Novofem

Package leaflet: Information for the user

Novofem, coated tablets
estradiol + norethisterone acetate
Read the entire leaflet carefully before starting to use the medicine, as it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm others, even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Leaflet contents

1. What Novofem is and what it is used for
2. Important information before taking Novofem
3. How to take Novofem
4. Possible side effects
5. How to store Novofem
6. Contents of the pack and other information

1. What Novofem is and what it is used for

Novofem is a medicine used in sequential combined hormone replacement therapy (HRT), taken daily without interruption in postmenopausal women who have had at least 6 months since their last natural menstrual period.
Novofem contains two female sex hormones – an oestrogen (estradiol) and a progestagen (norethisterone acetate). The estradiol in Novofem is identical to the estradiol produced by the ovaries in women and is classified as a natural oestrogen. Norethisterone acetate is a synthetic progestagen that acts similarly to progesterone – another important female sex hormone.
Novofem is used to:
relieve symptoms occurring after menopause
During menopause, the amount of oestrogen produced by a woman's body decreases. This leads to symptoms such as sudden feelings of heat in the face, neck, and chest (‘hot flushes’). Novofem helps relieve these symptoms. Novofem may be recommended only if these symptoms significantly interfere with daily life.
prevent osteoporosis
After menopause, some women develop brittle bones (osteoporosis). All available options should be discussed with your doctor.
If you are at increased risk of fractures due to osteoporosis and other treatments are not suitable, Novofem may be used to prevent postmenopausal osteoporosis. Experience in treating women over 65 years of age is limited.

2. Important information before using Novofem

Medical history and regular medical examinations
Hormone replacement therapy (HRT) carries risks that should be considered when deciding whether to start or continue HRT. Experience with treating women experiencing premature menopause (due to ovarian failure or surgical intervention) is limited. If you are experiencing premature menopause, the risks associated with HRT may differ. In such cases, you should consult your doctor.
Before starting (or resuming) HRT, your doctor will take a medical and family history. Your doctor may decide to perform tests, including breast and/or gynecological examination, if necessary.
If you decide to use Novofem, you should have regular medical check-ups (at least once a year). During these visits, you should discuss the benefits and risks of continuing Novofem with your doctor.
You should have regular mammograms as recommended by your doctor.

When not to use Novofem
If any of the conditions listed below are present, or if you are unsure, you must inform your doctor before taking Novofem.
Do not start using Novofem if:

• you have been diagnosed with, have had, or suspect breast cancer;
• you have been diagnosed with, have had, or suspect endometrial cancer (cancer of the lining of the womb) or any other oestrogen-dependent tumour;
• you have unexplained vaginal bleeding;
• you have endometrial hyperplasia (excessive growth of the lining of the womb) that is untreated;
• you have been diagnosed with or have had blood clots in the veins (venous thromboembolic disease), e.g. in the legs (deep vein thrombosis) or lungs (pulmonary embolism);
• you have a blood clotting disorder (a condition that increases the risk of thrombosis, such as protein C, protein S or antithrombin deficiency);
• you currently have or have had arterial thrombotic disorders such as myocardial infarction (heart attack), stroke or angina pectoris;
• you currently have or have had liver disease, and liver function tests have not returned to normal;
• you have hypersensitivity and/or allergy to estradiol, norethisterone acetate, or any of the other ingredients of Novofem (listed in section 6, "Contents of the pack and other information");
• you have porphyria, a rare inherited blood disorder.

If any of the above conditions occur for the first time while taking Novofem, you must stop taking the medicine immediately and consult your doctor.

