Novofem 1 mg. FC tablet.

u2022 Novofem u00ae is indicated for the treatment of symptoms associated with estrogen deficiency in postmenopausal women with an intact uterus.

u2022 To reduce the risk of bone loss in postmenopausal women. The experience of treating women over 65 years is limited. Novofem u00ae has no contraceptive effect.

Novofem u00ae is a continuous sequential preparation for hormone replacement therapy. The estrogen is dosed continuously. The progestagen is added for 12 days of every 28 day cycle, in a sequential manner.

Take one tablet daily, preferably at the same time each day, until all the 28 tablets have been taken. Begin by taking the red tablets for 16 days followed by the white tablets for 12 days. After intake of the last white tablet, treatment is continued with the first red tablet of a new pack on the next day.

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.

A switch to a higher dose combination product could be indicated if the response after three months is insufficient for satisfactory symptom relief.

A menstruation-like bleeding usually occurs at the beginning of a new treatment cycle. If you forget to take one tablet, the forgotten tablet is to be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

Instructions for use of the calendar dial pack

1. Set the day reminder: Turn the inner disc to set the selected day of the week opposite the little plastic tab.
2. How to take the first tablet: Break the plastic tab and tip out the first tablet.
3. Every day: Simply move the transparent dial clockwise one space as indicated by the arrow. Tip out the next tablet. The transparent dial can only be turned after the tablet in the opening has been removed.

u2022 Known hypersensitivity to estradiol, norethisterone acetate or to any of the excipients of Novofem u00ae (see section 6.1)

u2022 Known or suspected breast cancer or history (personal and/or family) of breast cancer

u2022 Known, past or suspected estrogen-dependent malignant tumours (e.g., endometrial cancer)

u2022 Undiagnosed genital bleeding

u2022 Current or previous idiopathic venous thromboembolism (deep venous thrombosis, pulmonary embolism)

u2022 Inherited thrombophilia or known thrombophilic disorders (e.g., protein C, protein S or antithrombin deficiency (see section 4.4)

u2022 Active or recent arterial thromboembolic events (e.g., angina, myocardial infarction)

u2022 Active liver disease. Acute liver disease or a history of liver disease, as long as liver function tests have failed to return to normal

u2022 Porphyria

u2022 Untreated endometrial hyperplasia

u2022 Known or suspected pregnancy, and lactation (see section 4.6)

u2022 Patients with known inherited genetic mutations: BRCA1 and BRCA2 genes

u2022 Early menstrual periods (before the age of 12 years)

u2022 History of non-cancerous breast diseases (atypical hyperplasia or lobular carcinoma in situ )

u2022 Previous treatment using radiation therapy to the chest or breast

u2022 Previous exposure to diethylstilbestrol (DES)

For the treatment of post-menopausal symptoms, Novofem u00ae 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 Novofem u00ae should only be continued as long as the benefit outweighs the risk.

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.

Endometrial hyperplasia and carcinoma

In women with an intact uterus, the use of estrogens is associated with an increased incidence of endometrial hyperplasia and carcinoma, when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment, the risk may remain elevated for at least 10 years. The addition of progestagen for at least 12 days per cycle in non-hysterectomised women 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.

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestagen or estrogen-only HRT. The relative risk of CAD during use of combined estrogen-progestagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen-progestagen use is very low in healthy women close to menopause, but will rise with more advanced age.

Stroke

Combined estrogen-progestagen and estrogen-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 (see section 4.8).

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).

Hypothyroidism

Patients who require thyroid hormone replacement therapy should have their thyroid function monitored regularly while on Novofem u00ae to ensure that thyroid hormone levels remain in an acceptable range.

Angioedema

Estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

Other conditions

Estrogens such as Novofem u00ae may cause fluid retention and, therefore, patients with cardiac or renal dysfunction should be carefully observed. Women with pre-existing/familial hypertriglyceridaemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis and other complications 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 globulins (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 estrogen-only HRT after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

Patients with advanced renal impairment should be closely monitored as it might be expected that the circulating levels of the active components of Novofem u00ae would be increased. In case of aggravation of asthma, epilepsy or diabetes mellitus Novofem u00ae should be reconsidered.

An increase in the risk of surgically confirmed gallbladder disease in postmenopausal women receiving estrogens has been reported.

The use of estrogen may influence the results of certain endocrine tests and liver enzymes.

