Diazepam Tablets BP 5mg

1. Name Of The Medicinal Product

DIAZEPAM TABLETS BP 5mg

2. Qualitative And Quantitative Composition

Each tablet contains 5mg Diazepam PhEur.

3. Pharmaceutical Form

Yellow uncoated tablets.

Yellow, circular, flat, bevelled-edge uncoated tablets, impressed “C” and the identifying letters “DB” either side of a central division line on one face.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults

1) The short-term relief (2-4 weeks) only, of anxiety which 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.

2) Cerebral palsy.

3) Muscle spasm.

4) As an adjunct to certain types of epilepsy (eg myoclonus).

5) Symptomatic treatment of acute alcohol withdrawal.

6) As oral premedication for the nervous dental patient.

7) For premedication before surgery

Children

1) Control of tension and irritability in cerebral spasticity in selected cases

2) As an adjunct to the control of muscle spasm in tetanus

3) Oral premedication (see section 4.4)

4.2 Posology And Method Of Administration

Posology

As an anxiolytic, the lowest effective dose should be employed; dosage regimes should not exceed beyond 4 weeks and treatment should be gradually withdrawn. Patients who have received benzodiazepines for a long time may require an extended withdrawal period. Long-term chronic use is not recommended.

Adults:

Anxiety states, obsessive-compulsive neuroses, and other psychiatric disorders: 5-30mg daily in divided doses.

Insomnia associated with anxiety: 5-15mg before retiring.

Cerebral palsy: 5-60mg daily in divided doses.

Upper motor neuronic spasticity: 5-60mg daily in divided doses.

Muscle spasm of varied aetiology, fibrositis, cervical spondylosis: 5-15mg daily in divided doses.

Adjunct to the management of some types of epilepsy: 2-60 mg daily in divided doses.

Alcohol withdrawal: 5-20mg, repeated if necessary in 2 to 4 hours.

Oral premedication in dental patients: 5mg the night before, 5mg on waking and 5mg two hours before the appointment.

Oral Premedication before surgery: 5mg-20mg.

Children:

Alternative presentations of diazepam are recommended for paediatric usage in order to obtain suitable doses of less than 5mg.

Spastic children with minimal brain damage: 5-40mg daily in divided doses.

Oral Premedication before surgery (see section 4.4): 2mg-10mg

Elderly and debilitated patients:

Doses should be half the above recommended doses.

Renal and hepatic impairment (see section 4.4):

The use of diazepam in hepatic impairment may precipitate coma, therefore the dose should be reduced or an alternative drug considered. In severe renal impairment the dose should be reduced.

Method of Administration

For oral administration.

4.3 Contraindications

• Known hypersensitivity to benzodiazepines and any other ingredients in diazepam tablets

• Phobic or obsessional states; chronic psychosis (paradoxical reactions may occur)

• Acute pulmonary insufficiency; respiratory depression (ventilatory failure may be exacerbated)

• Myasthenia gravis (condition may be exacerbated)

• Sleep apnoea (condition may be exacerbated)

• Severe hepatic insufficiency (elimination half-life of diazepam may be prolonged)

• Acute porphyria

• Diazepam should not be used as monotherapy in patients with depression or those with anxiety and depression as suicide may be precipitated in such patients.

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

4.4 Special Warnings And Precautions For Use

• 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. Treatment should not continue beyond 4 weeks without re-evaluation of the patient's condition. Where long-term therapy is essential, it is recommended that the patient's requirements be reviewed on a regular basis.

It may be useful to inform the patient when treatment is started 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 minimizing anxiety over such symptoms should they occur while diazepam is being discontinued.

• Dependence and Withdrawal - Withdrawal symptoms occur with benzodiazepines following normal therapeutic doses given for short periods of time.

Use of diazepam may lead to the development of physical and psychic dependence. The risk of dependence increases with the dose and duration of treatment, and in patients with a history of alcoholism and drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (see Section 4.8 Undesirable Effects).

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with diazepam may recur in an enhanced form on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

As sudden discontinuation of benzodiazepines may result in convulsions, particular care should be taken in patients with epilepsy, other patients who have had a history of seizures or in alcohol dependants.

