Diazepam

(BAN, USAN, rINN)
Diazepam Chemical formula
Synonyms: Diatsepaami; Diazépam; Diazepám; Diazepamas; Diazepamum; LA-III; NSC-77518; Ro-5-2807; Wy-3467. 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
Cyrillic synonym: Диазепам.

💊 Chemical information

Chemical formula: C16H13ClN2O = 284.7.
CAS — 439-14-5.
ATC — N05B A01.
ATC Vet — QN05BA01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, US, and Viet.

Ph. Eur. 6.2

(Diazepam). A white or almost white, crystalline powder. Very slightly soluble in water; soluble in alcohol. Protect from light.

USP 31

(Diazepam). An off-white to yellow, practically odourless, crystalline powder. Soluble 1 in 333 of water, 1 in 16 of alcohol, 1 in 2 of chloroform, and 1 in 39 of ether. Store in airtight containers. Protect from light.

Incompatibility.

Incompatibility has been reported between diazepam and several other drugs. Manufacturers of diazepam injection (Roche and others) have advised against its admixture with other drugs.

Sorption.

Substantial adsorption of diazepam onto some plastics may cause problems when giving the drug by continuous intravenous infusion. More than 50% of diazepam in solution may be adsorbed onto the walls of PVC infusion bags and their use should, therefore, be avoided. Giving sets should contain the minimum amount of PVC tubing and should not contain a cellulose propionate volume-control chamber. Suitable materials for infusion containers, syringes, and giving sets for diazepam include glass, polyolefin, polypropylene, and polyethylene. 1. Cloyd JC, et al. Availability of diazepam from plastic containers. Am J Hosp Pharm 1980; 37: 492–6. 2. Parker WA, MacCara ME. Compatibility of diazepam with intravenous fluid containers and administration sets. Am J Hosp Pharm 1980; 37: 496–500. 3. Kowaluk EA, et al. Interactions between drugs and intravenous delivery systems. Am J Hosp Pharm 1982; 39: 460–7. 4. Kowaluk EA, et al. Factors affecting the availability of diazepam stored in plastic bags and administered through intravenous sets. Am J Hosp Pharm 1983; 40: 417–23. 5. Martens HJ, et al. Sorption of various drugs in polyvinyl chloride, glass, and polyethylene-lined infusion containers. Am J Hosp Pharm 1990; 47: 369–73.

Stability.

Care should be observed when diluting diazepam injections for infusion because of problems of precipitation. The manufacturer’s directions should be followed regarding diluent and concentration of diazepam and all solutions should be freshly prepared.

💊 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. High doses of diazepam and other benzodiazepines, injected intravenously, have been abused for their euphoriant effects.

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 or, as in the case of very short-acting drugs such as triazolam, to rapid benzodiazepine elimination. 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. The dependence induced by short- and long-acting benzodiazepines appears to be qualitatively similar although withdrawal symptoms may be more severe with short-acting benzodiazepines. Rebound effects are also more likely with short-acting benzodiazepines. Rebound and withdrawal symptoms develop particularly rapidly with the very short-acting drug triazolam. 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 shortterm psychosomatic, organic, or psychotic illness. These recommendations are similar to those of the UK Royal College of Psychiatrists. 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. Clinicians often favour transferring the patient to an equivalent dose of diazepam given at night and the following rough dosage equivalents to diazepam 5mg have been recommended in the UK:
chlordiazepoxide 15 mg
loprazolam 0.5 to 1 mg
lorazepam 500 micrograms
lormetazepam 0.5 to 1 mg
nitrazepam 5 mg
oxazepam 15 mg
temazepam 10 mg 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.
1. CSM. Benzodiazepines, dependence and withdrawal symptoms. Current Problems 21 1988. Available at: http:// www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2024428&RevisionSelectionMethod= LatestReleased (accessed 21/08/08
2. Marriott S, Tyrer P. Benzodiazepine dependence: avoidance and withdrawal. Drug Safety 1993; 9: 93–103
3. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction 1994; 89: 1455–59
4. Ashton H. The treatment of benzodiazepine dependence. Addiction 1994; 89: 1535–41
5. The Royal College of Psychiatrists. Benzodiazepines: risks, benefits or dependence—a re-evaluation. Council Report CR59; London: January, 1997 [under review]. Available at: http:// www.rcpsych.ac.uk/publications/collegereports/cr/cr59.aspx (accessed 31/05/06
6. DoH. Drug misuse and dependence: guidelines on clinical management. London: The Stationery Office, 1999. Available at: http://www.dh.gov.uk/assetRoot/04/07/81/98/04078198.pdf (accessed 28/04/04
7. Denis C, et al. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2006 (accessed 14/03/08).

💊 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 (but see Effects on Mental Function, below), slurred speech or dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation, and amnesia. 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. This topic is reviewed under Pregnancy below. Use of diazepam in late pregnancy has been associated with intoxication of the neonate.

Carcinogenicity.

The International Agency for Research on Cancer concluded1 that there was sufficient evidence from human studies that diazepam did not produce breast cancer, and that there was inadequate data to support its potential carcinogenicity at other sites. For most other benzodiazepines the lack of human studies meant that the carcinogenic risk to humans was not classifiable. However, there appeared to be sufficient evidence of carcinogenicity in animal studies for oxazepam to be classified as possibly carcinogenic in humans.
1. IARC/WHO. Some pharmaceutical drugs. IARC monographs on the evaluation of carcinogenic risks to humans volume 66 1996. Also available at: http://monographs.iarc.fr/ENG/Monographs/ vol66/volume66.pdf (accessed 15/05/06)

Effects on body temperature.

