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Orion Pharma (Ireland) Ltd

Orion Pharma (Ireland) Ltd

Summary of Product Characteristics last updated on medicines.ie: 6/6/2016

Divigel 0.1% Gel

1. NAME OF THE MEDICINAL PRODUCT

Divigel 0.1% w/w Gel, 1 mg/dose

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Estradiol hemihydrate corresponding to 1.0 mg estradiol per single dose container .

Excipient with known effect: propylene glycol

For full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Gel, single-dose container.

Smooth, opalescent gel

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

• Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

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

4.2 Posology and method of administration

Divigel is a gel for the transdermal use. Divigel can be used for continuous, cyclic or sequential treatment. The usual starting dose is 1.0 mg oestradiol (1.0 g gel) daily but the selection of the initial dose can be based on the severity of the patients' symptoms. Depending on the clinical response, the dosage can be readjusted after 2 to 3 cycles individually from 0.5g to 1.5g per day, corresponding to 0.5 to 1.5 mg oestradiol per day.

In patients with an intact uterus, it is necessary to combine Divigel with an adequate dosage of progestagen for adequate duration, at least 12-14 consecutive days per month/28 day cycle or to oppose oestrogen-stimulated hyperplasia of the endometrium.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

Method of Administration

Apply on dry and clean skin.

The Divigel dose is applied once daily, on the skin of the lower trunk or the right or left thigh, on alternate days. The application surface should be 1-2 times the size of a hand. Divigel should not be applied on the breasts, on the face or irritated skin. After application the gel should be allowed to dry for a few minutes and the application site should not be washed within one hour. Contact of the gel with eyes should be avoided. Hands should be washed after application.

In women who are not using hormone replacement therapy (HRT), or women transferring from continuous combined HRT-product, treatment with Divigel may be started on any convenient day. In women transferring from a continuous sequential or cyclic HRT regimen, treatment should begin the day following completion of the prior 28 days regimen.

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.

If the patient has forgotten to apply one dose, the forgotten dose is to be applied as soon as possible if the dose is not more than 12 hours late. If the dose is more than 12 hours late the dose should be forgotten and continue as normal. Forgetting a dose may increase the likelihood of break-through bleeding and spotting.

4.3 Contraindications

• Known, past or suspected breast cancer

• Known or suspected oestrogen 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 has failed to return to normal

• Known hypersensitivity to the active substances or any of the excipients listed in section 6.1

• Porphyria

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 favourable than in older women.

Medical examination/follow up:

• Before initiating or reinstituting hormone replacement therapy (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 Divigel, in particular:

• Leiomyoma, (uterine fibroids) or endometriosis

• Risk factors for, thromboembolic disorders (see below)

• Risk factors for oestrogen 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

• Hereditary angioedema

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 and carcinoma

• 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.

• Break-through bleeding and spotting may occur during the first months of treatment. If break-through 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.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-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 oestrogen-progestagen for HRT that becomes apparent after about 3 years (see section 4.8).

Oestrogen-only therapy

• 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 substantially lower than that found in users of oestrogen-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 oestrogen-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 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 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 a history of VTE or 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 oestrogens, 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 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, 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 oestrogen-progestagen or oestrogen-only HRT.

Combined oestrogen-progestagen therapy

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.

Oestrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

Ischaemic stroke

• 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).

Other conditions

• Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal sufficiency should be closely observed.

• Women with pre-existing hypertriglyceridaemia, 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-1-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.

• 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.

• Divigel is not a contraceptive and adequate non-hormonal contraception should be advised.

This medicinal product contains propylene glycol and therefore may cause skin irritation.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Herbal preparations containing St John's wort (Hypericum Perforatum) may induce the metabolism of oestrogens.

At transdermal administration the first-pass effect in the liver is avoided and thus, transdermally applied oestrogens 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Divigel is not indicated during pregnancy. If pregnancy occurs during therapy with Divigel, 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.

Breastfeeding

Divigel is not indicated during lactation.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

During the first few months of treatment, breakthrough bleeding, spotting and breast tenderness or enlargement can occur. These are usually temporary and normally disappear after continued treatment.

