1. Name Of The Medicinal Product
Kliofem®
2. Qualitative And Quantitative Composition
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Excipients: lactose monohydrate
For a full list of excipients, see 6.1.
3. Pharmaceutical Form
Film-coated tablet for oral administration.
4. Clinical Particulars
4.1 Therapeutic Indications
1 Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in women more than one year after menopause.
2 Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.
See also section 4.4
The experience of treating women older than 65 years is limited.
4.2 Posology And Method Of Administration
Kliofem is a continuous combined hormone replacement product intended for use in women with an intact uterus. One tablet should be taken orally once a day without interruption, preferably at the same time every 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 women with amenorrhea and not taking HRT or women transferring from another continuous combined HRT product, treatment with Kliofem may be started on any convenient day. In women transferring from sequential HRT regimens, treatment should start as soon as their withdrawal bleeding has ended.
Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.
If the patient has forgotten to take one tablet, the forgotten tablet should be taken within the next twelve hours. Otherwise the tablet should be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.
4.3 Contraindications
- Known, past or suspected breast cancer.
- Known or suspected oestrogen-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 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 contra-indications 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' section 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 Kliofem, in particular:
• Leiomyoma (uterine fibroids) or endometriosis
• A history of, or risk factors for, thromboembolic disorders (see below)
• Risk factors for oestrogen 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 progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.
Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting occurs 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 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-progestogen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine 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-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Venous thromboembolism
HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.
Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI>30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.
Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism, or recurrent spontaneous abortion, should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (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 oestrogens 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 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 combined HRTs and oestrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer (see Section 4.8).
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 ingredients in Kliofem will be increased.
- Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, 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 (TGB), 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 biologically 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.
- Kliofem tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The metabolism of oestrogens and progestogens 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 progestogens.
Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
Drugs that inhibit the activity of hepatic microsomal drug metabolising enzymes, e.g. ketoconazole, may increase circulating levels of the active substances in Kliofem.
4.6 Pregnancy And Lactation
Kliofem is not indicated during pregnancy. If pregnancy occurs during medication with Kliofem, treatment should be withdrawn immediately.
Data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At dose levels higher than normally used in OC and HRT formulations masculinisation of female foetuses was observed. The results of most of epidemiological studies to-date have not indicated a teratogenic or foetotoxic effect when combinations of oestrogens with progestogens at dose levels relevant for Kliofem were taken inadvertently during pregnancy.
Lactation
Kliofem is not indicated during lactation.
4.7 Effects On Ability To Drive And Use Machines
No effects known.
4.8 Undesirable Effects
Clinical experience:
The most frequently reported adverse events in the clinical trials with Kliofem were vaginal bleedings and breast pain/tenderness, reported in approximately 10% to 30% of patients. Vaginal bleedings usually occurred in the first months of treatment. Breast pain usually disappears after a few months of therapy. All adverse events observed in the randomised clinical trials with a higher frequency in patients treated with Kliofem or similar HRT products as compared to placebo and which on an overall judgement were considered as possibly related to treatment are presented below.
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Post-marketing experience:
In addition to the above-mentioned adverse drug reactions, those presented below have been spontaneously reported, and by an overall judgement considered possible related to Kliofem treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (<1/10,000 patient years):
Neoplasms benign and malignant (incl. cysts and polyps): Endometrial cancer
Psychiatric disorders: Insomnia, anxiety, libido decreased, libido increased
Nervous system disorders: Dizziness, stroke
Eye disorders: Visual disturbances
Vascular disorders: Hypertension aggravated
Cardiac disorders: Myocardial infarction
Gastrointestinal disorders: Dyspepsia, vomiting
Hepatobiliary disorders: Gallbladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis re-occurrence
Skin and subcutaneous tissue disorder: Seborrhoea, rash, angioneurotic oedema
Reproductive system and breast disorders: Hyperplasia endometrial, vulvovaginal pruritus
Investigations: Weight decreased, blood pressure increased
Other adverse reactions have been reported in association with oestrogen/progestogen treatment:
- Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
- Probable dementia (see section 4.4).
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 progestogen 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-progestogen 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-progestogen 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:
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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-progestogen combined HRT (CEE + MPA) per 10,000 women years. According to calculations from the trial data, it is estimated that:
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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 progestogen to oestrogen-only therapy greatly reduces this increased risk.
