Consumer medicine information

Ovestin Cream

Estriol

BRAND INFORMATION

Brand name

Ovestin Cream (Vaginal cream)

Active ingredient

Estriol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ovestin Cream.

What is in this leaflet

What Ovestin Cream is used for

Before using Ovestin Cream

How to use Ovestin Cream

Side effects of Ovestin Cream

After using Ovestin Cream

Product description

This leaflet answers some common questions about Ovestin Cream.

It does not contain all of the available information and it does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Ovestin Cream against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet.

You may need to read it again.

What Ovestin Cream is used for

Ovestin Cream is a Hormone Replacement Therapy (HRT). It contains the female hormone estriol (an oestrogen). Ovestin is used in postmenopausal women with at least 12 months since their last natural period. Ovestin is used for relief of symptoms occurring after menopause. During menopause, the amount of oestrogens produced by a woman's body gradually drops. If the ovaries are removed surgically (ovariectomy) before menopause, the decrease in oestrogen production occurs very abruptly. The shortage of oestrogens during menopause may cause the vaginal wall to become thin and dry. As a result, sexual intercourse may become painful and vaginal itching and infections may occur. Oestrogen deficiency may also lead to symptoms like urinary incontinence and recurrent cystitis. Ovestin alleviates these symptoms after menopause. It may take several days or even weeks before you notice an improvement. You will only be prescribed Ovestin if your symptoms seriously hinder your daily life. In addition to the above uses, Ovestin Cream may also be prescribed to improve wound healing in postmenopausal women undergoing vaginal surgery or help assess cervical smears taken from postmenopausal women. After insertion into the vagina, estriol is slowly released and absorbed into the surrounding area and into the bloodstream.

A doctor's prescription is required to obtain this medicine.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before using it

When you must not use it

Do not use Ovestin Cream if:

  • you have or have ever had breast cancer, or if you are suspected of having it.
  • you are pregnant or think you may be pregnant
  • you have or if it is suspected that you have cancer which is sensitive to oestrogens, such as cancer of the lining of the womb
  • you have any unexplained vaginal bleeding, which has not been evaluated by your doctor
  • you have excessive thickening of the lining of your womb (endometrial hyperplasia) that is not being treated
  • you have or have had a blood clot (thrombosis in the veins of the legs (deep vein thrombosis) or the lungs (pulmonary embolism))
  • you have a blood clotting disorder (such as protein C, protein S, or antithrombin deficiency)
  • you have or have had a disease caused by blood clots in the arteries such a heart attack, stroke or angina
  • you have or ever have had a liver disease and your liver function tests have not returned to normal
  • you have had an allergic reaction to estriol, or any of the other ingredients of Ovestin
  • you have a rare blood problem called porphyria (an inherited or acquired disorder in the production of blood pigment).

Do not use Ovestin Cream if you have an allergy to:

  • any medicine containing estriol
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or troubled breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Ovestin Cream contains cetyl alcohol and stearyl alcohol. This may cause local skin reactions (e.g. contact dermatitis).

Take special care with Ovestin Cream

As well as benefits, Ovestin has some risks which you need to consider when you are deciding to start or continue treatment.

Medical check-ups
Before you start using Ovestin Cream, your doctor should ask about your own and your family's medical history. Your doctor may decide to examine your breasts and/or your abdomen, and may do an internal examination. You will also have periodic check-ups, especially examinations of the breasts. Your doctor will tell you how often these tests should be performed.

Once you have started using Ovestin Cream, you should see your doctor for regular check-ups (at least once every year). At these check-ups, your doctor may discuss with you the benefits and risks of continuing to use Ovestin.

