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Diazepam, 10 mg tablets

Drug formTablets

ATC categoryNeurology. Psychiatry

ATC subcategoryAnxiolytics

Brand nameDiazepam

Generic nameDiazepam

Composition

Each tablet of Diazepam 10 mg contains:

active ingredient: diazepam – 10 mg;

excipients: microcrystalline cellulose, lactose monohydrate, ethylcellulose, sodium starch glycolate, magnesium stearate.

Chemical name and CAS number

7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; 439-14-5.

Pharmacological group and ATC code

Benzodiazepine tranquilliser; N05BA01.

Pharmacology

Diazepam is a long-acting benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnestic properties.

The exact sites and mode of action of the benzodiazepines have not been fully elucidated, but the effects of the drugs appear to be mediated through the inhibitory neurotransmitter γ-aminobutyric acid (GABA). The drugs appear to act at the limbic, thalamic, and hypothalamic levels of the CNS, producing anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant effects. Benzodiazepines are capable of producing all levels of CNS depression—from mild sedation to hypnosis to coma. Specific binding sites with high affinity for benzodiazepines have been detected in the CNS, and the affinity of these sites for the drugs is enhanced by both GABA and chloride. The sites and actions of benzodiazepines within the CNS appear to involve a macromolecular (oligomer or possibly a tetramer) complex (GABAA-receptor-chloride ionophore complex) that includes GABAA receptors (GABA recognition sites), high-affinity benzodiazepine receptors, and chloride channels, although precise relationships between the sites of action of benzodiazepines and GABA-regulated (-gated) chloride channels remain to be more fully elucidated. Allosteric interactions of central benzodiazepine receptors with GABAA receptors and subsequent opening of chloride channels appear to be involved in eliciting the CNS effects of the drugs; the benzodiazpine receptors act as modulatory sites on the complex. Anxiolytic and possibly paradoxical CNS stimulatory effects of benzodiazepines are postulated to result from release of previously suppressed responses (disinhibition). After usual doses of benzodiazepines for several days, the drugs cause a moderate decrease in rapid eye movement (REM) sleep. REM rebound does not occur when the drugs are withdrawn. Stage 3 and 4 sleep are markedly reduced by usual doses of the drugs; the clinical importance of these sleep stage alterations has not been established. Benzodiazepines appear to produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, but the drugs may also inhibit monosynaptic afferent pathways. The drugs may inhibit monosynaptic and polysynaptic reflexes by acting as inhibitory neuronal transmitters or by blocking excitatory synaptic transmission. The drugs may also directly depress motor nerve and muscle function.

Pharmacokinetics

Diazepam is readily and completely absorbed from the gastrointestinal tract, peak plasma concentrations occurring within about 30 to 90 minutes of oral doses. Diazepam is rapidly absorbed when given as a rectal solution; peak plasma concentrations are achieved after about 10 to 30 minutes. Absorption may be erratic after intramuscular injection and lower peak plasma concentrations may be obtained compared with those after oral doses. Diazepam is highly lipid soluble and crosses the blood-brain barrier; it acts promptly on the brain, and its initial effects decrease rapidly as it is redistributed into fat depots and tissues.

Diazepam has a biphasic half-life with an initial rapid distribution phase and a prolonged terminal elimination phase of 1 or 2 days; its action is further prolonged by the even longer half-life of 2 to 5 days of its principal active metabolite, desmethyldiazepam (nordazepam). Diazepam and desmethyldiazepam accumulate on repeated dosage and the relative proportion of desmethyldiazepam in the body increases with long-term use. No simple correlation has been found between plasma concentrations of diazepam or its metabolites and their therapeutic effect.

Diazepam is extensively metabolised in the liver, notably via the cytochrome P450 isoenzyme CYP2C19; in addition to desmethyldiazepam, its active metabolites include oxazepam, and temazepam. It is excreted in the urine, mainly in the form of free or conjugated metabolites. Diazepam is 98 to 99% bound to plasma proteins.

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

Uses and administration
Diazepam is used in the short-term treatment of severe anxiety disorders, as a hypnotic in the short-term management of insomnia, as a sedative and premedicant, as an anticonvulsant (particularly in the management of status epilepticus and febrile convulsions), in the control of muscle spasm, and in the management of withdrawal symptoms.

