Patient Information Leaflet

Prolia 60 mg solution for injection in pre-filled syringe

denosumab
Please read all of this leaflet carefully before taking 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 they have the same symptoms as yours, as it may be harmful.
If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.
Your doctor will give you a patient reminder card containing important safety information that you must know before and during treatment with Prolia.

Contents of this leaflet

What Prolia is and what it is used for
What you need to know before using Prolia
How to use Prolia
Possible side effects
How to store Prolia
Contents of the pack and other information

1. What Prolia is and what it is used for

What Prolia is and how it works
Prolia contains denosumab, a protein (monoclonal antibody) that interferes with the action of another protein, used for the treatment of bone loss and osteoporosis. Treatment with Prolia makes bones stronger and less prone to fractures.
Bone is a living tissue that is constantly being renewed. Oestrogens help maintain healthy bones. After menopause, the reduction in oestrogen levels can make bones 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 can also occur in patients receiving glucocorticoids. Many patients with osteoporosis do not have symptoms, but are still at risk of bone fractures, especially in the spine, hip, and wrists.
Surgical procedures or medications that suppress the production of oestrogens 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 likely to fracture.

For which type of treatment is Prolia used
Prolia is used for the treatment of:

osteoporosis in postmenopausal women (postmenopausal osteoporosis) and in men who have an 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 medical 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 Prolia

Do not use Prolia

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

Warnings and precautions
Talk to your doctor or pharmacist before using Prolia.
While being treated with Prolia, 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 Prolia, you must also take calcium and vitamin D supplements. Your doctor will discuss this with you.
While being treated with Prolia, you may have low levels of calcium in your blood. Inform your doctor immediately if you notice any of the following symptoms: muscle spasms, twitches 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 hospitalisation and even life-threatening reactions. Therefore, your blood calcium levels will be monitored (through blood tests) before each dose and within two weeks after the initial dose in patients at risk of developing hypocalcaemia.
Inform your doctor if you have or have ever had severe kidney problems, kidney impairment, 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
A rare side effect called osteonecrosis of the jaw (severe deterioration of the jawbone) has been reported (may occur in up to 1 in 1,000 patients) in patients receiving Prolia for osteoporosis. The risk of osteonecrosis of the jaw increases in patients treated for a long time (may occur in up to 1 in 200 patients 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 starting treatment, inform your doctor or nurse (healthcare provider) if you:

have any mouth or dental problems, such as poor dental hygiene, gum disorders, or if you are scheduled for a tooth 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 problems);
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 Prolia.
During treatment, it is necessary to 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 Prolia.
Contact your doctor and dentist immediately if you notice any new mouth or dental problems such as loose teeth, pain or swelling, or failure of mouth sores to heal, or presence of discharge, as these may be signs of a side effect called osteonecrosis of the jaw (ONJ).

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

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

Other medicines and Prolia
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 Prolia together with other medicines containing denosumab.

Pregnancy and breastfeeding
Prolia has not been studied in pregnant women. It is important that you inform your doctor if you are pregnant, think you may be pregnant, or are planning a pregnancy. The use of Prolia is not recommended during pregnancy. Women of childbearing potential must use effective contraception while taking Prolia and for at least 5 months after stopping treatment with Prolia.
If you become pregnant during treatment with Prolia or within 5 months after stopping treatment with Prolia, please inform your doctor.
It is not known whether Prolia 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 stop breastfeeding or stop taking Prolia, considering the benefit of breastfeeding for the child and the benefit of taking Prolia for the mother.
If you are breastfeeding during treatment with Prolia, inform your doctor.
Ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines
Prolia has no or negligible effect on the ability to drive or use machines.

Prolia contains sorbitol
This medicine contains 47 mg of sorbitol per mL of solution.

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

3. How to use Prolia

The recommended dose is one 60 mg pre-filled syringe 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 giving you the injection, the upper outer arm may also be used. Consult your doctor regarding the timing of your next possible injection.
Each Prolia pack contains a reminder card, which can be removed from the box and used to keep track of the date of your next injection.
During treatment with Prolia, 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 for your assistant to administer the Prolia injection. Your doctor or nursing staff will show you or your assistant how to use Prolia. For instructions on how to inject Prolia, please refer to the section at the end of this leaflet.
Do not shake.
If you forget to take Prolia
If you have missed a dose of Prolia, the injection should be given as soon as possible. After that, injections should be given every 6 months from the date of the last injection.
If you stop using Prolia
To obtain the maximum benefit from treatment in reducing the risk of fractures, it is important to take Prolia 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 everyone will experience them.

