Divigel

Divigel

estradiol

Manufacturer:

Orion

Distributor:

Harn Thai

Marketer:

Orion Pharma Thai
Full Prescribing Info
Contents
Micronized estradiol hemihydrate.
Description
Divigel also contains the following excipients: Carbomer 974P, trolamine, propylene glycol, ethanol 96% and purified water.
Divigel name is 17β-estradiol; estra-1, 3, 5 (10)-triene-3, 17β-diol, hemihydrate.
Chemical Formula: C18H24O2.½ H2O.
Molecular Weight: 281.4.
CAS No. 50-28-2 (anhydrous).
Action
Pharmacotherapeutic Group: Natural and semisynthetic estrogens, plain. ATC Code: G03CA03.
Pharmacology: The active ingredient in Divigel, 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.
Clinical Trial Information: The pharmacodynamics of Divigel are similar to those of oral estrogens, 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 per oral estrogen.
Relief of Estrogen Deficiency Symptoms and Bleeding Patterns: Relief of menopausal symptoms was achieved during the 1st few weeks of treatment.
Prevention of Osteoporosis: Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of hormone replacement therapy (HRT), bone mass is lost at a rate similar to that in untreated women.
Evidence from the Women's Health Initiative (WHI) trial and meta-analyzed trials shows that current use of HRT, alone or in combination with a progestagen, given to predominantly healthy women, reduces the risk of hip, vertebral, and other osteoporotic fractures. Hormone replacement therapy may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.
Pharmacokinetics: Divigel is an alcohol-based estradiol gel. When applied to the skin, the alcohol evaporates rapidly and estradiol is absorbed through the skin, into the circulation. Application of Divigel on area of 200-400 cm2 (size of 1-2 hands) does not affect the amount of estradiol absorbed. However, if Divigel is applied to larger area, absorption decreases significantly. To some extent, however, the estradiol is stored in SC tissue from where it is released gradually into circulation. Percutaneous administration circumvents the hepatic first-pass metabolism. For these reasons, the fluctuations in the plasma estrogen concentrations with Divigel are less pronounced than with per oral estrogen.
A 0.5-, 1-, and 1.5-mg percutaneous dose of estradiol (Divigel 0.5, 1, 1.5 g) results in a plasma concentration (Cmax) of about 143, 247 and 582 pmol/L, respectively. The corresponding mean C average concentrations over the dosing interval are 75, 124 and 210 pmol/L. The corresponding mean minimum plasma concentration (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 <0.2. The mean estradiol exposure at steady state of Divigel is 82% compared with an equivalent oral dose of estradiol valerate.
Otherwise the metabolism and excretion of transdermal estradiol follow the fate of natural estrogens.
Toxicology: Preclinical Safety Data: 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 have been studied in rabbits and skin sensitization in guinea pig. 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.
Indications/Uses
Treatment of the climacteric syndrome associated with natural or artificial menopause (estrogenic deficiency eg, hot flushes, night sweatings, urogenital atrophy) and prevention of postmenopausal (type I) osteoporosis.
Dosage/Direction for Use
Divigel can be used for continuous, cyclical or sequential treatment.
The usual starting dose is estradiol 1 mg (1 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 re-adjusted after 2-3 cycles individually from 0.5-1.5 g/day, corresponding to estradiol 0.5-1.5 mg/day.
In patients with an intact uterus, it is recommended to combine Divigel, with an adequate dose of progestin for adequate duration eg, 12-14 consecutive days per month/28 day cycle or to oppose estrogen-stimulated hyperplasia of the endometrium.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.
Administration: Divigel is a gel for transdermal use.
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 1 hr. Contact of the gel with the eyes should be avoided. Hands should be washed after application.
In women who are not using 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 Precautions) should be used.
If the patient has forgotten to apply a dose, the forgotten dose is to be applied as soon as possible if the dose is not >12 hrs late. If the dose is >12 hrs late, the dose should be forgotten and continue as normal. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.
Overdosage
Generally, estrogens are well tolerated even in massive doses. Overdose effects generally lead to breast tenderness, abdominal or pelvis swelling, anxiety and irritability. These symptoms disappear when the treatment is stopped or when the dose is reduced.
Contraindications
Hypersensitivity to estradiol hemihydrate or to any of the excipients of Divigel.
Known or suspected estrogen-dependent malignant tumours (eg, endometrial cancer); undiagnosed genital bleeding; untreated endometrial hyperplasia; previous or current venous thromboembolism [deep venous thrombosis (DVT), pulmonary embolism]; known thrombophilic disorders [eg, protein C, protein S, or antithrombin deficiency (see Precautions); 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; porphyria; known, past or suspected breast cancer.
Special Precautions
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 precautions 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 physician or nurse (see Breast cancer as follows). Investigations, including appropriate imaging tools eg, 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 as follows); risk factors for estrogen dependent tumours eg, 1st degree heredity for breast cancer; hypertension; liver disorders (eg, liver adenoma); diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; a history of endometrial hyperplasia (see as follows); epilepsy; asthma; otosclerosis; hereditary angioedema.
Reasons for Immediate Withdrawal of Therapy: Therapy should be discontinued in case a contraindication is discovered and in the following situations: Jaundice or deterioration in liver function; significant increase in blood pressure; new onset of migraine-type headache; pregnancy.
Endometrial Hyperplasia and Carcinoma: In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see Adverse Reactions). After stopping treatment, risk may remain elevated for at least 10 years.
The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
Breakthrough bleeding and spotting may occur during the 1st 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 (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 Adverse Reactions).
