Datolan

Datolane is indicated for the short-term treatment of insomnia in adults.

Benzodiazepines and benzodiazepine-like agents are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress. Long term continuous use is not recommended. A course of treatment should employ the lowest effective dose.

The lowest effective dose should be used.

Datolane should be taken in a single dose and not re-administered during the same night.

Treatment duration

Treatment with Datolane should be as short as possible. Generally the duration of treatment varies from a few days to two weeks with a maximum, including the tapering off, of four weeks.

In certain cases an extension beyond the maximum treatment period may be necessary; if so it should take place after re-evaluation of the patient's status.

Posology

Adults:

The recommended dose for adults is 2 tablets (7.5 mg Datolane). This dose should not be exceeded. The tablet should be taken just before retiring.

Impaired renal function:

Although accumulation of Datolane and/or its metabolites has not been shown in patients with impaired renal function, a starting dose of 3.75 mg is recommended in these patients.

Impaired hepatic function:

As elimination of Datolane may be reduced in patients with hepatic dysfunction, a lower dose of 3.75 mg Datolane nightly is recommended.

The standard dose of 7.5 mg Datolane may be used with caution in some cases depending on effectiveness and acceptability.

Chronic respiratory insufficiency:

In patients with chronic respiratory insufficiency, a starting dose of 3.75 mg Datolane is recommended initially. The dosage subsequently may be increased to 7.5 mg.

Elderly:

A starting dose of 3.75 mg is recommended, this dose may consequently be increased to 7.5 mg if considered clinically necessary depending on patient effectiveness and acceptability.

Paediatric population:

Datolane should not be used in children and adolescents less than 18 years. The safety and efficacy of Datolane in children and adolescents aged less than 18 years have not been established.

Method of administration

Datolane is for oral use only.

Datolane is contraindicated in patients with any of the following:

-

- Myasthenia gravis

- Severe hepatic impairment

- Sleep apnoea syndrome

- Respiratory failure

Datolane should not be given to children or adolescents younger than 18 years of age.

Risk of dependence:

Clinical experience to date suggests that the risk of dependence is minimal when the duration of treatment is limited to not more than 4 weeks, however, as with the benzodiazepines and other benzodiazepine-like drugs (even at therapeutic doses), there is a risk of physical and psychological dependence or abuse. This risk increases with dose and length of treatment and use with alcohol or other psychotropics. Patients with a history of alcohol and/or drug abuse or those with personality disorders are more at risk of dependence and this should be considered when prescribing Datolane. If a patient does become dependent, abrupt cessation of treatment may result in withdrawal symptoms including: extreme anxiety, headaches, muscle pain, tension, confusion and restlessness and irritability. In severe cases symptoms may also include depersonalisation, derealisation, numbness and tingling of the extremities, hypersensitivity to noise, light and physical contact, hallucinations or epileptic seizures.

Rare cases of abuse have been reported.

Withdrawal:

Patients with a history of depression, anxiety or psychotic disorders:

Benzodiazepines and benzodiazepine-like substances, such as Datolane, are not recommended as the primary treatment of psychoses.

Datolane does not constitute a treatment for depression (or anxiety linked with depression) and may even mask its symptoms (suicide may be precipitated in such patients).

Zimovane should be administered with caution in patients exhibiting symptoms of depression. Suicidal tendencies may be present therefore the least amount of Zimovane that is feasible should be supplied to these patients to avoid the possibility of intentional overdosage by the patient. Pre-existing depression may be unmasked during use of Zimovane. Since insomnia may be a symptom of depression, the patient should be re-evaluated if insomnia persists.

Any underlying cause of the insomnia should also be addressed before symptomatic treatment to avoid under treating potentially serious effects of depression.

Tolerance:

Some loss of efficacy to the hypnotic effects of benzodiazepines and benzodiazepine-like agents may develop after repeated use for a few weeks. However, with Datolane no marked tolerance occurred during treatment periods of up to four weeks.

Rebound insomnia:

A transient syndrome where the symptoms which led to treatment with a benzodiazepine or benzodiazepine-like agent recur in an enhanced form on discontinuation of therapy. It may be accompanied by other reactions including mood changes, anxiety and restlessness. Since the risk of withdrawal/rebound phenomena may be increased after prolonged treatment, or abrupt discontinuation of therapy, it is therefore, recommended to decrease the dosage gradually and to advise the patient accordingly.

A course of treatment should employ the lowest effective dose for the minimum length of time necessary for the effective treatment. A course of treatment should not continue for longer than 4 weeks including any tapering off.

Amnesia:

Amnesia is rare, but anterograde amnesia may occur, especially if sleep is interrupted or when retiring to bed is delayed after taking the tablet. Situations when this might occur should therefore be avoided and the patient should ensure that they are able to have a full night's sleep (uninterrupted sleep of about 7 to 8 hours).

