Special Warning : אזהרת שימוש

4.4   Special warnings and 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.

• Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favorable than in older women.

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 (see “Breast cancer” below). 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

•     In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when systemic oestrogens are administered alone for prolonged periods.

•     For Ovestin vaginal cream, the systemic exposure of estriol remains closely to the normal postmenopausal range when used in a twice weekly administration, it is not recommended to add a progestagen.

•     Endometrial safety of long-term (more than one year) or repeated use of local vaginally administered estrogens is uncertain. Therefore, if repeated, treatment should be reviewed at least annually.

•     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.

•     If bleeding or spotting appears at any time on therapy, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

•     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 increased 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 tumors.

The following risks have been associated with systemic HRT and apply to a lesser extent for Ovestin vaginal cream of which the systemic exposure to estriol remains within the normal postmenopausal range when used in a twice weekly administration. However, they should be considered in case of long term or repeated use of this product

Breast cancer
Epidemiological evidence from a large meta-analysis suggests no increase in risk of breast cancer in women with no history of breast cancer taking low dose vaginally applied oestrogens. It is unknown if low dose vaginal oestrogens stimulate recurrence of breast cancer.
HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect 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 estrogens.

It is unknown whether Ovestin cream carries the same risk. In a several population-based case-control studies, estriol was found not to be associated with an increased risk of breast cancer, in contrast to other estrogens.
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.

Ovarian cancer
Ovarian cancer is much rarer than breast cancer.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only systemic HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

Venous thromboembolism
• Systemic HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.
• 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 section 4.3).
• 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.
• As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
• 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.
• Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
• 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 (e.g., painful swelling of a leg, sudden pain in the chest, dyspnea).
Coronary artery disease (CAD)
Oestrogen-only
Randomized controlled data found no increased risk of CAD in hysterectomized women using systemic oestrogen-only therapy.

Ischemic stroke
Systemic oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age- dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

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.
• Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
• Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin,
ceruloplasmin).
• HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.
• Ovestin cream contains cetyl alcohol and stearyl alcohol. This may cause local skin reactions (e.g. contact dermatitis).

Concomitant use of Hepatitis C medications
• During clinical trials with the combination drug regimen ombitasvir hydrate/paritaprevir hydrate/ritonavir with or without dasabuvir, ALT elevations to greater than 5 times the upper limit of normal (ULN) were significantly more frequent in female subjects using ethinyl estradiol- containing medications. Women using estrogens other than ethinyl estradiol, such as estradiol, estriol and conjugated estrogens had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of subjects taking these other estrogens, caution is warranted for co-administration with the combination drug regimen
ombitasvir hydrate/paritaprevir hydrate/ritonavir with or without dasabuvir.
(See section 4.5.)

Effects on Driving

4.7   Effects on ability to drive and use machines

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