Nabilone 0.25mg Capsule

Nabilone is indicated for the control of nausea and vomiting, caused by chemotherapeutic agents used in the treatment of cancer, in patients who have failed to respond adequately to conventional antiemetic treatments.

Posology

Adult

Nabilone is for administration to adults only.

The usual adult dosage is 1 mg or 2 mg twice a day. To minimise side-effects, it is recommended that the lower starting dose is used and that the dose is increased as necessary. The first dose should be administered the evening before initiation of chemotherapy, and the second dose should be given one to three hours before the first dose of the oncolytic agent is administered.

The maximum daily dose should not exceed 6 mg, given in three divided doses.

Nabilone may be administered throughout each cycle of chemotherapy and, if necessary, for 48 hours after the last dose of each cycle. Data on the chronic use of nabilone are not available.

Elderly patients

There are insufficient data from clinical trials on the use of Nabilone in patients aged 65 years and older. In general, the dose should be selected with caution for elderly patients (see section 4.4).

Patients with liver impairment

No data are available. Use should be undertaken with caution. Use in cases of severe liver impairment is not recommended.

Patients with renal impairment

No data are available. Use with caution.

Children and adolescents

The safety and efficacy of Nabilone in children and adolescents under 18 years of age have not been established. No data are available.

Method of administration

For oral use.

Nabilone is contra-indicated in patients with a known allergy to cannabinoid agents and when the nausea and vomiting arises from any cause other than cancer chemotherapy.

The use of the drug Nabilone may lead to positive results in doping tests.

Patients with liver impairment

There are no data available on patients with liver impairment. As nabilone is excreted primarily by the biliary route, the drug is not recommended for use in patients with severe liver dysfunction.

Patients with renal impairment

No studies have been conducted in patients with renal impairment. Caution is advised when treating these patients.

Patients receiving nabilone should be closely observed, if possible, within an inpatient setting. This is especially important during the treatment of naive patients. However, even patients experienced with cannabinoid agents may have serious untoward responses not predicted by prior uneventful exposures. Patients should be made aware of possible changes of mood and other adverse behavioural effects of the drug.

The effects of nabilone can persist for a variable and unpredictable period of time after oral administration. Adverse psychiatric reactions may occur for 48 to 72 hours after discontinuation of treatment.

Nabilone should be used with caution in patients with a history of substance or drug abuse, including alcohol abuse or alcohol dependence.

Nabilone should not be taken with alcohol, sedatives, hypnotics, or other psychoactive substances, as these substances may potentiate the effects of Nabilone on the CNS.

Since nabilone 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 and heart disease.

Patients with mental illnesses, including manic-depressive illness and depression, should not use Nabilone.

Children and adolescents

Nabilone is not recommended for children and adolescents under 18 years of age.

Nabilone should be administered with caution to patients who are taking other psychoactive drugs or CNS depressants, including alcohol, barbiturates and narcotic analgesics, or to those with a history of psychiatric disorder (including manic depressive illness and schizophrenia). Nabilone has been shown to have an additive CNS depressant effect when given with either diazepam, secobarbitone sodium, alcohol or codeine.

Interactions with the following substances have been observed when cannabinoids are administered concomitantly:

Amphetamines, cocaine, other sympathomimetics

Atropine, scopolamine, antihistamines, other anticholinergics

Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants

Barbiturates, benzodiazepines, lithium, opioids, buspirone, muscle relaxants,

CNS depressants:

Disulfiram

Fluoxetine

Phenazone

Theophylline

Naltrexone

Alcohol

Fertility

There are no data available on the effect of nabilone on fertility in humans. Animal studies with nabilone show no effect on fertility (see section 5.3). However, effects on fertility have been observed with other cannabinoids in animal studies.

Pregnancy

To date, there is no or very limited experience with the use of nabilone in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The use of Nabilone during pregnancy is not recommended.