Studies in healthy subjects1,2indicate that benzodiazepines can reduce body temperature. After a single dose of diazepam 10 mg by mouth in 11 subjects, body temperature on exposure to cold fell to a mean of 36.93° compared with 37.08° on exposure without the drug.1 An 86year-old woman developed hypothermia3 after being given nitrazepam 5 mg. After recovery she was mistakenly given another 5-mg dose of nitrazepam and again developed hypothermia. Midazolam (given as anaesthetic premedication) also produces modest decreases in core body temperature, which can be abolished by atropine,4 but its effects are negligible compared with other elements of the anaesthetic regimen.5 Hypothermia has been reported in the neonates of mothers given benzodiazepines during the late stages of pregnancy.
1. Martin SM. The effect of diazepam on body temperature change in humans during cold exposure. J Clin Pharmacol 1985; 25: 611–13
2. Matsukawa T, et al. I.M. midazolam as premedication produces a concentration-dependent decrease in core temperature in male volunteers. Br J Anaesth 1997; 78: 396–9
3. Impallomeni M, Ezzat R. Hypothermia associated with nitrazepam administration. BMJ 1976; 1: 223–4
4. Matsukawa T, et al. Atropine prevents midazolam-induced core hypothermia in elderly patients. J Clin Anesth 2001; 13: 504–8
5. Kurz A, et al. Midazolam minimally impairs thermoregulatory control. Anesth Analg 1995; 81: 393–8.

Effects on endocrine function.

Galactorrhoea with normal serum-prolactin concentrations has been noted in 4 women taking benzodiazepines.1 Gynaecomastia has been reported in a man taking up to 140 mg diazepam daily2 and in 5 men taking diazepam in doses of up to 30 mg daily.3 Serum-oestradiol concentrations were raised in the latter group. However, raised plasma-testosterone concentrations have also been observed in men taking diazepam 10 to 20 mg daily for 2 weeks.4
1. Kleinberg DL, et al. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977; 296: 589–600
2. Moerck HJ, Magelund G. Gynaecomastia and diazepam abuse. Lancet 1979; i: 1344–5
3. Bergman D, et al. Increased oestradiol in diazepam related gynaecomastia. Lancet 1981; ii: 1225–6
4. Argüelles AE, Rosner J. Diazepam and plasma-testosterone levels. Lancet 1975; ii: 607.

Effects on the eyes.

Brown opacification of the lens occurred in 2 patients who took diazepam 5 mg or more daily by mouth over several years.1 Severe visual field loss associated with very high doses (100 mg) of diazepam has also been described.2
1. Pau H. Braune scheibenförmige Einlagerungen in die Linse nach Langzeitgabe von Diazepam (Valium). Klin Monatsbl Augenheilkd 1985; 187: 219–20
2. Elder MJ. Diazepam and its effects on visual fields. Aust N Z J Ophthalmol 1992; 20: 267–70.

Effects on the liver.

Cholestatic jaundice1 and focal hepatic necrosis with intracellular cholestasis2 have been associated with the use of diazepam.
1. Jick H, et al. Drug-induced liver disease. J Clin Pharmacol 1981; 21: 359–64
2. Tedesco FJ, Mills LR. Diazepam (Valium) hepatitis. Dig Dis Sci 1982; 27: 470–2.

Effects on mental function.

The effects of benzodiazepines on psychomotor performance in laboratory tests1 are not easily extrapolated to the clinical situation. For example postoperative cognitive dysfunction in the elderly does not seem to be related to benzodiazepine concentration in the blood.2 Concern has been expressed over the possible effects of longterm benzodiazepine use on the brain. A detailed study3 found that performance of tasks involving visual-spatial ability and sustained attention was poor in patients taking high doses of benzodiazepines for long periods of time. There was no evidence of impairment in global measures of intellectual functioning such as memory, flexibility, and simple reaction time. The authors could draw no conclusions about the effect of benzodiazepine withdrawal on these changes. A study of 17 long-term users of benzodiazepines has indicated a dose-dependent increase in cerebral ventricle size.4 Sexual fantasies have been reported in women sedated with intravenous diazepam or midazolam.5 These appear to be doserelated.6 The view that benzodiazepines can cause depression, albeit infrequently, has been queried.7 Adverse effects of alprazolam on behaviour have also been reviewed.8
1. Woods JH, et al. Abuse liability of benzodiazepines. Pharmacol Rev 1987; 39: 251–413
2. Rasmussen LS, et al. Benzodiazepines and postoperative cognitive dysfunction in the elderly. Br J Anaesth 1999; 83: 585–9
3. Golombok S, et al. Cognitive impairment in long-term benzodiazepine users. Psychol Med 1988; 18: 365–74
4. Schmauss C, Krieg J-C. Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers. Psychol Med 1987; 17: 869–73.
5. Dundee JW. Fantasies during sedation with intravenous midazolam or diazepam. Med Leg J 1990; 58: 29–34
6. Brahams D. Benzodiazepine sedation and allegations of sexual assault. Lancet 1989; i: 1339–40
7. Patten SB, Love EJ. Drug-induced depression: incidence, avoidance and management. Drug Safety 1994; 10: 203–19
8. Cole JO, Kando JC. Adverse behavioral events reported in patients taking alprazolam and other benzodiazepines. J Clin Psychiatry 1993; 54 (suppl): 49–61.

Effects on the nervous system.

There are a few isolated reports of extrapyramidal symptoms in patients taking benzodiazepines.1-4 Benzodiazepines have been used to treat such symptoms induced by antipsychotics.
1. Rosenbaum AH, De La Fuente JR. Benzodiazepines and tardive dyskinesia. Lancet 1979; ii: 900
2. Sandyk R. Orofacial dyskinesias associated with lorazepam therapy. Clin Pharm 1986; 5: 419–21
3. Stolarek IH, Ford MJ. Acute dystonia induced by midazolam and abolished by flumazenil. BMJ 1990; 300: 614
4. Joseph AB, Wroblewski BA. Paradoxical akathisia caused by clonazepam, clorazepate and lorazepam in patients with traumatic encephalopathy and seizure disorders: a subtype of benzodiazepine-induced disinhibition? Behav Neurol 1993; 6: 221–3.
ENCEPHALOPATHY. Prolonged use of midazolam with fentanyl has been associated with encephalopathy in infants sedated under intensive care.1
1. Bergman I, et al. Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration. J Pediatr 1991; 119: 644–9.

