug [for] longer The ALJ then discussed data obtained implicated or suspected in the death.’’ than one month and 4.3 percent used from the National Forensic Laboratory Id. at 90. Quoting the testimony of the drug more than 360 days,’ ’’ and that Information System (NFLIS), the Meda’s Expert, the ALJ found that ‘‘ ‘[l]onger term use may contribute to National Survey on Drug Use and ‘‘ ‘carisoprodol may not have been the increased risks of misuse and abuse.’ ’’ Health (NSDUH), the Drug Abuse actual cause of death, and it is not Id. The ALJ then noted that she Warning Network (DAWN), Florida possible to conclude that carisoprodol ‘‘agree[d] with the FDA’s conclusion.’’ Medical Examiners, and the National ‘abuse’ was the cause of death in these Id. Poison Data System (NPDS). While cases.’ ’’ Id. However, the ALJ noted that With respect to Factor Six—the risk, noting that the NFLIS data, which the data ‘‘showed a link, even if not if any, to public health—the ALJ again showed that carisoprodol was direct evidence of a cause, between noted the testimony of the head of DEA consistently among the top twenty-five carisoprodol use in combination with Office of Diversion Control, the drugs being seized during criminal other drugs and death in 434 cases of Executive Director of the Ohio State investigations and analyzed by state and death in 2006.’’ Id. Board of Pharmacy, and the Special local forensic laboratories are ‘‘not Turning to the Florida Medical Agent in Charge with the Tennessee direct evidence of abuse,’’ the ALJ Examiner data, which show that 415 Bureau of Investigation to the effect that concluded these data ‘‘lead[] to an carisoprodol-related deaths occurred in ‘‘the failure to schedule carisoprodol inference that [the drug] has been 2008, and an increase of ‘‘about 62 poses a great risk to public health.’’ Id. diverted and abused.’’ Id. at 88. percent’’ in the ‘‘total occurrence of at 92–93. The ALJ further noted the As for the NSDUH data, the ALJ noted carisoprodol/meprobamate in Florida FDA’s conclusion that because that data for the years 2004 through drug abuse deaths,’’ the ALJ again noted carisoprodol is metabolically converted 2007 estimate that between 2,525,000 the testimony of Meda’s Expert that to meprobamate, a schedule IV and 2,840,000 million individuals have ‘‘carisoprodol may not be the cause of controlled substance, ‘‘the public health used carisoprodol during their lifetime death, but rather it may be merely risks of carisoprodol may be similar to for a non-medical reason. Id. at 89. present in the body at the time of those of meprobamate’’; the poison While observing that the yearly death.’’ Id. However, the ALJ then found control center data which ‘‘show that estimates ‘‘may remain relatively that the FDA ‘‘determined that ‘individuals are taking carisoprodol in consistent,’’ the ALJ observed that ‘‘they carisoprodol was considered the cause amounts sufficient to cause hazard to are still a significant number of of death in 88 cases in 2007.’’ Id. their health’ ’’; and FDA’s finding that nonmedical uses.’’ Id. However, the ALJ Next, the ALJ noted that the NPDS ‘‘ ‘the risks of carisoprodol to the public then noted that ‘‘these numbers are data show that in 2007, ‘‘ ‘carisoprodol health are typical of other central significantly lower than comparable was associated with 8,821 toxic nervous system depressants that are numbers for the nonmedical use of exposure cases, including 3,605 cases in controlled’ ’’ and that ‘‘ ‘[t]hese risks benzodiazepines.’’ Id. which [it] was the sole drug include central nervous system Next, the ALJ discussed the DAWN mentioned,’ ’’ and that ‘‘[c]ases of depression, respiratory failure, cognitive data. With respect to the DAWN individuals treated in health-care and motor impairment, addiction, Emergency Department data, the ALJ facilities because of a major adverse dependence, and abuse.’ ’’ Id. (citations noted that these data show that the health-outcome total 122 out of the omitted). The ALJ again found that the abuse frequency of carisoprodol ‘‘is 2,821 single exposure cases.’’ Id. at 91. FDA’s conclusions were ‘‘binding on similar to that of diazepam, a schedule The ALJ then acknowledged the this proceeding.’’ Id. at 93. IV drug,’’ and that the data show an testimony of Meda’s Expert that because The ALJ then noted Meda’s evidence ‘‘increasing frequency of nonmedical the cases are self-reported and ‘‘the showing a decline in the number of use emergency department visits reporting individual may misidentify prescriptions that occurred in four associated with carisoprodol.’’ Id. the substance during the call to the States which have controlled

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carisoprodol, as well as Meda’s induced a barbiturate intoxication would indicate an abuse potential.’’ Id. contention that controlling the drug pattern, [this] could be a possible at 101. The ALJ nonetheless found that would have a chilling effect on the indicator that carisoprodol possesses ‘‘there is substantial evidence in the legitimate prescribing of the drug barbiturate-like abuse liability.’’ Id. record based on the animal data, AERS because of the reluctance of physicians Finally with respect to Factor Eight— reports, and Mayo Clinic data that to prescribe a controlled substance and whether carisoprodol is an immediate carisoprodol produces dependence and that this would be ‘‘to the detriment of precursor to a substance already withdrawal symptoms similar to other those patients who would be best controlled—the ALJ found it undisputed controlled substances in schedule IV.’’ treated with carisoprodol.’’ Id. at 93–94. that the drug ‘‘is not an immediate Id. The ALJ further held that ‘‘FDA’s The ALJ found, however, that chemical precursor or intermediary of a conclusions regarding the psychological ‘‘anecdotal evidence in this record controlled substance.’’ Id. and physiological dependence of contradicts this prediction,’’ because The ALJ then addressed the three carisoprodol [were] binding on this one of Meda’s Experts testified that if section 812(b) placement factors. With proceeding.’’ Id. carisoprodol was controlled, he would respect to Factor One—whether the drug The ALJ thus concluded that continue to prescribe it. Id. at 94. The has a low potential for abuse relative to substantial evidence supports the ALJ then found that DEA data showed the drugs in schedule III—the ALJ began controlling of carisoprodol under the that controlling other drugs ‘‘did not by noting the FDA’s recommendation eight factors of section 811(c). Id. at 102. result in physicians ceasing to (and the concurrence of the National The ALJ further concluded that prescribe’’ them. Id. Institute on Drug Abuse (NIDA)), that substantial evidence supported the Finally, the ALJ found that carisoprodol should be placed in placement of carisoprodol in schedule ‘‘carisoprodol has been implicated in schedule IV. Id. The ALJ found that IV. Id. (citing 21 U.S.C. 812). cases of impaired driving, with ‘‘[e]mpirical evidence supports the Meda filed Exceptions to the ALJ’s symptoms consistent with other central FDA’s conclusion,’’ including the decision. Thereafter, the ALJ forwarded nervous system depressants, especially evidence that carisoprodol metabolizes the record to me for final agency action. alcohol,’’ and that ‘‘[a] Norwegian study into meprobamate, a schedule IV Having considered the entire record, also supported this proposition.’’ Id. controlled substance,’’ and that various including Meda’s Exceptions (which are The ALJ was unpersuaded by Meda’s studies support the conclusion that discussed more fully below), I agree argument ‘‘that many uncontrolled carisoprodol has effects similar to with its contention that the ALJ erred in drugs have labels warning against barbiturates, which are schedule III and holding that the FDA’s scientific and driving while taking such drugs,’’ noting IV controlled substances. Id. at 96–97. medical findings are binding on this that ‘‘[i]mpaired driving is a risk to the The ALJ also found that proceeding. However, because the ALJ public health,’’ and thus supports the notwithstanding that the DAWN ED allowed Meda to put on extensive ‘‘conclusion that published scientific data, which show that the ‘‘abuse evidence as to the scientific and medical reports indicate that taking carisoprodol frequency of carisoprodol is similar to matters considered by the FDA, and is associated with risk to the public that of diazepam, a schedule IV drug,’’ because, as ultimate factfinder (see 5 health.’’ Id. ‘‘may be overly inclusive,’’ this U.S.C. 557(b)), I have considered Meda’s With respect to Factor Seven—the limitation would not result in ‘‘any evidence in deciding whether drug’s psychic or physiological significant difference in ED visits substantial evidence supports the dependence liability—the ALJ observed between the reported drugs.’’ Id. at 98. scheduling of carisoprodol, I conclude that ‘‘[d]ependence includes both While acknowledging that the NSDUH that the ALJ’s error is not prejudicial. physical and psychological data show that ‘‘carisoprodol is being Because I hold that the record as a dependence.’’ Id. While noting that abused * * * at a rate significantly less whole contains substantial evidence to ‘‘there are noncontrolled drugs for than that of benzodiazepines,’’ the ALJ support the findings required to control which an individual may have a found that ‘‘the NSDUH and DAWN are carisoprodol and place it in schedule IV physical dependence,’’ a drug-taker’s two distinct studies, both on of the CSA, I will issue a rule placing conduct must be ‘‘viewed in total’’ to methodology and measurement, and carisoprodol in schedule IV. determine if the person ‘‘has a psychic therefore cannot adequately be The ALJ’s Ruling on the Binding Nature drive or craving to obtain the drug.’’ Id. compared.’’ Id. at 98–99. of the FDA’s Scientific and Medical at 95. The ALJ then noted that based on With respect to Factor Two—whether Evaluation various scientific studies, the FDA had the drug has a currently accepted ‘‘found that carisoprodol has a medical use in treatment in the United As noted above, ‘‘before initiating dependence liability that is similar to States—the ALJ found it undisputed proceedings * * * to control a drug or that of barbital, a Schedule IV central that carisoprodol has been approved by other substance,’’ the Attorney General nervous system depressant, in its the FDA for the treatment of ‘‘acute, is required to ‘‘request from the dependence potential,’’ and that the painful musculoskeletal conditions.’’ Id. Secretary a scientific and medical FDA’s finding was binding on the at 99–100. The ALJ thus found that evaluation, and [her] recommendations, proceeding. Id. The ALJ also cited the ‘‘carisoprodol has a currently accepted as to whether such drug or other testimony of a DEA witness that medical use in the United States.’’ Id. at substance should be so controlled.’’ 21 carisoprodol is abused by individuals to 100. U.S.C. 811(b). Congress specified that obtain a ‘‘mellow euphoria.’’ Id. With respect to Factor Three— ‘‘[i]n making such evaluation and The ALJ also found that two studies whether abuse of the drug may lead to recommendations, the Secretary shall had shown that carisoprodol produces limited physical or psychological consider the factors listed in paragraphs ‘‘subjective and objective effects’’ in dependence relative to the drugs in (2), (3), (6), (7), and (8) of subsection (c) ‘‘human subjects [that] were similar to schedule three—the ALJ credited the * * * and any scientific or medical those of barbiturates or alcohol,’’ the testimony of two of Meda’s experts to considerations involved in paragraphs former being controlled substances the effect that carisoprodol ‘‘does not (1), (4) and (5) of such subsection.’ ’’ Id. listed in both schedules III and IV. Id. create abuse liability patterns typical of The Secretary is directed to provide the at 96. The ALJ then noted the testimony controlled drugs’’ and that ‘‘[t]here does Attorney General with her ‘‘evaluation of Meda’s Expert that if ‘‘carisoprodol not appear to be any patient ‘liking’ that and * * * recommendations,’’ which

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‘‘shall include recommendations with I find the ALJ’s reasoning confusing,3 U.S.C. 811(b). However, an on-the- respect to the appropriate schedule, if and that she gave insufficient record hearing (as opposed to notice and any, under which such drug or other consideration to the most relevant comment rulemaking) would hardly be substances should be listed.’’ Id. judicial decisions; I therefore reject her necessary to determine whether the data Subsection (b) further provides that legal conclusion. To be sure, the proffered by the Agency is adequate to support the findings necessary to ‘‘[t]he recommendations of the Secretary Supreme Court has recognized that control a drug. As the DC Circuit to the Attorney General shall be binding ‘‘[t]he CSA allocates decision making explained in Reckitt,4 if HHS’s medical as to such scientific and medical powers among statutory actors so that medical judgments * * * are placed in and scientific findings are binding matters, and if the Secretary the hands of the Secretary,’’ and that the throughout a proceeding, ‘‘it is difficult recommends that a drug or other ‘‘[t]he structure of the CSA * * * to see what purpose the agency’s on-the- substance not be controlled, the conveys unwillingness to cede medical record hearing [would] serve[.]’’ 5 Attorney General shall not control the judgments to an Executive official who The ALJ’s also found unpersuasive drug or other substance.’’ Id. Moreover, lacks medical expertise.’’ Gonzales v. Grinspoon v. DEA, 828 F.2d 881 (1st Cir. ‘‘[i]f the Attorney General determines Oregon, 546 U.S. 243, 265 (2006). Yet, 1987). Grinspoon involved a petition to that these facts and all other relevant the ALJ’s sweeping conclusion that this review the Agency’s issuance of a final data constitute substantial evidence of ‘‘language supports the inference that rule placing MDMA in schedule I. 828 potential for abuse such as to warrant the Supreme Court interpreted 811(b) to F.2d at 882. In Grinspoon, the petitioner control * * * he shall initiate indicate that those medical judgments raised four different challenges to the proceedings for control * * * under are final and not subject to litigation Agency’s rule. Id. at 882–83. These subsection (a),’’ the provision which before the DEA,’’ ALJ at 13 (emphasis included, inter alia, that the requires that a rule scheduling a added), cannot be squared with other ‘‘Administrator applied the wrong legal substance ‘‘be made on the record after provisions of the statute. Moreover, the standard’’ because he interpreted the opportunity for a hearing pursuant to Court did not decide the issue. ‘‘phrases ‘accepted medical use in the rulemaking procedures prescribed As noted above, upon receiving the treatment in the United States,’ and by’’ 5 U.S.C. 556 and 557. Secretary’s evaluation and ‘accepted safety for use * * * under The ALJ held that ‘‘the CSA limits the recommendation, the Attorney General is charged with the duty to ‘‘determine 4 At issue in Reckitt & Coleman was a rulemaking scope of the administrative hearing to which rescheduled buprenorphine from schedule II those issues outside of the medical and that these facts and all other relevant to schedule V, but which designated the drug as a scientific fact-findings of the FDA.’’ ALJ data constitute substantial evidence of narcotic based on the ground that it is a derivative at 11. According to the ALJ, the ‘‘the potential for abuse such as to warrant of thebaine. See 788 F.2d at 22. In a footnote, the control.’’ 21 U.S.C. 811(b) (emphasis Court of Appeals discussed an argument advanced plain language and legislative history of in the brief of a third-party intervenor (which the [sections 811(a) and (b)] and federal case added). In the event the Secretary’s Department endorsed at oral argument) that the law indicate [that] Congress intended evaluation and the other relevant data Agency’s conclusion could be upheld on the ground constitute substantial evidence such as that ‘‘HHS’s initial communication to DEA stated that the Secretary’s scientific and that buprenorphine is a thebaine derivative, and the medical fact-findings bind the [Agency] to warrant control, the Attorney General Act makes HHS’s recommendations as to ‘scientific throughout the scheduling process.’’ Id. may then initiate proceedings to control and medical matters’ binding on the DEA.’’ 788 the drug. However, Congress further F.2d 27 n.8 (citing 21 U.S.C. 811(b)). While the The ALJ further rejected Meda’s court concluded that it was unnecessary to reach contention that construing the statute in provided that ‘‘Rules of the Attorney General [to control a drug] shall be the issue, as noted above, it expressed considerable this manner would deny it a meaningful skepticism as to the reasonableness of the view that made on the record after opportunity for hearing and render the hearing ‘‘largely the Attorney General is bound by the Secretary’s a hearing pursuant to the rulemaking finding on a scientific issue notwithstanding superfluous,’’ concluding that procedures prescribed by’’ the contrary evidence presented at a hearing. While the ‘‘Respondent will be afforded the DC Circuit’s discussion is not binding, it is dictum Administrative Procedure Act (APA). 21 opportunity for a meaningful APA which the Agency ignores at its peril. U.S.C. 811(a). 5 hearing without the opportunity to As support for her holding, the ALJ also cited Under this provision, a rule may not United States v. Spain, 825 F.2d 1426, 1428 (10th litigate the factual underpinnings of the be ‘‘issued except on consideration of Cir. 1987), and United States v. Pastore, 419 [HHS] report.’’ Id. the whole record or those parts thereof F.Supp. 1318 (S.D.N.Y. 1976). As for the ALJ’s reliance on Spain, that case addressed the Attorney The ALJ thus rejected Meda’s cited by a party and supported by and General’s authority under 21 U.S.C. 811(h), which contention that the FDA’s findings as to in accordance with the reliable, authorizes the ‘‘scheduling of a substance in medical and scientific matters are only probative, and substantial evidence.’’ 5 schedule I on a temporary basis [when] necessary to avoid an imminent hazard to the public safety.’’ binding on the Agency’s decision as to U.S.C. 556(d) (emphasis added). Were it See 825 F.2d at 1427. Under this provision, the whether to initiate a scheduling the case that the Secretary’s findings as Attorney General is not required to obtain a proceeding and that the Secretary’s to medical and scientific matters are not scientific and medical evaluation from the Secretary findings are not binding on either the subject to litigation in the subsequent before acting. Id. at 148–29. Thus, the case does not address the issue of whether the Secretary’s medical ALJ or the Administrator in evaluating rulemaking hearing, the only issues left and scientific evaluation and recommendations are the record of the hearing. Id. at 9–11 to be litigated would be the drug’s subject to re-litigation at the hearing. See 825 F.2d (discussing Meda Br. 15–18). As noted ‘‘actual’’ abuse, its ‘‘history and current at 1427. above, throughout her consideration of pattern of abuse’’ and the ‘‘scope, Pastore involved a motion to dismiss an indictment which charged various offenses the factors, the ALJ held that she was duration, and significance of abuse.’’ 21 involving the unlawful distribution and obtaining bound by FDA’s findings as to scientific of the controlled substances phendimetrazine and and medical matters and that Meda was 3 Compare ALJ at 11 (noting that dicta in Reckitt phentermine. See 419 F. Supp. at 1334–35. While not entitled to challenge the Secretary’s & Coleman, Ltd., v. Administrator, 788 F.2d 22, 27 the defendants raised various challenges to the n.8 (DC Cir. 1977), ‘‘highlights the inherent Attorney General’s decision scheduling these drugs, medical and scientific findings. See, ambiguity in the statutory language’’), with id. at 18 both drugs were scheduled without a formal on-the- e.g., ALJ at 85–86 (holding FDA’s (holding that ‘‘the plain language’’ of section 811(b) record hearing. Id. at 1346–48. Here again, the case findings as to Factor Two (Section ‘‘make[s] clear that Congress intended that the did not address the issue of whether the Agency is 811(c)) binding notwithstanding Meda’s Secretary’s scientific and medical fact-findings bind bound by the Secretary’s finding on a scientific or the DEA during the hearing and the subsequent medical issue in a formal rulemaking proceeding. contrary evidence). scheduling determination’’). See id.

