Paxium

For short term use (2 - 4 weeks only)

- Symptomatic relief of anxiety that is severe, disabling or subjecting the individual to unacceptable distress occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness

- Muscle spasm of varied aetiology

- Symptomatic relief of acute alcohol withdrawal

Paxium is not recommended; for long term use (i.e. longer than 4 weeks), mild anxiety or for use in children.

Posology:

Anxiety

Adults

Starting dose 5mg daily: usual dose up to 30mg in divided doses. For severe symptoms 20mg, 2-4 times a day. Maximum dose up to 100mg daily, in divided doses, adjusted on an individual basis.

Treatment should not continue as full dose for more than 4 weeks including 2 week tapering off process.

Insomnia associated with anxiety

Adults

10 - 30 mg at bedtime

Treatment would normally vary from a few days to two weeks with a maximum of four weeks, including two weeks tapering off.

Muscle Spasm

Adults

10mg to 30mg daily in divided doses

Symptomatic relief of acute alcohol withdrawal

Adults

25 to 100mg, repeated if necessary in 2 to 4hrs

Special populations

Elderly or debilitated patients, patients with organic brain damage, respiratory impairmentshould normally not exceed half of the doses normally recommended.

Patients with impaired hepatic or renal function

Dosage should not exceed half the adult dose and steps should be taken to ensure that there is no accumulation of plasma Paxium

Contraindicated in severe hepatic insufficiency

Paediatric patients

Paxium Capsules are not for paediatric use.

Treatment should be given at the lowest effective dose. The dosage and duration of treatment should be determined on an individual basis dependent by the patient's response and severity of the disorder. Given that Paxium is a long-acting benzodiazepine, the patient should be monitored regularly at the start of the treatment to decrease, if necessary, the dose or frequency of administration to prevent overdose due to accumulation.

Treatment should be as short as possible duration (not exceeding 4 weeks) and given under close medical supervision.).

When treatment is started the patient should be informed that the treatment will be of limited duration, the dosage will be progressively decreased and that there is a possibility of rebound phenomena. Treatment should be tapered off gradually. Patients who have taken benzodiazepines for a prolonged time may require a longer period of dosage reduction and specialist help may be appropriate.

Method of administration:

Paxium capsules are for oral administration and must be taken with water and not be chewed.

-

- Severe pulmonary insufficiency, respiratory depression, sleep apnoea syndrome (risk of further respiratory depression)

- Phobic and obsessional states (inadequate evidence of safety and efficacy).

- Chronic psychosis

- Severe hepatic insufficiency (may precipitate encephalopathy)

- Planning a pregnancy

- )

- Myasthenia gravis

Paxium should not be used alone in depression or anxiety with depression (may precipitate suicidal tendencies)

Tolerance

Loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.

Dependence

The dependent potential of the benzodiazepines is low, particularly when limited to short-term use. The risk of dependence (physical or psychological) increases when high doses are used, especially when given over long periods and is greater in patients with a history of alcoholism or drug abuse, or in patients with a marked personality disorder. Therefore, regular monitoring of such patients is essential. routine repeat prescriptions should be avoided treatment should be withdrawn gradually.

Withdrawal effects

The duration of treatment should be as short as possible. If physical dependence has developed, abrupt termination of treatment results in withdrawal symptoms. These include headache, muscle pain, extreme anxiety, tension, restlessness, nervousness, sweating, confusion and irritability; sleep disturbance, diarrhoea, depression, rebound insomnia and mood changes. In severe cases the following may occur: a feeling of unreality or of being separated from the body, depersonalisation, hyperacusis, confusional states, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, psychotic manifestations including hallucinations or epileptic seizures. Withdrawal symptoms will be worse in patients who have been dependent on alcohol or other narcotic drugs in the past, but can occur following abrupt cessation of treatment in patients receiving normal therapeutic doses for a short period of time.

Duration of treatment

The duration of treatment should be as short as possible depending on the indication, but should not exceed 4 weeks, including tapering-off process. Routine repeat prescriptions should be avoided.

It may be useful to inform the patient when treatment commences that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover, it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

When benzodiazepines with a long duration of action are being used, e.g. Paxium, it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Rebound insomnia and anxiety

This is a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. Symptoms including mood changes, insomnia, restlessness and anxiety may occur on withdrawal of treatment. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation, the dose should be decreased gradually.

