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Classification: B

Drug products: Alprazolam 2care4, Alprazolam Alternova, Alprazolam Krka, Alprazolam Krka d.d., Alprazolam Mylan, Alprazolam Orion, Alprazolam Sandoz, Alprazolam STADA®, Xanor®, Xanor® Depot

ATC code: N05BA12

Substances: alprazolam


The effect of alprazolam in panic disorder has been reported to be similar in men and women. Some studies have observed sex differences in alprazolam pharmacokinetics and some have not. One study found a reduced clearance in elderly men compared to young men, while this age effect was not seen in women.
There are conflicting results regarding interaction between some benzodiazepines and contraceptives containing ethinyl estradiol. Some studies have shown a considerably slower metabolism of benzodiazepines while other studies have not shown any interaction with ethinyl estradiol.

Additional information

Pharmacokinetics and dosing

There are conflicting results regarding sex differences in alprazolam pharmacokinetics. Several studies have analyzed the pharmacokinetics of single doses of 1 mg alprazolam. Two studies did not find significant sex differences on alprazolam pharmacokinetics [1, 3]. One study in young volunteers (8 men, 8 women) showed that women had higher clearance and a lower AUC (corrected for the dose per kg bodyweight) [5]. Another study (16 men and 16 women) found a reduced clearance and prolonged half-life in elderly men (mean age 70 years) compared with young men (mean age 31 years), but this age effect was not seen in women [6]. A bioavailability study comparing immediate release (1.5 mg four times daily) and controlled release (3 mg two times daily) form of alprazolam in healthy volunteers (10 men, 7 women, 20-74 years), did not find sex to be a predictor of clearance [7].In the approval documentation in the FDA application for alprazolam orally disintegrating tablets (NIRAVAM®), dose and weight normalized data suggested a sex difference in AUC and Cmax, which was not present in the raw data [8].Based on the observed age differences in clearance among men [6], the authors suggest that a need for reduced dose of alprazolam should be anticipated during treatment of elderly men [6].


According to the approval documents in the FDA application, four placebo-controlled clinical trials (63% women) have shown that both men and women treated with alprazolam extended-release tablets (XANAX XR®) had greater improvement in their overall clinical condition compared with placebo [9]. However, the pharmaceutical company did not formally explore the effect of sex on the efficacy and safety for the extended-release tablet and there is no information for the immediate-release tablet [9].

Adverse effects

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].According to the approval documents in the FDA application, patient's sex has minimal effect on adverse events from alprazolam treatment or discontinuation [9].

Reproductive health issues

A phase I study in healthy women found that low-dose estrogen can inhibit the metabolism of alprazolam and increase the  exposure of alprazolam with 35%, resulting in an enhanced effect of alprazolam [10]. However, another controlled study did not observe any significant effect of low-dose estrogen on alprazolam pharmacokinetics [11]. The clinical relevance of these interactions is considered to be minor [12]. 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

Elevation in blood cortisol levels between doses (inter-dose) after chronic alprazolam treatment could be an early manifestation of alprazolam dependence and/or drug withdrawal. The effects of chronic alprazolam treatment on cortisol response in healthy elderly has been examined in a double-blind, placebo-controlled study (12 men, 13 women, 60-79 years old). Patients received 1 mg alprazolam daily for 3 weeks. Elderly women had elevated inter-dose morning plasma cortisol levels compared to placebo, while men did not [13].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].

Updated: 2018-12-18

Date of litterature search: 2015-10-05


  1. Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam Therapeutic implications. Clin Pharmacokinet. 1993;24:453-71. PubMed
  2. Arbanas G, Arbanas D, Dujam K. Adverse effects of benzodiazepines in psychiatric outpatients. Psychiatr Danub. 2009;21:103-7. PubMed
  3. Kirkwood C, Moore A, Hayes P, DeVane CL, Pelonero A. Influence of menstrual cycle and gender on alprazolam pharmacokinetics. Clin Pharmacol Ther. 1991;50:404-9. 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. Kristjánsson F, Thorsteinsson SB. Disposition of alprazolam in human volunteers Differences between genders. Acta Pharm Nord. 1991;3:249-50. PubMed
  6. Greenblatt DJ, Divoll M, Abernethy DR, Moschitto LJ, Smith RB, Shader RI. Alprazolam kinetics in the elderly Relation to antipyrine disposition. Arch Gen Psychiatry. 1983;40:287-90. PubMed
  7. Hossain M, Wright E, Baweja R, Ludden T, Miller R. Nonlinear mixed effects modeling of single dose and multiple dose data for an immediate release (IR) and a controlled release (CR) dosage form of alprazolam. Pharm Res. 1997;14:309-15. PubMed
  8. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review - NIRAVAM (alprazolam). Food and Drug Administration [www]. [updated 2005-01-19, cited 2015-10-15]. länk
  9. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review - XANAX XR (alprazolam). Food and Drug Administration [www]. [updated 2003-01-17, cited 2015-10-15]. länk
  10. Stoehr GP, Kroboth PD, Juhl RP, Wender DB, Phillips JP, Smith RB. Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics. Clin Pharmacol Ther. 1984;36:683-90. PubMed
  11. Scavone JM, Greenblatt DJ, Locniskar A, Shader RI. Alprazolam pharmacokinetics in women on low-dose oral contraceptives. J Clin Pharmacol. 1988;28:454-7. PubMed
  12. Sfinx Interaktioner. Stockholm: Stockholm County Council. 2015 [cited 2015-10-05.] länk
  13. Pomara N, Willoughby LM, Ritchie JC, Sidtis JJ, Greenblatt DJ, Nemeroff CB. Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance. Psychopharmacology (Berl). 2005;182:414-9. PubMed
  14. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-05.] länk

Authors: Linnéa Karlsson Lind, Desirée Loikas

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson