DEA/OD/ODE 1 September 2010



### Basis for the Control of Generic equivalents of Marinol® in Schedule II I of the Controlled Substances Act

Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement

Administration, Washington DC 20537

September 2010

INTRODUCTIO N

The U.S. Drug Enforcement Administration ( DEA ) has received four petitions from companies that have products that are currently the subject of Abbreviated New Drug Applications (ANDAs) filed with the U.S. Food and Drug Administration (FDA). Each produ ct is a generic formulation of Marinol® and contains dronabinol, the (

- ) isomer of delta

- 9

- (trans)

- tetrahydrocannabinol (THC), which is a schedule I controlled substance. These petitions each request amendments to Controlled Substances Act (CSA) regulatio ns that would have the effect of transferring the proposed generic Marinol® product from schedule I to schedule III.

At present, the only formulation containing dronabinol that is in a schedule other than schedule I is the following, as set forth in 21 CFR 1308.13(g)(1) as schedule III:

“ Dronabinol (synthetic) in sesame oil and encapsulated in a soft gelatin capsule in a U.S. Food and Drug Administration approved product. ”

While the petitioners cite that their generic products are bioequivalent to Mar inol®, their products do not meet the current schedule III definition provided above. Therefore, these firms have requested that 21 CFR 1308.13 (g)(1) be expanded to include: (1) both naturally

- derived or synthetically produced dronabinol; and (2) both har d or soft gelatin capsules.

In response to these petitions, DEA prepared several scheduling review documents based upon petitioner

- provided data. On June 22, 2007 and August 15, 2007, these analyses were submitted to the Department of Health and Human S ervices (DHHS) with requests for scientific and medical evaluation and scheduling recommendations. The submissions to DHHS also requested that they consider (1) whether dronabinol extracted from Cannabis sativa (i.e. naturally

- derived) , is identical to s ynthetically

produced dronabinol found in Marinol®; and (2) whether a formulation encapsulated in hard gelatin capsules, instead of soft gelatin capsules, changes a product’s abuse potential.

On March 17, 2010 and June 1, 2010 , the Assistant Secretary for Health

, DHHS, sent the Deputy Administrator of DEA scientific and medical evaluations and letter s recommending that FDA

- approved drug products containing dronabinol (both naturally

derived or synthetic) in sesame oil in a gelatin capsule (either hard or so ft gelatin) be placed int o schedule III of the CSA. Enclosed with the March 17, 2010 letter , was aDEA/OD/ODE 2 September 2010

document prepared by the FDA entitled, “Basis for the Recommendation to Control FDA

- Approved Drug Products Containing Synthetic Dronabinol in Sesame Oil in a Hard Gelatin Capsule to Schedule III of the Controlled Substances Act

. ” The June 1, 2010 letter included a document entitled, “Basis for the Recommendation to Reschedule FDA

Approved Drug Products Containing Naturally

- Derived Dronabinol in Sesame Oil in a Gelatin Capsule to Schedule III of the Controlled Substances Act

. ” The se document s contained a review of the factors which the CSA requires the Secretary to consider 21 U.S.C. 811(b).

The following is a summary of each the factors that the CSA requir es to be considered pursuant to 21 U.S.C. 811(b):

FACTOR 1. ITS ACTUAL OR RELATIVE P OTENTIAL FOR ABUSE

G eneric products that reference Marinol® have the same Active Pharmaceutical Ingredient ( API ) ( e.g. dronabinol) as that found in Marinol®, an FDA

- appr oved schedule III drug product

, similar chemistry, pharmacology, and pharmacokinetics and therefore have similar potential for abuse. Dronabinol

, the (

- ) isomer of delta

- 9

- (trans)

- tetrahydrocannabinol (THC), is a schedule I controlled substance . It is an agonist at cannabinoid receptors and has a recognized abuse potential

. (see factor 2, below). The term “abuse” is not defined in the CSA. However, the legislative history of the CSA * suggests the following points in determining whether a particular drug or substance has a potential for abuse: a. Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community. b. There is significant diversion of the drug or substance from legitimate drug channels. c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substance.

d. The substance is so related in its action to a su bstance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant us e contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community. Approved generic drug products that reference Marinol® have the same API (dronabinol) as that found in Marinol®, and therefore have similar potentials for abuse. The source of the dronabinol, whether naturally

- derived or synthetic, does not alter the abuse potential of the substance. Additionally, the difference in formulation between the soft gela tin capsule of Marinol® and a hard gelatin capsule is not likely to confer any differences in abuse potential. Given these similarities, FDA

- approved generic drug products that reference Marinol®, as well as FDA

- approved generic drug products containing sy nthetic dronabinol or naturally derived dronabinol in sesame oil andDEA/OD/ODE 3 September 2010

encapsulated in a hard or soft gelatin capsule s , will be similar to Marinol® in terms of the amounts taken by individuals and the impact on the community resulting from the products’ dive rsion from legitimate drug channels or their use outside of legitimate medical practice.