Amnesia

Benzodiazepines may induce anterograde amnesia, occurring most often several hours after ingestion.).Psychiatric and 'paradoxical' reactions

Reactions such as restlessness, agitation, irritability, aggressiveness, excitement, confusion, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects can occur when using benzodiazepines. These reactions are more likely in children and the elderly, and extreme caution should be used in prescribing benzodiazepines to patients with personality disorders. Should they occur, treatment should be discontinued.

Specific patient groups

Elderly patients should be given a reduced dose. A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are contraindicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy and reduced doses should be given to patients with renal or hepatic disease.Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Paxium should not be used alone to treat depression or anxiety associated with depression as depression with suicidal tendencies may be precipitated in such patients. Extreme caution should be used in prescribing benzodiazepines to patients with personality disorders. Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (risk of abuse/dependence).

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

Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.

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

Patients should be advised that sedation, amnesia, impaired concentration, dizziness, blurred vision and impaired muscular function may occur and that, if affected, they should not drive or use machines, or take part in other activities where this would put themselves or others at risk. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. Patients should further be advised that alcohol may intensify any impairment, and should therefore be avoided during treatment. Other concurrent medication may increase effects.

Common adverse effects include light-headedness and drowsiness, sedation, dizziness, unsteadiness and ataxia; these are usually dose related but, even after a single dose, may persist into the following day. However, these phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. The elderly are particularly sensitive to the effects of central depressant drugs and may experience confusion, especially if organic brain changes are present; the dosage of Paxium should not exceed one-half that recommended for other adults.

Evaluation of undesirable effects is based on the following frequency information: 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 (frequency cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare: Bone marrow depression (e.g. thrombocytopenia, leukopenia, agranulocytosis, pancytopenia)

Not known: Blood dyscrasias.

Immune system disorders:

Very rare: Anaphylactic reaction, angioedema

Frequency not known: Hypersensitivity

Psychiatric disorders:

Frequency not known: Amnesia, hallucinations, dependence, depression, depressed level of consciousness, restlessness, agitation, irritability, aggression, delusion, nightmares, psychotic disorder, abnormal behaviour, emotional disturbances, paradoxical drug reaction (e.g. anxiety, sleep disorders, insomnia, suicide attempt, suicidal ideation) aggressive outbursts andinappropriate behaviour.

.

Rare: numbed emotions.

Nervous system disorders:

Common: Sedation, dizziness, confusional states, unsteadiness, somnolence, ataxia, balance disorder, Rare: Headache, vertigo, reduced alertness

Frequency not known: Dysarthria, gait disturbance, extrapyramidal disorder (e.g. tremor, dyskinesia)

Eye disorders:

Rare: Visual impairment including diplopia and blurred vision.

Vascular disorders:

Rare: Hypotension

Respiratory, thoracic and mediastinal disorders:

Frequency not known: Respiratory depression

Gastrointestinal disorders:

Rare: Gastrointestinal upsets

Frequency not known: Saliva altered.

Hepatobiliary disorders:

Frequency not known: Jaundice, blood bilirubin increased, transaminases increased, blood alkaline phosphatase increased

Skin and subcutaneous tissue disorders:

Rare: Skin reaction (e.g. rash)

Musculoskeletal and connective tissue disorders:

Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly Frequency not known: Muscle weakness.

Renal and urinary disorders:

Rare: Urinary retention, incontinence

Reproductive system and breast disorders:

Rare: Libido disorders, erectile dysfunction, menstrual disorder

General disorders and administration site conditions:

Common: Fatigue

Amnesia

Anterograde amnesia may occur at the therapeutic doses, with increasing risk at higher doses. This may be associated with inappropriate behaviour.

Depression

Pre-existing depression may be unmasked by benzodiazepines.

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 benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and the elderly.

Dependence

Use (even therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in the withdrawal or rebound phenomena. Psychological dependence may occur. Abuse of benzodiazepines 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

When taken alone in overdosage, Paxium presents few problems in management. Benzodiazepines potentiate the effects of other CNS depressants including alcohol. When taken with centrally-acting drugs, especially alcohol, effects of overdose are likely to be more severe and in absence of supportive measures, may prove fatal.

