BIJUVA 1 mg/100 mg SOFT CAPSULES

Do not take Bijuva

• If you are allergic to estradiol hemihydrate or progesterone or any of the other components of this medication (listed in section 6).
• If you have or have had breast canceror if you suspect you may have it.
• If you have a hormone-sensitive cancer, such as cancer of the lining of the uterus (endometrium), or if you suspect you may have it.
• If you have abnormal vaginal bleeding.
• If you have excessive thickening of the lining of the uterus(endometrial hyperplasia) that is not being treated.
• If you have or have had blood clots in a vein(thrombosis), e.g., in the legs (deep vein thrombosis) or lungs (pulmonary embolism).
• If you have a blood clotting disorder(such as protein C, protein S, or antithrombin deficiency).
• If you have or have recently had a disease caused by blood clots in the arteries, such as heart attack, stroke, or angina.
• If you have or have had liver diseaseand your liver function tests have not returned to normal.
• If you have a rare blood disorder called porphyriathat is inherited from parents to children (hereditary).

If any of these diseases occur for the first time while you are taking Bijuva, stop treatment and consult your doctor immediately.

When to be especially careful with Bijuva

Tell your doctor if you have ever had any of the following problems, before starting treatment, as they may come back or get worse during treatment with Bijuva. If so, you should consult your doctor more frequently for check-ups:

• fibroids in the uterus
• growth of the uterine lining outside the uterus (endometriosis) or a history of excessive growth of the uterine lining (endometrial hyperplasia)
• increased risk of developing blood clots (see "Blood clots in a vein (thrombosis)")
• increased risk of developing a hormone-sensitive cancer (e.g., having a mother, sister, or grandmother who has had breast cancer)
• high blood pressure
• a liver disorder, such as a benign liver tumor
• diabetes
• gallstones
• migraines or severe headaches
• a disease of the immune system that affects many organs of the body (systemic lupus erythematosus, SLE)
• epilepsy
• asthma
• a disease that affects the eardrum and ear (otosclerosis)
• a very high level of fats in the blood (triglycerides)
• fluid retention due to heart or kidney problems
• Hereditary and acquired angioedema

Stop taking Bijuva and go to the doctor immediately

If you notice any of the following disorders when taking HRT:

• any of the disorders mentioned in the "Do not take Bijuva" section
• yellowing of the skin or whites of the eyes (jaundice). This can be a sign of liver disease
• swelling of the face, tongue, or throat, and difficulty swallowing or hives accompanied by difficulty breathing, suggesting angioedema
• a significant increase in blood pressure (symptoms may be headache, fatigue, dizziness)
• migraine-like headaches that appear for the first time
• • painful swelling and redness of the legs;
  • sudden chest pain;
  • difficulty breathing;

for more information, see: "Blood clots in a vein (thrombosis)"

• a very high level of fats in the blood (triglycerides)
• fluid retention due to heart or kidney problems

Note:Bijuva is not a contraceptive. If it has been less than 12 months since your last menstrual period or if you are under 50 years old, you may still need to use an additional contraceptive method to prevent pregnancy. Ask your doctor for advice.

HRT and cancer

Excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)

Taking HRT with estrogens alone will increase the risk of developing excessive thickening of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer).

The progestogen in Bijuva protects against this additional risk.

Irregular bleeding

You may have irregular bleeding or spotting during the first 3-6 months of taking Bijuva. However, if irregular bleeding:

• continues for longer than the first 6 months
• starts after you have been taking Bijuva for more than 6 months
• continues after you have stopped taking Bijuva

consult your doctor as soon as possible.

Breast cancer

Existing data show that the use of hormone replacement therapy (HRT) with estrogen-progestogen combinations or with estrogen alone increases the risk of breast cancer. The additional risk depends on the duration of HRT use. The additional risk becomes apparent within 3 years of use. After stopping HRT, the additional risk will decrease over time, but the risk may persist for 10 years or more if HRT has been used for more than 5 years.

Comparison

In women aged 50-54 who are not using HRT, an average of 13-17 out of 1,000 will be diagnosed with breast cancer over a 5-year period.

In women aged 50 who start estrogen-only HRT for 5 years, there will be between 16 and 17 cases per 1,000 users (i.e., between 0 and 3 additional cases).

In women aged 50 who start HRT with estrogen-progestogen for 5 years, there will be 13-21 cases per 1,000 users (i.e., between 4-8 cases).

In women aged 50-59 who are not taking HRT, an average of 27 cases of breast cancer will be diagnosed per 1,000 women over a 10-year period.

In women aged 50 who start estrogen-only HRT for 10 years, there will be 34 cases per 1,000 users (i.e., 7 additional cases).

In women aged 50 who start HRT with estrogen-progestogen for 10 years, there will be 48 cases per 1,000 users (i.e., 21 additional cases).