• Tolerance - Limits of tolerance in patients with organic cerebral changes (particularly arteriosclerosis) or cardio-respiratory insufficiency may be very wide; care must be taken in adapting the dosage with such patients.

Some loss of efficacy to the hypnotic effects of diazepam may develop after repeated use for a few weeks.

• Alcohol should be avoided during treatment with diazepam (additive CNS depression).

• Amnesia - diazepam may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours. Anterograde amnesia may occur using therapeutic doses, the risk increases with higher doses.

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

• Diazepam should be used with caution in patients with a history of alcohol or drug abuse as these are patients predisposed to habituation and dependence.

• Hypo-albuminaemia may predispose patient to higher incidence of sedative side effects.

• Extreme caution should be used in prescribing diazepam to patients with personality disorders.

• Benzodiazepines should not be used in patients with severe hepatic insufficiency as they may precipitate encephalopathy.

• Cerebral sensitivity is increased in severe renal failure; therefore lower doses should be used (see section 4.2).

• 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 a lower dose (see section 4.2).

• Caution should be exercised when using diazepam peri-operatively in children, as effects and timing of response may be unreliable and paradoxical effects may occur.

• 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. Should this occur, use of the drug should be discontinued. They are more likely to occur in children and the elderly.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following drug interactions with diazepam should be considered:

• Increased sedation or respiratory or cardiovascular inhibition may occur if diazepam is given concomitantly with other CNS depressant properties such as; antipsychotics (for example clozapine), narcotic analgesics, antidepressants (for example fluvoxamine), hypnotics, general anaesthetics, antihistamines, lofexidine, nabilone, disulfiram, muscle relaxants, alcohol.

In case of narcotic analgesics, enhancement of euphoria may occur, resulting in an increase in dependence.

• Plasma concentrations of zotepine are increased.

• Cimetidine, oestrogen-containing contraceptives, disulfiram, erythromycin may inhibit hepatic metabolism of diazepam.

• Ulcer-healing-drugs: Omeprazole and cimetidine may increase the plasma concentration of diazepam.

• Antibacterials: Isoniazid may inhibit diazepam metabolism. Rifampicin may increase the metabolism of diazepam.

• Antivirals: Concomitant use of diazepam with amprenavir and ritonavir should be avoided, as there is an increased risk of prolonged sedation and respiratory depression.

• Antiepileptic drugs: Pharmacokinetic studies on potential interactions between diazepam 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. Therefore, special care should be taken in adjusting the dose in the initial stages of treatment.

• Alcohol: The sedative effects may be enhanced when diazepam is used in combination with alcohol. Concomitant intake with alcohol should be avoided.

• Antihypertensives, diuretics, nitrates: Enhanced hypotensive effects may occur. Enhanced sedative effect with alpha blockers or moxonidine.

• Dopaminergics: Concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa.

• Baclofen or tizanidine (enhanced sedative effect)

• Antacids (concurrent use may delay absorption of diazepam).

• Azoles (voriconazole, fluconazole): Itraconazole, ketoconazole, and to a lesser extent fluconazole 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.

• Theophylline increases metabolism of diazepam which possibly reduces the effect.

• Grapefruit juice inhibits CYP3A4 and may increase the plasma concentration of diazepam and may increase the extent of sedation and amnesia. This interaction may of little significant importance in healthy individuals; however what is not clear is whether other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.

4.6 Pregnancy And Lactation

The safety of diazepam in human pregnancy has not been established. It should not be used in the first and third trimesters. There may be a small increase in the risk of congenital malformation, particularly oral cleft with the use of benzodiazepines in the first trimester but a causal relationship has been established.

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

If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected, due to the pharmacological action of the compound.

Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

Benzodiazepines are found in the breast milk. Reports have demonstrated milk: plasma concentration ratios to vary between 0.2 and 2.7. There is therefore a risk of accumulation in the breastfeeding child. Benzodiazepines should not be given to breast feeding mothers.