Certain conditions may be made worse by hormone replacement therapy (HRT). If you have or have had any of the following conditions and/or which were worse during pregnancy or with previous use of hormones tell your doctor who will monitor you closely:

  • uterine (womb) fibroids
  • endometriosis
  • clots in the blood vessels (thrombosis, deep vein thrombosis, lung embolism) or an increased risk of developing this
  • if anyone in your family has ever had an oestrogen-dependent cancer, such as a close relative who has had breast cancer or cancer of the lining of the womb
  • high blood pressure
  • heart disease
  • liver disorders
  • kidney disorders
  • diabetes
  • gallstones
  • migraine or (severe) headache
  • systemic lupus erythematosus (SLE, an immune disorder affecting the skin and other organs)
  • endometrial hyperplasia (thickening of the lining of the womb)
  • epilepsy
  • asthma
  • otosclerosis (inherited deafness).

Tell your doctor if you notice any change in your condition while using Ovestin.

Reasons for immediately stopping Ovestin Cream:

  • jaundice (your skin goes yellow)
  • a sudden increase in blood pressure
  • if you get migraine, or severe headaches, for the first time
  • pregnancy.

Effects on your risk of developing cancer

Endometrial cancer

Every woman is at a small risk of getting endometrial cancer (cancer of the lining of the womb), whether or not HRT is used. The risk of cancer of the lining of the womb increases with the duration of treatment.

Breakthrough bleeding or spotting may occur during the first few months of using Ovestin.

Tell your doctor if the bleeding or spotting:

  • carries on for more than the first few months
  • starts after you have been on Ovestin for a while
  • carries on even after you have stopped using Ovestin.

Breast cancer

Women who have breast cancer, or have had breast cancer in the past, should not use Ovestin Cream.

Taking oestrogen or oestrogen-progestogen combined HRT or Ovestin for several years slightly increases the risk of breast cancer. The risk increases with the duration of use and returns to normal within about five years after stopping HRT. Women using combined HRT have a slightly greater risk of developing breast cancer than women using oestrogen-only HRT.

It is not known whether Ovestin is associated with the same higher chance of having breast cancer diagnosed as other hormone replacement therapies.

Nevertheless, if you are concerned about the risk of breast cancer, discuss the risk compared to the benefits of treatment with your doctor.

Be sure to regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel.

Ovarian Cancer

Ovarian cancer (cancer of the ovaries) is very rare, but it is a serious condition. It can be difficult to diagnose, because there are often no obvious signs of the disease. Some studies have indicated that taking oestrogen-only HRT for more than 5 years may increase the risk of ovarian cancer. It is not yet known whether other kinds of HRT or Ovestin increase the risk in the same way.

Effects on your heart or circulation

Blood clots (thrombosis)

All women have a very small chance of having a blood clot in the veins of the leg, lungs or other parts of the body. Using some forms of HRT may slightly increase this small chance. It is unknown if Ovestin increases the risk in the same way.

These blood clots are not always serious, but if one travels to the lungs, it can cause chest pain, breathlessness, collapse or even death. This condition is called pulmonary embolism.

You are more likely to have a blood clot if:

  • you are older
  • you are pregnant or have recently had a baby
  • you have had one or more miscarriages
  • you use oestrogens
  • you are seriously overweight
  • you have had a blood clot before in the leg, lung or another organ
  • blood clots run in your family
  • you have any blood clotting problem that needs treatment with a medicine such as warfarin
  • you have systemic lupus erythematosus (a disease of your immune system)
  • you are unable to move for long periods, for example after a long illness or major operation
  • you have cancer.

If any of these apply to you, you should talk to your doctor about whether you should use Ovestin Cream.

See a doctor as soon as possible and do not use any more Ovestin Cream if you get:

  • painful swelling in your leg
  • sudden chest pain
  • difficulty breathing,

These may be signs of a blood clot.

Tell your doctor and your surgeon if you are to be hospitalized or undergo surgery.

You may need to stop using Ovestin about 4-6 weeks before the operation, to reduce the risk of a blood clot. Your doctors will tell you when you can start using Ovestin again.

Stroke

Recent research with one type of HRT (containing conjugated oestrogen plus the progestogen MPA) has shown a slight increase in the risk of having a stroke.