Warnings and precautions
Before starting treatment, inform your doctor if you currently have or have had any of the following conditions, as they may recur or worsen during treatment with Novofem. In such cases, your doctor may decide that you require frequent monitoring:

• uterine fibroids (myomas);
• endometriosis or a history of endometrial hyperplasia;
• risk factors for venous thrombosis (see "Blood clots in the veins (venous thromboembolic disease)");
• risk factors for oestrogen-dependent cancers (e.g. breast cancer in mother, sister or grandmother);
• high blood pressure;
• liver disease, e.g. hepatic adenoma (a benign tumour);
• diabetes;
• gallstones;
• migraine or severe headaches;
• systemic lupus erythematosus (an autoimmune disease affecting multiple organs);
• epilepsy;
• bronchial asthma;
• otosclerosis (a condition of the ear leading to progressive hearing loss);
• high levels of blood fats (triglycerides);
• fluid retention due to heart or kidney dysfunction;
• hypothyroidism (underactive thyroid) requiring replacement therapy with thyroid hormones;
• hereditary angioedema (a hereditary condition causing recurrent episodes of swelling) or a history of sudden swelling of hands, face, feet, lips, eyes, tongue, throat (airway obstruction), or gastrointestinal tract (acquired angioedema);
• lactose intolerance.

If any of the following conditions occur while taking HRT, immediately stop taking Novofem and contact your doctor:

• if any of the conditions listed under "When not to use Novofem" occur;
• if your skin or the whites of your eyes turn yellow (jaundice), which may indicate liver problems;
• if you develop swelling of the face, tongue and/or throat, and/or difficulty swallowing, or hives together with breathing difficulties, indicating angioedema;
• if you develop significantly increased blood pressure (symptoms may include headache, fatigue and dizziness);
• if you experience a new onset of migraine-type headache;
• if you become pregnant;
• if you experience symptoms of blood clots such as:
  • painful swelling and redness in the legs,
  • sudden chest pain,
  • difficulty breathing. For further information, see "Blood clots in the veins (venous thromboembolic disease)".

Note: Novofem is not a contraceptive. If less than 12 months have passed since your last menstrual period, or if you are under 50 years of age, you may need to use an additional method of contraception. Please discuss this with your doctor.

HRT and cancer

Endometrial hyperplasia and endometrial cancer
Taking oestrogens alone in HRT increases the risk of endometrial hyperplasia and endometrial cancer.
The progestagen in Novofem helps reduce this additional risk.

Comparison
Among women aged 50 to 65 years with an intact uterus who do not use HRT, an average of 5 out of 1,000 will be diagnosed with endometrial cancer.
Among women aged 50 to 65 years with an intact uterus who take oestrogen-only HRT, depending on the duration of treatment and oestrogen dose, the number of cases will range from 10 to 60 per 1,000 (i.e. 5 to 55 additional cases).

Unexpected bleeding
While taking Novofem, you will have a monthly bleed (withdrawal bleed). However, if you experience unexpected bleeding or spotting between periods that:

• persists beyond the first 6 months of treatment,
• occurs after more than 6 months of taking Novofem,
• continues after stopping HRT,
  you should contact your doctor as soon as possible.

Breast cancer
Evidence confirms that taking combined oestrogen-progestagen HRT or oestrogen-only H0 increases the risk of developing breast cancer. The additional risk depends on how long HRT is used. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk gradually decreases, but may persist for 10 years or longer if HRT was used for more than 5 years.

Comparison
Among women aged 50 to 54 years not using HRT, breast cancer will be diagnosed in an average of 13 to 17 out of 1,000 women over 5 years.
Among women aged 50 who start 5 years of oestrogen-only HRT, the number of cases will be 16–17 per 1,000 (i.e. 0 to 3 additional cases).
Among women aged 50 who start 5 years of oestrogen-progestagen HRT, the number of cases will be 21 per 1,000 (i.e. 4 to 8 additional cases).
Among women aged 50 to 59 years not using HRT, breast cancer will be diagnosed in an average of 27 out of 1,000 women over 10 years.
Among women aged 50 who start 10 years of oestrogen-only HRT, the number of cases will be 34 per 1,000 (i.e. 7 additional cases).
Among women aged 50 who start 10 years of oestrogen-progestagen HRT, the number of cases will be 48 per 1,000 (i.e. 21 additional cases).

You should examine your breasts regularly. Contact your doctor if you notice any of the following changes:

• skin dimpling,
• changes in the nipple,
• lumps that are visible or palpable.

