BIJUVA

Package leaflet: information for the patient

Bijuva, 1 mg + 100 mg, soft capsules
Estradiol + Progesterone
Please read this leaflet carefully before taking the medicine, as it contains important information for the patient. The medicine should always be taken exactly as described in this patient leaflet or as directed by the pharmacist. Keep this leaflet so that you can read it again if necessary. If you have any doubts, please consult your pharmacist. If you experience any adverse reactions, including any not listed in this leaflet, you should inform your pharmacist. See section 4. If there is no improvement or if you feel worse, contact your doctor or pharmacist.
Table of contents

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

1. What Bijuva is and what it is used for

Bijuva is a hormone replacement therapy (HRT).
It contains two types of female hormones – estrogen and progestagen. Bijuva is used in postmenopausal women who have had at least 12 months (1 year) since their last natural menstrual period.
Relief of postmenopausal symptoms
During menopause, the amount of estrogens produced by a woman's body decreases. This may cause symptoms such as hot flushes affecting the face, neck, and chest ("hot flashes"). Bijuva helps relieve these menopausal symptoms.
Bijuva may be prescribed to a patient only when symptoms seriously interfere with her daily life.

2. Important information before using BIJUVA

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

When not to use BIJUVA:
Do not use BIJUVA if any of the following apply. If you have any doubts regarding any of the points below, consult your doctor before using BIJUVA.

Do not use BIJUVA:

• if you are allergic to estradiol hemihydrate or progesterone, or any of the other ingredients of this medicine (listed in section 6);
• if you currently have, suspect you may have, or have previously had breast cancer;
• if you currently have or suspect you may have estrogen-dependent cancer, such as cancer of the lining of the uterus (endometrium);
• if you have unexplained vaginal bleeding;
• if you have untreated excessive growth of the lining of the uterus (endometrial hyperplasia);
• if you currently have or have ever had blood clots in the veins (thrombosis), such as in the deep veins of the legs (deep vein thrombosis) or in the lungs (pulmonary embolism);
• if you have blood clotting disorders (such as protein C deficiency, protein S deficiency, or antithrombin deficiency);
• if you currently have or recently had an arterial disease caused by blood clots, such as myocardial infarction, stroke, or angina pectoris;
• if you currently have liver disease, or if liver function tests have not returned to normal values;
• if you have the rare inherited blood disorder - porphyria.

If any of the above conditions occur for the first time while taking BIJUVA, stop using the medicine immediately and consult your doctor without delay.

When to exercise particular caution when using BIJUVA
Before starting treatment, inform your doctor if you have ever had any of the following conditions, as they may recur or worsen during treatment with BIJUVA. In such cases, you should have more frequent check-ups:

• uterine fibroids;
• endometriosis (growth of the uterine lining outside the uterus) or a history of excessive growth of the uterine lining (endometrial hyperplasia);
• increased risk of blood clots (see "Blood clots in the veins (thrombosis)");
• increased risk of estrogen-dependent cancer (e.g. breast cancer in mother, sister, grandmother);
• high blood pressure;
• liver diseases, such as liver adenoma;
• diabetes;
• gallstones;
• migraine or severe headaches;
• autoimmune disease affecting multiple organs (systemic lupus erythematosus);
• epilepsy;
• bronchial asthma;
• a disease affecting the middle ear and hearing (otosclerosis);
• very high levels of triglycerides in the blood;
• fluid retention due to impaired heart or kidney function;
• hereditary or acquired angioedema.

When to stop using BIJUVA and contact your doctor immediately
Stop using BIJUVA and contact your doctor immediately if any of the following occur during HRT:

• if any of the conditions listed under "When not to use BIJUVA" occur;
• if your skin or the whites of your eyes turn yellow (jaundice), which may be a sign of liver disease;
• swelling of the face, tongue, and/or throat and/or difficulty swallowing or hives with breathing difficulties, which may indicate angioedema;
• in case of a significant increase in blood pressure (symptoms may include headache, fatigue, dizziness);
• if you experience a migraine-type headache for the first time;
• if you become pregnant;
• if symptoms of blood clots occur, such as:
  • painful swelling and redness in the legs,
  • sudden chest pain,
  • difficulty breathing;
    More information on this topic can be found in the section "Blood clots in the veins (thrombosis)";
• in case of very high levels of triglycerides in the blood;
• in case of fluid retention due to impaired heart or kidney function.