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medical supervision’ ’’ as meaning The procedure which the Attorney General challenges to the Secretary’s scientific ‘‘approved for interstate marketing must then follow to control a drug involves and medical findings be litigated in a * * * under the’’ Food, Drug and rulemaking proceedings on the record after proceeding before HHS. opportunity for a hearing. This provides In addition, both the statute and the Cosmetic Act, id. at 884 (quoting 21 opportunity for consideration of the views of U.S.C. 812(b)(1)(A)), as well as that ‘‘the persons who would be adversely affected by legislative history make plain that rule [was] based upon incomplete and control of a drug, with judicial review Congress was concerned that scheduling arbitrary recommendations from the available thereafter; however, this proceedings be done in an expeditious Secretary.’’ Id. at 883. administrative proceeding is more manner. For instance, section 811(b) The First Circuit held that the streamlined in its operation than the existing requires that the Secretary submit his Administrator had erroneously procedures under section 701(e) of the report ‘‘to the Attorney General within Federal, Food, Drug, and Cosmetic Act, so a reasonable time.’’ 21 U.S.C. 811(b) interpreted the phrases ‘‘accepted that controls may be established medical use in treatment in the United expeditiously where necessary, with full (emphasis added). Likewise, in States’’ and ‘‘accepted safety for use consideration of all factors involved in the discussing the hearing provision, the * * * under medical supervision’’ as decision-law enforcement problems, medical, House Report manifests Congress’ intent meaning that the drug had not been and scientific determinations, and the ‘‘that controls may be established approved by FDA for interstate interests of parties affected by the decision to expeditiously where necessary.’’ 1970 marketing. Id. at 891. The Court thus control. U.S.C.C.A.N. at 4589. The ALJ’s vacated the rule and ordered the Agency H. Rep. No. 91–1444, 1970 U.S.C.C.A.N. suggestion that Meda was required to to reconsider the scheduling at 4589. request a hearing under either 21 CFR determination. Id. The ALJ also reasoned that the FDA’s 14.172 or 21 CFR 15.1(a), see ALJ at 17 The Court, however, also addressed ‘‘detailed administrative process [for] & n.5,7 runs counter to Congress’s the Petitioner’s other challenges to the making its scientific and medical fact manifest interest in the expeditious rule, including that HHS had acted in an findings suggests that Congress did not resolution of proceedings to control a arbitrary and capricious manner because intend the DEA to secondarily review drug. it ‘‘failed to look beyond its own files those filings.’’ ALJ at 17. Citing a 1999 In its Exceptions, Meda contends that upon receiving the Administrator’s Hearing Report of the Subcommittee on ‘‘the ALJ’s decision in this proceeding is section 811(b) request,’’ that it did not Oversight and Investigations of the predicated upon an erroneous belief that ‘‘consult any organization of medical House Committee on Commerce, the Meda had an opportunity to challenge professionals’’ or FDA’s ‘‘Drug Abuse ALJ noted that the ‘‘ ‘the scientific and the scientific and medical fact-finding Advisory Committee,’’ that it simply medical evaluation process is a complex underlying’’ the HHS recommendation. rubber-stamped DEA’s eight-factor one which is part of the balancing of the Meda Exc. at 1. The exception is well analysis, and that it had failed to interests of various agencies’ ’’ and that taken. Indeed, as set forth in footnote forward a letter from NIDA which the process ‘‘may extend over many seven above, under both of these questioned evidence pertaining to years, [and] is subject to review by provisions, the decision as to whether to MDMA’s abuse potential in animals. Id. various components of the FDA and grant a hearing is discretionary. at 897. In rejecting the Petitioner’s interagency review.’’ Id. The ALJ further Requiring that Meda litigate the medical contention, the court explained: noted that under two different FDA and scientific findings before an FDA regulations, Meda could have requested forum would likely add several years of [T]he HHS recommendation to schedule a delay, and would raise a host of substance is not binding and, indeed, serves a hearing before the FDA. ALJ at 17–18 to trigger an administrative hearing at which n.5; see also id. at 4 n.2. additional issues, including whether interested persons may introduce evidence to However, in enacting subsection DEA was required to stay its proceeding rebut the Secretary’s scheduling 811(a), Congress did not bifurcate the while the findings were being recommendation. Ultimately, of course, hearing between the two Agencies. challenged before an FDA forum, responsibility rests with the Administrator, Rather, it tasked the Attorney General whether those findings are entitled to not HHS, to ensure that the final rule rests with the responsibility for conducting res judicata effect if a formal evidentiary on permissible legal standards and the hearing. Moreover, neither the hearing was not held, whether the substantial evidence. statute nor the legislative history FDA’s decision was a final decision Id. (footnote omitted). evidences that Congress intended that triggering the right to judicial review, As Grinspoon makes clear, while the and likely others. medical judgments are final and not subject to Also unpersuasive is the ALJ’s Secretary is the expert as to the litigation before the DEA.’’ Id. at 13. reasoning that because the FDA’s scientific and medical matters at issue However, after concluding that Grinspoon does process for evaluating a scheduling in the scheduling decision, the Attorney not support Meda and was distinguishable because request is complex and time-consuming, General is obligated to conduct a the Agency had blindly relied on FDA approval as the sine qua non of the ‘‘currently accepted medical ‘‘Congress did not intend the DEA to hearing and to consider contrary use’’ and ‘‘accepted safety for use * * * under secondarily review those findings.’’ ALJ evidence even as to these issues. The medical supervision’’ standards, the ALJ quoted the at 17. As the House Report makes plain, legislative history buttresses this passage set forth above and observed that ‘‘[i]n light conclusion.6 As the House Report of th[e Administrator’s] independence, and Meda’s opportunity to present evidence relevant to the 7 Under 21 CFR 14.172, ‘‘[a]ny interested person explains: Administrator’s decision, this tribunal would be may request, under § 10.30, that a specific matter hard-pressed to conclude that there was ‘‘ ‘no relating to a particular human prescription drug be 6 Throughout her discussion, the ALJ explained opportunity for consideration of the views of submitted to an appropriate advisory committee for that ‘‘the CSA limits the scope of the administrative persons who would be adversely affected by control a hearing and review and recommendations * * *. hearing to those issues outside of the medical and of the drug.’ ’’ Id. at 16 (quoting H. Rep. No. 91– The Commissioner may grant or deny the request.’’ scientific fact-findings of the FDA,’’ that ‘‘Congress 1444, at 23 (1970)). Yet, she subsequently Under 21 CFR 15.1(a), the Commissioner may intended that the Secretary’s scientific and medical concluded that ‘‘the plain language and legislative ‘‘conclude[], as a matter of discretion, that it is in fact-findings bind the DEA throughout the history * * *, federal case law, and [HHS’s] process the public interest to permit persons to present scheduling process,’’ that ‘‘Respondent will be for conducting its administrative review, make clear information and views at a public hearing on any afforded the opportunity for a meaningful APA that Congress intended that the Secretary’s matter pending before the Food and Drug hearing without the opportunity to litigate the scientific and medical fact-findings bind the DEA Administration.’’ Notably, under both provisions, factual underpinnings of the [HHS] report,’’ ALJ at during the hearing and the subsequent scheduling the decision as to whether to grant a hearing is 11, and that Gonzales ‘‘indicate[s] that [the FDA’s] determination.’’ Id. at 18. within the Commissioner’s discretion.

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in enacting the scheduling provisions, along with additional evidence not ‘‘required to wait until a number of Congress manifested its intention that provided by DEA’s witnesses and the lives have been destroyed or substantial scheduling proceedings would be done testimony and exhibits submitted by problems have already arisen before’’ in an expeditious fashion, but with ‘‘full Meda. controlling a drug. Id. The legislative history further consideration of all factors involved in Factor 1—Carisoprodol’s Actual or explains that ‘‘[i]n speaking of the decision,’’ including the medical Relative Potential for Abuse and scientific determinations involved ‘substantial’ potential the term in the decision. 1970 U.S.C.C.A.N. at The terms ‘‘abuse’’ and ‘‘potential for ‘substantial’ means more than a mere 4589 (emphasis added). The ALJ’s abuse’’ are not defined in the CSA. See scintilla of isolated abuse, but less than conclusion that the medical and generally 21 U.S.C. 802. However, the a preponderance.’’ Id. Thus, evidence scientific findings of FDA are binding legislative history of the CSA explains that ‘‘several hundred thousand dosage and cannot be ‘‘secondarily review[ed]’’ that a drug or ‘‘substance has a potential units of a drug have been diverted in this proceeding, is contrary to this for abuse because of its depressant or would be ‘substantial’ evidence of abuse intent. stimulant effect on the central nervous despite the fact that tens of millions of Accordingly, consistent with the system or its hallucinogenic effect’’ dosage units of that drug are APA’s requirement that the record as a based on the following indicators: legitimately used in the same time whole must be considered, I hold that, 1. Individuals are taking the substance in period.’’ Id. Moreover, ‘‘[m]isuse of a notwithstanding the Secretary’s amounts sufficient to create a hazard to their drug in suicides and attempted suicides, expertise as to the scientific and health or to the safety of other individuals or as well as injuries resulting from medical matters, the Agency is (and the to the community; or unsupervised use are regarded as 2. There is significant diversion of the drug indicative of a drug’s potential for ALJ was) obligated to consider Meda’s or substance from legitimate drug channels; contrary evidence even as to the or abuse.’’ Id. Secretary’s medical and scientific 3. Individuals are taking the substance on As the Assistant Secretary noted, findings and to determine whether their own initiative rather than on the basis ‘‘there is no single test or assessment substantial evidence supports the of medical advice from a practitioner procedure that, by itself, provides a full finding that carisoprodol ‘‘has a licensed by law to administer such and complete characterization of a potential for abuse,’’ as well as the substance; or substance’s abuse potential, as this is a 4. The substance is so related in its action findings made in support of placing the complex determination that is to a substance already listed as having a multidimensional.’’ GX 6, at 3. drug in schedule IV. See 21 U.S.C. potential for abuse to make it likely that it 811(a). will have the same potential for abuse as Accordingly, in ‘‘assessing the abuse However, while the ALJ misconstrued such substance, thus making it reasonable to potential of a substance, the Secretary the statute, she did allow Meda to put assume that there may be significant considers multiple factors, data sources on evidence to rebut the Secretary’s diversions from legitimate channels, and analyses,’’ including ‘‘the evaluation of the medical and scientific significant use contrary to or without medical prevalence, frequency and manner of evidence. Because ‘‘[t]he Agency, and advice, or that it has a substantial capability use in the general public and specific of creating hazards to the health of the user subpopulations, the amount of material not the ALJ, is the ultimate factfinder,’’ or to the safety of the community. Reckitt & Colman, 788 F.2d at 26, I that is available for illicit use, as well as conclude that ALJ did not commit Comprehensive Drug Abuse Prevention evidence relevant to populations that prejudicial error. Cf. 5 U.S.C. 706 (‘‘due and Control Act of 1970, H.R. Rep. No. may be of particular risk.’’ Id. account shall be taken of the rule of 91–1444, reprinted in 1970 U.S.C.C.A.N. The Assistant Secretary further prejudicial error’’). Accordingly, a 4566, 4601. explained that: remand is not necessary and I proceed The legislative history also explains [a]nimal, human, and epidemiological data to consider the evidence with respect to that a determination that a substance are all used in determining a substance’s the section 811(c) factors. has ‘‘potential for abuse’’ should not ‘‘be abuse potential. Scientifically, a determined on the basis of isolated or comprehensive evaluation of the relative Findings of Fact occasional nontherapeutic purposes.’’ abuse potential of a substance includes Since 1959, carisoprodol has been Id. at 4602 (other citation and int. consideration of the drug’s receptor binding quotations omitted). Rather, ‘‘there must affinity, preclinical pharmacology, approved for marketing in the United reinforcing effects, discriminative stimulus States under the brand name of Soma; exist a substantial potential for the effects, dependence producing potential, the drug, which is also available as a occurrence of significant diversions pharmacokinetics and routes of generic drug, is approved by the FDA from legitimate channels, significant use administration, toxicities, assessment[] of the for the ‘‘relief of discomfort associated by individuals contrary to professional clinical efficacy, safety database relative to with acute, painful musculoskeletal advice, or substantial capability of actual abuse, clinical abuse potential studies conditions.’’ GX 6, at 1 (letter of Howard creating hazards to the health of the user and the public health risks following or the safety of the community.’’ Id. marketing of the substance. Epidemiological H. Koh, M.D., Asst. Sec. for Health, data can also be an important indicator of HHS, to the Administrator (Oct. 6, However, the legislative history also makes clear that the Attorney General is actual abuse. Finally, evidence of clandestine 2009)). As noted above, on October 6, production and illicit trafficking of a 2009, HHS completed its review and substance are also important factors. recommended that carisoprodol be the HHS recommendation.’’ Meda. Br. 22. However, most of the findings in the FDA’s evaluation were Id. Set forth below is the parties’ controlled and placed in schedule IV of supported by citations to publicly available articles, evidence as to each of the four the CSA. Id. and it is not clear why an FDA witness was required indicators of carisoprodol’s potential for to testify as to the contents of articles which have FDA made extensive findings as to abuse.9 each of the eight section 811(c) factors. been published in scientific and medical journals. 8 Moreover, Meda did not seek to subpoena any of These findings are discussed below, the FDA officials who were involved in the review. 9 I have considered Meda’s argument that by Finally, while the Government did not call an FDA relying on the four indicators of abuse set forth in 8 Meda argues that the FDA review ‘‘is entitled to or HHS witness ‘‘to answer questions about the the legislative history, the Agency ‘‘has improperly very little weight’’ because ‘‘DEA counsel did not numerous weaknesses in the data,’’ Meda was attempted to redefine ‘abuse’ to mean something call any HHS or FDA witness to testify and justify clearly able to put on an effective challenge to some much broader than what the Committee the scientific, medical, and legal basis underlying of the data cited by the Government. contemplated (i.e., use for nontherapeutic

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1. Use of Carisoprodol Results in Harm dawninfo.samhsa.gov/). DAWN is a meet the definition of medical use.’’ Id. to Individuals and the Public national probability survey of U.S. Under this definition, ‘‘nonmedical use hospitals with emergency departments The FDA found that an evaluation of of pharmaceuticals includes taking more (EDs) which is designed to obtain published case reports and case series, than the prescribed dose of a information on ED visits in which the FDA Adverse Event Reporting prescription pharmaceutical * * *; recent drug use is implicated. The data System (AERS), and the SAMHSA taking a pharmaceutical prescribed for are gathered from a representative DAWN databases, show that another individual; deliberate poisoning sample of hospital EDs and are weighted carisoprodol as currently used raises with a pharmaceutical by another to produce national estimates. In concerns not only for the health and person; and documented misuse or addition to the DAWN ED data, DAWN safety of the users of this substance, but abuse of a prescription’’ pharmaceutical. also collects data on drug-related deaths also for the public because of exposure Id. Because of ‘‘the limitations of investigated by Medical Examiners and medical record documentation, [DAWN to those who use carisoprodol. More Coroners (ME/C).11 specifically, the FDA found that these has] concluded that distinguishing sources of information indicate that DAWN ED Data misuse from abuse reliably is not feasible.’’ Id. n.13. serious adverse events, including death, According to FDA, many factors can Selected data from DAWN for 2004– drug dependence, drug withdrawal impact the estimates of ED visits, GX 6, 2007 are shown in Table 1 below. These symptoms, and non-intentional and at 11; which ‘‘are identified through a data show an increase in the frequency deliberate overdose are related to the retrospective review of medical charts.’’ abuse of carisoprodol. MX 34, at 33 n.13. Individuals (whether of nonmedical use ED visits associated The FDA further noted that adverse patients or drug abusers) who use a drug with carisoprodol. More specifically, in events have occurred both when may visit EDs for a variety of reasons, 2004, DAWN estimated that there were carisoprodol is the sole drug of use, as including treatment of a life threatening 14,736 ED visits related to the well as when it is used in combination adverse event or to obtain a certification nonmedical use of carisoprodol, and with other drugs, both licit and illicit of need before entering a formal that in 2007, there were 27,505 (polypharmacy). In addition, the use of detoxification program. If multiple nonmedical ED visits related to the carisoprodol has been implicated as a drugs are involved, DAWN may not be nonmedical use of the drug. However, factor in vehicle accidents due to driver able to distinguish whether a single according to SAMHSA, the increase impairment. The FDA thus concluded drug or the interaction of drugs caused from 2004 through 2007 did not reach that there is evidence that individuals the ED visit. Moreover, while ‘‘DAWN statistical significance. GX 6, at 12. are taking the substance in amounts tries to capture only drugs that are Accordingly, the data do not support a sufficient to create a hazard to their related to the ED visit and actively finding that the rate of abuse of health or to the safety of other discourages the reporting of current carisoprodol is increasing. individuals or to the community.10 medications that are unrelated to the The data do, however, support a visit[,] * * * it is not possible, given the finding that carisoprodol is resulting in Drug Abuse Warning Network (DAWN) limitations of medical record ED visits at a level comparable to that Data documentation, to eliminate completely of diazepam, a benzodiazepine and The Substance Abuse Mental Health the reporting of current medications.’’ schedule IV controlled substance. As Service’s Administration (SAMHSA) MX 34, at 33. Table 1 shows, in 2004 there were an administers the Drug Abuse Warning In addition, DAWN defines estimated 15,619 ED visits related to Network (DAWN, 2007; http:// ‘‘nonmedical use’’ as ‘‘use that does not diazepam.12

TABLE 1—SELECTED PHARMACEUTICAL ED VISITS (NONMEDICAL USE): 2004–2007 FROM DAWN [Data output 08/02/2008]

Estimates Selected drugs 2004 2005 2006 2007

Carisoprodol ...... 14,736 20,082 24,505 27,128 Cyclobenzaprine ...... 6,183 7,629 7,142 6,197 Diazepam ...... 15,619 18,433 19,936 19,674

purposes).’’ Med. Br. 13. However, as the Assistant mortality component of DAWN is not national in present in the deceased as a result of carisoprodol Secretary noted, determining a substance’s potential scope, and Medical Examiners or Coroners (ME/Cs) metabolism.’’ Id. Finally, FDA noted that ‘‘[t]he for abuse is a complex and multi-dimensional that report to DAWN are concentrated in reporting of carisoprodol found by the ME/C determination which includes an analysis of metropolitan areas.’’ GX 6, at 17. The FDA then following a post mortem examination does not animal, human, and epidemiological studies, as acknowledged that because ‘‘the report does not necessarily imply that carisoprodol was the well as other factors, GX 6, at 3; and the record represent a scientific sample, results from ultimate cause of death * * *, only that it was contains extensive evidence as to the numerous participating jurisdictions cannot be extrapolated identified by the ME/C as involved in the death,’’ considerations relevant in assessing a drug’s abuse nationally,’’ and that ‘‘because participants can vary and that ‘‘[v]ery few deaths from 2003 and 2004 from year to year, it is not appropriate to compare potential. involve the use of carisoprodol by itself and are aggregated death data between years.’’ Id. Moreover, 10 consistent with other data indicating that The FDA more fully discussed the data under because ‘‘[c]ertain jurisdictions within the Factor Four—carisoprodol’s history and current metropolitan area may not participate in DAWN carisoprodol is used most often in combination patterns of use, and Factor Six—what, if any, risk * * * selected data can not necessarily be with a variety of other agents.’’ Id. at 18. Because there is to public health. GX 6, at 3. generalized to an entire metropolitan area.’’ Id. of the numerous limitations with this data, I give 11 According to the FDA’s report, DAWN FDA further noted that ‘‘[a]pproximately half of no weight to the DAWN ME/C data. mortality cases now include the following deaths: the carisoprodol-related deaths reported involve the 12 In 2007, DAWN ED carisoprodol visits also Completed suicides, Overmedication, Adverse use of meprobamate in combination with accounted for an increasing percentage of the reactions, Accidental ingestions, Homicide by carisoprodol’’ and that ‘‘[d]ue to reporting method nonmedical use ED visits associated with skeletal drugs, Underage drinking and Other deaths related variability, it is difficult to determine if both drugs muscle relaxants, increasing each year from 59 to drugs. The FDA further noted that ‘‘[t]he were taken in combination or if meprobamate was percent in 2004, to 70 percent in 2007.

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By dividing the number of ED visits 2 below, show that the ‘‘abuse cyclobenzaprine, another skeletal by the number of prescriptions, FDA frequency’’ of carisoprodol is in the muscle relaxant had a rate of 4.1 ED calculated ‘‘abuse frequencies’’ for same range as diazepam and greater visits per 10,000 prescriptions. Most carisoprodol; cyclobenzaprine, a non- than that of cyclobenzaprine. More significantly, even in 2004, and before scheduled muscle relaxant; and specifically, even in 2004, the the increase in the estimates of diazepam, which is also prescribed for carisoprodol rate was 15.1 ED visits per carisoprodol-related ED visits, its muscle relaxant properties. These 10,000 prescriptions, while diazepam’s carisoprodol had a greater frequency of calculations, which are found in Table rate was 12.5. By contrast, ED related visits than diazepam.

TABLE 2—FREQUENCY OF DAWN ED VISITS (NONMEDICAL USE) PER 10,000 RX FOR CARISOPRODOL, CYCLOBENZAPRINE AND DIAZEPAM [2004–2007]

Selected drugs 2004 2005 2006 2007

Carisoprodol ...... 15.1 19 .7 22.9 22.6 Cyclobenzaprine ...... 4.1 4 .61 4.1 3.3 Diazepam ...... 12.5 14 .5 15.0 14.1

Data derived from proprietary SDI data. SDI Vector One®: National, Years 2002–2007, Data Extracted April, 2008 File: VONA 2008–517 4– 15 13

the majority of the cases published in benzodiazepines (alprazolam, diazepam, Carisoprodol has been reported as a the scientific literature report that clonazepam), alcohol, and illicit drugs primary or sole drug of abuse in DAWN carisoprodol abuse has primarily been a (marijuana, cocaine). Table 3 below sets only since 2006. According to the 2006 component of multi-drug abuse. forth the respective levels of DAWN data, there were an estimated FDA reviewed DAWN data and found carisoprodol ED visits related to single 24,505 ED visits related to carisoprodol, that the drugs most frequently used in use and as a component of multi-drug of which it was reported as the sole drug combination with carisoprodol that use. in 21 percent of the cases. This is resulted in ED visits were opioids consistent with the FDA’s finding that (hydrocodone, oxycodone),

TABLE 3—ESTIMATED NONMEDICAL USE—CARISOPRODOL ED VISITS FROM DAWN 2006, AS SOLE DRUG AND IN COMBINATION WITH OTHER DRUGS

All patients Females only Males only Drug Number Percent Drug Number Percent Drug Number Percent

Total Carisoprodol ..... 24,505 ...... Total Carisoprodol .... 14,219 42 Total Carisoprodol .... 10,286 58 Carisoprodol single- 5,055 21 Carisoprodol single- 3.870 27 Carisoprodol single- 1,185 12 drug. drug. drug. Carisoprodol multi- 19,450 79 Carisprodol multi-drug 10,349 73 Carisoprodol multi- 9,101 88 drug. drug. Information received from SAMHSA on June 18, 2008.

