Consumer medicine information

Jubbonti

Denosumab

BRAND INFORMATION

Brand name

Jubbonti

Active ingredient

Denosumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Jubbonti.

SUMMARY CMI

JUBBONTI®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using JUBBONTI?

JUBBONTI contains the active ingredient denosumab. JUBBONTI is used to improve bone density and to reduce your risk of fracture. It is used to treat bone loss in women with osteoporosis after the menopause, men with osteoporosis, and men with prostate cancer who have reduced testosterone level caused by surgery or treatment with drugs. It is also used to improve bone density in patients treated with corticosteroids.

For more information, see Section 1. Why am I using JUBBONTI? in the full CMI.

2. What should I know before I receive JUBBONTI?

Do not use if you have ever had an allergic reaction to denosumab, medicines using Chinese Hamster Ovary cells or any of the ingredients listed at the end of the CMI.

Do not use in patients under 18 years of age.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

Tell your doctor if you have calcium deficiency.

For more information, see Section 2. What should I know before I receive JUBBONTI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with JUBBONTI and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given JUBBONTI?

The recommended dose of JUBBONTI is 60 mg given once every 6 months as a single injection under the skin.

More instructions can be found in Section 4. How will I be given JUBBONTI? in the full CMI.

5. What should I know while using JUBBONTI?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using JUBBONTI.
  • Take calcium and vitamin D supplements if your doctor has told you to.
  • Maintain good oral hygiene when being treated with JUBBONTI.
  • Attend all of your treatment and doctor's appointments so that your progress can be checked.
  • Tell your doctor immediately if you become pregnant while taking JUBBONTI.
Things you should not do
  • Do not stop using JUBBONTI without talking to your doctor.
Looking after your medicine
  • Store JUBBONTI in the refrigerator (2°C to 8°C) in the original pack to protect from light. Do not freeze.
  • Do not shake the pre-filled syringe.

For more information, see Section 5. What should I know while using JUBBONTI? in the full CMI.

6. Are there any side effects?

Side effects that require urgent medical attention include: signs of an allergic reaction; muscle aches, twitches or cramps; numbness or tingling in your fingers, toes or around your mouth; persistent pain or swelling and/or non-healing sores in your mouth or jaw; pain in your hip, groin, or thigh, which is sometimes severe; severe allergic reaction with skin rash, blisters or fever.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

JUBBONTI®

Active ingredient(s): denosumab (den”-os”-u”mab)

Consumer Medicine Information (CMI)

This leaflet provides important information about using JUBBONTI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using JUBBONTI.

Where to find information in this leaflet:

1. Why am I using JUBBONTI?
2. What should I know before I receive JUBBONTI?
3. What if I am taking other medicines?
4. How will I be given JUBBONTI?
5. What should I know while using JUBBONTI?
6. Are there any side effects?
7. Product details

1. Why am I using JUBBONTI?

JUBBONTI contains the active ingredient denosumab. Denosumab is a protein (monoclonal antibody) that attaches (binds) specifically to another unique protein in the body in order to stop the development of bone-removing cells before they reach the bones and cause damage. Treatment with JUBBONTI makes your bone stronger and less likely to break.

JUBBONTI is used to:

  • Treat osteoporosis in women after the menopause, to reduce the risk of spinal, non-spinal and hip fractures.
  • Treat bone loss in men with osteoporosis at increased risk of fracture.
  • Treat bone loss that results from a reduction in testosterone level caused by surgery or treatment with drugs in men with prostate cancer.
  • Improve bone density in patients treated with corticosteroids.

Bone is a living tissue and is renewed all the time. In women, the ovaries produce the hormone oestrogen which helps keep bones healthy. After menopause, the oestrogen level drops which affects the bone renewal cycle so that more bone is lost than made, resulting in a lower bone mass. This leaves bones thin and fragile.

Osteoporosis is the term used to describe an increased fracture risk, usually with low bone density. Osteoporosis becomes more common with increasing age. It is more common in women. It can also occur in patients receiving corticosteroids. Many people with osteoporosis have no symptoms but they are still at risk of breaking bones (developing fractures), especially in the spine, hips and wrists.

Other things that can increase the risk of fractures include:

  • age
  • existence of a previous fracture
  • family history of hip fractures
  • low body weight
  • drinking alcohol
  • smoking.

JUBBONTI is prescribed to improve your body density and to reduce your risk of fracture.

Surgery or medicines used in the treatment of men with prostate cancer to stop the production of testosterone can also lead to bone loss. The bones become weaker and break more easily.

Your doctor, however, may have prescribed JUBBONTI for another reason.

2. What should I know before I receive JUBBONTI?

Warnings

Do not use JUBBONTI if:

  • you have low calcium levels in your blood (hypocalcaemia). Your doctor may do a blood test to check your calcium levels before you use JUBBONTI.
  • you are pregnant, think you may be pregnant, or trying to get pregnant. JUBBONTI may harm your unborn baby.
  • you are breast-feeding. It is not known if the active ingredient, denosumab, passes into breast milk.
  • you are allergic to denosumab, any medicines that are produced using Chinese Hamster Ovary cells, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are a child or adolescent. JUBBONTI is not indicated for use in patients under 18 years of age.
  • you are taking another medicine containing denosumab.
  • the expiry date [EXP.] printed on the pack has passed.
    If you use it after the expiry date has passed, it may not work as well.
  • the packaging is torn or shows signs of tampering.
  • the JUBBONTI solution is cloudy or contains visible particles.

Check with your doctor if you:

  • have allergies to any other medicines, or any other substances such as foods, preservatives or dyes.
  • have calcium or vitamin D deficiency. If you are prone to low calcium levels, your doctor will monitor your blood especially in the first few weeks after starting JUBBONTI. Severe low blood calcium levels may lead to hospitalisation, life-threatening events and death.
  • are unable to take daily calcium or vitamin D supplements.
  • have or have had severe kidney problems, kidney failure or have needed dialysis, which may increase your chance of getting low blood calcium if you do not take calcium supplements.
  • had or have pain in the teeth, gums or jaw, swelling or numbness of the jaw, a "heavy jaw feeling" or loosening of a tooth. A dental condition called jaw osteonecrosis has been rarely reported in patients treated with denosumab. Your doctor should examine your mouth and may ask for a dental examination before you start JUBBONTI. You may need to have dental treatment completed before starting your medicine. You may have higher risk of developing jaw problems if you:
    - are undergoing chemotherapy, taking steroids, or are having a dental procedure
    - do not receive routine dental care, have gum disease or have taken JUBBONTI for a long time
  • have been told by a doctor or other healthcare professional that you have an intolerance to some sugars.
  • take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

JUBBONTI has not been tested in pregnant women. Do not use JUBBONTI if you are pregnant, think you may be pregnant, or trying to get pregnant. JUBBONTI may harm your unborn baby.

Do not use JUBBONTI if you are breast-feeding. It is not known if the active ingredient, denosumab, passes into breast milk. It is important to talk to your doctor if you are breast-feeding or plan to do so. Your doctor will then help you decide whether to stop breast-feeding or whether to stop taking JUBBONTI.

Use in Children

Do not use JUBBONTI in children or adolescents under 18 years of age.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor if you are taking another medicine containing denosumab. If you are taking another denosumab-containing medication, you should not take JUBBONTI.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect JUBBONTI.

4. How will I be given JUBBONTI?

How is JUBBONTI given

  • JUBBONTI is given as an injection under the skin. This is called a subcutaneous injection.

How much JUBBONTI will I be given

  • For each dose of JUBBONTI you will be given 60 mg as a single injection.

When you will be given JUBBONTI

  • JUBBONTI is injected once every 6 months.
  • It is important to take your dose of JUBBONTI on schedule. Do not skip or delay getting your injection.
    Each pack of JUBBONTI contains a calendar card with a sticker that can be removed from the carton. Use the peel-off stickers to mark the next injection date on your personal calendar and/or the calendar card be used to keep a record of the next injection date.

