Monograph: |
Norethisterone
A white or yellowish-white odourless crystalline powder.
Practically Insoluble in water; slightly to sparingly soluble in
alcohol; soluble in chloroform and in dioxan; slightly soluble
in ether. Protect from light.
Adverse Effects and Precautions
As for progestogens in general (see Progesterone).
Effects on the liver. There were 6 cases of jaundice among
107 patients with breast cancer treated with high-dose nor-
ethisterone acetate; the jaundice was reversible and of an ob-
structive type.
Pregnancy. Abnormalities seen in the offspring of women
who had received norethisterone during pregnancy (either
alone or in combination with ethinyloestradiol) included hyp-
ospadias, masculinisation of female infants' meningomye-
locele or hydrocephalus and neonatal choreoathetosis
associated with oral contraceptive use. For reference to the
fact that oral contraceptives have not generally been associat-
ed with teratogenicity, even when used inadvertently in preg-
nancy.
Venous thrombo-embolism. For mention that combined
oral contraceptives containing older progestogens such as
norethisterone appear to be associated with a lower incidence
of venous thrombo-embolism than desogestrel or gestodene-
containing preparations.
Interactions
As for progestogens in general (see Progesterone).
Pharmacokinetics
Norethisterone is absorbed from the gastro-intesti-
nal tract, undergoing first-pass hepatic metabolism,
with peak plasma concentrations occurring I to 2
hoars after a dose by mouth. It exhibits biphasic
pharmacokinetics; an initial distribution phase is
followed by a prolonged elimination phase with a
half-life of about 8 hours or more. Norethisterone is
highly protein bound; about 60% to albumin and
35% to sex. hormone binding globulin. Administra-
tion with an oestrogen increases the proportion
bound to sex hormone binding globulin. It is metab-
olised in the liver with 50 to 80% of a dose being
excreted in the urine and up to 40% in the faeces.
Norethisterone acetate is reported to show a more
prolonged elimination than norethisterone follow-
ing oral administration. It is hydrolysed to norethis-
terone, principally by intestinal tissue.
Following intramuscular injection of norethisterone
enanthate peak concentrations of norethisterone in
plasma are not attained for several days.
Uses and Administration
Norethisterone and its acetate and enanthate esters
are progestogens (see Progesterone) derived
from nortestosterone that have weak oestrogenic
and androgenic properties. They are commonly used
as hormonal contraceptives. Nor-
ethisterone and norethisterone acetate are both ad-
ministered by mouth. Typical daily doses are
0.35 mg for norethisterone and 0.6 mg for norethis-
terone acetate when used alone, or 0.5 to I mg for
norethisterone and 1.0 to 1.5 mg for norethisterone
acetate when combined with an oestrogen. Norethis-
terone enanthate is administered by intramuscular
injection; a dose of 200 mg provides contraception
for 8 weeks.
Norethisterone and norethisterone acetate are used
as the progestogen component of menopausal hor-
mone replacement therapy to oppose the
effects of oestrogens on the endometrium. Typical
regimens have included either continuous daily
doses of norethisterone 0.7 mg or norethisterone
acetate I mg, or cyclical regimens of norethisterone
or norethisterone acetate I mg daily for 10 to 12
days of a 28-day cycle, or 0.75 to 1.5 mg daily of
norethisterone cyclically from multiphasic prepara-
tions. Norethisterone acetate is also available as a
transdermal patch supplying 250 mcg per 24 hours
that is applied twice weekly for 2 weeks of a 4-week
cycle.
Norethisterone and norethisterone acetate may be
given by mouth for the treatment of conditions such
as menorrhagia and endometriosis. In menorrhagia
(dysfunctional uterine bleeding), norethisterone is given in
usual doses of
10 to 15 mg daily and norethisterone acetate in
doses of 2.5 to 10 mg daily, in a cyclical regimen. In
endometriosis the dosage of norethisterone is 10 to
25 mg daily and of norethisterone acetate 5 to 15 mg
daily. Treatment of endometriosis is usually contin-
uous for 4 to 9 months.
Norethisterone has been used in daily doses of up to
15 mg by mouth in a cyclical regimen in the treat-
ment of premenstrual syndrome .
In breast cancer doses of up to 60 mg daily
by mouth of either norethisterone or norethisterone
acetate have been used.
Menorrhagia. Although cyclical norethisterone has been
widely used for menorrhagia , it is of limited efficacy
during ovulatory cycles being most effective for anovulatory
bleeding, which occurs in a minority of women with
menorrhagia.
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