CESAMET Capsule Ref.[10771] Active ingredients: Nabilone

• 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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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 for 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 marijuana-like “high” at therapeutic doses.

It is not known what proportion of individuals exposed 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 motivation, 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 psychic distress, insomnia, and signs of autonomic hyperactivity (sweating, rhinorrhea, loose stools, hiccups). A protracted abstinence phase may have occurred in subjects who reported sleep disturbances for several weeks after delta-9-THC discontinuation.

Abuse

Cesamet may produce subjective side 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 delta-9-THC in the production of cannabis-like effects, thus demonstrating that Cesamet has a high potential for abuse.

Preclinical studies performed in both dogs and monkeys demonstrated that Cesamet was cannabinoid-like. As with delta-9-THC, tolerance develops rapidly 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 Cesamet 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.