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Diss Factsheets

Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
experimental study
Adequacy of study:
weight of evidence

Data source

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Year:
2017
Report date:
2017
Reference Type:
publication
Title:
A multicenter, open-label study to evaluate satisfaction and menopausal quality of life in women using transdermal estradiol/norethindrone acetate therapy for the management of menopausal signs and symptoms.
Author:
Adler et al.
Year:
2005
Bibliographic source:
Gynecol. Obstet. Invest. 59, 212-219
Reference Type:
publication
Title:
Pharmaceutical development and clinical effectiveness of a novel gel technology for transdermal delivery.
Author:
Alberti et al.
Year:
2005
Bibliographic source:
Expert Opin Drug Deliv. 2, 935-950
Reference Type:
publication
Title:
A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group.
Author:
Archer et al.
Year:
1999
Bibliographic source:
Obstet Gynecol. 4, 498-503
Reference Type:
publication
Title:
The lipid and clinical effects of sequential transdermal estradiol and estradiol/norethisterone acetate in 674 women.
Author:
Cano et al.
Year:
2003
Bibliographic source:
Arch. Gynecol. Obstet. 268, 317-322
Reference Type:
publication
Title:
Allergic contact dermatitis from estradiol and norethisterone acetate in a transdermal hormonal patch.
Author:
Koch, P
Year:
2001
Bibliographic source:
Contact Dermatitis 44, 112
Reference Type:
publication
Title:
comparison of effects of sequential transdermal administration versus oral administration of estradiol plus norethistherone acetate on serum NO levels in postmenopausal women.
Author:
Kurtay et al.
Year:
2006
Bibliographic source:
Maturitas 53, 32-38
Reference Type:
publication
Title:
Low-dose continuous combination of hormone therapy and biochemiocal surrogate marker for vascular tone and inflammation: transdermal versus oral application.
Author:
Mueck et al.
Year:
2007
Bibliographic source:
Menopause 14, 978-984
Reference Type:
publication
Title:
Parenteral administration of progestins forhormonal replacement therapy.
Author:
Nath & Sitruk-Ware
Year:
2009
Bibliographic source:
Europ. J. Contraception Reprod. Health 14, 88-96
Reference Type:
publication
Title:
Comparison of continuous and sequential transdermal progestogen with sequential oral progestogen in postmenopausal women using continuous transdermal estrogen: vasomotor symptoms, bleeding patterns, and serum lipids.
Author:
Rozenberg et al.
Year:
1997
Bibliographic source:
Int J Fertil Womens Med. 42 Suppl 2:376-87
Reference Type:
publication
Title:
One-year endometrial safety evaluation of a continuous combined transdermal matrix patch delivering low-dose estradiol-norethistherone acetate in postmenopausal women.
Author:
Samisoe et al.
Year:
2007
Bibliographic source:
Maturitas 57, 171-181
Reference Type:
publication
Title:
Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement therapy over 96 weeks: a randomized open-label study.
Author:
Samisoe et al.
Year:
2006
Bibliographic source:
Climacteric. Oct;9(5), 368-79
Reference Type:
publication
Title:
Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers.
Author:
Stevenson et al.
Year:
2004
Bibliographic source:
Br J Haematol. 124(6):802-808
Reference Type:
publication
Title:
Transdermal estradiol/norethistherone. A review of its pharmacological properties and clinical use in the postmenopausal women.
Author:
Wiseman & McTavish
Year:
1994
Bibliographic source:
Drugs Aging 4, 238-256

Materials and methods

Type of sensitisation studied:
skin
Study type:
other: case report and clinical trials
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Norethisterone acetate
EC Number:
200-132-0
EC Name:
Norethisterone acetate
Cas Number:
51-98-9
Molecular formula:
C22H28O3
IUPAC Name:
17-ethynyl-3-oxoestr-4-en-17-yl acetate

Method

Type of population:
general
Route of administration:
dermal

Results and discussion

Any other information on results incl. tables

Clinical studies are available in the published literature that assessed the effectiveness and safety of transdermal therapeutic systems containing norethisterone, typically in the form of norethisterone acetate:

In a study with 507 patients were treated with transdermal estradiol/norethisterone acetate as skin patches. The patients received continuous combined transdermal matrix patches every 3-4 days and the study duration was 52 weeks. Local skin tolerability of the transdermal matrix system was good. Only 5.9 % of the patients discontinued the treatment due to skin irritation. From the publication there is no evidence of a skin sensitization reaction and it was concluded that the system is well tolerated and can be safely used (Samisoe et al. 2007).

