Orazep

FOR SHORT TERM (2-4 weeks only) USE (adults 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 psychometric, organic or psychotic illness.

AS PREMEDICATION (adults and children 5 years and above)

Before operative dentistry and general surgery

NOT FOR USE

- Long term (i.e. longer than 4 weeks)

- For mild/moderate anxiety

- For insomnia or anxiety in children

Route of administration: oral

Treatment to be given:

- Under close medical supervision

- At the lowest effective dose

- For the shortest possible duration (not exceeding 4 weeks)

Doses should be individualised

Extension of use should not take place without further clinical evaluation

When treatment is started the patient should be informed that

- treatment will be of limited duration

- the dosage will be progressively decreased

- there is a possibility of rebound phenomena

Dosage:

Adults:

Anxiety: 1-4mg daily in divided doses.

Insomnia: 1-2mg before retiring

Premedication before operative dentistry or general surgery:

2-3mg the night before operation 2-4mg one to two hours before the procedure

Elderly:

The elderly may respond to lower doses (half normal adult dose or less)

Children (aged 5-13 years):

Premedication: 0.5-2.5mg at 0.05mg/kg to the nearest 0.5mg according to weight, not less than one hour before operation.

Patients with Renal or Hepatic impairment:

Lower doses may be sufficient in these patients. Use in patients with severe hepatic insufficiency is contraindicated..

- Hypersensitivity to benzodiazepines or to any of the other ingredients

- Acute pulmonary insufficiency: respiratory depression; sleep apnoea (risk of further respiratory depression)

- Obsessional states (inadequate evidence of safety and efficacy)

- Severe hepatic insufficiency (may precipitate encephalopathy)

- Planning a pregnancy

- Pregnancy

- Myasthenia gravis;

Benzodiazepines should not be used alone in depression or anxiety with depression (may precipitate suicide)

Patients should be advised that since their tolerance for alcohol and other CNS depressants will be diminished in the presence of Orazep, these substances should either be avoided or taken in reduced dosage.

Due to the potential adverse reactions including ataxia, muscle weakness, dizziness, drowsiness and fatigue , Benzodiazepines may be associated with an increased risk of falling especially in elderly patients. As a result, caution should be exercised particularly when getting up at night. The elderly should receive a reduced dose.

Orazep is not intended for the primary treatment of psychotic illness or depressive disorders, and should not be used alone to treat depressed patients. The use of benzodiazepines may have a disinhibiting effect and may release suicidal tendencies in depressed patients. Therefore, large quantities of Orazep should not be prescribed to these patients.

Pre-existing depression may emerge during benzodiazepine use.

The use of benzodiazepines may lead to physical and psychological dependence. The risk of dependence on Orazep is low when used at the recommended dose and duration, but increases with higher doses and longer-term use. The risk of dependence is further increased in patients with a history of alcoholism or drug abuse, or in patients with significant personality disorders. Therefore, use in individuals with a history of alcoholism or drug abuse should be avoided.

Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly. (see 4.8 Undesirable effects). Therefore, the drug should always be discontinued gradually.

It may be useful to inform the patient that treatment will be of limited duration and that it will be discontinued gradually. The patient should also be made aware of the possibility of "rebound" phenomena to minimise anxiety should they occur.

Abuse of benzodiazepines has been reported.

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.

Anxiety or insomnia may be a symptom of several other disorders. The possibility should be considered that the complaint may be related to an underlying physical or psychiatric disorder for which there is more specific treatment.

Caution should be used in the treatment of patients with acute narrow-angle glaucoma.

Patients with impaired renal or hepatic function should be monitored frequently and have their dosage adjusted carefully according to patient response. Lower doses may be sufficient in these patients. The same precautions apply to elderly or debilitated patients and patients with chronic respiratory insufficiency.

As with all CNS-depressants, the use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency. Therefore, use in these patients is contraindicated.

Some patients taking benzodiazepines have developed a blood dyscrasia, and some have had elevations in liver enzymes. Periodic haematology and liver-function assessments are recommended where repeated courses of treatment are considered clinically necessary.

Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines. This effect may be advantageous when Orazep is used as a premedicant. However, if Orazep is used for insomnia due to anxiety, patients should ensure that they will be able to have a period of uninterrupted sleep which is sufficient to allow dissipation of drug effect (e.g., 7-8 hours).

Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued (see Undesirable effects).

Although hypotension has occurred only rarely, benzodiazepines should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. This is particularly important in elderly patients.

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

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 to 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. Concurrent medication may increase these effects

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:

It may be useful to inform the patient that treatment will be of limited duration and that it will be discontinued gradually. The patient should also be made aware of the possibility of "rebound" phenomena to minimise anxiety should they occur.

Abuse of benzodiazepines has been reported.

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.

Anxiety or insomnia may be a symptom of several other disorders. The possibility should be considered that the complaint may be related to an underlying physical or psychiatric disorder for which there is more specific treatment.

Caution should be used in the treatment of patients with acute narrow-angle glaucoma.

Patients with impaired renal or hepatic function should be monitored frequently and have their dosage adjusted carefully according to patient response. Lower doses may be sufficient in these patients. The same precautions apply to elderly or debilitated patients and patients with chronic respiratory insufficiency.

As with all CNS-depressants, the use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency. Therefore, use in these patients is contraindicated.

Some patients taking benzodiazepines have developed a blood dyscrasia, and some have had elevations in liver enzymes. Periodic haematology and liver-function assessments are recommended where repeated courses of treatment are considered clinically necessary.

Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines. This effect may be advantageous when Orazep is used as a premedicant. However, if Orazep is used for insomnia due to anxiety, patients should ensure that they will be able to have a period of uninterrupted sleep which is sufficient to allow dissipation of drug effect (e.g., 7-8 hours).

Paradoxical reactions have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued (see Undesirable effects).

Although hypotension has occurred only rarely, benzodiazepines should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. This is particularly important in elderly patients.

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

Not recommended

Alcohol

Orazep should not be used together with alcohol (enhanced sedative effects; impaired ability to drive/operate machinery)

Sodium oxybate

Avoid concomitant use (enhanced effects of sodium oxybate)

HIV-protease inhibitors

Avoid concomitant use (increased risk of prolonged sedation - see below for zidovudine

Take into account

Centrally acting drugs

Enhancement of the central depressive effect may occur if Orazep is combined with drugs such as neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.

Anti-epileptic drugs

Pharmacokinetic studies on potential interactions between benzodiazepines and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change have been reported.

Phenobarbital taken concomitantly may result in an additive CNS effect. Special care should be taken in adjusting the dose in the initial stages of treatment.

Side effects may be more evident with hydantoins or barbiturates

Valproate may inhibit the glucuronidation of Orazep (increased serum levels: increased risk of drowsiness)

Narcotic analgesics

Enhancement of the euphoria may lead to increased psychological dependence

Clozapine

Reports of marked sedation, excessive salivation, hypotension, ataxia, delirium and respiratory arrest when given concurrently with Orazep.

Muscle Relaxants

When taken with muscle relaxants, the overall muscle-relaxing effect may be increased (accumulative) therefore caution is advised, especially in elderly patients and at higher doses

Other drugs enhancing the sedative effect of diazepam

Cisapride, lofexidine, nabilone, disulfiram and the muscle relaxants - baclofen and tizanidine

Compounds that affect hepatic enzymes (particularly cyctochrome P450)

- Inhibitors (e.g. cimetidine, isoniazid; erythyromycin; omeprazole; esomeprazole) reduce clearance and may potentiate the action of benzodiazepines. Itraconazole, ketoconazole and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiazepines. The effects of benzodiazepines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.

- Inducers (e.g. rifampicin) may increase clearance of benzodiazepines

Antihypertensives, vasodilators and diuretics: Enhanced hypotensive effect with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics

Enhanced sedative effect with alpha-blockers or moxonidine.

Dopaminergics

Possible antagonism of the effect of levodopa

Antacids

Concurrent use may delay absorption of Orazep

Zidovudine

Increased zidovudine clearance by Orazep

Oestrogen-containing contraceptives

Possible inhibition of hepatic metabolism of Orazep

Theophylline/aminophylline

Increases metabolism of Orazep which possibly reduces the effect

Caffeine

Concurrent use may result in reduced sedative and anxiolytic effects of Orazep.

Grapefruit juice

Inhibition of CYP3A4 may increase the plasma concentration of Orazep (possible increased sedation and amnesia). This interaction may be of little significance in healthy individuals, but it is not clear if other factors such as old age or liver cirrhosis increase the risk of adverse events with concurrent use.

Pregnancy: Benzodiazepines should not be used during pregnancy, especially during the first and last trimesters. Benzodiazepines may cause foetal damage when administered to pregnant women.

If the drug is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the drug if she intends to become, or suspects that she is, pregnant.

There is a possibility that infants born to mothers who take benzodiazepines chronically during the later stages of pregnancy may develop physical dependence. Infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to have withdrawal symptoms during the postnatal period. Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnoea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.

Lactation: Orazep is excreted in small amounts in breast milk. Mothers who are breast-feeding should not take benzodiazepines. Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines.

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 to 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. Concurrent medication may increase these effects

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:

Adverse reactions, when they occur, are usually observed at the beginning of therapy and generally decrease in severity or disappear with continued use or upon decreasing the dose.

Most frequently reported adverse reactions associated with benzodiazepines include daytime drowsiness, dizziness, muscle weakness, and ataxia.

Adverse reactions are listed by frequency:

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)

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, leucopenia, agranulocytosis, pancytopenia

Immune system disorders

Very rare: Hypersensitivity including anaphylaxis/anaphylactoid reactions

Endocrine disorders

Very rare: Inappropriate antidiuretic hormone secretion, hyponatraemia

Psychiatric disorders

Rare: Confusion, depression and unmasking of depression, numbed emotions, disinhibition, euphoria, appetite changes, sleep disturbance, change in libido, decreased orgasm.

Unknown: Dependence, Suicidal ideation/attempt

Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, insomnia, nightmares, hallucinations, psychoses, sexual arousal, and inappropriate behaviour have been occasionally reported during use.

Nervous system disorders

Very common: Daytime drowsiness, sedation

Common: Dizziness, ataxia

Rare: headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment.

Very rare: Tremor, extrapyramidal reactions, Coma (see

Eye disorders

Rare: Visual disturbances (diplopia, blurred vision)

Vascular disorders

Rare: Hypotension (see 4.4 Special warnings and precautions)

Respiratory thoracic and mediastinal disorders:

Rare: Apnoea, worsening of sleep apnoea, worsening of obstructive pulmonary disease. Respiratory depression (see 4.9 Overdose).

Gastrointestinal disorders

Rare: Nausea, constipation, salivation changes

Hepatobiliary disorders

Rare: Abnormal liver function test values (increases in bilirubin, transaminases, alkaline phosphatise), jaundice

Skin and subcutaneous tissue disorders

Rare: Rash, allergic dermatitis

Musculoskeletal disorders

Common: Muscle weakness

Reproductive system and breast disorders

Rare: Impotence

General disorders

Common: Asthenia, fatigue

Very rare: Hypothermia

Drug withdrawal symptoms (see 4.4 Special warnings and precautions)

Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, and the occurrence of “rebound” phenomena whereby the symptoms that led to treatment with benzodiazepines recur in an enhanced form. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

In severe cases the following symptoms may occur: derealisation; depersonalisation; hyperacusis; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movements; hyperreflexia, tremor, nausea, vomiting; diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium; catatonia; hyperthermia, convulsions. Convulsions may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.

Injury, poisoning and procedural complications

Not known: Fall

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.

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

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, and especially when other CNS-depressant drugs or alcohol are ingested, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, coma, and very rarely, death.

If ingestion was recent, induced vomiting and/or gastric lavage should be undertaken followed by general supportive care, monitoring of vital signs and close observation of the patient. If there is no advantage in emptying the stomach, activated charcoal may be effective in reducing absorption. Hypotension, though unlikely, may be controlled with noradrenaline. Orazep is poorly dialysable.

The benzodiazepine antagonist, flumazenil may be useful in hospitalised patients for the management of benzodiazepine overdose. Flumazenil product information should be consulted prior to use.

Orazep is a benzodiazepine with anxiolytic, sedative and hypnotic properties.

Orazep is almost completely absorbed from the gastrointestinal tract and peak serum levels are reached in 2 hours. It is metabolised by a simple one-step process to a pharmacologically inert glucuronide. There are no major active metabolites. The elimination half-life is about 12 hours and there is minimal risk of excessive accumulation.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

Oesophageal dilation occurred in rats treated with Orazep for more than one year at 6mg/kg/day.

None known.

None stated.