FDA also found that although MEDA’s Evidence Regarding the DAWN More specifically, Mr. Dasgupta carisoprodol is approved for short term Data criticized the sampling methodology use (3 weeks), SDI Vector One data from Meda offered the testimony of used by DAWN, noting that DAWN uses 2002–2006 14 show that more than 25 Mr. Nabarun Dasgupta as an expert an oversample of hospitals in select percent of patients used the drug for witness in epidemiology and metropolitan areas and a sample of longer than one month, and 4.3 percent pharmacoepidemiology. MX 173; Tr. hospitals from the rest of the country used the drug for more than 360 days. 628. Mr. Dasgupta offered a lengthy and that ‘‘[t]he number of hospitals GX 6, at 15. FDA concluded that longer critique of the DAWN ED data and sampled is relatively small compared to term use may contribute to increased opined that ‘‘the DAWN ED data are the national estimates that are risks of misuse and abuse. Id. subject to constraints that limit their extrapolated from the sample.’’ Id. Mr. potential reliability for use in scientific Dasgupta noted that for the year 2007, research and public health policy.’’ ‘‘207 hospitals submitted provided data MX 173, at 3. on 300,983 drug related ED visits * * *.

13 According to FDA, SDI’s Vector OneTM The Vector OneTM database integrates pharmacies throughout the United States, and National (VONA) measures retail dispensing of prescription activity from a variety of sources represents approximately half of retail prescriptions prescriptions or the frequency with which drugs including national retail chains, mass dispensed nationwide. Id. SDI receives all move out of retail pharmacies into the hands of merchandisers, pharmacy benefits managers and prescriptions from approximately one-third of the consumers via formal prescriptions. GX 6, at 13 n.7. their data systems, and provider groups. Id. Vector stores and a significant sample of prescriptions Information on the physician’s specialty, the One receives over 1.8 billion prescription claims from the remaining stores. Id. patient’s age and gender, and estimates for the per year, representing over 150 million unique 14 See Table 6 from the OSE ‘‘Duration of Use numbers of patients that are continuing or new to patients. Id. The number of dispensed prescriptions Analysis’’ for Soma (NDA 11–792) dated June 27, therapy are available. Id. is obtained from a sample of virtually all retail 2007.

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which resulted in a national estimate of epidemiologists considers to be estimates is attributable to changes in 3,998,228 drug-related ED visits.’’ Id. at necessary to establish the validity of a methodology versus changes in the 3–4. Mr. Dasgupta further stated that methodology and the statistical methods actual number of DAWN cases ‘‘[t]he location of all hospitals used to extrapolate the data to develop associated with a particular drug’’ and participating * * * is not disclosed due a national estimate. While Mr. ‘‘[t]his hinders any effort to interpret the to privacy reasons,’’ and that ‘‘the Dasgupta’s criticisms of the DAWN ED meaning of time trends.’’ Id. number of hospitals can change post data may be based on the generally On examination by the ALJ, Mr. hoc in the published annual report accepted standards of epidemiology, in Dasgupta testified that this, i.e., the tables.’’ Id. at 4. As support for the latter the absence of evidence establishing increase ‘‘attributable to enhanced case- assertion, Mr. Dasgupta cited the 2005 those standards, there is no basis for finding versus [that] attributable to the and 2006 annual reports; however, only concluding that his criticisms of DAWN underlying actual abuse * * * is one of these (the 2006 report) was ED data reflect those of the community something that is routinely looked at in submitted for the record. of epidemiologists rather than his epidemiologic studies.’’ Tr. 657. He also Later in his testimony, Mr. Dasgupta personal opinion. suggested that in such circumstances, ‘‘a asserted that ‘‘[o]nce the cases in the Mr. Dasgupta further asserted that the validation study’’ would be done to participating hospitals are counted, scientific validity of the data ‘‘is determine how well those persons who DAWN applies statistical methods to questionable’’ because it ‘‘does not review the case files were doing. Id. at extrapolate to a ‘national estimate,’ ’’ conform with the FDA’s published 658. However, even acknowledging the and that each case is given ‘‘a weight guidance on Good Pharmacovigilance validity of this criticism, the FDA’s from 1 to 60 to arrive at the national Practices and Pharmacoepidemiologic recommendation stated that the increase estimates,’’ and that while it is ‘‘routine Assessments.’’ MX 173, at 4–5. in the estimates of carisoprodol-related to describe how weights are derived,’’ According to Mr. Dasgupta, this ‘‘call[s] ED visits between 2004 and 2007 was DAWN does not ‘‘completely describe into question whether DAWN ED data not statistically significant. the process.’’ Id. at 14. Mr. Dasgupta should be used by FDA and FDA- Mr. Dasgupta also observed that also explained that while such factors as regulated entities for post-marketing ‘‘DAWN has acknowledged the ‘‘‘non-response,’ missing data, hospital surveillance.’’ Id. However, Mr. difficulty in identifying cases of abuse’’ size, physical location, whether it is an Dasgupta did not identify in what because of the limitation of medical academic training hospital, and other respect DAWN does not comply with record documentation. Id. at 7. As Mr. factors are accounted for in the weight, the FDA’s guidance. See id. Nor is it Dasgupta observed, because DAWN * * * the method for doing this is not clear why compliance with the FDA’s defines ‘‘nonmedical use’’ to include a published.’’ Id. Mr. Dasgupta concluded guidance is necessary to establish that variety of scenarios beyond misuse/ that ‘‘the credibility of the national the DAWN ED data, which is only an abuse, ‘‘ED visits counted as DAWN data * * * hinges on the estimate, is not sufficiently reliable to ‘nonmedical use’ ’’ by DAWN ‘‘do not statistical methods employed to analyze support a finding that carisoprodol ‘‘has necessarily represent cases of abuse as the sample data, but SAMHSA does not a potential for abuse.’’ 21 U.S.C. that term is commonly understood,’’ publicly disclose the current methods. 811(a)(1)(A). and as ‘‘used for purposes of We do not know how the weights of the Mr. Dasgupta’s next criticism was that scheduling.’’ Id. at 9–10. individual hospitals are being applied, the reporters of DAWN ED data ‘‘may Mr. Dasgupta also noted that and we do not know what impact the identify an ED visit as a DAWN case ‘‘[a]lthough current medications extrapolations may be having on the even if the patient has a valid unrelated to the visit are not supposed reported national estimates.’’ Id. prescription for the drug(s) mentioned to be recorded, distinguishing Mr. Dasgupta thus opined that ‘‘[t]he in the ED chart and is taking the drug(s) medications that pertain to the ED visit lack of information provided by DAWN for therapeutic purposes.’’ Id. at 5. Mr. from those that do not requires a concerning its statistical extrapolation Dasgupta noted that ‘‘[w]hile Reporters complex toxicological determination,’’ methods hinders interpretation and are trained on selecting cases, no which hospitals may not conduct ‘‘in hence limits the weight that can be published studies have evaluated the the interest of providing expedient given the DAWN national estimates.’’ consistency between Reporters or medical care.’’ Id. at 10. Mr. Dasgupta Id. at 14–15. between hospitals, or over time.’’ Id. Mr. stated that differences in how toxicology On examination by the ALJ, Mr. Dasgupta also noted that this ‘‘calls into testing is conducted at different Dasgupta was asked if, ‘‘within the question the reliability of reporting hospitals ‘‘may influence whether a community of epidemiologists, * * * across sites, given the lack of published drug is detected,’’ and that ‘‘the simple the DAWN ED national estimation [is] validation of the consistency between presence of a drug in toxicology results still relied upon?’’ Tr. 652. Mr. Dasgupta Reporters at different sites.’’ Id. is not sufficient to implicate its replied that ‘‘[t]he DAWN ED data are Mr. Dasgupta further noted that ‘‘there involvement in an ED visit.’’ Id. at 12. important to look at,’’ and that ‘‘others has been a concerted effort by SAMHSA He further noted that ‘‘it is highly and the contractor to improve [the] would agree * * * in that it sets * * * probable that to some extent the selection of cases, [which is] aimed at it’s the data that is used for policy determination of the involvement of identifying more ED visits for making.’’ Id. Mr. Dasgupta then asserted unrelated medications may be inclusion.’’ Id. at 5–6. Mr. Dasgupta that ‘‘[f]rom a scientific perspective, it inherently subjective, [and may] vary stated that because there has been ‘‘no doesn’t carry much weight.’’ Id. between Reporters,’’ who have different public documentation of this process,’’ However, DAWN ED does not purport to training and experience.15 Id. at 10. be anything other than an estimate, and it is not clear if ‘‘the increases in cases Mr. Dasgupta’s testimony suggests that over time is due to better case finding 15 Mr. Dasgupta also testified that the DAWN data epidemiologists still consider the or due to increases in the underlying may be affected by diagnostic suspicion bias in that estimates sufficiently reliable to make sociobiologic phenomena that give rise DAWN reporters may have become sensitized by policy decisions. to DAWN cases.’’ Id. at 6. According to news reports or other information as to the abuse of a particular drug, and therefore, may over-report Moreover, Mr. Dasgupta generally did Mr. Dasgupta, ‘‘it is impossible to such cases. MX 173, at 12. However, Mr. Dasgupta not identify what practices (including conclusively say what proportion of the produced no evidence as to the existence of this what level of disclosure) the field of increases in DAWN ED national Continued

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However, Mr. Dasgupta then opined that withdrawal syndrome. GX 6, at 15. In www.fda.gov/Drugs/Guidance ‘‘drugs are most often identified by the majority of cases, multiple drugs ComplianceRegulatoryInformation/ patient self-reporting,’’ that ‘‘[o]nly a were used, but there are 61 unique Surveillance/AdverseDrugEffects/ small percentage is confirmed by reports where carisoprodol was the only default.htm. Accordingly, ‘‘AERS toxicology tests,’’ and that therefore, suspect drug. Id. cannot be used to calculate the ‘‘DAWN data are subject to all of the Meda’s Chief Medical Officer (CMO) incidence of an adverse event in the uncertainties and potential provided more up-to-date data. In his U.S. population.’’ Id. Indeed, the misidentifications associated with self- written direct testimony, MEDA’s CMO voluntary nature of the reports suggests reporting.’’ 16 Id. at 13. stated that ‘‘MEDA’s database contains a that they are likely to under-represent As explained above, DAWN explicitly total of 731 spontaneous adverse events the actual number of adverse events. recognizes the limitations inherent in for carisoprodol from January 1979 Florida Medical Examiners Commission medical record documentation. through May 1, 2010,’’ of which ‘‘only Data Moreover, even crediting Mr. Dasgupta’s 83 reports included the terms abuse, criticisms, as even he recognized, ‘‘[t]he dependency, or withdrawal.’’ MX 171, In 2008, Florida’s medical examiners DAWN ED data are important to look at 10. MEDA’s CMO further noted that reported 8,556 drug-related deaths at’’ and ‘‘it’s the data that is used for in the five-year period of 2005–2009, (whether the drug was the cause of policymaking.’’ Tr. 652. The DAWN ED more than 54 million prescriptions, death or merely present) through data provide only an estimate; the data totaling nearly four billion tablets of toxicology reports submitted to the constitute just one of many pieces of carisoprodol, were dispensed. Id. at 11. Medical Examiners Commission. GX 7, evidence which support the conclusion While the AERS data appears at 11. The presence of carisoprodol and/ that persons are taking carisoprodol ‘‘in relatively small when compared with or its metabolite, meprobamate, was amounts sufficient to create a hazard to the total number of prescriptions, as found in 415 deaths (5 percent of the their health.’’ explained in footnote fifteen, this data is drug related deaths). Id. In 84 of these obtained from health care professionals deaths (20%), carisoprodol was FDA Adverse Event Reporting System 17 and consumers, both of whom determined to be the cause of death. Id. (AERS) Data voluntarily submit the reports. As FDA The following table lists, for the years As noted above, FDA also reviewed notes, it ‘‘does not receive all adverse 2003 through 2008, the number of the AERS data and found that through event reports that occur with a product’’ deaths in which carisoprodol and June 2007, there were a total of 472 as ‘‘[m]any factors can influence meprobamate were found in toxicology reports related to potential carisoprodol whether or not an event will be testing and the number of deaths in abuse, including 48 reports identifying reported.’’ FDA, Adverse Events which carisoprodol and meprobamate dependence and 19 identifying Reporting System, available at http:// were found to be a cause of death.

TABLE 4—FLORIDA MEDICAL EXAMINER’S DATA 2003–2008

Total Cause % Change Year Drugs found in body occurrences (% total) Present from prior year

2003 18 ...... Carisoprodol/Meprobamate ...... 208 45 (22) 163 ND 2004 ...... Carisoprodol/Meprobamate ...... 289 81 (28) 208 39 2005 ...... Carisoprodol/Meprobamate ...... 314 96 (31) 218 9 2006 ...... Carisoprodol/Meprobamate ...... 313 74 (24) 239 ¥0.3 2007 ...... Carisoprodol/Meprobamate ...... 337 88 (26) 249 8 2008 ...... Carisoprodol/Meprobamate ...... 415 84 (20) 331 23

Id.; see also GX 7, at 11. carisoprodol/meprobamate was present where the deaths were found to be With respect to this data, Mr. in a body and those in which a medical caused by an overdose. Dasgupta stated that ‘‘[t]he presence of examiner concluded that the ingestion Mr. Dasgupta further concluded that a drug in the body does not establish it of carisoprodol or meprobamate was a because the data combines carisoprodol as a cause of death’’ or necessarily cause of death. Likewise, while a drug’s and meprobamate, ‘‘it is not possible to ‘‘indicate drug abuse.’’ MX 173, at 23. presence in the body does not determine * * * which drug * * * was As for the first contention, the data necessarily establish that the person was a cause of death.’’ Id. at 23. However, recognizes as much as it differentiates engaged in ‘‘drug abuse,’’ it nonetheless carisoprodol metabolizes into between those instances in which is an indicator of drug abuse, especially meprobamate, and other data in the toxicology testing established that record (more specifically, the NSDUH

phenomenon among DAWN reporters either missing data like these, and the choice of which of for all approved drug and therapeutic biologic generally or with respect to carisoprodol. those imputation methods * * * can very strongly products. GX 6, at 15. The FDA receives adverse 16 Mr. Dasgupta further noted that DAWN may at influence your results,’’ that ‘‘the onus is on the drug reaction reports from manufacturers as times impute data when data is missing from researcher to show that those assumptions have required by regulation. Id. Health care professionals been met and that the method selected is the certain hospitals. MX 173, at 18–19. While Mr. and consumers send reports voluntarily through the Dasgupta suggested that this practice is of appropriate one,’’ and that ‘‘if there is kind of [a] MedWatch program, which become part of a ‘‘questionable validity,’’ id., this is not the same as referenced imputation[,] it’s odd to not see those saying that this practice is not generally accepted kinds of descriptions on which statistical database; the database complies with the by experts in the field. Indeed, on examination by imputation method is used.’’ Id. at 669–70. international safety reporting guidance (ICH E2B) the ALJ, Mr. Dasgupta testified that ‘‘it is valid to However, Respondent produced no evidence that issued by the International Conference on use imputation methods to fill in missing data, but the use of imputed data has affected the DAWN Harmonization. Id. it’s a very, very sensitive issue that needs to be done data for carisoprodol. 18 Carisoprodol was scheduled as C–IV in Florida carefully.’’ Tr. 669. Mr. Dasgupta then stated that 17 The Adverse Event Reporting System (AERS) is ‘‘[t]here are three, four, maybe five major ways in a computerized database designed to support the in July 2002, but was not tracked until 2003. GX which imputation is done in epidemiology to fill in FDA’s postmarketing safety surveillance program 6, at 18.

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data, see Table 7) indicates that more occurrences * * * has generally been the American Association of Poison than eleven times as many persons have decreasing annually since 2005.’’ Id. at Control Centers (AAPCC), show that engaged in the nonmedical use of 24. However, it is doubtful that this carisoprodol products are involved in a carisoprodol than have engaged in the change is statistically significant, and number of toxic exposures (Table 5). nonmedical use of meprobamate. This even if it is, the data still show that a Some of these carisoprodol exposures supports the conclusion that the great significant and disturbing number of led to major adverse health outcomes majority of the Florida Medical persons have died from carisoprodol (Table 6). For example, in 2007, Examiner cases in which carisoprodol/ overdoses and are dying each year in carisoprodol was associated with 8,821 meprobamate was determined to be a this State alone. toxic exposure cases, including 3,605 cause of death are attributable to cases in which it was the sole drug National Poison Data System carisoprodol.19 mentioned. A total of 122 of the 2,821 Finally, Mr. Dasgupta asserted that Data from the National Poison Data single exposure cases, which were the Florida data shows that ‘‘the Systems (NPDS), formerly known as the treated in a health-care facility, had a proportion of total fatal overdose Toxic Exposure Surveillance System of major adverse health outcome.

TABLE 5—CARISOPRODOL EXPOSURES DATA FROM NATIONAL POISON DATA SYSTEM (NPDS)

2003 2004 2005 2006 2007

Case Mentions...... 8,248 8,765 8,613 8,187 8,821 Single Exposures ...... 3,515 3,605 Note: Single exposure data is not available prior to 2006.

TABLE 6—SERIOUS ADVERSE HEALTH OUTCOMES IN CARISOPRODOL EXPOSURES CASES WHO WERE TREATED IN HEALTH CARE FACILITIES

2003 2004 2005 2006 2007

Treated in Health Care Facility * ...... 6,617 7,032 7,501 2,687 2,821 Deaths ...... 28 30 18 1 1 Major Effect** ...... 406 468 525 105 122 Moderate Effect*** ...... 1,710 1,882 1,953 688 720

Total ...... 2,144 2,878 2,496 794 843 * The data for 2006 and 2007 are from single exposure cases. ** Major effect: The patient exhibited signs or symptoms as a result of the exposure that were life-threatening or resulted in significant residual disability or disfigurement. *** Moderate effect: The patient developed signs or symptoms as a result of the exposure that were more pronounced, more prolonged or more systemic in nature than minor effects.

Regarding the NPDS data, Mr. ‘‘presence and levels of drug * * * Senate Report, which accompanied the Dasgupta acknowledged that the make it impossible to conclude that a CSA’s enactment, expressly stated that persons who answer the calls to the mentioned drug was causally implicated ‘‘[m]isuse of a drug in suicides and regional poison centers ‘‘are nurses, in the exposure.’’ Id. attempted suicides, as well as injuries pharmacists, and physicians who have Mr. Dasgupta also maintained that resulting from unsupervised use are been trained in medical toxicology and ‘‘the single exposure data presented by regarded as indicative of a drug’s are instructed on the proper ways of DEA combines single-entity potential for abuse.’’ S. Rep. 91–613, completing case report forms in a carisoprodol and carisoprodol/aspirin 1970 U.S.C.C.A.N., at 4602. Thus, systematic manner’’ and that the data combination products.’’ Id. at 31 (citing contrary to Mr. Dasgupta’s collection software has ‘‘[a]n extensive Meda Ex. 63).20 However, as the data for understanding, the fact that Table 6 data quality assurance process.’’ MX 2007 show, even if single entity and includes suicides, ‘‘suicide attempts,’’ 173, at 29–30. Mr. Dasgupta then stated combination products should not be and ‘‘accidental pediatric exposures,’’ that there is the ‘‘potential counted together, the amount of case see MX 173, at 34; does not reduce the misidentification of the substance mentions and single exposures data’s probative value in assessing during the initial call to the poison attributable to combination products is carisoprodol’s abuse potential. center’’ and that researchers have a small fraction of both the case Mr. Dasgupta criticized Table 6 ‘‘determined that, for some drugs, 25– mentions (163 v. 8658) and single because it ‘‘purports to show ‘serious 30% are misclassified during the first exposures (69 v. 3536) attributable to adverse health outcomes in carisoprodol call.’’ Id. at 30. However, Meda did not single entity products. See MX 64, at exposure cases,’ ’’ but ‘‘[i]ntentional provide this research and Mr. Dasgupta 1020, 1026. exposure cases can also include did not provide evidence as to what the Mr. Dasgupta also criticized the use of associated medical outcomes that are rate of misclassification is for the NPDS data because the intentional not serious.’’ Id. at 32. Mr. Dasgupta carisoprodol. He then opined that the exposures data includes suicide further asserted that ‘‘[t]he DEA Review self-reporting and (apparently the lack attempts and accidental pediatric does not present enough detail of toxicology test results) showing the exposures. MX 173, at 34. However, the concerning methodology to determine

19 Mr. Dasgupta also raised the possibility that the diagnostic suspicion bias. MX17, at 23. Again, this 20 As support for this assertion, Mr. Dasgupta Florida Medical Examiner data is subject to is simply speculation. cited the 2008 annual report (MX 63); however, the above tables do not include data for that year.