Ovarian cancer
Long-term use of oestrogen-only and combined oestrogen-progestogen 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.
4.9 Overdose
Overdosage may be manifested by nausea and vomiting. Treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Oestrogen and progestagen for continuous combined hormone replacement therapy, ATC code: G03F A01
Estradiol: The active ingredient, synthetic 17 beta-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.
Oestrogens prevent bone loss following menopause or ovariectomy.
Norethisterone acetate: As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Relief of menopausal symptoms is achieved during the first few weeks of treatment.
Kliofem is a continuous combined HRT given with the intention of avoiding the regular withdrawal bleeding associated with cyclic or sequential HRT. Amenorrhoea (no bleeding and spotting) was seen in 94% of the women during months 10-12 of treatment. Bleeding and/or spotting appeared in 30% of the women during the first three months of treatment and in 6% during months 10-12 of treatment.
Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of oestrogens 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 predominantly 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 for that is limited.
The effects of Kliofem on bone mineral density were examined in a 2-year, randomised, double-blind, placebo-controlled trial in postmenopausal women (n=327, including 48 on Kliofem). All women received calcium supplementation 1000 mg daily. Kliofem significantly prevented bone loss at the lumbar spine, total hip, distal radius and total body in comparison with calcium supplemented placebo-treated women. In early postmenopausal women (1 to 5 years since last menses), the percentage change from baseline in bone mineral density at lumbar spine, femoral neck and femoral trochanter after 2 years of treatment with Kliofem was 5.4±0.7%, 2.9±0.8% and 5.0±0.9%, respectively. The percentage of women who maintained or gained bone mineral density during treatment with Kliofem was 91% after 2 years of treatment.
5.2 Pharmacokinetic Properties
Following oral administration of 17β-estradiol in micronised form, rapid absorption from the gastrointestinal tract occurs. It undergoes extensive first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration of approximately 44 pg/ml (range 30-53 pg/ml) within 5-8 hours after intake of 1 Kliofem tablet. The half life of 17β-estradiol is about 12-14 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound. Metabolism of 17β-estradiol occurs mainly in the liver and the gut but also in target organs and involves the formation of less active or inactive metabolites, including oestrone, catecholoestrogens and several oestrogen sulphates and glucuronides. Oestrogens are excreted with the bile, where they are hydrolysed and reabsorbed (enterohepatic circulation), and mainly in urine in biologically inactive form.
After oral administration norethisterone acetate is rapidly absorbed and transformed to norethisterone (NET). It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration of approximately 9 ng/ml (range 6-11 ng/ml) within 0.5 - 1.5 hours after intake of 1mg. The terminal half-life of NET is about 8-11 hours. NET binds to SHBG (36%) and to albumin (61%). The most important metabolites are isomers of 5α-dihydro-NET and of tetrahydro-NET, which are excreted mainly in the urine as sulphate or glucuronide conjugates.
The pharmacokinetics in the elderly have not been studied.
5.3 Preclinical Safety Data
Acute toxicity of oestrogens is low. Because of marked differences between animal species and between animal species and humans, preclinical results possess a limited predictive value for the use of oestrogens in humans.
In experimental animals estradiol and estradiol valerate displayed an embryolethal effect at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses was observed.
Norethisterone, like other progestogens, caused virilisation of female foetuses in rats and monkeys. After high doses of norethisterone embryolethal effects were observed.
Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential revealed no particular human risks beyond those discussed in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core:
Lactose monohydrate
Maize starch
Hydroxypropylcellulose
Magnesium stearate
Film-coating:
Hypromellose (E464)
Triacetin
Talc
6.2 Incompatibilities
None known.
6.3 Shelf Life
48 months (max 25˚C)
6.4 Special Precautions For Storage
Do not refrigerate. Keep the container in the outer carton in order to protect from light.
6.5 Nature And Contents Of Container
Polypropylene/polystyrene calendar dial pack containing 28 tablets. Calendar dial packs (3 x 28 tablets) are contained within outer carton.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Novo Nordisk Limited
Broadfield Park, Brighton Road
Crawley, West Sussex, RH11 9RT
8. Marketing Authorisation Number(S)
PL 3132/0080
9. Date Of First Authorisation/Renewal Of The Authorisation
18/06/2008
10. Date Of Revision Of The Text
07/04/2011
LEGAL CATEGORY
POM.
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