|1. NAME OF THE
AND QUANTITATIVE COMPOSITION
Hormone replacement therapy (HRT) for treatment of atrophic
vaginitis (due to estrogen deficiency) in peri- and post-menopausal
As pre-surgery therapy for vaginal operations and during
and method of administration
Ovestin Cream is an estrogen-only product for intravaginal
One applicator-dose (applicator filled to the red mark) is
0.5g Ovestin Cream containing 0.5 mg estriol.
• Treatment of atrophic vaginitis
For initiation and continuation of treatment of
postmenopausal symptoms, the lowest effective dose for the shortest
duration (see also section 4.4) should be used.
The usual dose for atrophic vaginitis associated with the
menopause is one applicator-dose per day for 2 to 3 weeks.
As maintenance dosage, one applicator-dose twice a week is
Medication should be discontinued every 2 to 3 months for a
period of 4 weeks to assess the necessity for further treatment.
• Pre-surgery therapy
One applicator-dose per day should begin 2 weeks before the
• Post-surgery therapy
Following surgery a period of at least 2 weeks should be
allowed before resuming therapy using one applicator-dose twice a
In women not taking HRT or women who switch from another
continuous combined HRT product, treatment with Ovestin Cream may be
started on any day. Women who switch from cyclic HRT regimen should
start Ovestin Cream treatment one week after completion of the
Ovestin Cream is administered intravaginally by means of a
The following 'Instructions for Use' should be given to the
patient and are included in the Patient Information Leaflet:
How to Apply the
Use the applicator to apply the cream in the vagina. It is a
good idea to do this before going to bed.
1. Remove cap from the tube, invert it, and use the sharp
point to open the tube.
2. Screw the end of the applicator onto the tube.
3. Squeeze tube to fill the applicator with the cream until
the plunger stops (at the ring mark).
4. Unscrew applicator from tube and replace cap on tube.
5. To apply the cream, lie down, insert the end of the
applicator deep into the vagina and slowly push plunger all the way
After use, pull the plunger out of the barrel. Wash the
plunger and barrel in hand hot, soapy water. Do not use detergents.
Rinse well with clean water afterwards.
DO NOT PUT THE APPLICATOR IN BOILING WATER.
A missed dose should be administered as soon as remembered,
unless it is more than 12 hours overdue. In the latter case the
missed dose should be skipped and the next dose should be
administered at the normal time. Two doses should never be
administered on the same day.
Cyclic administration of a progestagen to prevent endometrial
stimulation is not necessary provided the daily dose does not exceed
1 applicator-dose (0.5mg estriol) and this maximum dose is not used
for more than several weeks (see section 4.4 Endometrial
There are no clinical trials to support the use in children.
- Known, past or suspected breast cancer;
- Known or suspected estrogen-dependent malignant tumours
(e.g endometrial cancer);
- Undiagnosed genital bleeding;
- Untreated endometrial hyperplasia;
- Previous idiopathic or current venous thromboembolism (deep
venous thrombosis, pulmonary embolism);
- Active or recent arterial thromboembolic disease (e.g.
angina, myocardial infarction);
- Acute liver disease, or a history of liver disease as long
as liver function tests have failed to return to normal;
- Known hypersensitivity to the active substances or to any
of the excipients;
warnings and special precautions for use
For the treatment of postmenopausal symptoms, HRT should only
be initiated for symptoms that adversely affect quality of life. In
all cases, a careful appraisal of the risks and benefits should be
undertaken at least annually and HRT should only be continued as
long as the benefit outweighs the risk.
Before initiating or reinstituting HRT, a complete personal
and family medical history should be taken. Physical (including
pelvic and breast) examination should be guided by this and by the
contraindications and warnings for use. During treatment, periodic
check-ups are recommended of a frequency and nature adapted to the
individual woman. Women should be advised what changes in their
breasts should be reported to their doctor or nurse. Investigations,
including mammography, should be carried out in accordance with
currently accepted screening practices, modified to the clinical
needs of the individual.
In case of vaginal infections, these should be treated before
therapy with Ovestin Cream is started.
Conditions which need
If any of the following conditions are present, have occurred
previously, and/or have been aggravated during pregnancy or previous
hormone treatment, the patient should be closely supervised. It
should be taken into account that these conditions may recur or be
aggravated during treatment with Ovestin Cream, in particular:
- Leiomyoma (uterine fibroids) or endometriosis
- A history of, or risk factors for, thromboembolic disorders
- Risk factors for estrogen dependent tumours, e.g. 1st
degree heredity for breast cancer
- Liver disorders (e.g. liver adenoma)
- Diabetes mellitus with or without vascular involvement
- Migraine or (severe) headache
- Systemic lupus erythematosus.