  • Continue using JUBBONTI for as long as your doctor tells you to. JUBBONTI can treat osteoporosis and bone loss only for as long as you keep having treatment. Please talk to your doctor before you consider stopping treatment.
  • You should also take calcium and vitamin D supplements while receiving JUBBONTI. JUBBONTI may lower the calcium levels in your blood. Your doctor, nurse or pharmacist will discuss how much calcium and vitamin D you should take to help prevent low calcium levels.

Instructions for Use

These “Instructions for Use” contain information on how to inject JUBBONTI.

If your doctor decides that you or your caregiver may be able to give your injections of JUBBONTI at home, ensure that your doctor or nurse shows you or your caregiver how to prepare and inject with the JUBBONTI pre-filled syringe before you use it for the first time.

Be sure that you read and understand these Instructions for Use before injecting with the JUBBONTI pre-filled syringe. Talk to your doctor if you have any questions.

Important information you need to know before injecting JUBBONTI

  • JUBBONTI is for subcutaneous injection only (inject directly into fatty layer under the skin).
  • Do not use the pre-filled syringe if any of the safety seals on the outer carton or the seal of the plastic tray is broken.
  • Do not shake the pre-filled syringe at any time.
  • Do not use if the pre-filled syringe has been dropped onto a hard surface or dropped after removing the needle cap.
  • The pre-filled syringe has a safety guard that activates to cover the needle after the injection is finished. The safety guard helps to prevent needle stick injuries to anyone who handles the pre-filled syringe after injection.
  • Be careful not to touch the safety guard wings before use. Touching them may cause the safety guard to activate too early.
  • Do not attempt to re-use or disassemble the pre-filled syringe.
  • Do not pull back on the plunger.

Prepare to inject JUBBONTI

Step 1: Bring to room temperature

Take the carton containing the pre-filled syringe out of the refrigerator and leave it unopened for about 15 to 30 minutes so that it reaches room temperature.

Step 2: Gather supplies

Ensure that you have the following (not included in the carton):

  • Alcohol wipe
  • Cotton ball or gauze pad
  • Sharps disposal container
  • Adhesive plaster

Step 3: Unpack

Open the plastic tray by peeling away the cover. Remove the pre-filled syringe by holding it in the middle as shown.

Do not remove the needle cap until you are ready to inject.

Step 4: Perform safety checks

Look through the viewing window of the pre-filled syringe. The liquid inside should be a clear, colourless to slightly yellowish or slightly brownish solution. You may see air bubbles in the liquid, which is normal.

Do not attempt to remove the air.

  • Do not use the pre-filled syringe if liquid is cloudy or contains visible particles.
  • Do not use the pre-filled syringe if it appears to be damaged or if it has leaked.
  • Do not use the pre-filled syringe after the expiry date (EXP), which is printed on the pre-filled syringe label and carton.

In all of these cases, contact your doctor, nurse or pharmacist.

Step 5: Choose injection site

You should inject into the front of the thighs or the lower stomach area but not the area 5 cm around the belly button.

Do not inject into skin that is tender, bruised, red, scaly, hard or into areas with scars or stretch marks.

If your caregiver, doctor or nurse is giving you the injection, they may also inject into the upper arm.

Inject with JUBBONTI

Step 6: Clean injection site

Wash your hands with soap and water.

Clean the chosen injection site with an alcohol wipe. Leave it to dry before injecting.

Do not touch or blow on the cleaned area before injecting.

Step 7: Remove needle cap

Firmly pull straight to remove the needle cap from the pre-filled syringe. You may see a drop of liquid at the end of the needle. This is normal.

Do not put the needle cap back on. Throw away the needle cap.

Step 8: Insert needle

Gently pinch the skin at the injection site and hold the pinch throughout the injection. With the other hand insert the needle into the skin at an angle of approximately 45 degrees as shown.

Do not press the plunger while inserting the needle.

Step 9: Start injection

Continue to pinch the skin. Slowly press the plunger as far as it will go. This will ensure that a full dose is injected.

Step 10: Complete injection

Confirm that the plunger head is between the safety guard wings as shown. This will ensure that the safety guard has been activated and will cover the needle after the injection is finished.

Step 11: Release plunger

Keeping the pre-filled syringe at the injection site, slowly release the plunger until the needle is covered by the safety guard.

Remove the pre-filled syringe from the injection site and release the pinch.

There may be a small amount of blood at the injection site. You can press a cotton ball or gauze pad over the injection site until any bleeding stops.

Do not rub the injection site. If needed, cover the injection site with a small adhesive plaster.

After the injection

Step 12: Dispose of the pre-filled syringe

Put the pre-filled syringe in a sharps disposal container immediately after use. Do not throw away the pre-filled syringe into household waste.

Talk to your doctor or pharmacist about proper disposal of the sharps disposal container. There may be local regulations for disposal.

If you miss a dose of JUBBONTI

If you miss a dose, JUBBONTI should be administered as soon as possible. From then on, JUBBONTI should be scheduled every 6 months from the date of the last injection.

If you are given too much JUBBONTI

If you think that you or anyone else has received too much JUBBONTI, you should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using JUBBONTI?

Things you should do

  • take calcium and vitamin D supplements if your doctor has told you to. Most people do not get enough calcium and vitamin D in their diet and supplements are needed to help strengthen bones.
  • practice good dental hygiene while being treated with JUBBONTI.
    Your routine dental hygiene should include brushing your teeth and tongue after every meal, including the evening and gentle flossing once a day to remove plaque.
    Use a mirror and check your teeth and gums regularly for any changes such as sores or bleeding gums. If you notice any problems, tell your doctor and dentist immediately.
  • tell any doctor, dentist, nurse, or pharmacist you visit that you are using JUBBONTI.
  • if you are about to be started on any other medicine,
  • remind your doctor, nurse or pharmacist that you are being treated with JUBBONTI.
  • attend all your doctor's appointments so that your progress can be checked. Your doctor may recommend you to have some tests, X-rays and/or bone density scans from time to time to make sure the medicine is working.

Call your doctor straight away if you:

  • have spasms, twitches, aches or cramps in your muscles, and/or numbness or tingling in your fingers, toes or around your mouth, or have seizures. You may have low levels of calcium in your blood.
  • experience any problems with your mouth or teeth such as loose teeth or ill-fitting dentures, pain, or swelling while being treated with JUBBONTI.
  • develop a swollen, red area of skin, most commonly in the lower leg, that feels hot and tender (cellulitis) and sometimes experienced with fever and chills.
  • experience new or unusual pain in your hip, groin, or thigh. Some people have developed unusual fractures in their thigh bone while being treated with JUBBONTI. These fractures may occur with little or no trauma and may involve both thigh bones. This side effect is very rare.
  • experience shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin. If you experience any of these side effects you may be having an allergic reaction to JUBBONTI. These side effects are rare.
  • have a severe allergic reaction with skin rash, blisters or fever
  • notice any purple or brownish-red spots, hives or skin sores. This may be an allergic reaction that can damage blood vessels mainly in the skin. This side effect is very rare.
  • become pregnant while using JUBBONTI. Your doctor can discuss with you the risks of having it while you are pregnant.
    Females that are menstruating should ensure they have adequate contraception while taking JUBBONTI.

Things you should not do

  • Do not stop using JUBBONTI without talking to your doctor. After your treatment with JUBBONTI is stopped, or if you skip or delay taking a dose, your risk of breaking bones in your spine is increased, especially if you have a history of broken bones in the spine. If your JUBBONTI treatment is stopped, discuss other available treatment options with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how JUBBONTI affects you.

JUBBONTI has no known effects on the ability to drive or use machines but, as a general precaution, if you are driving soon after an injection, arrange to have someone else drive.