Adverse drug reactions were recorded e.g. in 3 phase III clinical studies (n = 611 women at risk) and were included in the table when considered at least possibly related to treatment with 50 mcg/day estradiol or 100 mcg/day estradiol, respectively, following transdermal application.

The table below lists adverse drug reactions recorded in clinical studies as well as adverse drug reactions reported post-marketing. The experience of adverse drug reactions is overall expected in 76% of the patients. Adverse drug reactions appearing in >10% of patients in clinical trials were application site reactions and breast pain.

Undesirable effects according to system organ class associated with transdermal estradiol treatment are presented in the table below:

Organ system class

Common ADRs, ≥1/100,<1/10

Uncommon ADRs, ≥1/1,000,<1/100

Rare ADRs, ≥1/10,000, <1/1,000

Adverse events reported post marketing with frequency not known (cannot be estimated from the available data)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Benign breast neoplasm, benign endometrial neoplasm

Uterine fibroids

Immune system disorders

Hypersensitivity reaction

Exacerbation of hereditary angioedema

Metabolism and nutrition disorders

Oedema, weight increase, weight decrease

Increased appetite, Hypercholesterolemia1

Psychiatric disorders

Depression, nervousness, lethargy

Anxiety, insomnia, apathy, emotional lability, impaired concentration, changes in mood or libido, euphoria1, agitation1

Nervous system disorders

Headache, dizziness

Migraine, paraesthesia, tremor1

Eye disorders

Visual impairment, dry eye1

Contact lens intolerance

Cardiac disorders

Palpitations

Vascular disorders

Hot flushes

Hypertension1, superficial phlebitis1, purpura1

Venous thromboembolism(i.e. deep leg or pelvic venous thrombosis and pulmonary embolism) 2

Cerebral ischaemic events

Respiratory, thoracic and mediastinal disorders

Dyspnoea1, rhinitis1

Gastrointestinal disorders

Nausea, vomiting, stomach cramps, flatulence

Constipation, dyspepsia1, diarrhoea1, rectal disorder1

Abdominal pain, bloating (abdominal distension)

Hepatobiliary disorders

Alterations in liver function and biliary flow

Cholestatic jaundice

Skin and subcutaneous tissue disorders

Acne, alopecia, dry skin, nail disorder1, skin nodule1, hirsutism1,erythema nodosum, urticaria

Rash

Contact dermatitis, eczema

Musculoskeletal and connective tissue disorders

Joint disorders, muscle cramps

Renal and urinary disorders

Increased urinary frequency/urgency, urinary incontinence1, cystitis1, urine discoloration1, haematuria1

Reproductive system and breast disorders

Breast pain/tension, unscheduled vaginal bleeding or spotting, vaginal discharge, disorder of vulva/vagina, menstrual disorder

Breast enlargement, breast tenderness, endometrial hyperplasia, uterine disorder1

Dysmenorrhea, pre-menstrual like syndrome

General disorders and administration site conditions

Skin irritation, application site pruritus, pain, increased sweating

Fatigue, abnormal laboratory test1, asthenia1, fever1, flu syndrome1, malaise1

1 have been reported in single cases in clinical trials. Given the small study population (n=611) it cannot be determined based on these results if the events are uncommon or rare.

2 see sections 4.3 and 4.4.

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:

• Oestrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer.

• Myocardial infarction and stroke.

• Gall bladder disease.

• Skin and subcutaneous disorders: chloasma, erythema multiformeProbable dementia over the age of 65 (see section 4.4).

Breast cancer risk

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

- Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-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

Age range (years)

Additional cases per 1000 never-users of HRT over a 5 year period*2

Risk ratio

Additional cases per 1000 HRT users over 5 years (95%CI)

Oestrogen only HRT

50–65

9–12

1.2

1–2 (0–3)

Combined oestrogen-progestagen

50–65

9–12

1.7

6 (5–7)

*2 Taken from baseline incidence rates in developed countries.

#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use. 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 1000 women in placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT users over 5 years (95%CI)

CEE oestrogen-only

50–79

21

0.8 (0.7–1.0)

-4 (-6–0)*3

CEE+MPA oestrogen & progestagen‡

50–79

17

1.2 (1.0–1.5)

+4 (0–9)

*3 WHI study in women with no uterus, which did not show an increase 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.

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 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]).