• You should have regular breast examinations. Consult your doctor if you detect any changes such as:

• dimpling of the skin
• changes in the nipple
• any lump that you can see or feel

In addition, it is recommended that you join breast cancer screening programs when offered. For breast cancer screening, it is important to inform the nurse/healthcare professional performing the X-ray that you are taking HRT, as these medications can increase breast density, which can affect the outcome of the mammogram. When breast density increases, the mammogram may not detect all lumps.

Ovarian cancer

Ovarian cancer occurs less frequently than breast cancer. The use of HRT with estrogen alone or with estrogen-progestogen combinations has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50-54 who are not taking HRT, about 2 cases of ovarian cancer are observed per 2,000 women over a 5-year period. In women taking HRT for 5 years, about 3 cases are observed per 2,000 patients (i.e., about 1 additional case).

Effects of HRT on the heart and circulation. Blood clots in a vein (thrombosis)

The risk of blood clots in the veinsis approximately 1.3 to 3 times higher in HRT users compared to non-users, especially during the first year of use. Blood clots can be serious and, if one moves to the lungs, can cause chest pain, difficulty breathing, fainting, or even death.

You are more likely to have a blood clot in the veins with age and if any of the following apply to you. Inform your doctor if any of these situations apply to you:

• you are unable to walk for a long time due to major surgery, injury, or illness (see also section 3, If you need to have surgery)
• you have severe obesity (BMI > 30 kg/m²)
• you have a blood clotting disorder that requires long-term treatment with a medication used to prevent blood clots
• any of your close relatives have ever had a blood clot in the leg, lung, or other organ
• you have systemic lupus erythematosus (SLE)
• you have cancer

For symptoms of a blood clot, see "Stop taking Bijuva and go to the doctor immediately".

Comparison

In women in their fifties who are not taking HRT, it is expected that an average of 4 to 7 out of 1,000 will have a blood clot in a vein over a 5-year period.

In women in their fifties who have been taking HRT with estrogen-progestogen, there will be 9-12 cases per 1,000 users (i.e., 5 additional cases) over a 5-year period.

Coronary artery disease (heart attack)

There is no evidence that HRT prevents heart attacks. Women over 60 years old taking HRT with estrogen-progestogen are slightly more likely to develop heart disease than those not taking HRT.

Stroke

The risk of having a stroke is approximately 1.5 times higher in HRT users compared to non-users. The number of additional stroke cases due to HRT use will increase with age.

Comparison

In women in their fifties who are not taking HRT, it is expected that an average of 8 out of 1,000 will have a stroke over a 5-year period. For women in their fifties taking HRT, there will be 11 cases per 1,000 users over a 5-year period (i.e., 3 additional cases).

Other diseases

HRT does not prevent memory loss. There is some evidence of greater memory loss in women who start using HRT after the age of 65. Consult your doctor.

Children

Bijuva should not be used in children.

Using Bijuva with other medicines

Bijuva may affect the way other medicines work. Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. Some medicines may interfere with the effect of Bijuva, which may lead to irregular bleeding. These medicines are:

• medicines for epilepsy(such as phenobarbital, phenytoin, and carbamazepine);
• medicines for tuberculosis(such as rifampicin, rifabutin);
• medicines for HIV infection(such as nevirapine, efavirenz, ritonavir, and nelfinavir);
• herbal preparations containing St. John's Wort(Hypericum perforatum);
• bromocriptine used for pituitary gland problems or Parkinson's disease;
• ketoconazole, griseofulvin (for fungal infection treatment);
• cyclosporin (used to suppress the immune system);

HRT may affect the way other medicines work:

• a medicine for epilepsy (lamotrigine), as it may increase the frequency of seizures)
• The combination therapies for hepatitis C virus (HCV) ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin; glecaprevir/pibrentasvir sofosbuvir/velpatasvir/voxilaprevir (see section 4.4), may cause elevations in blood test results for liver function (increase in liver enzyme ALT) in women using HRT with ethinylestradiol. Bijuva contains estradiol instead of ethinylestradiol. It is not known whether an increase in liver enzyme ALT can occur when using Bijuva with this combination therapy for HCV. Your doctor will inform you about this.

Tell your doctor or pharmacist if you are using or have recently used other medicines, including those obtained without a prescription, herbal medicines, and other natural products.

Your doctor will advise you.

Lab tests

If you need a blood test, inform your doctor or the laboratory staff that you are taking Bijuva, as this medication may affect the results of some tests.

Pregnancy and breastfeeding

Bijuva is indicated only in postmenopausal women. If you become pregnant while taking Bijuva, you should stop treatment and contact your doctor.

Excipients

Bijuva contains the colorant Allura Red. Bijuva contains 0.042 mg of Allura Red (E129) per capsule. It may cause allergic reactions. It may trigger asthma, especially in patients allergic to acetylsalicylic acid.

3. How to take Bijuva