Infections of the skin (particularly cellulitis) may occur uncommonly in patients treated with Prolia. Contact your doctor immediately if you experience any of the following symptoms while taking Prolia: skin redness and swelling, most commonly in the lower leg, accompanied by warmth, pain, and possibly fever.

Rarely, patients treated with Prolia may develop mouth and/or jaw pain, swelling or non-healing sores in the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw, or loose teeth. These could be signs of a serious deterioration of the bone tissue in the jaw (osteonecrosis). Contact your doctor and dentist immediately if you experience such symptoms during or after stopping treatment with Prolia.

Rarely, patients treated with Prolia 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 an electrocardiogram (ECG).

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

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

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

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

Common side effects (may affect 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,
rash,
itching, redness and/or dryness of the skin (eczema),
hair loss (alopecia).

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

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

Very rare side effects (may affect 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).

Frequency not known (cannot be estimated from the available data):

contact 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, tell your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Prolia

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 on the carton after
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 its 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 any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Prolia 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 Prolia and contents of the pack
Prolia is a clear, injectable solution, colourless to slightly yellow, supplied in a ready-to-use pre-filled syringe.
Each pack contains one pre-filled syringe with needle protection.
Each pack contains one pre-filled syringe.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands

Manufacturer
Amgen Technology (Ireland) Unlimited Company
Pottery Road
Dun Laoghaire
Dublin
Ireland

Manufacturer
Amgen NV
Telecomlaan 5-7
1831 Diegem
Belgium

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

België/Belgique/Belgien Lietuva
s.a. Amgen n.v. Amgen Switzerland AG Vilniaus filialas
Tél/Tel: +32 (0)2 7752711 Tel: +370 5 219 7474

България Luxembourg/Luxemburg
Амджен България ЕООД s.a. Amgen
Тел.: +359 (0)2 424 7440 Belgique/Belgien
Tél/Tel: +32 (0)2 7752711

Česká republika Magyarország
Amgen s.r.o. Amgen Kft.
Tel: +420 221 773 500 Tel.: +36 1 35 44 700

Danmark Malta
Amgen, filial af Amgen AB, Sverige Amgen S.r.l.
Tlf: +45 39617500 Italy
Tel: +39 02 6241121

Deutschland Nederland
Amgen GmbH Amgen B.V.
Tel.: +49 89 1490960 Tel: +31 (0)76 5732500

Eesti Norge
Amgen Switzerland AG Vilniaus filialas Amgen AB
Tel: +372 586 09553 Tlf: +47 23308000

Ελλάδα Österreich
Amgen Ελλάς Φαρμακευτικά Ε.Π.Ε. Amgen GmbH
Τηλ: +30 210 3447000 Tel: +43 (0)1 50 217

España Polska
Amgen S.A. Amgen Biotechnologia Sp. z o.o.
Tel: +34 93 600 18 60 Tel.: +48 22 581 3000

France Portugal
Amgen S.A.S. Amgen Biofarmacêutica, Lda.
Tél: +33 (0)9 69 363 363 Tel: +351 21 4220606

Hrvatska România
Amgen d.o.o. Amgen România SRL
Tel: + 385 (0)1 562 57 20 Tel: +4021 527 3000

Ireland Slovenija
Amgen Ireland Limited AMGEN zdravila d.o.o.
Tel: +353 1 8527400 Tel: +386 (0)1 585 1767

Ísland Slovenská republika
Vistor hf. Amgen Slovakia s.r.o.
Sími: +354 535 7000 Tel: +421 2 321 114 49

Italia Suomi/Finland
Amgen S.r.l. Amgen AB, sivuliike Suomessa/Amgen AB, filial
Tel: +39 02 6241121 i Finland
Puh/Tel: +358 (0)9 54900500