Adminsitration

Diazepam is administered orally with the risk of dependence very much influencing the doseand duration of treatment. Doses should be the lowest that can control symptoms and courses of treatment should be short, not normally exceeding 4 weeks, with diazepam being withdrawn gradually. Elderly and debilitated patients should be given not more than one-half the usual adult dose. Dosage reduction may also be required in patients with hepatic or renal impairment.

Diazepam may be given for severe anxiety in oral doses of 2 mg three times daily to a maximum of 30 mg daily. A wider dose range of 4 to 40 mg daily in divided doses is used in the USA with children over 6 months of age receiving up to 10 mg daily.

The benzodiazepines have a limited role in insomnia and diazepam is used for the short-term management of insomnia associated with anxiety. The BNF recommends a dose of 5 to 15 mg by mouth at bedtime. Doses of 1 to 5 mg at bedtime have been used in children and adolescents aged from 12 to 18 years to control night terrors and sleepwalking.

Diazepam may be given for premedication before general anaesthesia or to provide sedative cover for minor surgical or investigative procedures. Doses by mouth are in the range of 5 to 15 mg. The BNFC has suggested giving oral doses to children based on age as follows: 1 month to 1 year, 250 micrograms/kg; 1 to 5 years, 2.5 mg; 5 to 12 years, 5 mg. Some regard the perioperative use of diazepam in children undesirable since its effect and onset of action are unreliable and paradoxical effects may occur.

Diazepam may also be given for sedation during minor surgical and medical procedures; the BNFCsuggests an oral dose may be given to children and adolescents, 45 to 60 minutes beforehand, as follows: 1 month to 12 years, 200 to 300 micrograms/kg (maximum of 5 mg); 12 to 18 years, 100 to 200 micrograms/kg (maximum of 20 mg).

Diazepam may be given by mouth in daily divided doses of 2 to 15 mg to alleviate muscle spasm. The dose may be increased in severe spastic disorders, such as cerebral palsy, to up to 60 mg daily in adults. The BNFC suggests initial oral doses in children and adolescents, based on age and given twice daily, as follows: 1 to 12 months, 250 micrograms/kg; 1 to 5 years, 2.5 mg; 5 to 12 years, 5 mg; 12 to 18 years, 10 mg (maximum of 40 mg daily).

Symptoms of the alcohol withdrawal syndrome may be controlled by diazepam given by mouth in a dose of 5 to 20 mg, repeated if required after 2 to 4 hours; another approach is to give 10 mg three or four times on the first day reducing to 5 mg three or four times daily as required.

Overdosage

Symptoms

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, nausea, vomiting .

Impairment of consciousness is fairly rapid in poisoning by benzodiazepines. Deep coma or other manifestations of severe depression of brainstem vital functions are rare; more common is a sleep-like state from which the patient can be temporarily roused by appropriate stimuli. There is usually little or no respiratory depression, and cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension. Since tolerance to benzodiazepines develops rapidly, consciousness is often regained while concentrations of drug in the blood are higher than those which induced coma. Anxiety and insomnia can occur during recovery from acute overdosage, while a full-blown withdrawal syndrome, possibly with major convulsions, can occur in patients who have previously been chronic users.

Treatment

Drug should be withdrawed

The treatment of benzodiazepine overdosage is generally symptomatic and supportive. Activated charcoal may be given orally within one hour of ingestion of more than 100 mg of diazepam by adults, or 1 mg/kg by children, provided they are not too drowsy. Gastric lavage is generally not advocated in overdoses of benzodiazepines alone. The specific benzodiazepine antagonist, flumazenil, is rarely required and can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodiazepine-dependent patients; the UK Poisons Information Service, contra-indicates its use in mixed overdoses. The BNF recommends that flumazenil should be used on expert advice only.

Hemodialysis is ineffective.