Additionally, screening mammograms are recommended as advised by your doctor. Before the examination, inform the nurse or radiology technician performing the X-ray that you are taking HRT, as this medicine may increase breast density, which may affect the mammogram results. Not all lumps may be detected on a mammogram in areas of increased breast density.

Ovarian cancer
Ovarian cancer is rare—much rarer than breast cancer. Taking HRT containing oestrogen alone or combined oestrogen-progestagen is associated with a slightly increased risk of ovarian cancer.
The risk of ovarian cancer depends on age. For example, among women aged 50 to 54 years not using HRT, ovarian cancer will be diagnosed in about 2 out of 2,000 women over 5 years.
Among women who have taken HRT for 5 years, it will occur in about 3 out of 2,000 users (i.e. about 1 additional case).

Effects of HRT on the heart and circulation

Blood clots in the veins (venous thromboembolic disease)
The risk of venous blood clots is 1.3 to 3 times higher in women taking HRT compared to non-users, especially during the first year of treatment.
Venous blood clots can be life-threatening; if they travel to the lungs, they may cause chest pain, shortness of breath, loss of consciousness, or even death.

The risk of venous blood clots is higher if you are older or if any of the following risk factors are present. Inform your doctor if:

• you are unable to walk for prolonged periods due to major surgery, injury, or illness (see also section 3, "If surgery is planned");
• you are obese (body mass index - BMI > 30 kg/m²);
• you have had previous thromboembolic events requiring anticoagulant therapy;
• you or a close family member have had blood clots in the legs, lungs, or other organs;
• you have systemic lupus erythematosus;
• you have been diagnosed with cancer.

If you experience symptoms of blood clots, see "If any of the following conditions occur while taking HRT..." and contact your doctor immediately.

Comparison
Among women aged 50 to 59 years not using HRT, the number of venous blood clot cases over 5 years is estimated at 4 to 7 per 1,000 women.
Among women aged 50 to 59 years taking oestrogen-progestagen HRT, the number of cases over 5 years will be 9 to 12 per 1,000 (i.e. 5 additional cases).

Coronary artery disease and heart attack
There is no evidence that HRT prevents heart attacks. Women over 60 years of age taking oestrogen-progestagen HRT have a slightly increased tendency to develop coronary heart disease compared to non-users.

Ischaemic stroke
The risk of stroke is about 1.5 times higher in women taking HRT compared to non-users. The risk of stroke increases strongly with age, so the number of additional stroke cases due to HRT use will increase with age.

Comparison
Among women aged 50 to 59 years not using HRT, the average number of stroke cases over 5 years is estimated at 8 per 1,000 women.
Among women aged 50 to 59 years taking HRT, the number of cases over 5 years will be 11 per 1,000 women (i.e. 3 additional cases).

Other conditions
HRT does not prevent memory loss. The risk of memory loss may be somewhat higher in women who start HRT after the age of 65. Consult your doctor for advice.

Novofem and other medicines
Some medicines may reduce the effectiveness of Novofem, which may lead to irregular bleeding. These include:

• antiepileptic drugs (e.g. phenobarbital, phenytoin, carbamazepine);
• antituberculosis drugs (e.g. rifampicin, rifabutin);
• drugs used in HIV infection (e.g. nevirapine, efavirenz, ritonavir, nelfinavir);
• drugs used in hepatitis C (e.g. telaprevir);
• herbal products containing St. John's wort (Hypericum perforatum).

HRT may affect the action of other medicines:

• the antiepileptic drug lamotrigine, which may lead to increased seizure frequency;
• drugs used in hepatitis C virus (HCV) infection (e.g. the combination regimen of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, or the regimen of glecaprevir/pibrentasvir) may cause increased liver function blood test results (increased liver enzyme AlAT activity) in women taking combined hormonal contraceptives containing ethinylestradiol. Novofem contains estradiol, not ethinylestradiol. It is unknown whether increased AlAT activity may occur when Novofem is used together with these HCV treatment regimens.

Other medicines may increase the effect of Novofem:

• medicines containing ketoconazole (an antifungal agent).