A randomized study over 48 or 96 weeks at 32 centers across five European countries included 306 patients with transdermal continuous estradiol/norethisterone acetate treatment. Local skin tolerability was good. Whereas skin irritation was observed at some time during the study only 8.2% discontinued due to local skin reactions. From the publication there is no evidence of a skin sensitization reaction and it was concluded that the system is well tolerated (Samisoe et al. 2009)

In an earlier randomized 1 year study at 35 centers across five European countries two doses of norethisterone acetate combined with estradiol were examined in 309 patients (n = 153 + 156), compared to other transdermal delivery systems. Number for the norethisterone acetate combined with estradiol groups were not given in the publication, but it was overall stated that transient, mild skin reactions were observed at the application site for the transdermal delivery systems, with slightly higher percentage in the higher dose groups, compared to the smaller systems (obviously independent from the chemical delivered) (Rozenberg et al. 1997). Therefore from the publication there is no evidence of a skin sensitization reaction related to norethisterone acetate.

A randomized study also examined continuous combined transdermal delivery of estradiol and norethisterone acetate across 37 centers in the USA (compared to estradiol patch alone). The patches were applied every 3.5 days and the study duration was 52 weeks. 440 patients were treated with respective patches in three dose groups (140, 250 or 400 μg/day norethisterone acetate; n = 163 + 149 + 158). Erythema was the most frequent application site reaction and it was concluded that the estradiol-norethisterone acetate combination showed skin tolerance comparable to estradiol alone (Archer et al. 1999). From the publication there is no evidence of a skin sensitization reaction related to norethisterone acetate or the transdermal delivery system.

In a multicenter study on the satisfaction in women using transdermal estradiol/norethisterone acetate therapy 216 patients were enrolled and 183 patients completed the study; the study duration was 12 weeks. At week 6 92.6% of the patients had no irritation or skin reaction and 5.8% had minimal erythema; 30 minutes after patch removal 16.3% had minimal erythema at the patch application site. Similar values were observed after 12 weeks and it was mentioned that the skin irritation was comparable between the present study and previous studies of transdermal estradiol treatment (Adler et al. 2004). From the publication there is no evidence of a skin sensitization reaction related to norethisterone acetate or the transdermal delivery system.

In a 96 week, double-blind, randomized, multicenter, parallel study healthy women after menopause were either treated with transdermal continuous combined estradiol/norethisterone acetate or placebo for 24 treatment cycles. The incidence of erythema after 3 months of treatment was lower in the treatment group compared to the placebo control group (29 versus 33%), and this decreased to 9 and 14%, respectively after 24 months. It was concluded that from this study the good local tolerability of the transdermal patch examined is confirmed (Rubinacci et al. 2003). It can be concluded that in this study there is no evidence of a skin sensitization reaction related to norethisterone acetate, and the skin irritation effects observed are assumed to be related to the transdermal delivery system.

On a prospective study from 42 different hospital services and clinics in Spain that included 674 women that received transdermal treatment with patches delivering estradiol for 14 days and estradiol and norethisterone acetate for another 14 days. The focus of the study was on lipid and clinical effects. 20.4% of the patients reported adverse reactions, with patch-induced skin irritation and bleeding accounting for 69.2% of the reactions reported. Overall the safety was concluded to be acceptable (Cano et al. 2003). From the publication there is no evidence of a skin sensitization reaction related to norethisterone acetate or the transdermal delivery system.

In a prospective 6 month clinical trial in which 28 women received transdermal estradiol-norethisterone acetate and 27 received placebo cardiovascular risk markers were examined and no skin effects were described (Stevenson et al. 2004). Also other studies examined the therapeutic use of transdermal estradiol-norethisterone acetate applications without pointing on skin responses (e.g. Mueck et al. 2007; Kurtay et al. 2006).

In a review from 1994 it was concluded from earlier studies that “the combined estradiol/norethisterone transdermal delivery system appeared to cause a similar incidence of skin reactions as that observed with estradiol-only patch in clinical trials with more than 400 patients” and that “Skin reactions can be minimised by selecting new sites when applying the systems, and by application to the buttocks rather than the abdomen or lower back” (Wiseman & McTavish 1994). Therefore also from this review there is no evidence of a skin sensitization reaction related to norethisterone acetate or the transdermal delivery system.

Applicant's summary and conclusion

Executive summary:

Overall there is proven broad exposure related to the therapeutic topical use of norethisterone related substances in transdermal therapeutic systems and there is only one isolated positive patch test reaction of unclear relevance published, compared to the substantial therapeutic use in postmenopausal patients.

Therefore based on the available reliable and relevant human data the assessment of the skin sensitization potential (hazard identification) is possible. Based on all available data there is no evidence of skin sensitization properties of norethisterone and structurally related substances.