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what type of cases were included in carisoprodol has been found during law rank substantially higher in the NFLIS Table [6].’’ Id. enforcement seizures supports a finding data were it controlled nationally. However, it is apparent that Table 6 that the drug is being abused and The testimony of various officials simply replicates the NPDS’s diverted. Moreover, because further supports a finding that classification of carisoprodol incidents carisoprodol is not controlled in most carisoprodol is being diverted. The by the severity of the outcome. See MX States, there is reason to believe that Deputy Assistant Administrator of 64, at 940–41, 1020, 1026 (2007 report). many laboratories may not report those DEA’s Office of Diversion Control Moreover, even if single entity and incidents in which they have identified testified that carisoprodol was being combination carisoprodol products a substance as carisoprodol. GX 9, at 3. distributed in combination with should not have been added together, Mr. Dasgupta opined that the NFLIS narcotic drugs and benzodiazepines the number of cases attributable to data are of ‘‘limited utility for making through Internet schemes in which combination products is a small fraction public health decisions.’’ MX 173, at 26. patients were issued prescriptions by of those attributable to single entity While he acknowledged that physicians they never saw and could products (15 v. 705 moderate effects carisoprodol has been among the top simply order the drugs through a Web outcomes, 2 v. 120 major effect twenty-five drugs analyzed, Mr. site. GX 9, at 2–3; Tr. 343–44. As several outcomes, and 0 v. 1 death). Compare Dasgupta explained that ‘‘[t]he courts have recognized, the dispensing id. at 1020, with id. at 1026. likelihood of a particular sample being of controlled substances in this manner analyzed is substantially affected by the is a violation of 21 U.S.C. 841(a)(1). See 2. Is there significant diversion of prosecutor’s perceptions of the available United States v. Nelson, 383 F.3d 1227, carisoprodol from legitimate drug criminal charges, as well as politics, 1231–32 (10th Cir. 2004); United States channels? prosecutorial priorities, and v. Smith, 573 F.3d 639, 657–58 (8th Cir. The NFLIS Data bureaucratic influences.’’ Id. at 25. Mr. 2009); United States v. Fuchs, 467 F.3d Current data shows that there is Dasgupta then noted that ‘‘[p]rosecutors 889 (5th Cir. 2006). The Deputy significant diversion of carisoprodol in states where carisoprodol is a Assistant Administrator also noted that from legitimate drug channels. Data controlled substance would be more ‘‘DEA investigations reveal that collected by DEA establishes that likely to submit a sample to NFLIS for thousands of customers throughout the 22 carisoprodol has been seized from identification, as the state-level United States seek carisoprodol, either persons engaged (and places used) in scheduling would be more likely to alone or, most frequently, in illegal activities involving other result in a stiffer criminal penalty,’’ and combination with controlled substances controlled substances, including that ‘‘[f]orensic laboratory data from from pain clinics, physicians, and from diazepam, marijuana, cocaine, these states may be an artifact of state- illicit street dealers.’’ GX 9, at 3. methamphetamine, codeine, and level scheduling because more A Special Agent in Charge with the hydrocodone. DEA has found suspected carisoprodol samples may be Tennessee Bureau of Investigation, who carisoprodol present during the sent for analysis once a controlled oversees drug enforcement execution of search warrants at substance criminal charge is potentially responsibilities in twenty-eight of the residences, offices, and pharmacies. available in a particular state.’’ Id. at 26. State’s counties and who was formerly According to data retrieved from DEA’s As Mr. Dasgupta noted, only seventeen Coordinator of the Tennessee Drug National Forensic Lab Information States have controlled carisoprodol. Id. Diversion Task Force, testified that in System (NFLIS) database, which n.7. his experience, ‘‘carisoprodol has been includes data on samples analyzed by This argument, however, actually used for non-medical purposes and DEA laboratories (STRIDE), as well as supports the Government’s view that illicitly distributed in circumstances state and local forensic laboratories,21 many laboratories do not report that are similar to the non-medical use since 2000, carisoprodol has carisoprodol that is seized during and illicit trafficking in controlled consistently ranked in the top 25 of the criminal investigations, and thus the substances such as oxycodone, drugs most frequently seized and drug is being diverted at even greater hydrocodone, and alprazolam. Law identified by state and local forensic levels than the NFLIS data suggests. enforcement investigations have laboratories during the course of According to U.S. Census data, of which revealed that many Tennesseans seek criminal investigations. I take official notice, the seventeen carisoprodol, either alone or, most In terms of the number of seizures, in States, which have controlled frequently, in combination with 2008, NFLIS reported 4,291 carisoprodol, have a total population of controlled substances from pain clinics identifications of carisoprodol, thus approximately 108 million and thus [and] physicians,’’ who ‘‘conduct little ranking it above such controlled comprise only 35% of the national or no physical examination of the 23 substances as codeine, psilocin, population. See Appendix A. This patients’’ and who ‘‘issue prescriptions lorazepam, MDA, hydromorphone, and suggests that carisoprodol would likely for the specific drugs requested by the methylphenidate. MX 53, at 9. In 2007, ‘patients.’ ’’ GX 10, at 3–4. The official NFLIS reported 4,420 identifications of 22 Contrary Mr. Dasgupta’s understanding, drug also related that carisoprodol is being samples are not submitted ‘‘to NFLIS for carisoprodol, thus ranking it above such sold on the street. Id. at 4. identification.’’ MX 173, at 26. Rather, NFLIS The official also testified that controlled substances as phencyclidine collects reports of drugs items which have been (PCP), psilocin, buprenorphine, MDA, seized and analyzed and identified as a drug by a ‘‘carisoprodol abuse has been implicated in many overdose events in methylphenidate, ketamine, lorazepam, forensic laboratory. However, I agree with Mr. Dasgupta’s opinion that if a criminal charge is not Tennessee including overdose and hydromorphone. MX 54, at 7. available in a State, it is less likely that evidence fatalities,’’ and that reports from the Because the primary focus of law which looks like carisoprodol tablets will be sent State’s medical examiner ‘‘from 2006 enforcement agencies is on investigating to a lab for analysis and subsequently reported to through 2008’’ show that carisoprodol the unlawful distribution of controlled the NFLIS. 23 Pursuant to 5 U.S.C. 556(e), Meda ‘‘is entitled, has been ‘‘associated with drugs, the incidents in which on timely request, to an opportunity to show the approximately 100 deaths.’’ Id. at 3, 5. contrary.’’ In the event Meda disputes the census 21 Participating state and local laboratories handle data, it may file a motion for reconsideration within This official further stated that ‘‘[i]n the 88% of the nation’s 1.2 million analyses of state and fifteen days of the date of service of this rule, which majority of these cases[,] carisoprodol is local drug cases. shall begin on the date of mailing. seen in combination with a ‘cocktail’ of

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other drugs[,]’’ such as ‘‘oxycodone or opiate and a benzodiazepine is rarely 3. Non-Medical Use of Carisoprodol hydrocodone.’’ Id. at 5. clinically indicated,’’ 24 the official The Executive Director of the Ohio ‘‘found that our top ten prescribers of Review of the currently available data State Board of Pharmacy, who has this ‘trinity’ have prescribed this and other information shows that worked as a pharmacist as well as held combination [of drugs] to a range of 140 individuals are taking the substance on oversight/investigatory positions at the [to] 1,376 patients.’’ Id. at 5. The official their own initiative rather than on the Board, testified that he has ‘‘personally further found that ‘‘many patients basis of medical advice from a investigated cases involving received carisoprodol from multiple practitioner licensed by law to carisoprodol,’’ and that ‘‘carisoprodol prescribers,’’ that during 2009, the top administer such substances. More has been abused in the State of Ohio for ten patients ‘‘received prescriptions specifically, the National Survey on 25 more than 20 years.’’ GX 8, at 3. The from 8 [to] 13 different prescriptions,’’ Drug Use and Health (NSDUH) data official testified that he was ‘‘aware and that these ‘‘patients received show that from 2004 through 2007, from [his] experience that many abusers between 1,020 [and] 1,863 days’ between 2.5 and 2.8 million persons of narcotics and other drugs abuse supply’’ of the drug during the ‘‘365 day admitted to having used carisoprodol carisoprodol to mellow the effect of the period.’’ Id. However, carisoprodol is for a non-medical purpose during their 26 narcotics or other drugs.’’ Id. indicated only for short-term use of up lifetime. As Table 7 below shows, in The official further testified that to two to three weeks, ‘‘because 2007, approximately 2.7 million persons under Ohio law, pharmacies are adequate evidence of effectiveness for have at some point engaged in the non- required to report the dispensing of any more prolonged use has not been medical use of carisoprodol. This figure controlled substance as well as established and because acute, painful is more than eleven times the number of carisoprodol. He then related that he musculoskeletal conditions are persons who have used meprobamate had run a search of the Ohio generally of short duration.’’ MX 6, at 2 products for a non-medical purpose. prescription reporting system and found (prescribing information). As the official Moreover, many reports of that carisoprodol ‘‘is always prescribed concluded, these statistics provide carisoprodol abuse have been published in combination with an opiate, a evidence of improper prescribing by both in the United States and in other benzodiazepine, or both.’’ Id. at 4–5. physicians, as well as doctor shopping countries. These cases include the use Moreover, ‘‘even though * * * the use and over-utilization by patients, and of carisoprodol by itself and in of a muscle relaxant such as show that ‘‘carisoprodol is a drug of combination with other drugs of abuse. carisoprodol in conjunction with an abuse in Ohio.’’ Id. See also infra Factor 5.

TABLE 7—NSDUH DATA ON NONMEDICAL USE OF SPECIFIC TRANQUILIZER IN LIFETIME [Numbers in thousands and percentage]

2004 2005 2006 2007 Drugs # (%) # (%) # (%) # (%)

Benzodiazepines ...... 18,643 (7.8) 19,686 (8.1) 19,662(8.0) 18,934 (7.6) Valium or Diazepam ...... 14,607(6.1) 14,914 (6.1) 14,824 b (6 b) 13,172 (5.3) Meprobamate Products 1 ...... 245 (0.1) 305 (0.1) 216 (0.1) 236 (0.1) Muscle Relaxants 2 ...... 3,907 (1.6) 3,773 (1.6) 4,449 (1.8) 4,274 (1.7) Soma® ...... 2,616 (1.1) 2,525 (1.0) 2,840 (1.2) 2,709 (1.1) Flexeril® ...... 1,968 (0.8) 1,891 (0.8) 2,405 (1.0) 2,438 (1.0) 1 Includes Equanil®, meprobamate, and Miltown®, 2 Includes Flexeril® and Soma®, bdifference between 2006 and 2007 estimates statistically significant, p. ≤ 0.01. Source: SAMHSA, office of Applied Studies, National Survey on Drug Use and Health.

Mr. Dasgupta acknowledged that essentially flat over time and not rate of abuse is increasing in order to ‘‘NSDUH is a validated and generally increasing.’’ Id. at 29. control it. scientifically defensible survey.’’ MX Nonetheless, that the NSDUH survey 173, at 28. However, he then criticized has consistently shown that between 2.5 4. Carisoprodol’s Pharmacological the study because it relies on self- million and 2.8 million persons have Activities Are Similar to Other Drugs reporting and because the study does engaged in non-medical use of With Known Abuse Liabilities not specifically ask whether carisoprodol is not evidence of ‘‘isolated According to the FDA, when carisoprodol or Soma have been used in or occasional nontherapeutic’’ use. S. originally marketed in 1959, the ‘‘past year’’ or ‘‘past 30 days,’’ Rep. 91–613; reprinted in 1970 carisoprodol was described as having although a survey participant may U.S.C.C.A.N., at 4602. Rather, it is ‘‘spontaneously offer[]’’ that he/she has substantial evidence of ‘‘significant use qualitatively different kinds of central used the drug within the respective time by individuals contrary to professional muscle relaxant properties than frame. Id. Mr. Dasgupta further noted advice.’’ Id. Where, as here, a drug has meprobamate, a schedule IV depressant that the NSDUH data show that the level been this widely abused, DEA is not of lifetime nonmedical use ‘‘is required to develop evidence that the

24 On cross-examination, the official explained cocaine, heroin, hallucinogens, and inhalants; and past year abuse or dependence. Substance Abuse that both carisoprodol and benzodiazepines have the nonmedical use of prescription-type pain and Mental Health Services Administration muscle relaxant and anti-anxiety effects, and that relievers, tranquilizers, stimulants, and sedatives in (SAMHSA), Office of Applied Studies, Results from prescribing both drugs simultaneously ‘‘is the civilian, non-institutionalized population of the the 2007 National Survey on Drug Use and Health: duplication of therapy,’’ which is rarely warranted. United States age 12 or older. The survey interviews National Findings (2008). Tr. 464–65. approximately 67,500 persons each year. The 26 25 The NSDUH is an annual survey sponsored by NSDUH provides yearly national and state level ‘‘Lifetime prevalence’’ is a cumulative indicator SAMHSA that obtains information on nine different estimates of drug abuse, and includes prevalence of the total number of people who have ever tried categories of illicit drug use: use of marijuana, estimates by lifetime (i.e., ever used), past year and drugs, including many in the distant past.

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(FDA Reference 1).27 However, the drugs is not known, it is believed to elicited the testimony of Dr. Donald specific mechanisms of action of occur by depressing interneuronal cells Robert Jasinski, who is a Professor of carisoprodol are not completely and diminishing the facilitatory Medicine at the Johns Hopkins understood (2, 3). background activity on spinal motor University School of Medicine and the FDA found that although carisoprodol neurons and by also inhibiting Chief of the Center for Chemical is classified as a muscle relaxant, it has supraspinal influences, primarily in the Dependence, Johns Hopkins Bayview little direct effect on skeletal muscle. GX lateral reticular area of the brain stem. Medical Center. MX 172, at 1. Dr. 6, at 5. According to FDA, both Id. The polysynaptic reflexes are more Jasinski testified that even assuming carisoprodol and meprobamate possess readily depressed than monosynaptic that the model used in this study was sedative properties and their therapeutic reflexes. Id. These drugs produce ‘‘sufficiently robust to establish an utility in acute painful musculoskeletal sedation and drowsiness as their affinity of carisoprodol at a GABAa problems may be in part due to these common side effects, which may reflect receptor, this does not establish that sedative properties. Id. FDA also found depressed neuronal activity essential for carisoprodol has barbiturate-like that the drugs may be abused for their wakefulness, in the medial reticular activity, but merely that it, like many sedative properties and that in vitro ascending system. Id. Despite chemical other drugs including other non- studies demonstrate that carisoprodol structures that are unrelated, all muscle controlled CNS depressants, has an elicits barbiturate-like effects. Id; See relaxants possess sedative properties. Id. affinity to attach to a GABAa also discussion infra under Factor Two. The drugs also exhibit anticonvulsant receptor[].’’ Id. at 3. Dr. Jasinski then Recent clinical reports addressing activity in several animal models (3). explained that ‘‘while barbiturates as a carisoprodol’s abuse potential and its class have an affinity for GABAa Receptor Binding Studies metabolic conversion to meprobamate receptors, not all drugs that have affinity have been published in scientific and According to FDA, the complete for GABAa receptors have barbiturate- medical journals. According to FDA, it binding profile of carisoprodol has not like activity and/or abuse liability was initially believed that been characterized. One study showed profiles similar to the carisoprodol’s abuse potential was that carisoprodol has negligible affinity barbiturates.’’ 28 Id. at 4. Dr. Jasinski primarily related to its metabolic for the benzodiazepine site, using [3H]- further opined that the finding that conversion to meprobamate. Id. at 6. diazepam as a ligand in rat brain tissue ‘‘bemegride, a non-specific barbiturate However, new animal data from NIDA (8). antagonist, apparently reduced the demonstrate that the abuse potential In Vitro Studies amplit[ude] of carisoprodol-mediated and pharmacology of carisoprodol may currents by 24% [does not] indicate that be independent of the metabolic The FDA concluded that the findings carisoprodol will have barbiturate like pathway in humans to meprobamate. of in vitro studies demonstrate that effects.’’ Id. More specifically, FDA cited NIDA carisoprodol elicits barbiturate-like While Dr. Jasinski may be correct that studies by Gatch, et al., which show that effects. Whole-cell patch clamp studies the findings of the aforementioned carisoprodol can be easily recognized by were conducted to examine mechanistic study do not conclusively establish that animals in drug discrimination studies similarities between carisoprodol and carisoprodol has barbiturate-like effects, as Schedule II, III or IV CNS barbiturates (Schedules II, III or IV, there is substantial other evidence in the depressants. (4–6). These studies are depending on the particular barbiturate) record (including human studies) which discussed more fully below under using recombinant rat a1b2 GABAAR. supports this finding. See discussion Factors Two (Scientific Evidence of the GX 6, at 6. GABA-gated currents were under Factor Five. potentiated by micromolar carisoprodol Drug’s Pharmacological Effect) and Animal Pharmacology Studies Seven (Psychic or Physiological (EC50 = 89 mM)). Id. At millimolar Dependence Potential). concentrations, currents began to be Berger, et al. (1, 10), described the inhibited, and rebound currents were muscle relaxant and analgesic Factor 2—The Scientific Evidence of apparent upon termination of drug properties of carisoprodol in animals. Carisoprodol’s Pharmacological Effect administration. Id. Reversible paralysis of voluntary Carisoprodol is a centrally-acting According to FDA, this barbiturate- muscles that lasts for nearly 15 minutes muscle relaxant used medically for like trend was consistent with a occurs in most mice administered relief of discomfort associated with previous description of carisoprodol carisoprodol (180 mg/kg, i.p.). Paralysis acute, painful musculoskeletal effects on human a1b2y2 GABAAR was preceded by signs of excitement conditions, including spasms and function, demonstrating that manifested by aimless running and spasticity. GX 6, at 6. The original carisoprodol, like barbiturates, does not staggering, hyperextension of the neck, approved therapeutic dose of require the y subunit for its activity. Id. and clonic movement of extremities. carisoprodol was 350 mg three times a at 6–7. Carisoprodol directly activated After administration of high doses, pre- day, and at bedtime. Id. In placebo- human a1b2y2 GABAAR, producing narcotic excitement was absent. During controlled studies, carisoprodol was inward currents in a concentration- paralysis, respiration and heartbeat were found more effective than placebo in dependent manner (EC50 = 410 mM). Id. regular, skeletal muscles were relaxed, treatment of acute musculoskeletal The amplitude of carisoprodol mediated tremors and twitchings were absent, and disorders (7) and less effective or not currents (EC40) was reduced to 24 corneal reflex was present. Stimulation different from placebo in chronic percent of control following incubation of the sciatic nerve during paralysis disorders. In 2007, FDA approved a 250 with bemegride (a barbiturate antagonist produced prompt muscular response of mg tablet to be taken three times a day that has not been demonstrated to be the leg, indicating that the peripheral and at bedtime, for up to three weeks. specific for barbiturates). Id. By contrast, GX 6, at 6. the benzodiazepine antagonist, 28 Dr. Jasinski further testified that in a Although the exact mechanism of flumazenil, had no significant effect on subsequent article, the authors of this study wrote either the allosteric or direct effects of that ‘‘[a]lthough both our in vivo and in vitro studies muscle relaxant action of this group of are consistent with barbiturate-like effects of carisoprodol (9). carisoprodol, we are not concluding that 27 The complete list of FDA References 1–58 is MEDA challenged the FDA’s reliance carisoprodol is acting at the barbiturate site of the attached as Appendix B. on this study. More specifically, MEDA receptor.’’ MX 172, at 3 n.1.