- A history of endometrial hyperplasia (see below)
Reasons for immediate
withdrawal of therapy:
Therapy should be discontinued in case a contra-indication is
discovered and in the following situations:
- Jaundice or deterioration in liver function
- Significant increase in blood pressure
- New onset of migraine-type headache
• The risk of endometrial hyperplasia and carcinoma is
increased when systemic estrogens are administered alone for
prolonged periods of time. The endometrial safety of long-term or
repeated use of topical vaginal estrogens is uncertain. Therefore,
if repeated, treatment should be reviewed at least annually, with
special consideration given to any symptoms of endometrial
hyperplasia or carcinoma.
• If breakthrough bleeding or spotting appears at any time on
therapy, the reason should be investigated which may include
endometrial biopsy to exclude endometrial malignancy.
• Unopposed estrogen stimulation may lead to premalignant
transformation in the residual foci of endometriosis. Therefore,
caution is advised when using this product in women who have
undergone hysterectomy because of endometriosis, especially if they
are known to have residual endometriosis.
A randomised placebo-controlled trial, the Women's Health
Initiative study (WHI), and epidemiological studies, including the
Million Women Study (MWS), have reported an increased risk of breast
cancer in women taking estrogens, estrogen-progestagen combinations
or tibolone for HRT for several years (see section 4.8). For all
HRT, an excess risk becomes apparent within a few years of use and
increases with duration of intake but returns to baseline within a
few (at most five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with
conjugated equine estrogens (CEE) or estradiol (E2) was greater when
a progestagen was added, either sequentially or continuously, and
regardless of type of progestagen. There was no evidence of a
difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine
estrogen and medroxyprogesterone acetate (CEE + MPA) product used
was associated with breast cancers that were slightly larger in size
and more frequently had local lymph node metastases compared to
placebo. HRT, especially estrogen-progestagen combined treatment,
increases the density of mammographic images which may adversely
affect the radiological detection of breast cancer.
• HRT is associated with a higher relative risk of developing
venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary
embolism. One randomised controlled trial and epidemiological
studies found a two- to threefold higher risk for users compared
with non-users. For non-users it is estimated that the number of
cases of VTE that will occur over a 5 year period is about 3 per
1000 women aged 50-59 years and 8 per 1000 women aged between 60-69
years. It is estimated that in healthy women who use HRT for 5
years, the number of additional cases of VTE over a 5 year period
will be between 2 and 6 (best estimate = 4) per 1000 women aged
50-59 years and between 5 and 15 (best estimate = 9) per 1000 women
aged 60-69 years. The occurrence of such an event is more likely in
the first year of HRT than later.
• Generally recognised risk factors for VTE include a
personal history or family history, severe obesity (BMI > 30
kg/m2) and systemic lupus erythematosus (SLE). There is
no consensus about the possible role of varicose veins in VTE.
• Patients with a history of VTE or known thrombophilic
states have an increased risk of VTE. HRT may add to this risk.
Personal or strong family history of thromboembolism or recurrent
spontaneous abortion should be investigated in order to exclude a
thrombophilic predisposition. Until a thorough evaluation of
thrombophilic factors has been made or anticoagulant treatment
initiated, use of HRT in such patients should be viewed as
contraindicated. Those women already on anticoagulant treatment
require careful consideration of the benefit-risk of use of HRT.
• The risk of VTE may be temporarily increased with prolonged
immobilisation, major trauma or major surgery. As in all
postoperative patients, scrupulous attention should be given to
prophylactic measures to prevent VTE following surgery. Where
prolonged immobilisation is liable to follow elective surgery,
particularly abdominal or orthopaedic surgery to the lower limbs,
consideration should be given to temporarily stopping HRT 4 to 6
weeks earlier, if possible. Treatment should not be restarted until
the woman is completely mobilised.
• If VTE develops after initiating therapy, the drug should
be discontinued. Patients should be told to contact their doctors
immediately when they are aware of a potential thromboembolic
symptom (eg, painful swelling of a leg, sudden pain in the chest,
Coronary artery disease
• There is no evidence from randomised controlled trials of
cardiovascular benefit with continuous combined conjugated estrogens
and medroxyprogesterone acetate (MPA). Two large clinical trials
(WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study)
showed a possible increased risk of cardiovascular morbidity in the
first year of use and no overall benefit. For other HRT products
there are only limited data from randomised controlled trials
examining effects in cardiovascular morbidity or mortality.
Therefore, it is uncertain whether these findings also extend to
other HRT products.