* Comprehensive Drug Abuse Prevention and Control Act of 1970. H.R. Rep. No. 91

- 1444, 91st Cong.. Sess. I (1970) reprinted in U.S.C.C.A.N. 4566,4603.

FACTOR 2. SCIENT IFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFE CT FDA approved generic products that reference Marinol® have the same API (dronabinol) as that found in Marinol®, an FDA

- approved schedule III drug product, similar chemistry, pharmacology, and pharmacokinetics. Dr onabinol, the (

- ) isomer of delta

- 9

- (trans)

- tetrahydrocannabinol (THC), is a schedule I controlled substance

. The source of the dronabinol, whether naturally

- derived or synthetic, does not alter the pharmacological effect of the substance. Additionally, th e difference in formulation between soft gelatin capsule of Marinol® and a hard gelatin capsule is not likely to confer any differences in pharmacological effect. A. Neurochemistry and Pharmacology of Dronabinol

Dronabinol is a cannabinoid that can be der ived naturally from cannabis as well as by a synthetic chemical process. Dronabinol is considered the major psychoactive cannabinoid constituent of cannabis (Wachtel Ct al., 2002). The structure and function of dronabinol was first described in 1964 by Gao ni and Mechoula m . Two cannabinoid receptors, CB 1 and CB 2 have been characterized (Piomelli, 2005). Autoradiographic studies have provided information on the distribution of cannabinoid receptors. CB 1 receptors are found in the basal ganglia

, hippoca m pus an d cerebellum of the brain (Howlett et al., 2004) as well as in the immune system. It is believed that the localization of these receptors may explain cannabinoid interference with movement coordination and effects on memory and cognition. Concentration of CB 1 receptors is considerably lower in peripheral tissues than in the central nervous system ( H enkerham et al., 1990 and 1992). CB 2 receptors are found primarily in the immune system, predominantly in B lymphocytes and natural killer cells (Bouaboula et al ., 1993). It is believed that the CB 2 - type receptor is responsible for mediating the immuno logical effects of cannabinoids (Galiegue et a., 1995). However, CB 2 receptors also have recently been localized in the brain, primarily in the cerebellum and hippo campus (Gong et a l

, 2006). Dronabinol displays similar affinity for CB 1 and CB 2 receptors, but behaves as a weak agonist for CB 2 receptors, based on inhibition of adenylate cyclase. The identification of synthetic cannabinoid ligands that selectively bind to CB 2 receptors
, but do not have the typical dronabinol

- like psychoactive properties suggests that the psychotropic effects of cannabinoids are mediated through the activation of CB 1 (Hanus et al., 1999). Naturally

- occurring cannabinoid agonists, such as dronabinol, and the synthetic cannabinoid agonists such as WIN

- 55,212

- 2 and CP

- 55,940, produce the classic cannabinoid effects of hypothermia, analgesia, hypoactivity and cataplexy, in addition to their psychoactive effects.DEA/OD/ODE 4 September 2010

B. Central Nervous System Effec ts Human Physiological and Psychological Effects Subjective Effects The physiological, psychological and behavioral effects of dronabinol vary among individuals. Common responses to cannabinoids, as described by Adams and Martin (1996) and others (Holliste r 1986a, 1988a) are listed below: 1) Dizziness, nausea, tachycardia. facial flushing, dry mouth and tremor initially 2) Merriment, happiness and even exhilaration at high doses 3) Disinhibition, relaxation, increased sociability, and talkativeness 4) Enhan ced sensory perception , giving rise to increased appreciation of music, art and touch 5) Heightened imagination leading to a subjective sense of increased creativity 6) Time distortions 7) Illusions, delusions and hallucinations, especially at high doses

8 ) Impaired judgment, reduced co

- ordination and ataxia, which can impede driving ability or lead to an increase in risk

