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.
Absorption and plasma concentrations.
CHRONIC ORAL ADMINISTRATION.
In 36 patients who had received diazepam 2 to 30 mg daily for periods from one month to 10 years, plasma-diazepam concentrations were directly related to dose and inversely related to age. There was a close association between the plasma concentrations of diazepam and its metabolite desmethyldiazepam and both concentrations were independent of the duration of therapy. Plasma-diazepam concentration ranges were 0.02 to 1.01 micrograms/mL, and plasma-desmethyldiazepam concentration ranges were 0.055 to 1.765 micrograms/mL. A similar study reached the same general conclusions.
RECTAL.
In 6 adults given diazepam 10 mg by mouth or as a solution (Valium injection) by rectum, mean bioavailability was 76 and 81%, respectively compared with the same dose by intravenous injection. Bioavailability was lower with suppositories than with the solution given rectally. Studies support the use of rectal solution rather than suppositories in children.
Distribution into breast milk.
Concentrations of diazepam and desmethyldiazepam transferred from mother to infant via breast milk have been measured. See also under Precautions, above.
The elderly.
For mention of pharmacokinetics in the elderly, see under Precautions, above.
Hepatic impairment.
For reference to the altered pharmacokinetics of diazepam in patients with hepatic impairment see Administration in Hepatic Impairment, below.
Metabolism.
Most benzodiazepines are highly lipophilic compounds requiring biotransformation before excretion from the body, and many form active metabolites that affect the duration of action. The benzodiazepines may be classified as long-, intermediate-, or short-acting compounds.
- Long-acting benzodiazepines are either N1-desalkyl derivatives (delorazepam and nordazepam) or are oxidised in the liver to N1-desalkyl derivatives (benzodiazepines so oxidised include chlordiazepoxide clobazam, clorazepate, cloxazolam, diazepam, flurazepam, halazepam, ketazolam, medazepam, oxazolam, pinazepam, prazepam, and quazepam). Clorazepate and prazepam may be considered as prodrugs since the metabolite is the expected active principle. Both parent drug and metabolites contribute to the activity of the other long-acting drugs. Further biotransformation of N1-des-alkylated metabolites proceeds much more slowly than for the parent drug, and they therefore accumulate in the body after a few days of treatment. The rate-limiting step of their metabolism (with the exception of the 1,5-derivatives) is C3-hydroxylation to the pharmacologically active oxazepam or its 2′-halogenated analogues.
- Intermediate-acting benzodiazepines are 7-nitrobenzodi-azepines such as clonazepam,flunitrazepam, and nitrazepam which are metabolised by nitroreduction with no important known active metabolites. The metabolites of long- and intermediate-acting benzodiazepines require conjugation before excretion in the urine.
- Short-acting benzodiazepines include the C3-hydroxylated benzodiazepines such as lorazepam, lormetazepam, oxazepam, and temazepam which undergo rapid conjugation with glucuronic acid to water-soluble inactive metabolites that are excreted in the urine, and drugs such as alprazolam, brotizolam, estazolam, etizolam, midazolam, tofisopam, and triazolam which require oxidation involving aliphatic hydroxyla-tion before subsequent conjugation. Although these hydroxylated metabolites may retain pharmacological activity, they are unlikely to contribute significantly to clinical activity because of their negligible plasma concentrations and rapid inactivation by glucuronidation. Drug-metabolising capacity is influenced by many factors including genetics, age, sex, endocrine and nutritional status, smoking, disease, and concurrent drug therapy. This results in wide interindividual variation in both parent drug concentrations and metabolite-to-parent drug ratios.
Pregnancy.
The passage of diazepam across the placenta depends in part on the relative degrees of protein binding in mother and fetus. This in turn is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus. Adverse effects may persist in the neonate for several days after birth because of immature drug-metabolising enzymes. Competition between diazepam and bilirubin for protein binding sites could result in hyperbilirubinaemia in the neonate.
For further adverse effects associated with the use of benzodiazepines during pregnancy, see under Precautions, above.
Uses and Administration
Diazepam is a long-acting benzodiazepine with anti-convulsant, anxiolytic, sedative, muscle relaxant, and amnestic properties. Its actions are mediated by enhancement of the activity of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. 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 (see also the references below).
Diazepam is administered orally, rectally, and parenterally with the risk of dependence very much influencing the dose and 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 (see above). 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. Oral use is appropriate for many indications and modified-release formulations are available in some countries. Rectal use may be by suppository or rectal solution or gel.