Note: BIJUVA 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.

Hormone replacement therapy (HRT) and cancer

Excessive growth of the uterine lining (endometrial hyperplasia) and cancer of the uterine lining (endometrial cancer)
HRT with estrogen alone increases the risk of excessive growth of the uterine lining (endometrial hyperplasia) and the risk of endometrial cancer.
The progestagen contained in BIJUVA prevents this additional risk.

Irregular bleeding
During the first 3–6 months of taking BIJUVA, irregular bleeding or spotting may occur. However, if you experience irregular bleeding that:

• lasts longer than the first 6 months,
• occurs after more than 6 months of taking BIJUVA,
• continues despite stopping BIJUVA,
  you should contact your doctor as soon as possible.

Breast cancer
Evidence confirms that taking hormone replacement therapy (HRT) in the form of combined estrogen and progestagen, or estrogen alone, increases the risk of breast cancer. The additional risk depends on the duration of HRT use. This additional risk becomes apparent after 3 years of HRT use. After stopping HRT, the additional risk gradually decreases, but the risk may persist for 10 years or longer if HRT lasted more than 5 years.

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

You should regularly examine your breasts. Consult your doctor if you notice any changes, such as:

• skin wrinkling,
• changes in the nipple,
• any noticeable or palpable lumps.
  Additionally, participation in recommended screening mammography programs is advised.
  For screening mammograms, it is important to inform the nurse or medical staff performing the X-ray about your use of HRT, as this medicine may increase breast density, which in turn may affect the mammogram results. A mammogram may not detect all lumps in areas of increased breast density.

Ovarian cancer
Ovarian cancer is much rarer than breast cancer. The use of estrogen-only HRT or combined estrogen-progestagen HRT causes a slight increase in the risk of ovarian cancer. The risk of ovarian cancer varies depending on age. For example, among women aged 50–54 who do not use HRT, ovarian cancer will be diagnosed in about 2 out of 2,000 women over 5 years. Among women who have used HRT for 5 years, the number of cases will be about 3 out of 2,000 women (i.e., about 1 additional case).

HRT and effects on the heart and circulation

Blood clots in the veins (thrombosis)
The risk of blood clots in the veins is approximately 1.3 to 3 times higher in women taking HRT compared to women who do not use HRT. This complication is most likely to occur during the first year of HRT use. 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 apply. Inform your doctor if:

• you are unable to walk for long periods due to major surgery, serious injury, or illness (see also section 3 "If surgery is required");
• you are obese (BMI > 30 kg/m²);
• you have clotting disorders requiring long-term anticoagulant therapy;
• a close family member has previously had blood clots in the legs, lungs, or other organs;
• you have systemic lupus erythematosus (SLE);
• you have cancer.
  Symptoms of blood clots are listed in the section "When to stop using BIJUVA and contact your doctor immediately."

Comparison
Among women aged 50 to 60 who do not use HRT, venous blood clots will likely occur in 4 to 7 out of 1,000 women over 5 years. Among women aged 50 to 60 who have used estrogen-progestagen HRT for more than 5 years, the number of cases will be 9 to 12 per 1,000 women (i.e., 5 additional cases).

Ischemic heart disease (myocardial infarction)
There is no evidence that HRT prevents myocardial infarction. Women over 60 years of age using estrogen-progestagen HRT are slightly more likely to develop ischemic heart disease than women not using HRT.

Stroke
The risk of stroke is approximately 1.5 times higher in women using HRT compared to women not using HRT. The number of additional stroke cases caused by HRT use increases with age.

Comparison
Among women aged 50 to 60 who do not use HRT, stroke will likely occur in 8 out of 1,000 women over 5 years. Among women aged 50 to 60 who use HRT, the number of cases will be 11 per 1,000 women over 5 years (i.e., 3 additional cases).

