ZADENVI

Package leaflet: Information for the user

ZADENVI 60 mg injection solution in pre-filled syringe

denosumab
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.
• Your doctor will provide you with a patient alert card containing important safety information that you need to know before and during treatment with ZADENVI.

Contents of this leaflet

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

1. What ZADENVI is and what it is used for

What ZADENVI is and how it works
ZADENVI contains denosumab, a protein (monoclonal antibody) that interferes with the action of
another protein, for the treatment of bone loss and osteoporosis. Treatment with
denosumab makes bones stronger and less likely to fracture.
Bone is living tissue that is constantly being renewed. Oestrogens help maintain healthy bones. After
menopause, reduced oestrogen levels can cause bones to become thin and fragile, which
may lead to the development of a condition called osteoporosis. Osteoporosis can also
occur in men due to various causes, including ageing and/or low levels of the male hormone, testosterone. It may also occur in patients receiving
glucocorticoids. Many patients with osteoporosis do not have symptoms, but are still at
risk of bone fractures, particularly in the spine, hip, and wrists.
Surgical procedures or medications that suppress the production of oestrogen or testosterone,
used in the treatment of patients with breast or prostate cancer, can also cause
bone loss. As a result, bones become more fragile and more prone to fractures.
For what type of treatment is ZADENVI used?
ZADENVI is used for the treatment of:

• osteoporosis in postmenopausal women (postmenopausal osteoporosis) and in men who are at increased risk of fractures (broken bones), to reduce the risk of vertebral,
  non-vertebral, and hip fractures.

• bone loss in men due to reduced hormone levels (testosterone) caused by surgery or drug therapy in patients with prostate cancer.

• bone loss due to long-term treatment with glucocorticoids in patients at increased risk of fracture.

2. What you should know before using ZADENVI

Do not use ZADENVI

• if you have low levels of calcium in your blood (hypocalcemia).
• if you are allergic to denosumab or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before using ZADENVI.
While being treated with ZADENVI, you may develop a skin infection with symptoms such as swelling, redness, most commonly in the lower leg, with a feeling of warmth and pain (cellulitis), and possibly fever. Inform your doctor immediately if you experience any of these symptoms.
While being treated with ZADENVI, you must also take calcium and vitamin D supplements. Your doctor will discuss this with you.
While being treated with ZADENVI, you may have low levels of calcium in your blood. Inform your doctor immediately if you notice any of the following symptoms: muscle spasms, twitching or cramps, and/or numbness or tingling in your fingers, toes or around your mouth, and/or seizures, confusion or loss of consciousness.
In rare cases, severe low levels of calcium in the blood have been reported, leading to hospitalization and even life-threatening reactions. Therefore, your blood calcium levels will be monitored (through blood tests) before each dose and, in patients at risk of developing hypocalcemia, within two weeks after the initial dose.
Inform your doctor if you have or have ever had severe kidney problems, impaired kidney function, if you are on dialysis, or if you are taking medicines called glucocorticoids (such as prednisolone or dexamethasone), as these may increase your risk of low blood calcium levels if you do not take calcium supplements.

Problems with mouth, teeth or jaw
An adverse effect called osteonecrosis of the jaw (severe deterioration of the jaw bone tissue) has been reported rarely (may occur in up to 1 in 1,000 people) in patients receiving denosumab for osteoporosis. The risk of osteonecrosis of the jaw increases in patients treated for a long period (may occur in up to 1 in 200 people if treated for 10 years).
Osteonecrosis of the jaw may also occur after stopping treatment. It is important to try to prevent the development of osteonecrosis of the jaw, as it is a painful condition that may be difficult to treat. To reduce the risk of developing osteonecrosis of the jaw, take the following precautions:
Before receiving treatment, inform your doctor or nurse (healthcare professional) if you:

• have any mouth or dental problems, such as poor dental hygiene, gum disorders, or if you are scheduled for a dental extraction;
• do not regularly receive dental care or have not had a dental check-up for a long time;
• are a smoker (as this may increase the risk of dental disorders);
• have previously been treated with a bisphosphonate (used to treat or prevent bone disorders);
• are taking medicines called corticosteroids (such as prednisolone or dexamethasone);
• have cancer.

