Divigel Special Precautions

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 favourable 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 precautions 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 physician or nurse (see Breast cancer as follows). Investigations, including appropriate imaging tools eg, mammography should be carried out in accordance with currently accepted screening practices, modified 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 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 Divigel, in particular: Leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders (see as follows); risk factors for estrogen dependent tumours eg, 1st degree heredity for breast cancer; hypertension; liver disorders (eg, liver adenoma); diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; a history of endometrial hyperplasia (see as follows); epilepsy; asthma; otosclerosis; hereditary angioedema.
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 headache; pregnancy.
Endometrial Hyperplasia and Carcinoma: In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see Adverse Reactions). After stopping treatment, risk may remain elevated for at least 10 years.
The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
Breakthrough bleeding and spotting may occur during the 1st months of treatment. If breakthrough bleeding or spotting appears after some time on therapy or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to estrogen replacement therapy should be considered in women, who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.
Breast Cancer: The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen-progestagen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.
Combined Estrogen-Progestagen Therapy: The randomised placebo-controlled trial (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestagen for HRT that becomes apparent after about 3 years (see Adverse Reactions).
Estrogen Only Therapy: The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestagen combinations (see Adverse Reactions).
The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most 5) years after stopping treatment.
Hormone replacement therapy, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian Cancer: Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use of estrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see Adverse Reactions). Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar or slightly smaller risk (see Adverse Reactions).
Venous Thromboembolism: Hormone replacement therapy is associated with a 1.3 to 3-fold risk of developing venous thromboembolism (VTE) ie, deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the 1st year of HRT than later (see Adverse Reactions).
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 estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI >30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily, stopping HRT 4-6 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 1st degree relative with a history of thrombosis at young age, screening may be offered after careful counselling 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' (eg, 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, Divigel should be discontinued. Patients should be told to contact their physicians immediately, when they are aware of a potential thromboembolic symptom (eg, painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary Artery Disease (CAD): There is no evidence from randomised controlled trials of protection against myocardial infarction in women, with or without existing CAD, who received combined estrogen-progestagen or estrogen-only HRT.
Combined Estrogen-Progestagen Therapy: The relative risk of CAD during use of combined estrogen+progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen+progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.
Estrogen Only: Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.
Ischaemic Stroke: Combined estrogen-progestagen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic 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 Adverse Reactions).
Other Conditions: Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed.
Women, with preexisting 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.
Estrogens 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 6 radioimmunoassay) or T3 levels (by radioimmunoassay). 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 ie, 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, α₁-antitrypsin, ceruloplasmin).
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum.
Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.
Hormone replacement therapy 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.
Divigel is not a contraceptive and adequate nonhormonal contraception should be advised.
Divigel contains propylene glycol and therefore may cause skin irritation.
Effects on the Ability to Drive or Operate Machinery: No influence on ability to drive or use machines.
Use in Pregnancy: Divigel is not indicated during pregnancy. If pregnancy occurs during medication with Divigel, 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 effect.
Use in Lactation: Divigel is not indicated during lactation.