Other conditions
HRT does not prevent memory loss. There is some evidence of an increased risk of memory loss in women who start HRT after age 65. Please discuss this with your doctor.

Children
BIJUVA should not be used in children.

BIJUVA and other medicines
BIJUVA may affect the action of certain medicines. Some medicines may affect the action of BIJUVA. This may lead to irregular bleeding. This applies to the following medicines:

• antiepileptic drugs (such as phenobarbital, phenytoin, and carbamazepine);
• antituberculosis drugs (such as rifampicin, rifabutin);
• drugs used in HIV infection (such as nevirapine, efavirenz, ritonavir, and nelfinavir);
• herbal preparations containing St. John's wort (Hypericum perforatum);
• bromocriptine used for pituitary gland disorders or Parkinson's disease;
• ketoconazole, griseofulvin (used in fungal infections);
• cyclosporine (used to suppress immune system activity).

Hormone replacement therapy may affect the action of other medicines:

• the antiepileptic drug (lamotrigine), as it may increase the frequency of seizures;
• drugs for hepatitis C virus (HCV), such as combination regimens of ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, or glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir, which may cause increased liver function test results in the blood (increased ALT liver enzyme activity) in women using combined hormonal products containing ethinylestradiol. BIJUVA contains estradiol instead of ethinylestradiol. It is not known whether increased ALT liver enzyme activity may occur when using BIJUVA with these combination HCV treatment regimens.

Tell your doctor or pharmacist about all medicines you are currently taking or have recently taken, including over-the-counter medicines, herbal supplements, or other natural products. Discuss this with your doctor.

Laboratory tests
If blood tests are required, inform your doctor or laboratory staff that you are taking BIJUVA, as it may affect the results of certain tests.

Pregnancy and breastfeeding
BIJUVA is intended for use only in postmenopausal women.
If you become pregnant, stop using BIJUVA and contact your doctor.

BIJUVA contains Allura Red
BIJUVA contains 0.042 mg of Allura Red (E129), which may cause allergic reactions.

3. How to use BIJUVA

This medicine should always be taken exactly as prescribed by your doctor or pharmacist. If in doubt,
you should consult your doctor or pharmacist. Your doctor should prescribe the lowest effective dose
for the shortest possible duration that provides relief of symptoms. If you think the dose is too high or too low,
you should consult your doctor.
Take one capsule daily, with food.
This medicine should be taken every day, without interruption.
Taking more BIJUVA than prescribed
If you take more BIJUVA than prescribed, contact your doctor or go to a hospital immediately.
Bring the medicine package with you.
Symptoms may include: drowsiness, dizziness, fatigue.
Missing a dose of BIJUVA
If you miss a dose, take it as soon as possible. However, if more than 12 hours have passed, do not
take the missed dose.
Do not take a double dose to make up for a missed dose.
Missing a dose may increase the likelihood of intermenstrual bleeding or spotting.
Stopping BIJUVA treatment
Do not stop taking BIJUVA without first consulting your doctor. If you have any further questions about
using this medicine, consult your doctor or pharmacist.
If surgery is required
If you are scheduled for surgery, inform the surgeon that you are taking BIJUVA. It may be necessary
to stop taking BIJUVA approximately 4 to 6 weeks before surgery to reduce the risk of blood clots
(see section 2, "Venous thromboembolism"). Before restarting BIJUVA, consult your doctor.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, 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 endometrial cancer);
• ovarian cancer;
• blood clots in the veins of the legs or lungs (venous thromboembolic disease);
• ischaemic heart disease;
• stroke;
• possible memory loss if HRT is started after the age of 65. More information about these adverse effects can be found in section 2.

You should inform your doctor if any of the following adverse effects occur while taking BIJUVA:
Very common adverse effects (may occur in more than 1 in 10 patients):

• breast tenderness.

Common adverse effects (may occur in less than 1 in 10 patients):

• headache, dizziness,
• mood changes,
• fatigue,
• back pain,
• abdominal pain, indigestion,
• pelvic pain,
• weight gain,
• acne, dry skin,
• breast pain,
• nausea,
• vaginal discharge (white or yellow vaginal discharge),
• vaginal bleeding or strong uterine cramps,
• hair loss,
• limb pain (e.g. pain in the back, arms, legs, wrists, ankles).