Breast-feeding

It is not known whether nabilone or its metabolites are excreted in breast milk. Since other cannabinoids are excreted and accumulate in breast milk, a risk to the breastfed child cannot be ruled out. Breastfeeding should be discontinued during treatment and for 7 days after the end of treatment.

Nabilone may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as operating machinery or driving a car; therefore the patient should be advised accordingly. The effects of Nabilone 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.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called 'statutory defence') if:

- The medicine has been prescribed to treat a medical or dental problem,
- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine, and
- It was not affecting your ability to drive safely

Within each frequency grouping, side effects are listed in order of decreasing severity.

Frequency according to MedDRA convention

Very common (≤1/10)

Common (≤1/100, <1/10)

Uncommon (≤1/1,000, <1/100)

Rare (≤1/10,000, <1/1,000)

Very rare (<1/10,000)

Not known (frequency cannot be estimated from the available data)

Nervous system disorders

Common: Somnolence, ataxia, headache

Rare: Coordination abnormal, tremor

Psychiatric disorders

Common: Euphoric mood, sleep disorder, dysphoria

Rare: Confusional state, disorientation, hallucination, psychosis, depression, anxiety, depersonalization/derealization disorder

Not known: Sedation

Eye disorders

Common: Visual impairment

Ear and labyrinth disorders

Common: Vertigo

Metabolic and nutritional disorders

Rare: Decreased appetite

Heart disease

Common: Hypotension

Rare: Tachycardia

Disorders of the gastrointestinal tract

Common: Dry mouth, nausea

Rare: Abdominal pain

In controlled clinical trials with nabilone, patients experienced at least one adverse reaction.

Tolerance to CNS effects such as relaxation, somnolence, and euphoria develops rapidly and is reversible.

Nabilone is potentially addictive at therapeutic doses, with possible subjective side effects such as euphoria. Prescriptions should therefore be limited to the necessary duration (a few days) during chemotherapy. The potential for physical dependence of nabilone is unknown. Patients in clinical trials lasting up to 5 days did not experience withdrawal symptoms after discontinuation of the drug.

During controlled clinical trials of nabilone, virtually all patients experienced at least one adverse reaction. These included pyschotomimetic reactions.

In these trials, the commonest statistically significant adverse events (in decreasing order of incidence) were: drowsiness, vertigo/dizziness, euphoria (high), dry mouth, ataxia, visual disturbance, concentration difficulties, sleep disturbance, dysphoria, hypotension, headache and nausea.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Signs and symptoms are an extension of the psychotomimetic and physiological effects of nabilone. Overdosage may be considered to have occurred, even at prescribed dosages, if disturbing psychiatric symptoms are present. Subsequent doses should be withheld until patients have returned to their baseline mental status; routine dosing, possibly at a lower dose, may then be resumed if clinically indicated. In controlled clinical trials, alterations in mental status, related to the use of nabilone, resolved within 72 hours without specific medical therapy. Vital signs should be monitored, since hypertension, hypotension and tachycardia have occurred.

No cases of overdosage with more than 10 mg/day of nabilone have been reported during clinical trials. Signs and symptoms to be anticipated in large overdose situations are psychotic episodes, including hallucinations and anxiety reactions, respiratory depression and coma.

Treatment Conservative management, if possible (i.e. verbal support and comfort). In more severe cases, antipsychotic drugs may be useful, although they have not been systematically evaluated. Such patients should be closely monitored because of the potential for drug interactions (eg., additive CNS depressant effects due to nabilone and chlorpromazine).

General supportive care is recommended. Consider giving activated charcoal to decrease absorption from the gastrointestinal tract. The use of forced diuresis, peritoneal dialysis, haemodialysis, charcoal haemoperfusion, or cholestyramine, has not been reported. Most of a dose of nabilone is eliminated through the biliary system.

Treatment for respiratory depression and comatose state consists of symptomatic and supportive therapy. Attention should be paid to the occurrence of hypothermia. Consider fluids, inotropes and/or vasopressors for hypotension.

