Orion Pharma (Ireland) Ltd

Divigel 0.1% Gel, 1 mg/dose

Estradiol 1 mg/g gel (as Estradiol Hemihydrate).

Gel

Hormone replacement therapy (HRT) for estrogen 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 prevention of osteoporosis.

The experience treating women older than 65 years is limited.

The usual starting dose is 1.0 mg estradiol (1.0 g gel) daily

Divigel is a gel for transdermal use. Divigel can be used for continuous, cyclic or sequential treatment. The usual starting dose is 1.0 mg estradiol (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 0.5mg to 1.5 mg per day, corresponding to 0.5 to 1.5 mg estradiol per day.

In patients with an intact uterus, it is necessary to combine Divigel with an adequate dosage of progestogen for adequate duration, at least 12-14 consecutive days per month or to oppose estrogen-stimulated hyperplasia of the endometrium

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

Method of Administration

The Divigel dose is applied once daily, on the skin of the lower trunk or the right or left thighs, 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 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.

• Known, past or suspected breast cancer

• Known or suspected estrogen-dependent malignant tumours (eg, endometrial cancer)

• Undiagnosed genital bleeding

• Untreated endometrial hyperplasia

• Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary embolism)

• Active or recent arterial thromboembolic disease (eg angina, myocardial infarction)

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

• Known hypersensitivity to the active substances or to any of the excipients

• Porphyria

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.

Medical examination/follow up:

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breasts) 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. Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

Reasons for immediate withdrawal:

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 headaches

− Pregnancy

Endometrial hyperplasia

• The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. (see section 4.8). The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk (see section 4.8).

• 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 estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogen 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

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

• HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate =4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

• Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI> 30 kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

• Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

• 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 (eg, painful swelling of a leg, sudden pain in the chest, dyspnea).

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long-term (at least 5-10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRTs confers to a different risk than estrogen-only products.

Other conditions

• Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Divigel is increased.

• Women with pre-existing hypertriglyceridaemia, 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).

• There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

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

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

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 of estrogens indicate no teratogenic or foetotoxic effect.

Lactation

Divigel is not indicated during lactation.

No effects on ability to drive or use machines have been observed.

Adverse drug reactions occur most commonly during the first months of treatment. They are usually mild and subside with continued treatment.

The most frequent adverse reaction of Divigel is breast pain/tenderness, which occurs in 4.7% of users.

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

Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which > 80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

For 1000 women in the placebo group

• about 16 cases of invasive breast cancer would be diagnosed in 5 years

For 1000 women who used estrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

• between 0 and 9 (best estimate = 4) for 5 years' use

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Endometrial Cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestogen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with estrogen/progestogen treatment:

− Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer

− Venous thromboemolism, i.e. deep leg and pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information, see sections 4.3 and 4.4

− Myocardial Infarction and stroke

− Gall bladder disease

− Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

− Probable dementia (see section 4.4)

Generally, estrogens are well tolerated even in massive doses. Overdose effects generally lead to breast tenderness, abdominal or pelvis swelling, anxiety, irritability. These symptoms disappear when treatment is stopped or when the dose is reduced.

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

The active ingredient, a 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. Estrogens prevent bone loss following menopause or ovariectomy. Estrogens prevent bone loss following menopause or ovariectomy.

The pharmacodynamics of Divigel are similar to those of oral estrogens but the major difference to oral administration lies in the pharmacokinetic profile.

Relief of estrogen-deficiency symptoms

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

Prevention of osteoporosis

Estrogen deficiency at menopause is associated with increasing bone turnover and decline in bone mass. The effect of estrogens 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.

Divigel is an alcohol based estradiol gel. When applied to the skin the alcohol evaporates rapidly and estradiol 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 estradiol absorbed. However, if Divigel is applied to a larger area, absorption decreases significantly. To some extent, however, the estradiol 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 estrogen concentrations with Divigel are less pronounced than with peroral estrogen.

Percutaneous doses of 0.5, 1.0 and 1.5 mg estradiol (0.5, 1.0 and 1.5 mg Divigel) results in mean C_max 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 treatment the estradiol / estrone ratio remains between 0.4 and 0.7, while for oral estrogen treatment it usually drops to less than 0.2. The mean estradiol exposure at steady state of Divigel is 82% compared to the equivalent oral dose of estradiol valerate.

Otherwise the metabolism and excretion of transdermal estradiol will follow the fate of natural estrogens.

Estradiol 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 sensitisation 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.

No incompatibilities have been found.

2 years.

Store below 25°C

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

None

Orion Pharma A/S,

Bøgeskovvej 9,

DK-3490 Kvistgård,

Denmark

PA 1327/2/1

3rd December 1996/3^rd December 2001

June 2006