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Document last updated on the eMC: Thu 04 November 2004
Ovestin Cream
Table of Contents





4.1 Therapeutic indications

4.2 Posology and method of administration

4.3 Contraindications

4.4 Special warnings and special precautions for use

4.5 Interaction with other medicinal products and other forms of Interaction

4.6 Pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

4.9 Overdose


5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

5.3 Preclinical safety data


6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

6.6 Instructions for use and handling





1. NAME OF THE MEDICINAL PRODUCT To the top of the page

Ovestin Cream


1mg estriol in 1g cream

3. PHARMACEUTICAL FORM To the top of the page

Vaginal cream

4. CLINICAL PARTICULARS To the top of the page

4.1 Therapeutic indications To the top of the page

Hormone replacement therapy (HRT) for treatment of atrophic vaginitis (due to estrogen deficiency) in peri- and post-menopausal women.

As pre-surgery therapy for vaginal operations and during subsequent convalescence.

4.2 Posology and method of administration To the top of the page

Ovestin Cream is an estrogen-only product for intravaginal use.

One applicator-dose (applicator filled to the red mark) is 0.5g Ovestin Cream containing 0.5 mg estriol.

Adults and Elderly

• 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 recommended.

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 operation.

• Post-surgery therapy

Following surgery a period of at least 2 weeks should be allowed before resuming therapy using one applicator-dose twice a week.

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 cycle.

Route of Administration

Ovestin Cream is administered intravaginally by means of a calibrated applicator.

The following 'Instructions for Use' should be given to the patient and are included in the Patient Information Leaflet:

How to Apply the Cream

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 in.

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.


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 hyperplasia).


There are no clinical trials to support the use in children.

4.3 Contraindications To the top of the page

- 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;

- Porphyria.

4.4 Special warnings and special precautions for use To the top of the page

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.

Medical examination/follow -up

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 supervision

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 (see below)

- Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus.

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

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

- Pregnancy

Endometrial hyperplasia

• 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.

Breast cancer

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.

Venous thromboembolism

• 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, dyspnea).

Coronary artery disease (CAD)

• 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.

Ovarian cancer

• 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.

Other conditions

• 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 this condition.

• 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 HRT products.

4.5 Interaction with other medicinal products and other forms of Interaction To the top of the page

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 estrogens.

Clinically, an increased metabolism of estrogens may lead to decreased effect.

4.6 Pregnancy and lactation To the top of the page

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 To the top of the page

None stated.

4.8 Undesirable effects To the top of the page

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 in nature.

Breast cancer

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 64 years.

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 estimated that:

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. endometrial cancer.

• 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,

vascular purpura.

• Probable dementia (see section 4.4).

4.9 Overdose To the top of the page

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.

5. PHARMACOLOGICAL PROPERTIES To the top of the page

5.1 Pharmacodynamic properties To the top of the page

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 inflammation.

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.

5.2 Pharmacokinetic properties To the top of the page

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 pg/ml.

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 enterohepatic enzymes.

5.3 Preclinical safety data To the top of the page

No particulars

6. PHARMACEUTICAL PARTICULARS To the top of the page

6.1 List of excipients To the top of the page

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.

6.2 Incompatibilities To the top of the page

None stated.

6.3 Shelf life To the top of the page

3 years

6.4 Special precautions for storage To the top of the page

Store at room temperature (15-25C)

6.5 Nature and contents of container To the top of the page

15g Collapsible aluminium tube with styrene acrylonitrile (copolymer) applicator.

6.6 Instructions for use and handling To the top of the page

Please see Section 4.2


Organon Laboratories Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 OFL


PL 0065/0074


20 August 1982/ 16 December 1999.

10. DATE OF REVISION OF THE TEXT To the top of the page

August 2004

Ref: USovc6.6