Arotril

Arotril Rosemont Oral Solution is indicated in all clinical forms of epileptic disease and seizures in adults, especially absence seizures (petit mal) including atypical absence; primary or secondarily generalised tonic-clonic (grand mal), tonic or clonic seizures; partial (focal) seizures with elementary or complex symptomatology; various forms of myoclonic seizures, myoclonus and associated abnormal movements.

Posology

The 0.5mg/5ml oral solution may facilitate the administration of lower daily doses in the initial stages of treatment or treatment for the elderly.

The 2mg/5ml oral solution should be used for maintenance and maximum dosage regimens.

Adults

Initial dosage should not exceed 1mg/day. The maintenance dosage for adults normally falls within the range 4 to 8mg.

Elderly

The elderly are particularly sensitive to the effects of centrally depressant drugs and may experience confusion. It is recommended that the initial dosage of Arotril should not exceed 0.5mg/day.

These are total daily dosages which should be divided into 4 doses taken at intervals throughout the day. If necessary, larger doses may be given at the discretion of the physician, up to a maximum of 20mg daily. The maintenance dose should be attained after 2 to 4 weeks of treatment.

Paediatric Population

Due to the presence of ethanol in the formulation, this product is not indicated for paediatric use.

Method of administration

A 2.5ml/ 5ml double ended spoon with a further 1.25ml graduation is supplied with the pack.

Suitable for administration via non-PVC nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes. When these instructions are followed over 95% of the dose is delivered.

The product is incompatible with polystyrene or PVC and therefore, other devices may react with the product.

It should be noted that for oral syringes, the product may cause the plunger to stop moving smoothly or the markings may fade over time.

Treatment should be started with low doses. The dose may be increased progressively until the maintenance dose suited to the individual patient has been found.

The dosage of Arotril must be adjusted to the needs of each individual and depends on the individual response to therapy. The maintenance dosage must be determined according to clinical response and tolerance.

The daily dose should be divided into 4 equal doses. If doses are not equally divided, the largest dose should be given before retiring. Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening.

Simultaneous administration of more than one antiepileptic drug is a common practice in the treatment of epilepsy and may be undertaken with Arotril. The dosage of each drug may be required to be adjusted to obtain the optimum effect. If status epilepticus occurs in a patient receiving oral Arotril, administration of an intravenous Arotril injection may still control the status. Before adding Arotril to an existing anticonvulsant regimen, it should be considered that the use of multiple anticonvulsants may result in an increase of undesired effects.

Arotril must not be used in patients in a coma, or in patients known to be abusing pharmaceuticals, drugs or alcohol.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Arotril.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Patients with a history of depression and/or suicide attempts should be kept under close supervision.

Arotril should be used with caution in patients with chronic pulmonary insufficiency, or with impairment of renal or hepatic function, and in the elderly or the debilitated. In these cases dosage should generally be reduced.

As with all other antiepileptic drugs, treatment with Arotril even if of short duration, must not be abruptly interrupted, but must be withdrawn by gradually reducing the dose in view of the risk of precipitating status epilepticus. In such cases a combination with other antiepileptics is indicated. This precaution must also be taken when withdrawing another drug while the patient is still receiving Arotril therapy.

Prolonged use of benzodiazepines may result in dependence development with withdrawal symptoms on cessation of use.

Arotril may be used only with particular caution in patients with spinal or cerebellar ataxia, in the event of acute intoxication with alcohol or drugs and in patients with severe liver damage (e.g. cirrhosis of the liver).

The concomitant use of Arotril with alcohol or/and CNS depressants should be avoided.).

Arotril should be used with extreme caution in patients with a history of alcohol or drug abuse.

Arotril is considered to be probably nonporphyrinogenic, although there is some conflicting evidence. Therefore in patients with porphyria, Arotril should be used with care.

As a general rule, epileptic patients are not allowed to drive. Even when adequately controlled on Arotril, it should be remembered that any increase in dosage or alteration in timings of dosage may modify patients' reactions, depending on individual susceptibility.

In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Dependence

Use of benzodiazepines may lead to the development of physical and psychological dependence upon these products. In particular long-term or high-dose treatment, may lead to reversible disorders such as dysarthria, reduced coordination of movements and gait disorder (ataxia), nystagmus and vision (diplopia). Furthermore, the risk of anterograde amnesia, which may occur using benzodiazepines at therapeutic dosages, increases at higher dosages. Amnestic effects may be associated with inappropriate behavior. With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.