- taking behavior 9) Emotional liability, incongruity of affect, dysphoria, disorganized thinking, inability to converse logically, agitati on, paranoia, confusion, restlessness, anxiety, drowsiness and panic attacks, especially in inexperienced users or in those who have taken a large dose 10) Increased appetite and short

- term memory impairment These subjective responses to cannabinoids are p leasurable to many humans and are associated with drug

- seeking and drug

- taking (Maldonado, 2002). Animal behavioral effects

Self

- Administration

Self

- administration is a method that assesses whether a drug produces rewarding effects that increase the likeli hood of behavioral responses in order to obtain additional drug. Drugs that are self

- administered by animals are likely to produce rewarding effects in humans, which is indicative of abuse liability. Generally, a goad correlation exists between those drugs that are self

- administered by rhesus monkeys and those that are abused by humans ( Blaster and Bigelow, 2003). Interestingly, self

- administration of hallucinogenic

- like drugs, such as cannabinoids, LSD, and mescaline, has been difficult to demonstrate in a nimals (Yanagita, 1980). However, when it is known that humans voluntarily consume a particular drug (such as cannabis) for its pleasurable effects, the inability to establish self

administration with that drug in animals has no practical importance in the assessment of abuse potential. This is because the animal test is a predictor of human behavioral response in the absence of naturalistic data.DEA/OD/ODE 5 September 2010 The scientific literature generally reports that naïve animals do not self

- administer cannabinoids unless they have had previous experience with other drugs of abuse. However, when squirrel monkeys are first trained to self

- administer intravenous cocaine, they continue to bar

- press at the same rate as when d ron abinol is substituted for cocaine, at doses that are co mparable to those used by humans who smoke cannabis (Tanda e t al., 2000). This effect is blocked by drugs with cannabinoid receptor antagonist properties, such as rimonabant. New studies show that monkeys without a history of any drug exposure can be succe ssfully trained to self

- administer dronabinol intravenously (Justinova et a l ., 2003). These data demonstrate that under specific pretreatment conditions, an animal model of reinforcement by cannabinoids now exists for future investigations. Rats self

admin ister dronabinol when it is applied intracerebroventricularly (i.c.v.), but only at the lowest doses tested (0.01

- 0.02 micro g ram /infusion) (Braida et a l , 2004). This effect is antagonized by rimonabant and by the opioid antagonist naloxone (Braida et al., 2004). There may be a critical dose

- dependent effect, though, since aversive effects, rather than reinforcing effects, are described in rats that receive high doses of dronabinol (Sanudo

- Pena et al., 1997). Rimonabant reverses these aversive effects.

Cond itioned Place Preference Conditioned place preference (CPP) is a less rigorous method than self

administration of determining whether drugs have rewarding properties. In this behavioral test, animals are given the opportunity to spend time in two distinct environments: one where they previously received a drug and one where they received a placebo. If the drug is reinforcing, animals choose to spend more time in the environment paired with the drug than the one paired with the placebo, when both options are presented simultaneously. Animals show CPP to dronabinol, but only at the lowest doses tested (0.075

- 0.75
mg /kg, i.p.) (Braida et a l ., 2004). This effect is antagonized by rimonabant, as well as by naloxone (Braida et al., 2004). Drug Discrimination Studi es Drug discrimination is a method in which animals indicate whether a test drug produces physical or psychic perceptions similar to those produced by a known drug of abuse. In this test, an animal learns to press one bar when it receives the known drug of abuse and another bar when it receives placebo. A challenge session with the test drug determines which of the two bars the animal presses more often, as an indicator of whether the test drug is like the known drug of abuse. Animals, including monkeys and rats (Gold et at., 1992), as well as humans (Chait, 1988), can discriminate cannabinoids from other drugs or placebo. Discriminative stimulus effects of dronabinol are pharmacologically specific for cannabinoids (Balster and Prescott, 1992, Barrett et al. , 1995, Browne and Weissman, 1981, Wiley Ct al., 1993, Wile y et al., 1995). Additionally, the major active metabolite of dronabinol, 11

- hydroxy

delta

- 9

- THC, also generalizes to the stimulus cue elicited by dronabinol (Browne and Weissman, 1981).DEA/OD/ODE 6 September 2010 The discr iminative stimulus effects of the cannabinoid group appear to provide unique effects because stimulants, hallucinogens, opioids, benzodiazepines, barbiturates, NMDA antagonists and antipsychotics do not f ull y substitute for dronabinol.

