OVESTIN CREAM

Oestriol 1mg/gm

Presentation

Cream - a white to almost white, smooth homogeneous creamy mass, containing 1mg oestriol per 1gm cream.

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Ovestin cream contains the natural female hormone, oestriol. In the years just before and after the menopause (which can be natural, or surgically induced) oestriol can be used in the treatment of symptoms and complaints related to oestrogen deficiency. Oestriol is particularly effective in the treatment of urogenital symptoms. In case of atrophy of the lower urogenital tract oestriol 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.

Unlike other oestrogens, oestriol is short-acting since it has only a short retention time in the nuclei of endometrial cells. Therefore, no endometrial proliferation is to be expected when the total recommended daily dose is taken at one time. Hence cyclic administration of a progestagen is not necessary, and postmenopausal withdrawal bleedings do not occur.

Pharmacokinetics

Intravaginal administration of oestriol ensures optimal availability at the site of action. Oestriol is also absorbed into the general circulation, as is shown by a sharp rise in the plasma levels of unconjugated oestriol. Peak plasma levels are reached 1-2 hours after application.

Nearly all (90%) oestriol is bound to albumin in the plasma and in contrast with other oestrogens, hardly any oestriol is bound to sex hormone-binding globulin (SHBG). The metabolism of oestriol consists principally of conjugation and deconjugation during the enterohepatic circulation. Oestriol, being a metabolic end product, is mainly excreted via the urine in the conjugated form. Only a small part (± 2%) is excreted via the faeces, mainly as unconjugated oestriol.

Indications

Atrophy of the lower urogenital tract related to oestrogen deficiency, notably

• for the treatment of vaginal complaints such as dyspareunia, dryness and itching.
• for the prevention of recurrent infections of the vagina and lower urinary tract.
• in the management of micturition complaints (such as frequency and dysuria) and mild urinary incontinence.

Pre- and post-operative therapy in postmenopausal women undergoing vaginal surgery.

A diagnostic aid in case of a doubtful atrophic cervical smear.

Dosage

Atrophy of the lower urogenital tract

1 application per day for the first weeks, followed by a gradual reduction, based on relief of symptoms, until a maintenance dosage (e.g. 1 application twice a week) is reached.

Pre- and post-operative therapy in postmenopausal women undergoing vaginal surgery

1 application per day in the 2 weeks before surgery; 1 application twice a week in the 2 weeks after surgery.

A diagnostic aid in case of a doubtful atrophic cervical smear

1 application on alternate days in the week before taking the next smear.

Administration

Ovestin cream should be administered intravaginally by means of a calibrated applicator before retiring at night.

One application (applicator filled to the red mark) contains 0.5g OVESTIN cream which corresponds with 0.5mg oestriol.

Instructions For Use For The Patient

1. Apply the vaginal cream before retiring at night.
2. Remove the cap from tube, invert it, and use the sharp point to open the tube.
3. Screw the end of the applicator onto the tube.
4. Squeeze tube to fill the applicator with the cream until the plunger stops.
5. Unscrew applicator from tube and replace cap on tube.
6. To apply cream, lie down, insert end of applicator deep into the vagina and slowly push plunger all the way in.

After use, pull plunger out of barrel and wash both in warm, soapy water. Do not use detergents. Rinse well afterwards.

DO NOT PUT THE APPLICATOR IN HOT OR BOILING WATER.

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.

Contra-Indications

• Pregnancy.
• Active or recent (e.g. within the past year) arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke).
• Known or suspected malignant conditions, especially breast cancer and/or endometrial cancer, if sex steroid influenced.
• Confirmed active venous thromboembolism (deep venous thrombosis, pulmonary embolism) within the last 2 years.
• A history of recurrent venous thromboembolism (VTE) or known thrombophilic disease in a patient who is not already on anticoagulant treatment (see Warnings and Precautions.
• Undiagnosed vaginal bleeding.