Effects on sexual function.

The sedative effects of benzodiazepines may reduce sexual arousal and lead to impotence in some patients. Conversely sexual performance may be improved by therapy if it was previously impaired by anxiety. Increased libido and orgasmic function has been reported in 2 women after withdrawal of long-term benzodiazepine use.1
1. Nutt D, et al. Increased sexual function in benzodiazepine withdrawal. Lancet 1986; ii: 1101–2.

Effects on skeletal muscle.

In a report1 of 2 patients who developed rhabdomyolysis secondary to hyponatraemia it was suggested that the use of benzodiazepines might have contributed to the rhabdomyolysis. Of 8 reported cases of rhabdomyolysis associated with hyponatraemia, 5 had received benzodiazepines. Rhabdomyolysis associated with intravenous drug abuse of oral temazepam formulations has also been reported.2
1. Fernández-Real JM, et al. Hyponatremia and benzodiazepines result in rhabdomyolysis. Ann Pharmacother 1994; 28: 1200–1
2. Deighan CJ, et al. Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse. Q J Med 2000; 93: 29–33.

Effects on the skin.

There have been rare reports of cutaneous reactions to benzodiazepines, including contact dermatitis, fixed drug eruptions, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Analysis by the Boston Collaborative Drug Surveillance Program of data on 15 438 patients hospitalised between 1975 and 1982 detected 2 allergic skin reactions attributed to diazepam among 4707 recipients of the drug.1 A reaction rate of 0.4 per 1000 recipients was calculated from these figures.
1. Bigby M, et al. Drug-induced cutaneous reactions. JAMA 1986; 256: 3358–63.

Hypersensitivity.

Hypersensitivity reactions including anaphylaxis are very rare after use of diazepam. Reactions have been attributed to the polyoxyl castor oil vehicle used for some parenteral formulations.1 There is also a report of a type I hypersensitivity reaction to a lipid emulsion formulation of diazepam.2 See also under Effects on the Skin, above.
1. Hüttel MS, et al. Complement-mediated reactions to diazepam with Cremophor as solvent (Stesolid MR). Br J Anaesth 1980; 52: 77–9
2. Deardon DJ, Bird GLA. Acute (type 1) hypersensitivity to iv Diazemuls. Br J Anaesth 1987; 59: 391.

Local reactions.

Ischaemia and gangrene have been reported after accidental intra-arterial injection of diazepam.1,2 Clinical signs may not occur until several days after the event. Pain and thrombophlebitis after intravenous use may be similarly delayed. Local reactions after intravenous injection have been attributed to the vehicle, and have been observed more often when diazepam is given as a solution in propylene glycol than in polyethoxylated castor oil.3 An emulsion of diazepam in soya oil and water has been associated with a lower incidence of local reactions.3 Pain and phlebitis may also be caused by precipitation of diazepam at the site of infusion.4 Arterial spasm experienced by a patient given diazepam intravenously was probably due to pressure from a cuff on the arm being inflated causing extravasation of diazepam out of the vein and into the radial artery.5 Local irritation has also occurred after rectal use of diazepam.6 For a report of the exacerbation of diazepam-induced thrombophlebitis by penicillamine.
1. Gould JDM, Lingam S. Hazards of intra-arterial diazepam. BMJ 1977; 2: 298–9
2. Rees M, Dormandy J. Accidental intra-arterial injection of diazepam. BMJ 1980; 281: 289–90
3. Olesen AS, Hüttel MS. Local reactions to iv diazepam in three different formulations. Br J Anaesth 1980; 52: 609–11
4. Hussey EK, et al. Correlation of delayed peak concentration with infusion-site irritation following diazepam administration. DICP Ann Pharmacother 1990; 24: 678–80
5. Ng Wing Tin L, et al. Arterial spasm after administration of diazepam. Br J Anaesth 1994; 72: 139
6. Hansen HC, et al. Local irritation after administration of diazepam in a rectal solution. Br J Anaesth 1989; 63: 287–9.

Overdosage.

Impairment of consciousness is fairly rapid in poisoning by benzodiazepines.1 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. During the years 1980 to 1989, 1576 fatal poisonings in Britain were attributed to benzodiazepines.2 Of these, 891 were linked to overdosage with benzodiazepines alone and another 591 to overdosage combined with alcohol. A comparison of these mortality statistics with prescribing data for the same period, to calculate a toxicity index of deaths per million prescriptions, suggested that there were differences between the relative toxicities of individual benzodiazepines in overdosage. A later study of another 303 cases of benzodiazepine poisoning3 supported these findings of differences in toxicity as well as pointing to the relative safety of the benzodiazepines in overdosage.
1. Ashton CH, et al. Drug-induced stupor and coma: some physical signs and their pharmacological basis. Adverse Drug React Acute Poisoning Rev 1989; 8: 1–59
2. Serfaty M, Masterton G. Fatal poisonings attributed to benzodiazepines in Britain during the 1980s. Br J Psychiatry 1993; 163: 386–93
3. Buckley NA, et al. Relative toxicity of benzodiazepines in overdose. BMJ 1995; 310: 219–21.

💊 Treatment of Adverse Effects

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 (or its equivalent) 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.

