1. Name Of The Medicinal Product
Sandrena 1 mg gel
2. Qualitative And Quantitative Composition
Estradiol hemihydrate corresponding to 1.0 mg estradiol per single-dose container.
For a 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.
Experience of treating women more than 65 years old is limited.
4.2 Posology And Method Of Administration
Sandrena is a gel for transdermal use. Sandrena can be used for continuous or cyclical 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 patient's symptoms. Depending on the clinical response, the dosage can be readjusted after 2-3 cycles individually from 0.5 g to 1.5 g per day, corresponding to 0.5 to 1.5 mg estradiol per day. 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.
In patients with an intact uterus, it is recommended to combine Sandrena with an adequate dose of progestagen, for adequate duration for at least 12-14 consecutive days per month 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.
In women who are not using hormone replacement therapy (HRT), or women transferring from continuous combined HRT-product, treatment with Sandrena may be started on any convenient day. In women transferring from a sequential HRT regimen, treatment should begin the day following completion of the prior regimen.
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.
There is no relevant indication for use of Sandrena in children.
Method of administration
The Sandrena dose is applied once daily on the skin of the lower trunk of the right or left thigh, on alternate days. The application surface should be 1-2 times the size of a hand. Sandrena 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 hour. Contact of the gel with eyes should be avoided. Hands should be washed after application.
4.3 Contraindications
- Known, past or suspected breast cancer
- Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)
- Undiagnosed genital bleeding
- Untreated endometrial hyperplasia
- Previous idiopathic or current venous thromboembolism [deep venous thrombosis, pulmonary embolism]
- 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
- Known hypersensitivity to the active substances or to any of the excipients
- 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.
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 mammography should be carried out in accordance with current accepted screening practices, modified according 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 Sandrena, in particular:
- Leiomyoma (uterine fibroids) or endometriosis
- A history of, or risk factors for thromboembolic disorders (see below)
- Risk factors for estrogen-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
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
- The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.
- 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
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 oestrogens, oestrogen-progestagen 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 oestrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine oestrogen 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 oestrogen-progestagen 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 (e.g. 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 oestrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Oestrogen/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 and 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 oestrogens 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 oestrogens 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 oestrogen-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 HRT confers a different risk than oestrogen-only products.
Other conditions
- Oestrogens 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 ingredient in Sandrena is increased.
- Women with pre-existing hypertriglyceridemia should be followed closely during HRT, 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.
- 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.
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 (and progestagens) 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, carbamezapine) 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 and progestagens.
With transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied oestrogens (and progestagens) 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 Pregnancy And Lactation
Pregnancy
Sandrena is not indicated during pregnancy. If pregnancy occurs during medication with Sandrena, treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertent fetal exposure to oestrogens indicate no teratogenic or fetotoxic effect.
Lactation
Sandrena is not indicated during lactation
4.7 Effects On Ability To Drive And Use Machines
Sandrena has no or negligible influence on ability to drive and use machines.
4.8 Undesirable Effects
The most common adverse drug reactions such as headache and breast tenderness occur during the first months of treatment, however they usually subside with continued treatment.
The most frequent adverse reaction of Sandrena is breast pain/tenderness, which occurs in 4.7 % of users.
Undesirable effects according to organ system class associated with Sandrena treatment are presented in the table below.
Organ system class
|
Common ADRs, (
|
Uncommon ADRs, (
|
Rare ADRs, (
|
Metabolism and nutrition disorders
|
Oedema, weight increase
|
|
|
Psychiatric disorders
|
|
Changes in libido and mood
|
|
Nervous system disorders
|
Headache
|
Migraine
|
|
Vasculardisorders
|
|
|
Hypertension, venous thromboembolism
|
Gastrointestinal disorders
|
Nausea, vomiting, stomach cramps
|
|
|
Hepatobiliary disorders
|
|
|
Alterations in liver function and biliary flow
|
Skin and subcutaneous tissue disorders
|
|
|
Rash
|
Reproductive system and breast disorders
|
Unscheduled vaginal bleeding or spotting Breast pain/tension
|
|
|
General disorders and administration site conditions
|
Skin irritation
|
|
|
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 oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80 % of HRT use was oestrogen-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 oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.
The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens 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 oestrogen-progestagen 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:
- For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.
- For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be:
|
- For users of oestrogen-only replacement therapy:
|
|
- between 0 and 3 (best estimate = 1.5) for 5 years' use
|
|
- between 3 and 7 (best estimate = 5) for 10 years' use.
|
|
- For users of oestrogen plus progestagen combined HRT:
|
|
- between 5 and 7 (best estimate = 6) for 5 years' use
|
|
- between 18 and 20 (best estimate = 19) for 10 years' use.
|
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 oestrogen-progestagen 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 oestrogen + progestagen 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 oestrogens. 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 oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2-to 12-fold greater compared with non-users. Adding a progestagen to oestrogen-only therapy greatly reduces this increased risk.
Other adverse reactions have been reported in association with oestrogen/progestagen treatment:
- Oestrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer.
- Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information see sections 4.3 Contraindications and 4.4 Special warnings and special precautions for use.
- Myocardial infarction and stroke.
- Gall bladder disease.
- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
- Probable dementia (see section 4.4)
4.9 Overdose
Generally, oestrogens are well tolerated even in massive doses. Overdose effects generally lead to breast tenderness, abdominal or pelvis swelling, anxiety, irritability. These symptoms disappear when the treatment is stopped or when the dose is reduced.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain, ATC code G03CA03.
The active ingredient in Sandrena, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.
Clinical trial information
The pharmacodynamics of Sandrena are similar to those of oral oestrogens, but the major difference to oral administration lies in the pharmacokinetic profile. The clinical efficacy of Sandrena 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.
5.2 Pharmacokinetic Properties
Sandrena 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 Sandrena on area of 200-400 cm2 (size of one to two hands) does not affect the amount of estradiol absorbed. However, if Sandrena is applied to larger area absorption decreases significantly. To some extent, however, the estradiol is stored in the subcutaneous 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 oestrogen concentrations with Sandrena are less pronounced than peroral oestrogen.
Percutaneous doses of 0.5, 1.0 and 1.5 mg of estradiol (0.5, 1.0 and 1.5 g Sandrena) result in mean Cmax concentrations in 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 Sandrena treatment the estradiol/oestrone ratio remains between 0.4 and 0.7, while for oral oestrogen treatment it usually drops to less than 0.2.
The mean estradiol exposure at steady state of Sandrena is 82 per cent compared with an equivalent oral dose of estradiol valerate. Otherwise the metabolism and excretion of transdermal estradiol follow the fate of natural oestrogens.
5.3 Preclinical Safety Data
Estradiol is a natural female hormone with an established clinical use, therefore no toxicological studies have been performed with Sandrena. The necessary studies on the irritant effects of the gel were studied in rabbits and skin sensitisation in guinea pig. Based on the results from these studies it can be concluded that Sandrena 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 974P
Trolamine
Propylene glycol
Ethanol 96 %
Water, purified
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 container (PET/Aluminium/PE) supplied in packages containing 28 or 91 single-dose containers. Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Orion Corporation, Orionintie 1, P.O. Box 65, FIN-02101, Espoo, Finland
8. Marketing Authorisation Number(S)
PL 27925/0016
9. Date Of First Authorisation/Renewal Of The Authorisation
19/11/1996 / 31/03/2010
10. Date Of Revision Of The Text
31/03/2010
