Lenzetto 1.53 mg/spray, transdermal spray, solution

Each spray delivers 90 microliter of transdermal spray, solution containing 1.53 mg of estradiol (equivalent to 1.58 mg of estradiol hemihydrate).

For the full list of excipients, see section 6.1

Transdermal spray, solution.

The solution is clear, colourless to pale yellow.

Hormone Replacement Therapy (HRT) for estrogen deficiency symptoms in postmenopausal women (in women at least 6 months since last menses or surgical menopause, with or without a uterus).

The experience in treating women older than 65 years is limited.

Posology

Lenzetto is administered once daily, either as a monotherapy or as a continuous sequential treatment (when combined with a progestogen).

One metered-dose spray is administered once daily to the dry and healthy skin of the forearm as a starting dose. The dose may be increased to two metered-dose sprays daily to the forearm based on clinical response. Dose increase should be based on the degree of the woman's menopausal symptoms and should be made only after at least 4 weeks of continuous treatment with Lenzetto. The maximum daily dose is 3 metered-dose sprays (4.59 mg/day) to the forearm. Dose increase should be discussed with the physician. For patients who have difficulty applying the prescribed dose to distinct, non-overlapping areas of the same forearm, {Invented name}may also be applied to sites on the alternate forearm, or to sites on the inner thigh.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

When the degree of the woman's menopausal symptoms is not reduced after a dose increase, the patient should be back-titrated to the previous dose.

Patients should be re-evaluated periodically as clinically appropriate (e.g. 3-month to 6-month intervals) to determine if treatment is still necessary (see section 4.4).

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestagen approved for addition to estrogen treatment should also be initiated to reduce the risk of endometrial cancer. Only progestagens approved for addition to estrogen treatment should be administered.

In women with a uterus

In women with an intact uterus, the product should be combined with a progestagen approved for addition to estrogen treatment in a continuous - sequential dosing scheme: the estrogen is dosed continuously. The progestagen is added for at least 12 to 14 days of every 28-day cycle, in a sequential manner.

Advice on how to initiate treatment should be given for treatment naive patients and for patients changing from other HRTs (cyclic, sequential or continuous combined).

In the period in which the estrogen is combined with the progestagen, a withdrawal bleeding can occur. A new 28-day treatment cycle is started without a break.

In women without a uterus

Unless there is a previous diagnosis of endometriosis, it is not recommended to add progestagen for women without a uterus.

Overweight and obese women

There is some limited data that the rate and extent of absorption of Lenzetto can be reduced in overweight and obese women. During the treatment, the dose of Lenzetto may require adjustment. Dose modification should be discussed with the physician.

Paediatric population

There is no relevant use of Lenzetto in the paediatric population.

Missed dose

If a dose is missed, the patient should make up for the missed dose as soon as she remembers and take the next dose at the usual time. If it is almost time for the next dose, she should skip the missed dose and take the next dose at the usual time. If one or more doses are missed one primer spraying with the cover on is needed. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

Method of administration

The container should be held upright and vertical for spraying. Before a new applicator is used for the first time, the pump should be primed by spraying three times into the cover.

The daily dose is one metered-dose spray on the inner forearm. If two or three sprays are prescribed as the daily dose, they should be applied to adjacent non-overlapping (side-by-side) 20 cm² areas on the inner surface of the arm between the elbow and the wrist and allowed to dry for approximately 2 minutes. Women should cover the application site with clothing if another person may come into contact with that area of skin after the spray dries. The site of application should not be washed for 60 minutes. Do not allow another person to touch the site of application within 60 minutes of application.

Do not allow children to come in contact with the area of the arm where Lenzetto was sprayed. If a child comes in contact with the part of the arm where Lenzetto was sprayed, wash the child's skin with soap and water as soon as possible.

Do not allow pets to lick or touch the arm where Lenzetto was sprayed. Small pets may be especially sensitive to the estrogen in Lenzetto. Contact a veterinarian if your pet exhibits mammary/nipple enlargement and/or vulvar swelling, or any other sign of illness.

Studies suggest that compared to applying it to the inner surface of the forearm, absorption of estradiol is similar when Lenzetto is applied to the skin of the thigh, but is lower when applied to the skin of the abdomen.

If the product is used according to the instructions, irrespective of different spray shape or pattern on the skin each puff will deliver the same amount of ingredient on the skin.