Contraindications
  • Myasthenia gravis,
  • Sleep apnoea,
  • Exacerbated chronic pulmonary insufficiency,
  • Severe hepatic and renal impairment,
  • Hypersensitivity to benzodiazepines or any of the ingredients,
  • Angle-closure glaucoma,
  • Acute alcohol intoxication,
  • Acute intoxication by psychotropic drugs,
  • Pregnancy ( first 3 months)
  • Adverse effects
    Drowsiness, sedation, muscle weakness, and ataxia are the most frequent adverse effects of diazepam use. They generally decrease on continued dosage and are a consequence of CNS depression. Less frequent effects include vertigo, headache, confusion, depression, slurred speech or dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation, and amnesia, hallucinations, insomnia,increased muscle tone, bradicardia, disphagia, nausea, diarrhea, constipation,appetite disturbances . Some patients may experience a paradoxical excitation which may lead to hostility, aggression, and disinhibition. Jaundice, blood disorders, and hypersensitivity reactions have been reported rarely. Respiratory depression and hypotension occasionally occur with high dosage and parenteral use.

    Pain and thrombophlebitis may occur with some intravenous formulations of diazepam; raised liver enzyme values have occurred.

    Overdosage can produce CNS depression and coma or paradoxical excitation. However, fatalities are rare when taken alone.

    Use of diazepam in the first trimester of pregnancy has occasionally been associated with congenital malformations in the infant but no clear relationship has been established. Use of diazepam in late pregnancy has been associated with intoxication of the neonate.

    Dependence and Withdrawal

    The development of dependence is common after regular use of benzodiazepines, even in therapeutic doses for short periods. Dependence is particularly likely in patients with a history of alcohol or drug abuse and in those with marked personality disorders. Benzodiazepines should therefore be withdrawn by gradual reduction of the dose after regular use for even a few weeks; the time needed for withdrawal can vary from about 4 weeks to a year or more. The extent to which tolerance occurs has been debated but appears to involve psychomotor performance more often than anxiolytic effects. Drug-seeking behaviour is uncommon with therapeutic doses of benzodiazepines.

    Benzodiazepine withdrawal syndrome

    Development of dependence to benzodiazepines cannot be predicted but risk factors include high dosage, regular continuous use, the use of benzodiazepines with a short half-life, use in patients with dependent personality characteristics or a history of drug or alcohol dependence, and the development of tolerance. The mechanism of dependence is unclear but may involve reduced gamma-aminobutyric acid (GABA) activity resulting from down-regulation of GABA receptors.

    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.

    Symptoms typical of withdrawal have occurred despite continued use of benzodiazepines and have been attributed either to the development of tolerance. Pseudowithdrawal has been reported in patients who believed incorrectly that their dose of benzodiazepine was being reduced. Benzodiazepine withdrawal syndrome can theoretically be distinguished from these reactions and from rebound phenomena (return of original symptoms at greater than pretreatment severity) by the differing time course. A withdrawal syndrome is characterised by its onset, by the development of new symptoms, and by a peak in intensity followed by resolution. Onset of withdrawal symptoms depends on the half-life of the drug and its active metabolites. Symptoms can begin within a few hours after withdrawal of a short-acting benzodiazepine, but may not develop for up to 3 weeks after stopping a longer-acting benzodiazepine. Resolution of symptoms may take several days or months.

    With increased awareness of the problems of benzodiazepine dependence, emphasis has been placed on prevention by proper use and careful patient selection. For example, the UK CSM has recommended that benzodiazepines should be reserved for the short-term relief (2 to 4 weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress and is occurring alone or in association with insomnia or short-term psychosomatic, organic, or psychotic illness.

    Withdrawal from long-term benzodiazepine use should generally be encouraged. Established dependence can be difficult to treat; the patient should have professional and family support and behavioural therapy may be helpful. Withdrawal in a specialist centre may be required for some patients. Since abrupt withdrawal of benzodiazepines may result in severe withdrawal symptoms dosage should be tapered. The BNF considers that benzodiazepines can be withdrawn in steps of about one-eighth of the daily dose every fortnight (range one-tenth to one-quarter). There are no comparative studies of the efficacy of various withdrawal schedules and in practice the protocol should be titrated against the response of the patient.

    The daily dosage of diazepam can then be reduced in steps of 0..5 to 2.5 mg at fortnightly intervals. If troublesome abstinence effects occur the dose should be held level for a longer period before further reduction; increased dosage should be avoided if possible. It is better to reduce too slowly than too quickly. Time required for withdrawal can vary from about 4 weeks to a year or longer. In many cases the rate of withdrawal is best decided by the patient.