Looking after your medicine

If you need to store your JUBBONTI before use, follow the instructions in the carton on how to take care of your medicine properly.

  • Store JUBBONTI in the refrigerator between 2 and 8°C. Do not freeze.
  • Keep your medicine in the original carton to protect from light. If you remove the medicine from the carton it may not keep well.
  • Your medicine may be left outside the refrigerator to reach room temperature (up to 25°C) before injection. This will make the injection more comfortable.
  • Once your medicine has been left to reach room temperature (up to 25°C), it must be used within 30 days. Throw away the pre-filled syringe that has been stored at room temperature after 30 days.
  • Do not keep JUBBONTI at temperatures above 25°C. Warm temperatures will affect how JUBBONTI works.
  • Do not shake the pre-filled syringe.

Keep it where young children cannot reach it.

When to discard your medicine

JUBBONTI is for single-use in one patient only. Dispose of any unused or expired medicine as instructed below.

Getting rid of any unwanted medicine

Your doctor or nurse is likely to dispose of JUBBONTI for you. However, if you need to get rid of this medicine because you no longer need to use it or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Muscle and skeleton:
  • back, muscle or joint pain, or stiffness, most commonly affecting the hips, knees and spine
  • pain in the arms or legs
  • aching muscle, muscle tenderness or weakness, not caused by exercise
Skin and hair:
  • unusual hair loss or thinning
  • itchy, red or dry skin
Ears:
  • ear pain, discharge from the ear and/or an ear infection. These could be signs of bone damage in the ear
Eyes:
  • blurred or cloudy vision
General:
  • high cholesterol levels in the blood
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of an allergic reaction:
  • shortness of breath
  • wheezing or difficulty breathing.
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.
  • rash that may occur on the skin or sores in the mouth
Signs of low blood calcium (hypocalcaemia):
  • muscle spasms, twitches, aches or cramps
  • numbness or tingling in your fingers, toes or around your mouth
  • seizures
Signs of problems with your mouth, teeth or jaw:
  • persistent pain or swelling and/or non-healing sores in your mouth or jaw
  • loose teeth
Signs of bone fractures:
  • bone, joint and/or muscle pain, including pain in your hip, groin, or thigh, which is sometimes severe
  • pain in spine
Signs of skin infection:
  • develop a swollen, red area of skin that feels hot and tender (cellulitis) and sometimes experienced with fever and chills
  • skin rash or blisters with fever
Gut and digestion:
  • pain in upper abdomen (belly) that may be accompanied by back pain, nausea, vomiting, fever and/or sweating
Brain and nerves:
  • pain in the extremities, such as hands and feet
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What JUBBONTI contains

Active ingredient
(main ingredient)		denosumab
Other ingredients
(inactive ingredients)
  • glacial acetic acid
  • sorbitol
  • polysorbate 20
  • hydrochloric acid
  • sodium hydroxide
  • water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What JUBBONTI looks like

JUBBONTI is a clear, colourless to slightly yellowish or slightly brownish solution supplied in a pre-filled syringe with safety guard.

JUBBONTI comes in a single pack size containing 60 mg of denosumab in a volume of 1.0 mL (60 mg/1.0 mL) (Aust R 418515).

Each pack contains one ready to use single-use pre-filled syringe and one calendar card with a sticker.

The needle cover on the pre-filled syringe is not made with natural rubber latex.

Who distributes JUBBONTI

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

This leaflet was prepared in August 2024.

®Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS August 2025

BRAND INFORMATION

Brand name

Jubbonti

Active ingredient

Denosumab

Schedule

S4

 

1 Name of Medicine

Denosumab.
Jubbonti (denosumab) is a biosimilar medicine to Prolia.
The evidence for comparability supports the use of Jubbonti for the listed indications.

2 Qualitative and Quantitative Composition

Each 1 mL single-use pre-filled syringe contains 60 mg denosumab.
Denosumab is a human monoclonal IgG2 antibody with high affinity and specificity for RANK ligand (RANKL). Denosumab has an approximate molecular weight of 145 kDa and is produced in genetically engineered mammalian (Chinese Hamster Ovary, CHO) cells.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Jubbonti is a sterile, preservative-free, clear, colourless to slightly yellowish or slightly brownish solution for injection at pH approx. 5.2.

4 Clinical Particulars

4.1 Therapeutic Indications

The treatment of osteoporosis in postmenopausal women. Jubbonti significantly reduces the risk of vertebral, non-vertebral and hip fractures.
Treatment to increase bone mass in men with osteopaenia receiving androgen deprivation therapy for non-metastatic prostate cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Treatment to increase bone mass in men with osteoporosis at increased risk of fracture.
Treatment to increase bone mass in women and men at increased risk of fracture due to long-term systemic glucocorticoid therapy.

4.2 Dose and Method of Administration

Dosage (dose and interval).

Administration should be performed by an individual who has been adequately trained in injection techniques.
The recommended dose of Jubbonti is a single subcutaneous (SC) injection of 60 mg, once every 6 months. If Jubbonti treatment is discontinued, consider transitioning to an alternative antiresorptive therapy.
To reduce the risk of hypocalcaemia, patients must be adequately supplemented with calcium and vitamin D (see Section 4.4 Special Warnings and Precautions for Use, Hypocalcaemia). In the major clinical trials of denosumab, daily supplementation with 1,000 mg of calcium and at least 400 IU vitamin D was recommended.

Method of administration.

For subcutaneous use.
Jubbonti is a sterile and preservative-free product. Before administration, the Jubbonti solution should be inspected for particulate matter and discolouration. Do not use if the solution is cloudy or contains visible particles. Do not shake the pre-filled syringe. To avoid discomfort at the site of injection, allow the pre-filled syringe to reach room temperature (up to 25°C) before injecting, and inject slowly. Inject the entire contents of the pre-filled syringe.
Product is for single-use in one patient only. Dispose of any medicinal product remaining in the pre-filled syringe.

Dosage adjustment.

Elderly patients.

No dose adjustment is necessary in elderly patients (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Renal impairment.

No dose adjustment is necessary in patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

4.3 Contraindications

Hypocalcaemia (see Section 4.4 Special Warnings and Precautions for Use).
Hypersensitivity to the active substance, to CHO-derived proteins or to any of the excipients (see Section 6.1 List of Excipients).
Pregnancy and in women trying to get pregnant (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Hypocalcaemia.

Hypocalcaemia must be corrected prior to initiating therapy with Jubbonti. In the post-marketing setting, severe symptomatic hypocalcaemia (resulting in hospitalisation, life-threatening events and fatal cases) has been reported (see Section 4.8 Adverse Effects (Undesirable Effects)), particularly in patients with severe renal impairment, receiving dialysis or treatment with other calcium lowering drugs. While most cases occurred in the first few weeks of initiating therapy, it has also occurred later. Clinical monitoring of calcium levels is recommended before each dose.
In patients predisposed to hypocalcaemia (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment [creatinine clearance < 30 mL/min], receiving dialysis or treatment with other calcium lowering drugs), clinical monitoring of calcium levels is recommended during treatment, especially in the first two weeks of initiating therapy.
Hypocalcaemia following denosumab administration is a significant risk in patients with severe renal impairment [creatinine clearance < 30 mL/min], receiving dialysis or treatment with other calcium lowering drugs. These patients may also develop marked elevations of serum parathyroid hormone (PTH). Concomitant use of calcimimetic drugs may worsen the risk of hypocalcaemia.
Instruct all patients about the symptoms of hypocalcaemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.
Adequate intake of calcium and vitamin D is important in all patients (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Skin infections.

Patients receiving Jubbonti may develop skin infections (predominantly cellulitis) leading to hospitalisation (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.

Osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with denosumab or bisphosphonates, another class of antiresorptive agents. Most cases have been in cancer patients; however some have occurred in patients with osteoporosis.
ONJ has been reported rarely in clinical studies in patients receiving denosumab at a dose of 60 mg every 6 months for osteoporosis. There have been reports of ONJ in clinical studies in patients with advanced cancer treated with denosumab at the studied dose of 120 mg administered monthly.
Known risk factors for ONJ include a diagnosis of cancer with bone lesions, concomitant therapies (e.g. chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck), poor oral hygiene, invasive dental procedures (e.g. tooth extraction), and co-morbid disorders (e.g. pre-existing dental disease, anaemia, coagulopathy, infection). The risk of ONJ may increase with duration of exposure to Jubbonti.
It is important to evaluate patients for risk factors for ONJ before starting treatment. If risk factors are identified, a dental examination with appropriate preventive dentistry is recommended prior to treatment with Jubbonti. Good oral hygiene practices should be maintained during treatment with Jubbonti.
Avoid invasive dental procedures during treatment with Jubbonti. For patients in whom invasive dental procedures cannot be avoided, the clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Patients who are suspected of having or who develop ONJ while on Jubbonti should receive care by a dentist or an oral surgeon. In patients who develop ONJ during treatment with Jubbonti, a temporary interruption of treatment should be considered based on individual risk/benefit assessment until the condition resolves.

Atypical femoral fractures.

Atypical femoral fractures have been reported in patients receiving denosumab. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur and may be bilateral. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. During treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture, and the contralateral femur should also be examined.

Multiple vertebral fractures (MVF) following treatment discontinuation.

Multiple vertebral fractures (MVF) may occur following discontinuation of treatment with Jubbonti, particularly in patients with a history of vertebral fracture.
Patients being treated with Jubbonti, should be advised not to interrupt Jubbonti therapy without prior consultation with their treating physician. The individual benefit/risk should be evaluated before discontinuing treatment. If Jubbonti treatment is discontinued, consider transitioning to an alternative antiresorptive therapy.

Hypercalcaemia in paediatric patients with osteogenesis imperfecta.

Denosumab is not indicated for use in paediatric patients. In clinical trials, hypercalcaemia has been reported very commonly in paediatric patients with osteogenesis imperfecta treated with denosumab. Some cases required hospitalisation and were complicated by acute renal injury (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Drugs with same active ingredient.

Patients being treated with JUBBONTI should not be treated concomitantly with other denosumab-containing medicinal products (used for the treatment of skeletal related events in patients with bone metastasis from solid tumours).

Use in glucocorticoid induced osteoporosis (GIOP).

In GIOP, fractures occur at a higher bone mineral density (BMD) than postmenopausal osteoporosis. There is limited data about the impact of denosumab on fractures in this setting.

Use in special populations.

Use in hepatic impairment.

The safety and efficacy of denosumab has not been studied in patients with hepatic impairment.

Use in renal impairment.

No dose adjustment is necessary in patients with renal impairment.
In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcaemia.
Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis (see Section 4.4 Special Warnings and Precautions for Use, Hypocalcaemia).

Use in the elderly.

Of the total number of patients in clinical studies of denosumab, 9,943 patients were ≥ 65 years, while 3,576 were ≥ 75 years. No overall differences in safety or efficacy were observed between these patients and younger patients.
Of the patients in the osteoporosis study in men, 133 patients (55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old.

Paediatric use.

Denosumab is not indicated for use in paediatric patients. In clinical trials, hypercalcaemia has been reported very commonly in paediatric patients with osteogenesis imperfecta treated with denosumab. Some cases required hospitalisation and were complicated by acute renal injury (see Section 4.4 Special Warnings and Precautions for Use, Hypercalcaemia in paediatric patients with osteogenesis imperfecta).
Adolescent primates dosed with denosumab at 27 and 150 times (10 and 50 mg/kg dose) the clinical exposure based on AUC had abnormal growth plates. In neonatal rats, inhibition of RANKL (target of denosumab therapy) with a construct of osteoprotegerin bound to immunoglobulin Fc segment (OPG-Fc) at high doses was associated with inhibition of bone growth and tooth eruption. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition.

Effects on laboratory tests.

No interactions with laboratory and diagnostic tests have been identified.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Calcimimetics.

Concomitant use of calcimimetic drugs (e.g. cinacalcet) may worsen the risk of hypocalcaemia.
In an interaction study conducted on 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered two weeks after a single dose of denosumab (60 mg subcutaneous injection), which approximates the Tmax of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolised by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokinetics of drugs metabolised by CYP3A4.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data are available on the effect of denosumab on human fertility. Denosumab had no effect on female fertility or male reproductive organs or sperm motility in cynomolgus monkeys at subcutaneous doses up to 12.5 mg/kg/week (females) or 50 mg/kg/month (males), yielding exposures that were approximately 150-fold higher than the human exposure at 60 mg subcutaneous administered once every 6 months.
(Category D)
There are no adequate and well-controlled studies of denosumab in pregnant women. Jubbonti is contraindicated for use during pregnancy and in women trying to get pregnant. Premenopausal women with reproductive potential should be advised of the potential effects of denosumab in pregnancy. Contraception should be discussed. Women should be advised not to become pregnant during and for at least 5 months after treatment with Jubbonti.
Developmental toxicity studies have been performed with denosumab in cynomolgus monkeys and have shown serious adverse events on development (including foetal and infant lethality). Denosumab was shown to cross the placenta in monkeys (see Section 5.3 Preclinical Safety Data, Reproductive toxicity).
 It is unknown whether denosumab is excreted in human milk. Only limited excretion of denosumab in milk was observed in a study in monkeys. A decision on whether to abstain from breast-feeding or to abstain from therapy with Jubbonti should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of therapy to the woman.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive or use machinery have been performed.

4.8 Adverse Effects (Undesirable Effects)

Treatment of postmenopausal osteoporosis.

Denosumab has been studied in over 10,500 women with postmenopausal osteoporosis in clinical trials representing up to 10 years of continued denosumab treatment.
The safety of denosumab in the treatment of postmenopausal osteoporosis was assessed in FREEDOM, a large, 3-year, randomised, double-blind, placebo-controlled, multinational phase III study of 7,808 postmenopausal women aged 60 to 91 years with osteoporosis. A total of 3,886 women were exposed to denosumab and 3,876 women were exposed to placebo administered once every 6 months as a single 60 mg subcutaneous dose.
The safety of denosumab was also assessed in a second phase 3 study of similar design. A total of 322 postmenopausal women aged 43 to 83 years with low bone mass were enrolled in this 2-year study. A total of 164 women were exposed to denosumab and 165 women were exposed to placebo administered once every 6 months as a single 60 mg subcutaneous dose.
In both studies, all women received at least 1,000 mg of calcium and 400 IU of vitamin D supplementation per day.
Across the two phase III studies the incidence of all-cause mortality was 1.7% (n = 70) in the denosumab group and 2.2% (n = 90) in the placebo group. The incidence of serious adverse events was 25.3% in the denosumab group and 24.3% in the placebo group. The percentage of patients who withdrew from the studies due to adverse events was 2.3% and 2.1% for the denosumab and placebo groups, respectively.
The most common adverse events reported in studies of women with postmenopausal osteoporosis or low bone mass (n = 8,091), occurring in ≥ 10% of patients either in the denosumab-treated or placebo group, were back pain (34.1% denosumab, 34.0% placebo), arthralgia (20.4% in each group), hypertension (15.3% denosumab, 16.1% placebo), nasopharyngitis (14.8% denosumab, 15.6% placebo), pain in extremity (11.8% denosumab, 11.2% placebo) and osteoarthritis (10.9% denosumab, 11.1% placebo).
Adverse events reported in at least 2% of postmenopausal women with osteoporosis or low bone mass (n = 8,091) and at least 1% more frequently in the denosumab-treated women than in the placebo-treated women were: hypercholesterolaemia (7.0% denosumab, 5.9% placebo) and eczema (includes dermatitis, allergic dermatitis, atopic dermatitis and contact dermatitis) (3.1% denosumab, 1.7% placebo).
In STAND, a double-blind, randomised, alendronate-controlled, study in postmenopausal women with low bone mass who had received alendronate for at least 6 months preceding study entry, patients received either denosumab 60 mg Q6M SC (n = 253) or alendronate orally 70 mg weekly for 12 months (n = 249). The safety profile was similar for patients transitioning from alendronate to denosumab and those continuing on alendronate therapy, including the overall incidence of adverse events and serious adverse events. Eight patients (3.2%) in the denosumab group and 4 patients (1.6%) in the alendronate group reported adverse events of fracture.