If you have symptoms that might indicate that you have a stroke (such as unexplained migraine-type headaches, with or without disturbed vision), see a doctor as soon as possible. Do not use any more Ovestin until your doctor says you can.

Dementia

It is not known if there is an increased risk of dementia when using Ovestin.

Tell your doctor if you are pregnant.

Ovestin should not be used.

Tell your doctor if you are breast-feeding.

There is insufficient information on the use of Ovestin Cream during breast-feeding. Small amounts of the active estriol can be excreted in the breast milk and milk production could also be reduced.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Other medicines may interfere with the effects of estriol, or estriol may affect other medicines. This might lead to irregular bleeding. These include:

  • anticoagulants (medicines to stop blood clots);
  • corticosteroid hormones (includes many anti-asthmatic drugs);
  • succinylcholine (medicine for muscle relaxation);
  • theophyllines (medicine for asthma);
  • medicines for epilepsy (such as barbiturates (phenobarbital), hydantoins (phenytoin) and carbamazepine);
  • medicines for fungal or bacterial infections (such as griseofulvin, rifamycins (rifampicin, rifabutin); troleandomycin);
  • medicines for viral infections (nevirapine, efavirenz, ritonavir, nelfinavir);
  • herbal preparations containing St John's Wort (Hypericum Perforatum).

How to use it

How much to use

For vaginal complaints, the usual dosage is 1 application daily during the first weeks. Later on the dose is gradually decreased to, for instance, 1 application twice a week. Each dose of cream contains 0.5 mg estriol. However your doctor may well prescribe different quantities for other conditions.

Your doctor may ask you to stop using Ovestin every 2 to 3 months for 4 weeks to check the need for further treatment.

For vulvo-vaginal complaints associated with menopause:

  • initially one dose of cream per day for 3 weeks
  • later you may only need one dose of cream twice a week.

Before surgery:

  • one dose of cream daily beginning 2 weeks before the operation.

When having a Pap smear your doctor may recommend a daily application of cream for 7 days.

How to apply the cream

Use the applicator to apply the cream into the vagina.

It is a good idea to do this before retiring/going to sleep at night.

One application (applicator filled to the ring mark) contains 0.5 g of Ovestin cream, which contains 0.5 mg estriol.

Do not completely fill the whole applicator.

  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. Make sure the plunger is fully inserted into the barrel.
  1. Squeeze the tube slowly to fill the applicator to the ring-mark (where the plunger stops).
  1. Unscrew the applicator from the tube and put the cap on the tube.
  2. To apply the cream, lie down, insert the applicator deep into the vagina.
  3. Slowly push the plunger all the way in until the applicator is empty.
  1. After use, pull the plunger out of the barrel beyond the point of resistance and wash both parts in warm, soapy water. Do not use detergents. Rinse well and dry afterwards.
    Do NOT put the applicator in hot or boiling water.
  2. The applicator can be re-assembled by fully inserting the plunger into the barrel beyond the point where resistance is felt.
    Discard the applicator once the tube is empty.

If you forget to use it

If you forget a dose, use it as soon as you remember. But if you remember your missed dose at the time of your next dose, do not use an extra dose.

Do not use a double dose to make up for the missed dose.

This may increase the chance of you getting an unwanted side effect.

Then go back to using the cream as you would normally.

If you use too much (overdose)

If you may have used more Ovestin than you should, talk to a doctor or pharmacist.

If someone has swallowed some cream, there is no need for great concern. However, you should consult a doctor. Symptoms that may arise are nausea and vomiting. Vaginal bleeding in females may occur after a few days.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Ovestin Cream.

The medicine helps most women with menopausal symptoms, but it may have unwanted side effects in a few people. All medicines have side effects. Sometimes they are serious, most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Dependent on dosage and sensitivity of the patient, Ovestin may sometimes cause side effects, such as:

  • local irritation or itching
  • swelling and increased tenderness of the breasts.
  • increased vaginal discharge.
  • nausea.
  • fluid retention in the tissues, usually marked by swollen ankles or feet.
  • flu-like symptoms

In most patients these side effects will disappear after the first weeks of treatment. Tell your doctor if vaginal bleeding occurs or if any side effect becomes troublesome or persists.