4.7 Effects On Ability To Drive And Use Machines

Sedation, amnesia and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also Interactions).

Impaired function and sedation may occur the following morning and for several days after.

4.8 Undesirable Effects

During the first week of administration or when high doses are used they may have a sedative effect and cause some degree of drowsiness. In such cases there is an advantage in administering half the total daily intake at night, the remainder being given in divided doses during the day.

The elderly and debilitated are particularly sensitive to the effects of central depressant drugs and may experience confusion, especially if organic brain changes are present; the dosage of diazepam should not exceed one-half that recommended for other adults.

Skin and appendages disorders

Allergic reactions (skin rash or itching) occur rarely.

Central and peripheral nervous disorders

Drowsiness, sedation, unsteadiness, ataxia is common (these effects are dose-related and may persist into the following day even after a single dose). Headache, vertigo, dystonic effects occur rarely. Impaired motor ability, dizziness, muscle weakness, tremor, slurred speech.

Vision disorders

Visual disturbances occur rarely.

Psychiatric disorders

Libido fluctuations occur rarely. Anterograde amnesia, concentration difficulties, abnormal psychological reactions, behavioural adverse effects include paradoxical aggressive outbursts, excitement, confusion and the uncovering of depression with suicidal tendencies.

Gastro-intestinal system disorders

Gastrointestinal upsets occur rarely. Increased salivary secretion.

Liver and billiary system disorders

Jaundice occurs rarely.

Endocrine disorders

Gynaecomastia.

Cardio disorders

Hypotension occurs rarely.

Respiratory system disorders

Respiratory depression.

Blood disorders

Blood dyscrasias occur rarely.

Urinary system disorders

Urinary retention occurs rarely.

Body as a whole-general disorders

Fatigue, anaphylaxis.

Withdrawal effects

Withdrawal symptoms: Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation of the therapy may result in withdrawal or rebound phenomena (see 4.4 Special Warnings and Special Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension.

Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.

4.9 Overdose

Features

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required.

Extreme overdosage may lead to coma, areflexia, cardio-respiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.

Management

Maintain a clear airway and adequate ventilation.

Consider activated charcoal (50g for an adult, 1g/kg for a child) in adults who have taken more than 100mg or children who have taken more than 1mg/kg within one hour, provided they are not too drowsy.

Monitoring level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.

Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.

Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10-30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure.

If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.

Supportive measures are indicated depending on the patient's clinical state.

Benzodiazepines are not significantly removed from the body by dialysis.

Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may be suppressing seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.

Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients post-cardiac arrest is also contraindicated.

It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.

Occasionally a respirator may be required but generally few problems are encountered, although behavioural changes are likely in children.

If excitation occurs, barbiturates should not be used.

Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: N05B A01

Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties.

5.2 Pharmacokinetic Properties

Diazepam is readily and completely absorbed from the GI tract, peak plasma concentrations occurring within about 30-90 minutes of oral administration. Diazepam crosses the blood-brain barrier and is highly lipid soluble. Diazepam has a biphasic half-life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2-5 days of its principle active metabolite, desmethyldiazepam (nordiazepam), the relative proportion of which increases in the body on long-term administration.

Diazepam is extensively metabolised in the liver and, in addition to desmethyldiazepam, its active metabolites include oxazepam and temazepam. It is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form. Diazepam is very extensively bound to plasma proteins.

The plasma half-life of diazepam is prolonged in neonates, in the elderly, and in patients with kidney or liver disease. In addition to crossing the blood-brain barrier, diazepam and its metabolites also cross the placental barrier and are excreted in breast milk.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Also contains: lactose, magnesium stearate, maize starch, stearic acid, E104.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-6g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

The product may be contained in blister packs which enhances security of the pack increasing resistance to deliberate contamination, pilfering, etc.

Pack size: 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500, 1000.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0088

9. Date Of First Authorisation/Renewal Of The Authorisation

15.7.77

(Renewed: 15.7.82; 15.7.87; 3.9.92)

10. Date Of Revision Of The Text

16/09/2010

11 DOSIMETRY

IF APPLICABLE

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

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