C. Tolerance to the Effects of Dronabinol Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time (American Academy of Pain Medicine, American Pain Society and American Society o f Addiction Medicine consensus document, 2001). The presence of tolerance does not determine whether a drug has abuse potential, in the absence of other abuse indicators such as reinforcing or rewarding properties. Tolerance to the psychotomimetic and amne sic effects of dronabinol develops in humans following chronic exposure (D’Souza et al., 2008). Tolerance also develops in humans to the cardiovascular and autonomic changes, decreased intraocular pressure, and sleep alterations induced by dronabinol (Jone s et a l ., 1981). Down

- regulation of cannabinoid receptors has been suggested as the mechanism underlying tolerance to the effects of dronabinol (Wu Ct at., 2008, Rodriguez de Fonseca et al., 1994, Oviedo et al., 1993). However, in performance tasks, humans have a variable response to chronic use of cannabinoids. In long

- term cannabis users, performance on neurocognitive tasks such as perceptual motor control and dual task processing following administration of dronabinol was not reduced compared to moderate cannabis users (Ramaekers et al., 2008). Additionally, reaction times are not altered by administration of dronabinol in long term cannabis users (Block and Wittenborn, 1985). This may be related to electro physiological data showing that the ability of d ronabinol to increased neuronal firing in the ventral tegmental area (a region known to play a critical role in drug reinforcement and reward) is not reduced following chronic administration of the drug (Wu and French, 2000).

FACTOR 3. THE STATE OF CURRE NT SCIENTIFIC KNOWLE DGE

REGARDING THE DRUG O R OTHER SUBSTANCE The third factor DEA is required to consider is the current scientific knowledge regarding the drug or other substance. However, since approved generic products that reference Marinol® have the same API (dronabinol), they have similar chemistry, pharmacology, and pharmacokinetics as Marinol®, an FDA

- approved schedule III drug product. A. Chemistry The active ingredient in Marinol® and its generic drug products is synthetic dronabinol. Dronabinol is a cannabinoid designated chemically as (6aR

- trans)

- 6a,7,8, 1 0 a

- tetrahydro 6,6,9

- trimethyl

- 3

- pentyl

- 6H

- dibenzo

- [b,d]pyran

- 1

- ol. Dronabinol is a naturally occurring component of Cannabis sativa L. (Marijuana). Dronabinol is a light yellow resinous oil th at is sticky at room temperature and softens upon refrigeration. Its molecular formula is C 21 H 30 O 2 and it has a molecularDEA/OD/ODE 7 September 2010

weight of 314.47. Dronabinol is insoluble in water but is very soluble in sesame oil. It has a pKa of 10.6 and an octanol

- water parti tion coefficient: 6,000:1 at pH 7.

Dronabinol in Marinol® and the generic drug products that reference Marinol®

are formulated with sesame oil. The three dosage formulations of Marinol® contain 2.5, 5 and 10 mg of dronabinol in sesame oil in soft gelatin c apsules. This formulation is intended for oral administration only. It is difficult to separate dronabinol in pure form from sesame oil because of these two substances have similar physi c oc he m ical properties. Intravenous use is difficult because an aqueous solution of pure dronabinol cannot be created easily. Additionally, attempts to smoke dronabinol formulated in sesame oil results in an undesirable production of soot and oil ignition, based on the presence of long

- chain hydrocarbons in the sesame oil. Th e ability of sesame oil to catch fire easily is verified by its historical use as a lamp oil (Copley et a l , 2005).

B. Human Pharmac o kinet i cs
The h um an pha rm acokinetics of dronabinol in Marinol® capsules are described in the drug label. Clinical pharmacolog y assessment ensures that generic drug products that

r e fer e nce Marinol® ar e bio e quivalent to Marinol®, thus meet ing th e requi rement f o r generic drug approval by FDA. Following single oral doses, synthetic dronabinol is almost completely absorbed (90 to 95% ). However, after dronabinol absorption, first

- pass hepatic elimination from blood leads to a low and variable bioavailability, ranging from 5 to 20 percent. Dronabinol is very lipid soluble, leading to a large apparent volume of distribution (approximatel y 10 L/kg) and efficient delivery to the brain. The plasma protein binding of dronabinol and its metabolites is approximately 97%. The pharmacokinetics of synthetic dronabinol after single doses (2.5, 5 or 10 mg) and multiple doses (2.5, 5 or 10mg given tw ice a day; BID) were studied in healthy volunteers and are reported in the drug label for Marinol®, as shown in Table 2 below: Table 2: Summary of Multi p le

