Haloperidol

Additional information

Pharmacokinetics and dosing

Two pharmacokinetic studies addressed possible sex differences in pharmacokinetics of oral haloperidol. Neither a four-week study in patients treated with haloperidol 2-20 mg/day (10 men, 16 women) [1] nor a single dose study (haloperidol 10 mg) in healthy poor and extensive metabolizers of CYP2D6 (8 men, 8 women) could detect a statistically significant difference between man and women with respect to clearance or half-life [2]. Due to the low statistical power of these two studies it is hard to draw any conclusion on sex differences of haloperidol pharmacokinetics.

Effects

The optimal dosing of haloperidol may be as low as 4 mg/day [3], but many clinical trials on haloperidol used doses up to 20 mg/day.   

In general, possible sex differences of haloperidol have not been studied to any larger extent.  The results of a 6 week randomized clinical trial of haloperidol versus olanzapine in patients with schizophrenia spectrum disorder (426 men, 233 women in the treatment arm with haloperidol (5-20 mg/d)) [4] have been analysed with regard to sex differences in efficacy in two publications [5, 6]. Men and women were not found to significantly differ on any of the clinical outcome measures (Brief Psychiatric rating scale, BPRS) total score or positive or negative subscale. When the data was analyzed in women only after stratifying by age group < 47 years versus > 47 years (as a proxy for menopausal status), there was a significant overall difference in treatment response between pre- and postmenopausal women (BPRS, respectively: 22.8 ± 1.3 vs. 27.7 ± 2.1) [6].

Postoperative nausea and vomiting (PONV) can be treated by intravenous haloperidol 0.5 mg. In a register-based study of 2617 surgical procedures haloperidol was administered (523 men, 749 women. The results indicate a reduced risk of PONV by haloperidol in men but not in women [7].

A Cochrane meta-analysis noted that haloperidol decreased aggression among patients with agitated dementia. However, the data were insufficient to examine response to treatment in relation to patient’s sex and cause of dementia [8].

Adverse effects

The optimal dosing of haloperidol may be as low as 4 mg/day [3], but many clinical trials on haloperidol used doses up to 20 mg/day.   

An analysis of reported adverse effects of haloperidol, compiled by Johnson & Johnson, identified 229 cases of abnormally long QTc intervals, among which were 73 cases of Torsade de Pointes (TdP). Eleven (15%) of the TdP cases were fatal, and 8 (73%) of these deaths occurred after haloperidol had been given intravenously. However, the data provided in this review did not analyse the risk for adverse events separately in men and women. But female sex is among known risk factors for drug-induced ventricular arrhythmias [9, 10].

Haloperidol elevates serum prolactin levels to 20–40 ng/ml when used at therapeutic doses and sexual dysfunction is reported by 45% of men and 25% of women treated with haloperidol [11, 12]. Reduced libido (in around 31% of men and 24% of women) is the most commonly reported disturbance. In men, reports of erectile dysfunction varies between 30–50% [11-13] and gynecomastia has been reported in 3.3% [12]. In women, amenorrhea/menstrual disturbances has been reported in 14% in one clinical trial and in 54% in another trial [13].

The effect of haloperidol on prolactin levels in men and women was analysed in the above mentioned randomized clinical trial of haloperidol versus olanzapine [4]. Haloperidol administered to women increased the average serum prolactin levels from 24 ng/ml at baseline to 53 ng/ml during week 1-8 and to 66 ng/ml at week 34-52 respectively. Administration of haloperidol to men increased average baseline prolactin levels from 11 ng/ml to 24 ng during week 1-8 and 23 during week 34-52 respectively [14, 15].

In a study of children and adolescents with a mean age of 13 years (9 boys, 6 girls) an average dose of 15.3 mg/d of haloperidol increased prolactin from 10.2 ng/ml to 67.7 ng/ml in girls and from 8.5 ng/ml to 34.7 ng/ml in boys [16].

Due to an inhibition of dopamine-transmission in basal ganglia first generation antipsychotic drugs have been linked to an increased risk of extrapyramidal side effects (parkinsonism).  A cross-sectional study in patients with or without antipsychotic-related parkinsonism (47 men, 103 women) suggests that carriership of the j759 T allele of the HTR2C gene in women may be protective against development of parkinsonism in elderly patients during treatment with haloperidol [17].

According to a Korean cross-sectional study of 51 patients (30 men, 21 women) treated with haloperidol and 57 normal controls a decreased bone mass density (BMD) was detected in 86% of women and 50% of men treated with haloperidol. Among women with decreased BMD, 17 of 18 had hyperprolactinemia. In the control group, BMD was not correlated with patient’s sex [18].

Reproductive health issues

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