Novofem may affect concomitant treatment with cyclosporine.
You must tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including over-the-counter medicines, herbal remedies, or other natural products. Your doctor will advise you accordingly.

Laboratory tests
If you need to have a blood test, inform your doctor or laboratory staff that you are taking Novofem. The medicine may affect the results of certain tests.

Novofem with food and drink
Tablets may be taken with or without food and drink.

Pregnancy and breastfeeding
Pregnancy: Novofem is intended for use only in postmenopausal women. If pregnancy occurs, stop taking Novofem immediately and contact your doctor.
Breastfeeding: Do not take Novofem while breastfeeding.

Driving and using machines
The effect of Novofem on driving or operating machinery is unknown.

Important information about some ingredients of Novofem
Novofem contains lactose monohydrate. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking Novofem.

3. How to use Novofem

This medicine should always be taken exactly as prescribed by your doctor. If in doubt, consult
your doctor or pharmacist.
Women who have not previously used any other hormonal replacement therapy may start taking
Novofem on any day. Women currently using another hormonal replacement therapy should
contact their doctor to determine the appropriate time to start treatment.
Take one tablet daily, at approximately the same time each day.
Each pack contains 28 tablets.
Days 1 – 16: Take one red tablet daily for 16 days.
Days 17 – 28: Take one white tablet daily for 12 days.
Tablets should be taken with a glass of water.
After finishing a pack, continue treatment without a break. Bleeding similar to a menstrual period
(typically) occurs during the course of the next pack.
Instructions for using the calendar pack can be found at the end of this leaflet, in the section
entitled “DIRECTIONS FOR USE”.
Your doctor will prescribe the lowest effective dose for the shortest duration necessary to relieve
your symptoms. If you feel the dose is too high or too low, consult your doctor.
Inform your doctor if there is no satisfactory improvement in symptoms after 3 months of
treatment. Treatment should continue only as long as the benefits outweigh the risks.
Taking more Novofem than prescribed
If you take more than the recommended dose, contact your doctor or pharmacist immediately.
Estrogen overdose may cause breast tenderness, nausea, vomiting, and/or irregular vaginal
bleeding. Progestogen overdose may lead to low mood, fatigue, acne, and excessive hair growth.
Missing a dose of Novofem
If you forget to take a tablet at your usual time, take it within the next 12 hours. If more than 12
hours have passed, take the next tablet at your usual time the following day. Do not take a double
dose to make up for a missed tablet.
Missing a dose may increase the likelihood of breakthrough bleeding or spotting.
Stopping Novofem treatment
If you wish to stop taking Novofem, inform your doctor, who can explain the consequences of
stopping treatment and discuss alternative therapies.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.
If surgery is planned
If you are scheduled for surgery, inform your surgeon that you are taking Novofem. It may be
necessary to stop taking Novofem 4 to 6 weeks before surgery to minimize the risk of blood clots
(see section 2. “Blood clots in the veins (venous thromboembolic disease)”). Before restarting
Novofem, consult your doctor.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will experience them.
In women using hormone replacement therapy (HRT), there is an increased risk of developing the following conditions
compared to women not using HRT:

• breast cancer;
• overgrowth or cancer of the lining of the womb (endometrial hyperplasia or cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolic disease);
• coronary heart disease;
• stroke;
• possibly cognitive decline (perception, attention, memory), if HRT is initiated at age over 65.

For further information, see section 2. "Important information before taking
Novofem".
Hypersensitivity and (or) allergy (uncommon adverse reaction – affects from 1 to 10
women in 1000).
Although this is an uncommon event, hypersensitivity and (or) allergy may occur. Symptoms of
hypersensitivity and (or) allergy may include one or more of the following: urticaria,
itching, swelling, difficulty breathing, low blood pressure (pale and cold skin, rapid
heartbeat), dizziness, sweating, which may be signs of an anaphylactic reaction and (or)
anaphylactic shock.
If any of the above symptoms occur, you must stop taking Novofem and seek medical help immediately.
Very common adverse reactions (affects more than 1 in 10 women)

• headache;
• breast tenderness.