    Adjuvant therapy should generally be avoided. Although a beta blocker may be given for prominent sympathetic overactivity the BNF recommends that this be tried only if other measures fail; antidepressants should be used only for clinical depression or panic attacks. Antipsychotic drugs should be avoided as they may aggravate symptoms.

    Symptoms gradually improve after withdrawal but postwithdrawal syndromes lasting for several weeks or months have been described. Continued support may be required for the first year after withdrawal to prevent relapse.

    Precautions

    Diazepam should be given with care to elderly or debilitated patients who may be more prone to adverse effects. Caution is required in patients with muscle weakness, or those with hepatic or renal impairment, who may require reduced doses; The sedative effects of diazepam are most marked during the first few days of use; affected patients should not drive or operate machinery. Monitoring of cardiorespiratory function is generally recommended when benzodiazepines are used for deep sedation.

    Diazepam should be abolished in the development of paradoxical reactions (acute agitation, anxiety, sleep disturbances and hallucinations). Diazepam long term therapy requires periodic monitoring of peripheral blood.

    Diazepam treatment is recommended to start at the end of the workweek.

    You can use Diazepam at open-angle glaucoma, if patients receive adequate disease therapy.

    A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

    Diazepam is not appropriate for the treatment of chronic psychosis or for phobic or obsessional states. Diazepam-induced disinhibition may precipitate suicide or aggressive behaviour and it should not, therefore, be used alone to treat depression or anxiety associated with depression; it should also be used with care in patients with personality disorders. Caution is required in patients with organic brain changes particularly arteriosclerosis. In cases of bereavement, psychological adjustment may be inhibited by diazepam.

    Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks. Dependence characterised by a withdrawal syndrome may develop after regular use of diazepam, even in therapeutic doses for short periods; because of the risk of dependence, diazepam should be used with caution in patients with a history of alcohol or drug addiction.

    Withdrawal symptoms consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion 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 or epileptic seizures. To prevent it duration of treatment should be as short as possible.

    During the period of Diazepam should abstain from alcohol (because of mutual reinforcement inhibitory action on the central nervous system and the possible appearance of pathological intoxication syndrome).

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

    Elderly

    If use of a diazepam is considered necessary in elderly patients, a short-acting drug is to be preferred. It should also be remembered that the elderly are at increased risk of sleep-related breathing disorders, such as sleep apnoea and the use of hypnotics such as diazepam should be avoided in these patients.

    Fertility,pregnancy and lactation

    Breast feeding.

    Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.

    Animal studies with benzodiazepines have shown minor effects on the foetus while a few studies have reported late behavioural disturbances in offspring exposed in utero. Do not use during pregnancy, especially during the first and last trimesters, unless there are compelling reasons.

    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, effects on the neonate, such as hypothermia, hypotonia, irregularities in the foetal heart rate, poor sucking and moderate respiratory depression, can be expected, due to the pharmacological action of the compound. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants).

    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.

    Drug interactions

    Enhanced sedation or respiratory and cardiovascular depression may occur if diazepam is given with other drugs that have CNS-depressant properties; these include alcohol, antidepressants, sedative antihistamines, antipsychotics, general anaesthetics, other hypnotics or sedatives, and opioid analgesics.

    The sedative effect of diazepam may also be enhanced by cisapride. Adverse effects may also be produced by use with drugs that interfere with the metabolism of diazepam. Diazepam which is metabolised primarily by hepatic microsomal oxidation may be more susceptible to pharmacokinetic changes than those eliminated primarily by glucuronide conjugation.

    Diazepam has the following interactions:

    Amprenavir – increased risk of prolonged sedation and respiratory depression when diazepam given with amprenavir
    Esomeprazole – metabolism of diazepam possibly inhibited by esomeprazole (increased plasma concentration)
    Isoniazid – metabolism of diazepam inhibited by isoniazid
    Omeprazole – metabolism of diazepam possibly inhibited by omeprazole (increased plasma concentration)
    Phenytoin – diazepam increases or decreases plasma concentration of phenytoin
    Rifampicin – metabolism of diazepam accelerated by rifampicin (reduced plasma concentration)
    Ritonavir – plasma concentration of diazepam possibly increased by ritonavir (risk of extreme sedation and respiratory depression —avoid concomitant use)
    Valproate – plasma concentration of diazepam possibly increased by valproate
    Zotepine – diazepam increases plasma concentration of zotepine.

