Alprazolam

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].

Effects

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].