The requirement of insulin or oral anti diabetics can be increased as a consequence of reduced glucose tolerance.

Medical examination/follow-up

Before initiating or reinstituting Novofem u00ae a complete personal and family history should be taken. Physical (including pelvic and breast) examinations should be guided by this and contraindications and warnings for use (see section 4.3 and 4.4). During treatment, periodic check-ups are recommended.

A careful appraisal of the risks and benefits should be undertaken at least annually and treatment with Novofem u00ae should not exceed a period of 5 years. 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 to the clinical needs of the individual. Regular breast examination and, where appropriate, mammography should be carried out in women on Novofem u00ae .

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy with Novofem u00ae , or continues after treatment has been discontinued, the cause should be investigated.

Conditions which need supervision

If any of the following conditions are present, have occurred previously and/or have aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised, as these conditions may recur or be aggravated during treatment with Novofem u00ae :

• Leiomyoma (uterine fibroids), endometriosis, endometrial hyperplasia
• Risk factors for thromboembolic disorders (see section 4.3)
• Risk factors for estrogen dependent tumours, e.g., 1 st degree heredity for breast cancer
• Hypertension
• Liver disorders (e.g., liver adenoma, icterus) (see section 4.3)
• Diabetes mellitus with or without vascular involvement
• Cholelithiasis
• Sudden hearing loss
• Migraine or (severe) headache
• Systemic lupus erythematosus
• A history of endometrial hyperplasia
• Epilepsy
• Asthma
• Otosclerosis.

Reasons for immediate withdrawal of therapy:

• Venous or arterial thromboembolic disorders;
• Arterial disease;
• Jaundice or deterioration in liver function;
• Significant increase in blood pressure;
• Sudden partial or complete loss of vision or a sudden onset of proptosis or diplopia;
• New onset of migraine-type headache;
• Pregnancy.

Venous thromboembolism (see section 4.3)

In women with risk factors for venous thromboembolism (VTE), the benefits of treatment with Novofem u00ae need to be carefully weighed against risks (see section 4.3). Novofem u00ae 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 three - fold higher risk for users of HRT 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 1 000 women aged 50 - 59 years and 8 per 1 000 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 1 000 women aged 50 - 59 years and between 5 and 15 (best estimate = 9) per 1 000 women aged 60 - 69 years. 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 (see section 4.3).

Generally recognised risk factors for VTE include use of estrogens, older age, a personal history or family history, severe obesity (body mass index > 30 kg/m 2 ), pregnancy/postpartum period, cancer and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

Women already on anticoagulant treatment require careful consideration of the benefit-risk of Novofem u00ae . The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. 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 Novofem u00ae 4 to 6 weeks earlier. Treatment should not be restarted until the woman is completely mobilised.

In 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. If VTE develops after initiating therapy, Novofem u00ae 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).

Depressed mood, depression and risk of suicidality

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well- known risk factor for suicidal behaviour and suicide. Women should be advised to contact their medical practitioner in case of mood changes and depressive symptoms including shortly after initiating the treatment.

Breast cancer

Hormone replacement therapy, including Novofem u00ae , contains estrogen and progestagen which, on prolonged use, may increase the risk of developing breast cancer. A meta-analysis of prospective epidemiological studies from 1992 to 2018 reported a significant increase in the risk of developing breast cancer in 55 575 women 40 u2013 59 years of age who used menopausal hormone therapy (MHT). The risk increased steadily with duration of use and was slightly greater for estrogen- progestagen than estrogen-only preparations, and the risk persisted for more than 10 years after stopping the treatment. The relative risk (RR) to develop breast cancer for estrogen-progestagen preparations was 1,60 at 1 u2013 4 years and RR = 2,08 at 5 u2013 14 years, while that for estrogen-only preparations were 1,17 at 1 u2013 4 years and 1,33 at 5 u2013 14 years. There was no risk to develop breast cancer in women who started MHT at 60 years of age.

All women on Novofem u00ae should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. Mammography evaluations should be done based on patient age, risk factors, and prior mammogram results.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

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 1 000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2- to 12- fold greater compared with non-users. Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

The metabolism of Novofem u00ae may be increased by concomitant use of substances known to induce medicine-metabolising enzymes, specifically cytochrome P450 enzymes such as anticonvulsants (e.g., phenobarbitone, phenytoin, carbamazepine) and anti-infectives (e.g., rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir, telaprevir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St Johnu2019s wort ( Hypericum perforatum ) may induce the metabolism of Novofem u00ae . Clinically, an increased metabolism of Novofem u00ae may lead to decreased effect and changes in the uterine bleeding profile.