Hypocalcaemia.

In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis, approximately 0.05% (2 of 4,050) of patients had declines of serum calcium levels (less than 1.88 mmol/L) following denosumab administration.
Skin infections. In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis, skin infections leading to hospitalisation were reported more frequently in the denosumab (0.4%, 16 of 4,050) versus the placebo (0.1%, 3 of 4,041) groups, respectively. These cases were predominantly cellulitis. The overall incidence of skin infections was similar between the denosumab (1.5%, 59 of 4,050) and placebo groups (1.2%, 50 of 4,041).

Pancreatitis.

Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the denosumab groups. Several patients had a prior history of pancreatitis or a confounding event (e.g. gallstones). The time from product administration to event occurrence was variable.

Osteonecrosis of the jaw (ONJ).

In the osteoporosis clinical trial program, ONJ was reported rarely in patients treated with denosumab.

Atypical femoral fractures.

In the osteoporosis clinical trial program, atypical femoral fractures were reported rarely in patients treated with denosumab.

Multiple vertebral fractures (MVF) following discontinuation of denosumab treatment.

In the osteoporosis clinical trial program, MVF were reported in patients following discontinuation of treatment with denosumab, particularly in those with a history of vertebral fracture.

Long-term safety in postmenopausal osteoporosis.

A total of 4,550 women who completed FREEDOM (Study 20030216, N = 7,808) enrolled into FREEDOM extension (Study 20060289), a 7-year, multinational, multicentre, open-label, single-arm extension study to evaluate the long-term safety and efficacy of denosumab. All patients in the extension study received denosumab every 6 months as a single SC 60 mg dose, as well as daily calcium (1,000 mg) and vitamin D (at least 400 IU).
During the FREEDOM extension study, the rates of adverse events observed through month 84 have not shown an increase over time and were similar to those observed in the initial 3 years of FREEDOM. Thirteen adjudicated cases of osteonecrosis of the jaw (ONJ) and two atypical fractures of the femur have occurred during the extension study.

Treatment of osteoporosis in men.

The safety of denosumab in the treatment of men with osteoporosis was assessed in ADAMO, a randomised, double-blind, placebo-controlled study; a 1-year double-blind phase followed by a 1-year open-label extension. During the double-blind phase, a total of 120 men were exposed to denosumab and 120 men were exposed to placebo administered subcutaneously once every 6 months as a single 60 mg dose. All men were instructed to take at least 1,000 mg of calcium and 800 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was 0.8% (n = 1) in the denosumab group and 0.8% (n = 1) in the placebo group. The incidence of serious adverse events was 9.2% in the denosumab group and 8.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 2.5% and 0% for the denosumab and placebo groups, respectively.
Adverse events in men with osteoporosis (n = 240) occurring in at least 5% of denosumab-treated men and more frequently than in the placebo-treated patients were: back pain (8.3% denosumab, 6.7% placebo), arthralgia (6.7% denosumab, 5.8% placebo), and nasopharyngitis (6.7% denosumab, 5.8% placebo).

Treatment of bone loss associated with androgen deprivation.

The safety of denosumab in the treatment of bone loss associated with androgen deprivation in men with non-metastatic prostate cancer was assessed in a 3-year, randomised, double-blind, placebo-controlled, multinational study of 1,468 men aged 48 to 97 years. A total of 731 men were exposed to denosumab and 725 men were exposed to placebo administered once every 6 months as a single 60 mg subcutaneous dose. The incidence of all-cause mortality was 6.0% (n = 44) in the denosumab group and 6.3% (n = 46) in the placebo group. The incidence of serious adverse events was 34.6% in the denosumab group and 30.6% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 7.0% and 6.1% for the denosumab and placebo groups, respectively.
Adverse events reported in men with bone loss associated with androgen deprivation (n = 1,456) occurring in at least 2% of denosumab-treated men and at least 1% more frequently in denosumab-treated men than placebo-treated men were: arthralgia (12.6% denosumab, 11.0% placebo), pain in extremity (9.0% denosumab, 7.0% placebo), musculoskeletal pain (5.6% denosumab, 3.6% placebo), dizziness (5.6% denosumab, 4.3% placebo), metastases to bone (4.7% denosumab, 3.4% placebo), osteoarthritis (4.2% denosumab, 3.2% placebo), cataract (4.7% denosumab, 1.2% placebo), bronchitis (4.1% denosumab, 2.9% placebo), urinary retention (3.1% denosumab, 1.5% placebo), angina pectoris (2.3% denosumab, 1.1% placebo) and procedural pain (2.1% denosumab, 0.4% placebo).

Treatment of bone loss associated with systemic glucocorticoid therapy.

The safety of denosumab in the treatment of bone loss associated with systemic glucocorticoid therapy in men and women was assessed over the first 12 months of a 24 month, randomised, double-blind, double-dummy, active-controlled study. Subjects received either denosumab 60 mg Q6M SC (n = 394) or risedronate orally 5 mg daily (n = 384). All subjects were instructed to take at least 1,000 mg of calcium and 800 IU of vitamin D supplementation per day.
The incidence of all-cause mortality during the first 12 months of the study was 1.5% (n = 6) in the denosumab group and 0.5% (n = 2) in the risedronate group. Three additional deaths were reported for subjects in the risedronate group but were not included because it was not possible to confirm exposure to risedronate during the study. The incidence of serious adverse events was 16.0% in the denosumab group and 16.9% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 3.8% and 3.6% for the denosumab and risedronate groups, respectively. The percentage of patients who discontinued investigational product due to adverse events was 6.3% and 7.6% for denosumab and risedronate, respectively.
Adverse events occurring in subjects during the first 12 months of the study in at least 3% of denosumab-treated subjects and more frequently in the denosumab-treated group were: back pain (4.6% denosumab, 4.4% risedronate), hypertension (3.8% denosumab, 3.4% risedronate), bronchitis (3.8% denosumab, 2.9% risedronate), headache (3.6% denosumab, 1.8% risedronate), dyspepsia (3.0% denosumab, 2.6% risedronate), urinary tract infection (3.0% denosumab, 2.1% risedronate), upper abdominal pain (3.0% denosumab, 1.8% risedronate) and bone pain (1.0% denosumab, 0% risedronate). Subject incidence of fractures are shown in Table 1.

Post-marketing experience.