Ovarian cancer risk

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 2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 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 HRT (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 1000 women in placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT users

Oral oestrogen-only*4

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)

*4 Study in women with no uterus

Risk of coronary artery disease

- 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).

Risk of ischaemic stroke

- The use of oestrogen-only and oestrogen + 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 stroke*5 over 5 years' use

Age range (years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT users

50–59

8

1.3 (1.1–1.6)

3 (1–5)

*5 no differentiation was made between ischaemic and haemorrhagic stroke.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie or Email: medsafety@hpra.ie.

4.9 Overdose

Generally, oestrogens are well tolerated even in massive doses. Acute toxicity studies did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose. Nausea, vomiting and withdrawal bleeding may occur in some women.

Overdose effects generally lead to breast tenderness, abdominal or pelvis swelling, anxiety and irritability. These symptoms disappear when treatment is stopped or when the dose is reduced.

Overdosage is unlikely with transdermal application. There is no specific antidote and treatment should be symptomatic. The gel should be washed.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural and semisynthetic estrogens, plain, ATC code: G 03 CA 03.

The active ingredient, synthetic 17β-oestradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.

Clinical trial information

The pharmacodynamics of Divigel are similar to those of oral oestrogens but the major difference to oral administration lies in the pharmacokinetic profile. The clinical efficacy of Divigel in the treatment of menopausal symptoms is comparable to that of peroral oestrogen.

Relief of oestrogen-deficiency symptoms and bleeding patterns

Relief of menopausal symptoms was achieved during the first few weeks of treatment.

Prevention of osteoporosis

• Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.

• The effect of oestrogens on bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

• Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and /or established osteoporosis, but the evidence for that is limited.

5.2 Pharmacokinetic properties

Divigel is an alcohol based oestradiol gel. When applied to the skin the alcohol evaporates rapidly and oestradiol is absorbed through the skin into circulation. Application of Divigel on area of 200-400 cm² (size of one to two hands) does not affect the amount of oestradiol absorbed. However, if Divigel is applied to a larger area, absorption decreases significantly. To some extent, however, the oestradiol is stored in subcutaneous tissue from where it is released gradually into circulation. Percutaneous administration naturally circumvents the hepatic first-pass metabolism. For these reasons the fluctuations in the plasma oestrogen concentrations with Divigel are less pronounced than with peroral oestrogen.

Percutaneous dose of 0.5, 1.0 and 1.5 mg estradiol (0.5, 1.0 and 1.5 mg Divigel) results in mean Cmax concentrations in the plasma of 143, 247 and 582 pmol/l, respectively. The corresponding mean Caverage concentrations over the dosing interval are 75, 124, and 210 pmol/l. The corresponding mean Cmin concentrations were 92, 101 and 152 pmol/l, respectively.

During Divigel treatement the estradiol/estrone ratio remains between 0.4 and 0.7, while for oral oestrogen treatment it usually drops to less than 0.2. The mean oestradiol exposure at steady state of Divigel is 82% compared to the equivalent oral dose of oestradiol valerate.

Otherwise the metabolism and excretion of transdermal oestradiol will follow the fate of natural oestrogens.

5.3 Preclinical safety data

Oestradiol is a natural female hormone with an established clinical use. Therefore no toxicological studies have been performed with Divigel. The necessary studies on the irritant effects of the gel were studied in rabbits and skin sensitization in guinea pigs. Based on the results from these studies it can be concluded that Divigel very infrequently could cause mild skin irritation. Skin irritation can be reduced by daily change of the application site.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Carbomer 974 P

Trolamine

Propylene glycol (E1520)

Ethanol (96 per cent)

Purified water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

Single dose aluminium foil sachets packed in cardboard outer cartons containing 28 x 1.0 g or 91 x 1.0 g.

Not all pack sizes may be marked.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Orion Corporation

Orionintie 1

FIN-02200 Espoo

Finland

8. MARKETING AUTHORISATION NUMBER(S)

PA 1327/2/1

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization:

3rd December 1996

Date of last renewal:

3rd December 2006

10. DATE OF REVISION OF THE TEXT

May 2016

It is recommended that you also refer to http://www.medicines.ie as the Summary of Product Characteristics may have been updated since this copy was printed.