Other side effects which may occur with HRT:

  • benign and malignant hormone-dependent tumours such as endometrial cancer
  • heart attack and stroke
  • gall bladder disease
  • skin problems such as rashes, discolouration or red patches on the skin
  • various skin diseases with blisters and nodules or bleeding into the skin
  • venous thromboembolismor deep leg or pelvic venous thrombosis and pulmonary embolism (see Before you use Ovestin Cream)
  • using HRT for several years slightly increases the risk of breast cancer.

Tell your doctor or pharmacist if you notice any side effects not mentioned in this leaflet.

Other side effects not listed above may also occur in some people.

After using it

Storage

Keep your Ovestin Cream in a safe place out of the reach of children.

Keep your Ovestin Cream in the original package in a cool dry place where the temperature stays below 30°C.

Do not use after the expiry date stated on the tube and outer box.

Do not use if the product does not look quite right.

Product description

What it looks like

Ovestin Cream is a homogeneous, smooth, white to nearly white mass of creamy consistency. Ovestin cream is filled in a collapsible tube of 15 g. Each tube is packed together with a CE-marked applicator and a patient-instruction leaflet.

Do not use the product if the pack or cream is damaged or appears unusual.

Ingredients

Ovestin Cream contains 0.5 mg of estriol in each 0.5 g dose as the active ingredient.

It also contains:

  • octyldodecanol
  • cetyl esters wax
  • glycerol
  • cetyl alcohol
  • stearyl alcohol
  • polysorbate 60
  • sorbitan monostearate
  • lactic acid
  • chlorhexidine hydrochloride
  • sodium hydroxide
  • water purified.

Supplier

Aspen Pharmacare Pty Ltd
34-36 Chandos St
St Leonards
NSW 2065
Australia

Manufacturer of the Ovestin applicator:

Aspen Bad Oldesloe GmbH
Industriestrasse 32-36
23843 Bad Oldesloe
Schleswig-Holstein
Germany
inst

AUST R 14515

This leaflet was revised in January 2018.

BRAND INFORMATION

Brand name

Ovestin Cream (Vaginal cream)

Active ingredient

Estriol

Schedule

S4

 

Name of the medicine

Estriol.

Excipients.

Octyldodecanol, cetyl esters wax, glycerol, cetyl alcohol, stearyl alcohol, polysorbate 60, sorbitan monostearate, lactic acid, chlorhexidine hydrochloride, sodium hydroxide and purified water.

Description

Chemical name: estra-1,3,5(10)-triene-3,16α,17β-triol. Molecular formula: C18H24O3. MW: 288.4. CAS: 50-27-1. Estriol the active ingredient of Ovestin is a synthetic white odourless micronised powder. Like other oestrogenic substances it is practically insoluble in water but is soluble in ethanol, chloroform, dioxane, ether and vegetable oils.
Each 0.5 g of Ovestin Cream contains 0.5 mg of estriol.
Pharmacotherapeutic group: natural and semisynthetic oestrogens.
ATC code: G03C-A04.

Pharmacology

Pharmacodynamic properties.

Ovestin contains the natural female hormone estriol. Unlike other oestrogens, estriol is short acting since it has only a short retention time in the nuclei of endometrial cells. It substitutes for the loss of estrogen production in menopausal women and alleviates menopausal symptoms. Estriol is particularly effective in the treatment of urogenital symptoms.
In case of atrophy of the lower urogenital tract estriol induces the normalization of the urogenital epithelium and helps to restore the normal microflora and the physiological pH in the vagina. As a result, it increases the resistance of the urogenital epithelial cells to infection and inflammation reducing vaginal complaints such as dyspareunia, dryness, itching, vaginal and urinary infections, micturition complaints and mild urinary incontinence.