Rare events of drug-related hypersensitivity reactions: rash, urticaria, facial swelling, erythema and anaphylactic reactions.
Rare events of severe symptomatic hypocalcaemia (resulting in hospitalisation, life-threatening events, and fatal cases) have been reported predominantly in patients at increased risk of hypocalcaemia, particularly in patients with severe renal impairment, receiving dialysis or treatment with other calcium lowering drugs receiving denosumab. Most cases occurred in the first few weeks of initiating therapy. Examples of the clinical manifestations of severe symptomatic hypocalcaemia have included QT prolongation, tetany, seizures and altered mental status (see Section 4.4 Special Warnings and Precautions for Use, Hypocalcaemia). Symptoms of hypocalcaemia in denosumab clinical studies included paraesthesia, muscle stiffness, twitching, spasms and muscle cramps.
Musculoskeletal pain, including severe cases, has been reported in patients receiving denosumab. There have been reports of osteonecrosis of the external auditory canal in patients using denosumab.
Very rare events of hypersensitivity vasculitis.
Uncommon events of lichenoid drug eruptions (e.g. lichen planus-like reactions) have been observed.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome has been observed.
Common events of alopecia have been reported.
The development or progression of lens opacification events (cataracts) were comparable between patients treated with denosumab and those receiving placebo for up to 12 months in a clinical study in men with non-metastatic prostate cancer with bone loss due to androgen deprivation therapy.

Comparability of Jubbonti with reference medicine (Prolia).

The types, frequency and severity of adverse events were comparable between Jubbonti and the reference medicine.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience with overdosage with denosumab. Denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks (cumulative doses up to 1080 mg over 6 months), and no additional adverse effects were observed.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Osteoclasts play an important role in bone loss associated with postmenopausal osteoporosis and hormone ablation. Denosumab binds with high affinity and specificity to RANKL, preventing RANKL from activating its only receptor, RANK, on the surface of osteoclasts and their precursors, independent of bone surface. Prevention of RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Pharmacodynamics.

In clinical studies, treatment with 60 mg of denosumab resulted in rapid reduction in the bone resorption marker serum type 1 C-telopeptides (CTX) within 6 hours of SC administration by approximately 70%, with reductions of approximately 85% occurring by 3 days. CTX reductions were maintained over the 6-month dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximal reduction of ≥ 87% to ≥ 45% (range 45% to 80%), reflecting the reversibility of the effects of denosumab on bone remodelling once serum denosumab levels diminish. These effects were sustained with continued treatment. Consistent with the physiological coupling of bone formation and resorption in skeletal remodelling, subsequent reductions in bone formation markers (e.g. bone specific alkaline phosphatase [BSAP] and serum N-terminal propeptide of type 1 collagen [P1NP]) were observed beginning 1 month after the first dose of denosumab.
Bone turnover markers (bone resorption and formation markers) generally reached pretreatment levels within 9 months after the last 60 mg subcutaneous dose. Upon re-initiation, the degree of inhibition of CTX by denosumab was similar to those observed in patients initiating denosumab.
In a clinical study of postmenopausal women with low bone mass (n = 504) who were previously treated with alendronate for a median of 3 years, those transitioning to receive denosumab experienced additional reductions in serum CTX, compared with women who remained on alendronate. In this study, the changes in serum calcium were similar between the two groups.

Comparative non-clinical pharmacology and toxicology.

Pharmacodynamic comparability between Jubbonti and the reference medicine (Prolia) was demonstrated in in vitro studies.

Comparability of Jubbonti with reference medicine (Prolia).

The pharmacodynamic equivalence of Jubbonti and the reference medicine, in terms of inhibition of the serum bone turnover marker CTX (as percent change from baseline), was demonstrated via the area under the effect curve up to 39 weeks following administration in healthy male volunteers and up to 26 weeks in postmenopausal women with osteoporosis.

Clinical trials.

Treatment of osteoporosis in postmenopausal women. Independent risk factors, for example, low (BMD), age, the existence of previous fracture, family history of hip fractures, high bone turnover and low body mass index (BMI) should be considered in order to identify women at increased risk of osteoporotic fractures who could benefit from treatment.

Fracture reduction evaluation of denosumab in osteoporosis every 6 months (FREEDOM).

The efficacy and safety of denosumab in the treatment of postmenopausal osteoporosis was demonstrated in FREEDOM (Study 20030216), a 3 year, randomised, double-blind, placebo-controlled, multinational study of women with baseline BMD T-scores at the lumbar spine or total hip between -2.5 and -4.0. 7,808 women aged 60 to 91 years were enrolled of whom 23.6% had prevalent vertebral fractures. Women with other diseases or on therapies that may affect bone (e.g. rheumatoid arthritis, osteogenesis imperfecta and Paget's disease) were excluded from this study.
BMD and other individual risk factors were collected for women enrolled in the FREEDOM study. The mean absolute 10-year fracture probability for women enrolled was 18.60% (deciles: 7.9-32.4%) for major osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture, as derived from FRAX, the WHO Fracture Risk Assessment Tool algorithm.
Women were randomised to receive subcutaneous injections of either denosumab 60 mg (n = 3,902) or placebo (n = 3,906) once every 6 months. Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily. The primary efficacy variable was the incidence of new vertebral fractures. Secondary efficacy variables included the incidence of non-vertebral fractures and hip fractures, assessed at 3 years.

Effect on vertebral fractures.

Denosumab significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (see Table 2).
The reductions in the risk of new vertebral fractures by denosumab over 3 years were consistent and significant regardless of whether or not women had a prevalent vertebral fracture or history of a non-vertebral fracture, and regardless of baseline age, BMD, bone turnover level and prior use of a medicinal product for osteoporosis.
Denosumab also reduced the risk of new vertebral fracture by 65% (6.5% absolute risk reduction, p < 0.0001) in patients at high risk of fractures (defined as women who met ≥ 2 of the 3 following criteria at baseline: age ≥ 70 years, BMD T-score ≤ -3.0 [at lumbar spine, total hip, or femoral neck] or prevalent vertebral fracture).
Denosumab also reduced the risk of new and worsening vertebral fractures (67% relative risk, reduction, 4.8% absolute risk reduction) as well as multiple vertebral fractures (61% relative risk reduction, 1.0% absolute risk reduction) at 3 years, when compared to placebo (all p < 0.0001).

Effect on hip fractures.

Denosumab demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the risk of hip fracture over 3 years (p < 0.05) (see Figure 1). The incidence of hip fracture was 0.7% in the denosumab group compared to 1.2% in the placebo group at 3 years.
In women with high fracture risk as defined above by baseline age, BMD and prevalent vertebral fracture, a 48% relative risk reduction was observed with denosumab (1.1% absolute risk reduction, p < 0.05).

Effect on all clinical fractures.

Denosumab demonstrated superiority to placebo in reducing the risk of any clinical fractures, clinical (symptomatic) vertebral fractures, non-vertebral fractures (including hip), major non-vertebral fractures and major osteoporotic fractures (see Table 3).
Women in the FREEDOM study had a mean baseline BMD T-score of -2.2 at the femoral neck. In women with baseline femoral neck BMD ≤ -2.5, denosumab reduced the incidence of non-vertebral fracture (35% relative risk reduction, 4.1% absolute risk reduction, p < 0.001).
The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by denosumab over 3 years were consistent regardless of the 10-year baseline fracture risk as assessed by FRAX.

Effect on bone mineral density.

Denosumab significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 1, 2 and 3 years in FREEDOM. Denosumab increased BMD by 9.2% at the lumbar spine, 6.0% at the total hip, 4.8% at the femoral neck, 7.9% at the hip trochanter, 3.5% at the distal 1/3 radius and 4.1% at the total body over 3 years (all p < 0.0001). Increases in BMD at lumbar spine, total hip and hip trochanter were observed as early as 1 month after the initial dose. Denosumab increased lumbar spine BMD from baseline in 95% of postmenopausal women at 3 years. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, weight/BMI, BMD and bone turnover level. The effects of denosumab on bone architecture were evaluated using quantitative computed tomography (QCT) in postmenopausal women with BMD T-score below -2.5 at the lumbar spine or total hip. Treatment with denosumab increased volumetric trabecular BMD at the lumbar spine, volumetric BMD at the total hip and the volumetric cortical BMD and cortical thickness at the distal radius.
Study of Transitioning from Alendronate to Denosumab (STAND, Study 20050234) was a double-blind, randomised, alendronate-controlled, study in postmenopausal women with low BMD (T-score between -2.0 and -4.0 at the lumbar spine or total hip) who had received alendronate (70 mg weekly [or equivalent] orally) for at least 6 months preceding study entry. Patients received either denosumab 60 mg Q6M SC (n = 253) or alendronate orally 70 mg weekly for 12 months (n = 251).
Women who transitioned to receive denosumab had greater increases in BMD at the total hip (1.9% versus 1.1%, p < 0.001; primary efficacy endpoint) after 1 year, compared to those who continued to receive alendronate therapy. Consistently greater increases in BMD were also seen at the lumbar spine, femoral neck, hip trochanter, and distal 1/3 radius in women treated with denosumab, compared to those who continued to receive alendronate therapy (all p < 0.05).
In clinical studies examining the effects of discontinuation of denosumab, BMD returned to approximately pre-treatment levels and remained above placebo within 18 months of the last dose. These data indicate that continued treatment with denosumab is required to maintain the effect of the drug. Re-initiation of denosumab resulted in gains in BMD similar to those when denosumab was first administered.