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nerve, myoneural junction, and muscle limited solubility of carisoprodol, doses the response rate to 79 percent of the were not significantly affected by the larger than 0.3 mg/kg injection could carisoprodol control group. Gatch, et al. drug. Depression of motor activity, as not be tested. NIDA Research (6), also studied the effects of measured by loss of the righting reflex, Monograph, volume 146:423–433 carisoprodol in the presence of occurred in 50 percent of animals after (1999). This dose (0.3 mg/kg/injection) Cimetidine, to determine if the effects of oral administration of 400 mg/kg of is lower than the doses used orally in carisoprodol are produced by its active carisoprodol in mice and 750 mg/kg in humans. GX 6, at 8. metabolite, meprobamate. Cimetidine, a rats. P450 enzyme inhibitor, which prevents Drug-Discrimination Studies According to FDA, carisoprodol is a the conversion of carisoprodol to relatively poor strychnine antagonist in According to the FDA, ‘‘drug meprobamate, failed to inhibit the mice, which differs from other muscle discrimination studies in animals are discriminative stimulus effects relaxants such as mephenesin (a believed to be predictive of subjective produced by 100 mg/kg of carisoprodol centrally-acting muscle relaxant that is effects in humans and are thus useful in in rats trained to discriminate not marketed in the United States). assessing the abuse potential of drugs.’’ carisoprodol. According to FDA, these Carisoprodol depresses the electro- Id. Carisoprodol can stimulate the results suggest that carisoprodol can cortical activation response to electrical barbiturate site on the GABA–A produce discriminative stimulus effects stimulation of the sciatic nerve, the receptor. In drug discrimination studies, directly without being converted into midbrain reticular formation or of the pentobarbital (C–II) fully substitutes in meprobamate. diffuse thalamic system (nucleus carisoprodol-trained rats and bemegride Dr. Jasinski disputed the FDA’s centralis lateralis). Carisoprodol showed fully antagonizes the subjective effects reliance on the various animal studies it an antinociceptive action in response to of carisoprodol. used to assess carisoprodol’s abuse injection of silver nitrate into joints of FDA also noted that another study potential. MX 172, at 4–7. While Dr. rats. Carisoprodol differs from found that in dogs tolerant and Jasinski acknowledged that ‘‘in these meprobamate (Schedule IV) by not dependent on barbital (C–IV), oral doses studies the animals reflected behavior affecting the hippocampal seizures of 200 mg/kg of carisoprodol every six patterns with respect to carisoprodol produced by stimulation of the fornix hours were completely effective and that suggest patterns similar to (10). equivalent to 100 mg/kg of barbital in barbiturates,’’ he then opined that ‘‘due More recently, the National preventing the appearance of abstinence to the inherent limitations of animal Toxicology Program of the National phenomena (12). studies they simply do not provide an Institutes of Environmental Health Bemegride fully blocked the adequate basis to make decisions Sciences examined the toxicity of discriminative stimulus effects of the concerning abuse potential in humans.’’ carisoprodol (11). Male rodents in the training dose of carisoprodol (100 mg/kg Id. at 4. Dr. Jasinski offered no further 200 mg/kg carisoprodol group and p.o.), whereas the benzodiazepine explanation as to what those limitations female rodents in the 100 and 800 mg/ antagonist, flumazenil, produced a are. Moreover, at the hearing, Dr. kg carisoprodol groups had significantly moderate attenuation of the Jasinski testified that it is appropriate to greater mean body weight gains than discriminative stimulus effects of rely on animal studies as one aspect of animals that received vehicle (control carisoprodol across a wide range of assessing a drug’s abuse potential in doses. According to FDA, these findings group). The incidence of adverse events humans.29 Tr. 721. was dose-related, and females were suggest that carisoprodol may directly With respect to the self- more sensitive than males to the effects activate or allosterically modulate administration study involving rhesus of carisoprodol. Carisoprodol induced GABAA receptors which mediate the monkeys, Dr. Jasinski explained that the ataxia and prostration in rats and mice, discriminative stimulus effects of fact that ‘‘the monkeys seem[ed] to increases in liver weights in rats and carisoprodol. FDA further found that the prefer carisoprodol over a saline, but mice, and nephropathy in male rats. actions of carisoprodol at the barbiturate less than a schedule IV substance, In cats, carisoprodol was very site may be more relevant than actions merely indicates that the * * * monkey effective in abolishing decerebrate at the benzodiazepine site and that prefers carisoprodol over saline’’ and rigidity, whereas meprobamate and certain effects of carisoprodol may be that ‘‘[t]his preference could be due to mephenesin had no effect on spasticity. independent of its metabolism to factors unrelated to any potential for Carisoprodol appeared to be eight times meprobamate (C–IV) (9). abuse in humans.’’ Id. at 5. more potent than these drugs in Gatch, et al., (4) assessed the ability of As for the drug-discrimination studies alleviating decerebrate spasticity (10). rats to discriminate carisoprodol from involving rats, Dr. Jasinski In dogs, carisoprodol (100 mg/kg p.o.) vehicle. Rats were trained to acknowledged that the study showed produced loss of muscle tone. At larger discriminate carisoprodol and a that ‘‘pentobarbital substitutes for doses (200 mg/kg p.o.), signs of carisoprodol dose-effect curve was carisoprodol in rats trained to excitement characterized by tail established for doses from 25 to 100 mg/ discriminate carisoprodol and that’’ wagging and howling were observed kg. Meprobamate (C–IV), pentobarbital bemegride, a barbiturate antagonist, along with muscular weakness and (C–II/C–III), and chlordiazepoxide (C– ‘‘blocked the discriminate stimulus ataxia with no tremors, convulsions or IV) were each tested for their ability to salivation (10). substitute for the discriminative 29 In its brief, Meda argues that animal studies stimulus effects of carisoprodol; each ‘‘are significantly less probative than human Self-Administration Studies was found to substitute fully for the studies’’ in assessing a drug’s abuse potential. Meda The FDA found that carisoprodol has discriminative stimulus effects Br. 25. However, Meda did not establish the degree to which animal studies are less probative than positive reinforcing effects, in that produced by 100 mg/kg of carisoprodol. human studies and even its Expert conceded that rhesus monkeys maintained self In another study, Gatch, et al. (5), it is appropriate to rely on animal studies in administration responding that was found that 5 mg/kg bemegride assessing abuse potential in humans. Tr. 721. While greater than rates maintained by saline, antagonized the discriminative stimulus Meda cites human data—in particular, the results of recent clinic trials it conducted and the Fraser although less than rates maintained by effects produced by 100 mg/kg of study—and argues that this data should be given i.v. injections of methohexital (C–IV). carisoprodol in rats trained to greater weight than the animal studies, as discussed GX 6, at 8. However, because of the discriminate carisoprodol and decreased below, both studies have significant limitations.

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effects.’’ Id. Dr. Jasinski then opined that Clinical Experience and Human Studies 1,050 mg to 2,500 mg (three to seven ‘‘these data at most are only indicative Pharmacodynamic Effects times the usual dose of 350 mg) were that carisoprodol may have certain administered orally in capsules to effects similar to those of barbiturates Beebe, et al. (13), reviewed the fasting, non-tolerant opiate addicts. Id. pharmacodynamic effects of (e.g., they have activity at the GABA Assessments were carried out hourly for carisoprodol. Lethargy, drowsiness, receptor site) and not that any such six hours with the single-dose opiate ataxia, dysmetria and fatigue are similarity translates into a similar questionnaire. Id. common side effects at therapeutic The study found that carisoprodol’s potential abuse liability.’’ Id. Dr. doses 30 and in overdose (14). More Jasinski further explained that ‘‘it is effects were not consistent at doses severe CNS-related effects including lower than 2,000 mg. Id. at 1–2. Only well known that certain drugs will confusion, amnesia and coma occur less substitute for drugs of abuse without one of fifteen subjects that received the frequently at therapeutic doses, but 2,500 mg dose identified the drug as themselves being subject to any occur with overdose (15; 16). significant drug abuse.’’ Id. ‘‘dope.’’ Id. In the same dose-range Respiratory depression may occur in group, most subjects became sleepy one patients with significant CNS As for the study showing that 200 mg/ or two hours after receiving 2,500 mg of depression (17; 18). kg of carisoprodol substituted for 100 carisoprodol, and when awakened, did The primary toxic effect with mg/kg in dogs which are dependent on not show as much dysarthria as would barbital, Dr. Jasinski noted that the poisoning or exposure to carisoprodol is CNS depression and, in severe cases, have been anticipated from an authors had concluded that carisoprodol coma. Euphoria, CNS stimulation, equivalent dose of barbiturates. Id. at 2. was an exception to the general rule that muscular incoordination, confusion, According to the FDA, the subjective ‘‘whenever drugs produce physiological headache, hallucinations and dystonic and objective effects noted in this group dependence in which abstinence reactions have also been reported. Anti- were similar to those of barbiturates or syndrome is similar, these drugs must cholinergic effects (tachycardia, dry, alcohol and different from those of possess a common mechanism of action warm skin) are reported following opiates. GX 6, at 10. and abuse liability profiles.’’ Id. at 6 carisoprodol poisoning. Fever is In the second arm of the study, 3,600 (citing MX 91). As Dr. Jasinski observed, reported following carisoprodol to 4,800 mg of carisoprodol, which was based on several unpublished studies overdose (14; 19). Both mild divided into three equal oral doses, which showed that ‘‘the chronic hypertension and mild hypotension are were substituted for morphine in six administration of carisoprodol in 4 reported in conjunction with serotonin and three morphine-stabilized patients, divided doses of 1 gm/day for 6 months syndrome after carisoprodol overdose respectively. Fraser, at 2. The study was [did] not result in the development of (19). Horizontal nystagmus, mydriasis, controlled ‘‘negatively, by substitution physiological dependence,’’ the authors and blurred vision have also been of a placebo for morphine, and concluded that ‘‘[t]he fact that reported with carisoprodol overdose positively, by continuing the customary dose morphine in the same subjects.’’ carisoprodol did effectively substitute (20). Id. Moreover, because ‘‘carisoprodol for sodium barbital in [their] study In addition to the above adverse seemed to be barbiturate-like in many indicates that false positive results are effects, drug abuse, dependence and tolerance are reported following long- respects, the study was also controlled possible from the substitution term use of carisoprodol. See infra by substituting’’ an average dose of 1.11 evaluation of barbiturate-like Factor Seven. g of pentobarbital for morphine, which physiological dependence capacity.’’ was divided among five doses, in MX 91; see also MX 172, at 6. Human Behavioral Studies another experiment which involved However, as the authors made clear, Fraser, et al. (21), evaluated whether eleven other subjects. Id. Following their conclusion that carisoprodol carisoprodol possessed morphine-like substitution, hourly ‘‘[o]bservations for produced a false positive was based on (C–II) or barbiturate like (C–II, C–III and the intensity of abstinence were made studies which showed that taking one C–IV) addictive properties in human * * * from the 11th through the 24th gram per day of the drug did not cause subjects, all of whom ‘‘were former hour of abstinence.’’ Id. physiological dependence. Thus, this opiate addicts.’’ H.F. Fraser, et al., This arm of the study concluded that study does not foreclose the possibility Evaluation of carisoprodol and ‘‘carisoprodol partially but significantly phenyramidol for addictiveness, that chronic use of carisoprodol in daily suppressed symptoms of abstinence.’’ Bulletin on Narcotics 1 (Oct–Dec. 1961). doses of greater than one gram per day Id. The study found that the patients The study had three arms: the first could cause physiological dependence receiving the 4,800 mg dose of evaluated the effect of single oral doses carisoprodol ‘‘were quite sedated and and calls into question the validity of in non-addicted patients, the second the authors’ conclusion that somewhat difficult to arouse, but evaluated the 24-hour substitution of showed only a slight degree of carisoprodol caused a false positive carisoprodol for morphine in morphine- dysarthria and ataxia.’’ Id. when substituted for barbital. stabilized patients and was used to The FDA did not discuss the third Accordingly, even discounting the assess whether carisoprodol can prevent arm of the study. See GX 6, at 10. rhesus monkey study, I find that symptoms of abstinence from morphine, Instead, it concluded that this study was substantial evidence supports the FDA’s and the third assessed physical conducted before the advent of modem conclusion that the drug-discrimination dependence following chronic human abuse liability testing that uses studies in both dogs and rats indicate administration of carisoprodol and validated measures, and that it therefore that carisoprodol has positive abrupt discontinuation of the drug. See does not directly address the issue of reinforcing and discriminative effects id. the human abuse potential of In the first arm of the study, single similar to other drugs currently carisoprodol. Id. However, the FDA doses of carisoprodol ranging from regulated under C–IV, including further found that ‘‘the study results indicate that carisoprodol has sedative- barbital, meprobamate, and 30 See current label information for carisoprodol chlordiazepoxide. (Soma) (http://www.fda∼gov/cder/foil1abe1l2007/ like effects, as opposed to opiate-like 0_11792s0411bl.pdf). effects.’’ Id.

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Dr. Jasinski expressed his patients, who were then given placebo. definitive conclusion from the findings disagreement with the FDA’s Id. with respect to the single patient who assessment of the validity of the study The study found that with the received the drug for 54 days. results, opining that ‘‘[w]hile there have exception of changes in the patients’ Meda also cites recent clinical trials it been enhancements in methodologies EEG (electroencephalogram) patterns, conducted in support of its application use[d] to assess abuse liability in ‘‘the outstanding feature was a complete to market carisoprodol in 250 mg intervening years, * * * the absence of any significant subjective strength as evidence that the drug does methodology used by Fraser yielded effects even when the dosage was not cause withdrawal symptoms and is valid scientific results and should not increased to 4,800 mg daily.’’ Id. not subject to diversion, misuse, or be discounted based solely upon the fact Continuing, the authors noted that ‘‘it abuse. MX 171, at 5. MEDA’s CMO that different methodologies would be was not possible to differentiate maintains that these studies, which used today.’’ MX 172, at 7. Dr. Jasinski carisoprodol from a placebo.’’ Id. involved several thousand patients at found it ‘‘significant that in the Fraser Moreover, following the cessation of hundreds of clinical research centers, carisoprodol, none of the patients study[,] the chronic administration of ‘‘provide the only evidence-based body showed signs of abstinence and all were carisoprodol for a period of 18 to 54 of human data from which [to] evaluate unaware that their medication had been days at doses that progressed from 1200 the likelihood of drug diversion, drug changed. Id. mg/day to 4800 mg/day * * * did not seeking behavior, and withdrawal While the study found that the symptoms in a controlled setting.’’ Id. at induce a characteristic barbiturate patients’ EEGs showed a ‘‘barbiturate- intoxication pattern,’’ and that ‘‘the 9 (emphasis in original). According to like effect’’ when the patients were MEDA’s CMO, during these studies, abrupt withdrawal of carisoprodol [did receiving 4200 to 4800 mg, it also found not] reveal any signs of barbiturate-like there was no evidence of diversion and that all of the patients’ EEGs had ‘‘there was no evidence whatsoever of abstinence.’’ Id. at 7–8. Dr. Jasinski thus returned to normal within thirty-six opined that ‘‘these data show that carisoprodol-induced withdrawal hours of the last dose. Id. Moreover, syndrome following abrupt cessation of carisoprodol does not possess ‘‘[n]one of these patients showed focal up to two weeks of treatment.’’ Id. at 10. barbiturate-like abuse liability and that or generalized abnormalities of the Meda’s CMO then opined that ‘‘[u]nlike in light of these data[,] it is not paroxysmal type during withdrawal, other drugs, such as opioids, this scientifically sound to reach a contrary such as those seen following withdrawal suggests that if dependence occurs, it is conclusion based solely upon less of barbiturates.’’ Id. The study thus only following prolonged treatment reliable animal or in vitro data.’’ Id. at concluded that ‘‘[c]hronic with carisoprodol.’’ Id. 8. administration on a progressive dosage As for the lack of evidence of Both parties and the ALJ cited the schedule did not induce a characteristic withdrawal, diversion or drug seeking barbiturate intoxication pattern’’ and Fraser study as being an exhibit in the behavior, the short-term nature of the that the abrupt withdrawal of the drug record. See Gov. Br. at 19 (citing Meda studies (which involved administration did not result in ‘‘barbiturate-like Ex. 98); Meda Br. at 56–57 (citing same), of the drug at therapeutic levels for ALJ at 32 (¶ 46). However, this exhibit abstinence’’ symptom. Id. However, the authors noted that ‘‘it either one or two weeks at most, MX was not included in the record remains to be seen whether 171, at 8) renders this evidence of forwarded to this office, and a review of administering carisoprodol minimal value in determining whether the transcripts contains no indication continuously in larger doses would carisoprodol causes dependency. that Meda Exhibit 98 was ever entered induce a chronic state of intoxication Moreover, FDA found that there is into evidence. Because both parties and and whether abrupt withdrawal under extensive evidence in the scientific the ALJ have cited the Fraser study as such circumstance would provoke a literature establishing that carisoprodol if it were in evidence, I take official barbiturate or meprobamate type of can cause dependency in humans. See notice of it. Moreover, given the dispute abstinence.’’ Id. The authors further discussion under Factors Five, Six, and as to significance of the study’s findings, noted that ‘‘[s]uch a possibility is Seven, infra. Finally, that short-term a discussion of the third arm is suggested by the fact that carisoprodol administration of carisoprodol does not warranted. is a congener of meprobamate and cause dependency is not dispositive The third arm of the Fraser study, exhibits many barbiturate-like because the CSA does not impose an which was only single-blinded,31 pharmacological effects.’’ Id. at 3–4. arbitrary time frame for assessing involved the administration of large As for Dr. Jasinski’s testimony that the whether the taking of a drug can cause 32 doses of carisoprodol to five patients, Fraser study ‘‘yielded valid scientific dependency. with four of the patients receiving the results,’’ another of Meda’s Exhibits (the FDA’s Draft Guidance on Assessment of 32 Dr. Jasinski also noted that in his experience as drug for 18 days and one receiving the the Chief of the Center for Chemical Dependence at drug for 54 days. Fraser, at 3. Each Abuse Potential of Drugs) states that Johns Hopkins Bayview Medical Center, he could patient received an initial dose of 1,200 ‘‘[h]uman abuse potential studies are not ‘‘recall a single incidence in which an mg, which was increased by 200 mg usually double blind, double dummy, individual has visited our center to be treated for placebo, and positive comparator carisoprodol addiction/dependence.’’ MX 172, at 9. each day for 16 days, and then by 300 While that may be, this may simply reflect that mg on days 17 and 18 for a maximum controlled, and are crossover designed.’’ different drugs are more popular with drug abusers daily dose of 4800 mg. Id. The patient MX 12, at 14. Moreover, such studies in the geographic area served by Johns Hopkins. who was given the drug for 54 days typically involve a substantially greater Dr. Jasinski also noted that according to the number of patients than the Fraser study Treatment Episode Data Set, a database maintained received a daily dose of 4800 mg from by SAMHSA of admissions to substance abuse days 18 through 54. Id. Following the involved and both ‘‘[t]he investigator treatment centers, ‘‘there were no mentions of respective 18 and 54-day periods, the and the staff who interact with subjects carisoprodol in any of the TEDS reports from 2002 drug was abruptly withdrawn from the should not know the sequence of through 2007.’’ Id. (citing MXs 31 & 32). However, substances administered.’’ Id. In short, the TEDS reports do not separately list carisoprodol, but rather use broader categories such 31 While the patients ‘‘were unaware of the nature the Fraser study did not meet most of as ‘‘Other non-Benzodiazepine Tranquilizers,’’ and schedule of medication,’’ the observers were these criteria. Moreover, it seems which ‘‘[i]ncludes meprobamate, tranquilizers, etc.’’ not. Fraser, at 3. unlikely that scientists would draw a Continued

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Factor 3—The State of Current elimination halflife of 2.44 ± 0.93 hr. Id. 2.5 and 2.84 million persons have used Scientific Knowledge Regarding at 10–11. carisoprodol for non-medical purposes. Carisoprodol To be sure, the NSDUH data may not Factor 4—Carisoprodol’s History and reflect a statistically significant increase Current Pattern of Abuse The current scientific knowledge in the number of persons who have used regarding carisoprodol includes In 1959, carisoprodol was introduced carisoprodol for a non-medical purpose. information about the drug’s chemistry into the U.S. market as a single-agent However, the fact that approximately and pharmacokinetics. drug, and in 1960, as a combination 2.5 to 2.8 million persons have engaged Chemistry product with aspirin. Id. at 11. In 1983, in non-medical use of carisoprodol is carisoprodol was marketed in itself significant. Chemically, Carisoprodol is (l- combination with aspirin and codeine. methylethyl) carbamic acid 2- Id. Numerous generic products have Demographic and Epidemiological [[(aminocarbonyl)oxy]methyl]-2- been introduced into the U.S. market. Factors Associated With Nonmedical methylpentyl ester; N-isopropyl-2- Id. Carisoprodol is also marketed Use of Carisoprodol methyl-2-propyl-l, 3-propanediol worldwide under various trade names FDA’s review found that the majority dicarbamate; isopropyl meprobamate. including Artifar, Carisoma, of cases reported in the scientific GX 6, at 10. Carisoprodol is also Carisoprodol Sintesina, Listaflex, Mio literature note that carisoprodol abuse identified by CAS number 78–44–4. Relax, Sanoma, Soma, Somadril, and has primarily been a component of Carisoprodol has a molecular weight of Somflam. Id. multi-drug abuse. GX 6, at 13. 260.33; its molecular formula is In assessing carisoprodol’s history According to FDA, DAWN data C12H24N204. Id. and current pattern of abuse, DEA and indicates that the drugs most frequently Carisoprodol is a bitter tasting, FDA relied on multiple data sources. As used in combination with carisoprodol odorless, white crystalline powder. Its discussed above, these include DAWN, that resulted in ED visits were opioids melting point (without decomposition) NSDUH, AERS, and Florida Medical (hydrocodone, oxycodone), ranges from 92–94 °C and it has low Examiners Commission Data. In benzodiazepines (alprazolam, diazepam, water solubility (30 mg/100 ml at 25 °C). addition, reports from the scientific clonazepam), alcohol, and illicit drugs Id. Carisoprodol is soluble in many literature were reviewed. (marijuana, cocaine). Id. at 14. Beginning in 2006, carisoprodol has organic solvents and practically DAWN ED Data insoluble in vegetable oils. Id. been reported as a primary or sole drug Carisoprodol is stable in dilute acid and As discussed above under Factor One of abuse in DAWN. Additional analysis alkali and is not altered by artificial (and as set forth in Table One), DAWN of DAWN data specifically addresses gastric or intestinal juices. Id. It is a data suggest that there has been an details of this issue for carisoprodol racemic compound with one increase in the frequency of nonmedical nonmedical use in 2006 (see Table 3). asymmetric center. Id. Qualitative and use ED visits associated with As set forth in Table 3, the DAWN quantitative methods for detection of carisoprodol. In 2004, DAWN estimated 2006 data estimated that there were a carisoprodol and other drugs by gas the number of ED visits related to total of 24,505 ED visits related to the chromatography/mass spectrometry nonmedical use of carisoprodol as nonmedical use of carisoprodol. Of (GC/MS) or thin layer chromatography 14,736; in 2007, it estimated that there these, 42 percent involved females and in combination with GC/MS have been were 27,128 nonmedical ED visits 58 percent males. In twenty-one percent published (22–25). related to carisoprodol. By comparison, of the cases, carisoprodol was reported DAWN estimated that in 2004, there as the sole drug, with it being the sole Pharmacokinetics were 15,619 ED visits related to the drug in twenty-seven percent of the The pharmacokinetics of carisoprodol nonmedical use of diazepam, and in female cases, and twelve percent of the have been investigated in several animal 2007, there were an estimated total of male cases. The FDA’s analysis and human studies. At a dose of 350 mg, 19,674 nonmedical ED visits related to concluded that these gender-based the mean peak plasma concentration diazepam. However, according to differences may suggest effects related (Cmax) achieved was 2.29 ± 0.68 mg/ml; SAMHSA, the increase in the number of to dosage and pharmacokinetic/ women tended to reach peak plasma carisoprodol visits between 2004 and pharmacodynamic effects that could concentrations earlier than men (1.45 2007 was not statistically significant. influence abuse potential. The DAWN data also suggest that vs. 2.5 hrs) and had a faster apparent Nonetheless, even if there were only an there are some age-related differences in oral clearance (0.772 vs. 0.38 l/h/kg). GX estimated 14,736 ED visits related to the use of carisoprodol, with greater 6, at 10. Carisoprodol is metabolized in carisoprodol, this is still a significant reports of single use among those 12–17 the liver via cytochrome 2D6. Id. number of visits when compared with years old (27 percent) and those 45–54 Meprobamate (C–IV) is one of the the number of diazepam-related visits. years old (30 percent) than other age products of carisoprodol metabolism. Id. In addition, as found above under groups.33 Following a single 350 mg dose of Factor One (and set forth in Table 2), A study by Forrester (26) carisoprodol, the corresponding when the number of estimated found that adolescents accounted for normalized peak concentration of nonmedical use ED visits is adjusted for 17 percent of the abuse calls related to meprobamate was 2.08 ± 0.48 mg/ml; the number of prescriptions issued (by carisoprodol in an analysis of Texas these levels are approximately 25 dividing the number of visits by 10,000 33 According to FDA, ‘‘such abuse may represent percent those observed following a prescriptions), in 2007 the carisoprodol rate was 22.6/10,000 Rx, while a significant change in the pattern of abuse of single 400 mg dose of meprobamate. Id. carisoprodol, as abuse of carisoprodol without other Carisoprodol is eliminated by both renal diazepam’s rate was 14.1/10,000 Rx. By substances and significant single drug use by such and non-renal routes with a terminal contrast, cyclobenzaprine, another a large young population has not previously been skeletal muscle relaxant, had a rate of documented in national data.’’ GX 6, at 14. 3.3/10,000 Rx. However, prior to 2006, carisoprodol was not MX 31, at 28. Thus, admissions to treatment centers previously reported as a sole drug in the DAWN ED for carisoprodol abuse might well be reported under As also found above under Factor data. Thus, it is unclear whether there has been a this category. Accordingly, I place no weight on this One, NSDUH survey data for the years significant change in the abuse of carisoprodol by testimony. 2004 through 2007 show that between adolescents.

