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`CESAMET™
`(nabilone)
`Capsules
`For Oral Administration
`DESCRIP
`TION
`Cesamet™ (nabilone) is a synthetic cannabinoid for oral administration. Nabilone as a raw material
`occurs as a white to off-white polymorphic crystalline powder. In aqueous media, the solubility of
`nabilone is less than 0.5 mg/L, with pH values ranging from 1.2 to 7.0.
`Chemically, nabilone is similar to the active ingredient found in naturally occurring Cannabis sativa L.
`[Marijuana; delta-9-tetrahydrocannabinol (delta-9-THC)]. Nabilone is (±)-trans-3-(l,l-dimethylheptyl)-
`6,6a,7,8,10,10a-hexahydro-l-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one and has the empirical
`formula C24H36O3. It has a molecular weight of 372.55. The structural formula is as follows:
`Each Cesam
`et capsule contains 1 mg (2.7 µmol) nabilone and the following inactive ingredients:
`povidone and corn starch. The capsule shells contain the following inactive ingredients:
`F D & C Blue No. 1, Red D&C Nos. 28 and 33, gelatin, and titanium dioxide.
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`Cesamet™ (nabilone) is an orally active synthetic cannabinoid which, like other cannabinoids, has
`complex effects on the central nervous system (CNS). It has been suggested that the antiemetic effect
`of nabilone is caused by interaction with the cannabinoid receptor system, i.e. the CB (1) receptor,
`which has been discovered in neural tissues.
`Nontherapeutic Effects: Cesamet, a synthetic canna binoid, has the potential to be abused and to
`produce psychological dependence. Cesamet has complex e ffects on the central nervous system. Its
`effects on the mental state (i.e., "inner mental life" ) are similar to those of cannabis. Subjects given
`Cesamet may experience changes in mood (e.g., e uphoria, detachment, depression, anxiety, panic,
`paranoia), decrements in cognitive performance and memory, a decreased ability to control drives and
`impulses, and alterations in the experience of real ity (e.g., distortions in the perception of objects and
`the sense of time, hallucinations). These phenomena appear to be mo re common when larger doses of
`Cesamet are administered; however, a full-blown pi cture of psychosis (psychotic organic brain
`syndrome) may occur in patients receiving doses within the lower portion of the therapeutic range.
`Tolerance to these effects develops rapidly and is readily reversible.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`HELSINN EXHIBIT 2043
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 11
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`Data on the chronic use of Cesamet are not available; experience with cannabis suggests that chronic
`use of cannabinoids may be associated with a vari ety of untoward effects on motivation, cognition,
`judgment, as well as other mental status changes. Whether these phenomena reflect the underlying
`character of individuals chronically abusing cannabi s or are a result of the use of cannabis is not
`known.
`
`The simultaneous use of Cesamet a nd alcohol or barbiturates may pr oduce additive depressive effects
`on central nervous system function. Possible change s in mood and other adverse behavioral effects
`may occur in patients receiving Ce samet. Patients should remain under supervisi on of a responsible
`adult while using Cesamet.
`
`Cesamet has central nervous system activity. It pr oduces relaxation, drowsine ss, and euphoria in the
`recommended dosage range. Tolerance to these effects develops rapidly and is readily reversible.
`
`In addition to effects on the mental state, Cesame t has several systemic actions; most prominent are
`dry mouth and hypotension. Cesamet has been observed to elevate supine and standing heart rates and
`to cause supine and orthostatic hypotension. In clinical studies, oral administration of
`2 mg of Cesamet did produce some decrease in airway resistance in normal controls but had no effect
`in patients with asthma. No other nontherapeutic effects of clinical significance due to Cesamet have
`been reported.
`
`Pharmacokinetics
`Absorption and Distribution: Cesamet (nabilone) appears to be completely absorbed from the human
`gastrointestinal tract when administered orally. Following oral administration of a 2-mg dose of
`radiolabeled nabilone, peak plasma concentratio ns of approximately 2 ng/mL nabilone and 10 ng
`equivalents/mL total radioactivity are achieved within 2.0 hours. The plasma half-life (T
`1/2) values for
`nabilone and total radio activity of identified and unidentified metabolites are about 2 and 35 hours,
`respectively. The initial rapid disappearance of radioactivity represents uptake and distribution of
`nabilone into tissue and the slower phase elimination by metabolism and excretion. The apparent
`volume of distribution of nabilone is about 12.5 L/kg.
