1. Name Of The Medicinal Product
Femapak 40
2. Qualitative And Quantitative Composition
Femapak 40 consists of a pack containing eight Fematrix 40 transdermal patches and a blister strip of 14 Duphaston tablets. Each Fematrix 40 patch contains 1.25 mg estradiol (each patch delivers approximately 40 micrograms of estradiol per 24 hours).
Each Duphaston tablet contains 10 mg Dydrogesterone.
For excipient, see 6.1
3. Pharmaceutical Form
Trandermal patch
Fematrix 40 self adhesive, flexible transdermal delivery system comprising a layer of clear adhesive sandwiched between a translucent patch and a metallised polyester backing. Fematrix 40 is a rectangular shape with rounded corners and has an active surface area of 14.25 cm².
Duphaston film-coated tablets: Round, white tablet, scored on one side with the inscriptions '155' on each half of the tablet and '
4. Clinical Particulars
4.1 Therapeutic Indications
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in peri and postmenopausal women.
The experience of treating women older than 65 years is limited.
4.2 Posology And Method Of Administration
Femapak 40 is a continuous sequential hormone replacement therapy. Unless there is previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.
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 general, treatment should start with Femapak 40. Depending on the clinical response, the dosage can afterwards be adjusted to individual need. If the complaints linked to estrogen deficiency are not ameliorated the dosage can be increased by using Femapak 80.
Starting Femapak 40
In women who are not taking hormone replacement therapy and who are amenorrhoeic or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient has regular menstruation periods, treatment is started within five days of the start of bleeding.
Administration
One Fematrix 40 transdermal patch should be applied twice weekly on a continuous basis. Each patch should be removed after 3 to 4 days and replaced with a new patch applied to a slightly different site. Patches should be applied to clean, dry and intact areas of skin below the waist on the lower back or buttocks. Patches should not be applied on or near the breasts. During the second two weeks of the cycle, that is from the 15th day after applying the first patch, one Duphaston tablet should be taken each day for the next 14 days. Most patients will commence bleeding towards the end of the Duphaston therapy.
If a tablet has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may have increased.If a patch has been forgotten, it should be changed as soon as possible. The next patch should be applied on the usual day.
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 vein 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 substance 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 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 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 Femapak, 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 cases where 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 estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk.
Break-through bleeding and spotting may occur during the first few 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.
Breast cancer
A randomised placebo-controlled trial, the Womens 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-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 estrogens (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 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-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 epidermiological 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 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 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 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 to 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 HRT confers 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 Femapak is increased.
• Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
• Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex--hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-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.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Women who may be at risk of pregnancy should be advised to adhere to non-hormonal contraceptive methods.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
- The metabolism of estrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg. 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 estrogens and progestagens.
- Clinically an increased metabolism of estrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.
- At transdermal administration, the first-pass effect of the liver is avoided and, thus, transdermally applied estrogens might be less affected than oral hormones by enzyme inducers.
4.6 Pregnancy And Lactation
Pregnancy
Femapak is not indicated during pregnancy. If pregnancy occurs during medication with Femapak, treatment should be withdrawn immediately. Clinically, data on a large number of exposed pregnancies indicate no adverse effects of dydrogesterone on the foetus.
The results of most epidemiological studies to date relevant to inadvertant foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.
Lactation
Femapak is not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
Fempak does not affect the ability to drive or use machines.
4.8 Undesirable Effects
Application site reactions to patches
Some patients experience mild and transient local erythema at the site of application with or without itching; this usually disappears rapidly on removal of the patch. The overall incidence of general patch irritation in clinical studies is less than 5%. In a clinical study 3% of 102 patients showed well defined erythema (Draize scale) 30 minutes after patch removal. No instances of permanent skin damage have been reported. If unacceptable topical side effects do occur discontinuation of treatment should be considered.
The following undesirable effects have been reported with Femapak 40 and /or with other estrogen/progestagen therapy:
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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 progestagen 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-progestagen 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-progestagen combined HRT (CEE + MPA) in all users compared with placebo.
The absolute risks calculated from the MWS and the WHI trials 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 estrogen-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 estrogen 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 estrogen-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 estrogen + 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 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 progestagen to estrogen-only therapy greatly reduces this increased risk.
Other adverse reactions have been reported in association with estrogen/progestagen treatment:
- Estrogen-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 hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.
- Probable dementia (see section 4.4)
4.9 Overdose
Fematrix 40 Patches
This is not likely due to the mode of administration. If it is necessary to stop delivery then the patch can be removed and plasma oestradiol levels will fall rapidly.