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Poison Centers’ data from 1998–2003, a rate similar to that reported in RADARS rate similar to that reported in RADARS (27). (27). TABLE 8—ESTIMATED NONMEDICAL-USE CARISOPRODOL ED VISITS FROM DAWN 2006 BY AGE AND MOST COMMON DRUG COMBINATIONS 34

Age Carisoprodol All 0–5 6–11 12–17 18–20 21–24 25–29 30–34 35–44 45–54 55–64 65+

Carisoprodol-single drug...... 5,053 ...... 307 256 553 494 287 1,030 1,873 228 26 Carisoprodol-multi-drug ...... 19,444 0 . . . 820 1,135 2,342 2,318 2,150 5,119 4,286 752 515

Total by Age...... 24,497 0 . . . 1,127 1,391 2,895 2,812 2,437 6,149 6,159 980 541

956,000 and 1,056,000 eighteen to having engaged in the non-medical use NSDUH data for the years 2004 twenty-five year olds reported having of meprobamate.35 These figures were through 2007 show that in each year, used carisoprodol for non-medical approximately thirty-three percent (in more than 100,000 twelve to seventeen- reasons. As the table below shows, these the 12–17 age group) and forty-two year olds reported having used age groups reported having engaged in percent (in the 18–25 age group) of carisoprodol for non-medical reasons. the non-medical use of carisoprodol to those persons reporting non-medical use During this same timeframe, between a far greater extent than they report of diazepam.

TABLE 9—NSDUH—NONMEDICAL USE OF CARISOPRODOL (SOMA®) AND OTHER DRUGS IN LIFETIME, BY AGE GROUP [Numbers in thousands (%), 2004–2007]

2004 2005 2006 2007 Age Groups #(%) #(%) #(%) #(%)

Carisoprodol (Soma®)

Ages 12–17 ...... 138 (0.5) 118 (0.5) 111(0.4) 106 (0.4) Ages 18–25 ...... 975 (3.0) 1,056 (3.3) 1,034 (3.2) 956 (2.9) Ages 26 or Older ...... 1,503 (0.8) 1,351 (0.7) 1,695 (0.9) 1,647 (0.9)

Cyclobenzaprine (Flexeril®)

Ages 12–17 ...... 34a (0.1a) 64 (0.3) 53 (0.2) 56 (0.2) Ages 18–25 ...... 461 (1.4) 479 (1.5) 533 (1.6) 568 (1.7) Ages 26 or Older ...... 1,473 (0.8) 1,348 (0.7) 1,819 (1.0) 1,813 (1.0)

Diazepam (Valium®)

Ages 12–17 ...... 380 (1.5) 351 (1.4) 320 (1.3) 314 (1.2) Ages 18–25 ...... 2,434 (7.6) 2,650 (8.2) 2,480 a (7.6 a) 2,252 (6.9) Ages 26 or Older ...... 11,794 (6.4) 11,913 (6.4) 12,024 a (6.4 b) 10,606 (5.6)

Meprobamate Products 1

Ages 12–17 ...... 34 (0.1) 22 (0.1) 24 (0.1) 18 (0.1) Ages 18–25 ...... 39 (0.1) 49 (0.2) 42 (0.1) 27 (0.1) Ages 26 or Older ...... 173 (0.1) 234 (0.1) 150 (0.1) 192 (0.1) 1 Includes Equanil® meprobamate, and Miltown®. a Difference between year and succeeding year (e.g., 2004 and 2005) estimates are statis- tically significant, p ≤ 0.05. b Difference between year and succeeding year statistically significant, p ≤ 0.01. Source: SAMHSA, Office of Applied Studies, National Survey on Drug Use and Health.

As found above, AERS data through years 2004 through 2008 identifies cases of intoxication with carisoprodol. June 2007 contains a total of 472 reports carisoprodol as the cause of death in The FDA further found that there are related to potential abuse of between 74 and 96 deaths each inconsistencies in the literature with carisoprodol. GX 6, at 15. Of these, year.36 See Table Four above. regard to what is considered a toxic 48 reports identified dependence as the concentration level (17, 22, 28–31). As Scientific Literature Reports adverse event and 19 identified carisoprodol is frequently abused in withdrawal syndrome. Id. As also found The FDA review concluded that there combination with other drugs, the above, data obtained from the Florida are relatively few reports in the specific contribution of carisoprodol to Medical Examiners Commission for the scientific literature describing fatal a fatality may be difficult to ascertain.

34 Where age was known. Information received 35 Nearly twice as many persons reported non- 36 The data for the years 2004 through 2008 show from SAMHSA on June 18, 2008. Three dots (. . .) medical use of carisoprodol than reported non- that carisoprodol was present in between 289 and indicate that an estimate or count of less than 30 medical use of cyclobenzaprine, another muscle 415 cases each year. GX 6, at 18. or with a relative standard error greater than 50, has relaxant which is unscheduled. GX 6, at 17. been suppressed.

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However, several publications have acknowledged using carisoprodol for at a defined daily dose (DDD) of 1400 attributed therapeutic levels of non-medical reasons. These data are mg (350 mg three times a day and at carisoprodol at 10–40 mg/l, toxic levels consistent with DEA data indicating that bedtime). at 30–50 mg/l, and a lethal level at carisoprodol is being diverted. The investigation included the 110 mg/l (31–33). dispensing of 3,772,154 DDDs to 83,713 Davis and Alexander (31) reviewed Factor 5—The Scope, Duration, and Significance of Abuse patients of 18 years of age or older. carisoprodol-related deaths in Jefferson Measured parameters included the one County, Alabama, from January 1, 1986 According to the FDA, examination of year prevalence of use (i.e., the number to October 31, 1997. Of a total of 8,162 the case reports and studies of abuse in of individuals who had received at least Medical Examiner cases, toxicology the United States and other countries one prescription of carisoprodol per 100 analysis found 24 cases in which are useful in assessing the scope, inhabitants) and parameters for carisoprodol was in the decedent’s duration, and significance of potential abuse including high use (high blood. Blood carisoprodol carisoprodol abuse. GX 6, at 19. Because users were defined as those receiving concentrations in decedents ranged carisoprodol has been marketed since >15 DDDs during the year), high from <1 mg/l to 96.8 mg/l, with a mean 1959, there is a substantial body of post- intensity use (high intensity over carisoprodol concentration of 16.4 marketing epidemiologic abuse-related different lengths of time), doctor mg/l and a standard deviation of 21.0 data in the published scientific shopping, and concomitant use of mg/l. In no case was carisoprodol the literature and from AERS. Id. at 19–20. potential drugs of abuse. The possible only drug detected, nor was it ever the Drug abuse and dependency are drug abuse parameters for carisoprodol sole cause of death. The authors also determined by the evaluation of a were compared to five other commonly noted the frequent association in their patient’s drug-seeking behavior, as prescribed drugs. evidenced by the use of multiple series and in the DAWN data of Of those meeting the study’s prescribers, the increased frequency of carisoprodol with co-ingested requirements, the following groups refills, the use of increasing doses, and respiratory depressants (propoxyphene, emerged: therapeutic users, 62 percent; reports of withdrawal symptoms when a diazepam, codeine). As carisoprodol pseudo-therapeutic long-term users of drug is suddenly withdrawn. Id. at 20. also can cause respiratory depression, carisoprodol, 16 percent; ‘‘pure’’ Withdrawal symptoms vary and include the authors concluded that it was a carisoprodol abusers, 1 percent; anxiety, tremor, insomnia, probable contributor to the cause of concomitant benzodiazepine abusers, hallucinations, and seizures. Id. death (31). 8 percent; and concomitant opioid Hoiseth, et al. (34), investigated all Reports in the scientific literature abusers, 14 percent. The therapeutic forensic autopsies at the Norwegian document that carisoprodol can cause users received only 12 percent of the Institute of Public Health during the dependency (35–39) and there are cases period 1992–2003 and found five cases where withdrawal symptoms have been carisoprodol dispensed in 2004, while which reported the median reported (40–42). While the presence of those considered primary opioid concentrations of carisoprodol other drugs of abuse complicates the abusers received 48 percent of the total associated with intoxication. In another assessment, there are reports where amount of dispensed. Eighty-nine 93 intoxication cases, levels of carisoprodol is the sole drug of abuse percent of the patients received their carisoprodol relative to the other drugs (35, 43) (see Factor 7 for further details carisoprodol from a single prescribing varied. When the number of of these reports). doctor, with the remainder having intoxications with carisoprodol each There are other reports in addition to multiple prescribers. Eighty-two percent year was divided by the number of those discussed under Factor Four. A of the patients were defined as high defined daily doses (DDD) sold, a fatal report from India describes sixteen cases users (received 15 DDDs) of of carisoprodol abuse, mainly among carisoprodol and 14 percent of the toxicity index (FTI) of between 5.6 and ≥ 6.9 deaths/million DDD was obtained. young male polydrug abusers (15). patients received 75 DDDs. The carisoprodol FTI was higher than Carisoprodol was purportedly taken to Reports in the scientific literature data for the schedule IV CNS attenuate opioid withdrawal, but its indicate that relatively few physicians depressants diazepam (5.2), oxazepam abuse for pleasurable effects was also are aware of the addictive potential of (4.9), nitrazepam (2.8), and zopiclone described. Carisoprodol thus gained a the drug (39; 46; 47). The lack of (1.9), but lower than those for reputation among addicts for producing medical and public awareness regarding alprazolam (16.0) and clonazepam psychic effects. Isaac, et al. (44), the abuse potential of carisoprodol may (16.1). The total number of cases reported a case of abuse from Canada contribute to the abuse of the drug. involving carisoprodol increased during that was recognized through a In summary, carisoprodol’s post- the time period observed, as did sales pharmacist hotline. marketing history indicates that the figures for the same period. Only a small Bramness, et al. (45), conducted a drug can, and is, being abused, in both number of deaths could be attributed to pharmacoepidemiological study on the the United States and other countries. use of carisoprodol alone. use and abuse of carisoprodol in The growing evidence includes In summary, multiple national and Norway. The study used the Norwegian epidemiologic abuse-related data in the state data systems used in the United Prescription Database (NorPD), which published scientific literature (e.g., States provide substantial evidence that contains information on prescription Bramness) and from AERS, as well as carisoprodol is being abused. This drugs dispensed in Norway. An data from national and state data conclusion is corroborated by various advantage to this database is that systems that track drug abuse. While reports published in the scientific patients were followed over time. In recent data show that carisoprodol is literature. While carisoprodol is most 2004, 53,889 Norwegian women (2.4 most commonly abused in combination often abused in combination with other percent) and 29,824 men (1.3 percent), with other drugs, DAWN data show that drugs, in about 20 percent of the reports age 18 or older, received carisoprodol at it is abused as a single drug in carisoprodol is the only drug of abuse. least once. At the time of the study, 20 percent of the cases. Other data (the In addition, national survey data show carisoprodol was approved in Norway NSDUH survey) show that carisoprodol that in excess of one million people for the treatment of acute low back pain, is being widely abused by adolescents under the age of twenty-six have for short term use only (up to 1 week) and young adults.

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The human data showing abuse are toxicology, patterns of drug use, driving probably has an impairing effect by reinforced by recent animal self- behaviors, and symptoms observed in itself at blood concentration levels administration and drug-discrimination the drivers were considered. The greater than those observed after studies indicating that carisoprodol has symptomatology and level of driving therapeutic doses. positive reinforcing and discriminative impairment were consistent with that of In 2007, Jones, et al. (52), reported the effects similar to other drugs currently other CNS depressants, most notably concentrations of scheduled controlled under schedule IV, including alcohol. Reported driving behaviors prescription drugs found in blood barbital, meprobamate, and included erratic lane travel, weaving, samples from people arrested in Sweden chlordiazepoxide. driving slowly, swerving, stopping in during 2004 [n=7052] and 2005 traffic, and hitting parked cars and other [n=7759] for driving under the Factor 6—The Risk to the Public Health stationary objects. Drivers stopped by influence. In Sweden, both carisoprodol The scientific literature and other the police displayed poor balance and and meprobamate are C–IV drugs, but data, including DAWN, NSDUH, and coordination, horizontal gaze meprobamate is no longer registered for AERS, document the adverse health nystagmus; bloodshot eyes; use. Carisoprodol was found in 66 consequences of the use, misuse, and unsteadiness; slurred speech; slow specimens (0.9% of the total abuse of carisoprodol. According to the responses; a tendency to doze off or fall specimens); the mean concentration was FDA, the risks of carisoprodol to the asleep; difficulty standing, walking or 3.8 mg/l (median 2.8 mg/l and highest public health are typical of other CNS exiting their vehicles; and 11.9 mg/l) and meprobamate in 63 depressants that are controlled in the disorientation. (0.8%) (mean concentration 15.7 mg/l, CSA. GX 6, at 21. These risks include Many of these cases involved drivers median 11 mg/l, and highest 64.0 mg/ CNS depression, respiratory failure, who had also taken alcohol or other l). In eight specimens, only cognitive and motor impairment, CNS active drugs, making it difficult to meprobamate was found. In twenty- addiction, dependence, and abuse. Id. attribute the documented impairment seven percent of the carisoprodol cases, Because carisoprodol metabolizes to solely to carisoprodol and the blood concentrations were higher meprobamate (C–IV), carisoprodol may meprobamate. However, in twenty-one than what would be expected for normal pose similar risks to the public health as cases, no other drugs were detected and therapeutic use (2.5–10 mg/l), thus those exhibited by meprobamate. Olsen, similar signs and symptoms were suggesting overdose or abuse of the et al. (48), concluded that the present. In these cases, impairment was drug. Multi-drug use was not evaluated meprobamate formed during possible at any concentration of these separately. carisoprodol metabolism may contribute two drugs, but the most severe The FDA also noted evidence in the to the effects of carisoprodol. A case impairment was noted when the medical literature that the use of report of a pediatric death due to CNS combined concentration was greater carisoprodol in the elderly and the depression and respiratory failure as a than 10 mg/L, which is still within the nursing home population should be consequence of a carisoprodol overdose therapeutic range. The authors done with great care (53, 54). As with indicates that oral ingestion of speculated that the toxicology findings other CNS depressants, because of carisoprodol alone could produce in these cases resulted from recent use recognized age-related changes in drug significant serum levels of both or overuse of the drug, but they also metabolism and excretion and increased carisoprodol and meprobamate (17). suggested that chronic use may be a sedation, seniors could have an Backer, et al. (22), reported three factor, particularly in those with increased risk of adverse events cases involving overdoses of impaired metabolisms. including falls and auto accidents. carisoprodol and measured the Bramness, et al. (51), reported on 62 The FDA further noted that the effects concentration of carisoprodol and cases of impaired driving where induced by carisoprodol are meprobamate in urine, vitreous humor, carisoprodol and meprobamate were the characteristic of CNS depressants, and heart and femoral blood by GC/MS. In only drugs identified in the database of include altered attention, coordination, the first case, which involved a 43-year the Norwegian Institute of Public reaction time, judgment, decision old woman, an empty bottle of 30 Health, Division for Forensic Toxicology making and other skills necessary to tablets of carisoprodol was found next and Drug Abuse. The study found that safe driving. Consequently, individuals to her. The prescription had been filled impaired drivers (73 percent) had higher under the influence of both therapeutic 3 days earlier. Only carisoprodol and blood carisoprodol concentrations than and supra-therapeutic doses of meprobamate were detected, but the drivers who were not impaired (27 carisoprodol present a public health risk concentrations varied by anatomical percent), but found no difference in that needs to be considered when site. blood meprobamate concentration for carisoprodol is prescribed. Carisoprodol has been implicated in all the drivers viewed together. Representative cases are described cases of impaired driving (49–52). However, among occasional users of below. Logan, et al. (50), reported the analytical carisoprodol, there was a difference in As documented in the scientific and results from a Washington State blood meprobamate concentration medical literature, carisoprodol may Toxicology Laboratory (WSTL) review between non-impaired and impaired produce dependence and a withdrawal of drivers suspected of driving under drivers. The risk of being judged syndrome characterized by anxiety, the influence of drugs and further impaired rose with increasing blood insomnia, and irritability. Moreover, in reviewed the pharmacology of the carisoprodol concentration, but not with some cases, muscular pain has been carisoprodol and meprobamate, increasing blood meprobamate described upon abrupt cessation including literature implicating these concentration. The clinical effects of following long-term use. See Factor 7. drugs in impaired driving. They found carisoprodol as measured by the clinical 104 cases submitted to the WSTL test for impairment (CTI) resembled Adverse Events Report in the Scientific between January 1996 and July 1998 in those of benzodiazepines (C–IV). Literature which meprobamate and/or Additional effects included tachycardia, The FDA also discussed several carisoprodol was detected in the blood involuntary movements, hand tremor adverse events reported in the scientific of drivers involved in accidents or and horizontal gaze nystagmus. The literature. A two-year old ingested 700 arrested for impaired driving. Analytical authors concluded that carisoprodol milligrams (two 350 mg tablets) of