`
`Nabilone exhibits dose linearity within its therapeutic range. Clinical data suggests that the intake of
`food does not significantly affect either the rate or extend of absorption.
`
`Metabolism: Metabolism of nabilone is extensive and several metabolites have been identified. Precise
`information concerning the metabo lites that may accumulate is not available. The relative activities of
`the metabolites and the parent drug have not been established. There are at least two metabolic
`pathways involved in the biotransformation of nabilone. A minor pathwa y is initiated by the
`stereospecific enzymatic reduction of the 9-keto moie ty of nabilone to produce the isomeric carbinol
`metabolite. The peak concentrations of nabilone and its carbinol metabolites are comparable, but their
`combined exposures in plasma do not account for more than 20% of that of total radioactivity.
`Secondly, a metabolite of na bilone in feces has been identified as a diol formed by reduction of the 9-
`keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. In addition, there
`is evidence of extensive metabolism of Ce samet by multiple P 450 enzyme isoforms. In vitro P450
`inhibition studies using human liver microsomes showed that nabilone did not significantly inhibit
`CYP1A2, 2A6, 2C19, 2D6, and 3A4 (using midazolam and nifedipine as substrates). Nabilone had a
`weak inhibitory effect on CYP 2E1 and 3A4 (using testosterone; IC
`50 > 50 µM) and had a moderate
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`inhibitory effect on CYP2C8 and 2C9 (IC 50 > 10 µM). However, in clinical use, the very low nabilone
`plasma concentration is unlikely to interfere with the P450-mediated degrad ation of co-administered
`drugs. Chronic oral administration of
`1 mg t.i.d. for 14 days to 3 subjects gave no indication there was any significant accumulation of
`nabilone. Available evidence suggests that one or more of the metabolites has a terminal elimination
`half-life that exceeds that of nab ilone. Consequently, in repeated us e, the metabolites may accumulate
`at concentrations in excess of the parent drug.
`
`Elimination: The route and rate of the elimination of nabilone and its metabolites are similar to those
`observed with other cannabinoids, including delta-9-THC (dronabinol). When nabilone is administered
`intravenously, the drug and its metabolites are eliminated mainly in the feces (approximately 67%) and
`to a lesser extent in the urine (approximately 22%) within 7 days.
` Of the 67% recovered from the feces,
`5% corresponded to the parent com pound and 16% to its carbinol metabolite. Following oral
`administration about 60% of nabilone and its metabolites were recovered in the feces and about 24% in
`urine. Therefore, it appears that the major excretory pathway is the biliary system.
`
`The effects of age, gender,
` hepatic dysfunction, a nd renal insufficiency on the metabolism and
`elimination of nabilone have not been determined.
`Special Populations: The pharmacokinetic profile of Cesamet has not been investigated in either
`pediatric (See PRECAUTIONS, Pediatric Use) or geriatric patients (See PRECAUTIONS,
`Geriatric Use).
`
`CLINICAL TRIALS
`Cesamet was evaluated for its effectiveness and safety in the treatment of nausea and vomiting induced
`by cancer chemotherapy in patients receiving a wide variety of chemotherapy regimens, including low-
`dose cisplatin (20 mg/m
`2) in both placebo-controlled and active controlled (prochlorperazine) trials.
`
`During Cesamet treatment patients re ported a higher incidence of adverse effects. The most frequent
`were drowsiness, vertigo, dry m outh and euphoria. However, most of the adverse effects occurring
`with Cesamet were of mild to moderate severity (See ADVERSE REACTIONS).
`
`
`INDICATIONS AND USAGE
`Cesamet capsules are indicated for the treatment of the nausea and vomiting associated with cancer
`chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
`This restriction is required beca use a substantial proportion of an y group of patients treated with
`Cesamet can be expected to experience disturbing psychotomimetic reactions not observed with other
`antiemetic agents.