The risk of dependence increases with dose and duration of treatment and is particularly pronounced in predisposed patients with a history of alcoholism and/or drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. During long-term treatment, withdrawal symptoms may develop after a lengthy period of use, especially with high doses or if the daily dose is reduced rapidly or abruptly discontinued. The symptoms include tremor, sweating, agitation, sleep disturbances and anxiety, headaches, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability and epileptic seizures which may be associated with the underlying disease. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact or hallucinations. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, abrupt withdrawal of the drug should therefore be avoided and treatment - even if only of short duration - should be terminated by gradually reducing the daily dose. The risk of withdrawal symptoms is increased when benzodiazepines are used together with day-time sedatives (crossed tolerance).

Due to the oily nature of this medicine caution should be used when administering this medicine via a nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes.

Excipient warnings:

This product contains the following excipients:

Ethanol: This medicinal product contains 2.6% (v/v) ethanol (alcohol), i.e. up to 100mg per 5ml dose.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women and high-risk groups such as patients with liver disease, or epilepsy.

As this product is indicated for epilepsy, special consideration should be given to the amount of ethanol administered in the dose.

As a general rule, epileptic patients are not allowed to drive. Even when adequately controlled on Arotril, it should be remembered that any increase in dosage or alteration in timings of dosage may modify patients' reactions, depending on individual susceptibility. Even if taken as directed, Arotril can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is impaired. This effect is aggravated by consumption of alcohol. Driving, operating machinery and other hazardous activities should therefore be avoided altogether or at least during the first few days of treatment. The decision on this question rests with the patient's physician and should be based on the patient's response to treatment and the dosage involved.

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:

- Arotril Rosemont Oral Solution is likely to affect your ability to drive and use machines

- 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 and

- 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.

Immune System Disorders

Allergic reactions and very few cases of anaphylaxis and angioedema have been reported to occur with benzodiazepines.

Endocrine Disorders

Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported.

Psychiatric Disorders

Impaired concentration, restlessness, confusional state and disorientation have been observed. Depression may occur in patients treated with Arotril, but it may be also associated with the underlying disease. The following paradoxical reactions have been observed: excitability, irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares, vivid dreams and psychotic disorders and activation of new types of seizures may be precipitated. If these occur, the benefit of continuing the drug should be weighed against the adverse effect. The addition to the regimen of another suitable drug may be necessary or, in some cases, it may be advisable to discontinue Arotril therapy. In rare cases loss of libido may occur. Arotril generally has a beneficial effect on behaviour disturbances in epileptic patients.

Nervous System Disorders

Somnolence, slowed reaction, muscular hypotonia, dizziness, ataxia, light-headedness, co-ordination disturbances, fatigue and muscle weakness. These undesirable effects occur relatively frequently and are usually transient and generally disappear spontaneously in the course of the treatment or on reductions of the dosage. They can be partially prevented by increasing the dose slowly at the start of treatment.

Headache was observed in rare cases. Causing of generalized fits was observed very rarely.

Particularly in long-term or high-dose treatment, reversible disorders such as a slowing or slurring of speech (dysarthria), reduced co-ordination of movements and gait (ataxia) and nystagmus may occur. Anterograde amnesia may occur using benzodiazepines at therapeutic dosages, the risks increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior. With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.

Eye Disorders

Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur.

Common: nystagmus

Cardiac Disorders

Cardiac failure including cardiac arrest has been reported.

Respiratory, Thoracic and Mediastinal System Disorders

Rarely respiratory depression may occur with intravenous Arotril, particularly if pre-existing airways obstruction or brain damage or if other depressant drugs have been administered. As a rule, this effect can be avoided by careful adjustment of the dose in individual requirements.

In infants and small children, and particularly those with a degree of mental impairment, Arotril may give rise to salivary or bronchial hypersecretion with drooling. Supervision of the airway may be required.

Gastrointestinal Disorders

The following effects have been reported in rare cases: nausea, gastrointestinal and epigastric symptoms.

Skin and Subcutaneous Tissue Disorders

The following effects may occur in rare cases: urticaria, pruritus, rash, transient hair loss, pigmentation changes and angioedema.

Musculoskeletal and Connecting Tissue Disorders

Muscle weakness, this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of the treatment.

Renal and Urinary Disorders

In rare cases urinary incontinence may occur.

Reproductive System and Breast Disorders

In rare cases erectile dysfunction, decrease in sexual drive (loss of libido) and impotence may occur.

General Disorders and Administration Site Conditions

Fatigue (tiredness, lassitude), this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of treatment. Paradoxical reactions including irritability have been observed (see also psychiatric disorders).

Injury, Poisoning and Procedural Complications

There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Investigations

In rare case decreased platelet count may occur. Isolated cases of blood dyscrasias and abnormal liver function tests have been reported.

Dependence and withdrawal

Although Arotril has been given uneventfully to patients with porphyria, rarely it may induce convulsions in these patients.