Pharmacokinetic properties.

Absorption.

Intravaginal administration of estriol ensures optimal availability at the site of action. Estriol is also absorbed into the general circulation, as is shown by a sharp rise in the plasma levels of unconjugated estriol. Systemic absorption of estriol from Ovestin Cream can produce significant plasma levels. Furthermore the initial circulation through the liver, which reduces the effectiveness of oral estriol by conjugation, is bypassed. However, with the doses recommended, absorption has not been sufficient to produce endometrial proliferation or any untoward systemic effect.
Following vaginal administration of 0.5 mg of estriol, plasma levels of unconjugated and conjugated estriol reach a maximum within 1 to 2 hours. After vaginal administration of 0.5 mg estriol, Cmax is approximately 100 picogram/mL (pg/mL), Cmin is approximately 25 picogram/mL and Caverage is approximately 70 picogram/mL of unconjugated, presumably biologically active estriol. The proportion of unconjugated hormone was similar to that reported during pregnancy about 10%. After 3 weeks of daily administration of 0.5 mg vaginal estriol, Caverage had decreased to 40 picogram/mL.

Distribution.

Nearly all (90%) estriol is bound to albumin in the plasma and in contrast with other oestrogens hardly any estriol is bound to sex hormone-binding globulin.

Metabolism.

In contrast to oestradiol and oestrone, apart from being conjugated, estriol is not metabolised before excretion. It is also less strongly protein-bound and thus more rapidly cleared from the plasma. The metabolism of estriol consists principally of conjugation and deconjugation during the enterohepatic circulation. Various conjugates of estriol are found in both the urine and the faeces. The half-life has been estimated as approximately 5 to 7 hours.

Excretion.

Estriol, a metabolic end product, is mainly excreted via the urine in the conjugated form. Only a small fraction (2%) is excreted via the faeces, mainly as unconjugated estriol.

Indications

Vulvo-vaginal complaints due to oestrogen deficiency associated with the climacteric and the postmenopause or after ovariectomy:
Atrophic vaginitis.
Pruritus vulvae.
Dyspareunia due to vulvovaginal atrophy.
As auxiliary therapy in the treatment of vaginal infections.
As preoperative therapy for vulvovaginal surgery and during subsequent convalescence.
Ulcers in cases of prolapse of the uterus or vagina.
To avoid misinterpretation of a cytological smear.

Contraindications

Pregnancy.
Known, past or suspected breast cancer.
Known or suspected oestrogen dependent malignant tumours such as carcinoma of the endometrium.
Undiagnosed genital bleeding.
Previous or current active venous thromboembolism (deep venous thrombosis, pulmonary embolism).
Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see Precautions below).
A history of recurrent venous thromboembolism (VTE) or known thrombophilic disease in a patient who is not already on anticoagulant treatment (see Precautions).
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).
Thrombophlebitis, or a past history of this condition.
A history during pregnancy or previous use of steroids of a manifestation or deterioration of otosclerosis.
Endometriosis.
Untreated endometrial hyperplasia.
Porphyria.
Severe liver dysfunction or a history of liver disease as long as liver function tests failed to return to normal.
Disturbed lipid metabolism, particularly in the presence of other risk factors which may indicate a predisposition to cardiovascular disorders.
Hypersensitivity to the active substances or to any of the excipients.
See Precautions, Use in pregnancy and Use in lactation.

Precautions

Special warnings and precautions for use.

For the treatment of postmenopausal symptoms, hormone replacement therapy (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 initiation or reinstituting HRT, a complete personal and family medical history should be taken, together with a thorough general and gynaecological examination. 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 breast should be reported to their doctor or nurse (see Breast cancer below). Investigations, including appropriate imaging tools e.g. mammography, should be carried out in accordance with current accepted practices, modified according to the clinical needs of the individual.

Conditions which need supervision.