`
`Because of its potential to alter the mental state, Cesamet is intended for use under circumstances that
`permit close supervision of the patient by a respons ible individual particularly during initial use of
`Cesamet and during dose adjustments.
`
`Cesamet contains nabilone , which is controlled in Schedule II of the Controlled Substances Act.
`Schedule II substances have a high potential for abus e. Prescriptions for Cesamet should be limited to
`the amount necessary for a single cycle of chemotherapy (i.e., a few days).
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 3 of 11
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`Cesamet capsules are not intended to be used on as needed basis or as a first antiemetic product
`prescribed for a patient.
`
`As with all controlled drugs, prescribers should monitor patients receiving nabilone for signs of
`excessive use, abuse and misuse. Patients who may be at increase risk for substance abuse include
`those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental
`illness.
`
`
`CONTRAINDICATIONS
`Cesamet is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid.
`
`Warnings
`• The effects of Cesamet may persist for a variable and unpredictable period of time following its
`oral administration. Adverse psychiatric reactions can persist for 48 to 72 hours following
`cessation of treatment.
`
`• Cesamet has the potential to affect the CNS, which might manifest itself in dizziness,
`drowsiness, euphoria “high”, ataxia, anxiety, disorientation, depressi on, hallucinations and
`psychosis.
`
`• Cesamet can cause tachycardia and orthostatic hypotension.
`
`• Because of individual variation in response and tolerance to the effect s of Cesame t, patients
`should remain under supervision of a responsible adult especially during initial use of Cesamet
`and during dose adjustments.
`
`• Patients receiving treatment with Cesamet should be specifically warned not to drive, operate
`machinery, or engage in any hazardous activity while receiving Cesamet.
`
`• Cesamet should not be taken with alcohol, sedatives, hypnotics, or other psychoactive
`substances because these substa nces can potentiate the central nervous system effects of
`nabilone.
`
`PRECAUTIONS
`General
`The benefit/risk ratio of Cesamet use should be carefully eval uated in patients with the following
`medical conditions because of individual variation in response and tolerance to the effects of Cesamet.
`• Since Cesamet can elevate supine and standing heart rates and cause postural hypotension, it
`should be used with caution in the elderly, and in patients with hypertension or heart disease.
`• Cesamet should also be used with caution in patients with current or previous psychiatric
`disorders, (including manic depr essive illness, depression, and schizophrenia) as the symptoms
`of these disease states may be unmasked by the use of cannabinoids.
`• Cesamet should be used with caution in indi viduals receiving concomitant therapy with
`sedatives, hypnotics, or other psychoactive drugs because of the potential for additive or
`synergistic CNS effects.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 4 of 11
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`• Cesamet should be used with cau tion in patients with a history of substance abuse, including
`alcohol abuse or dependence and marijuana us e, since Cesamet cont ains a similar active
`compound to marijuana.
`
`• The safety aspects of the effects of hepatic and renal impairment have not been investigated.
`
`• Nabilone is purportedly highly bound to plasma proteins and undergoes extensive first pass
`hepatic metabolism. Those properties have the potential to lead to drug-drug interactions
`affecting the pharmacokinetics of similar behaving co-administered drugs or of Cesamet itself.
`
`• The effects of QT prolongation potential by Cesamet have not been determined.
`
`• Cesamet should be used with cau tion in pregnant patients, nur sing mothers, or pediatric
`patients because it has not been studied in these patient populations.
`
`Information for Patients
`Persons taking Cesamet should be alerted to the potential for additive central nervous system
`depression resulting from simultaneous use of Cesamet and alcohol or other central nervous system
`depressants such as benzodiazepines and barbiturate s. This combination should be avoided. Patients
`receiving treatment with Cesamet should be specifical ly warned not to drive, operate machinery, or
`engage in any hazardous activity. Patients using Cesame t should be made aware of possible changes
`in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such
`manifestations. Patients should remain under supervision of a responsible adult while using Cesamet.