Duphaston Tablets
If overdosage is discovered within two or three hours and is so large that treatment seems desirable, gastric lavage can safely be used. There is no specific antidote and further treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Estradiol
The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.
Dydrogesterone
Dydrogesterone is an orally-active progestagen. The addition of a progestagen greatly reduces the estrogen-induced risk of endometrial hyperplasia and cancer in non-hysterectomised women, by reducing the growth of the endometrium.
Clinical trial information
• Relief of estrogen-deficiency symptoms and bleeding patterns.
- Relief of menopausal symptoms was achieved during the first few weeks of treatment.
5.2 Pharmacokinetic Properties
Estradiol
Absorption
Estradiol is absorbed from the patch across the stratum corneum and is delivered systemically at a low but constant rate throughout the period of application (3 to 4 days). The estimated delivery of estradiol is around 40 µg/day.
The primary unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the estrogen effect, both directly and after conversion to estradiol. Estrogens are excreted in the bile and reabsorbed from the intestine. During this enterohepatic cycle the estrogens are broken down. Estrogens are excreted in the urine as biologically inactive glucuronide and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated. Estrogens are excreted in mothers' milk.
Steady state plasma estradiol concentrations have been demonstrated in the range of Cmin is 26 pg/ml and the Cmax is 34 pg/ml for the Fematrix 40 patch and Cmin is 34 pg/ml and the Cmax is 62 pg/ml for the Fematrix 80 patch (including baseline levels) and these are maintained throughout the dose interval (for up to four days). Absorption rate may vary between individual patients. After removal of the last patch plasma estradiol and estrone concentrations return to baseline values in less than 24 hours. The median terminal half-life for estradiol following patch removal has been determined as 5.24h.
Dydrogesterone
After oral administration of labelled dydrogesterone, on average 63% of the dose is excreted into the urine. Within 72 hours, excretion is complete.
In man, dydrogesterone is completely metabolised. The main metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD) and is present in the urine predominantly as the glucoronic acid conjugate. A common feature of all metabolites characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This explains the absence of estrogenic and androgenic activity.
After oral administration of dydrogesterone, plasma concentrations of DHD are substantially higher as compared to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. Dydrogesterone is rapidly absorbed. The Tmax values of dydrogesterone and DHD vary between 0.5 and 2.5 hours.
Mean terminal half lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively.
The dihydrodydrogesterone Caverage is 13 ng/ml, the Cmin is 4.1 ng/ml and the Cmax is 63 ng/ml. The dydrogesterone Caverage is 0.38 ng/ml the Cmin is <0.1 ng/ml and the Cmax is 2.5 ng/ml.
Dydrogesterone is not excreted in urine as pregnanediol, like progesterone. Analysis of endogenous progesterone production based on pregnanediol excretion therefore remains possible.
5.3 Preclinical Safety Data
Supraphysiological doses (prolonged overdoses) of estradiol have been associated with the induction of tumours in estrogen-dependent target organs for all rodent species tested.
The changes observed with dydrogesterone in animal toxicity studies are characteristic for progesterone-like compounds. In-vitro and in-vivo data gave no indications of mutagenic effects of dydrogesterone. In long-term studies, doses administered to rats and mice were sufficient to produce hormone-mediated changes, but did not provide tumorogenic potential.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Fematrix
Diethyltoluamide
Acrylic adhesive (Dow Corning MG-0560)
Acrylic thickener (Acrysol 33)
Backing: Polyester film
Release liner: Aluminised/Polyester film.
Duphaston
Tablet core: Lactose
Hypromellose
Maize starch
Colloidal anhydrous silica
Magnesium stearate
Film-coat: Hypromellose
Macrogol 400
Titanium dioxide (E171)
6.2 Incompatibilities
None known.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 25ºC.
Store in original package.
6.5 Nature And Contents Of Container
Fematrix: Sealed laminated sachet (paper/polyethylene/aluminium foil/polyethylene) containing one transdermal patch. Duphaston: Blister strip containing 14 tablets. Each carton contains eight Fematrix patches and 14 Duphaston HRT tablets sufficient for one 28 day cycle.
6.6 Special Precautions For Disposal And Other Handling
After use, fold the Fematrix patch in two with the adhesive surface to the inside and dispose with the normal household waste.
7. Marketing Authorisation Holder
Solvay Healthcare Ltd
Mansbridge Road
West End
Southampton
SO18 3JD
United Kingdom
8. Marketing Authorisation Number(S)
PL 00512/0175
9. Date Of First Authorisation/Renewal Of The Authorisation
01 February 2002
10. Date Of Revision Of The Text
January 2006
Legal category
POM
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