Estrogen Only Therapy: The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestagen combinations (see Adverse Reactions).
The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most 5) years after stopping treatment.
Hormone replacement therapy, 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. Long-term (at least 5-10 years) use of estrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see Adverse Reactions). Some studies including the WHI trial suggest that the long-term use of combined HRTs may confer a similar or slightly smaller risk (see Adverse Reactions).
Venous Thromboembolism: Hormone replacement therapy is associated with a 1.3 to 3-fold risk of developing venous thromboembolism (VTE) ie, deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the 1st year of HRT than later (see Adverse Reactions).
Patients, with known thrombophilic states, have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see Contraindications).
Generally recognised risk factors for VTE include use of estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI >30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery temporarily, stopping HRT 4-6 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 1st 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' (eg, 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, Divigel should be discontinued. Patients should be told to contact their physicians immediately, when they are aware of a potential thromboembolic symptom (eg, 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: Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.
Ischaemic Stroke: Combined estrogen-progestagen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women, who use HRT, will increase with age (see Adverse Reactions).
Other Conditions: Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed.
Women, with preexisting 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 6 radioimmunoassay) or T3 levels (by radioimmunoassay). 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 ie, 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, α1-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.
Hormone replacement therapy 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.
Divigel is not a contraceptive and adequate nonhormonal contraception should be advised.
Divigel contains propylene glycol and therefore may cause skin irritation.
Effects on the Ability to Drive or Operate Machinery: No influence on ability to drive or use machines.
Use in Pregnancy: Divigel is not indicated during pregnancy. If pregnancy occurs during medication with Divigel, 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 effect.
Use in Lactation: Divigel is not indicated during lactation.
Use In Pregnancy & Lactation
Use in Pregnancy: Divigel is not indicated during pregnancy. If pregnancy occurs during medication with Divigel, 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 effect.
Use in Lactation: Divigel is not indicated during lactation.
Adverse Reactions
Adverse drug reactions occur most commonly during the 1st months of treatment. They are usually mild and subside with continued treatment.
Adverse drug reactions were recorded eg, 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 estradiol 50 mcg/day or estradiol 100 mcg/day, respectively, following transdermal application.
Adverse drug reactions recorded in clinical studies as well as adverse drug reactions reported post-marketing are listed as follows. 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 as follows: Common (>1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); frequency not known (cannot be estimated from the available data).
Benign, Malignant and Unspecified Neoplasms (Including Cysts and Polyps):
Uncommon: Benign breast and endometrial neoplasm. Frequency Not Known: Uterine fibroids.
Immune System Disorders:
Frequency Not Known: Exacerbation of hereditary angioedema.
Metabolism and Nutrition Disorders: Common: Oedema, increased weight. Uncommon: Increased appetite, hypercholesterolemia1.
Psychiatric Disorders: Common: Depression, nervousness, lethargy. Uncommon: Anxiety, insomnia, apathy, emotional lability, impaired concentration, changes in mood or libido, euphoria1, agitation1.
Nervous System Disorders: Common: Headache, dizziness. Uncommon: Migraine, paraesthesia, tremor1.
Eye Disorders: Uncommon: Abnormal vision1, dry eye1.
Cardiac Disorders: Uncommon: Palpitations.
Vascular Disorders: Common: Hot flushes. Uncommon: Hypertension1, superficial phlebitis1, purpura1. Rare: Venous thromboembolism. Frequency Not Known: Cerebral ischaemic events.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnoea1, rhinitis1.
Gastrointestinal Disorders: Common: Nausea, vomiting, stomach cramps, flatulence. Uncommon: Constipation, dyspepsia1, diarrhoea1, rectal disorder. Frequency Not Known: Abdominal pain, bloating (abdominal distension).
Hepatobiliary Disorders: Rare: Alterations in liver function and biliary flow. Frequency Not Known: Cholestatic jaundice.
Skin and Subcutaneous Tissue Disorders: Uncommon: Acne, alopecia, dry skin, nail disorder1, skin nodule1, hirsutism1. Rare: Rash. Frequency Not Known: Contact dermatitis, eczema.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Joint disorders, muscle cramps.
Renal and Urinary Disorders: Uncommon: Increased urinary frequency/urgency, urinary incontinence1, cystitis1, urine discoloration1, haematuria1.
Reproductive System and Breast Disorders: Common: Breast pain/tension, unscheduled vaginal bleeding or spotting, vaginal discharge, disorder of vulva/vagina, menstrual disorder. Uncommon: Breast enlargement and tenderness; endometrial hyperplasia, uterine disorder1.
General Disorders and Administration Site Conditions: Common: Skin irritation, application site pruritus, pain, increased sweating. Uncommon: Fatigue, abnormal laboratory test1, asthenia1, fever1, flu syndrome1, malaise1.
1Have 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.
Other Adverse Reactions Have Been Reported in Association with Estrogen/Progestagen Treatment: Estrogen-dependent neoplasms benign and malignant eg, endometrial cancer; venous thromboembolism ie, deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users (see Contraindications and Precautions); myocardial infarction and stroke; gall bladder disease.
Skin and Subcutaneous Disorders: Chloasma, erythema multiforme, erythema nodosum and vascular purpura.
Probable dementia >65 (see Precautions).
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 >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 Precautions).
Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented. (See Tables 1 and 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