`
`Drug Interactions
`Potential interactions between Cesamet 2 mg, and diazepam 5 mg; sodium secobarbital 100 mg;
`alcohol 45 mL (absolute laboratory alcohol); or code ine 65 mg, were evaluated in 15 subjects. Only a
`single combination was utilized at any one time. Th e subjects were evaluated according to physiologic
`(i.e., heart rate and blood pressure), psychometric, psychomotor, and subjective parameters. In this
`study, as expected, the depressant effects of the combinations were additive. Psychomotor function
`was particularly impaired with concurrent use of diazepam. Caution must thus be used when
`administering nabilone in combination with any CNS depressant.
`Nabilone is purportedly highly bound to plasma proteins, and therefore, might displace other protein-
`bound drugs. Therefore, practitioners should monito r patients for a change in dosage requirements
`when administering nabilone to patients receiving other highly protein-bound drugs. Published reports
`of drug/drug interactions involving cannabinoids are summarized in the following table.
`CONCOMITANT DRUG CLINICAL EFFECT(S)
`Amphetamines, cocaine, other sympathomimetic
`agents
`Additive hypertension, tachycardia, possibly cardiotoxicity
`Atropine, scopolamine, antihistamines, other
`anticholinergic agents
`Additive or super-additive tachycardia, drowsiness
`Amitriptyline, amoxapine, desipramine, other
`tricyclic antidepressants
`Additive tachycardia, hypertension, drowsiness
`Barbiturates, benzodiazepines, ethanol, lithium,
`opioids, buspirone, antihistamines, muscle relaxants,
`other CNS depressants
`Additive drowsiness and CNS depression
`Disulfiram A reversible hypomanic reaction was reported in a 28 y/o
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`man who smoked marijuana; confirmed by dechallenge and
`rechallenge
`Fluoxetine A 21 y/o female with depression and bulimia receiving 20
`mg/day fluoxetine X 4 wks became hypomanic after
`smoking marijuana; symptoms resolved after 4 days
`Antipyrine, barbiturates Decreased clearance of these agents, presumably via
`competitive inhibition of metabolism
`Theophylline Increased theophylline metabolism reported with smoking o f
`marijuana; effect similar to that following smoking tobacco
`Opioids Cross-tolerance and mutual potentiation
`Naltrexone Oral THC effects were enhanced by opioid receptor
`blockade.
`Alcohol Increase in the positive subjective mood effects of smoked
`marijuana
`
`
`Animal Pharmacology and/or Toxicology
`Monkeys treated with Cesamet at doses as high as 2 mg/kg/day for a year experienced no
`significant adverse events. This result contrasts with the findings in a planned 1-year dog study that
`was prematurely terminated because of deaths a ssociated with convulsions in dogs receiving as
`little as 0.5 mg/kg/day. The earliest deaths, however, occurred at 56 days in dogs receiving 2
`mg/kg/day. The unusual vulnerability of the dog to Cesamet is not understood; it is hypothesized,
`however, that the explanation lies in the fact that the dog differs markedly from other species in its
`metabolism of Cesamet.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`No long-term studies in animals have been pe rformed to evaluate th e carcinogenic potential of
`nabilone.
`
`Nabilone was not genotoxic in the Ames test, th e rat hepatocyte unscheduled DNA synthesis (UDS)
`test, the Chinese hamster bone marrow cell sister chromatid exchange (SCE ) test, the male rat
`dominant lethal tests nor the rat micronucleus test.
`
`Dietary administration of nabilone up to 4 mg/kg/day (about 6 times the recommended maximum
`human dose based on body surface area) was found to have no effect on fe rtility and reproductive
`performance of male and female rats.
`
`Pregnancy: Teratogenic Effects. Pregnancy Category C
`Teratology studies conducted in pregnant rats at doses up to 12 mg/kg/day (about 16 times the human
`dose on a body surface area basis) and in pregnant ra bbits at doses up to 3.3 mg/kg/day (about 9 times
`the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential
`of nabilone. However, there was dose related developmental toxicity in both species as evidenced by
`increases in embryo lethality, fetal resorptions, decreased fetal weights and pregnancy disruptions. In
`rats, postnatal developmental toxicity was also ob served. There are no adequate and well-controlled
`studies in pregnant women. Becau se animal studies cannot rule out the possibility of harm, Cesamet
`should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 6 of 11
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`Nursing Mothers
`It is not known whether this drug is excreted in breast milk. Because many drugs including some
`cannabinoids are excreted in breast milk it is not recommended that Cesame t be given to nursing
`mothers.