Diazepam is also given by deep intramuscular or slow intravenous injection, although absorption after intramuscular injection may be erratic and provides lower blood concentrations than those after oral doses. Intravenous injection should be carried out slowly into a large vein of the antecubital fossa at a recommended rate of no more than 1 mL of a 0.5% solution (5 mg) per minute. It is advisable to keep the patient in the supine position and under medical supervision for at least an hour after the dose. Diazepam may be given by continuous intravenous infusion because of the risk of precipitation of diazepam, solutions should be freshly prepared following the manufacturer’s directions regarding diluent and concentration of diazepam. Diazepam is substantially adsorbed onto some plastics (see Sorption, above). Facilities for resuscitation should always be available when diazepam is given intravenously.
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. Diazepam may be given as a rectal solution in a dose of 500 micrograms/kg repeated after 12 hours if necessary or as suppositories in a dose of 10 to 30 mg. Diazepam may sometimes have to be given by intramuscular or intravenous injection when a dose of up to 10 mg maybe used, repeated if necessary after 4 hours. 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 an oral dose of 5 to 15 mg at bedtime, although doses up to 30 mg are licensed. 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. In adults, oral doses are in the range of 5 to 20 mg and when given by intravenous injection the dose is usually 100 to 200 micrograms/kg. Diazepam may also be given for sedation during minor surgical and medical procedures in adults doses of 10 to 20 mg, given by intravenous injection over 2 to 4 minutes, are recommended. Diazepam 500 micrograms/kg may also be given as a rectal solution. For premedication and sedation in children and adolescents aged from 1 month to 18 years, the BNFC suggests that an oral dose of 200 to 300 micrograms/kg may be given 45 to 60 minutes beforehand the maximum dose is 10 mg for those aged up to 12 years and 20 mg for adolescents aged up to 18 years.
Diazepam 100 to 200 micrograms/kg may be given by intravenous injection over 2 to 4 minutes, immediately before the procedure, to those aged 1 month and older the maximum dose is 5 mg for children aged up to 12 years and 20 mg for adolescents aged up to 18 years. When given as a rectal solution, the BNFC suggests the following doses based on age: 1 to 3 years, 5 mg 3 to 12 years, 5 to 10 mg 12 to 18 years, 10 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 is used in a variety of seizures. It is given orally as an adjunct in some types of epilepsy for this purpose, 2 to 60 mg may be given daily in divided doses. A rectal gel formulation is also available for adjunc-tive use in the management of episodes of increased seizure activity in adults and children aged 2 years and over with refractory epilepsy doses range from 200 to 500 micrograms/kg, depending on age, repeated after 4 to 12 hours if necessary. For febrile convulsions, status epilepticus, and convulsions due to poisoning, giving a rectal solution may be appropriate suppositories are not suitable because absorption is too slow.
Recommended doses for the rectal solution differ but a typical dose is 500 micrograms/kg for adults and children over 10 kg, repeated every 12 hours if necessary if convulsions are not controlled by the first dose the use of other anticonvulsive measures is recommended. Rectal solutions are not licensed for such use in children under 1 year of age in the UK, but the BNFC suggests giving the following doses, repeated after 10 minutes if necessary, based on age: neonates, 1.25 to 2.5 mg 1 month to 2 years, 5 mg. For older children it recommends: 2 to 12 years, 5 to 10 mg 12 to 18 years, 10 mg. Alternatively, diazepam may be given intravenously to adults in a dose of 10 to 20 mg given at a rate of 5 mg/minute and repeated if necessary after 30 to 60 minutes.
Other schedules involve giving smaller amounts more frequently or giving diazepam intramuscularly, though again absorption may be too slow. Once the seizures have been controlled, a slow intravenous infusion providing up to 3 mg/kg over 24 hours has been used to protect against recurrence. Doses by intravenous injection in children are within the range of 200 to 300 micrograms/kg alternatively 1 mg may be given for each year of age. The BNFC has suggested that neonates and children aged from 1 month to 12 years may be given doses of 300 to 400 micrograms/kg by intravenous injection over 3 to 5 minutes, repeated after 10 minutes if necessary.
Diazepam may be given orally 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). If given by intramuscular or slow intravenous injection the dose is 10 mg repeated if necessary after 4 hours. Larger doses are used in tetanus in adults and children aged 1 month and over with 100 to 300 micrograms/kg being given every 1 to 4 hours by intravenous injection.