Open-label extension study in the treatment of postmenopausal osteoporosis (FREEDOM extension study).

A total of 4,550 women, (2,343 denosumab and 2,207 placebo) who missed no more than one dose of denosumab in the FREEDOM pivotal study (study 20030216, N = 7,808) and completed the month 36 study visit, enrolled in FREEDOM extension (study 20060289), a 7 year, multinational, multicentre, open-label, single-arm extension study to evaluate the long-term safety and efficacy of denosumab. All women in the FREEDOM extension study were to receive denosumab every 6 months in an open-label manner as a single 60 mg SC dose, as well as daily calcium (at least 1,000 mg) and vitamin D (at least 400 IU). Safety was the primary endpoint; BMD and fracture incidence were two of the many secondary endpoints. At month 84 of the extension study, after 10 years of denosumab treatment, the long-term group increased BMD by 21.7% (95% CI: 21.2, 22.2) at the lumbar spine, 9.2% (8.9, 9.5) at the total hip, 9.0% (8.6, 9.4) at the femoral neck and 13.0% (12.6, 13.4) at the trochanter from the pivotal FREEDOM study baseline. In years 4 through 10 of denosumab treatment, the rates of new vertebral and non-vertebral fractures did not increase over time; annualised rates were approximately 1.0% and 1.3%, respectively.
Comparability of Jubbonti with Prolia.

Results of study CGP24112301 in postmenopausal women with osteoporosis.

Study CGP24112301 demonstrated similar clinical efficacy of Jubbonti and Prolia in women with postmenopausal osteoporosis (PMO) in terms of the percentage change from baseline (% CfB) of lumbar spine bone mineral density (LS-BMD) at Week 52. Improvement in LS-BMD was similar in both treatment groups. The results are shown in Table 4.

Bone histology.

Fifty-three trans-iliac crest bone biopsy specimens were obtained at either 2 years and/or 3 years from 47 postmenopausal women with osteoporosis treated with denosumab in the FREEDOM study. Fifteen bone biopsy specimens were also obtained after 1 year of treatment with denosumab from 15 postmenopausal women with low bone mass who had transitioned from previous alendronate therapy. Histology assessments in both studies showed bone of normal architecture and quality, as well as the expected decrease in bone turnover relative to placebo treatment. There was no evidence of mineralisation defects, woven bone or marrow fibrosis.
Fifty-nine women participated in the bone biopsy sub-study at month 24 (N = 41) and/or month 84 (N = 22) of the FREEDOM extension study, representing up to 5 and 10 years of treatment with denosumab, respectively. Bone biopsy results showed bone of normal architecture and quality with no evidence of mineralisation defects, woven bone or marrow fibrosis as well as the expected decrease in bone turnover.
Histomorphometry findings in the FREEDOM extension study in postmenopausal women with osteoporosis showed that the antiresorptive effects of denosumab, as measured by activation frequency and bone formation rates, were maintained over time.
Treatment of osteoporosis in men.

A multicentre randomised double-blind placebo-controlled study to compare the efficacy and safety of denosumab versus placebo in males with osteoporosis (ADAMO).

The efficacy and safety of denosumab in the treatment of men with osteoporosis was demonstrated in ADAMO (Study 20080098), a 1 year, multinational study of men with low bone mass, who had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck and with history of prior fragility fracture were also enrolled. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease), or with significantly impaired renal function (GFR of ≤ 30 mL/min), or on therapies that may affect bone were excluded from this study (see Table 5).
The 242 men enrolled in the ADAMO study ranged in age from 31 to 84 years and were randomised to receive subcutaneous injections of either denosumab 60 mg (n = 121) or placebo (n = 121) once every 6 months. Men received calcium (at least 1,000 mg) and vitamin D (at least 800 IU) supplementation daily.
The primary efficacy variable was percent change in lumbar spine BMD at 1 year. Secondary efficacy variables included percent change in total hip, hip trochanter, femoral neck, and distal 1/3 radius BMD at 1 year, and change in CTX at day 15.
Denosumab significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 1 year in men with osteoporosis. Denosumab increased BMD by 4.8% at the lumbar spine, 2.0% at the total hip, 2.3% at the hip trochanter, 2.2% at the femoral neck and 0.9% at the distal 1/3 radius, relative to placebo. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, weight/body mass index (BMI), BMD, and level of bone turnover.
A total of 29 trans-iliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in denosumab group, 12 specimens in placebo group). Qualitative histology assessments showed normal architecture and quality with no evidence of mineralisation defects, woven bone, or marrow fibrosis.
Treatment of bone loss associated with androgen deprivation. The efficacy and safety of denosumab in the treatment of bone loss associated with androgen deprivation was assessed in a 3-year randomised, double-blind, placebo-controlled, multinational study of 1,468 men with non-metastatic prostate cancer aged 48 to 97 years. All men regardless of age had histologically confirmed prostate cancer. Men less than 70 years of age also had either a BMD T-score at the lumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture. Men over the age of 70 years did not have to meet the latter requirements. Men were randomised to receive subcutaneous injections of either denosumab 60 mg (n = 734) or placebo (n = 734) once every 6 months. All men received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD.
Independent risk factors for osteoporosis other than BMD and advanced age (> 70 years of age) in males undergoing androgen deprivation, such as family history of hip fracture, alcohol or tobacco use, have not been validated to the same extent as females with postmenopausal osteoporosis. See Tables 6, 7 and 8.
Denosumab significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 3 years: 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the hip trochanter, 6.9% at the distal 1/3 radius and 4.7% at the total body (all p < 0.0001). Significant increases in BMD were observed at the lumbar spine, total hip, femoral neck and the hip trochanter as early as 1 month after the initial dose. Consistent effects on BMD were observed at the lumbar spine across subgroups of men regardless of baseline age, race, geographical region, weight/BMI, lumbar spine BMD T-score, bone turnover level; duration of androgen deprivation and presence of vertebral fracture at baseline.
Denosumab demonstrated a significant relative risk reduction of new vertebral fractures as early as 1 year: 85% (1.6% absolute risk reduction) at 1 year, 69% (2.2% absolute risk reduction) at 2 years and 62% (2.4% absolute risk reduction) at 3 years (all p < 0.01).
Treatment of bone loss associated with systemic glucocorticoid therapy. The efficacy and safety of denosumab in the treatment of bone loss associated with systemic glucocorticoid therapy were demonstrated by the 12-month primary analysis of a 24 month randomised, multicentre, double-blind, double-dummy, parallel-group, active-controlled study of 795 patients (70% women and 30% men) aged 20 to 94 years (mean age of 63.1 years) treated with ≥ 7.5 mg daily oral prednisone (or equivalent). The primary efficacy objective of the study was to demonstrate non-inferiority of denosumab to oral risedronate with respect to percentage change from baseline in lumbar spine BMD at 12 months. The secondary objectives were to compare percentage change from baseline in lumbar spine and total hip BMD between denosumab and risedronate at 12 and 24 months.
Two subpopulations were studied: glucocorticoid-continuing (≥ 7.5 mg daily prednisone or its equivalent for ≥ 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months; n = 505) and glucocorticoid-initiating (≥ 7.5 mg daily prednisone or its equivalent for < 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months; n = 290). Within each subpopulation, randomisation was stratified by gender and patients were randomised (1:1) to receive either denosumab 60 mg subcutaneously once every 6 months (n = 398) or oral risedronate 5 mg once daily (active control) (n = 397). All patients were to receive at least 1,000 mg calcium and 800 IU vitamin D supplementation daily.
Enrolled patients < 50 years of age were required to have a history of osteoporotic fracture. Enrolled patients ≥ 50 years of age who were in the glucocorticoid-continuing subpopulation were required to have a baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture. See Table 9.