Kύπρος Sverige
C.A. Papaellinas Ltd Amgen AB
Τηλ: +357 22741 741 Tel: +46 (0)8 6951100

Latvija United Kingdom (Northern Ireland)
Amgen Switzerland AG Rīgas filiāle Amgen Limited
Tel: +371 257 25888 Tel: +44 (0)1223 420305

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

Instructions for use:

Guide to the Parts
Before use	After use
Piston Base for fingers Syringe label Syringe barrel Syringe safety shield Needle safety spring Inserted grey needle cap	Used piston Syringe label Used syringe barrel Used needle Used needle safety spring Removed grey needle cap

Important
Before using a pre-filled Prolia syringe with automatic needle protection, read
these important instructions:

It is important that you do not attempt to administer the injection unless you have received proper instructions from your doctor or healthcare professional.
Prolia is administered as an injection into the tissue just beneath the skin (subcutaneous injection). Do not remove the gray needle cap from the pre-filled syringe until you are ready for
the injection.
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 professional.
Do not attempt to activate the pre-filled syringe before the injection.

Do not attempt to remove the transparent safety shield from the pre-filled syringe.

Contact your doctor or healthcare professional for any questions.

Step 1: Preparation
A	Remove the prefilled syringe from its packaging and prepare the materials needed for injection: alcohol swabs, a cotton ball or gauze, a bandage, and a sharps disposal container (not included).
For a more comfortable injection, allow the prefilled syringe to reach room temperature for about 30 minutes before injecting. Wash your hands thoroughly with soap and water. Place the new prefilled syringe and other necessary materials on a clean, well-lit work surface. Do not attempt to warm the syringe using a heat source such as hot water or a microwave. Do not expose the prefilled syringe to direct sunlight. Do not shake the prefilled syringe excessively. •Keep the prefilled syringe out of sight and reach of children.
B	Open the wrapper by tearing off the cover. Grasp the safety shield of the prefilled syringe to remove the syringe from the wrapper.
Grasp here For safety reasons: Do not grasp the plunger. Do not grasp the gray needle cap.
C	Inspect the medicine and the prefilled syringe.
Medicine
Do not use the prefilled syringe if: •The medicine is cloudy or particles are visible inside. It should be a clear, colorless to slightly yellow solution. •Any parts appear cracked or broken. •The gray needle cap is missing or not securely attached. •The expiration date printed on the label has passed the last day of the stated month. In all cases, contact your doctor or healthcare provider.
Step 2: Preparation
A	Wash your hands thoroughly. Prepare and clean the injection site.
You may use: Upper arm Abdomen Upper thigh •The upper thigh. •The abdomen, except for an area of 5 centimeters around the navel. •The outer upper arm (only if someone else is administering the injection). Clean the injection site with an alcohol swab. Let the skin dry. Do not touch the injection site before injecting. Do not inject into areas where the skin is tender, bruised, red, or hardened. Avoid injecting into areas with scars or stretch marks.
B	Carefully remove the gray needle cap by pulling it straight outward and away from the body.

C	Lift the injection site to create a stable surface.
It is important to keep the skin lifted during injection.
Step 3: Injection
A	Keep the skin lifted. INSERT the needle into the skin.
Do not touch the cleaned area of the skin.
B	PUSH the plunger with slow, steady pressure until you feel or hear a "click". Push all the way until the click is heard.
"CLICK" It is important to push all the way to the "click" to deliver the full dose.
C	Remove your thumb. Then REMOVE the syringe from the skin.
After releasing the plunger, the safety shield of the prefilled syringe will automatically cover the injection needle securely. Do not recap used prefilled syringes with the gray needle cap.
Step 4: Completion
A	Dispose of the used prefilled syringe and other materials in a sharps disposal container.
Medicines must be disposed of in accordance with local regulations. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help protect the environment. Keep the syringe and sharps disposal container out of sight and reach of children. Do not reuse the prefilled syringe. Do not recycle prefilled syringes or dispose of them in household waste.
B	Examine the injection site.
If you see blood, press a cotton ball or gauze onto the injection site. Do not rub the injection site. Apply a bandage if needed.