Warnings And Precautions

• Before initiating or reinstituting hormone replacement therapy (HRT), a complete personal and family medical history should be taken, together with a thorough general and gynaecological examination guided by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman and follow-up examinations of the breasts and/or mammography should be carried out in accordance with current accepted practices for the healthy woman, modified according to the clinical needs of the individual. All prospective and current users of HRT should be advised of the risks and benefits of oestrogen and progestogens. The need for continued treatment with HRT should be reviewed on a yearly basis.
• In a large randomised trial involving women who received hormone replacement therapy for an average of 5.2 years using conjugated equine oestrogens (0.625 mg/day) continuously combined with medroxyprogesterone acetate (2.5 mg/day), adverse effects on cardiovascular disease and the incidence of breast cancer were observed. This Women's Health Initiative study was designed to investigate the efficacy and safety of long term HRT in preventing coronary heart disease in healthy postmenopausal women with an intact uterus. After a mean of 5.2 years of follow-up, the study was prematurely stopped because the preset criterion for invasive breast cancer was fulfilled and the global index supported risks exceeding benefits. Estimated hazard ratios (HRs)(nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63); breast cancer, 1.26 (1.00-1.59); stroke, 1.41 (1.07-1.85); PE, 2.13 (1.39-3.25); colorectal cancer, 0.63 (0.43-0.92); endometrial cancer, 0.83 (0.47-1.47); hip fracture, 0.66 (0.45-0.98), and death due to other causes, 0.92 (0.74-1.14). Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer and 1.15 (1.03-1.28) for the global index. The HR for combined fractures was 0.76 (0.69-0.85) while total mortality was unchanged [0.98 (0.82-1.18)]. The study was prematurely stopped, so it is unknown whether some time dependent risks and benefits would have reached statistical significance, had the study continued.
• In this study, the absolute excess risks per 10,000 person-years attributable to oestrogen plus progestin were small, i.e. 7 more cases of CHD (37 vs 30), 8 more strokes (29 vs 21), 8 more pulmonary emboli (15 vs 7) and 8 more invasive breast cancers (38 vs 30), while the absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers (10 vs 16) and 5 fewer hip fractures (10 vs 15) than in women not using that form of HRT It is not known if the results of this study apply to Ovestin cream as the study did not look at topical oestrogens such as oestriol. The no-effect dose level of conjugated equine oestrogens and medroxyprogesterone acetate in respect of these risks is unknown. The risks and benefits in women receiving treatment for the short-term management of menopausal symptoms of oestrogen deficiency or for the management of premature menopause were not examined in the aforementioned study. If prescribing HRT, the potential for increased cardiovascular, thrombotic and neoplastic adverse events must be considered. Combined hormone replacement therapy should not be used for long-term maintenance of general health, including primary prevention of cardiovascular disease.. 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. Other doses of conjugated oestrogens and medroxyprogesterone acetate, and other combinations of oestrogens and progestogens were not studied in the WHI and, in the absence of comparable data these risks should be assumed to be similar. Because of these risks, oestrogens and progestogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
• Oestrogens increase the risk of endometrial cancer. Close clinical surveillance of all women taking oestrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" oestrogens results in a different endometrial risk profile than synthetic oestrogens of equivalent oestrogen dose.
• In order to prevent endometrial stimulation with oestriol (a weak oestrogen), the daily dose should not exceed 1 application (0.5 mg oestriol), nor should this maximum dose be used for longer than several weeks.
• An increased risk of ovarian cancer in menopausal women taking oestrogen only replacement therapy was observed in a large US study enrolling over 40,000 women on HRT. These women were followed up for a mean duration of 13.4 years (range 1 month to 19.8 years). The increased risk of ovarian cancer in those taking oestrogen replacement therapy was 80%, RR 1.8 (95% CI, 1.1-3.0) at 10 to 19 years. This risk increased with duration of use; RR for 20 years or more years of use was 3.2 (95% CI, 1.7-5.7). This equates to approximately 3 and 8 additional cases per 10,000 women-years at these time points; (the incidence of ovarian cancer in non-users was 4.4 per 10,000 women years). This observation was most obvious in those women on long-term oestrogen replacement therapy who had a prior history of hysterectomy (defined as simple hysterectomy or hysterectomy with unilateral oophorectomy). In this subpopulation, the RR was 2.0 (95% CI, 0.96-4.3) for between 10 and 19 years of use and 3.4 (95% CI, 1.6-7.5) for 20 years or more. It is not known if the results of this study apply to Ovestin cream as the study did not look at topical oestrogens such as oestriol.
• A reanalysis of original data from 51 epidemiological studies reported a small or moderate increase in the probability of having breast cancer diagnosed in women currently or recently using HRT. , in a recent population-based case-control study in 3,345 women with invasive breast cancer and 3,454 controls, oestriol was found not to be associated with an increased risk of breast cancer, in contrast to other oestrogens. However, the clinical implications of these findings are as yet unknown. Therefore, it is important that the risk of being diagnosed with breast cancer is discussed with the patient and weighed against the known benefits of HRT.
• Epidemiological studies have suggested that HRT is associated with a higher relative risk of developing VTE, i.e. deep vein thrombosis or pulmonary embolism. The studies find a 2-3 fold higher risk for users compared with non-users, which for healthy women amounts to one to two additional cases of VTE in 10,000 patient-years of treatment with HRT. 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 is distinct in this regard.
  Generally recognized risk factors for VTE include a personal history or family history, severe obesity (Body Mass Index >30kg/m 2 ) and systemic lupus erythematosus (SLE). There is no consensus about the role of varicose veins in VTE.
  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.
  The risk of VTE may be temporarily increased with prolonged immobilization, major trauma or major surgery. As in all post-operative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilization 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. If OVESTIN is used for the indication 'pre-and post operative therapy in postmenopausal women undergoing vaginal surgery' c onsideration should be given to prophylactic treatment against thrombosis.
  If VTE develops after initiating Ovestin therapy, the medicine 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).
• 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:
  • A history of thromboembolic disorders or the presence of risk factors (see below)
  • Severe liver disorders
  • Porphyria
  • Severe pruritus
  • Cholestatic jaundice
  • Herpes gestationis
  • Otosclerosis
  • With vaginal infections, a concomitant specific treatment is recommended.
  • Ovestin cream may have an unfavourable effect on latex rubber condoms. Concurrent use might increase the incidence of rupture or unnoticed slipping of the condoms.