Your doctor may ask you to have a dental examination (by a dentist) before starting treatment with ZADENVI.
During treatment, you must maintain good oral hygiene and have regular dental check-ups. If you wear dentures, make sure they fit properly. If you are undergoing dental treatment or are scheduled for dental surgery (e.g. tooth extractions), inform your doctor about the dental treatment and inform your dentist that you are being treated with ZADENVI.
Contact your doctor and dentist immediately if you notice any new problems with your mouth or teeth, such as tooth loss, pain or swelling, or failure of mouth sores to heal, or presence of discharge, as these could be signs of an adverse effect called osteonecrosis of the jaw (ONJ).

Atypical femoral fractures
Some people have developed atypical fractures of the femur during treatment with denosumab.
Contact your doctor if you experience new or unusual pain in your hip, groin or thigh.

Children and adolescents
ZADENVI must not be used in children and adolescents under 18 years of age.

Other medicines and ZADENVI
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. It is particularly important that you inform your doctor if you are taking other medicines containing denosumab.
You must not take ZADENVI together with other medicines containing denosumab.

Pregnancy and breastfeeding
ZADENVI has not been studied in pregnant women. If you are pregnant, suspect you may be pregnant, or are planning to become pregnant, ask your doctor for advice before taking this medicine.
The use of ZADENVI is not recommended during pregnancy. Women of childbearing potential must use effective contraception while taking ZADENVI and for at least 5 months after stopping treatment with ZADENVI.
If you become pregnant during treatment with ZADENVI or within 5 months after stopping treatment with ZADENVI, inform your doctor.
It is not known whether ZADENVI passes into breast milk. It is important that you inform your doctor if you are breastfeeding or planning to breastfeed. Your doctor will then help you decide whether to discontinue breastfeeding or discontinue ZADENVI, taking into account the benefits of breastfeeding for the child and the benefits of ZADENVI for the mother.
If you are breastfeeding during treatment with ZADENVI, inform your doctor.
Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
ZADENVI has no effect or has a negligible effect on the ability to drive vehicles or use machinery.

ZADENVI contains sorbitol
This medicine contains 46 mg of sorbitol per ml of solution.

ZADENVI contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per 60 mg dose, i.e. essentially ‘sodium-free’.

ZADENVI contains polysorbate
This medicine contains 0.1 mg of polysorbate 20 (E 432) per syringe, equivalent to 0.1 mg/mL. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How to use ZADENVI

Use this medicine exactly as instructed by your doctor. If you have any doubts, consult your doctor.

The recommended dose is one pre-filled syringe containing 60 mg, administered once every 6 months as a single subcutaneous (under the skin) injection. The most suitable injection sites are the upper thighs and the abdomen. If an assistant is administering the injection, the upper outer arm may also be used. Consult your doctor regarding the timing of the next possible injection. Each ZADENVI package contains a reminder card that can be used to keep track of the date of the next injection.

During treatment with ZADENVI, you must also take calcium and vitamin D supplements. Your doctor will discuss this with you.

Your doctor will decide whether it is better for you or your assistant to administer the ZADENVI injection. Your doctor or nursing staff will show you or your assistant how to administer ZADENVI. For instructions on how to inject ZADENVI, refer to the section at the end of this leaflet.

Do not shake.

Before administration, inspect the solution. Do not inject the solution if it contains particles, appears cloudy, or shows any discoloration.

If you forget to use ZADENVI

If you have missed a dose of ZADENVI, the injection should be given as soon as possible. After that, injections should be administered every 6 months from the date of the last injection.

If you stop using ZADENVI

To achieve the maximum benefit from treatment in reducing the risk of fractures, it is important to use ZADENVI for the entire duration prescribed by your doctor. Do not stop treatment without consulting your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Uncommonly, patients treated with ZADENVI may develop skin infections (especially cellulitis). Contact your doctor immediately if you experience any of the following symptoms while taking ZADENVI: redness and swelling of the skin, most commonly in the lower leg, with a sensation of warmth and pain, possibly accompanied by fever.