💊 Precautions

Diazepam should be avoided in patients with pre-existing CNS depression or coma, respiratory depression, acute pulmonary insufficiency, myasthenia gravis, or sleep apnoea, and used with care in those with chronic pulmonary insufficiency. 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; its use should be avoided in severe hepatic impairment. The sedative effects of diazepam are most marked during the first few days of use; affected patients should not drive or operate machinery (see also Driving, below). Monitoring of cardiorespiratory function is generally recommended when benzodiazepines are used for deep sedation. 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. Many manufacturers of diazepam and other benzodiazepines advise against their use in patients with glaucoma, but the rationale for this contra-indication is unclear. For warnings on benzodiazepines during pregnancy and breast feeding, see below. Dependence characterised by a withdrawal syndrome may develop after regular use of diazepam, even in therapeutic doses for short periods (see above); because of the risk of dependence, diazepam should be used with caution in patients with a history of alcohol or drug addiction. Since hypotension and apnoea may occur when benzodiazepines are given intravenously it has been recommended that this route should only be used when facilities for reversing respiratory depression with mechanical ventilation are available. Patients should remain supine and under medical supervision for at least one hour after intravenous injection. Intravenous infusion is best undertaken in specialist centres with intensive care facilities where close and constant supervision can be undertaken.

Administration.

INTRAVENOUS. Prolonged use of high-dose intravenous infusions of diazepam preparations containing benzyl alcohol can result in benzyl alcohol poisoning.1
1. López-Herce J, et al. Benzyl alcohol poisoning following diazepam intravenous infusion. Ann Pharmacother 1995; 29: 632.

Breast feeding.

The American Academy of Pediatrics considers that benzodiazepine use by nursing mothers for long periods was a cause for concern; anxiolytic drugs appear in breast milk and could conceivably alter CNS function in the infant both in the short and long term.1 Similarly, in the UK the CSM has recommended2 that benzodiazepines should not be given to breast-feeding mothers. In one reviewer’s opinion3 the limited distribution into breast milk did not constitute a hazard to the breast-fed infant but the infant should be monitored for sedation and the inability to suckle. Another group has also reported a low incidence of toxicity and adverse effects in the breast-fed infants of mothers taking psychotropic drugs including benzodiazepines.4 It has been suggested5 that if a benzodiazepine must be used during breast feeding it would be preferable to use a short-acting drug with minimal distribution into breast milk and inactive metabolites; oxazepam, lorazepam, alprazolam, or midazolam might be suitable.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 28/04/04
2. Committee on Safety of Medicines/Medicines Control Agency. Reminder: avoid benzodiazepines in pregnancy and lactation. Current Problems 1997; 23: 10. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023240&RevisionSelectionMethod= LatestReleased (accessed 15/05/06
3. McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8: 461–75
4. Birnbaum CS, et al. Serum concentrations of antidepressants and benzodiazepines in nursing infants: a case series. Abstract: Pediatrics 1999; 104: 104. Full version: http://pediatrics.aappublications.org/cgi/content/full/104/1/e11 (accessed 28/04/04
5. Chisholm CA, Kuller JA. A guide to the safety of CNS-active agents during breastfeeding. Drug Safety 1997; 17: 127–42.

Cardiovascular disorders.

See under Respiratory System Disorders, below.

Driving.

Most benzodiazepines can adversely affect parameters of driving performance in healthy subjects.1 It is not entirely clear to what extent benzodiazepines contribute to the risk of driving accidents. A large case-control cohort study2 in elderly drivers suggested that the risk of accidents was increased in those who took longer-acting benzodiazepines. However, younger drivers are more susceptible to the effects of benzodiazepines or zopiclone as a group;3,4 the risk is increased by alcohol consumption.3 Patients affected by drowsiness while taking benzodiazepines should not drive or operate machinery. In the UK, it is an offence to drive while unfit due to the influence of any drug, and benzodiazepines are considered to be the most likely psychotropic medication to impair driving performance, particularly the long-acting compounds.5 However, it is also noted that drivers with psychiatric illnesses may be safer when well controlled with regular medication than when ill. Drowsiness often becomes less troublesome with continued use of these drugs.
1. Woods JH, et al. Abuse liability of benzodiazepines. Pharmacol Rev 1987; 39: 251–413
2. Hemmelgarn B, et al. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 1997; 278: 27–31
3. Barbone F, et al. Association of road-traffic accidents with benzodiazepine use. Lancet 1998; 352: 1331–6
4. Vanakoski J, et al. Driving under light and dark conditions: effects of alcohol and diazepam in young and older subjects. Eur J Clin Pharmacol 2000; 56: 453–8
5. Driver and Vehicle Licensing Agency. For medical practitioners: at a glance guide to the current medical standards of fitness to drive (updated February 2008). http://www.dvla.gov.uk/media/ pdf/medical/aagv1.pdf (accessed 14/08/08)

The elderly.

Old age may alter the distribution, elimination, and clearance of benzodiazepines.1,2 Metabolic clearance of benzodiazepines metabolised principally by oxidation appears to be reduced but not clearance of those biotransformed by glucuronide conjugation or nitroreduction. Prolonged half-life in the elderly may be a result of such a decrease in clearance or of an increase in the volume of distribution. The clinical consequence of these changes depends on factors such as dosage schedule and extent of first-pass extraction by the liver. Irrespective of pharmacokinetic changes, the elderly may exhibit increased sensitivity to acute doses of benzodiazepines.1-3 Impairment of memory, cognitive function, and psychomotor performance and behaviour disinhibition may be more common than with younger patients.4 Long-term use commonly exacerbates underlying dementia in elderly patients.4 The upshot of the pharmacokinetic and pharmacodynamic changes of benzodiazepines in the elderly is that adverse effects may be more frequent in these patients and lower doses are commonly required. An epidemiological study of persons 65 years and older found an increased rate of hip fracture among current users of long-acting benzodiazepines (chlordiazepoxide, clorazepate, diazepam, and flurazepam), but not among users of short-acting drugs (alprazolam, bromazepam, lorazepam, oxazepam, and triazolam).5 A case-control study6 of patients with falls leading to femur fractures suggested that the most important factor in increasing risk was the dose of benzodiazepine. However, another case-control study7 found no correlation between hip fracture and benzodiazepines either as a group or according to half-life or to characterisation as an anxiolytic or a hypnotic; there might, though, be an increase in risk with lorazepam. There was also an increased risk associated with use of two or more benzodiazepines. Nonetheless, if use of a benzodiazepine 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 benzodiazepines should be avoided in these patients (see Respiratory System Disorders, below).
1. Greenblatt DJ, et al. Implications of altered drug disposition in elderly: studies of benzodiazepines. J Clin Pharmacol 1989; 29: 866–72
2. Greenblatt DJ, et al. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly: therapeutic considerations. Clin Pharmacokinet 1991; 21: 165–77 and 262–73
3. Swift CG. Pharmacodynamics: changes in homeostatic mechanisms, receptor and target organ sensitivity in the elderly. Br Med Bull 1990; 46: 36–52
4. Juergens SM. Problems with benzodiazepines in elderly patients. Mayo Clin Proc 1993; 68: 818–20
5. Ray WA, et al. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA 1989; 262: 3303–7
6. Herings RMC, et al. Benzodiazepines and the risk of falling leading to femur fractures: dosage more important than elimination half-life. Arch Intern Med 1995; 155: 1801–7
7. Pierfitte C, et al. Benzodiazepines and hip fractures in elderly people: case-control study. BMJ 2001; 322: 704–8.

