1. Name Of The Medicinal Product
Hormonin
2. Qualitative And Quantitative Composition
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3. Pharmaceutical Form
Tablets
4. Clinical Particulars
4.1 Therapeutic Indications
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in peri- and post-menopausal women.
Prevention of osteoporosis in post-menopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis (see Section 4.4).
The experience of treating women older than 65 years is limited.
4.2 Posology And Method Of Administration
Hormonin is an estrogen-only product which may be given to women with or without a uterus.
Hormonin may be given continuous sequentially or cyclically (three weeks out of four).
Continuous sequential therapy: 1-2 tablets should be taken daily without a break in therapy.
Cyclical therapy: Hormonin 1-2 tablets should be taken cyclically (three weeks on followed by one week off).
In women with an intact uterus the addition of an adequate dose and duration of progestogen (for 12-14 days) in each 28 day cycle is recommended to reduce the risk to the endometrium. Only progestogens approved for addition to estrogen treatment should be recommended e.g. Provera, Micronor HRT.
Unless there is a previous diagnosis of endometriosis, it is not normally recommended to add a progestogen in hysterectomised women.
For initiation and continuation of treatment of post-menopausal symptoms, the lowest effective dose for the shortest duration (see Section 4.4) should be used.
Starting Treatment
Therapy with Hormonin may be initiated with one tablet daily. This may be increased to 2 tablets daily if symptoms are not fully controlled.
In women who are not taking HRT and are not menstruating regularly, or women transferring from a continuous combined HRT product, treatment may be started on any convenient day.
If the patient is menstruating regularly, therapy can be started within the first five days of bleeding.
In women transferring from a sequential HRT regimen, treatment should begin on the day following the end of the previous 28 day cycle. In women transferring from a cyclical HRT regimen, treatment should begin within five days following the end of the previous 28 day cycle.
In hysterectomised women, treatment should be started on any convenient day.
Missed Tablet
If a tablet is missed it should be taken within 12 hours of when normally taken, otherwise the tablet should be discarded, and the usual tablet should be taken the following day.
If one extra tablet is taken inadvertently, the usual tablet should still be taken the following day.
Missing a dose may increase the likelihood of break-through bleeding and spotting.
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 recent 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 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 breast 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 Hormonin, 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. first degree heredity for breast cancer
• Hypertension
• Liver disorders (e.g. liver adenoma)
• Diabetes mellitus with or without vascular involvement (see Other Conditions below)
• 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 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
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 of HRT 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 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.
Endometrial hyperplasia and cancer
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.
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 progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.
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.
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 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. When 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 doctor immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate. 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.
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 Hormonin is increased.
Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or HRT, 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.
Glucose tolerance may be lowered and Hormonin may, therefore, increase the need for insulin or other anti-diabetic drugs in diabetics.
Hormonin is not an oral contraceptive. Non-hormonal contraception should be used if required.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Hormonin Tablets contain sunset yellow colouring (E110), which can cause allergic-type reactions including asthma. This allergy is more common in people who are allergic to aspirin.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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, carbamazepine) and antiinfectives (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.
Clinically, an increased metabolism of estrogens may lead to decreased effect and changes in the uterine bleeding profile.
4.6 Pregnancy And Lactation
Hormonin is not indicated during pregnancy. If pregnancy occurs during medication with Hormonin, 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 effects.
Hormonin is not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
None known.
4.8 Undesirable Effects
From clinical trial data, approximately 42% of patients have experienced adverse reactions. These are mainly dose dependent and due to the pharmacological effects of the medicinal product.
The most commonly reported undesirable effects for Hormonin and other estrogen treatments are detailed in the following table.
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Breast cancer
According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the 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 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:
• 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
o 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
o For users of estrogen plus progestogen 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-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
o 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
o 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 unapposed 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.
4.9 Overdose
Ingestion of large doses of estrogen containing oral contraceptives by young children have often been reported and show that acute serious ill effects do not occur. Overdosage of estrogen may cause nausea and withdrawal bleeding in females.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
The active ingredients, synthetic 17β-estradiol, estriol and estrone are chemically and biologically identical to endogenous human estrogens. They substitute for the loss of estrogen production in menopausal women and alleviate menopausal symptoms.
The three natural hormone estrogens vary considerably in their potency. Estradiol is the most potent and estrone and estriol notably weaker. Pharmacologically, estriol occupies a unique position in that it has a shallow dose response curve and quickly reaches a plateau where substantially increased doses produce no increase in activity. It binds to its receptor site in competition with estradiol.
Estrogens prevent bone loss following menopause or ovariectomy. 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 HRT, bone mass is lost at a rate similar to that in untreated women.
Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestogen – given to predominately healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence is limited.
5.2 Pharmacokinetic Properties
The natural estrogens are generally quickly and well absorbed from the gastrointestinal tract, there being little difference between estrone, estradiol and estriol. Estrogens are inactivated in the liver. A proportion of absorbed estrogen is excreted in the bile and then reabsorbed from the intestine. In the liver estradiol is readily oxidised to estrone and both estradiol and estrone are converted by hydration to estriol. Metabolites of estrogens are mainly excreted in the urine as conjugates of glucuronic and sulphuric acid.
Following administration of Hormonin, physiological estrogen concentrations are achieved at different rates. The maximum plasma levels and the time to reach the peak in the plasma level varied between subjects and was; estrone 750-2116 pmol/litre, 0.5-6.0 hours; estradiol 246-813 pmol/litre, 1-8 hours; estriol 173-241 pmol/litre, 5-12 hours. Following steady state conditions after cessation of Hormonin therapy, estrogen levels remained in the pre-menopausal range for approximately 48 hours.
5.3 Preclinical Safety Data
None stated.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sunset yellow (E110)
Amaranth (E123)
Lactose
Potato starch
Pregelatinised potato starch
Magnesium stearate
Methyl alcohol
Chloroform
6.2 Incompatibilities
None.
6.3 Shelf Life
36 months in securitainers
36 months in blister packs
6.4 Special Precautions For Storage
Store in the original package. Do not store above 25ºC.
6.5 Nature And Contents Of Container
Securitainers containing 90 and 100 tablets.
Blister packs of 21, 28, 63 and 84 tablets.
6.6 Special Precautions For Disposal And Other Handling
No special conditions.
7. Marketing Authorisation Holder
Amdipharm PLC
Regency House
Miles Gray Road
Basildon
Essex
SS14 3AF
United Kingdom
8. Marketing Authorisation Number(S)
PL 20072/0046
9. Date Of First Authorisation/Renewal Of The Authorisation
8 July 1988 (review licence)
10. Date Of Revision Of The Text
December 2007
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