Contraindicated use of 5‐alpha‐reductase inhibitors in women

Table of Links

LIGANDS
Dutasteride
Finasteride

This Table lists key ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1.

Finasteride (Proscar®) and dutasteride (Avodart®) are 5‐alpha‐reductase inhibitors indicated for the treatment of symptomatic benign prostatic hyperplasia, and for treatment of male pattern hair loss (finasteride, Propecia® only). Both indications are for men only and both drugs are contraindicated for use by women 2, 3. 5‐alpha‐reductase inhibitors should not be used during pregnancy as they inhibit the conversion of testosterone to 5‐alpha‐ dihydrotestosterone. This may cause abnormalities of the external genitalia of a male fetus 4. In clinical practice, finasteride and dutasteride are both used off‐label for the treatment of women with alopecia or hirsutism, although these treatments are only partially effective at best 5, 6, 7, 8, 9, 10, 11. The effectiveness of finasteride treatment in women varies and only some studies concluded that finasteride may be considered for treatment of female pattern hair loss in patients who fail other treatment and adhere to reliable contraception during finasteride use 6, 7, 8, 9, 11. Consequently, the Dutch Healthcare Inspectorate and the Dutch Association for Dermatology advised negatively on the off‐label use of both finasteride and dutasteride to treat female hair loss 12. Recently, the Dutch pharmacovigilance centre Lareb reported on 389 cases of finasteride and 157 of dutasteride use in women at the end of 2014 from the database of the Uppsala Monitoring Centre of the World Health Organization 13. Because these worldwide numbers seem much too low, we investigated finasteride and dutasteride dispensings to women in the Netherlands and assessed how many women of childbearing potential were on systemic, intrauterine or intravaginal contraceptives (IUD) concomitantly. Detailed information on all dispensed medication was available from the Dutch Foundation of Pharmaceutical Statistics 14. Data were collected annually from 2011 to 2015 from all community pharmacies that delivered the data needed to determine dispensing of 5‐alpha‐reductase inhibitors and contraceptives. Within the eligible community pharmacies, we included all women dispensed finasteride, defined by the codes D11AX10 (Finasteride 1 mg) and G04CB01 (Finasteride 5 mg), or dutasteride by the code G04CB02 from the Anatomic Therapeutic Chemical system (ATC) 15, 16. We defined the annual number of all women dispensed finasteride or dutasteride medication and of those aged between 15 and 50 years as women within reproductive age. For the latter group, we additionally assessed numbers without concomitant dispensing of a contraceptive. Contraceptives could be filled for IUDs by the ATC code G02B and for oral contraceptives by the ATC codes G03 A and G03H. Use of an IUD was assumed for a dispensing within the year of 5‐alpha inhibitor use or the 4 preceding years, and use of an oral contraceptive was assumed for a dispensing within the year of 5‐alpha inhibitor use or the preceding year. Periods of drug use were calculated from the number of drugs dispensed divided by the prescribed daily dosage, corrected for stock piling 17. Although in the Netherlands patients seldom fill prescriptions at a pharmacy that is not their usual one 18, ‘drop in patients’ were excluded 19. For each study year, data were extrapolated to the total number of community pharmacies in the Netherlands. Data were available in 2011 from 1100 of the total of 1997 pharmacies, in 2012 from 1231 of 1981 pharmacies, in 2013 from 1389 of 1974 pharmacies, in 2014 of 1484 from 1979 pharmacies and in 2015 from 1550 of 1981 pharmacies.

Overall, the total number of women dispensed 5‐alpha‐reductase inhibitor in the Netherlands decreased from 920 in 2011 to 651 in 2015 (Table 1). Among these, between 42% (2011) and 33% (2015) were aged 15–50 years. During the study period, between 37% (2014) and 48% (2015) of women aged between 15 and 50 years with 5‐alpha‐reductase inhibitor dispensings did not concomitantly use any contraceptive (Figure 1). Their absolute number decreased from 152 in 2014 to 98 in 2015.

Table 1.

Annual assessment of women using 5‐alpha‐reductase inhibitorsa

Year		5‐alpha reductase inhibitors	Finasteride 1 mg	Finasteride 5 mg	Dutasteride
2011	All women	920	223	595	102
	Women aged 15–50 years	390	96	263	31
2012	All women	1004	240	563	201
	Women aged15–50 years	388	87	225	76
2013	All women	824	183	503	138
	Women aged 15–50 years	325	75	203	47
2014	All women	724	165	437	121
	Women aged 15–50 years	267	63	164	40
2015	All women	651	119	413	119
	Women aged 15–50 years	213	46	130	37

^aData were extrapolated to the total number of community pharmacies in the Netherlands. Within our study period of 2011–2015, data were available in 2012 from 1100 of 1997 community pharmacies, in 2013 from 1231 of 1981 pharmacies, in 2013 from 1380 of 1974 pharmacies, in 2014 of 1484 of 1979 pharmacies and in 2015 from 1550 of 1981 pharmacies

Figure 1.

Annual evaluation of concomitant contraceptive use in females aged 15–50 years with 5‐alpha‐reductase inhibitor dispensings in the Netherlands: Black line: females aged 15–50 years with 5‐alpha reductase inhibitor dispensings. Green line: subgroup with dispensings of systemic hormonal contraceptives within the study year or the prior year. Red line: subgroup without concomitant availability of local or systemic contraceptives due to dispensings. Blue line: subgroup with dispensings of local intrauterine or intravaginal contraceptives within the study year or the prior 4 years

We might have missed other forms of contraceptives not covered by pharmacy dispensing data (e.g. condoms or vasectomy). However, these numbers are low and unlikely to explain our findings fully with 9% of the women using condoms, 8% of the women or their partners being sterilized and 8% nonfertile 20. Furthermore, no information was available on supply of oral contraceptives from internet pharmacies. However, we cannot exclude that women obtained finasteride and dutasteride through illegal channels or through prescriptions in the name of their husband.

The Periodic Safety Update Report Reference Member State (P‐RMS) considered the contraindication in the Summary of Product Characteristics (SmPC) as an adequate risk minimization activity without further additional pharmacovigilance activities needed. However, the substantial number of 5‐alpha‐reductase inhibitor dispensings to women aged between 15 and 50 years and among those about 50% at potentially inadequate anticonception urge for additional risk minimization measures. As a first step, the automated medication surveillance systems for prescribers and pharmacists should develop alerts for prescriptions of 5‐alpha‐reductase inhibitors to women and warn for omitting contraceptives.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: B.S. and E.v.P. had no support from any organization for the submitted work. M.T. had support from the Dutch Inspectorate of Health Care for the submitted work; M.T., B.S. and E.v.P. had no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Teichert, M. , van Puijenbroek, E. , and Stricker, B. H. (2017) Contraindicated use of 5‐alpha‐reductase inhibitors in women. Br J Clin Pharmacol, 83: 429–431. doi: 10.1111/bcp.13118.