Pharmacotherapeutic group: Antiemetics and antinausea agents, other antiemetics

ATC code: A04AD11

Nabilone is a synthetic cannabinoid which has been shown to have significant antiemetic activity in patients undergoing chemotherapy for malignant neoplasms. The mode of action of nabilone has been studied in cats and dogs. Although its antiemetic action is not yet fully understood, it is apparent that there are a number of points in the control systems of the body at which nabilone could block the emetic mechanism.

The pharmacokinetic properties of nabilone have been documented only very fundamentally, and a significant number of important pharmacokinetic properties remain unknown. This is considered particularly relevant for the target population, which is highly likely to belong to special population groups (elderly people, those with kidney and liver disease) and is highly likely to be taking concomitant medications with potential drug interactions. Safe use of the drug cannot be guaranteed.

Absorption

Two fasted subjects were given an oral dose of 2 mg ¹⁴C-nabilone. Nabilone was readily absorbed from the gastrointestinal tract. Pharmacokinetic comparison between the oral and intravenous routes of administration suggested that most of the drug was available after oral dosage. Similarly, the percentages of radioactivity in the faeces and urine were approximately sixty per cent and twenty-four per cent respectively whichever route was employed, supporting the view that most of the oral dose was absorbed.

Half-life

The plasma half-life of unchanged nabilone in these volunteers was approximately two hours. The estimated half-life of the carbinol metabolite was somewhat longer at between five and ten hours. Total radioactivity had a half-life of approximately thirty-five hours.

Distribution

The rapid disappearance of absorbed drug from the plasma has been related to extensive tissue distribution and to rapid metabolism and excretion.

Metabolism

Two metabolic pathways have been suggested. The major pathway probably involves the direct oxidation of nabilone to produce hydroxylic and carboxylic analogues. These compounds are thought to account for the remaining plasma radioactivity when carbinol metabolites have been extracted.

Excretion

When 2 mg of ¹⁴C-nabilone was administered orally, over sixty per cent of the total radioactivity was eliminated in the faeces and about twenty five per cent in the urine. The discrepancy is probably due to additive analytical errors, since respiratory ¹⁴C CO₂ did not account for the remaining fifteen per cent. Comparison with intravenous administration indicated no significant differences in the excretion pattern suggesting the biliary system to be the major excretory pathway.

Nabilone has been inadequately tested in rats, dogs, and monkeys. Long-term administration in dogs, in contrast to short-term administration, led to sudden convulsions and death. A safety margin was not established.

Long-term studies on the carcinogenicity of nabilone are not available.

Nabilone was negative for mutagenicity in vitro (Ames test) and in vivo (rat UDS test in hepatocytes, hamster sister chromatid exchange (SCE) test in bone marrow cells, rat dominant lethal test, rat micronucleus test).

Oral treatment with nabilone for 70 days at a dose 40 times the maximum daily human dose showed no effect on fertility in male rats. However, other synthetic cannabinoids in the same species led to changes in hormonal balance and in the male and female reproductive organs after 13 weeks of oral administration of 8 times the maximum dose.

In animal studies in rats and rabbits, effects on the fetus and offspring were observed. Doses 5 to 6 times higher than the maximum daily human dose led to an increase in stillbirths and miscarriages, as well as a reduction in the survival rate of the offspring. Teratogenic effects were not observed. Transfer of nabilone into breast milk has not yet been studied. However, in monkeys, THC was detected in breastfed offspring of the F1 generation after intramuscular treatment of the F0 generation.

Povidone

Pre-gelatinised Starch

Isopropyl alcohol

Capsule Shell Components

Gelatin

Water

Indigo carmine (E132)

Quinoline yellow (E104)

Titanium Dioxide (E171)

Printing Ink Composition Shellac

Propylene glycol

Black iron oxide (E172)

Potassium hydroxide

None known.

3 Years.

This medicine does not require any special storage conditions.

HDPE container with CRC closure or Alu//Alu/PVC/OPA blister pack of 20 capsules.

None.