Common adverse reactions (affects up to 1 in 10 women)

• increased blood pressure, worsening of hypertension;
• vaginal fungal infection;
• dizziness (central origin), insomnia, depression;
• indigestion, abdominal pain, bloating with flatulence;
• nausea;
• rash, itching;
• vaginal bleeding (see section 2., subsection "Unexpected bleeding");
• enlargement of uterine fibroids (benign uterine tumours);
• oedema (swelling of hands, ankles and feet);
• weight gain.

Uncommon adverse reactions (affects up to 1 in 100 women)

• migraine;
• changes in libido (changes in sexual desire);
• peripheral thromboembolism and thrombosis (blood clots);
• vomiting;
• gallbladder disease or gallstones;
• hair loss (alopecia);
• muscle cramps.

Rare adverse reactions (affects up to 1 in 1000 women)

• allergic reactions;
• nervousness;
• dizziness (vestibular origin);
• diarrhoea;
• bloating;
• acne;
• uterine fibroids (benign uterine tumours).

Unknown (frequency cannot be estimated from available data)

• endometrial hyperplasia (excessive growth of the lining of the womb);
• excessive body and facial hair growth (hirsutism);
• anxiety;
• visual disturbances;
• seborrhoea;
• vaginal itching.

Other adverse reactions associated with combined HRT
The following adverse reactions have been reported during use of other HRT medicines:

• various skin disorders:
  • skin pigmentation changes, especially on the face or neck, known as "chloasma" (melasma),
  • red, tender nodules (erythema nodosum),
  • rash, including erythematous-edematous ring-shaped lesions (erythema multiforme),
  • red or purple skin and (or) mucosal discolorations (purpura);
• dry eyes;
• changes in tear film composition.

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions not listed
in this leaflet, you should inform your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices
and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: 22 49-21-301,
fax: 22 49-21-309, website: https://smz.ezdrowie.gov.pl.
Adverse reactions can also be reported to the responsible entity.
By reporting adverse reactions, additional information on the safety of the medicine can be collected.

5. How to store Novofem

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and outer packaging following “Expiry”. The expiry date refers to the last day of the stated month.
Do not store above 25°C. Do not store in a refrigerator. To protect from light, keep in the outer packaging.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the pack and other information

What Novofem contains

• The active substances are: estradiol and norethisterone acetate. The red coated tablets contain 1 mg of estradiol (as estradiol hemihydrate). The white coated tablets contain 1 mg of estradiol (as estradiol hemihydrate) and 1 mg of norethisterone acetate.
• The other ingredients are: monohydrate lactose, corn starch, hydroxypropylcellulose, talc, and magnesium stearate. The red film-coating contains: hypromellose, talc, titanium dioxide (E171), propylene glycol, and red iron oxide (E172). The white film-coating contains: hypromellose, glyceryl trioctate, and talc.

What Novofem looks like and contents of the pack
The coated tablets are round, 6 mm in diameter. The red tablets are marked with the engraved
code NOVO 282. The white tablets are marked with the engraved code NOVO 283.
Each 28-tablet pack contains 16 red tablets and 12 white tablets.
Pack sizes:

• 28 coated tablets

Marketing Authorisation Holder and Manufacturer
Novo Nordisk A/S
Novo Allé
DK–2880 Bagsværd, Denmark
This medicinal product is authorised in the European Economic Area countries and in the United Kingdom (Northern Ireland) under the following names:
European Economic Area countries: Novofem – except:
France: Novofemme
Spain: Duofemme
Other sources of information
Detailed information about this medicinal product is available on the website of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: http://www.urpl.gov.pl
DIRECTIONS FOR USE
How to use the calendar pack
1. Setting the day indicator
Rotate the inner disc to align the day of the week with the small plastic flap.

2. How to remove the first tablet
Break open the plastic flap and remove the first tablet.

3. Subsequent tablets
The next day, rotate the transparent disc clockwise by one position, as indicated by the arrow. Remove the next tablet. Remember to take only one tablet per day.
The outer transparent part may only be rotated after the tablet in the recess has been removed.