- Dose Pha rm acokinetic Parameters of Dronabinol in Healthy Volunteers Mean (SD) P Parameter Values

BID Cmax Median Tmax A U C(O

- 12)

Dose ng/mL (range), hr ng•hr/mL 2.5mg 1.32 (0.62) 1.00 (0.50

- 4.00) 2.88 (1.57) 5 mg 2.96 (1.81) 2.50 (0.50

- 4.00) 6.16 (1.85) 10mg 7.88 (4.54) 1.50 (0.50

- 3.50) 15.2 (5.52) A slight increase in dose proportionality on mean Cmax and AUC ( 0

- 12) of dronabinol was observed with increasing dose over the dose range studied. The onset of effects after oral administration of dronabinol is 30

- 90 mm, with a peak at approximately 2

- 3 hours and continuing effects for 4

- 12 hours (Groten hermen, 2003; Adams and Martin 1996; Agurell et al. 1984, 1986). Following oral administration of radioactive

- labeled dronabinol, plasma levels of dronabinol are low relative to those levels after smoking orDEA/OD/ODE 8 September 2010

intravenous administration. There is inter

- and intra

- subject variability, even when repeated dosing occurs under controlled conditions.

Cannabinoid metabolism is extensive. Dronabinol is metabolized via microsomal hydroxylation to both active and inactive metabolites (Lemberger et al., 1970, 1972a, 1 97 2b; Agurell et al., 1986; Hollister, 1 988a) of which the primary active metabolite is 11

- hydroxy

- delta

- 9

- THC

. This metabolite is approximately equipotent to dronabinol in producing cannabinoid

- like subjective effects ( Agurell et al., 1986, Lemberger and R ubin, 1975). In addition to II

- hydroxy

- delta

- THC, some inactive carboxy metabolites have terminal half

- lives of 50 hours to 6 days or more. The majority of the absorbed dronabinol dose is eliminated in feces, and about 33 percent in urine. Dronabinol ent ers enterohepatic circulation and undergoes hydroxylation and oxidation to 1 1

- nor

- 9

- carboxy

- delta

- 9

- THC. The glucuronide is excreted as the major urine metabolite along with about 18 nonconjugated metabolites. According to the drug label for Marinol®, the elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half

- life of about 4 hours and a terminal (beta) half

- life of 25 to 36 hours. Bec ause of its large volume of dist ribution, dronabinol and its me tabolites may be excreted at low levels for prolonged periods of time. The terminal half

- life of dronabinol is estimated to range from approximately 20 hours to as long as 10 to 13 days (Hunt and Jones, 1980), though reported estimates vary as expected with any slo wly cleared substance and the use of assays of variable sensitivities. Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio

labeled or a l dose bein g recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. Following single dose administration, low levels of dronabinol metabolites have been detected fo r more than 5 weeks in the urine and feces.

FACTOR 4. ITS HISTO RY AND CURRENT PATTE RN OF ABUSE The fourth factor DEA is required to consider is the history and current pattern of abuse. Since drug products that contain naturally

- derived dronabinol, or products that contain synthetic dronabinol in sesame oil in a hard gelatin capsule, are not currently marketed, no information is available regarding a pattern of abuse. However, generic drug products that reference Marinol® have the same API (synthetic dr onabinol) and similar chemistry and pharmacokinetics as Marinol®, an FDA

- approved Schedule III drug product. Dronabinol is an agonist at cannabinoid receptors and has a known abuse potential in humans (see Factor 2, above). The eight factor analysis and re commendation for place ment of Marinol® into Schedule III (HHS, 1998) stated that, “A pattern of abuse of Marinol® has not been uncovered. Only sporadic reports of small amount of diversion have been documented. Comparisons of patterns of abuse [ between mar ijuana and Marinol ] illustrate that there is considerable abuse of marijuana and virtually none of Marinol®. One factor contributingDEA/OD/ODE 9 September 2010

to these few occurrences of diversion and abuse is no doubt the limited general availability of Marinol®, worldwide or nat ionally, relative to that of marijuana.” Thus, it is expected that the FDA

- approved generic drug products that reference Marinol®, as well as generic drug products approved for marketing by FDA that contain synthetic dronabinol in sesame oil in a hard gela tin capsule, will have a similar pattern of abuse to that of Marinol®. The abuse potential of generic drug products approved pursuant to an ANDA is considered to be similar to the Reference Listed Drug (R LD ) based on equivalent quantities of the API prese nt in the dosage form. Thus, the abuse potential of the dronabinol in sesame oil in approved ANDAs for generic drug products that reference Marinol® will be similar regardless of whether the API is from synthetic or natural

source, or encapsulated in hard or soft gelatin capsules, since the two formulations are considered to be similar. Given these similarities, generic drug products that reference Marinol® will have a similar pattern of abuse as that of Marinol®.