If any of the following conditions are present, have occurred previously and/or have aggravated during pregnancy or previous hormone treatment, the benefits of treatment should be weighed against the possible risks. In these cases the patient should be closely supervised. It should be taken into account that these conditions may, in rare cases, recur or be aggravated during treatment with Ovestin.
Leiomyoma (uterine fibroids) or endometriosis.
A history of thromboembolic disorders or the presence of risk factors (see below).
Risk factors for oestrogen 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.
Epilepsy.
Asthma.
Otosclerosis.
Severe pruritus.
Cholestatic jaundice.
Herpes gestationis.

Reasons for immediate withdrawal of therapy.

Therapy should be discontinued in case a contraindication is discovered and in the following situations.
Jaundice or deterioration in liver function.
Significant increase in blood pressure.
New onset of migraine type headaches.
Pregnancy.

Endometrial hyperplasia and carcinoma.

In order to prevent endometrial stimulation, the daily dose should not exceed 1 application (0.5 mg estriol) nor should this maximum dose be used for longer than several weeks. One epidemiological study has shown that long-term treatment with low doses of oral estriol, but not vaginal estriol, may increase the risk for endometrial cancer. This risk increases with the duration of treatment and disappeared within one year after the treatment was terminated. The increased risk mainly concerned less invasive and highly differentiated tumours. Vaginal bleeding during medication should always be investigated. The patient should be informed to contact a doctor if vaginal bleeding occurs.

Breast cancer.

HRT may increase mammographic density. This may complicate the radiological detection of breast cancer. Clinical studies reported that the likelihood of developing increased mammographic density was lower in subjects treated with estriol than in subjects treated with other oestrogens.
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 oestrogens, oestrogen-progestogen combinations or tibolone for HRT for several years (see Adverse Effects). 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 oestradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. 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.
It is unknown whether Ovestin carries the same risk. In a population based case control study in 3,345 women with invasive breast cancer and 3,454 controls, estriol was found not to be associated with an increased risk of breast cancer, in contrast to other oestrogens. Another, large observational study, the Million Women Study, has shown that compared to never-users, use of oestrogen-progestogen combined HRT is associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88-2.12). In the small number of women using vaginal or other topical HRT preparations, no increased risk of breast cancer was observed (RR = 0.67, 95% CI 0.30-1.49). For all HRT, including Ovestin, the benefits and risks of treatment should be carefully considered. It is recommended that women are encouraged to report any changes in their breasts to their doctor. Regular breast examinations and, where appropriate, mammography should be carried out, particularly in women with risk factors for 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 randomized controlled trial and epidemiological studies found a 2-3 fold 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 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. These studies did not include Ovestin and, in the absence of data, it is unknown whether Ovestin carries the same risk.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see Contraindications).
Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged immobilization, a personal history or family history, obesity (body mass index > 30 kg/m2), pregnancy/ postpartum period, systemic lupus erythematosus (SLE) and breast cancer. There is no consensus about the role of varicose veins in VTE. 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 surgery or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT four to six weeks earlier, if possible.
Use of HRT in patients with a history of recurrent VTE or known thrombophilic states already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT (see also Contraindications). The presence of a personal or strong family history of recurrent thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a definitive diagnosis has been made or anticoagulant treatment initiated use of HRT in such patients should be viewed as contraindicated. Women already on anticoagulant treatment requires careful consideration of the benefit-risk of use of HRT.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at young age, screening may be offered after careful counseling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is severe (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
If VTE develops after initiating Ovestin therapy the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD).

There is no evidence from randomized 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 randomized controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
It is suspected that oestrogen replacement therapy in post-menopausal women may increase the risk of myocardial infarction. Women who use oestrogens should therefore be strongly advised against smoking as it may further increase the risk of adverse cardiovascular effects.
Combined hormone replacement therapy should not be used for long-term maintenance of general health, including primary prevention of cardiovascular disease. Ovestin does not fall in to this category. The concurrent use of Ovestin and other oestrogenic agents, or partial oestrogenic agents has not been studied and is, therefore, not recommended as its use with other oestrogenic agents, or partial oestrogenic agonists, may contribute to long-term risk.