Symptoms

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, dysarthria, hypotonia, nystagmus, hypotension, respiratory depression, rarely coma and very rarely deathComa usually lasts a few hours but in the elderly may be more contracted and cyclical. Respiratory depression is more serious in those with severe obstructive airways disease. If excitation occurs, barbiturates should not be used. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.

Management

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Treatment is symptomatic.

- Maintain clear airways and adequate ventilation, if indicated

- The value of gastric decontaminants is uncertain. Consider activated charcoal (50g for an adult: 1g/kg for a child) within 1 hour of ingestion if more than 1mg/kg has been taken provided the patient is not too drowsy.

- Gastric lavage - unnecessary if only benzodiazepine taken

- Supportive measures as indicated by the patients clinical condition

- The value of dialysis has not been determined. Flumazenil, a benzodiazepine antagonist, is available but should rarely be required. It may be required in children who are naïve to benzodiazepines or patients with COPD as alternative to ventilation. Flumazenil may be used as an antidote; however it has a short half-life (about 1 hour) and in this situation an infusion may therefore be required. Flumazenil should not normally be used in patients with mixed overdoses, a history of seizures, head injury, chronic benzodiazepine use, co-ingestion of a benzodiazepine and tricyclic antidepressant or other proconvulsantor as a “diagnostic test”.

If excitation occurs, barbiturates should not be used.

Pharmacotherapeutic group: Psycholeptics, anxiolytics, benzodiazepine derivatives.

ATC code: N05BA02

Paxium has anxiolytic and central muscle relaxant properties. It has little autonomic activity.

Paxium acts as depressant of the central nervous system producing all levels of CNS depression, from mild sedation to hypnosis, to coma depending on the dose. The precise sites and mechanisms of action have not been fully established but various mechanisms have been proposed. It is believed that Paxium enhances or facilitates the inhibitory neurotransmitter action of gama-aminobutyric acid (GABA) which mediates both pre- and post synaptic inhibition in all regions of the CNS following interaction between Paxium and a specific neuronal membrane receptor. Anti-anxiety action of Paxium is believed to result from stimulation of GABA receptors in the ascending reticular activating system, since GABA in inhibitory receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brainstem reticular formation.

The exact mechanism of action of Paxium is not fully established. Skeletal muscle relaxation primarily occurs by inhibiting spinal polysynaptic afferent pathways but it may also inhibit monosynaptic afferent pathways.

.

Absorption:

Paxium is well absorbed with peak blood levels being achieved one or two hours after administration. Rate of absorption is age-related and tends to be delayed in the elderly. After absorption it is highly bound to plasma proteins. The drug has a half-life of 6-30 hours.

Steady state levels are usually reached within 3 days.

Distribution:

Paxium is extensively metabolised in the liver by hepatic microsomal enzymes and exhibits capacity limited, protein binding sensitive, hepatic clearance.

Paxium is metabolised to desmethyl-Paxium. Pharmacologically active metabolites of Paxium include desmethylPaxium, demoxepam, desmethyldiazepam and oxazepam.

Demoxepam and desmethyldiazepam are also found in the plasma of patients on continuous treatment. The active metabolite desmethylPaxium has an accumulation half-life of 10-18 hours and Demoxepam has an accumulation half-life of approximately 21-78 hours.

Steady state levels of these active metabolites are reached after 10-15 days with metabolite concentrations which are similar to those of the parent drug.

Paxium is distributed in the CSF corresponding to the free fraction of Paxium. It enters the brain following a rapid distribution phase in grey matter with its high blood flow, followed by a longer accumulation phase of Paxium and its metabolites in the white matter. The accumulation is more marked following repeated dosage. Paxium has a high affinity for lipids.

Elimination:

Paxium is excreted mainly in the urine mainly in the form of its metabolites; only a small percent of this is in free form most being excreted as conjugates with glucuronide or sulphate. There is no biliary excretion.

Pharmacokinetic / pharmacodynamic relationship:

No clear correlation has been demonstrated between the blood levels of Paxium and its clinical effects.

Reproductive effects:

(Registry of Toxic Effects of Chemical Substances 1985-86)

There are no known incompatibilities.

None