Novofem

/ Novo Nordisk

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 post menopausal symptoms, the lowest effective dose for the shortest duration 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 tablet should be taken as soon as possible within the next 12 hours. If more than 12 hours has passed, the tablet is to be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

HRT for estrogen deficiency symptoms in postmenopausal women with an intact uterus. Prevention of postmenopausal osteoporosis in women with an increased risk for future osteoporotic fractures.

Undiagnosed abnormal genital bleeding. Known, suspected, or history of cancer of the breast. Known or suspected estrogen dependent neoplasia. Untreated endometrial hyperplasia. Active deep vein thrombosis, pulmonary embolism or a history of these conditions. Active or recent (e.g. within past year) arterial thromboembolic disease (e.g. stroke, myocardial infarction). Porphyria. Acute liver disease or a history of liver disease, as long as liver function tests have failed to return to normal. Known hypersensitivity to ingredients.
Pregnancy and lactation: Not indicated in pregnancy. There appears to be little or no increased risk of birth defects in women who have used estrogen and progestins from oral contraceptives inadvertently during pregnancy.
For full details see prescribing information.

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 risks.
Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.
Medical examination/follow-up: Before initiating or reinstituting Hormone Replacement Therapy (HRT), a complete personal and family medical history should be taken. Physical (including pelvic and breast) examinations 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. Investigations including appropriate imaging tools e.g. mammography, should be carried out in accordance with currently accepted screening practices and modified according to the clinical needs of the individual.
Conditions which need supervision: If any of the following conditions are present, have occurred previously and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Novofem, in particular: Leiomyoma (uterine fibroids) or endometriosis, Risk factors for thromboembolic disorders, Risk factor 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, Otosclerosis, Migraine or (severe) headache, Systemic lupus erythematosus, A history of endometrial hyperplasia, Epilepsy, Asthma.
Reason 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.
Endometrial hyperplasia and carcinoma: In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose. After stopping treatment the risk may remain elevated for at least 10 years.
The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.
Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting continues after the first months of treatment, appears after sometime during therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Breast cancer: The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestagen or oestrogen-only HRT that is dependent on the duration of taking HRT.
The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen HRT that becomes apparent after about 3 (1-4) years.
Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more. HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian cancer: Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.
Venous thromboembolism: HRT is associated with a 1.3- to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients.
As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
n women with no personal history of VTE but with a first degree relative with a history of venous thromboembolism at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).
If a thrombophilic defect is identified which segregates with venous thromboembolism in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
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).
Smoking: This product should not be prescribed to a woman who is a smoker, especially if she is older than 35, without careful medical evaluation.
Ischaemic stroke: Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age.
Hypothyroidism: Patients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on HRT to ensure that thyroid hormone levels remain in an acceptable range.
Other conditions
 * Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
* Women with pre-existing hypertriglyceridaemia 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.
* Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
* 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 radioimmunoassay) or T3 levels (by radioimmunoassay). 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 and ceruloplasmin).
* HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
ALT elevations: During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the following combination drug regimens: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir.
For full details see prescribing information.

The most frequently reported adverse event during treatment in clinical trials conducted with an HRT product similar to Novofem is breast tenderness and headache (reported in ≥10% of patients).
For full details see prescribing information.

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.
Effect of HRT with oestrogens on other medicinal products: Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.
Pharmacodynamic interactions:
Direct acting antiviral agents (DAAs) and ethinylestradiol-containing medicinal products such as CHCs. During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs.
Drugs that inhibit the activity of hepatic microsomal drug metabolising enzymes, e.g. ketoconazole, may increase circulating levels of the active substances in this medical product.
Concomitant administration of cyclosporine may cause increased blood levels of cyclosporine, creatinine and transaminases due to the decreased metabolism of cyclosporine in the liver.
For full details see prescribing information.

Pregnancy: Novofem is not indicated during pregnancy. If pregnancy occurs during medication with Novofem, treatment should be withdrawn immediately. Clinically, 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.

Overdose may be manifested by nausea and vomiting. Treatment should be symptomatic.