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Diazepam

Klassificering: A

Preparat: Diazemuls Novum, Diazepam, Diazepam Autoinjector, Diazepam Desitin, Diazepam Pilum, Diazepam ratiopharm, Diazepam-Ratiopharm, Stesolid Novum, Stesolid®, Stesolid® novum, Stesolid® Rektal Prefill, Valium, Valium Roche

ATC kod: N05BA01

Substanser: diazepam

Sammanfattning

Diazepam har effekt hos både kvinnor och män. Det finns beskrivna könsskillnader i biverkningsmönster men det är oklart vad som är direkt relaterat till läkemedlet. De rapporterade farmakokinetiska skillnaderna är motsägelsefulla och av tveksam klinisk relevans.
 
Det finns motsägande information kring interaktion mellan vissa bensodiazepiner och p-piller som innehåller etinylestradiol. Vissa studier har visat påtagligt långsammare nedbrytning av bensodiazepiner medan andra studier inte har visat någon interaktion med etinylestradiol.

Additional information

Pharmacokinetics and dosing

Several studies have been conducted to assess differences between men and women in single-dose diazepam pharmacokinetics. The results are somewhat conflicting. Some studies demonstrate larger volume of distribution in women than in men [5-7] while other show no difference [8]. Similarly, clearance of diazepam (total and free) has in some studies been shown to be higher in women [5, 6] while others find it to be higher in men [8]. Clearance of the active metabolite desmethyldiazepam has been shown to be higher in men [9]. Results are inconsistent also regarding elimination half-life. Some studies show shorter half-life in men [8] while other studies find no sex difference [5].

Analysis of diazepam metabolites in urine samples has shown higher fractions of temazepam and lower fractions of oxazepam and desmethyldiazepam in samples from women. This may be due to increased CYP3A4 activity in women compared to men [10].

Free fraction of diazepam was shown to be higher in women than in men with renal insufficiency (16 men, 12 women) receiving single-dose diazepam 10 mg [11].

Effects

Hydroxyzine was compared with diazepam as premedication before surgery (49 men, 59 women) in a double-blind randomized manner. In men, there was no difference between the effect of diazepam and hydroxyzine. In women, hydroxyzine was better than diazepam in relieving anxiety [1].

Adverse effects

Sex differences in the effect of diazepam on psychomotor skills were investigated in two placebo-controlled double-blind trials. In the first trial, healthy volunteers (78 men, 78 women) were divided into four groups receiving either an oral dose of 10 mg diazepam, placebo, alcohol in addition to diazepam, or a nonalcoholic drink in addition to placebo. In the second trial, subjects received diazepam or placebo in doses corrected for body weight. Results showed that in women receiving diazepam, psychomotor skills (cognitive, motor and sensory performances) were impaired more than in men. Also, after diazepam administration women experienced clumsiness to a greater extent than men did. The effect of diazepam combined with alcohol did not differ between men and women [12].The frequency of adverse effects of benzodiazepines experienced in psychiatric outpatients has been evaluated in a questionnaire (60 men, 19 women). All women and 91% of men had at least one adverse effect. The mean number of adverse events was 4.8 in both men and women. The most commonly reported adverse effects in both men and women were sleepiness, slowness and fatigue. The most evident sex difference was the higher prevalence of dizziness in women (31%) than men (6%) [2].The risk of falls when using benzodiazepines was studied in a registry study (124009 men, 197413 women). Higher age and female sex was associated with a higher incidence of falls among benzodiazepine users and controls. The risk of falling was higher among benzodiazepine users, more pronouncedly so in men. A history of treatment of alcohol abuse was an important risk factor for falls in this group with an odds ratio of 10.7 in men and 4.3 in women. The benzodiazepines showing the highest increase in risk of falls were flurazepam and triazolam followed by, oxazepam, lorazepam and diazepam in falling order [3].

Reproductive health issues

Ethinyl estradiol may increase exposure of diazepam, possibly due to inhibition of CYP2C19 and CYP3A4 catalysed metabolism of diazepam by ethinyl estradiol. The extent of this is not of that magnitude that dose adjustment normally will be needed [13].In vitro data has shown that free fraction of diazepam was higher in women taking oral contraceptives than in women not taking oral contraceptives. Women without oral contraceptives had higher free fraction of diazepam than men [14]. In part, these findings are supported by a small single-dose study (6 men, 5 women on oral contraceptives) on diazepam disposition. Women had lower plasma clearance of diazepam than men. Theoretically, long-term treatment will therefore result in higher plasma concentrations of diazepam in women than in men. In contrast, no difference between men and women without oral contraceptives was shown in the control group (11 men, 10 women) [15]. A third study (16 women, 8 of them on oral contraceptives) failed to show any difference in diazepam free fraction between women on and free from oral contraceptives. Women on oral contraceptives were shown to have longer elimination half-life of diazepam and also, lower total metabolic clearance [16]. One study (10 men, 8 women on oral contraceptives, no control group without oral contraceptives) also showed that the psychomotor effects of diazepam varied depending on time in the cycle [17]. Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

In a small double-blind Mexican study in young healthy volunteers (9 men, 9 women), EEG was recorded after administration of an oral dose of 5 mg diazepam as well as after placebo. During the recording session the subjects were awake and had their eyes open. The influence of diazepam on EEG activity (alpha, theta, and delta rhythm) differed between men and women.  This may be associated with female sex hormones and sex differences in brain organization [18].A Swedish register-based study conducted on a geriatric population (280623 men, 450482 women, age ≥75) has shown a higher probability for women to use  benzodiazepines/benzodiazepine related drugs [4].