Ischaemic stroke.

One large randomized clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens 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 oestrogens 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 oestrogen-only HRT products in hysterectomized 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 or low potency oestrogens (such as Ovestin) confers a different risk than oestrogen-only products.

Other conditions.

Oestrogens 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 is increased.
Estriol is a weak gonadotrophin inhibitor without other significant effects on the endocrine system.
Benign hepatic adenoma and hepatocellular carcinoma appear to be associated with the use of oral contraceptives but such lesions have not been reported with the use of other oestrogen preparations.
A two fold increase has been reported in the risk of gall bladder disease in women receiving oral oestrogen preparations (including oral contraceptives). However, there have been no reports of gall bladder disease in association with estriol tablets, cream or pessaries.
Susceptible women may experience a rise in blood pressure. Care should be exercised in prescribing oestrogens for patients with hypertension; regular measurement of blood pressure and careful observation for progressive hypertension is recommended.
Because oestrogens may increase the size of uterine fibroids, the pathologist should be advised of oestrogen therapy when relevant specimens are submitted.
Patients with diabetes, severe migraine, epilepsy, asthma, fibrocystic mastopathy, significant cardiac or renal dysfunction should be observed carefully during administration of oestrogens.
Patients with metabolic bone disease or renal insufficiency should be treated with caution because of the effect of oestrogens on the metabolism of calcium and phosphorus.
There is no conclusive evidence for improvement of cognitive function. There is some evidence from the 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.
Ovestin Cream contains cetyl alcohol and stearyl alcohol. This may cause local skin reactions (e.g. contact dermatitis).
Ovestin is not intended for contraceptive use.

Carcinogenicity/ mutagenicity.

Long term continuous administration of natural and synthetic oestrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver. The clinical relevance of these findings is uncertain.

Effects on fertility.

Ovestin is intended for treatment in postmenopausal (naturally and surgically induced) women only.

Use in pregnancy.

(Category B1)
Oestrogen must not be used during pregnancy (see Contraindications). If pregnancy occurs during medication with Ovestin, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or fetotoxic effects.

Use in lactation.

There are insufficient data on the use of this medicine during breastfeeding to assess potential harm to the infant. Estriol is excreted in breast milk and may decrease milk production.

Effects on laboratory tests.

Unknown.

Effects on ability to drive and use machines.

There is no information to suggest that Ovestin affects a patient's ability to drive or operate machinery.

Interactions

No examples of interactions between Ovestin and other medicines have been reported in clinical practice. Although data are limited, interactions between Ovestin and other medicinal products may occur. The following interactions have been described with use of combined oral contraceptives which may also be relevant for Ovestin.
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug metabolizing enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. hydantoins (phenytoin), barbiturates (phenobarbital), carbamazepine) and anti-infectives (e.g. griseofulvin, rifamycins (rifampicin, rifabutin), antiretroviral agents (nevirapine, efavirenz)).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of oestrogens.
Clinically, an increased metabolism of oestrogens may lead to decreased effect and changes in the uterine bleeding profile.
Estriol may possibly increase the pharmacological effects of corticosteroids, succinylcholine, theophyllines and troleandomycin. If necessary the dosage should be reduced.
Estriol may possibly change the effectiveness of oral anticoagulants.

Adverse Effects

From literature and safety surveillance monitoring, the following adverse effects have been reported. See Table 1.
As with any product that is to be applied to mucosal surfaces, Ovestin Cream may cause local irritation or itching in very sensitive persons at the beginning of treatment. Breast tension or pain may occasionally occur (frequency 0.1-1%). In general, this is of a temporary nature, but may also be indicative of too high a dosage.
Other adverse effects have been reported in association with oestrogen-only and oestrogen-progestogen combined treatment. In the absence of data, it is unknown whether Ovestin is distinct in this regard.
Oestrogen dependent neoplasms benign and malignant, e.g. endometrial cancer and breast cancer. For further information see Contraindications and Precautions.
Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. In the absence of data, it is unknown whether Ovestin is distinct in this regard. For further information see Contraindications and Precautions.
Myocardial infarction and stroke.
Gall bladder disease.
Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpure.
Probable dementia over the age of 65 (see Precautions).