`Pediatric Use
`Safety and effectiveness have not been established in patients younger than 18 years of age. Caution is
`recommended in prescribing Cesamet to children because of psychoactive effects.
`Geriatric Use
`Clinical studies of Cesamet did not include suff icient numbers of subjects aged 65 and over to
`determine whether they respond differently from youn ger subjects. In general, dose selection for an
`elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the
`greater frequency of decreased hepatic, renal, or ca rdiac function, and of conc omitant disease or other
`drug therapy. Cesamet should be used with caution in elderly patients aged 65 and over because they
`are generally more sensitive to the psychoactive effects of drugs and Cesamet can elevate supine and
`standing heart rates and cause postural hypotension.
`Adverse Reactions
`Commonly Encountered Reactions: During controlled clinical trials of Cesamet, virtually all patients
`experienced at least one adverse reaction. The most commonly enc ountered events were drowsiness,
`vertigo, dry mouth, euphoria (feeling “high”), ataxia, headache, and concentration difficulties.
`
`Comparative Incidence of Reactions : Accurate estimates of the incidence of adverse events
`associated with the use of any drug are difficult to obtain. Estimates are influenced by factors such as
`drug dose, detection technique, setting, and physician judgments, among others. Consequently, the
`tables presented below are presented solely to indicate the relative frequency of adverse events
`reported in representative c ontrolled clinical studies conducted to evaluate the safety and efficacy of
`Cesamet under relatively similar c onditions of use. The figures cited cannot be used to predict
`precisely the incidence of untoward events in the course of usual medical pr actice, in which patient
`characteristics and other factors may differ from those that prevailed in the clinical trials. These
`incidence figures also cannot be compared with those obtained from other c linical studies involving
`related drug products because each group of drug trials is conducted under a different set of conditions.
`Finally, it is important to emphasize that these ta bulations do not reflect the relative severity and/or
`clinical importance of the adverse events. A better pe rspective on the serious adverse events associated
`with the use of Cesamet is provided in the WARNINGS and PRECAUTIONS sections.
`The following tables list in order of decreasing frequency the adverse reactions encountered by a
`substantial proportion of pa tients treated with Cesa met participating in re presentative controlled
`clinical trials.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 7 of 11
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`Incidence of Adverse Reactions in Placebo-Controlled Studies
` Nabilone (n=132) Placebo (n=119)
`Adverse Event Patients Percent Patients Percent
`Vertigo 69 52 3 3
`Drowsiness 69 52 6 5
`Dry Mouth 47 36 2 2
`Ataxia 19 14 0 0
`Euphoria 14 11 1 1
`Sleep Disturbance 14 11 1 1
`Dysphoria 12 9 0 0
`Headache 8 6 0 0
`Nausea 5 4 0 0
`Disorientation 3 2 0 0
`Depersonalization 2 2 1 1
`
`Incidence of Adverse Reactions in Active-Controlled Studies
` Nabilone
`(n=250)
`Prochlorperazine
`(n=232)
`Adverse Event Patients Percent Patients Percent
`Drowsiness 165 66 108 47
`Vertigo/Dizziness 147 59 53 23
`Euphoria 95 38 12 5
`Dry Mouth 54 22 11 5
`Depression 35 14 37 16
`Ataxia 32 13 4 2
`Visual Disturbance 32 13 9 4
`Concentration Difficulties 31 12 3 1
`Hypotension 20 8 3 1
`Asthenia 19 8 10 4
`Anorexia 19 8 22 9
`Headache 18 7 14 6
`Sedation 7 3 2 1
`Increased Appetite 6 2 2 1
`
`Adverse Reactions by Body System—The following list of adverse events is organized by
`decreasing frequency within body systems for patients treated with Cesamet in controlled
`clinical trials. All events are listed regardless of causality assessment.
