Drug: Cesamet

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:

Source: http://www.rxlist.com

Commonly Encountered Reactions: During controlled clinical trials of Cesamet (nabilone capsules) , 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 (nabilone capsules) 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 (nabilone capsules) participating in representative controlled clinical trials. Incidence of Adverse Reactions in Placebo-Controlled Studies
Adverse Event Nabilone
(n=132) Placebo
(n=119) 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
Adverse Event Nabilone
(n=250) Prochlorperazine
(n=232) 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 (nabilone capsules) 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 (nabilone capsules) has been marketed internationally since 1982. The following adverse reactions listed in order of decreasing frequency by body system have been reported since Cesamet (nabilone capsules) 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 (nabilone capsules) , a synthetic cannabinoid pharmacologically related to Cannabis sativa L. (Marijuana; (delta-9-THC) is a highly abusable substance. Cesamet (nabilone capsules) is controlled under Schedule II (CII) of the Controlled Substances Act. Prescriptions for Cesamet (nabilone capsules) should be limited to the amount necessary for a single cycle of chemotherapy (i.e., a few days). Cesamet (nabilone capsules) 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 (nabilone capsules) 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 (nabilone capsules) may produce subjective side effects that may be interpreted as a euphoria or marijuana-like "high" at therapeutic doses. Cesamet (nabilone capsules) 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 (nabilone capsules) 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 (nabilone capsules) and delta-9-THC was demonstrated in the monkey. Dependence - The physical dependence capacity of Cesamet (nabilone capsules) 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. Read the Cesamet (nabilone capsules) Side Effects Center for a complete guide to possible side effectsLearn More »

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The usual adult dosage is 1 or 2 mg b.i.d. 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 t.i.d. Cesamet (nabilone capsules) may be administered 2 or 3 times daily during the entire course of each cycle of chemotherapy and, if needed, for 48 hours after the last dose of each cycle of chemotherapy.

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Potential interactions between Cesamet (nabilone capsules) 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 Read the Cesamet Drug Interactions Center for a complete guide to possible interactions Learn More »

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Cesamet (nabilone capsules) 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 (nabilone capsules) can be expected to experience disturbing psychotomimetic reactions not observed with other antiemetic agents. Because of its potential to alter the mental state, Cesamet (nabilone capsules) 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 (nabilone capsules) should be limited to the amount necessary for a single cycle of chemotherapy (i.e., a few days). Cesamet (nabilone capsules) 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.

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Cesamet (nabilone capsules) is contraindicated in any patient who has a history of hypersensitivity to any cannabinoid. Last reviewed on RxList: 2/26/2009
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Signs and Symptoms - Signs and symptoms of overdosage are an extension of the psychotomimetic and physiologic effects of Cesamet (nabilone capsules) . 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 (nabilone capsules) 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).

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Cesamet™ (nabilone capsules) capsules (purple and white): 1 mg (bottles of 20 capsules) NDC 0187-0247-01. Capsules will be imprinted with Valeant on the white body and a four-digit code (0247) on the purple cap. Store at controlled room temperature, 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]. Revised July 2006. Valeant Pharmaceuticals International, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. (877) 361-2719. Last reviewed on RxList: 2/26/2009
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

General The benefit/risk ratio of Cesamet (nabilone capsules) 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 (nabilone capsules) .
  • Since Cesamet (nabilone capsules) 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 (nabilone capsules) 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 (nabilone capsules) 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 (nabilone capsules) should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence and marijuana use, since Cesamet (nabilone capsules) 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 (nabilone capsules) itself.
  • The effects of QT prolongation potential by Cesamet (nabilone capsules) have not been determined.
  • Cesamet (nabilone capsules) should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations.
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. 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 (nabilone capsules) 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 (nabilone capsules) 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 (nabilone capsules) to children because of psychoactive effects. Geriatric Use Clinical studies of Cesamet (nabilone capsules) 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 (nabilone capsules) 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 (nabilone capsules) can elevate supine and standing heart rates and cause postural hypotension. Last reviewed on RxList: 2/26/2009
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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