Breast cancer risk.

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. Topical (vaginally administered) products were not included in the WHI study and there are limited data in the Million Women Study. At present, there is uncertainty whether these data apply to estriol.
For oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which > 80% of HRT use was oestrogen-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 oestrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.
The MWS reported that, compared to never users, the use of various types of oestrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88-2.12) than use of oestrogens 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 oestrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.
The absolute risks calculated from the MWS and the WHI trials are presented as follows.
The MWS has estimated, from the known average incidence of breast cancer in developed countries, that 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.
For 1000 current or recent users of HRT, the number of additional cases during the responding period will be as follows.
For users of oestrogen-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.
For users of oestrogen plus progestogen 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 oestrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.
According to calculations from the trial data, it is estimated that for 1000 women in the placebo group, about 16 cases of invasive breast cancer would be diagnosed in 5 years.
For 1000 women who used oestrogen + progestogen 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 Special warnings and precautions for use).

Dosage and Administration

Ovestin is an oestrogen only product that may be given to women with or without a uterus.
Ovestin Cream is intended for intravaginal administration by means of a calibrated applicator.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration of time should be used (see Special warnings and precautions for use).
Each applicator dose (applicator filled to the embossed mark) is 0.5 g of Ovestin Cream which contains 0.5 mg estriol.
Usual dosage for vulvo-vaginal complaints associated with the menopause: one application (0.5 mg estriol) per day for 3 weeks initially.
As maintenance dosage, one application of cream 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.
Presurgery therapy (one application of cream (0.5 mg estriol) per day) should begin 2 weeks before the operation (see Precautions).
In the case of a suspect cytological smear a daily application of 0.5 mg estriol for 7 days is recommended before re-evaluating the cytology.
A missed dose should be administered as soon as remembered, unless the missed dose is noticed at the day of the next dose. In the latter case the missed dose should be skipped and the regular dosing scheme continued. Two doses must never be administered on the same day.
In women not taking HRT or women who switch from a continuous combined HRT product, treatment with Ovestin may be started on any day. Women who switch from cyclic HRT regimen should start Ovestin treatment 1 week after completion of the cycle.

Administration.

Patient instructions.

The cream should be used before retiring at night.
1. Remove the 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. Make sure the plunger is fully inserted into the barrel.
3. Squeeze the tube slowly to fill the applicator to the ring mark (where the plunger stops at the red ring).
4. Unscrew the applicator from the tube and put the cap back on the tube.
5. To apply the cream, lie down and insert the end of applicator deep into the vagina.
6. Slowly push the plunger all the way in until the applicator is empty.
7. After use, pull the plunger out of the barrel beyond the point of resistance and wash both parts in warm, soapy water. Do not use detergents. Rinse well and dry.
Do not put the applicator in hot or boiling water.
8. The applicator can be reassembled by fully inserting the plunger into the barrel beyond the point where resistance is felt.
Discard the applicator once the tube is empty.

Overdosage

Contact the Poisons Information Centre for advice on management.
The acute toxicity of estriol in animals is very low. Overdose with Ovestin cream after vaginal administration is unlikely. However, in cases where large quantities of cream are ingested, nausea, vomiting and withdrawal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary.

Presentation

Vaginal cream (white to nearly white, homogeneous), 0.5 mg/0.5 g: 15 g.
Ovestin Cream is filled in collapsible aluminium tubes. The tubes are provided with a plastic cap. Each tube is packed with a CE marked applicator and a patient instruction leaflet.

Storage

Store below 30°C.

Poison Schedule

S4.