`Blood and Hematopoietic—Anemia
`Cardiovascular— Orthostatic hypotension, hypotension, tachycardia, syncope, palpitation,
`flushing, hypertension, arrhythmia, and cerebral vascular accident.
`Eye and Ear— Vision disturbance, ear tightness, eye irritation, eye dryness, equilibrium
`dysfunction, tinnitus, eye disorder, amblyopia, eye swelling, eyelid diseases, pupil dilation,
`photophobia, and visual field defect.
`Gastrointestinal — Dry mouth, nausea, anorexia, vomiting, diarrhea, abdominal pain,
`constipation, aphthous ulcer, mouth irritation, gastritis, and dyspepsia.
`Genitourinary — Increased urination, decreased urination, hot flashes, urinary retention,
`and frequency of micturition.
`Infection— Bacterial infection
`Metabolic and Endocrine — Thirst
`Musculoskeletal— Muscle pain, back pain, neck pain, joint pain, and unspecified pain.
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 8 of 11
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`Nervous System — Drowsiness, vertigo, ataxia, decreased concentration, sedation,
`hallucinations, paresthesia, tremor, memory disturbance, perception disturbance,
`convulsions, dystonia, numbness, and akathisia.
`Psychiatric— Euphoria (feeling “high”), sleep disturbance, depression, confusion,
`disorientation, anxiety, depersonalization syndrome, speech disorder, abnormal dreams,
`insomnia, mood swings, inebriated feeling, toxic psychosis, paranoia, apathy, thought
`disorder, withdrawal, panic disorder, phobic neurosis, emotional disorder, and
`hyperactivity.
`Respiratory— Dyspnea, pharyngitis, nasal congestion, sinus headache, thick t ongue, dry
`throat, dry nose, wheezing, nosebleed, cough, voice change, and chest pain.
`Skin and Appendages— Anhidrosis, photosensitivity, pruritus, rash, and allergic reactions.
`Miscellaneous and Ill-Defined Conditions— Headache, fatigue, lightheadedness,
`coordination disturbance, asthesia, dysphoria, dizziness, taste change, excessive appetite,
`chills, excessive sweating, nervousness, malaise, postural dizziness, twitch, irritability,
`fever, inhibited walking, unconsciousness, hypotonia, and impaired urination.
`Postmarketing Adverse Reactions — Cesamet has been marketed internationally since 1982.
`The following adverse reactions listed in order of decreasing frequency by body system have been
`reported since Cesamet has been marketed. All events are listed regardless of causality
`assessment.
`Blood and Hematopoietic— Leukopenia
`Cardiovascular— Hypotension and tachycardia
`Eye and Ear— Visual disturbances
`Gastrointestinal— Dry mouth, nausea, vomiting, and constipation
`Nervous System—Hallucinations, CNS depression, CNS stimulation, ataxia, stupor, vertigo,
`convulsion, and circumoral paresthesia
`Psychiatric— Somnolence, confusion, euphoria, depression, dysphoria, depersonalization, anxiety,
`psychosis, and emotional lability
`Miscellaneous and Ill-Defined Conditions— Dizziness , headache, insomnia, abnormal thinking,
`chest pain, lack of effect, and face edema
`
`DRUG ABUSE AND DEPENDENCE
`Controlled Substance — Cesamet, a synthetic cannabinoid pharmacologically related to Cannabis
`sativa L. (Marijuana; (delta-9-THC) is a highly abusable substance. Cesamet is controlled under
`Schedule II (CII) of the Controlled Substances Act. Prescriptions fo r Cesamet should be limited to the
`amount necessary for a single cycle of chemotherapy (i.e., a few days). Cesamet may produce
`subjective side effects which may be interpreted as a euphoria or mar ijuana-like "high" at therapeutic
`doses.