Uncommon adverse effects (may occur in less than 1 in 100 patients):

• low iron levels in the blood,
• high blood pressure,
• fluid retention in the lower limbs,
• increased cholesterol levels,
• increased appetite,
• problems with urination and defecation,
• muscle pain,
• breast cancer,
• shorter sleep duration,
• uterine or fallopian tube tumors,
• memory loss, severe headaches,
• tingling sensation,
• loss of smell,
• difficulty falling asleep or unusual dreams,
• mood changes or irritability,
• vomiting,
• dry mouth,
• constipation,
• diarrhoea,
• weight loss, dizziness,
• chills,
• acute pancreatitis,
• anxiety, depression,
• increased interest in sexual activity than usual,
• hot flushes,
• vaginal irritation or burning,
• vaginal infections, e.g. candidiasis,
• blood clots,
• dry, itchy skin or skin discoloration,
• rash or appearance of red lines on the skin,
• vertigo,
• excessive hair growth,
• visual disturbances,
• discomfort in the abdominal cavity, abdominal tenderness,
• indigestion,
• hyperphagia (excessive increase in appetite),
• discomfort in the mouth,
• taste disturbances,
• bloating,
• hypersensitivity,
• gastritis and enteritis,
• boils,
• acute otitis media,
• abnormal liver function test results,
• limb pain,
• adnexal cysts,
• attention disturbances,
• paraesthesia (abnormal sensation),
• olfactory hallucinations,
• restlessness,
• breast disorders,
• nipple dysplasia,
• nipple pain,
• benign breast tumor,
• endometrial hyperplasia (thickening of the lining of the womb),
• abnormal biopsy result,
• postmenopausal bleeding,
• itching of the vulva and vagina, and telangiectasia.

Rare adverse effects (may occur in less than 1 in 1000 patients):

• muscle weakness,
• benign smooth muscle tumors of the uterus,
• cysts near the fallopian tubes.

Very rare adverse effects (may occur in less than 1 in 10,000 patients):

• itching, dark urine.

The following adverse effects have been reported during use of other HRT products:

• gallbladder disease,
• various skin disorders:
  • skin pigmentation, particularly on the face or neck, known as "chloasma" (melasma),
  • painful red nodules on the skin (erythema nodosum),
  • rash with redness or ring-shaped ulcers (erythema multiforme).

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

5. How to store BIJUVA

Keep this medicine out of the sight and reach of children.
This medicinal product does not require storage at a specific temperature. To protect from light,
keep the blister in the outer packaging.
Do not use this medicine after the expiry date stated on the packaging after "Expiry date". The expiry date refers to the last day of the stated month.
Do not use this medicine if you notice any visible signs of deterioration.
Medicines should not be disposed of down the drain or in household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Bijuva contains
The active substances are estradiol (in the form of estradiol hemihydrate) and progesterone.
Other components are: mono/diglycerides of medium-chain fatty acids, macrogol glycerides laurates 32, gelatine, hydrolysed gelatine, glycerol, Allura Red (E 129), titanium dioxide (E 171), propylene glycol, polyvinyl acetate phthalate, polyethylene glycol, and ammonium hydroxide.

What Bijuva looks like and contents of the pack
Bijuva soft capsules are oval, opaque, light pink on one side and dark pink on the other side, with the imprint “1C1” in white ink.
They are packed in blisters made of PVC/PE/PCTFE/Aluminium foil, containing 28 or 84 soft gelatin capsules in a cardboard box.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Theramex Ireland Limited
3rd Floor, Kilmore House
Spencer Dock, Park Lane
Dublin 1, D01 YE64
Ireland

Manufacturer
Pfizer Italia S.R.L.
Localita Marino Del Tronto
63100 Ascoli Piceno
Italy

This medicinal product is authorised in the European Economic Area countries under the following name:
Belgium, France, Germany, Italy, Luxembourg, Netherlands, Poland, Spain: Bijuva

Other sources of information