Psychomotor impairment

Like other sedative/hypnotic drugs, Datolane has CNS-depressant effects. The risk of psychomotor impairment, including impaired driving ability, is increased if: Datolane is taken within 12 hours of performing activities that require mental alertness, a dose higher than the recommended dose is taken, or Datolane is co-administered with other CNS depressants, alcohol or with other drugs that increase the blood levels of Datolane. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle following administration of Datolane and in particular during the 12 hours following that administration.

Risks from concomitant use of opioids and benzodiazepines:

Concomitant use of benzodiazepines, including Datolane, and opioids may result in sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of opioids and benzodiazepines for use in patients for whom alternative treatment options are inadequate.

If a decision is made to prescribe Datolane concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation.

Psychiatric and 'paradoxical' reactions:

It is known that reactions such as restlessness, agitation, irritability, aggression, delusion, outbursts of rage, nightmares, hallucinations, psychoses, unsuitable behaviour and other behavioural disturbances may occur during the use of benzodiazepines and benzodiazepine-like substances. If this is the case administration of the medicinal product should be discontinued. These reactions are more likely to occur in the elderly.

Somnambulism and associated behaviours:

Sleepwalking and other associated behaviours such as 'sleep driving', preparing and eating food or making phone calls with amnesia for the event, have been reported in patients who have taken Datolane 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 or the use of Datolane at doses exceeding the maximum recommended dose. If such behaviours are reported, administration of Datolane should be discontinued.

Specific patient groups:

Use in elderly

Hypnotics should be avoided in the elderly who are at risk of becoming ataxic and confused and so liable to fall and injure themselves. If, based on clinical need, a decision to treat is nevertheless taken, treatment should be initiated at a lower dose and co-administration of Datolane with CYP3A4 inhibitors should be avoided.

Use in respiratory insufficiency

As hypnotics have the capacity to depress respiratory drive, precautions should be observed if Datolane is prescribed to patients with compromised respiratory function. A lower dose is advised for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Use in hepatic insufficiency

A reduced dosage is recommended,. Benzodiazepines and benzodiazepine-like substances are not suitable for the treatment of patients with severe hepatic insufficiency, since they may promote the occurrence of encephalopathy.

Use in renal insufficiency

A reduced dosage is recommended,.

Period of treatment:

The period of treatment should be as short as possible but not longer than 4 weeks including the tapering off process. This period should only be exceeded after re-evaluation of the patient's condition. It may be of benefit to inform the patient at the beginning of treatment that the treatment will be of short duration, and to explain precisely how to reduce the dose gradually. It is also important to point out to the patient the possibility of the occurrence of rebound phenomena in order to keep to a minimum any worries about the occurrence of such symptoms during the tapering off period of the treatment. In the case of benzodiazepines and benzodiazepine-like substances with a short period of action, there are indications that withdrawal symptoms may occur within the dosage interval, especially if the dose is high.

Paediatric population:

Datolane should not be used in children and adolescents less than 18 years. The safety and efficacy of Datolane in children and adolescents aged less than 18 years have not been established.

Excipients:

Lactose:

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ponceau 4R (E124):

May cause allergic reactions.

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 Datolane adversely affects driving ability is increased by the concomitant intake of alcohol. Therefore, it is recommended not to drive while taking Datolane and alcohol concomitantly. This may also affect the patient's ability to drive and use machinery the following morning.

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)

Withdrawal syndrome has been reported upon discontinuation of Datolane. 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 Datolane 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 Datolane at doses exceeding the maximum recommended dose.

Dependence:

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.

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 Datolane overdose.

For current practice, refer to local poison centre (or equivalent information sources) regarding management of overdose.

Pharmacotherapeutic group: Hypnotic and sedatives; benzodiazepine related drugs, ATC code: N05C F01.

Datolane is a hypnotic agent belonging to the cyclopyrrolone class of psychotherapeutic agents. Although structurally unrelated to the benzodiazepines, Datolane binds with high affinity and specificity to the GABA_A-benzodiazepine chloride channel macromolecular receptor complex. Datolane 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

Datolane 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

Datolane 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 Datolane (on average 8.4 ml/min compared to the plasma clearance (232 ml/min) shows that Datolane is cleared chiefly by metabolism. Datolane 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 Datolane 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 Datolane or its metabolites have been detected after prolonged administration. Datolane crosses the dialysing membrane.

In patients with cirrhosis of the liver the slow demethylating process causes the plasma clearance of Datolane to be delayed by approximately 40%. For this reason the dosage should be adjusted for these patients.

Hepatotoxic effects were observed in repeat dose toxicity studies conducted in rats and dogs. In dogs anaemia was observed in some studies.

Datolane 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 Datolane has no effects on thyroid hormones.

Fertility was impaired in two rat studies.

Datolane 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.

Not applicable

None.