Elevated skin temperature

The effect of increased ambient temperature with Lenzetto has been studied and clinically relevant difference in the extent of absorption of Lenzetto was not observed. However, Lenzetto should be use with caution in extreme temperature conditions, such as sun bathing or sauna.

Application of sunscreen

When sunscreen is applied about one hour following Lenzetto, estradiol absorption may be decreased by 10%. If women use sunscreen 1 hour after they use Lenzetto, it may reduce the amount of Lenzetto absorbed by their skin.

- Known, past or suspected breast cancer;

- Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer);

- Undiagnosed genital bleeding;

- Untreated endometrial hyperplasia;

- Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism);

- Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4);

- Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction);

- Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal;

- Porphyria;

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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' 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.

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 below)

- 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 below)

- 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 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 estrogen–progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-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 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, the Women's Health Initiative study (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 section 4.8).

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 section 4.8).

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five) years after stopping treatment.

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 section 4.8).

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 section 4.8).

- 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, 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 section 4.8).

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.

Alcohol based products are flammable

Avoid fire, flame or smoking until the spray has dried.

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 section 5.2).

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 section 5.2). Nevertheless, Lenzetto should be used with caution in extreme temperature conditions, such as sun bathing or sauna.

Paediatric population

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 estrogens 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 estrogens (and progestagens).

At transdermal administration, the first-pass effect in the liver is avoided, and thus, transdermally applied estrogens (and progestagens) HRT might be less affected than oral hormones by enzyme inducers.

Clinically, an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.

No interaction studies have been conducted for Lenzetto.

Pregnancy

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 estrogens indicate no teratogenic or foetotoxic effects.

Breast-feeding

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

From post-marketing surveillance additionally, the following adverse events have been reported:

Skin and subcutaneous tissue disorders

- Alopecia

- Chloasma

- Skin discolouration

Breast cancer risk

- An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for more than 5 years.

- Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations.

- The level of risk is dependent on the duration of use (see section 4.4).

- Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.

Million Women study– Estimated additional risk of breast cancer after 5-years' use

US WHI studies - additional risk of breast cancer after 5-years' use

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of estrogen-only use and estrogen 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 estrogen-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)).

Ovarian cancer

Use of estrogen-only or combined estrogen-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.

Risk of venous thromboembolism

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

³ Study in women with no uterus

Risk of coronary artery disease

- The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

- The use of estrogen-only and estrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

- This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke⁴ over 5 years' use

⁴ No differentiation was made between ischaemic and haemorrhagic stroke.

The following additional adverse reactions have also been reported with estrogen 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 of suspected adverse reactions

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.

Effects have not been reported following acute ingestion of large doses of estrogen-containing products. Overdosage of estrogen may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Lenzetto together with institution of appropriate symptomatic care.

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, Estrogens, Natural and semisynthetic estrogens, plain; Estradiol, ATC Code: G03CA03

Lenzetto provides systemic estrogen replacement therapy by releasing estradiol, the major estrogenic hormone secreted by the ovaries. The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.

Absorption

When Lenzetto was applied to the skin, the average drying time was 90 sec (median = 67 sec).

In a multiple-dose study, postmenopausal women were treated for 14 days with one-, two- or three-90 microliter sprays of Lenzetto on the inner forearm. Serum concentrations of estradiol appeared to reach a steady state after 7-8 days of application of Lenzetto.

Following morning administration, blood levels remained relatively stable and within the therapeutic range throughout the 24-hour period following administration with peak levels between 2 AM and 6 AM.

In a clinical study, postmenopausal women were treated for 12 weeks with one, two or three 90 microliter sprays of Lenzetto on the inner forearm and blood levels of estradiol were measured at Week 4, 8 and 12. The estradiol exposure increased with increasing dose (one, two, three sprays respectively) but the increase was slightly less than proportional to dose.

Pharmacokinetic parameters for estradiol and estrone from one, two or three 90 microliter sprays of Lenzetto were further examined in a clinical study and are described in Table 2.

Table 2. Pharmacokinetic parameters on Day 14 (Unadjusted for Baseline)

A second pharmacokinetic study assessed serum estradiol concentrations in 20 postmenopausal women treated for 18 days with three 90 microliter sprays of Lenzetto on the inner forearm. In this study, application of sunscreen one hour prior to the application of Lenzetto caused no significant difference in absorption of estradiol. When sunscreen was applied one hour after the application of Lenzetto, there was approximately a 10% decrease in the absorption of estradiol (see section 4.4).

