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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 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 as follows). Investigations, including appropriate imaging tools, e.g. 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 Lenzetto, in particular: Leiomyoma (uterine fibroids) or endometriosis; Risk factors for thromboembolic disorders (see as follows); Risk factors for estrogen dependent tumours, e.g. first-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 as follows); Epilepsy; Asthma; Otosclerosis.
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.
For estradiol transdermal spray (1.53 mg/spray), the endometrial safety of added progestagens has not been studied.
Breakthrough bleeding and spotting may occur during the first 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 shows an increased risk of breast cancer in women taking combined estrogen-progestagen or estrogen-only HRT, that is dependent on the duration of taking HRT.
Combined estrogen-progestagen therapy: The randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and a meta-analysis of prospective 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 (1 - 4) 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 lower than that found in users of estrogen-progestagen combinations (see Adverse Reactions).
Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.
HRT, 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.
Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Some other studies, including the WHI trial suggest that the use of combined HRTs may be associated with a similar, or slightly smaller, risk (see Adverse Reactions).
Venous thromboembolism: HRT is associated with a 1.3-3 fold 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 (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 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 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' (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 must 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 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 therapy: 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).
Visual abnormalities: Retinal vascular thrombosis has been reported in women receiving estrogens. Medication must be discontinued immediately, pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.
Other conditions: Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
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.
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 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.
Application of sunscreen: When sunscreen is applied about one hour following Lenzetto, estradiol absorption may be decreased by 10%. When sunscreen was applied about one hour prior to Lenzetto, no effect on absorption was observed (see Pharmacology: Pharmacodynamics/Pharmacokinetics under Actions).
Elevated skin temperature: The effect of increased ambient temperature has been studied and approximately 10% difference was observed in the absorption of Lenzetto. This effect is not expected to be of clinical relevance for daily administration of Lenzetto (see Pharmacology: Pharmacodynamics/Pharmacokinetics under Actions). Nevertheless, Lenzetto should be used with caution in extreme temperature conditions, such as sunbathing or sauna.
Excipient: This medicine contains 65.47 mg alcohol (96% ethanol) in each dose which is equivalent to 72.74% w/v. It may cause burning sensation on damaged skin.
Alcohol-based products are flammable: Fire, open flame, smoking or use of devices like hairdryers should be avoided until the spray has dried.
Effects on ability to drive and use machines: No studies of the effects of Lenzetto on the ability to drive and use machines have been performed.
Use in Children: Post-marketing reports of breast budding and breast masses in prepubertal females, precocious puberty and gynaecomastia and breast masses in prepubertal males following unintentional secondary exposure to Lenzetto have been reported. In most cases, the condition resolved with removal of Lenzetto exposure.
The possibility of unintentional secondary exposure to Lenzetto should be brought to the attention of a physician. The physician should identify the cause of abnormal sexual development in the child. If unexpected breast development or changes are determined to be the result of unintentional exposure to Lenzetto, the physician should counsel the woman on the appropriate use and handling of Lenzetto when around children. Women should cover the Lenzetto application site with clothing if another person (especially children) may come into contact with the site. Consideration should be given to discontinuing Lenzetto if conditions for safe use cannot be met.