Novofem u00ae can enhance the effects of imipramine.

If ciclosporin is given concomitantly, there may be increased blood levels of ciclosporin, creatinine and transferases due to the decreased hepatic excretion of ciclosporin.

The requirement of treatment with oral antidiabetic medicines or with insulin may change due to the estrogen 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 reduced glucose tolerance.

Some laboratory tests may be influenced by estrogen therapy, such as tests for glucose tolerance or thyroid function.

Medicines that inhibit the activity of hepatic microsomal medicine-metabolising enzymes, e.g., ketoconazole, may increase circulating levels of the active substances in Novofem u00ae . 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.

Novofem u00ae is contraindicated during pregnancy (see section 4.3).

If pregnancy occurs during medication with Novofem u00ae , treatment should be withdrawn immediately. Data on exposed pregnancies indicate adverse effects of norethisterone on the foetus. Masculinisation of female foetuses was observed.

Lactation

Novofem u00ae is contraindicated during lactation (see section 4.3). Mothers on Novofem u00ae should not breastfeed.

Novofem u00ae can cause side effects, such as dizziness, that may interfere with the ability to drive and use machines (see section 4.8). Caution is advised until the effects of Novofem u00ae are known.

The most frequently reported side effects during treatment in clinical trials conducted with an HRT product similar to Novofem u00ae were breast tenderness and headache. The side effects listed below may occur during Novofem u00ae treatment.

System organ class Frequent Less frequent

Infections and infestations Vaginal candidiasis

Immune system disorders Allergic reaction

Psychiatric disorders Nervousness

Nervous system disorders Headache Dizziness Insomnia Migraine Libido disorder Vertigo

Depression

Vascular disorders Increased blood pressure; Aggravated hypertension Venous thromboembolism Peripheral embolism and thrombosis

Gastrointestinal disorders Dyspepsia Abdominal pain Flatulence Nausea Vomiting Diarrhoea Bloating

Hepatobiliary disorders Gallbladder Disease; Gallstones

Skin and subcutaneous tissue disorders Rash Pruritus Alopecia Acne

Musculoskeletal and connective tissue disorders Muscle cramps

Reproductive system and breast disorders Breast tenderness Vaginal haemorrhage Uterine fibroids aggravated Uterine fibroids

General disorders and administration site conditions Oedema

Investigations Weight increased

Post- marketing side effects

In addition to the above-mentioned side effects, those presented below have been spontaneously reported:

u2022 Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer

u2022 Immune system disorders: Generalised hypersensitivity reactions (e.g., anaphylactic reaction/shock)

u2022 Psychiatric disorders: Anxiety

u2022 Nervous system disorders: Stroke

u2022 Eye disorders: Visual disturbances

u2022 Cardiac disorders: Myocardial infarction

u2022 Reproductive system and breast disorder: Hyperplasia of endometrium, vulvovaginal pruritus

u2022 Skin and subcutaneous tissue disorders: Seborrhoea, angioedema, hirsutism

u2022 Investigations: Body mass decreased.

Other side effects have been reported in association with Novofem u00ae treatment:

u2022 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.

u2022 Skin and subcutaneous disorders: Chloasma, erythema multiforme, erythema nodosum, haemorrhagic eruption, vascular purpura

u2022 Probable dementia over the age of 65 (see section 4.4)

u2022 Gall bladder disease

u2022 Dry eyes

u2022 Tear film composition changes

u2022 Severe depression with a higher risk of suicidal thoughts/behaviour and suicide.

Ovarian cancer

Use of estrogen-only or combined estrogen-progestagen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4). A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1,43, 95 % CI 1,31 - 1,56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2 000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2 000 will be diagnosed with ovarian cancer over a 5-year period.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of Novofem u00ae is important. It allows continued monitoring of the benefit/risk balance of Novofem u00ae . Healthcare providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

In overdose, side effects will be exacerbated & exaggerated (see section 4.8). Symptoms of over dosage with oral estrogens are breast tenderness, nausea, vomiting and/or metrorrhagia. Overdosage of progestagens may lead to a depressive mood, fatigue, acne and hirsutism.

Treatment should be symptomatic.