Hangover effects.

Long-acting benzodiazepines accumulate in the body to a greater extent than ones with a shorter half-life. Although this might be expected to increase the frequency of daytime sedation and impairment of performance (so-called hangover effects) after a hypnotic dose, such a straightforward relationship has not always been observed in practice.1 Anterograde amnesia is more common with short-acting drugs such as triazolam; ‘traveller’s amnesia’ has been used to describe amnesia in persons taking benzodiazepines for sleep disturbances resulting from jet lag.2
1. Greenblatt DJ, et al. Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs. Am J Med 1990; 88 (suppl 3A): 18S–24S
2. Meyboom RHB. Benzodiazepines and pilot error. BMJ 1991; 302: 1274–5.

High-altitude disorders.

Sleep may be impaired at high altitude due to frequent arousals associated with pronounced oxygen desaturation and periodic breathing. Traditional advice has been that sedatives should not be given at high altitude.1 Caution may also be warranted at moderate altitudes especially in nonacclimatised climbers.2 It has been argued that since diazepam, and possibly other sedatives, blunt the hypoxic ventilatory response, sleep hypoxaemia might be exacerbated. A small study3has suggested that small doses of a short-acting benzodiazepine, such as temazepam, might actually improve the subjective quality of sleep and reduce episodes of arterial desaturation without changing mean oxygen saturation. However the possibility of an interaction between acetazolamide taken for prophylaxis or treatment of acute mountain sickness and the benzodiazepine should be borne in mind; ventilatory depression in a mountain climber with acute mountain sickness was considered to be due to the potentiation of triazolam by acetazolamide.4
1. Sutton JR, et al. Insomnia, sedation, and high altitude cerebral oedema. Lancet 1979; i: 165
2. Röggla G, et al. Effect of temazepam on ventilatory response at moderate altitude. BMJ 2000; 320: 56
3. Dubowitz G. Effect of temazepam on oxygen saturation and sleep quality at high altitude: randomised placebo controlled crossover trial. BMJ 1998; 316: 587–9
4. Masuyama S, et al. ‘Ondine’s curse’: side effect of acetazolamide? Am J Med 1989; 86: 637.

Neonates.

A retrospective review of records from 63 infants given lorazepam or midazolam in a neonatal intensive-care unit indicated that there were 14 cases of adverse effects associated with benzodiazepine use (seizures in 6 cases, hypotension in 5, and respiratory depression in 3).1 Seven of these were associated with intravenous bolus doses of lorazepam and the remainder with continuous midazolam infusions. Despite the limitations of the study, the incidence of adverse effects in this group seemed high, and the authors recommended that benzodiazepine use in neonates be accompanied by close monitoring.
1. Ng E, et al. Safety of benzodiazepines in newborns. Ann Pharmacother 2002; 36: 1150–5.

Nervous system disorders.

Benzodiazepines can reduce cerebral perfusion pressure and blood oxygenation to an extent that results in irreversible neurological damage in patients with head injuries. Consequently, they should be given with great care to such patients.1,2 Their use should be avoided for the control of seizures in patients with head injuries or other acute neurological lesions as these patients can be managed effectively with phenytoin.
1. Eldridge PR, Punt JAG. Risks associated with giving benzodiazepines to patients with acute neurological injuries. BMJ 1990; 300: 1189–90
2. Papazian L, et al. Effect of bolus doses of midazolam on intracranial pressure and cerebral perfusion pressure in patients with severe head injury. Br J Anaesth 1993; 71: 267–71.
EPILEPSY. As with other antiepileptic drugs,1 there have been rare reports of benzodiazepines producing paradoxical exacerbation of seizures in patients with epilepsy.2-5
1. Guerrini R, et al. Antiepileptic drug-induced worsening of seizures in children. Epilepsia 1998; 39 (suppl 3): S2–S10
2. Prior PF, et al. Intravenous diazepam. Lancet 1971; 2: 434–5
3. Tassinari CA, et al. A paradoxical effect: status epilepticus induced by benzodiazepines (Valium and Mogadon). Electroencephalogr Clin Neurophysiol 1971; 31: 182
4. Di Mario FJ, Clancy RR. Paradoxical precipitation of tonic seizures by lorazepam in a child with atypical absence seizures. Pediatr Neurol 1988; 4: 249–51
5. Borusiak P, et al. Seizure-inducing paradoxical reaction to antiepileptic drugs. Brain Dev 2000; 22: 243–5.

Porphyria.

Diazepam has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients. Intravenous diazepam has been used successfully, however, to control status epilepticus occurring after the acute porphyric attack. For a discussion of the management of seizures associated with acute porphyric attacks.

Pregnancy.