FACTOR 5. THE SCOPE , DURATION, AND SIGN I FICANCE OF ABUSE The fifth factor DEA is required to consider is the scope, duration and significance of abuse. Since drug products that contain naturally

- derived dronabinol, or products that contain synthetic dronabinol in sesame oil in a hard gelatin c apsule, are not currently marketed, no information is available regarding a pattern of abuse. Once again, approved generic products that reference Marinol® have the same API (dronabinol) and similar chemistry, pharmacology, and pharmacokinetics as Marinol®

, an FDA

- approved schedule III drug product. Approved ANDAs for generic drug products are considered to be similar in activity to the RLD based on equivalent quantities of the API present in the dosage form. The eight factor analysis and recommendation for placement of Marinol® into Schedule III (HHS, 1998) stated that. “Adverse reaction reports have failed to generate any reports of drug abuse, dependence, withdrawal, overdose (intentional or accidental) or tolerance development” with Marinol®. Thus, the abuse potential of synthetic dronabinol in sesame oil in approved ANDAs for generic drug products that reference Marinol® will be similar regardless of whether the API is encapsulated in hard or soft gelatin capsules. Given these similarities, generic drug products that reference Marinol® will have a scope, duration, and significance of abuse similar to that of Marinol®.

FACTOR 6 . WHAT, IF ANY, RIS K THERE IS TO THE PU BLIC HEALTH The sixth factor DEA must consider is whether there is any risk to the publi c health from FDA

- approved generic drug products that contain naturally

- derived dronabinol, or products that contain synthetic dronabinol in sesame oil in a hard gelatin capsule and reference Marinol®. The public health risks can be assessed by evaluatin g the adverse events and overdose symptoms associated with Marinol®, since dronabinol is the API in both Marinol® and in generic drug products that reference Marinol®.

A. Adverse EventsDEA/OD/ODE 10 September 2010 The AEs associated with the use of Marinol® are described in the prod uct label. Central nervous system AEs include euphoria, amnesia, anxiety, confusion, depersonalization, hallucination, paranoia, somnolence and abnormal thinking. Peripheral AEs include asthenia, palpitations, vasodilation, abdominal pain, nausea, and vomi ting. For purposes of assessing abuse potential, euphoria is a significant AE. However , the other listed AEs can contribute to medical emergencies when individuals use Marinol® for abuse purposes.

B. Overdose The product label for Marinol® states that the signs and symptoms of overdose include drowsiness, euphoria, heightened sensory awareness, a l tered time perception, reddened conjunctiva, dry mouth, tachycardia, memory impairment, mood alteration, urinary retention, decreased motor coordination, lethargy, postural hypotension, panic and seizure disorders. There is no known antidote for Marinol® overdose and the treatment is appropriate supportive care.

FACTOR 7. ITS PSYCH IC OR PHYSIOLOGICAL DEPENDENCE LIABILITY

The seventh factor DEA must consider is the psychic and physiologic dependence liability of FDA

- approved generic drug products that contain naturally

- derived dronabinol, or products that contain synthetic dronabinol in sesame oil in a hard gelatin capsule and reference Marinol®. Given that the AP I in these products is dronabinol, the dependence liability is likely the same. Physical dependence is a state of adaptation manifested by a drug class