• One large randomised clinical trial (WHI-trial) found, as a
secondary outcome, an increased risk of ischaemic stroke in healthy
women during treatment with continuous combined conjugated estrogens
and MPA. For women who do not use HRT, it is estimated that the
number of cases of stroke that will occur over a 5 year period is
about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged
60-69 years. It is estimated that for women who use conjugated
estrogens and MPA for 5 years, the number of additional cases will
be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59
years and between 1 and 9 (best estimate = 4) per 1000 users aged
60-69 years. It is unknown whether the increased risk also extends
to other HRT products.
• Long-term (at least 5-10 years) use of estrogen-only HRT
products in hysterectomised women has been associated with an
increased risk of ovarian cancer in some epidemiological studies. It
is uncertain whether long-term use of combined HRT confers a
different risk than estrogen-only products.
• Estrogens may cause fluid retention, and therefore patients
with cardiac or renal dysfunction should be carefully observed.
Patients with terminal renal insufficiency should be closely
observed, since it is expected that the level of circulating active
ingredients in Ovestin Cream is increased.
• Women with pre-existing hypertriglyceridemia should be
followed closely during estrogen replacement or hormone replacement
therapy, since rare cases of large increases of plasma triglycerides
leading to pancreatitis have been reported with estrogen therapy in
• There is no conclusive evidence for improvement of
cognitive function. There is some evidence from WHI trial of
increased risk of probable dementia in women who start using
continuous combined CEE and MPA after the age of 65. It is unknown
whether the findings apply to younger post-menopausal women or other
Interaction with other medicinal products and other forms of
No examples of interactions between Ovestin Cream and other
medicines have been reported in clinical practice. The metabolism of
estrogens may be increased by concomittant use of substances known
to induce drug-metabolising enzymes, specifically cytochrome P450
enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin,
carbamezapin) and anti-infectives (e.g. rifampicin, rifabutin,
nevirapine, efavirenz). Ritonavir and nelfinavir, although known as
strong inhibitors, by contrast exhibit inducing properties when used
concomitantly with steroid hormones. Herbal preparation containing
St John's wort (Hypericum Perforatum) may induce the metabolism of
Clinically, an increased metabolism of estrogens may lead to
Ovestin Cream is not indicated during pregnancy. If pregnancy
occurs during medication with Ovestin Cream treatment should be
withdrawn immediately.The results of most epidemiological studies to
date relevant to inadvertent foetal exposure to estrogens indicate
no teratogenic or foetotoxic effects.
Ovestin Cream is not indicated during lactation. Estriol is
excreted in breast milk and may decrease milk production.
||4.7 Effects on
ability to drive and use machines
The following adverse reactions, associated with estrogen
treatment may occur during estriol therapy or overdose: Nausea and
vomiting, breast tenderness or pain in the breasts, vaginal bleeding
or spotting during or on withdrawal of therapy, excessive production
of cervical mucus, headache.
As with any preparation that is to be applied to mucosal
surfaces, Ovestin Cream may cause local irritation or itching at the
beginning of treatment. In general, these complaints are transient
An uncommon adverse reaction is the occurrence of breast
cancer (0.1-1%). According to evidence from a large number of
epidemiological studies and one randomised placebo-controlled trial,
the Women's Health Initiative (WHI), the overall risk of breast
cancer increases with increasing duration of HRT use in current or
recent HRT users.
For estrogen-only HRT, estimates of relative risk (RR)
from a reanalysis of original data from 51 epidemiological studies
(in which >80% of HRT use was estrogen-only HRT) and from the
epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI
1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.
For estrogen plus progestagen combined HRT, several
epidemiological studies have reported an overall higher risk for
breast cancer than with estrogens alone. The MWS reported that,
compared to never users, the use of various types of
estrogen-progestagen combined HRT was associated with a higher risk
of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of
estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone
(RR=1.45; 95%CI 1.25-1.68). The WHI trial reported a risk estimate
of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of
estrogen-progestagen combined HRT (CEE + MPA) in all users compared
with placebo.The absolute risks calculated from the MWS and the WHI
trial are presented below: The MWS has estimated, from the known
average incidence of breast cancer in developed countries, that:
Ø For women not using HRT, about 32 in every 1000 are
expected to have breast cancer diagnosed between the ages of 50 and
Ø For 1000 current or recent users of HRT, the number of
additional cases during the corresponding period will be
Ø For users of estrogen-only replacement therapy
• between 0 and 3 (best estimate = 1.5) for 5 years' use
• between 3 and 7 (best estimate = 5) for 10 years' use.