Benzodiazepines have been widely used in pregnant patients.1 Use of benzodiazepines in the third trimester and during labour seems to be associated in some infants with neonatal withdrawal symptoms or the floppy infant syndrome. Also a small number exposed in utero to benzodiazepines have shown slow development in the early years but by 4 years of age most had developed normally, and for those that had not it was not possible to prove a cause-effect relationship with benzodiazepine exposure. In a meta-analysis2 of live births after benzodiazepine use during the first trimester of pregnancy, pooled data from cohort studies showed no apparent association between benzodiazepine use and the risk of major malformations or oral cleft alone. There was, however, a small but significantly increased risk of oral cleft according to data from case-control studies. Although benzodiazepines did not appear to be a major human teratogen, use of ultrasonography was advised to rule out visible forms of cleft lip. The UK CSM has recommended3 that women of child-bearing potential prescribed benzodiazepines should be advised to contact the physician about stopping the drug if they intend to become, or suspect that they are, pregnant.
1. McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8: 461–75
2. Dolovich LR, et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and casecontrol studies. BMJ 1998; 317: 839–43
3. Committee on Safety of Medicines/Medicines Control Agency. Reminder: avoid benzodiazepines in pregnancy and lactation. Current Problems 1997; 23: 10. Also available at: http:// www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023240&RevisionSelectionMethod= LatestReleased (accessed 15/05/06)

Respiratory system disorders.

Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnoea or other sleep-related breathing disorders especially in patients with chronic obstructive pulmonary disease or cardiac failure.1 Risk factors for sleep apnoea, which often goes undiagnosed, include old age, obesity, male sex, postmenopausal status in women, and a history of heavy snoring. Although benzodiazepines may reduce sleep fragmentation, their long-term use may result in conversion from partial to complete obstructive sleep apnoea in heavy snorers or in short repetitive central sleep apnoea in patients with recent myocardial infarction.
1. Guilleminault C. Benzodiazepines, breathing, and sleep. Am J Med 1990; 88 (suppl 3A): 25S–28S.

💊 Interactions

Enhanced sedation or respiratory and cardiovascular depression may occur if diazepam or other benzodiazepines are given with other drugs that have CNSdepressant properties; these include alcohol, antidepressants, sedative antihistamines, antipsychotics, general anaesthetics, other hypnotics or sedatives, and opioid analgesics. The sedative effect of benzodiazepines may also be enhanced by cisapride. Adverse effects may also be produced by use with drugs that interfere with the metabolism of benzodiazepines. Drugs that have been reported to alter the pharmacokinetics of benzodiazepines are discussed in detail below but few of these interactions are likely to be of clinical significance. Benzodiazepines such as diazepam that are metabolised primarily by hepatic microsomal oxidation may be more susceptible to pharmacokinetic changes than those eliminated primarily by glucuronide conjugation.

Analgesics.

The peak plasma concentration of oxazepam was significantly decreased when diflunisal was given to 6 healthy subjects, while the renal clearance of the glucuronide metabolite was reduced and its mean elimination half-life increased from 10 to 13 hours.1 Diflunisal also displaced oxazepam from plasma protein binding sites in vitro. Aspirin shortened the time to induce anaesthesia with midazolam in 78 patients also possibly due to competition for plasma protein binding sites.2 Paracetamol produced no significant change in plasma concentrations of diazepam or its major metabolite and only marginal changes in urine concentrations in 4 healthy subjects.3 Benzodiazepines such as diazepam, lorazepam, and midazolam may be used with opioid analgesics in anaesthetic or analgesic regimens. An additive sedative effect is to be expected4 but there are also reports of severe respiratory depression with midazolam and fentanyl5 or sudden hypotension with midazolam and fentanyl6 or sufentanil.7 The clearance of midazolam appears to be reduced by fentanyl,8 possibly as a result of competitive inhibition of metabolism by the cytochrome P450 isoenzyme CYP3A. Careful monitoring is therefore required during use of midazolam with these opioids and the dose of both drugs may need to be reduced. Synergistic potentiation of the induction of anaesthesia has been reported between midazolam and fentanyl,9but one study has suggested that midazolam can reduce the analgesic effects of sufentanil.10 Pretreatment with morphine or pethidine has decreased the rate of oral absorption of diazepam. This has been attributed to the effect of opioid analgesics on gastrointestinal motility.11 Dextropropoxyphene prolonged the half-life and reduced the clearance of alprazolam but not diazepam or lorazepam in healthy subjects.12
1. Van Hecken AM, et al. The influence of diflunisal on the pharmacokinetics of oxazepam. Br J Clin Pharmacol 1985; 20: 225–34
2. Dundee JW, et al. Aspirin and probenecid pretreatment influences the potency of thiopentone and the onset of action of midazolam. Eur J Anaesthesiol 1986; 3: 247–51
3. Mulley BA, et al. Interactions between diazepam and paracetamol. J Clin Pharm 1978; 3: 25–35
4. Tverskoy M, et al. Midazolam-morphine sedative interaction in patients. Anesth Analg 1989; 68: 282–5
5. Yaster M, et al. Midazolam-fentanyl intravenous sedation in children: case report of respiratory arrest. Pediatrics 1990; 86: 463–7
6. Burtin P, et al. Hypotension with midazolam and fentanyl in the newborn. Lancet 1991; 337: 1545–6
7. West JM, et al. Sudden hypotension associated with midazolam and sufentanil. Anesth Analg 1987; 66: 693–4
8. Hase I, et al. I.V. fentanyl decreases the clearance of midazolam. Br J Anaesth 1997; 79: 740–3
9. Ben-Shlomo I, et al. Midazolam acts synergistically with fentanyl for induction of anaesthesia. Br J Anaesth 1990; 64: 45–7
10. Luger TJ, Morawetz RF. Clinical evidence for a midazolam-sufentanil interaction in patients with major trauma. Clin Pharmacol Ther 1991; 49: 133
11. Gamble JAS, et al. Some pharmacological factors influencing the absorption of diazepam following oral administration. Br J Anaesth 1976; 48: 1181–5
12. Abernethy DR, et al. Interaction of propoxyphene with diazepam, alprazolam and lorazepam. Br J Clin Pharmacol 1985; 19: 51–7.