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carisoprodol and became increasingly California. Carisoprodol was detected in to one of Meda’s Experts, he had drowsy over 60 minutes with symptoms the urine specimens of nineteen patients ‘‘personally asked a number of progressing to lethargy and hypoxia who became the study population; physicians if they would use (18). The patient’s level of demographic and clinical information carisoprodol if scheduled, and many consciousness declined significantly was then obtained by a retrospective indicated they would not.’’ Id. requiring respiratory ventilation. review of the patients’ medical records. As support for this contention, Meda Following activated charcoal and In only one case was carisoprodol and/ also submitted two bar charts which supportive care, the patient recovered or meprobamate the sole drug(s) show the percentage decrease in the fully within 12 hours. detected; benzodiazepines, opiates and number of carisoprodol prescriptions in Roberge, et al. (55), reported the case cannabinoids were the other drugs most Indiana, Nevada, Texas, and Louisiana of a 52-year-old woman who presented frequently identified. after the drug was scheduled in these with CNS depression and a Glasgow The most common clinical States. MX 21. More specifically, the Coma Score of 9, secondary to ingestion abnormality was depressed levels of charts show that in Indiana and Nevada, of carisoprodol. She reportedly took her consciousness which occurred in twelve the amount of prescriptions decreased carisoprodol tablets in an erratic fashion cases; eight patients were lethargic, by approximately five percent following (taking an estimated thirty-five extra 350 three obtunded but were responsive to scheduling, and that in Texas and milligram tablets over a thirteen-day pain, and one obtunded and was non- Louisiana, the amount of prescribing period) and developed stupor along responsive to pain. The clinical history decreased by approximately two to three with confusion and garbled speech. suggested that in seven cases, the drug percent and four percent respectively.37 After administration of i.v. flumazenil was abused or implicated in a suicide However, in the first quarter of 2010, the (0.2 mg IV), the patient’s neurologic attempt or gesture. In another seven number of prescriptions in Louisiana status normalized and she required no cases, the drug was used primarily for had actually increased over the baseline further therapy. Carisoprodol and its medical purposes, and in five cases, the level. Id. metabolite meprobamate are y- reason for use could not be determined. Meda’s evidence does not establish aminobutyric acid receptor indirect Additional findings were tachycardia that scheduling carisoprodol will harm agonists with CNS chloride ion channel (eight cases), dysarthria (seven cases), patients. As for the testimony of Meda’s conduction effects similar to the hypotension (six cases), and seizure Expert that many physicians had told benzodiazepines, thus making activity (five cases, including the one him that they would not prescribe flumazenil a potentially useful antidote case where no other drugs were carisoprodol and his conclusion that ‘‘a in toxic presentations. identified). Approximately half of the not insubstantial number would’’ stop Siddiqi and Jennings reported the time, the patient was hospitalized. In prescribing, Meda’s Expert produced no case of a near-fatal overdose involving a each case, supportive care alone led to evidence to establish that his conclusion 40-year old male (14). The patient, who recovery. While the authors was based on a statistically valid had a history of hypertension, ingested acknowledged the potential sample. More specifically, Meda’s 60 carisoprodol tablets (21 grams) and contribution of the other drugs Expert offered no evidence as to how an unknown quantity of identified to the symptomatology found many physicians he had asked, what chlordiazepoxide and temazepam. He in these cases, they recommended that their specialties were, how the developed a coma (with absent tendon carisoprodol and its metabolite questions were phrased, and how many and plantar reflexes), sinus tachycardia meprobamate be included in had said they would stop prescribing (130 bpm) with a prolonged QT interval, comprehensive drug screening as it had the drug. mild respiratory acidosis (pH 7.31; become an unrecognized drug of abuse Likewise, the data showing a decrease pCO2 50.1 mmHg, partially in the community. in the amount of prescriptions following compensated with artificial ventilation), Goldberg (20) reported that the scheduling of the drug in the above fever (100.5° F), hypertension (220/ manifestations of acute carisoprodol States do not support Meda’s argument, 118_mmHg), and dry and warm skin. toxicity were due chiefly to stimulation because it assumes that the baseline Following supportive care, he recovered and depression of the CNS. Drowsiness, level of prescribing reflects legitimate completely without further sequelae. dizziness, headache, diplopia, and prescriptions. However, the evidence in Reeves, et al. (40), studied the case of vertigo predominated. Impaired this record clearly establishes that a 43-year-old male who took up to 30 or coordination, nystagmus on lateral gaze, carisoprodol is being diverted; thus, to more tablets per day (a dose equal to or and an altered state of consciousness the extent the baseline level of greater than 10,500 mg/day) of were prominent findings. Acute prescribing includes illegitimate carisoprodol for several weeks, to treat symptomatology was present at prescriptions, the decrease in chronic back and shoulder pain. After carisoprodol levels above 33 mg/ml, prescriptions may reflect nothing more the patient abruptly stopped taking which lasted from eight to fifteen hours. than doctors recognizing that certain carisoprodol, he developed anxiety, Gastric lavage and supportive measures patients are seeking carisoprodol for tremors, muscle twitching, insomnia, are the accepted methods of treating non-medical reasons, and are therefore auditory and visual hallucinations, and acute carisoprodol overdose. being more cautious in evaluating their bizarre behavior. The patient was patients and declining to prescribe the treated with olanzapine and tapering Meda’s Factor Six Evidence drug to drug-seeking patients. The doses of lorazepam and his symptoms Meda contends that scheduling decrease may also reflect that doctors gradually resolved. The authors carisoprodol ‘‘will have a negative who have knowingly prescribed the suggested that this drug withdrawal impact on patient care.’’ MX 174, at 4. drug for non-medical reasons have syndrome was due to the accumulation According to Meda, some physicians ceased this activity because the of meprobamate, the active metabolite of will stop writing prescriptions for the carisoprodol. drug and use other non-scheduled 37 According to the chart, Indiana scheduled Bailey, et al. (47), published a muscle relaxants due to ‘‘concerns that carisoprodol on July 1, 2004, and Nevada on July 14, 2004. MX 21. However, Meda’s chart shows retrospective analysis of drug screening their prescribing may be second guessed prescribing levels only through the fourth quarter performed for patient care during a six- by government regulators or law of 2005, at which time the reduction in prescribing month period at a laboratory in enforcement personnel.’’ Id. According levels in both States had begun to decrease. Id.

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scheduling of the drug creates effect, such as analgesia, in the absence a withdrawal syndrome. Reeves and additional consequences for prescribing of disease progression or other external Parker (58) studied changes in the it without a medical purpose. Also, even factors. Id. Physical dependence is a occurrence of somatic dysfunctions in if some doctors may have chosen to state of adaptation manifested by a drug five patients during an eight-day period prescribe non-controlled muscle class-specific withdrawal syndrome following discontinuation from large relaxants instead of carisoprodol after produced by abrupt cessation, rapid doses of carisoprodol. The results the drug was scheduled, this alone does dose reduction, decreasing blood level showed that the number of somatic not establish that patients have been of the drug and/or administration of an dysfunctions changed significantly harmed or that they have received ‘‘sub- antagonist. See American Academy of during the withdrawal period. Each optimal treatment.’’ MX 174, at 5. In any Pain Medicine, American Pain Society patient had an increase in the number event, as long as doctors follow and American Society of Addiction of somatic dysfunctions during the first accepted standards of medical practice Medicine Consensus Document (2001). three days after cessation of in evaluating their patients and Tolerance is a state of adaptation in carisoprodol with a return to the establish a legitimate medical purpose which exposure to a drug induces baseline by the eighth day. This was for prescribing carisoprodol to their changes that result in a diminution of reflected statistically in a significant- patients, they have nothing to fear from one or more of the drug’s effects over within-subjects effect for time. The DEA. Furthermore, doctors are expected time. Id. results of supplemental analyses to use their best professional judgment The FDA found that early animal drug revealed a significant component of the in determining which of various drugs dependence studies demonstrated that effect and a trend for the quadratic they should prescribe to properly treat carisoprodol has a similar dependence component to be significant. Increases their patients.38 liability to barbital, a schedule IV CNS in the number of somatic dysfunctions I thus find unavailing Meda’s depressant. Id. (citing FDA Reference during carisoprodol discontinuation contention that scheduling carisoprodol 12). In dogs tolerant and dependent on support the existence of a carisoprodol will create a risk to public health. To the barbital, 200 mg/kg p.o. of carisoprodol withdrawal syndrome. contrary, the record contains substantial every six hours was completely effective Finally, FDA found that the evidence establishing that the abuse of and equivalent to 100 mg/kg of barbital development of dependence or carisoprodol poses a substantial risk to in preventing the appearance of tolerance is also evidenced by several those persons who abuse the drug, as abstinence phenomena. Id. published reports (35, 40, 49, 57, 59). well as others. See also Factor Four. Wyller, et al. (56), studied the Patients increased their doses to toxic occurrence of abstinence symptoms levels and appeared to be exhibiting Factor 7—Its Psychic or Physiological during carisoprodol withdrawal in Dependence Potential drug-seeking behavior. FDA further humans. In this study, carisoprodol was found that prolonged misuse of According to FDA, the term psychic gradually withdrawn over a two-week carisoprodol can lead to physical dependence is not in current use and period in nine male prisoners who had dependence and that patients who refers to impaired control over drug use, been taking the drug in daily doses abruptly stop carisoprodol can develop such as craving. This term was ranging from 700 mg to 2,100 mg for at a withdrawal syndrome that includes introduced in the late 1950’s by the least 9 months. Patients were assessed symptoms such as anxiety, insomnia, World Health Organization Expert clinically during the withdrawal period. irritability, and worsening muscular Committee on Addiction-Producing Most of the patients reported mental Drugs, as one of the factors that, in pain (40). distress, such as anxiety, insomnia, and Subsequent to the FDA forwarding its conjunction with physical dependence, irritability. Cranial and muscular pain evaluation to DEA, doctors at the Mayo defined the addiction phenomena and vegetative symptoms were also Clinic published a clinical report (Savage et al., 2003). FDA further frequently reported. Most of the documenting withdrawal symptoms in a explained that physical or physiological symptoms observed were transient, with 51-year old man who was taking up to dependence is a form of physiologic neither seizures nor psychotic reactions 8400 mg per day of carisoprodol, which adaptation to the continuous presence being reported. of certain drugs in the body. GX 6, at 24. Rohatgi, et al. (57), reported the he obtained from both his physician and Tolerance and physical dependence treatment of a case of carisoprodol an internet pharmacy, but which he had examine the responses to repeated exhausted at some point before he was dependence involving a 46-year old 39 administration of a drug. Id. at 25. An male who self-treated his anxiety when hospitalized. GX 18, at 2. On assessment of tolerance or physical his doctor stopped his narcotic admission, the patient ‘‘was anxious, dependence is needed as part of the prescriptions. The patient purchased distractable, [and] disoriented,’’ and safety assessment of a drug and is a carisoprodol over the internet and self- exhibited ‘‘[a] high frequency, postural, factor considered in scheduling. Id. medicated. The patient was admitted to and kinetic tremor in [his] extremities.’’ Tolerance is the need for increasing a treatment center and withdrawn from Id. at 1. While the patient was placed on doses of a drug to maintain a defined carisoprodol. Withdrawal symptoms a tapering schedule, on the third day of included heart palpitations, diaphoresis, his hospitalization, ‘‘the patient’s 38 In its brief, Meda cites an article which states chills, stomach cramps, nausea, tremor, agitation and confusion that ‘‘[d]espite concerns about the potential risk of insomnia, restlessness, myalgias, worsened, and he experienced visual abuse from carisoprodol because of its metabolism hallucinations and myoclonic jerks in to meprobamate, the available literature provides no arthralgias, tremors, diarrhea, severe data regarding the comparative risk of abuse and psychomotor agitation, feelings of the extremities.’’ Id. at 2. addiction from skeletal muscle relaxants.’’ Meda Br. depersonalization, and anxiety with While the doctors were able to at 48 (citing Meda Ex. 83, Chou, et al., Comparative successfully treat the patient and taper Efficacy and Safety of Skeletal Muscle Relaxants for suicidal ideation. The patient’s symptoms were managed with him off of the drug, they concluded that Spasticity and Musculoskeletal Conditions: A ‘‘[t]his case demonstrates adverse effects Systematic Review, 28 J. of Pain & Symptom Mgmt. risperidone, clonazepam, mirtazapine, 140, 167 (2004)). The CSA does not, however, and fluoxetine. require that the Agency (or the Secretary) conduct 39 According to the case report, the doctors were a comparative analysis of the abuse/addiction risk The FDA also noted that several other not initially aware of the quantity of carisoprodol of the drugs in a therapeutic category in order to reports found that patients who abruptly that the patient was taking and that he purchased schedule a particular drug. stop the intake of carisoprodol may have it online. GX 18, at 2.

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of both carisoprodol toxicity and their pain and may not be ‘‘evidence of MX 6, at 2.42 The FDA also required that withdrawal.’’ Id. More specifically, the any physical dependence,’’ the Meda change the label to include the authors noted that ‘‘[t]he abrupt symptoms which have been following statement: discontinuation of high-dose documented upon the abrupt cessation SOMA is not a controlled substance * * *. carisoprodol may result in withdrawal of the drug are far more extensive than Discontinuation of carisoprodol in animals or in humans after chronic administration symptoms including anxiety, psychosis, anxiety. tremors, myoclonus, ataxia, and can produce withdrawal signs, and there are published case reports of human seizures.’’ Id. The authors also opined Furthermore, several of the case carisoprodol dependence. that ‘‘[t]his withdrawal syndrome is reports involved patients who had taken In vitro studies demonstrate that likely under-recognized.’’ Id. carisoprodol for extensive periods. The carisoprodol elicits barbiturate-like effects. Regarding the individual case reports, prescribing information for carisoprodol Animal behavior studies indicate that Dr. Jasinski opined that care should be states, however, that the drug ‘‘should carisoprodol produces rewarding effects. taken in evaluating the significance of only be used for short periods (up to Monkeys self administer carisoprodol. Drug discrimination studies using rats indicate them because the subjects may have two or three weeks) because adequate taken the drug for therapeutic reasons that carisoprodol has positive reinforcing and evidence of effectiveness for more discriminative effects similar to barbital, ‘‘or for non-therapeutic uses unrelated prolonged use has not been meprobamate, and chlordiazepoxide. to any abuse liability,’’ such as to established.’’ MX 6, at 2. Thus, it does commit suicide. MX 172, at 9. Dr. See MX 30, at 8; MX 6, at 3. While not seem likely that the patients’ Meda initially objected to the proposed Jasinski further opined that the reported anxiety upon the cessation of individual case reports should be changes, it eventually agreed to them. the drug was due to ‘‘the interruption of considered in light of the facts that ‘‘all MX 30, at 1. effective treatment of their discomfort or I therefore conclude that substantial drugs produce untoward effects if taken 41 at doses significantly above the pain.’’ MX 172, at 10. evidence supports a finding that recommended therapeutic dose,’’ that a Finally, in October 2009, based on carisoprodol has dependence liability patient’s having anxiety upon new safety information, the FDA similar to that of barbital, a schedule IV discontinuation of carisoprodol ‘‘could required that Meda make several CNS depressant. very well be a function of the changes to the approved label. The first Factor 8—Whether the Substance Is an interruption of effective treatment of of these involved the insertion of a Immediate Precursor of a Substance their discomfort or pain,’’ or that the sentence into section 5.2 (entitled ‘‘Drug Already Controlled ‘‘the untoward effect reported with Dependence, Withdrawal, and Abuse’’) Carisoprodol metabolizes to carisoprodol’’ could ‘‘have been caused that ‘‘there have been post-marketing- meprobamate, a schedule IV controlled by other substances which the patient adverse event reports of SOMA was’’ taking concurrently. Id. at 9–10. substance. However, the FDA found that associated abuse when used without carisoprodol is not an immediate As for Dr. Jasinski’s suggestion that other drugs with abuse potential.’’ MX individual case reports should be given precursor of meprobamate or any other 30, at 5. Thus, this section of the label controlled substance. GX 6, at 26. less weight because the patient may now states: have taken the drug for therapeutic Conclusions of Law reasons, whether a patient initially took In the postmarketing experience with a drug to treat a legitimate medical SOMA, cases of dependence, withdrawal, Under 21 U.S.C. 811(a)(1)(a), to ‘‘add’’ condition is not relevant in assessing and abuse have been reported with prolonged a drug to one of the schedules of whether the drug causes dependence. use. Most cases of dependence, withdrawal, controlled substances, the Agency must Indeed, many patients who have and abuse occurred in patients who have had first find that carisoprodol ‘‘has a become addicted to controlled a history of addiction or who used SOMA in potential for abuse.’’ If such a finding is substances started taking them to treat a combination with other drugs with abuse supported by the record, the Agency legitimate medical condition.40 potential. However, there have been post- must then make the ‘‘findings Moreover, while it is undoubtedly marketing-adverse event reports of SOMA prescribed by subsection 812 of this title true that all drugs have ‘‘untoward associated abuse when used without other for the schedule in which such drug is effects if taken at doses significantly drugs with abuse potential. Withdrawal to be placed.’’ 21 U.S.C.811(a)(1)(B). above the recommended therapeutic symptoms have been reported following Having considered all eight of the dose,’’ the evidence establishes that abrupt cessation after prolonged use. To section 811(c) factors, I conclude that a patients engage in drug-seeking reduce the chance of SOMA dependence, preponderance of the evidence supports behavior and that the abrupt withdrawal withdrawal, or abuse, SOMA should be used the conclusion that carisoprodol ‘‘has a of carisoprodol produces a withdrawal with caution in addiction-prone patients and potential for abuse’’ such as to warrant syndrome that includes a variety of in patients taking other CNS depressants control and that it should be placed in symptoms such as anxiety, insomnia, including alcohol, and SOMA should not be schedule IV. irritability, tremors, and muscle pain. used more than two to three weeks for the The Section 811(a)(1)(a) Finding— Contrary to Dr. Jasinski’s contention that relief of acute musculoskeletal discomfort. Carisoprodol Has A Potential for Abuse the anxiety experienced by these Soma, and one of its metabolites, A preponderance of the evidence patients may have been caused by the meprobamate (a controlled substance), may supports the conclusion that interruption of effective treatment of cause dependence. carisoprodol has a potential for abuse, and indeed, is being widely abused.43 40 As for Dr. Jasinski’s contention that the 41 As for the contention that in two of the case individual case reports should be given less weight reports, ‘‘the untoward effect reported with because the person may have taken carisoprodol to carisoprodol would appear to have been caused by 42 With the exception of the third sentence commit suicide, I need not decide whether such other substances the patient had taken (‘‘However, there have been post-marketing adverse evidence is probative of whether a drug has concurrently,’’ Dr. Jasinski identified these reports reports of SOMA-associated abuse when used dependence liability. However, as explained above, only by their exhibit numbers and the publication without other drugs with abuse potential.]’’), this the Senate Report expressly stated that the Agency they appeared in. See MX at 172, at 10 (citing MXs portion of the label repeats verbatim the 2007 label. can consider such evidence ‘‘as indicative of a 110 & 161). However, neither of these exhibits was See MX 25, at 5. drug’s potential for abuse.’’ S. Rep. 91–6134, entered into evidence. I thus cannot evaluate the 43 In both its brief and its exceptions, Meda notes reprinted in 1970 U.S.C.C.A.N., at 4602. validity of Dr. Jasinski’s contention. that ‘‘DEA did not present any witnesses from FDA

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The NSDUH data establish that a large years 2004 through 2008, establish that either perform no physical exam or a number of persons are taking carisoprodol (or its metabolite cursory physical examination; and (3) carisoprodol on their own initiative meprobamate) was the cause of death in street dealing. The Executive Director of rather than on the basis of a physician’s between 74 and 96 cases each year. It the Ohio Board also testified to data recommendation. The NSDUH data— bears noting that this is but one State’s obtained through the Board’s which Meda’s Expert acknowledged was data. prescription monitoring program generally reliable—consistently show Also, NPDS data for the years 2006 showing that persons are engaging in that between 2.5 and 2.8 million and 2007 show that carisoprodol (as a doctor shopping to obtain large persons have used carisoprodol for non- sole drug) has been involved in more quantities of the drug. The officials also medical reasons, including than 3500 toxic exposures cases. Of testified to the practice of drug abusers approximately 1 million 18–25 year these, between 2687 and 2821 cases using carisoprodol as part of a cocktail olds, and more than 100,000 12–17 year were serious enough to require which includes narcotics (such as olds. As explained above, given the treatment in a health care facility, and oxycodone and hydrocodone) and magnitude of the nonmedical use of in more than 100 cases, the patient had benzodiazepines. carisoprodol, the Agency is not required life-threatening symptoms or a While carisoprodol is indicated for to show that the rate of abuse is significant residual disability. only short-term use of up to two to three increasing in order to support a finding Finally, while Meda notes that data weeks, prescription data for a recent that the drug has a potential for abuse from the FDA AERS system show that, five-year period show that more than 25 such as to warrant control.44 between January 1979 and May 2001, percent of patients used the drug for In addition, the evidence shows that ‘‘only 83 reports’’ have ‘‘included the more than one month and 4.3 percent individuals are taking carisoprodol in terms abuse, dependency, or used the drug for more than 360 days. amounts sufficient to create a hazard to withdrawal,’’ and that this must be Similarly, Bramness, who studied the health and safety of both themselves compared with the total number of carisoprodol use and abuse in Norway and others. Notwithstanding the carisoprodol prescriptions, these data (where the drug is only approved for use criticism of the DAWN data, the are compiled from reports which have of up to one week) during 2004, found estimates as to the number of emergency been voluntarily submitted by that 8 percent of the patients who room visits related to carisoprodol are consumers and health care obtained the drug were also abusing comparable to those for diazepam, a professionals. Thus, these data likely benzodiazepines and 14 percent of the schedule IV controlled substance. substantially underreport the number of patients were also abusing opioids. Next, data obtained from the Florida such incidents. Moreover, while those patients who The evidence further shows that there Medical Examiners Commission for the were using carisoprodol for therapeutic is significant diversion of carisoprodol purposes received only 12 percent of the to justify their findings or * * * provide [it with] from legitimate channels. First, NFLIS carisoprodol which was dispensed, the an opportunity * * * to challenges the bases for data show that carisoprodol has such witnesses’ findings.’’ Meda’s Exceptions at 1. opioid abusers received 48 percent. Of It further argues that it has been denied a consistently ranked among the top twenty-five drugs which have been further note, 14 percent of the patients meaningful hearing because it ‘‘never had an had received an amount of the drug opportunity to challenge the medical and scientific analyzed and identified by forensic findings that formed the basis of the scheduling laboratories following seizures which equal to 75 daily doses or more. determination.’’ Id. at 2. See also Meda. Br. at 22. occurred during the course of criminal While Meda cites both the Fraser (‘‘DEA counsel did not call any HHS or FDA study (in particular, the third arm) and witness to testify and justify the scientific, medical, investigations. Moreover, because and legal basis underlying the HHS carisoprodol is controlled in only its recent clinical trials, both items of recommendations. No FDA or HHS witness was seventeen States, which comprise evidence suffer from significant made available to answer questions about the approximately thirty-five percent of the limitations and are of limited probative numerous weaknesses in the data cited [by the value. As noted above, the third arm of FDA], or otherwise explain the FDA analysis and United States’ population, and as conclusions.’’). Meda’s expert recognized, the the Fraser study, involved only five As explained above, many of HHS’s findings were likelihood of a sample ‘‘being analyzed patients (only one of whom received the based on published articles, and Meda raises no is substantially affected by the drug for 54 days), and Meda’s recent contention that any unpublished articles cited by clinical trials involved only short term HHS were not provided to it. Meda does not explain prosecutor’s perceptions of the available why additional testimony was required to explain criminal charges,’’ it is likely that the use at therapeutic levels. Accordingly, I the contents of the articles. Moreover, Meda’s NFLIS data substantially understate the conclude that the record as a whole Experts testified as to various issues with both the extent to which carisoprodol is being establishes that carisoprodol has a Government’s data sources and the FDA’s reliance potential for abuse (and is being abused on several articles. In addition, Meda does not found during criminal investigations. contend that it sought (and was denied) a subpoena Of particular significance, the at such a level) as to warrant control. to require the testimony of any FDA employees who testimonies of the DEA Deputy Assistant See 21 U.S.C. 811(a)(1). were involved in preparing the report. I thus reject Administrator; a Tennessee Bureau of Meda’s contention. The Section 812(b) Placement Findings Investigation Special Agent in Charge, 44 In its brief, Meda also cites to admittedly The FDA recommended that anecdotal evidence that an analysis by RADARS of who was the former Coordinator of the Web site postings in Erowid, ‘‘an online member- Tennessee Drug Diversion Task Force; carisoprodol be placed in schedule IV. supported organization where individuals and the Executive Director of the Ohio Under 21 U.S.C. 812(b), the Attorney anonymously post [their] experiences with State Board of Pharmacy; provide General is required to make the psychoactive substances, including prescription 45 drugs,’’ and that Skelaxin, another muscle relaxant, substantial evidence that carisoprodol is following findings to do so. These are: ‘‘was among the ten most frequently mentioned being unlawfully distributed, typically (A) The drug * * * has a low potential for prescription drugs [but] carisoprodol was not.’’ with narcotics and benzodiazepines, abuse relative to the drugs or other Meda Br. 35. Contrary to Meda’s understanding, substances in schedule III. whether Skelaxin is being abused more often than and is being abused. These officials carisoprodol is irrelevant in assessing whether the testified that carisoprodol is being latter has ‘‘a potential for abuse’’ and warrants distributed by: (1) Internet pharmacies 45 While Meda challenged the Government’s (and control. 21 U.S.C. 811(a). It is further noted that based on prescriptions issued by doctors FDA’s) finding that carisoprodol has a potential for while Meda cites the RADARS analysis as an abuse such as to warrant control, it did not exhibit, see Meda Br. 97 (citing Meda Exh. 15), the who never see their patients; (2) doctors, challenge the FDA’s placement findings. See record does not contain this exhibit. who while they meet their patients, Meda’s Br. at 111–14.