Ø For users of estrogen plus progestagen combined HRT,
• between 5 and 7 (best estimate = 6) for 5 years' use
• between 18 and 20 (best estimate = 19) for 10 years' use.
The WHI trial estimated that after 5.6 years of follow-up of
women between the ages of 50 and 79 years, an additional 8
cases of invasive breast cancer would be due to
estrogen-progestagen combined HRT (CEE + MPA) per 10,000
women years. According to calculations from the trial data, it is
Ø For 1000 women in the placebo group,
• about 16 cases of invasive breast cancer would be diagnosed
in 5 years.
Ø For 1000 women who used estrogen + progestagen combined HRT
(CEE + MPA), the number of additional cases would be
• between 0 and 9 (best estimate = 4) for 5 years' use.
The number of additional cases of breast cancer in women who
use HRT is broadly similar for women who start HRT irrespective of
age at start of use (between the ages of 45-65) (see section 4.4).'
Other adverse reactions have been reported in association
with estrogen/progestagen treatment:
• Estrogen-dependent neoplasms benign and malignant, e.g.
• Venous thromboembolism, i.e. deep leg or pelvic venous
thrombosis and pulmonary
embolism, is more frequent among hormone replacement therapy
users than among non-users.
For further information, see section 4.3 Contraindications
and 4.4 Special warnings
and precautions for use.
• Myocardial infarction and stroke
• Gall bladder disease.
• Skin and subcutaneous disorders: chloasma, erythema
multiforme, erythema nodosum,
• Probable dementia (see section 4.4).
The acute toxicity of estriol in animals is very low.
Symptoms that may occur in the case of an acute oral overdosage are
nausea, vomiting and possibly withdrawal bleeding in females. No
specific antidote is known. If necessary a symptomatic treatment
should be instituted.
Estriol: The active ingredient, synthetic estriol, is
chemically and biologically identical to human estriol. It
substitutes for the loss of estrogen production in menopausal women,
and alleviates atrophic vaginitis.
Ovestin Cream contains the synthetic hormone estriol. In the
years just before and after the menopause (whether naturally or
surgically induced) estriol can be used in the treatment of
urogenital symptoms and complaints related to estrogen deficiency.
In cases of vaginal atrophy estriol induces normalisation of the
vaginal epithelium and thus helps to restore the normal microflora
and a physiological pH in the vagina. As a result it increases the
resistance of the vaginal epithelial cells to infection and
Estriol is relatively short-acting estrogen due to its short
nuclear retention time in endometrial cells, its low affinity for
plasma proteins and partly as a result of this, its rapid metabolic
clearance. Endometrial proliferation is not expected when estriol is
given in a single daily dose, since this requires sustained,
occupancy of the nuclear estrogen receptor. As a consequence,
undesired vaginal bleeding rarely occurs during treatment with
estriol and an increased risk of endometrial carcinoma is unlikely.
Relief of urogenital symptoms was achieved during the first
weeks of treatment.
After administration of Ovestin Cream, estriol is also
absorbed from the vagina into the general circulation, shown by a
sharp rise in plasma estriol, followed by a gradual decline. After 3
weeks of administration of a single daily dose, a similar absorption
pattern to that seen for a single application was observed. Daily
treatment with 0.5 mg of estriol (in 0.5 g of cream) leads to a
sharp rise in unconjugated plasma estriol levels to 110 pg/ml at one
hour from previously undetectable levels (<12 pg/ml). This was
followed by a gradual decline during the next 5 hours to around 60
On day 21 of treatment, mean baseline estriol levels of about
26 pg/ml rose to a mean peak value of 95 pg/ml at 1 hour. A decline
similar to that seen on day 1 was observed during the next 5 hours.
Vaginal administration permits the absorption of the active
(unconjugated, or free) form of estriol into the blood for transport
to the target tissues, prior to its inactivation via conjugation by
Preclinical safety data
||6.1 List of
2 octyl-dodecanol (eutanol G); cetyl palmitate; glycerin;
cetyl alcohol; stearyl alcohol; Polysorbate 60; sorbitan
monostearate; chlorhexidine hydrochloride; lactic acid; sodium
hydroxide to pH 4, purified water.
precautions for storage
Store at room temperature (15-25C)
||6.5 Nature and
contents of container
15g Collapsible aluminium tube with styrene acrylonitrile
Instructions for use and handling
Organon Laboratories Limited, Cambridge Science Park, Milton
Road, Cambridge, CB4 OFL
|9. DATE OF FIRST
AUTHORISATION/RENEWAL OF THE AUTHORISATION
20 August 1982/ 16 December 1999.
|10. DATE OF
REVISION OF THE TEXT