Alternatively 3 to 10 mg/kg may be given over 24 hours by continuous intravenous infusion or by nasoduodenal tube using a suitable liquid oral dose form. Diazepam may also be given by the rectal route as a rectal solution in a dose of 500 micrograms/kg for adults and children over 10 kg in weight, repeated every 12 hours if necessary. Symptoms of the alcohol withdrawal syndrome may be controlled by diazepam given orally 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. Diazepam may need to be given by injection if the symptoms are severe and if delirium tremens has developed 10 to 20 mg by intramuscular or intravenous injection may be adequate, although some patients may require higher doses.
Administration in hepatic impairment.
Oxidative metabolism of diazepam is apparently reduced in patients with hepatic impairment, resulting in a prolonged half-life and reduced clearance. A reduction in dosage was generally required in these studies, but no specific advice is given in licensed information for the UK or USA.
Administration in renal impairment.
Diazepam and its metabolites are excreted in urine, and licensed drug information suggests that dosage reduction may be required in patients with renal impairment, but gives no specific advice on how to do this.
Cardiac arrhythmias.
Although not considered to be an antiarrhyfhmic, diazepam has been tried with good effect in treating the cardiotoxicity of chloroquine poisoning. However, diazepam has been reported to possess both antiarrhyfhmic and pro-arrhythmic properties, possibly depending on the dose.
Chloroquine poisoning.
For reference to the possible use of diazepam to decrease the cardiotoxic effects of chloroquine.
Conversion and dissociative disorders.
Conversion and dissociative disorders (formerly known as hysteria) are characterised by physical symptoms that occur in the absence of organic disease. Medication has no part to play in the treatment of these disorders unless they are secondary to conditions such as depression or anxiety disorders requiring treatment in their own right.
There have been suggestions that sedatives such as diazepam or midazolam may be used to confirm the diagnosis of hysterical paralysis. The test tends to exacerbate organic disease while psychiatric dysfunction may improve.
Disturbed behaviour.
For a discussion of the management of behaviour disturbances associated with various psychotic disorders, and the value of benzodiazepines. Benzodiazepines may sometimes be useful in palliative care for the relief of terminal restlessness. Midazolam is often used although other benzodiazepines such as diazepam have also been tried. A suggested dose for diazepam is 5 to 10 mg given slowly as a rectal solution and repeated every 8 to 12 hours. In practice, however, haloperidol may be preferred a review suggested that benzodiazepines used alone might exacerbate the problem. If agitation was severe haloperidol or risperidone could be combined with lorazepam, reserving subcutaneous midazolam for refractory cases.
Dyspnoea.
Despite the hazards of use in patients with any form of respiratory depression or pulmonary insufficiency (see Respiratory System Disorders under Precautions, above) benzodiazepines such as diazepam have been tried in the treatment of dyspnoea, in the belief that reduction of an elevated respiratory drive may alleviate respiratory distress. However, benefits have not been confirmed. Benzodiazepines may be of use in patients with advanced cancer who have rapid shallow respiration. A daily dose of 5 to 10 mg has been suggested for diazepam.
Eclampsia and pre-eclampsia.
Diazepam has been used for the initial control of impending or actual eclampsia, but magnesium sulfate is now generally the preferred treatment.
Epilepsy and other convulsive disorders.
Some benzodiazepines such as diazepam are used for the control of status epilepticus, including status epilepticus in patients with porphyria (see also Porphyria under Precautions, above), and for febrile convulsions diazepam has also been used in eclampsia (see above) and for neonatal seizures. Benzodiazepines such as clobazam and clonazepam may be used in the management of epilepsy, but their long-term use is limited by problems of sedation, dependence, and tolerance to the antiepileptic effects. Diazepam has been used as an adjunct in the management of some types of epilepsy including myoclonus.
Extrapyramidal disorders.
For reference to the use of benzodiazepines in the treatment of antipsychoticinduced extrapyramidal disorders, see Chlorpromazine.
Irritable bowel syndrome.
Although some benzodiazepines have been used in the management of irritable bowel syndrome there is no evidence to support their use in this condition. The related compound dextofisopam is under investigation.
Mania.
Benzodiazepines have been used as short-term adjuncts in the initial control of manic episodes in patients with bipolar disorder until lithium has achieved its full effect.