Försäljning på recept

Fler kvinnor än män hämtade ut läkemedel innehållande diazepam (ATC-kod N05BA01) på recept i Sverige år 2015, totalt 52 537 kvinnor och 39 049 män. Det motsvarar 11 respektive 8 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 70 år och äldre hos båda könen. I genomsnitt var läkemedel innehållande diazepam 1,3 gånger vanligare hos kvinnor [19].

Uppdaterat: 2017-03-27

Litteratursökningsdatum: 2015-04-17

Referenser

  1. Herr GP, Conner JT, Schehl D, Dorey F. Comparison of i m diazepam and hydroxyzine as premedicants. Br J Anaesth. 1982;54:3-9. PubMed
  2. Arbanas G, Arbanas D, Dujam K. Adverse effects of benzodiazepines in psychiatric outpatients. Psychiatr Danub. 2009;21:103-7. PubMed
  3. Neutel CI, Hirdes JP, Maxwell CJ, Patten SB. New evidence on benzodiazepine use and falls: the time factor. Age Ageing. 1996;25:273-8. PubMed
  4. Johnell K, Fastbom J. The use of benzodiazpines and related drugs amongst older people in Sweden: associated factors and concomitant use of other psychotropics. Int J Geriatr Psychiatry. 2009;24:731-8. PubMed
  5. Ochs HR, Greenblatt DJ, Divoll M, Abernethy DR, Feyerabend H, Dengler HJ. Diazepam kinetics in relation to age and sex. Pharmacology. 1981;23:24-30. PubMed
  6. Greenblatt DJ, Allen MD, Harmatz JS, Shader RI. Diazepam disposition determinants. Clin Pharmacol Ther. 1980;27:301-12. PubMed
  7. Divoll M, Greenblatt DJ, Ochs HR, Shader RI. Absolute bioavailability of oral and intramuscular diazepam: effects of age and sex. Anesth Analg. 1983;62:1-8. PubMed
  8. MacLeod SM, Giles HG, Bengert B, Liu FF, Sellers EM. Age- and gender-related differences in diazepam pharmacokinetics. J Clin Pharmacol. 1979;19:15-9. PubMed
  9. Yeates RA, Laufen H, Räder K, Leitold M. Preliminary study of the pharmacokinetics of desmethyldiazepam administered as drops or tablets. Arzneimittelforschung. 1986;36:138-40. PubMed
  10. Luk S, Atayee RS, Ma JD, Best BM. Urinary diazepam metabolite distribution in a chronic pain population. J Anal Toxicol. 2014;38:135-42. PubMed
  11. Greenblatt DJ, Harmatz JS, Shader RI. Sex differences in diazepam protein binding in patients with renal insufficiency. Pharmacology. 1978;16:26-9. PubMed
  12. Palva ES. Gender-related differences in diazepam effects on performance. Med Biol. 1985;63:92-5. PubMed
  13. Sfinx Interaktioner. Stockholm: Stockholm County Council. 2015 [cited 2015-10-05.] länk
  14. Routledge PA, Stargel WW, Kitchell BB, Barchowsky A, Shand DG. Sex-related differences in the plasma protein binding of lignocaine and diazepam. Br J Clin Pharmacol. 1981;11:245-50. PubMed
  15. MacLeod SM, Giles HG, Bengert B, Liu FF, Sellers EM. Age- and gender-related differences in diazepam pharmacokinetics. J Clin Pharmacol. 1979;19:15-9. PubMed
  16. MacLeod SM, Giles HG, Bengert B, Liu FF, Sellers EM. Age- and gender-related differences in diazepam pharmacokinetics. J Clin Pharmacol. 1979;19:15-9. PubMed
  17. MacLeod SM, Giles HG, Bengert B, Liu FF, Sellers EM. Age- and gender-related differences in diazepam pharmacokinetics. J Clin Pharmacol. 1979;19:15-9. PubMed
  18. Abernethy DR, Greenblatt DJ, Divoll M, Arendt R, Ochs HR, Shader RI. Impairment of diazepam metabolism by low-dose estrogen-containing oral-contraceptive steroids. N Engl J Med. 1982;306:791-2. PubMed
  19. Ellinwood EH, Easler ME, Linnoila M, Molter DW, Heatherly DG, Bjornsson TD. Effects of oral contraceptives on diazepam-induced psychomotor impairment. Clin Pharmacol Ther. 1984;35:360-6. PubMed
  20. Romano-Torres M, Borja-Lascurain E, Chao-Rebolledo C, del-Río-Portilla Y, Corsi-Cabrera M. Effect of diazepam on EEG power and coherent activity: sex differences. Psychoneuroendocrinology. 2002;27:821-33. PubMed
  21. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-30.] länk

Författare: Anna Garmén, Desirée Loikas

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson