1. Name Of The Medicinal Product
Novofem film-coated tablet
2. Qualitative And Quantitative Composition
One red film-coated tablet contains:
Estradiol 1 mg (as estradiol hemihydrate)
One white film-coated tablet contains:
Estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg
Excipients: lactose monohydrate
For a full list of excipients, see 6.1
3. Pharmaceutical Form
Film-coated tablet
Red film-coated, biconvex tablets engraved with NOVO 282. Diameter: 6 mm.
White film-coated, biconvex tablets engraved with NOVO 283. Diameter: 6 mm.
4. Clinical Particulars
4.1 Therapeutic Indications
Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women with an intact uterus.
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.
The experience of treating women older than 65 years is limited.
4.2 Posology And Method Of Administration
Novofem is a continuous sequential preparation for hormone replacement therapy. The oestrogen is dosed continuously. The progestagen is added for 12 days of every 28 day cycle, in a sequential manner.
One tablet is taken daily in the following order: oestrogen therapy (red film-coated tablet) over 16 days, followed by 12 days of oestrogen/progestagen therapy (white film-coated tablet).
After intake of the last white tablet, treatment is continued with the first red tablet of a new pack on the next day. A menstruation-like bleeding usually occurs at the beginning of a new treatment cycle.
In women who are not taking HRT or women transferring from a continuous combined HRT product, treatment 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.
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.
A switch to a higher dose combination product could be indicated if the response after three months is insufficient for satisfactory symptom relief.
If the patient has forgotten to take one tablet, the forgotten tablet is to 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 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 (please see the “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 Novofem 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 progestagen, 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 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 Women's Health Initiative study (WHI), and epidemiological studies, including the Million Woman 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
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 four to six 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 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 or 10 years) use of oestrogen-only HRTs and oestrogen plus progestogen HRTs has been associated with an increased risk of ovarian cancer in some epidemiological studies.
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 Novofem will increase.
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 (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-I-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.
Novofem 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 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, carbamezapin) 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.
Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.
Reduced estradiol levels have been observed under the simultaneous use of antibiotics e.g., penicillins and tetracycline.
Oestrogens can enhance the effects and side effects of imipramine.
If cyclosporine is given concomitantly, there may be increased blood levels of cyclosporine, creatinine and transaminases due to the decreased hepatic excretion of cyclosporine.
The requirement of treatment with oral antidiabetic drugs or with insulin may change due to the oestrogen effect on glucose tolerance (will be decreased) and the response to insulin, i.e. the requirement of insulin or oral antidiabetics can be increased as a consequence of a reduced glucose tolerance.
4.6 Pregnancy And Lactation
Novofem is not indicated during pregnancy.
If pregnancy occurs during medication with Novofem, treatment should be withdrawn immediately.
Data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in OC and HRT formulations masculinisation of female foetuses was observed.
The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens indicate no teratogenic or foetotoxic effect.
Lactation
Novofem 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 event during treatment in clinical trials conducted with an HRT product similar to Novofem is breast tenderness and headache (> 1/10).
The adverse events listed below may occur during oestrogen-progestagen treatment.
The frequencies are derived from clinical trials conducted with an HRT product similar to Novofem and from a Post Marketing Surveillance study on Novofem
5 Organ system class
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Very common
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Common
1/100; < 1/10
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Uncommon
1/1000; < 1/100
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Rare
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Infections and infestations
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Vaginal candidiasis
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Immune system disorders
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Allergic reaction
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Psychiatric disorders
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Nervousness
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Nervous system disorders
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Headache
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Dizziness
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Migraine
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Vertigo
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Insomnia
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Libido disorder NOS (not otherwise specified)
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Depression
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Vascular disorders
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Increased blood pressure.
Aggravated hypertension
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Peripheral embolism and thrombosis
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Gastrointestinal disorders
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Dyspepsia
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Vomiting
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Diarrhoea
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Abdominal pain
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Bloating
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Flatulence
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Nausea
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Hepatobiliary disorders
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Gallbladder disease
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Gallstones
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Skin and subcutaneous tissue disorders
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Rash
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Alopecia
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Acne
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Pruritus
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Musculoskeletal and connective tissue disorders
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Muscle cramps
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Reproductive system and breast disorders
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Breast tenderness
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Vaginal haemorrhage
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Uterine fibroid
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Uterine fibroids aggravated.
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General disorders and administration site conditions
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Oedema
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Investigations
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Weight increased
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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 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 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
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• For users of oestrogen-only replacement therapy
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• between 0 and 3 (best estimate = 1.5) for 5 years' use
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• between 3 and 7 (best estimate = 5) for 10 years' use.
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• For users of oestrogen plus progestagen combined HRT,
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• between 5 and 7 (best estimate = 6) for 5 years' use
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• between 18 and 20 (best estimate = 19) for 10 years' use.
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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-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,
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• about 16 cases of invasive breast cancer would be diagnosed in 5 years.
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• For 1000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be
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• between 0 and 9 (best estimate = 4) for 5 years' use.
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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 progestagen to oestrogen-only therapy greatly reduces this increased risk.
Post-marketing experience:
In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported, and are by an overall judgment considered possibly related to Novofem treatment. The reporting rate of these spontaneous adverse drug reactions is very rare: (<1/10,000 patient years). Post-marketing experience is subject to underreporting especially with regard to trivial and well known adverse drug reactions. The presented frequencies should be interpreted in that light:
Reproductive system and breast disorders:
Hyperplasia of endometrium (for further information see section 4.4).
Skin and subcutaneous tissue disorders: Hirsutism.
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 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.
- Myocardial infarction and stroke
- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, haemorrhagic eruption, vascular purpura.
- Probable dementia (see section 4.4)
- Gall bladder disease
4.9 Overdose
Overdose may be manifested by nausea and vomiting. Treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Oestrogen and progestagen, sequential combination for continuous treatment, ATC Code: G03F B05
Oestrogen and progestagen, sequential combination for continuous treatment.
Estradiol: The active ingredient, 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.
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 progestagen 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.
In a PMS study regular withdrawal bleeding with a mean duration of 3-4 days occurred in 91% of women, who took Novofem over 6 month. Withdrawal bleeding usually started a few days after the last tablet of the progestagen phase.
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 progestagen – 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.
Randomised, double-blind, placebo-controlled studies showed that 1 mg estradiol prevents the postmenopausal loss of bone minerals and increases the bone mineral density. The responses in the spine, femoral neck and trochanter were 2.8%, 1.6% and 2.5%, respectively, over 2 years with 1mg 17ß-estradiol unopposed.
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 a peak plasma concentration of approximately 27 pg/ml (range 13-40 pg/ml) occurs within 6 hours after intake of 1 mg. The area under the curve (AUC(0-tz))= 629 h x pg/ml. The half-life of 17β-estradiol is about 25 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 gut but also in target organs, and involves the formation of less active or inactive metabolites, including estrone, catecholoestrogens and several oestrogen sulphates and glucuronides. Oestrogens are partly excreted with the bile, hydrolysed and reabsorbed (enterohepatic circulation), and mainly eliminated 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 a peak plasma concentration of approximately 9 ng/ml (range 6-11 ng/ml) occurs within 1 hour after intake of 1 mg. The area under the curve (AUC(0-tz)) = 29 h x pg/ml. The terminal half-life of NET is about 10 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
Animal studies with estradiol and norethisterone acetate have shown expected oestrogenic and progestagenic effects. Both compounds induced adverse effects in preclinical reproductive toxicity studies, in particular embryotoxic effects and anomalies in urogenital tract development. Concerning other preclinic effects, the toxicity profiles of estradiol and norethisterone acetate are well known and reveal no particular human risks beyond those discussed in other sections of the SPC and which generally apply to hormone substitution therapy.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Both the white and the red tablets contain:
Lactose monohydrate
Maize starch
Gelatin
Talc
Magnesium stearate
Film-coating
White film-coated tablet:
Hypromellose, triacetin and talc.
Red film-coated tablet:
Hypromellose, red iron oxide (E 172), titanium dioxide (E 171), propylene glycol and talc.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 25°C. Do not refrigerate. Keep the container in the outer carton in order to protect from light.
6.5 Nature And Contents Of Container
1 x 28 tablets or 3 x 28 tablets in calendar dial packs.
The calendar dial pack with 28 tablets consists of the following 3 parts:
- The base made of coloured non-transparent polypropylene,
- The ring-shaped lid made of transparent polystyrene,
- The centre-dial made of coloured non-transparent polystyrene.
Not all pack sizes may be marketed.
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 03132/0141
9. Date Of First Authorisation/Renewal Of The Authorisation
27 September 2000
10. Date Of Revision Of The Text
20 December 2008