Muscle spasm.
Diazepam and other benzodiazepines may be used for the relief of muscle spasm of various aetiologies including that secondary to muscle or joint inflammation or trauma, such as in acute low back pain, or resulting from spasticity, dystonias, stiff-man syndrome (see below), cerebral palsy, poisoning, or tetanus. High doses are often required and treatment may be limited by adverse effects or by risk of dependence.
STIFF-MAN SYNDROME.
Stiff-man syndrome is a rare condition characterised by painful intermittent spasms and rigidity of the axial and limb muscles. Its exact cause is unknown but there is some evidence to implicate autoantibodies against one of the enzymes involved in the synthesis of the neuro-transmitter gamma-aminobutyric acid. It is frequently associated with autoimmune diseases and type 1 diabetes mellitus. Patients typically respond to benzodiazepines and this may be of use in the differential diagnosis of the syndrome.
Diazepam has been the mainstay of treatment but clonazepam may also be of use, especially in familial startle disease, a rare congenital form of stiff-man syndrome. Although rigidity and spasms in stiff-man syndrome are not completely resolved by diazepam the degree of improvement can be sufficient to restore the functional level to near normal. However, large doses are often required and sedation might be a limiting factor in some patients. Other drugs that have been used when diazepam is ineffective or poorly tolerated include baclofen or sodium valproate but benefit may be less evident.
There have been isolated anecdotal reports of improvement with vigabatrin, tiagabine, and gabapentin. Antiepileptics or baclofen may sometimes be combined with benzodiazepines. Corticosteroids may be of benefit, although any response may take several weeks, and the chronic nature of the disorder and the high incidence of type 1 diabetes mellitus may make their use problematic. Other attempts at immunomodulation such as plasmapheresis have yielded variable results there is some evidence of the efficacy of immunoglobulins.
Nausea and vomiting.
Benzodiazepines, particularly lorazepam, are used as adjuncts in the management of nausea and vomiting induced by cancer chemotherapy, particularly anticipatory emesis.
Premenstrual syndrome.
For mention of the limited role of benzodiazepines in the management of premenstrual syndrome.
Schizophrenia.
Benzodiazepines may be useful adjuncts to antipsychotics in the initial management of schizophrenia.
Sleep-associated movement disorders.
Sleep-associated movement disorders rarely require treatment other than the symptomatic treatment of sleep-related medical problems. A number of such conditions, including restless legs syndrome, sleepwalking, and night terrors, have been reported to respond to benzodiazepines. Although the muscle relaxant and anxiolytic action of a benzodiazepine can be helpful in bruxism (teeth grinding) it has been recommended that they should only be prescribed on a short-term basis during the acute phase.
Substance dependence.
The benzodiazepines are used in the management of symptoms of alcohol withdrawal, of opioid withdrawal, and of cocaine withdrawal.
Vertigo.
Although intravenous diazepam has been used to abort acute attacks of vertigo of peripheral origin, it can prolong compensation and recovery from vestibular lesions.
Preparations
British Pharmacopoeia 2008: Diazepam Injection; Diazepam Oral Solution; Diazepam Rectal Solution; Diazepam Tablets
The United States Pharmacopeia 31, 2008: Diazepam Capsules; Diazepam Extended-release Capsules; Diazepam Injection; Diazepam Tablets
