nabilone 1 MG Oral Capsule
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.
DRUG INTERACTIONS
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
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, interaction 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 ventilation and perfusion.
Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, as well 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/or vasopressors.
The estimated oral median lethal dose in female mice is between 1,000 and 2,000 mg/kg; in the female rat, it is greater than 2,000 mg/kg, (See CLINICAL PHARMACOLOGY ).
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 C 24 H 36 O 3 .
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.
Chemical Structure
CLINICAL STUDIES
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 reported a higher incidence of adverse effects.
The most frequent were drowsiness, vertigo, dry mouth and euphoria.
However, most of the adverse effects occurring with Cesamet were of mild to moderate severity (See ADVERSE REACTIONS ).
HOW SUPPLIED
Cesamet ® capsules (blue and white): 1 mg (bottles of 50 capsules) NDC 0187-1221-03.
Capsules are imprinted with Valeant on the blue cap and a four-digit code (3101) on the white body.
Store at controlled room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
GERIATRIC USE
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.
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.
PEDIATRIC USE
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.
PREGNANCY
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 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.
NUSRING MOTHERS
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.
INFORMATION FOR PATIENTS
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.
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.
Adose 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.