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

As with other benzodiazepine drugs, overdosage should not present undue problems of management or threat to life. Patients have recovered from overdoses in excess of 60mg without special treatment. Severe somnolence with muscle hypotonia will be present.

Symptoms:

The symptoms of overdosage or intoxication vary greatly from person to person depending on age, bodyweight and individual response. Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Arotril is seldom life-threatening if the drug is taken alone, but may lead to coma, areflexia, apnoea, hypotension and cardiorespiratory depression. Coma, if it occurs, usually lasts only a few hours but in elderly people it may be more protracted and cyclical. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease.

Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.

Management:

1. Maintain a clear airway and adequate ventilation if indicated.

2. Supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.

3. Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients.

4. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure.

5. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.

6. Flumazenil, a benzodiazepine antagonist is available but should rarely be required. If CNS depression is severe consider the use of flumazenil. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after the effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this drug. Flumazenil is NOT TO BE USED IN MIXED OVERDOSE OR AS A 'DIAGNOSTIC TEST'.

7. The benefit of gastric decontamination is uncertain. Consider activated charcoal (50g for an adult, 10-15g for a child) in adults or children who have taken more than 0.4mg/kg within 1 hour, provided they are not too drowsy.

Warning

The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.

If excitation occurs, barbiturates should not be used.

Pharmacotherapeutic group: Antiepileptics, Benzodiazepine derivatives

ATC Code: N03 AE01

Arotril exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. Animal data and electroencephalographic investigations in man have shown that Arotril rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalised spike wave, spikes with temporal or other locations as well as irregular spikes and waves.

Generalised EEG abnormalities are more readily suppressed by Arotril than are focal EEG abnormalities such as focal spikes. Arotril has beneficial effects in generalised and focal epilepsies.

Absorption

Arotril is quickly and completely absorbed after oral administration. Peak plasma concentrations are reached in most cases within 1 - 4 hours after an oral dose. Bioavailability is 90% after oral administration.

Routine monitoring of plasma concentrations of Arotril is of unproven value since this does not appear to correlate well with either therapeutic response or side-effects.

Distribution

The mean volume of distribution of Arotril is estimated at about 3 l/kg. Arotril must be assumed to cross the placental barrier and has been detected in maternal milk.

Metabolism

The biotransformation of Arotril involves oxidative hydroxylation and reduction of the 7-nitro group by the liver with formation of 7-amino or 7-acetylamino compounds, with trace amounts of 3-hydroxy derivatives of all three compounds, and their glucuronide and sulphate conjugates. The nitro compounds are pharmacologically active, whereas the amino compounds are not.

Elimination

The elimination half-life is between 20 and 60 hours (mean 30 hours).

Within 4 - 10 days 50 - 70% of the total radioactivity of a radiolabeled oral dose of Arotril is excreted in the urine and 10 - 30% in the faeces, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% appears as unchanged Arotril in the urine.

Pharmacokinetics in special clinical situations

Based on kinetic criteria no dose adjustment is required in patients with renal failure.

Carcinogenicity

No 2-year carcinogenicity studies have been conducted with Arotril. However, in an 18-month chronic study in rats no treatment-related histopathological changes were seen up to the highest tested dose of 300 mg/kg/day.

Mutagenicity

Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for Arotril.

Impairment of Fertility

Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100 mg/kg/day.

Teratogenicity

No adverse maternal or embryo-fetal effects were observed in either mice or rats following administration of oral Arotril during organogenesis, at doses of up to 20 or 40 mg/kg/day, respectively.

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

This product should not be mixed with water.

This product is incompatible with polystyrene and PVC.

Instruction for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes:

Arotril Oral Solution is suitable for use with the following types of NG and PEG tubes:

This product is not compatible with PVC or polystyrene and therefore should not be used with NG or PEG tubes made from these materials.

Care should be taken during administration due to the oily nature of the product. It is recommended to administer the dose prior to delivering feed through the NG or PEG tube and to follow the instruction below.

Ensure that the enteral feeding tube is free from obstruction before administration.

1) Flush the enteral tube with water, a minimum flush volume of 10mL is required.

2) Administer the required dose of Arotril Oral Solution with a suitable measuring device.

3) Flush the enteral tube again by either of the methods below:

i) Flush the enteral tube 3 consecutive times, using a minimum volume of 5mL of water each time.

ii) Flush the enteral tube using a minimum volume of 5mL of water and then immediately deliver a minimum of 10ml of feed.

Healthcare professionals should be aware that if the instructions above cannot be followed (e.g. longer or wider tubes are used or in a specific clinical situations) there is a risk of under dosing (up to 15%) as the oily medicine may adsorb to the wall of the feeding tube. Extra flushing with water or feed may combat this. In these situations the patient should be monitored closely.

Any unused product or waste material should be disposed of in accordance with local requirements.