    Diazepam belongs to Benzodiazepines and will have the following interactions:

    Cimetidine – metabolism of benzodiazepines inhibited by cimetidine (increased plasma concentration)
    Disulfiram – metabolism of benzodiazepines inhibited by disulfiram (increased sedative effects)
    Fluvoxamine – plasma concentration of some benzodiazepines increased by fluvoxamine
    Levodopa – benzodiazepines possibly antagonise effects of levodopa
    Moxonidine – sedative effects possibly increased when benzodiazepines given with moxonidine
    Olanzapine – increased risk of hypotension, bradycardia and respiratory depression when parenteral benzodiazepines given with intramuscular olanzapine
    Phenytoin – benzodiazepines possibly increase or decrease plasma concentration of phenytoin
    Rifampicin – metabolism of benzodiazepines possibly accelerated by rifampicin (reduced plasma concentration)
    Sodium Oxybate – benzodiazepines enhance effects of sodium oxybate (avoid concomitant use)
    Theophylline – effects of benzodiazepines possibly reduced by theophylline.

    Diazepam belongs to Anxiolytics and Hypnotics and will have the following interactions:

    ACE Inhibitors – enhanced hypotensive effect when anxiolytics and hypnotics given with ACE inhibitors
    Adrenergic Neurone Blockers – enhanced hypotensive effect when anxiolytics and hypnotics given with adrenergic neurone blockers
    Alcohol – increased sedative effect when anxiolytics and hypnotics given with alcohol
    Alpha-blockers – enhanced hypotensive and sedative effects when anxiolytics and hypnotics given with alpha-blockers
    Anaesthetics, General – increased sedative effect when anxiolytics and hypnotics given with general anaesthetics
    Angiotensin-II Receptor Antagonists – enhanced hypotensive effect when anxiolytics and hypnotics given with angiotensin-II receptor antagonists
    Antidepressants, Tricyclic – increased sedative effect when anxiolytics and hypnotics given with tricyclics
    Antidepressants, Tricyclic (related) – increased sedative effect when anxiolytics and hypnotics given with tricyclic-related antidepressants
    Antihistamines – increased sedative effect when anxiolytics and hypnotics given with antihistamines
    Antipsychotics – increased sedative effect when anxiolytics and hypnotics given with antipsychotics
    Baclofen – increased sedative effect when anxiolytics and hypnotics given with baclofen
    Beta-blockers – enhanced hypotensive effect when anxiolytics and hypnotics given with beta-blockers
    Calcium-channel Blockers – enhanced hypotensive effect when anxiolytics and hypnotics given with calcium-channel blockers
    Clonidine – enhanced hypotensive effect when anxiolytics and hypnotics given with clonidine
    Diazoxide – enhanced hypotensive effect when anxiolytics and hypnotics given with diazoxide
    Diuretics – enhanced hypotensive effect when anxiolytics and hypnotics given with diuretics
    Hydralazine – enhanced hypotensive effect when anxiolytics and hypnotics given with hydralazine
    Lofexidine – increased sedative effect when anxiolytics and hypnotics given with lofexidine
    Methyldopa – enhanced hypotensive effect when anxiolytics and hypnotics given with methyldopa
    Minoxidil – enhanced hypotensive effect when anxiolytics and hypnotics given with minoxidil
    Mirtazapine – increased sedative effect when anxiolytics and hypnotics given with mirtazapine
    Moxonidine – enhanced hypotensive effect when anxiolytics and hypnotics given with moxonidine
    Nabilone – increased sedative effect when anxiolytics and hypnotics given with nabilone
    Nitrates – enhanced hypotensive effect when anxiolytics and hypnotics given with nitrates
    Opioid Analgesics – increased sedative effect when anxiolytics and hypnotics given with opioid analgesics
    Ritonavir – plasma concentration of anxiolytics and hypnotics possibly increased by ritonavir
    Sodium Nitroprusside – enhanced hypotensive effect when anxiolytics and hypnotics given with sodium nitroprusside
    Tizanidine – increased sedative effect when anxiolytics and hypnotics given with tizanidine.

    Identification

    White scored cylindrical tablets.

    Presentation

    1 blister packets with 24 tablets in the cardboard box.

    Expiry date

    3 years. Do not use after the expiration date.

    Storage conditions

    Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.