Rarely, patients treated with ZADENVI may experience mouth and/or jaw pain, swelling or lesions that do not heal in the mouth or jaw area, discharge, numbness or a feeling of heaviness in the jaw, or loose teeth. These could be signs of a serious deterioration of the jawbone tissue (osteonecrosis). Contact your doctor and dentist immediately if you experience any of these symptoms during or after stopping treatment with ZADENVI.

Rarely, patients treated with ZADENVI may develop low levels of calcium in the blood (hypocalcaemia). Severely low calcium levels can lead to hospitalisation and may even be life-threatening. Symptoms include muscle spasms, contractions or cramps, and/or numbness or tingling in the fingers, toes or around the mouth, and/or seizures, confusion, or loss of consciousness. Contact your doctor immediately if any of these symptoms occur. Low calcium levels may also lead to changes in heart rhythm known as QT interval prolongation, which can be detected by electrocardiogram (ECG).

Rarely, atypical fractures of the femur may occur in patients treated with ZADENVI. Contact your doctor if you develop new or unusual pain in the hip, groin or thigh, as this could be an early sign of a possible femoral fracture.

Rarely, allergic reactions may occur in patients treated with ZADENVI. Symptoms include swelling of the face, lips, tongue, throat or other body parts; skin rash, itching, hives, wheezing or difficulty breathing. Inform your doctor if you experience any of these symptoms during treatment with ZADENVI.

Very common side effects (may occur in more than 1 in 10 people):

• bone, joint and/or muscle pain, sometimes severe,
• pain in arms or legs (limb pain).

Common side effects (may occur in up to 1 in 10 people):

• frequent and painful urination, blood in urine, urinary incontinence,
• upper respiratory tract infections,
• pain, tingling or numbness radiating to the lower limbs (sciatica),
• constipation,
• abdominal discomfort,
• skin rash,
• itching, redness and/or dryness of the skin (eczema),
• hair loss (alopecia).

Uncommon side effects (may occur in up to 1 in 100 people):

• fever, vomiting, and abdominal pain or abdominal disorders (diverticulitis),
• ear infections,
• skin eruptions or mouth ulcers (drug-induced lichenoid eruptions).

Very rare side effects (may occur in up to 1 in 10,000 people):

• allergic reaction that may damage blood vessels, mainly affecting the skin (e.g. purple or red-brown spots, hives or skin ulcers) (hypersensitivity vasculitis).

Not known (frequency cannot be estimated from the available data):

• inform your doctor if you experience ear pain, ear discharge, and/or ear infection. These could be signs of damage to the ear bone.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system referred to in Annex V.* By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store ZADENVI

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and carton after
Exp/EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Keep the pre-filled syringe in the outer packaging to protect the medicine from light.
The pre-filled syringe may be removed from the refrigerator and allowed to reach room temperature (up to 25°C) before injection. This will make the injection more comfortable.
Once the syringe has reached room temperature (up to 25°C), it must be used within 30 days.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What ZADENVI contains

• The active substance is denosumab. Each 1 ml pre-filled syringe contains 60 mg of denosumab (60 mg/ml).
• The other components are glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 20, and water for injections.

Description of the appearance of ZADENVI and contents of the pack
ZADENVI is an injectable solution, from colourless to slightly yellow, supplied in a ready-to-use pre-filled syringe.
Each pack contains one pre-filled syringe with needle protection.

