Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Gedeon Richter Plc., Gyömrői út 19-21., 1103 Budapest, Hungary
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.
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 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.
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:
Therapy should be discontinued in case a contraindication is discovered and in the following situations:
In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see section 4.8). 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 oestrogen–progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.
For Lenzetto, 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 oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis if they are known to have residual endometriosis.
The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestagen or oestrogen-only HRT, that is dependent on the duration of taking HRT.
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 oestrogen-progestagen for HRT that becomes apparent after about 3 (1–4) years (see section 4.8).
The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-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 oestrogen-progestagen combinations (see section 4.8).
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 oestrogen-progestagen combined treatment, increases the density of mammographic images, which may adversely affect the radiological detection of breast 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 or combined oestrogen-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 section 4.8).
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.
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.
There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.
The relative risk of CAD during use of combined oestrogen + 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 oestrogen + progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.
Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Combined oestrogen-progestagen and oestrogen-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 section 4.8).
Retinal vascular thrombosis has been reported in women receiving oestrogens. 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, oestrogens should be permanently discontinued.
Oestrogens 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 oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
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 oestrogen-only HRT after the age of 65.
Avoid fire, flame or smoking until the spray has dried.
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 section 5.2).
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 section 5.2). Nevertheless, Lenzetto should be used with caution in extreme temperature conditions, such as sun bathing or sauna.
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.
The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. (Traditional) herbal preparations containing St John’s wort (Hypericum perforatum) may induce the metabolism of oestrogens (and progestagens).
At transdermal administration, the first-pass effect in the liver is avoided, and thus, transdermally applied oestrogens (and progestagens) HRT might be less affected than oral hormones by enzyme inducers.
Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.
No interaction studies have been conducted for Lenzetto.
Lenzetto is not indicated during pregnancy. If pregnancy occurs during medication with Lenzetto treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
Lenzetto is not indicated during lactation.
No studies of the effects of Lenzetto on the ability to drive and use machines have been performed.
In a 12-week, randomised, placebo-controlled trial of Lenzetto in 454 women, 80-90% of women who were randomised to active substance received at least 70 days of therapy and 75-85% of the women who were randomised to placebo received at least 70 days of therapy.
The adverse events are listed by organ class and frequency according to MedDRA frequency convention: Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000).
Table 1. Adverse Events Reported:
| System Organ Class (MedDRA 12.0) | Common (≥1/100 to <1/10) | Uncommon (≥1/1000 to <1/100) | Rare (≥1/10,000 to <1/1,000) |
|---|---|---|---|
| Immune system disorders | Hypersensitivity reaction | ||
| Psychiatric disorders | Depressed mood, Insomnia | Anxiety, Libido decreased, Libido increased | |
| Nervous system disorders | Headache | Dizziness | Migraine |
| Eye disorder | Visual disturbances | Contact lens intolerance | |
| Ear and labyrinth disorders | Vertigo | ||
| Cardiac disorders | Palpitations | ||
| Vascular disorders | Hypertension | ||
| Gastrointestinal disorders | Abdominal pain, Nausea | Diarrhoea, Dyspepsia | Bloating, Vomiting |
| Skin and subcutaneous tissue disorders | Rash, Pruritus | Erythema nodosum, Urticaria, Skin irritation | Hirsutism, Acne |
| Musculoskeletal and connective tissue disorders | Myalgia | Muscle spasms | |
| Reproductive system and breast disorders | Breast pain, Breast tenderness, Uterine/Vaginal bleeding including spotting, Metrorrhagia | Breast discolouration, Breast discharge, Cervical polyp, Endometrial hyperplasia, Ovarian cyst, Vaginitis | Dysmenorrhoea, Premenstrual-like syndrome, Breast enlargement |
| General disorders and administration site condition | Oedema, Axillary pain | Fatigue | |
| Investigations | Weight increased, Weight decreased | Gamma-glutamyltransferase increased, Blood cholesterol increased |
From post-marketing surveillance additionally, the following adverse events have been reported:
Skin and subcutaneous tissue disorders:
Largest meta-analysis of prospective epidemiological studies– Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m²)
| Age at start HRT (years) | Incidence per 1,000 never-users of HRT over a 5-year period (50–54 years)* | Risk ratio | Additional cases per 1,000 HRT users after 5 years |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50 | 13.3 | 1.2 | 2.7 |
| Combined oestrogen-progestagen | |||
| 50 | 13.3 | 1.6 | 8.0 |
* Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²).
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.
Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m²):
| Age at start HRT (years) | Incidence per 1,000 never-users of HRT over a 10-year period (50–59 years)* | Risk ratio | Additional cases per 1,000 HRT users after 10 years |
|---|---|---|---|
| Oestrogen only HRT | |||
| 50 | 26.6 | 1.3 | 7.1 |
| Combined oestrogen-progestagen | |||
| 50 | 26.6 | 1.8 | 20.8 |
* Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m²).
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.
US WHI studies – additional risk of breast cancer after 5-years' use
| Age range (years) | Incidence per 1,000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1,000 HRT users over 5 years (95%CI) |
|---|---|---|---|
| CEE oestrogen-only | |||
| 50-79 | 21 | 0.8 (0.7-1.0) | -4 (-6-0)*2 |
| CEE + MPA oestrogen & progestagen‡ | |||
| 50-79 | 17 | 1.2 (1.0-1.5) | +4 (0-9) |
*2 WHI study in women with no uterus, which did not show an increase in risk of breast cancer.
‡ When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.
CEE – Conjugated equine oestrogen
MPA – Medroxiprogesteron acetate
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).
Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study, the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).
Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4).
A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian cancer over a 5-year period.
HRT is associated with a 1.3-3-fold increased 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 using HT (see section 4.4). Results of the WHI studies are presented:
WHI Studies – Additional risk of VTE over 5-years use:
| Age range (years) | Incidence per 1,000 women in placebo arm over 5-years | Risk ratio and 95%CI | Additional cases per 1,000 HRT users |
|---|---|---|---|
| Oral oestrogen-only3 | |||
| 50-59 | 7 | 1.2 (0.6-2.4) | 1 (-3-10) |
| Oral combined oestrogen-progestagen | |||
| 50-59 | 4 | 2.3 (1.2-4.3) | 5 (1-13) |
3 Study in women with no uterus
The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).
WHI studies combined – Additional risk of ischaemic stroke4 over 5 years' use:
| Age range (years) | Incidence per 1,000 women in placebo arm over 5-years | Risk ratio and 95%CI | Additional cases per 1,000 HRT users over 5-years |
|---|---|---|---|
| 50-59 | 8 | 1.3 (1.1-1.6) | 3 (1-5) |
4 No differentiation was made between ischaemic and haemorrhagic stroke.
The following additional adverse reactions have also been reported with oestrogen and/or progestin therapy: angioedema, anaphylactoid/anaphylactic reactions, glucose intolerance, mental depression, mood disturbances, irritability, exacerbation of chorea, exacerbation of epilepsy, dementia (see section 4.4), exacerbation of asthma, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, enlargement of hepatic haemangiomas, chloasma or melasma, that may persist when drug is discontinued; erythema multiforme, haemorrhagic eruption, loss of scalp hair, arthralgias, galactorrhoea, fibrocystic breast changes, increase in size of uterine leiomyomata, change in amount of cervical secretion, changes in cervical ectropion, vaginal candidiasis, hypocalcaemia (pre-existing condition).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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