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(B) The drug * * * has a currently significantly, Bramness, et al., found reported the case of a 46-year old male accepted medical use in treatment in the that the clinical effects of carisoprodol who purchased carisoprodol over the United States. resemble those of benzodiazepines, internet and self-medicated to treat his (C) Abuse of the drug * * * may lead to which are schedule IV controlled anxiety after his physician stopped his limited physical dependence or substances. I therefore hold that narcotic prescriptions. Upon the psychological dependence relative to the drugs or other substances in schedule III. substantial evidence supports the FDA’s patient’s admission to a treatment center conclusion that carisoprodol has a low and being withdrawn from the drug, the 21 U.S.C. 812(b)(4). potential for abuse relative to the drugs patient exhibited heart palpitations, It is undisputed that carisoprodol has or other substances in schedule III. See diaphoresis, chills, stomach cramps, a currently accepted medical use in Grinspoon, 828 F.2d at 894 (upholding nausea, insomnia, restlessness, treatment in the United States and is Agency’s reliance of on studies which myalgias, arthralgias, tremors, diarrhea, FDA-approved for the relief of suggested that MDMA was ‘‘related in severe psychomotor agitation, feelings discomfort associated with acute, its effects to’’ other schedule I and II of depersonalization, and anxiety with painful musculoskeletal conditions. GX controlled substances). suicidal ideation. The FDA also cited 6, at 26. Finally, the FDA concluded that the five other published studies which The FDA further found that abuse of carisoprodol may lead to evidence that persons taking carisoprodol has a low potential for limited physical dependence or carisoprodol can become physically abuse relative to schedule III controlled psychological dependence relative to dependent and engage in drug-seeking substances. Id. FDA found that the drugs or other substances in behavior. carisoprodol is a CNS (central nervous schedule III. GX 6, at 27. In support of Finally, a case study published by system) depressant and that it is abused its conclusion, the FDA noted that upon physicians at the Mayo Clinic primarily in combination with other the withdrawal of barbital from dogs subsequent to the FDA’s report drugs of abuse including opioids and dependent on it, carisoprodol prevents documented the presence of withdrawal benzodiazepines, cocaine, and the abstinence syndrome. Id. FDA also symptoms in a 51-year old man who marijuana. Id. Carisoprodol metabolizes cited case studies which show that had taken up to 8400 mg per day before into meprobamate, a schedule IV carisoprodol causes psychological or he exhausted his supply (which he controlled substance. Based on the physical dependence and that obtained from both his physician and DAWN ED estimates, FDA calculated an ‘‘carisoprodol produces a withdrawal the internet). Upon his admission, the abuse frequency which suggests that syndrome characterized by clinical patient ‘‘was anxious, distractable, [and] carisoprodol is being abused at a rate depression, anxiety, drug craving, disoriented,’’ and exhibited ‘‘[a] high similar to that of diazepam, a schedule irritability and poor concentration.’’ Id. frequency, postural, and kinetic tremor IV controlled substance. See 21 CFR The record contains substantial in [his] extremities.’’ The patient was 1308.14(c). In vitro studies demonstrate evidence to support the FDA’s placed on a tapering schedule, but on that carisoprodol has an affinity for the conclusion. Meda cites both the Fraser the third day, his ‘‘tremor, agitation and GABAa receptor and elicits barbiturate- study and its recent clinical trials as confusion worsened, and he like effects. Likewise, in a drug- evidence that carisoprodol does not experienced visual hallucinations and discrimination study, carisoprodol was cause dependence. However, the Fraser myoclonic jerks in the extremities.’’ completely effective in preventing study expressly noted that ‘‘it remains While the doctors were able to abstinence syndrome in dogs tolerant to be seen whether administering successfully taper the patient off of the and dependent on barbital, a schedule carisoprodol continuously in larger drug, they concluded that ‘‘[t]he abrupt IV controlled substance. In a study doses would induce’’ a barbiturate-like discontinuation of high-dose involving rats trained to discriminate withdrawal pattern upon carisoprodol may result in withdrawal carisoprodol, various controlled discontinuation of the drug. Likewise, symptoms including anxiety, psychosis, substances including meprobamate, Meda’s clinical trials involved tremors, myoclonus, ataxia, and pentobarbital (C–II/C–III), and administration of the drug for no more seizures.’’ chlordiazepoxide (C–IV), substituted than two-weeks and at therapeutic In its Exceptions, Meda argues that fully for the discriminative stimulus levels. Moreover, Meda eventually the ALJ unfairly and unjustifiably relied effects of carisoprodol. In a further agreed to change the drug label to reflect on this study, which the Government study, bemegride, a barbiturate that ‘‘cases of dependence [and] introduced to rebut Dr. Jasinski’s antagonist, antagonized the withdrawal * * * have been reported testimony. Exceptions at 2–3. Meda discriminative stimulus effect of with prolonged use.’’ MX 6, at 2. objects that the document was offered carisoprodol in rats trained to A case study by Reeves found that after the ALJ had excused the last discriminate the drug. While Meda’s when a 43-year-old male, who had taken witness, thereby depriving it ‘‘of any Expert opined that these studies do not large doses for several weeks, stopped opportunity to subject the document to taking carisoprodol, he developed establish carisoprodol’s abuse expert scrutiny.’’ Id. at 2. Meda also anxiety, tremors, muscle twitching, liability,46 he acknowledged that they objects that the ALJ gave this report insomnia, auditory and visual do indicate that carisoprodol may have ‘‘significant weight’’ and ‘‘incorrectly hallucinations and engaged in bizarre effects similar to those of barbiturates. elevated [it] to that of a ‘study.’ ’’ Id. In addition, several human studies behavior. In a study of nine male (citing ALJ 34, 85). prisoners who had been taking However, Dr. Jasinski acknowledged establish that carisoprodol has effects carisoprodol in doses of 700 to 2100 mg that abuse of carisoprodol over a similar to that of CNS depressants. Most for at least nine months, Wyller found prolonged period could lead to limited 46 As found above, the record as a whole that when the drug was gradually physical or psychological dependence. establishes that carisoprodol has a potential for withdrawn over a two-week period, Tr. 706–07. While Dr. Jasinski further abuse and is being abused. I note Dr. Jasinski’s most of the patients reported mental maintained that this was ‘‘not the testimony that the animal studies do not establish distress including anxiety, insomnia, specific issue’’ and that ‘‘[t]he specific carisoprodol’s abuse liability only to provide context to his acknowledgement that the animal and irritability; cranial and muscular issue [is whether abuse] would lead to studies indicate that carisoprodol may have effects pain, as well as vegetative symptoms, drug seeking or * * * to a severe similar to those of barbiturates. were also frequently reported. Rohatgi withdrawal syndrome,’’ id., his view of

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the statute is mistaken. Under must be registered to conduct such Records. All registrants are required subsection 812(b), a finding that abuse activities in accordance with 21 CFR to keep records pursuant to 21 CFR of a drug ‘‘may lead to severe part 1301. Any person who is currently 1304.03, 1304.04, 1304.21, 1304.22, and psychological or physical dependence’’ engaged in any of the above activities 1304.23, after January 11, 2012. is only required if the drug is to be must submit an application for Prescriptions. All prescriptions for placed in schedule II. 21 U.S.C. registration by January 11, 2012 and carisoprodol or prescriptions for 812(b)(2)(C). By contrast, to place a drug may continue their activities until DEA products which contain carisoprodol in schedule IV, the necessary finding has approved or denied that application. shall comply with 21 CFR 1306.03– requires only that abuse of the drug Disposal of Stocks. Any person who 1306.06, 1306.21, and 1306.22–1306.27, ‘‘may lead to limited physical elects not to obtain a schedule IV after January 11, 2012. dependence or psychological registration, or who is not entitled to Importation and Exportation. All dependence relative to the drugs * * * such registration, must surrender all importation and exportation of in schedule III.’’ Id. 812(b)(4)(C). quantities of currently held carisoprodol carisoprodol is subject to 21 CFR part Even if—given Dr. Jasinski’s in accordance with the procedures of 21 1312, after January 11, 2012. acknowledgment that abuse of CFR 1307.21, on or before January 11, Criminal Liability. Any activity with carisoprodol may lead to limited 2012, or may transfer all quantities of carisoprodol not authorized by, or physical or psychological dependence— currently held carisoprodol to a person conducted in violation of, the the article does not constitute valid registered under the CSA and Controlled Substances Act or the rebuttal, Meda cannot claim that its authorized to possess schedule IV Controlled Substances Import and admission to the record was prejudicial. controlled substances, on or before Export Act, occurring on or after January The article (which had not been January 11, 2012. Any carisoprodol 11, 2012 is unlawful. published at the time the parties surrendered to DEA must be listed on a Regulatory Analyses exchanged their pre-hearing statements) DEA Form 41, ‘‘Inventory of Controlled is consistent with other case studies Substances Surrendered for Executive Orders 12866 and 13563 which Dr. Jasinski had ample Destruction.’’ DEA Form 41 may be In accordance with 21 U.S.C. 811(a), opportunity to criticize and was obtained at http:// this scheduling action is subject to therefore cumulative. While the ALJ did www.deadiversion.usdoj.gov/ formal rulemaking procedures done ‘‘on _ mischaracterize the report as the ‘‘Mayo 21cfr reports/surrend/, or from the the record after opportunity for a Clinic data,’’ ALJ at 101, it is just one nearest DEA office. hearing,’’ which are conducted pursuant of several clinical reports/case studies Security. Carisoprodol will be subject to the provisions of 5 U.S.C. 556 and that supports the conclusion that to the security requirements applicable 557. The CSA sets forth the criteria for prolonged abuse of carisoprodol may to controlled substances in schedules III scheduling a drug or other substance. lead to limited physical or through V including 21 CFR 1301.71, Such actions are exempt from review by psychological dependence, as Dr. 1301.72(b), (c), and (d), 1301.73, the Office of Management and Budget Jasinski acknowledged. I thus find that 1301.74, 1301.75(b) and (c), 1301.76, pursuant to Section 3(d)(1) of Executive the abuse of carisoprodol ‘‘may lead to and 1301.77. The requirements of 21 Order 12866 and the principles limited physical dependence or CFR 1301.71, 1301.72(d), 1301.74, reaffirmed in Executive Order 13563. psychological dependence relative to 1301.75(b) and (c), and 1301.76 shall be the drugs or other substances in applicable to carisoprodol January 11, Regulatory Flexibility Act schedule III.’’ 21 U.S.C. 812(b)(4)(C). 2012. The requirements of 21 CFR The Administrator hereby certifies Accordingly, I further find that 1301.72(b) and (c), 1301.73, and 1301.77 that this rulemaking has been drafted in substantial evidence supports the FDA’s shall be applicable to carisoprodol April accordance with the Regulatory recommendation that carisoprodol be 10, 2012. Flexibility Act (5 U.S.C. 601–612), has placed in schedule IV. Labelling and Packaging. All reviewed this regulation, and by Regulatory Requirements commercial containers of carisoprodol approving it certifies that this regulation that are packaged on or after April 10, will not have a significant economic 47 Effective January 11, 2012, 2012 shall be labeled as C–IV and impact on a substantial number of small carisoprodol will be placed in schedule packaged in accordance with 21 CFR entities. IV of the Controlled Substances Act. 1302.03–1302.07. Commercial container In considering the economic impact Thereafter, any person who engages in packaged before April 10, 2012 and not on small entities, the first question is the manufacture, distribution, meeting the requirement of 21 CFR whether a substantial number of small dispensing, importing, exporting, as 1302.03–1302.07 may be distributed entities are affected. In this instance, the well as any person who possesses the until June 11, 2012. On or after June 11, entities affected are those now selling drug will be subject to the provisions of 2012 all commercial containers of carisoprodol-containing products that the Act and DEA regulations, including carisoprodol must be labeled as C–IV do not hold a DEA registration. DEA the Act’s administrative, civil, and and comply with 21 CFR 1302.03– identified 22 firms that are criminal sanctions which are applicable 1302.07. manufacturing carisoprodol-containing to schedule IV controlled substances. Inventory. Pursuant to 21 CFR products. 74 FR at 59111. Fifteen of These include the following: 1304.03, 1304.04, and 1304.11, every these firms hold DEA registrations, Registration. Any person who registrant who is required to keep leaving seven firms that sell manufactures, distributes, dispenses, records and who possesses any quantity carisoprodol and do not hold a imports, exports, engages in research or of carisoprodol shall take an initial registration. DEA has no information on conducts instructional activities or inventory of all stocks of carisoprodol the number of non-registrants engaged chemical analysis with carisoprodol, on hand on or before January 11, 2012. in the distribution or importation of Thereafter, carisoprodol shall be carisoprodol, but there is reason to 47 I have considered the comments of the Healthcare Distribution Management Association in included in each inventory made by the believe that the number of such firms is setting the effective dates with respect to each of the registrant pursuant to 21 CFR well in excess of the seven already various requirements. 1304.11(c). identified. The Small Business

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Administration size standard for a small sales and dropping the product would based companies in domestic and wholesaler of drugs is 100 employees. It not result in the loss of significant export markets. is clearly possible to operate a drug customers. Accordingly, DEA finds that List of Subjects in 21 CFR Part 1308 distribution firm with fewer than 100 this rule will not have a significant employees. Therefore, a substantial economic impact on a substantial Administrative practice and number of small entities will be affected number of small entities.48 procedure, Drug traffic control, by this rule. Reporting and recordkeeping Executive Order 12988 The economic impact on non- requirements. Narcotics, Prescription registrants now selling carisoprodol will This regulation meets the applicable drugs. occur in two ways: The cost of standards set forth in sections 3(a) and registration and the cost of meeting the 3(b)(2) of Executive Order 12988 Civil Under the authority vested in the security requirements in 21 CFR part Justice Reform. Attorney General by section 201(a) of 1301. There is also a potential economic the CSA (21 U.S.C. 811(a)), and impact on those firms that do not Executive Order 13132 delegated to the Administrator of the currently distribute carisoprodol but This rulemaking does not preempt or Drug Enforcement Administration which might wish to enter the market. modify any provision of state law or pursuant to 28 CFR 0.100, 21 CFR part The annual registration fee for a impose enforcement responsibilities on 1308 is amended to read as follows: distributor, importer, or exporter is any state or diminish the power of any PART 1308—SCHEDULES OF $1,147. There is some uncertainty in state to enforce its own laws. CONTROLLED SUBSTANCES estimating the cost of meeting the Accordingly, this rulemaking does not security requirements, because most have federalism implications warranting ■ non-registrants already meet the the application of Executive Order 1. The authority citation for part 1308 security requirements, at least in part, 13132. continues to read as follows: for schedule III and IV substances. A Authority: 21 U.S.C. 811, 812, 871(b), conservative estimate assumes that Executive Order 13175 unless otherwise noted. every non-registrant will have to buy a This rule will not have tribal safe to store carisoprodol. A safe with a implications and will not impose ■ 2. Section 1308.14 is amended by capacity of 13.5 cubic feet should be substantial direct compliance costs on redesignating paragraphs (c)(5) through adequate and may be purchased for Indian tribal governments. (c)(52) as paragraphs (c)(6) through approximately $1,350, which, when (c)(53) and adding a new paragraph annualized over 15 years at 7.0 percent, Paperwork Reduction Act of 1995 (c)(5) to read as follows: results in a cost of $148 per year. This action does not impose a new § 1308.14 Schedule IV. Therefore, the total annual cost of collection of information under the compliance with this rule is $1,295. Paperwork Reduction Act of 1995, 44 * * * * * The usual standard for a significant U.S.C. 3501–3521. (c) * * * economic impact is 1.0 percent of revenue. For $1,295 per year to be a Unfunded Mandates Reform Act of 1995 (5) Carisoprodol ...... 8192 significant economic impact, a firm’s This rule will not result in the * * * * * annual revenue would have to be less expenditure by state, local, and tribal Dated: November 18, 2011. than $130,000. Any firm in the drug governments, in the aggregate, or by the Michele M. Leonhart, distribution business would need private sector, of $136,000,000 or more Administrator. annual revenue well in excess of this (adjusted for inflation) in any one year, amount to sustain itself. and will not significantly or uniquely Note: The following appendixes will not publish in the Code of Federal Regulations. It is acknowledged that, for a small affect small governments. Therefore, no firm, there may be some inconvenience actions were deemed necessary under APPENDIX A and expense in preparing the necessary the provisions of the Unfunded forms to obtain and renew a registration. Mandates Reform Act of 1995. These are minor costs. There are also STATES IN WHICH CARISOPRODOL ISA recordkeeping requirements, but these Congressional Review Act CONTROLLED SUBSTANCE AND will impose little or no incremental cost This rule is not a major rule as THEIR POPULATION for a firm that is already maintaining the defined by section 804 of the Small records needed for a wholesale Business Regulatory Enforcement State Population business. Accordingly, the costs of Fairness Act of 1996 (Congressional registration and the security Oklahoma ...... 3,751,351 Review Act). This rule will not result in Hawaii ...... 1,360,301 requirements will not cause a significant an annual effect on the economy of Kentucky ...... 4,339,367 economic impact. $100,000,000 or more, a major increase New Mexico ...... 2,059,179 If a firm chooses not to register and to in costs or prices, or significant adverse Oregon ...... 3,831,074 drop its carisoprodol line, the cost to the effects on competition, employment, Georgia ...... 9,687,653 firm would exceed its earnings on its investment, productivity, innovation, or Arkansas ...... 2,915,918 carisoprodol sales. The firm may also on the ability of United States-based Alabama ...... 4,779,736 West Virginia ...... 1,852,994 lose some customers who do not want companies to compete with foreign- to buy from a distributor that does not Florida ...... 18,801,310 Arizona ...... 6,392,017 carry carisoprodol. A competent 48 In the Notice of Proposed Rulemaking, DEA manager will recognize this cost, and in Indiana ...... 6,483,802 noted that it had no information regarding the Nevada ...... 2,700,551 light of the small cost of registering, number of persons who may distribute Louisiana ...... 4,533,372 would presumably choose to drop carisoprodol-contain products, but who do not manufacture, package, repackage, or relabel these Texas ...... 25,145,561 carisoprodol from the firm’s product products and sought comments from any entities Utah ...... 2,763,885 line only if the firm was earning a that might be affected by this action. See 74 FR Washington ...... 6,724,540 negligible profit from its carisoprodol 59111. No commenter provided such information.

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