Use During Pregnancy And Breast-Feeding

This medicine is contraindicated during pregnancy.

There are insufficient data on the use of this medicine during breast-feeding to assess potential harm to the infant. It is known, however, that oestriol is excreted in breast milk and may decrease milk production.

Effects on Ability to Drive and Use Machines

As far as is known Ovestin has no effect on alertness and concentration.

Adverse Effects

As with any product that is to be applied to mucosal surfaces, Ovestin cream may occasionally cause local irritation or itching. Breast tension or pain may occasionally occur. These adverse reactions are usually transient, but may also be indicative of too high a dosage. 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 Warnings and Precautions.

Interactions

No examples of interactions between OVESTIN and other medicines have been reported in clinical practice. There are, however, indications that oestrogens can increase the pharmacological effects of corticosteroids. If necessary, the dosage of the corticosteroids should be reduced.

Although data are limited it is considered possible that barbiturates, carbamazepine, griseofulvin, hydantoins, and rifampicin may decrease the effectiveness of oestriol.

Conversely, oestriol may possibly change the effectiveness of oral anticoagulants, and increase the pharmacological effects of succinylcholine, theophyllines, and troleandomycin.

Overdosage

The acute toxicity of oestriol in animals is very low. Overdosage with Ovestin cream after vaginal administration is unlikely. However, should large quantities be ingested, nausea, vomiting and withdrawal bleeding in females may develop. No specific antidote is known. Symptomatic treatment can be given if necessary.

Pharmaceutical Precautions

Ovestin cream should be stored at 2°C-25°C; do not allow to freeze. The shelf-life for Ovestin is 3 years if stored as indicated above. Ovestin should not be used after the expiry date on the package.

Package Quantities

Box containing a 15g tube of cream and one applicator.

Nature and contents of container

Ovestin cream is filled in collapsible aluminium tubes. The tubes are provided with a polyethylene screw cap. The applicator consists of a polystyrene barrel and a polyethylene plunger. Each tube is packed, together with an applicator in a cardboard box.

List of excipients

Eutanol G; Cetyl palmitate; Glycerol; Cetyl alcohol; Stearyl alcohol; Polysorbate 60; Sorbitan monostearate; Lactic acid; Chlorhexidine hydrochloride; Sodium hydroxide; Purified water.

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