NABILONE: 440 Adverse Event Reports & Safety Profile

DESCRIPTION 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-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-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 1 mg Cesamet capsule contains 1 mg of nabilone and the following inactive ingredients: povidone and corn starch. The capsule shells contain the following inactive ingredients: FD&C Blue No. 2 (indigo carmine), red iron oxide, gelatin, and titanium dioxide. Structural formula of Cesamet

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 because a substantial proportion of any 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 responsible 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 abuse. Prescriptions for Cesamet should be limited to the amount necessary for a single cycle of chemotherapy (i.e., a few days). 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 increased risk for substance abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness.

DOSAGE AND ADMINISTRATION The usual adult dosage is 1 or 2 mg 2 times a day. On the day of chemotherapy, the initial dose should be given 1 to 3 hours before the chemotherapeutic agent is administered. To minimize side effects, it is recommended that the lower starting dose be used and that the dose be increased as necessary. A dose of 1 or 2 mg the night before may be useful. The maximum recommended daily dose is 6 mg given in divided doses 3 times a day. Cesamet may be administered 2 or 3 times a day during the entire course of each cycle of chemotherapy and, if needed, for 48 hours after the last dose of each cycle of chemotherapy.

CONTRAINDICATIONS Cesamet is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid.

ADVERSE REACTIONS Commonly Encountered Reactions: During controlled clinical trials of Cesamet, virtually all patients experienced at least one adverse reaction. The most commonly encountered 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 controlled clinical studies conducted to evaluate the safety and efficacy of Cesamet under relatively similar conditions of use. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice, 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 clinical 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 tabulations do not reflect the relative severity and/or clinical importance of the adverse events. A better perspective 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 patients treated with Cesamet participating in representative controlled clinical trials. 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.

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 tongue, 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 To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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, depression, hallucinations and psychosis.
• Cesamet can cause tachycardia and orthostatic hypotension.
• Because of individual variation in response and tolerance to the effects of Cesamet, 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 substances can potentiate the central nervous system effects of nabilone.

PRECAUTIONS General The benefit/risk ratio of Cesamet use should be carefully evaluated 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 depressive 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 individuals receiving concomitant therapy with sedatives, hypnotics, or other psychoactive drugs because of the potential for additive or synergistic CNS effects.
• Cesamet should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence and marijuana use, since Cesamet contains 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 caution in pregnant patients, nursing 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 barbiturates. This combination should be avoided. Patients receiving treatment with Cesamet should be specifically warned not to drive, operate machinery, or engage in any hazardous activity. Patients using Cesamet 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 codeine 65 mg, were evaluated in 15 subjects. Only a single combination was utilized at any one time. The 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 monitor 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 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 of 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 associated 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 performed to evaluate the carcinogenic potential of nabilone. Nabilone was not genotoxic in the Ames test, the 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 fertility and reproductive performance of male and female rats. Pregnancy: Teratogenic Effects 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 rabbits 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 observed. There are no adequate and well-controlled studies in pregnant women. Because 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.

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 Cesamet 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 sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger 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 cardiac function, and of concomitant 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.

Drug Interactions Potential interactions between Cesamet 2 mg, and diazepam 5 mg; sodium secobarbital 100 mg; alcohol 45 mL (absolute laboratory alcohol); or codeine 65 mg, were evaluated in 15 subjects. Only a single combination was utilized at any one time. The 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 monitor 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 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 of 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 associated 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.