Fatal dose not known.
Symptoms
Symptoms of central nervous system depression, which can range from drowsiness to coma according to the quantity ingested. In mild cases, symptoms include drowsiness, confusion and lethargy; in more severe cases, symptoms may include ataxia, hypotonia, hypotension, methaemoglobinaemia, respiratory depression and coma. The effects of overdose may be magnified if combined with alcohol or any other CNS depressants and in severe cases may be life-threatening. Other risk factors, such as the presence of concomitant illness and the debilitated state of the patient may contribute to the severity of symptoms and very rarely can result in fatal outcome.
Management
Treatment of overdose should be symptomatic and supportive paying particular attention to respiratory and cardiac functions. Consider activated charcoal if an adult has ingested more than 150 mg or a child more than 1.5 mg/kg within an hour. Alternatively, consider gastric lavage in adults within one hour of a potentially life-threatening overdose. If CNS depression is severe consider the use of flumazenil. It has a short half-life (about an hour). NOT TO BE USED IN MIXED OVERDOSE OR AS A 'DIAGNOSTIC' TEST. Haemodialysis does not have any therapeutic effect in cases of Imovanee overdose.
For current practice, refer to local poison centre (or equivalent information sources) regarding management of overdose.
Not applicable
The following undesirable effects have been reported at the approximate frequencies shown: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data)
| Immune system disorders | |
| Rare: | Allergic reactions including skin reactions |
| Very rare: | Anaphylactic reactions and/or angioedema |
| Psychiatric disorders | |
| Uncommon: | Nightmares, agitation |
| Rare: | Confusional state, numbed emotions, irritability, aggressiveness, hallucinations, psychoses, libido disorder |
Not known: | Dependency, restlessness, delusion, anger, depressed mood, somnambulism and other abnormal behaviour (possibly associated with amnesia) |
| See below under 'Depression', 'Psychiatric and paradoxical reactions', 'withdrawal syndrome', 'Somnambulism and associated behaviours' and 'Dependency'. Nervous system disorders | |
| Common: | Somnolence (residual) during the following day, reduced alertness, dysguesia (bitter taste) |
| Uncommon: | Headaches, dizziness |
| Rare: | Anterograde amnesia |
| See below under 'Amnesia'. | |
| Not known: | Ataxia (predominantly at the start of therapy and usually disappears with repeated administration), paraesthesia, cognitive disorders such as memory impairment |
| Eye disorders | |
Not known: | Diplopia (predominantly at the start of therapy and usually disappears with repeated administration) |
| Respiratory, thoracic and mediastinal disorders | |
| Rare: | dyspnoea |
| Not known: | respiratory depression |
| Gastrointestinal disorders | |
| Common: | Dry mouth |
| Uncommon: | Nausea, vomiting |
| Not known: | Dyspepsia |
| Skin and subcutaneous tissue disorders | |
| Rare: | Urticaria or rash, pruritus |
| Musculoskeletal and connective tissue disorders | |
| Not known: | Muscle weakness |
| General disorders and administration site conditions | |
| Uncommon: | Fatigue |
| Not known: | Light headedness, incoordination |
| Investigations | |
| Very rare: | Mild to moderate increases in serum transaminases and/or alkaline phosphatase |
| Injury, poisoning and procedural complications | |
| Rare: | Fall (predominantly in elderly patients) |
Withdrawal syndrome has been reported upon discontinuation of Imovanee. Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, hallucinations, panic attacks, muscle aches/cramps, gastrointestinal disturbances and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations. In very rare cases, seizures may occur.
Amnesia:
Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnesiac effects may be associated with inappropriate behaviour.
Depression:
Pre-existing depression may be unmasked during use of benzodiazepines or benzodiazepine-like agents.
Psychiatric and 'paradoxical' reactions:
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like products. They are more likely to occur in the elderly.
Somnambulism and associated behaviours:
There is an increased risk of sleepwalking and other associated behaviours with amnesia for the event in patients who have taken Imovanee and were not fully awake. It appears that there is an increased risk of such behaviour with the concomitant use of alcohol, other CNS depressants and the use of Imovanee at doses exceeding the maximum recommended dose.
