Cesamet

Before taking nabilone,

• tell your doctor and pharmacist if you are allergic to nabilone, other cannabinoids such as dronabinol (Marinol) or marijuana (cannabis), any other medications, or any of the ingredients in nabilone capsules. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antidepressants, including amitriptyline (in Limbitrol), amoxapine, desipramine (Norpramin) and fluoxetine (Prozac); antihistamines; amphetamines such as amphetamine (in Adderall), dextroamphetamine (Dexedrine, Dextrostat, in Adderall), and methamphetamine (Desoxyn); anticoagulants ('blood thinners') such as warfarin (Coumadin); atropine (Atropen, in Hycodan, in Lomotil, in Tussigon); codeine (in some cough syrups and pain relievers); barbiturates, including phenobarbital (Luminal) and secobarbital (Seconal, in Tuinal); buspirone (BuSpar); diazepam (Valium); digoxin (Lanoxicaps, Lanoxin); disulfiram (Antabuse); ipratropium (Atrovent); lithium (Eskalith, Lithobid); medications for anxiety, asthma, colds, irritable bowel disease, motion sickness, Parkinson's disease, seizures, ulcers, or urinary problems; muscle relaxants; naltrexone (Revia, Vivitrol); narcotic medications for pain; propranolol (Inderal); scopolamine (Transderm-Scop); sedatives; sleeping pills; tranquilizers; and theophylline (TheoDur, Theochron, Theolair). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you or anyone in your family drinks or has ever drunk large amounts of alcohol or uses or has ever used street drugs such as marijuana. Also tell your doctor if you or anyone in your family has or has ever had a mental illness such as bipolar disorder (manic depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods), schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) or depression. Also tell your doctor if you have or have ever had high blood pressure or heart, liver, or kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking nabilone, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking nabilone.
• you should know that nabilone may make you drowsy and may cause changes in your mood, thinking, memory, judgment, or behavior. You may continue to have these symptoms for up to 72 hours after you finish your treatment with nabilone. You will need to be supervised by a responsible adult during and for several days after your treatment with nabilone. Do not drive a car operate machinery, or participate in dangerous activities while you are taking this medication and for several days after you finish your treatment.
• do not drink alcoholic beverages while you are taking nabilone. Alcohol can make the side effects from nabilone worse.
• you should know that nabilone may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Taking this medicine with other drugs that make you sleepy or slow your breathing can worsen these effects. Ask your doctor before taking nabilone with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Other drugs may interact with nabilone, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

>10%

Vertigo (52%)

Drowsiness (52%)

Dry mouth (36%)

Ataxia (14%)

Visual disturbance (13%)

Blurred vision (12.8%)

Concentration difficulties (12%)

Euphoria (11%)

Sleep disturbance (11%)

1-10%

Depersonalization

Disorientation

Dysphoria

Headache

Hypotension

Nausea

Cesamet is part of the drug class:

• Other antiemetics

You should not use nabilone if you have ever had an allergic reaction to natural or man-made marijuana such as dronabinol (Marinol).

To make sure nabilone is safe for you, tell your doctor if you have:

• high blood pressure;

• heart disease;

• liver or kidney disease;

• history of alcoholism or drug addiction; or

• past or present mental illness (depression, schizophrenia, bipolar disorder, psychosis).

Nabilone may be habit-forming. Never share nabilone with another person, especially someone with a history of drug abuse or addiction or habitual marijuana use. Keep the medication in a place where others cannot get to it.

FDA pregnancy category C. It is not known whether nabilone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether nabilone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Older adults may be more sensitive to the effects of this medication.

Do not give this medication to anyone under 18 years old.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using nabilone and call your doctor at once if you have:

• hallucinations (seeing or hearing things that are not real);

• confusion, unusual thoughts or behavior;

• anxiety, panic, paranoia, extreme fear;

• fast heart rate; or

• a light-headed feeling, like you might pass out.

Common side effects may include:

• headache, dizziness, drowsiness;

• feeling "high";

• weakness, lack of coordination;

• depressed mood;

• dry mouth; or

• trouble concentrating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Nabilone is used to treat the nausea and vomiting that may occur during treatment with cancer medicines. It is only used when other kinds of medicine for nausea and vomiting do not work.

Nabilone is only available with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

• Changes in mood
• confusion
• convulsions (seizures)
• delusions
• dizziness or fainting
• fast or pounding heartbeat
• hallucinations (seeing, hearing, or feeling things that are not there)
• mental depression
• nervousness or anxiety
• unusual tiredness or weakness (severe)

Symptoms of overdose

• Difficulty in breathing
• hallucinations (seeing, hearing, or feeling things that are not there)
• mental changes (severe)
• nervousness or anxiety (severe)

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Clumsiness or unsteadiness
• drowsiness
• dryness of mouth
• false sense of well-being
• headache

Less common or rare

• Blurred vision or any changes in vision
• dizziness or lightheadedness, especially when getting up from a lying or sitting position—more common with high doses
• loss of appetite

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking Cesamet as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

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. 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.

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.

To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-723-1400 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.

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 SystemThe 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 HematopoieticAnemia

CardiovascularOrthostatic hypotension, hypotension, tachycardia, syncope, palpitation, flushing, hypertension, arrhythmia, and cerebral vascular accident.

Eye and EarVision disturbance, ear tightness, eye irritation, eye dryness, equilibrium dysfunction, tinnitus, eye disorder, amblyopia, eye swelling, eyelid diseases, pupil dilation, photophobia, and visual field defect.

GastrointestinalDry mouth, nausea, anorexia, vomiting, diarrhea, abdominal pain, constipation, aphthous ulcer, mouth irritation, gastritis, and dyspepsia.

GenitourinaryIncreased urination, decreased urination, hot flashes, urinary retention, and frequency of micturition.

InfectionBacterial infection

Metabolic and EndocrineThirst

MusculoskeletalMuscle pain, back pain, neck pain, joint pain, and unspecified pain.

Nervous SystemDrowsiness, vertigo, ataxia, decreased concentration, sedation, hallucinations, paresthesia, tremor, memory disturbance, perception disturbance, convulsions, dystonia, numbness, and akathisia.

PsychiatricEuphoria (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.

RespiratoryDyspnea, pharyngitis, nasal congestion, sinus headache, thick tongue, dry throat, dry nose, wheezing, nosebleed, cough, voice change, and chest pain.

Skin and AppendagesAnhidrosis, photosensitivity, pruritus, rash, and allergic reactions.

Miscellaneous and Ill-Defined ConditionsHeadache, 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 ReactionsCesamet 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 HematopoieticLeukopenia

CardiovascularHypotension and tachycardia

Eye and EarVisual disturbances

GastrointestinalDry mouth, nausea, vomiting, and constipation

Nervous SystemHallucinations, CNS depression, CNS stimulation, ataxia, stupor, vertigo, convulsion, and circumoral paresthesia

PsychiatricSomnolence, confusion, euphoria, depression, dysphoria, depersonalization, anxiety, psychosis, and emotional lability

Miscellaneous and Ill-Defined ConditionsDizziness, headache, insomnia, abnormal thinking, chest pain, lack of effect, and face edema

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

Use of this drug by breastfeeding mothers is not recommended. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: Some cannabinoids are excreted in breast milk.

This drug is known to have an inhibitory effect on prolactin release, which may have contributed to reduced milk production observed in rats given doses 150 times the maximum recommended human dose.