Studies suggest that compared to applying it to the inner surface of the forearm, absorption of estradiol is similar when Lenzetto is applied to the skin of the thigh, but is lower when applied to the skin of the abdomen.

Estradiol transfer during administration of Lenzetto

In a clinical trial 20 postmenopausal women who were treated with three 90 microliter sprays of estradiol transdermal spray (1.53 mg/spray) to their inner forearm once daily were assessed for transfer risk, by holding their forearm to the inner forearm of a male for 5 minutes an hour after treatment. During the clinical study no significant transfer of estradiol was observed. Information on the transfer within one hour is not available (see section 4.4).

Elevated skin temperature

A bioavailability study assessed the effect of increased ambient temperature in 24 healthy postmenopausal women with 2 sprays on the forearm. In this study, increased ambient temperature of 35 °C for 4 hours caused similar rate and extent of absorption with approximately 10% differences compared to data obtained at room temperature.

Overweight and obese women

To evaluate the influence of obesity on the absorption, a single-dose, comparative bioavaliability study was carried out. The study was performed to compare the rate and extent of absorption of Estradiol 1.53 mg/spray (90 microliter) in obese and normal weight women under normal temperature conditions after application of two sprays on the forearm. Based on the point estimates of baseline corrected unconjugated estradiol and unconjugated estrone, the extent and rate of absorption are approximately 33-38% and 15-17% lower while the median peak of absorption is observed 12 to 14 hours earlier. For baseline corrected total estrone, the extent and rate of absorption are approximately 7% lower and approximately 22% higher respectively, in obese post-menopausal females. The T_max is delayed by approximately 6 hours in obese post-menopausal females for this analyte.

Distribution

Estrogens circulate in blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Biotransformation

Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Elimination

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Serum concentrations of estradiol, estrone and estrone sulfate returned to baseline levels in more than one week after discontinuation of therapy once steady-state had been achieved.

Conventional studies of general toxicity data revealed no additional risks in addition to what has already been reflected in the SmPC. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testes and liver (see section 4.4).

Animal studies with estradiol or estradiol valerate have shown embryolethal effects even at relatively low doses; malformation of urogenitalia and feminisation of male foetuses.

Octisalate is included in the formulation as an excipients to enhance skin penetration. Octisalate has been widely used in commercial dermal products for many years. Despite the absence of many formal toxicity studies, octisalate is unlikely to represent any special hazard for humans as both the acute oral toxicity of octisalate and that the subchronic toxicity following dermal or oral route of administration are low. Tests for photo-toxicity and photo-contact allergy in man were negative. Furthermore, tests for mutagenicity, clastogenicity, photo-mutagenicity and photo-clastogenicity, using bacterial and tissue culture tests systems were negative.

An effect of octisalate on human reproduction or carcinogenic actions are unlikely based on the hormone activity and genotoxicity studies conducted and bearing in mind the limited dermal penetration of octisalate, the relatively small dose of octisalate in the product (8.5%) and the absence of any reported effects from the extensive human use in sunscreens and cosmetics.

Environmental risk assessment studies have shown that the active ingredient estradiol hemihydrate may pose a risk for aquatic environment, especially for fish.

Octisalate

Ethanol 96%

Not applicable.

3 years.

Use within 56 days of first use.

Do not refrigerate or freeze.

Do not store above 25°C.

Contains ethanol which is flammable. Store away from heaters, open flames, and other sources of ignition.

The solution is packaged in a glass vial fitted with a metered dose pump. The unit is encased in a plastic housing with a conical bell opening that controls the distance, angle, and area of application of the metered dose spray.

One container is filled with 8.1 ml, transdermal spray solution and is designed to deliver 56 sprays after priming.

Pack sizes:

One plastic container 8.1 ml (56 sprays)

Three plastic containers 3x8.1 ml (3x56 sprays)

Not all pack sizes may be marketed.

After delivery of 56 sprays, the container must be discarded even if there is some leftover solution in it. The number of sprays made should be marked using the table on the carton. As drug residue will remain in the used up containers, they should not be disposed of via household waste. Empty containers should be returned to the pharmacy for destruction.

This medicinal product may pose a risk to the environment. (see section 5.3).

Gedeon Richter Plc.

Gyömrői út 19-21.

1103 Budapest

Hungary

PL 04854/0130

13/08/2015

12/06/2018