`
`It is not known what proportion of individuals ex posed chronically to Cesamet or other cannabinoids
`will develop either psychological or physical dependence. Long term use of these compounds has,
`however, been associated with disorders of motiva tion, judgment, and cognition. It is not clear,
`though, if this is a manifestation of the underlying personalities of chronic users of this class of drugs
`or if cannabinoids are directly responsible for these effects. An abstinence syndrome has been reported
`following discontinuation of delta-9-THC at high doses of 200 mg per day for 12 to 16 consecutive
`days. The acute phase was characterized by psyc hic distress, insomnia, and signs of autonomic
`hyperactivity (sweating, rhinorrhea, loose stools, hiccups). A protracted abstinence phase may have
`occurred in subjects who reported sleep distur bances for several weeks after delta-9-THC
`discontinuation.
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`Page 9 of 11
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`Abuse — Cesamet may produce subjective si de effects that may be interpreted as a euphoria or
`marijuana-like "high" at therapeutic doses. Cesamet was shown to be qualitatively and quantitatively
`similar to approved oral delta-9-THC in the production of cannabis-like effects, thus demonstrating its
`potential for abuse.
`
`Preclinical studies performed in both dogs and monkeys demonstrated that Cesamet was cannabinoid-
`like. As with delta-9-THC, tolerance develops rapi dly to the pharmacological effects in both the dog
`and the monkey. Cross-tolerance between Cesamet and delta-9-THC was demonstrated in the monkey.
`
`Dependence — The physical dependence capacity of Cesa met is unknown at this time. Patients who
`participated in clinical trials of up to 5 days' duration evidenced no withdrawal symptoms on cessation
`of dosing.
`
`OVERDOSAGE
`Signs and Symptoms - Signs and symptoms of overdosage are an extension of the psychotomimetic
`and physiologic effects of Cesamet.
`Treatment - To obtain up-to-date information about the treatment of overdose, a good resource is
`your certified Regional Poison Control Center. Telephone numbers of certified poison control
`centers are listed in the Physicians' Desk Reference (PDR). In managing overdosage, consider the
`possibility of multiple drug overdoses, interacti on among drugs, and unusual drug kinetics in your
`patient.
`Overdosage may be considered to have occurred, even at prescribed dosages, if disturbing
`psychiatric symptoms are present. In these cases, the patient should be observed in a quiet
`environment and supportive measures, including reassurance, should be used. Subsequent doses
`should be withheld until patients have returned to their baseline mental status; routine dosing may
`then be resumed if clinically indicated. In such instances, a lower initiating dose is suggested. In
`controlled clinical trials, alterations in mental status related to the use of Cesamet resolved within
`72 hours without specific medical therapy.
`In overdose settings, attention should be paid to vital signs, since both hypertension and
`hypotension have been known to occur; tachycardia and orthostatic hypotension were most
`commonly reported.
`No cases of overdosage with more than 10 mg/day of nabilone were reported during clinical trials.
`Signs and symptoms that would be expected to occur in large overdose situations are psychotic
`episodes, including hallucinations, anxiety reactions, respiratory depression, and coma.
`If psychotic episodes occur, the patient should be managed conservatively, if possible. For
`moderate psychotic episodes and anxiety reactions, verbal support and comforting may be
`sufficient. In more severe cases, antipsychotic drugs may be useful; however, the utility of
`antipsychotic drugs in cannabinoid psychosis has not been systematically evaluated. Support for
`their use is drawn from limited experience using antipsychotic agents to manage cannabis
`overdoses. Because of the potential for drug-drug interactions (e.g., additive CNS depressant effects
`due to nabilone and chlorpromazine), such patients should be closely monitored.
`Protect the patient's airway and support ventila tion and perfusion. Meticulously monitor and
`maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, as well
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`NDA 18-677/S-011
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`as other laboratory values and physical assessments. Absorption of drugs from the gastrointestinal
`tract may be decreased by giving activated charcoal, which, in many cases, is more effective than
`emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of
`charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the
`patient's airway when employing gastric emptying or charcoal.
`The use of forced diuresis, peritoneal dialysis, hemodialysis, charcoal hemoperfusion, or
`cholestyramine has not been reported. In the presence of normal renal function, most of a dose of
`nabilone is eliminated through the biliary system.
`Treatment for respiratory depression and comatose state consists in symptomatic and supportive
`therapy. Particular attention should be paid to the occurrence of hypothermia. If the patient becomes
`hypotensive, consider fluids, inotropes, and/