Antiarrhythmics.

An interaction between clonazepam and existing therapy with amiodarone was suspected in a 78-year-old man who experienced symptoms of benzodiazepine toxicity 2 months after starting with clonazepam 500 micrograms given at bedtime for restless leg syndrome;1 symptoms resolved on withdrawal of clonazepam.
1. Witt DM, et al. Amiodarone-clonazepam interaction. Ann Pharmacother 1993; 27: 1463–4.

Antibacterials.

Both erythromycin1 and troleandomycin2 have been reported to inhibit the hepatic metabolism of triazolam in healthy subjects. Peak plasma-triazolam concentrations were increased, half-life prolonged, and clearance reduced. Troleandomycin prolonged the psychomotor impairment and amnesia produced by triazolam.2 Loss of consciousness after erythromycin infusion in a child premedicated with midazolam was attributed to a similar interaction,3 and increases in peak plasma concentrations of midazolam with profound and prolonged sedation have been reported after use of erythromycin.4 Use of midazolam with erythromycin should be avoided or the dose of midazolam reduced by 50 to 75%. The clearance of midazolam is also reduced by clarithromycin, with an approximate doubling of the benzodiazepine’s oral bioavailability.5 The manufacturers of quinupristin/dalfopristin state that it too may increase plasma concentrations of midazolam. Roxithromycin has been reported6to have some effects on the pharmacokinetics and pharmacodynamics of midazolam but these changes were not thought clinically relevant. However, it was recommended that as a precaution the lowest possible effective dose of midazolam should be used when given with roxithromycin. In another study7 azithromycin did not appear to have any effect on the metabolism or psychomotor effects of midazolam. There is an isolated report of significant rises in steady-state blood-midazolam concentration coinciding with dosage of ciprofloxacin.8 Also ciprofloxacin has been reported to reduce diazepam clearance and prolong its terminal half-life,9 although psychometric tests did not show any changes in diazepam’s pharmacodynamics. However, ciprofloxacin appears to have no effect on the pharmacokinetics or pharmacodynamics of temazepam.10 Isoniazid has been reported to increase the half-life of a single dose of diazepam11 and triazolam12 but not of oxazepam12 in healthy subjects. In contrast, rifampicin has decreased the halflife of alprazolam,13 diazepam,14 midazolam,15 and nitrazepam16and more or less abolishes the effects of triazolam,17 while ethambutol has no effect on diazepam pharmacokinetics.11 In patients receiving therapy for tuberculosis with isoniazid, rifampicin, and ethambutol the half-life of a single diazepam dose was shortened and its clearance increased.11 Thus the enzymeinducing effect of rifampicin appears to predominate over the enzyme-inhibiting effect of isoniazid.
1. Phillips JP, et al. A pharmacokinetic drug interaction between erythromycin and triazolam. J Clin Psychopharmacol 1986; 6: 297–9
2. Warot D, et al. Troleandomycin-triazolam interaction in healthy volunteers: pharmacokinetic and psychometric evaluation. Eur J Clin Pharmacol 1987; 32: 389–93
3. Hiller A, et al. Unconsciousness associated with midazolam and erythromycin. Br J Anaesth 1990; 65: 826–8
4. Olkkola KT, et al. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 1993; 53: 298–305
5. Gorski JC, et al. The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin. Clin Pharmacol Ther 1998; 64: 133–43
6. Backman JT, et al. A pharmacokinetic interaction between roxithromycin and midazolam. Eur J Clin Pharmacol 1994; 46: 551–5
7. Mattila MJ, et al. Azithromycin does not alter the effects of oral midazolam on human performance. Eur J Clin Pharmacol 1994; 47: 49–52
8. Orko R, et al. Intravenous infusion of midazolam, propofol and vecuronium in a patient with severe tetanus. Acta Anaesthesiol Scand 1988; 32: 590–2
9. Kamali F, et al. The influence of steady-state ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of diazepam in healthy volunteers. Eur J Clin Pharmacol 1993; 44: 365–7
10. Kamali F, et al. The influence of ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of temazepam in the young and elderly. J Clin Pharm Ther 1994; 19: 105–9
11. Ochs HR, et al. Diazepam interaction with antituberculous drugs. Clin Pharmacol Ther 1981; 29: 671–8
12. Ochs HR, et al. Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation. Br J Clin Pharmacol 1983; 16: 743–6
13. Schmider J, et al. Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics 1999; 9: 725–34
14. Ohnhaus EE, et al. The effect of antipyrine and rifampin on the metabolism of diazepam. Clin Pharmacol Ther 1987; 42: 148–56
15. Backman JT, et al. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther 1996; 59: 7–13
16. Brockmeyer NH, et al. Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam. Int J Clin Pharmacol Ther Toxicol 1990; 28: 387–93
17. Villikka K, et al. Triazolam is ineffective in patients taking rifampicin. Clin Pharmacol Ther 1997; 61: 8–14.

Anticoagulants.

Plasma binding of diazepam and desmethyldiazepam was reduced, and free concentrations increased, immediately following heparin intravenously.1 Benzodiazepines do not usually interact with oral anticoagulants although there have been rare reports of altered anticoagulant activity.
1. Routledge PA, et al. Diazepam and N-desmethyldiazepam redistribution after heparin. Clin Pharmacol Ther 1980; 27: 528–32.

Antidepressants.