Instructions for Prolia Injection Using a Pre-filled Syringe
This section contains information on how to use the pre-filled syringe for Prolia. It is important
that you or the person assisting you does not administer the injection before receiving proper
instructions from your doctor or healthcare professional. Wash your hands before each injection. If you
have any questions about the injection, consult your doctor or healthcare professional for assistance.

Before Starting
Read all instructions carefully before using the pre-filled syringe.
Do not use the pre-filled syringe if the needle cap has been removed.

How to Use the Prolia Pre-filled Syringe
Your doctor has prescribed you a pre-filled syringe for subcutaneous (under the skin) injection of Prolia.
You must inject the entire contents (1 mL) of the Prolia pre-filled syringe, which should be administered
once every 6 months as directed by your doctor.

What You Need:
For self-injection, you will need:

A new pre-filled syringe of Prolia
Alcohol swabs or similar disinfectants

What to Do Before Subcutaneous Injection of Prolia

Remove the pre-filled syringe from the refrigerator. DO NOT handle the pre-filled syringe by the plunger or the needle cap, as this may damage it.
Leave the pre-filled syringe outside the refrigerator until it reaches room temperature. This will make the injection more comfortable. DO NOT heat the syringe in any other way (e.g., in a microwave or in hot water). DO NOT expose the syringe to direct sunlight.
DO NOT shake the pre-filled syringe.
DO NOT remove the needle cap from the pre-filled syringe until you are ready to administer the injection.
Check the expiry date on the label of the pre-filled syringe (EXP). DO NOT use it if this date is later than the last day of the month indicated.
Check the appearance of Prolia. It should be a clear, colourless to slightly yellow solution. Do not inject the solution if it contains particles or appears cloudy or discoloured.
Find a clean, well-lit, comfortable surface and keep all necessary supplies within reach.
Wash your hands thoroughly.

Anatomical diagram of the human body showing drug application sites on the

Where to Administer the Injection?
The most suitable injection sites are the upper thigh and the abdomen.
If someone is assisting you with the injection, the outer upper arm may also be used.

How to Administer the Injection?

Clean the skin using an alcohol swab.

Two illustrations showing hands holding a syringe, the first demonstrating how to grip it and the second with an arrow indicating the

To avoid bending the needle, gently remove the needle cap horizontally without twisting, as shown in figures 1 and 2. DO NOT touch the needle or press the plunger.
You may notice a small air bubble in the pre-filled syringe. You do not need to remove the air bubble before administering the injection. Injecting the solution with the air bubble is harmless.
Pinch the skin between your thumb and index finger (without squeezing too hard). Insert the needle fully into the skin as demonstrated by your doctor or healthcare professional.
Push the plunger slowly and steadily, keeping the skin pinched. Push the plunger all the way down until all the solution has been injected.
Remove the needle and release the skin.
If you see a drop of blood, gently wipe it with a cotton ball or gauze. Do not rub the injection site. If needed, you may cover the injection site with a plaster.
Use each pre-filled syringe for one injection only. DO NOT reuse any remaining Prolia in the syringe.

Remember: If you have any problems, do not hesitate to consult your doctor or healthcare professional for help or advice.

Disposal of Used Syringes

DO NOT recap used needles.
Keep used syringes out of the reach and sight of children.
Used syringes must be disposed of in accordance with local regulations. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help protect the environment.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS
OF THE MARKETING AUTHORISATION

Scientific Conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for denosumab, the scientific conclusions of the PRAC are as follows:
In light of the available data from clinical studies and as described in recently published literature regarding the reduction in bone mineral density following discontinuation of denosumab, the PRAC concluded that the product information for medicinal products containing denosumab (indicated for osteoporosis and for bone loss associated with androgen deprivation in prostate cancer) should be amended accordingly.

Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale behind the recommendation.

Reasons for the Variation of the Terms of the Marketing Authorisation
Based on the scientific conclusions regarding denosumab (indicated for osteoporosis and for bone loss associated with androgen deprivation in prostate cancer), the CHMP considers that the benefit-risk balance of the medicinal product containing denosumab (indicated for osteoporosis and for bone loss associated with androgen deprivation in prostate cancer) remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation.

Prolia