Dependence:
Psychological dependence may occur. Abuse has been reported.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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
Hepatotoxic effects were observed in repeat dose toxicity studies conducted in rats and dogs. In dogs anaemia was observed in some studies.
Imovanee is not mutagenic in either in-vitro or in vivo tests.
Increased incidence of mammary carcinomas in female rats at high multiples of the maximum plasma concentration from therapeutic doses in humans has been attributed to increased 17-beta-estradiol serum levels. Increased incidence of thyroid tumours in rats has been associated with increased TSH serum levels. In humans Imovanee has no effects on thyroid hormones.
Fertility was impaired in two rat studies.
Imovanee had no adverse effects on fertility in rabbits.
Foetal developmental retardations and foetotoxic effects in rats and rabbits were observed only at doses well above the maximum human dosage. There was no evidence of a teratogenic potential.
Pharmacotherapeutic group: Hypnotic and sedatives; benzodiazepine related drugs, ATC code: N05C F01.
Imovanee is a hypnotic agent belonging to the cyclopyrrolone class of psychotherapeutic agents. Although structurally unrelated to the benzodiazepines, Imovanee binds with high affinity and specificity to the GABAA-benzodiazepine chloride channel macromolecular receptor complex. Imovanee binds to a site different to the benzodiazepines and induces different conformational changes to the receptor complex thus modifying the activity of the chloride ion channel.
Pharmacological properties are: anxiolysis, sedation, hypnosis, anticonvulsion and muscle relaxation
Absorption
Imovanee is swiftly absorbed. Maximum plasma concentrations are achieved after 1½ - 2 hours and are approximately 30 and 60 ng/ml after administration of 3.75 mg and 7.5 mg respectively. Absorption is the same in men and women and is not affected by simultaneous ingestion of food or repetition of doses.
Distribution
Imovanee is swiftly distributed from the vascular compartment. The plasma protein binding is at least 45% and is not saturable.
The decrease in plasma level does not depend on the dose between 3.75 and 15 mg.
The elimination half-life is approximately 5 hours at the recommended doses.
No accumulation occurs after repeated administration and individual differences appear slight.
Less than 1.0% of the dose ingested by the mother is eliminated in breast milk.
Biotransformation
The most important metabolites are the N-oxide derivative (pharmacologically active in animals) and the N-desmethyl metabolite (pharmacologically inactive in animals). Their apparent half-life times are approximately 4.5 hours and 7.4 hours respectively. No significant accumulation of the compound as seen following repeat dosing. (15 mg) for 14 days. In animals, no enzyme induction has been observed even at high doses.
Elimination
The low renal clearance of Imovanee (on average 8.4 ml/min compared to the plasma clearance (232 ml/min) shows that Imovanee is cleared chiefly by metabolism. Imovanee is eliminated in the urine (approximately 80%) in the form of unconjugated metabolites (N-oxide and N-desmethyl derivatives) and in the faeces (approximately 16%).
Special patient groups:
In various trials with elderly patients, no accumulation of Imovanee was observed in the plasma after repeated doses, in spite of a slight reduction in the hepatic function and extension of the eliminated half-life to approximately 7 hours.
In renal insufficiency, no accumulation of Imovanee or its metabolites have been detected after prolonged administration. Imovanee crosses the dialysing membrane.
In patients with cirrhosis of the liver the slow demethylating process causes the plasma clearance of Imovanee to be delayed by approximately 40%. For this reason the dosage should be adjusted for these patients.
Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. Therefore, patients should not drive or use machinery after taking a dose.
Patients should be advised not to drive or operate machinery the day after treatment until it is established that their performance is unimpaired.
It has been reported that the risk that Imovanee adversely affects driving ability is increased by the concomitant intake of alcohol. Therefore, it is recommended not to drive while taking Imovanee and alcohol concomitantly. This may also affect the patient's ability to drive and use machinery the following morning.
None.
