Nabilone

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.

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.

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 concentrations of approximately 2 ng/mL nabilone and 10 ng equivalents/mL total radioactivity are achieved within 2.0 hours. The plasma half-life (T ½ ) values for nabilone and total radioactivity 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 extent of absorption. Metabolism: Metabolism of nabilone is extensive and several metabolites have been identified. Precise information concerning the metabolites 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 pathway is initiated by the stereospecific enzymatic reduction of the 9-keto moiety 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 nabilone 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 Cesamet by multiple P450 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 (testosterone; IC 50 > 50 µM) and had a moderate 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 degradation 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 nabilone. Consequently, in repeated use, 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 compound 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, and 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 ).