- specific withdrawal syndrome produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and administration of an antagonist (American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine consensus document, 2001). In chronic cannabis users, a withdrawal syndrome was described that consists of restlessness, irritability, mild agitation, insomnia, sleep EEG disturbances, nausea and cramping that resolve s within a few days (Haney et al , 1999). This indicates that cannabis produces physical dependence. Similarly, a review of clinical studies on can nabis discontinuation led to the conclusion that cannabis produces a withdrawal syndrome that includes such symptoms as sleep difficulties, strange dreams, decreased appetite, decreased weight, anger, irritability and anxiety (Budney et al., 2004). Based o n clinical descriptions, this syndrome appears to be mild compared to classical alcohol and barbiturate withdrawal syndromes, which can include more serious symptoms including agitation, paranoia, and seizures. A recent study comparing cannabis and tobacco withdrawal symptoms in humans demonstrates that the magnitude and time course of the two withdrawal syndromes are similar (Vandrey et al., 2005). Lane et al. (1998) describes milder cases of dependence including symptoms that are comparable to those from caffeine withdrawal, including decreased vigor, increased fatigue, sleepiness, headache, and reduced ability to work. The marijuana withdrawal syndrome is reported in adolescents admitted for substance abuseDEA/OD/ODE 11 September 2010

treatment or in individuals who were given marij uana on a daily basis during research conditions. The production of an overt withdrawal syndrome in animals following chronic dronabinol administration has been variably demonstrated under conditions of natural discontinuation. This may be the result of th e slow release of cannabinoids from adipose storage, as well as the presence of the major psychoactive metabolite, 11

- hydroxy

- delta

9

- THC. Investigators showed such a withdrawal syndrome in monkeys following the termination of cannabinoid administration: t he behaviors included transient aggression, anorexia, biting, irritability, scratching and yawning (Budney et al., 2004). However, in rodents treated subacutely with d ronabinol, administration of rim onabant, a drug with cannabinoid antagonist properties, p roduced pronounced withdrawal symptoms including wet dog shakes (Breivogel et al., 2003).

FACTOR 8. WHETHER T HE SUBSTANCE IS AN I MMEDIATE PRECURSOR

OF A SUBSTANCE ALREA DY CONTROLLED UNDER TH E CSA Generic drug products that contain naturally

- derived drona binol or products that contain synthetic dronabinol in sesame oil in a hard gelatin capsule, and reference Marinol®, contain the API dronabinol. Dronabinol is not an immediate precursor of any substance controlled under the CSA, as defined in 21 USC 811(e ).

Summary and Conclusions of the 8

- Factor Analysis

21 U.S.C. § 812(b) requires the evaluation of a substance’s abuse potential, legitimate medical use, and safety or dependence potential for placement in the CSA as a controlled substance. Upon consider ation of the eight

- factors required for control of a substance (21 U.S.C. § 811(c)), and the scientific and medical evaluation and scheduling recommendation by DHHS, DEA finds that Dro n abinol

, as summarized below

, meets the three criteria for placement in schedule I of the CSA under 21 U.S.C. § 812(b).

Based on the recommendation s of the As sistant Secretary for Health , received in accordance with section 201(b) of the Act [ 21 U.S.C. 811(b) ] , and the independent review of the available data by DEA, the Deput y Administrator of DEA, pursuant to sections 201(a) and 201(b) of the Act [ 21 U.S.C. 811(a) and 811(b) ] , find s that FDA

approved generic dronabinol products, both naturally

- derived or synthetically produced, in sesame oil and encapsulated in both hard gela tin or soft gelatin capsules meet the criteria for placement in schedule II I set in 21 U.S.C. 812(b), as follows:

A. The drug or other substance has a potential for abuse less than the

drugs or other substances in Schedule II.

FDA

- approved generic drug prod ucts that contain dronabinol (both naturally

derived or synthetically produced) in sesame oil in a gelatin capsule (both hard or soft gelatin) and reference Marinol®, have a similar potential for abuse as Marinol®, a schedule III drug product and have simi lar chemistry and pharmacokinetics as similar formulations in sesame oil.DEA/OD/ODE 12 September 2010 B. The drug or other substance has a currently accepted medical use in

treatment in the United States.

Marinol® was initially approved by FDA in 1985. When drug products that referen ce Marinol® receive FDA approval, they will have a currently accepted medical use in the United States.

C. Abuse of the drug or other substance may lead to moderate or low

physical dependence or psychological dependence and such dependence would be less than the drugs or other substances in Schedule II.

The withdrawal syndrome associated with dronabinol, the API in Marinol®, produces symptoms in humans such as restlessness, irritability, mild agitation, anxiety, anger, insomnia, sleep EEG disturbances, nause a, decreased appetite and decreased weight. Since a withdrawal syndrome is indicative of physical dependence, it is reasonable to conclude that generic dronabinol products (both naturally

- derived or synthetically produced, and in hard or soft gelatin caps ules) in sesame oil, will also produce physical dependence similar to those produced by Marinol®.DEA/OD/ODE 13 September 2010

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