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 Precautions).
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 5 years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer [RR of 1 (0.8-1.2)].
Ovarian Cancer: Long-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the million women study 5 years of HRT resulted in 1 extra case per 2500 users.
Risk of Venous Thromboembolism: Hormone replacement therapy (HRT) is associated with a 1.3 to 3-fold increased relative risk of developing venous thromboembolism (VTE) ie, deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the 1st year of using HRT (see Precautions). Results of the WHI studies are presented (see Table 3).

Click on icon to see table/diagram/image

Risk of Coronary Artery Disease: The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT >60 years (see Precautions).
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 Precautions). (See Table 4.)

Click on icon to see table/diagram/image
Drug Interactions
The metabolism of estrogens (and progestagens) may be increased by concomitant use of substances, known to induce drug-metabolising enzymes, specifically cytochrome P-450 enzymes eg, anticonvulsants (eg, phenobarbital, phenytoin, carbamazepine) and anti-infectives (eg, 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 (and progestagens) 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.
Incompatibilities: Not applicable.
Storage
Store at room temperature (below +25°C).
ATC Classification
G03CA03 - estradiol ; Belongs to the class of natural and semisynthetic estrogens used in estrogenic hormone preparations.
Presentation/Packing
Transdermal gel 1 mg/g (smooth, opalescent) x 28 sachets.
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