Marketing Authorization Holder
Zentiva k.s.
U Kabelovny 130
102 37 Prague 10
Czech Republic

Manufacturer
GH GENHELIX S.A.
Parque Tecnológico de León
Edificio GENHELIX
C/Julia Morros, s/n
Armunia, 24009 León
Spain

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:

België/Belgique/Belgien Lietuva
Zentiva, k.s. Zentiva, k.s.
Tél/Tel: +32 (78) 700 112 Tel: +370 52152025
[email protected] [email protected]

България Luxembourg/Luxemburg
Zentiva, k.s. Zentiva, k.s.
Тел: +359 24417136 Tél/Tel: +352 208 82330
[email protected] [email protected]

Česká republika Magyarország
Zentiva, k.s. Zentiva Pharma Kft.
Tel: +420 267 241 111 Tel.: +36 1 299 1058
[email protected] [email protected]

Danmark Malta
Zentiva Denmark ApS Zentiva, k.s.
Tlf.: +45 787 68 400 Tel: +356 2034 1796
[email protected] [email protected]

Deutschland Nederland
Zentiva Pharma GmbH Zentiva, k.s.
Tel: +49 (0) 800 53 53 010 Tel: +31 202 253 638
[email protected] [email protected]

Eesti Norge
Zentiva, k.s. Zentiva Denmark ApS
Tel: +372 52 70308 Tlf: +45 787 68 400
[email protected] [email protected]

Ελλάδα Österreich
Zentiva, k.s. Zentiva, k.s.
Τηλ: +30 211 198 7510 Tel: +43 720 778 877
[email protected] [email protected]

España Polska
Zentiva Spain S.L.U. Zentiva Polska Sp. z o.o.
Tel: +34 671 365 828 Tel: +48 22 375 92 00
[email protected] [email protected]

France Portugal
Zentiva France Zentiva Portugal, Lda
Tél: +33 (0) 800 089 219 Tel: +351 210601360
[email protected] [email protected]

Hrvatska România
Zentiva d.o.o. ZENTIVA S.A.
Tel: +385 1 6641 830 Tel: +4 021.304.7597
[email protected] [email protected]

Ireland Slovenija
Zentiva, k.s. Zentiva, k.s.
Tel: +353 818 882 243 Tel: +386 360 00 408
[email protected] [email protected]

Ísland Slovenská republika
Zentiva Denmark ApS Zentiva, a.s.
Sími: +354 539 5025 Tel: +421 2 3918 3010
[email protected] [email protected]

Italia Suomi/Finland
Zentiva Italia S.r.l. Zentiva Denmark ApS
Tel: +39 800081631 Puh/Tel: +358 942 598 648
[email protected] [email protected]

Κύπρος Sverige
Zentiva, k.s. Zentiva Denmark ApS
Τηλ: +30 211 198 7510 Tel: +46 840 838 822
[email protected] [email protected]

Latvija
Zentiva, k.s.
Tel: +371 67893939
[email protected]

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu/

Instructions for use

Read these instructions before starting to use the pre-filled syringes of ZADENVI with needle protection, and each time you receive a new package. There may be new information. You should also consult your healthcare provider regarding your medical condition or treatment.
Keep these Instructions for use so you can refer to them again if needed.
IMPORTANT INFORMATION
Important information to know before administering the ZADENVI injection:

• It is important that you do not attempt to perform the injection unless you have received adequate instructions from your doctor or healthcare provider on the correct way to inject ZADENVI.
• ZADENVI is administered only as a subcutaneous injection (an injection directly under the skin).
• Do not open the outer packaging until it is time to use this medicine.
• Do not remove the needle cap from the pre-filled syringe until you are ready to inject.
• Do not use the pre-filled syringe if it has been dropped on a hard surface. Use a new pre-filled syringe and contact your doctor or healthcare provider.
• Do not attempt to activate the pre-filled syringe before the injection.
• Do not attempt to remove the needle guard from the pre-filled syringe.

Contact your doctor or healthcare provider if you or the person assisting you has any questions about the correct way to inject ZADENVI.
Figure 1 shows the appearance of the pre-filled syringe with needle protection before (a) and after (b) use.