It has been recommended that the dosage of alprazolam should be reduced when given with fluvoxamine, as concomitant use has resulted in doubling of plasma-alprazolam concentrations.1 Since plasma concentrations of bromazepam2and of diazepam3 also appear to be affected by fluvoxamine, it has been suggested that patients taking fluvoxamine who require a benzodiazepine should preferentially receive one such as lorazepam, which has a different metabolic pathway.3 Small studies suggest that fluoxetine can also increase plasma concentrations of alprazolam.4,5 Fluoxetine appears to have a similar effect on diazepam but plasma concentrations of diazepam’s active metabolite desmethyldiazepam are reduced and it is considered that the overall effect is likely to be minor.6 The potential for a clinically significant interaction with sertraline, paroxetine, or citalopram is considered to be less.7 The US manufacturers have reported that alprazolam may increase the steady-state plasma concentrations of imipramine and desipramine, although the clinical significance of such changes is unknown. For a suggestion that benzodiazepines may increase the oxidation of amineptine to a toxic metabolite, see Effects on the Liver under Adverse Effects of Amitriptyline. Nefazodone has been reported to raise concentrations of alprazolam and triazolam, resulting in increased sedation, and impairment of psychomotor performance.8,9 Nefazodone may inhibit the oxidative metabolism of alprazolam and triazolam. Raised concentrations of midazolam have similarly been seen when given by mouth with nefazodone.10 No interaction was reported with lorazepam, which is primarily eliminated by conjugation. For reference to an isolated report of hypothermia after administration of diazepam and lithium. There have been occasional reports of sexual disinhibition in patients taking tryptophan with benzodiazepines.
1. Fleishaker JC, Hulst LK. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994; 46: 35–9
2. Van Harten J, et al. Influence of multiple-dose administration of fluvoxamine on the pharmacokinetics of the benzodiazepines bromazepam and lorazepam: a randomized crossover study. Eur Neuropsychopharmacol 1992; 2: 381
3. Perucca E, et al. Inhibition of diazepam metabolism by fluvoxamine: a pharmacokinetic study in normal volunteers. Clin Pharmacol Ther 1994; 56: 471–6
4. Lasher TA, et al. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology (Berl) 1991; 104: 323–7
5. Greenblatt DJ, et al. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther 1992; 52: 479–86
6. Lemberger L, et al. The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther 1988; 43: 412–19
7. Sproule BA, et al. Selective serotonin reuptake inhibitors and CNS drug interactions: a critical review of the evidence. Clin Pharmacokinet 1997; 33: 454–71
8. Greene DS, et al. Coadministration of nefazodone (NEF) and benzodiazepines I: pharmacokinetic assessment. Clin Pharmacol Ther 1994; 55: 141
9. Kroboth P, et al. Coadministration of nefazodone and benzodiazepines II: pharmacodynamic assessment. Clin Pharmacol Ther 1994; 55: 142
10. Lam YWF, et al. Effect of antidepressants and ketoconazole on oral midazolam pharmacokinetics. Clin Pharmacol Ther 1998; 63: 229.

Antiepileptics.

Carbamazepine, phenobarbital, and phenytoin are all inducers of hepatic drug-metabolising enzymes. Therefore, in patients receiving long-term therapy with these drugs the metabolism of benzodiazepines may be enhanced. For oral midazolam the effects of carbamazepine or phenytoin may be sufficient to virtually abolish the effects of a standard dose, with a more than 90% reduction in peak serum concentrations of the benzodiazepine.1 Results from a study2 involving 66 children and adults receiving clobazam as adjunctive therapy for epilepsy showed a significant increase in clobazam clearance, leading to accumulation of its principal active metabolite N-desmethylclobazam, in the 16 patients also taking felbamate. The metabolism of clobazam and Ndesmethylclobazam was reduced by stiripentol, a potent hepatic enzyme inhibitor, resulting in a threefold increase in the plasma concentrations of this metabolite.3 Serum-clonazepam concentrations fell markedly in 4 of 8 children who had lamotrigine added to their therapy.4 Sodium valproate has been reported to displace diazepam from plasma-protein binding sites.5 Sporadic reports exist of adverse effects when valproate is given with clonazepam6,7 with the development of drowsiness and, more seriously, absence status epilepticus, but the existence of an interaction is considered to be unproven.8 Drowsiness has also been reported when valproate was given with nitrazepam.9 Use of valproate semisodium with lorazepam has resulted in raised concentrations of lorazepam due to inhibition of glucuronidation of lorazepam.10
1. Backman JT, et al. Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia 1996; 37: 253–7
2. Contin M, et al. Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy. Ther Drug Monit 1999; 21: 604–8
3. Giraud C, et al. In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism. Drug Metab Dispos 2006; 34: 608–11
4. Eriksson A-S, et al. Pharmacokinetic interactions between lamotrigine and other antiepileptic drugs in children with intractable epilepsy. Epilepsia 1996; 37: 769–73
5. Dhillon S, Richens A. Valproic acid and diazepam interaction in vivo. Br J Clin Pharmacol 1982; 13: 553–60
6. Watson WA. Interaction between clonazepam and sodium valproate. N Engl J Med 1979; 300: 678
7. Browne TR. Interaction between clonazepam and sodium valproate. N Engl J Med 1979; 300: 679
8. Levy RH, Koch KM. Drug interactions with valproic acid. Drugs 1982; 24: 543–56
9. Jeavons PM, et al. Treatment of generalized epilepsies of childhood and adolescence with sodium valproate (Epilim). Dev Med Child Neurol 1977; 19: 9–25
10. Samara EE, et al. Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam. J Clin Pharmacol 1997; 37: 442–50.

Antifungals.

Both a single dose and multiple doses of ketoconazole decreased the clearance of a single intravenous injection of chlordiazepoxide.1 Studies2-4 have shown that ketoconazole and itraconazole can produce marked pharmacokinetic interactions with midazolam or triazolam and greatly increase the intensity and duration of action of these benzodiazepines. The area under the plasma concentration-time curve for midazolam was increased by 15 times by ketoconazole and by 10 times by itraconazole while peak plasma concentrations of midazolam were increased fourfold and threefold, respectively.2 The area under the curve for triazolam was increased by 22 times by ketoconazole and by 27 times by itraconazole;3 peak plasma concentrations of triazolam were increased about threefold by both
Published December 23, 2018.