Proprietary Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed
Argentina: Cuadel; Daiv; Dezepan; Diactal; Dipezona; Fabotranil; Glutasedan¤; Lembrol; Plidan; Rupediz¤; Saromet; Timab; Valium;
Australia: Antenex; Diazemuls¤; Ducene; Pro-Pam¤; Valium; Valpam;
Austria: Gewacalm; Psychopax; Stesolid; Umbrium; Valium;
Belgium: Valium; Brazil: Ansilive; Calmociteno; Compaz; Diazefast; Diazelong¤; Diazepan; Dienpax; Kiatrium; Letansil; Noan; Pazolini; Somaplus; Uni Diazepax; Valium; Valix¤; Vetansil;
Canada: Diastat; Diazemuls; Meval¤; Novo-Dipam¤; Valium; Vivol¤;
Chile: Cardiosedantol; Elongal¤; Pacinax;
Czech Republic: Apaurin; Seduxen; Stesolid;
Denmark: Apozepam; Hexalid; Stesolid; Valaxona; Valium;
Finland: Diapam; Medipam; Stesolid;
France: Novazam; Valium;
Germany: Diazemuls¤; Diazep; duradiazepam¤; Faustan; Lamra; Mandro-Zep¤; Neurolytril¤; Stesolid; Tranquase¤; Tranquo¤; Valaxona¤; Valiquid; Valium; Valocordin-Diazepam;
Greece: Apollonset; Atarviton; Stedon; Stesolid;
Hong Kong: Diazemuls¤; Kratium; Stesolid;
Hungary: Seduxen; Stesolid;
India: Calmpose; Elcion; Paxum; Placidox; Rec-DZ; Valium; Zepose;
Ireland: Anxicalm; Atensine¤; Calmigen¤; Diazemuls¤; Stesolid¤; Valium;
Israel: Assival; Diaz; Disopam¤; Stesolid; Valium¤;
Italy: Aliseum; Ansiolin; Diazemuls; Eridan¤; Micronoan; Noan; Tranquirit; Valitran¤; Valium; Vatran;
Malaysia: Diapine; Diapo;
Mexico: Alboral; Arzepam; AT-V¤; Benzyme; Diacepam; Diapanil; Diatex¤; Farmin¤; Freudal¤; Imepas¤; Laxyl; Nerolid¤; Onapan; Ortopsique; Paxate¤; Prizem; Rayne¤; Relasan¤; Relazepam¤; Sediver¤; Seredyn¤; Tandial¤; Valium; Vanzor¤; Zepan; Zeprat;
Netherlands: Diazemuls; Stesolid; Valium;
Norway: Stesolid; Valium; Vival;
New Zealand: D-Pam; Diazemuls; Propam; Stesolid;
Portugal: Bialzepam; Metamidol; Stesolid; Unisedil; Valium;
Russia: Apaurin (Апаурин); Relanium (Реланиум); Relium (Релиум); Seduxen (Седуксен);
South Africa: Benzopin; Betapam; Calmpose; Diaquel¤; Doval; Dynapam¤; Ethipam¤; Pax; Scriptopam¤; Valium; Singapore: Diapine; Stesolid; Valium¤;
Spain: Aneurol; Aspaserine B6 Tranq¤; Calmaven¤; Complutine; Diaceplex Simple¤; Diaceplex¤; Dicepin B6¤; Drenian¤; Gobanal; Neurocefal Tranqui¤; Pacium; Podium¤; Sedonervil Complex¤; Sico Relax¤; Stesolid; Valium; Vincosedan;
Sweden: Apozepam; Stesolid; Valium¤;
Switzerland: Paceum; Psychopax; Stesolid; Valium; Thailand: Azepam; Diano; Diapam; Diapine; Dizan; Dizepam; Sipam; Stesolid; V Day Zepam¤; Valenium¤; Valium; Zopam;
United Kingdom: Alupram¤; Atensine¤; Dialar; Diazemuls; Evacalm¤; Rimapam; Solis¤; Stesolid; Tensium; Valclair; Valium¤;
United States: Diastat; Dizac¤; T-Quil¤; Valium; Valrelease¤; Zetran¤;
Venezuela: Talema; Telsomet; Valium
Multi-ingredient Preparations
Argentina: Arnol; Dafne; Dislembral; Faradil; Pasminox Somatico; Plidex; Tratobes;
Austria: Acordin¤; Betamed; Harmomed;
Brazil: Dialudon¤; Dobesix; Fastium¤; Moderine; Nofagus¤;
Chile: Calmosedan; Diapam; Mesolona; Multisedil; Promidan; Sedantol; Sedilit;
Czech Republic: Seduxen RG;
Finland: Gastrodyn comp; Nitrapamil¤; Relapamil; Vertipam;
Germany: Elthon¤; Seda-Presomen¤;
Greece: Distedon; India: Depsonil-DZ; Dericip Plus;
Italy: Gamibetal Plus; Gastrausil D¤; Gefarnax¤; Spasen Somatico; Spasmeridan; Spasmomen Somatico; Valpinax; Valtrax;
Mexico: Adepsique; Esbelcaps; Numencial; Qual; Redotex;
Portugal: Gamibetal Compositum¤;
Spain: Ansium; Edym Sedante¤; Pertranquil¤; Tepazepan; Tropargal;
Switzerland: Silentan¤;
United States: Emergent-Ez;
Venezuela: Tepazepam
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