Figure 1

1. Preparation for injection of ZADENVI

Gather the necessary materials

• On a clean, well-lit work surface, gather the following materials needed for the injection:
  o ZADENVI package with pre-filled syringe
  o Alcohol wipes
  o Cotton ball or gauze
  o Adhesive bandage
  o Sharps disposal container

Allow the medication to reach room temperature

• For a more comfortable injection, leave the pre-filled syringe inside its packaging at room temperature for about 30 minutes before injecting ( Figure A ).
  o Do not attempt to warm the pre-filled syringe using a heat source such as hot water or microwave.
  o Do not expose the pre-filled syringe to direct sunlight.
  o Do not shake the pre-filled syringe.
  o Keep the pre-filled syringe out of sight and reach of children.

Figure A
Wash your hands

• Wash your hands thoroughly with water and soap ( Figure B ).

Figure B
Remove the pre-filled syringe from the packaging

• Open the package.
• Hold the pre-filled syringe by its barrel ( Figure C ).
• Lift and remove the syringe from the package.
• Place the syringe on a clean, flat work surface. For safety:
  o Do not touch the plunger.
  o Do not touch the needle cap.

Figure C
Check the medicine and pre-filled syringe

• Verify that the name “ZADENVI” is printed on the label ( Figure D ).
• Check the expiration date printed on the label ( Figure D ).
• Check that the medicine appears as a clear solution, colorless to slightly yellow ( Figure D ).
• Check whether the pre-filled syringe is damaged.

Do not use the pre-filled syringe if:

• The solution is cloudy or contains particles.
• Any parts appear cracked or broken.
• The needle cap is missing or not securely attached.
• The expiration date printed on the label has passed the last day of the indicated month.

In any of the cases listed above, contact your doctor or healthcare provider.

Figure D

2. Preparation

Prepare the injection site

• Choose the injection site ( Figure E ): You may use:
• The upper thigh.
• The abdomen, except for an area within 5 centimetres of the navel.
• The outer upper arm (only if someone else is giving you the injection).
  • Do not inject into areas where the skin is tender, bruised, red, or hardened. Avoid injecting into areas with scars or stretch marks.

Figure E
Clean the injection site

• Clean the injection site with an alcohol wipe ( Figure F ).
• Let the skin dry.
• Do not touch the injection site before injecting.

Figure F
Remove the needle cap

• Carefully remove the needle cap by pulling it straight off, away from your body ( Figure G ).
• Discard the needle cap.
• Do not attempt to re-cover the needle with the cap.

Figure G

3. ZADENVI Injection

Insert the needle

• Lift the injection site to create a stable surface ( Figure H ).
• Do not touch the cleaned area of skin. Note: It is important to keep the skin lifted during injection.
• Insert the needle at a 45–90 degree angle into the lifted skin ( Figure I ).

Figure H

Figure I
ZADENVI Injection

• Slowly and completely push the plunger until all the liquid has been injected and the syringe is empty ( Figure J ).

Note: The plunger must be fully depressed to ensure the complete dose has been administered and to activate the needle safety guard.

Figure J
Release the thumb

• Release your thumb from the plunger to allow the needle safety guard to cover the needle ( Figure K ).
• Then remove the syringe from the skin ( Figure L ).
• Let go of the lifted skin.

Contact your doctor or healthcare provider immediately if:

• You did not inject the full dose, or
• The needle safety guard does not activate after injection.

Figure K

Figure L

4. Disposal of ZADENVI

Dispose of the syringe

• Place the used pre-filled syringe and other materials into a sharps disposal container (Figure M). Note: Medicines must be disposed of in accordance with local regulations. Ask your doctor or healthcare provider how to dispose of medicines you no longer use. This will help protect the environment.
• Do not recap the needle on used pre-filled syringes.
• Do not reuse the pre-filled syringe, even if some medicine remains in it.
• Do not recycle pre-filled syringes or dispose of them in household waste.
• Keep the syringe and the sharps disposal container out of sight and out of reach of children.

Figure M
Examine the injection site

• If you see blood, press a cotton ball or gauze pad against the injection site.
• Do not rub the injection site. A bandage may be applied if needed.

Record the date of your next injection

• Record the date of your next injection on the reminder card included in the package (Figure N).

Figure N