Effect on bone mineral density (BMD).

The difference in mean percentage change from baseline in lumbar spine BMD at 12 months between treatment groups (denosumab - risedronate) was 2.2% (95% CI: 1.4, 3.0) in the glucocorticoid-continuing subpopulation and 2.9% (95% CI: 2.0, 3.9) in the glucocorticoid-initiating subpopulation, confirming non-inferiority.
The percentage change from baseline in lumbar spine and total hip BMD at 12 months was significantly greater with denosumab treatment than with risedronate treatment in both subpopulations (p < 0.001 in all comparisons) (see Table 10).
Consistent effects on lumbar spine BMD were observed regardless of gender; race; geographic region; menopausal status; age; and baseline lumbar spine BMD T-score, and glucocorticoid dose within each subpopulation.
In addition, exploratory endpoints measured the percentage change from baseline in femoral neck, hip trochanter and distal 1/3 radius BMD at 12 months (see Table 10). The study was not powered for reduction in risk of fracture. The correlation between increased bone mineral density and reduction of bone fracture incidence in patients with glucocorticoid-induced osteoporosis has not been directly established.

Bone histology.

Bone biopsy specimens evaluable for histology were obtained from 17 patients (6 in the denosumab treatment group and 11 in the risedronate treatment group) at month 12. Qualitative histology assessments showed normal architecture and quality with no evidence of mineralisation defects, woven bone, or marrow fibrosis in patients treated with denosumab.

5.2 Pharmacokinetic Properties

Absorption.

Following a 60 mg subcutaneous dose of denosumab, bioavailability was 61% and maximum serum denosumab concentrations (Cmax) of 6 microgram/mL (range 1 - 17 microgram/mL) occurred in 10 days (range 2 - 28 days).

Metabolism.

Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Based on nonclinical data, its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Excretion.

After Cmax, serum levels declined with a half-life of 26 days (range 6 - 52 days) over a period of 3 months (range 1.5 - 4.5 months). Fifty-three percent of patients had no measurable amounts of denosumab detected at 6 months post-dose.
No accumulation or change in denosumab pharmacokinetics over time was observed upon subcutaneous multiple-dosing of 60 mg once every 6 months. Denosumab pharmacokinetics was not affected by the formation of binding antibodies to denosumab and was similar in men and women.
Pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable difference in pharmacokinetics with age (28 to 87 years), race or body weight (36 to 140 kg), or disease state (low bone mass or osteoporosis; prostate cancer).

Special populations.

Elderly.

The pharmacokinetics of denosumab was not affected by age (28 to 87 years).

Paediatric.

The pharmacokinetic profile has not been assessed in those ≤ 18 years.

Impaired hepatic function.

The pharmacokinetic profile has not been assessed in patients with impaired hepatic function.

Impaired renal function.

In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab (see Section 4.4 Special Warnings and Precautions for Use, Hypocalcaemia, Use in renal impairment).

Comparability of Jubbonti with the reference medicine (Prolia).

Information in this section is based on studies which also include a higher concentration denosumab product (Wyost). Results of both studies confirmed biosimilarity between Jubbonti and the reference medicine.
A comparable pharmacokinetic (PK) profile of Jubbonti and the reference medicine (Prolia) was demonstrated in a randomised, double-blind trial in postmenopausal women with osteoporosis (Study CGP24112301). In this study, similarity with respect to the PK parameters AUCinf and Cmax after the first dose was shown between Jubbonti and the reference medicine.
A comparable PK profile of Wyost and the reference medicine (Xgeva) was also demonstrated in a randomised, double-blind, single-dose, three-arm parallel study in healthy male volunteers (Study CGP24112101). In this study, similarity with respect to the PK parameters AUCinf, AUClast, and Cmax was shown between Wyost and the reference medicine. A subtherapeutic dose of 35 mg was used to demonstrate comparable PK profiles in healthy volunteers. A 35 mg covers both elimination pathways, target mediated drug disposition (TMDD) i.e. non-linear and saturable target binding to RANKL and linear IgG clearance (binding to FcRn) and ensured a higher sensitivity to detect potential PK and PD differences between Wyost and the reference medicine (Xgeva) than the approved Xgeva dose of 120 mg.
Statistical summaries of the primary PK parameters of study CGP24112101 and study CGP24112301 are provided (see Tables 11 and 12).

Immunogenicity.

In clinical studies, no neutralising antibodies for denosumab have been observed. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non-neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Immunogenicity of Jubbonti.

In clinical studies comparing Jubbonti and Prolia, immunogenicity was assessed for 527 patients treated for 52 weeks and was observed to be similar in both treatment groups. Neutralising antibodies (NAb) were rare (~ 1%) and the vast majority of the non neutralising binding antibodies (ADA) was transient and only < 1% had a measurable titer. There was no evidence that immunogenicity was associated with altered pharmacokinetics, pharmacodynamics or clinical response.
The results were obtained using highly sensitive assays demonstrating comparable immunogenicity profiles between Jubbonti and Prolia.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of denosumab has not been evaluated. Denosumab is a recombinant protein comprised entirely of naturally occurring amino acids and contains no inorganic or synthetic organic linkers or other non-protein portions. Therefore, it is unlikely that denosumab or any of its derived fragments would react with DNA or other chromosomal material.

Carcinogenicity.

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies. In view of the mechanism of action of denosumab, it is unlikely that the molecule would be capable of inducing tumour development or proliferation.

Reproductive toxicity.

In a study of cynomolgus monkeys with denosumab at subcutaneous doses up to 12.5 mg/kg/week given during the period equivalent to the first trimester, and yielding AUC exposures up to 99-fold higher than the human dose (60 mg every 6 months), there was no evidence of maternal or foetal harm. In this study, foetal lymph nodes were not examined.
In another study of cynomolgus monkeys dosed with denosumab throughout pregnancy at 50 mg/kg/month, yielding AUC exposures 119-fold higher than the human exposure, there were increased stillbirths and postnatal mortality; abnormal bone growth resulting in reduced bone strength, almost complete obliteration of bone marrow spaces (leading to reduced haematopoiesis), and tooth malalignment, dental dysplasia and a shortened/straighter dental arch (although no effect on the pattern or date of tooth eruption); altered appearance of eyes (increased apparent size, exophthalmos); absence of peripheral lymph nodes; and decreased neonatal growth. Following a 6 month period after birth, bone-related changes showed incomplete recovery. The effects on lymph nodes, tooth malalignment and dental dysplasia persisted, and minimal to moderate mineralisation in multiple tissues was seen in one animal. There was no evidence of maternal harm prior to labour; adverse maternal effects occurred infrequently during labour. Maternal mammary gland development was normal. A no observed adverse effect level has not been established in animal studies and the findings are attributable to the primary pharmacological activity of denosumab.
Preclinical studies in RANK/RANKL knockout mice suggest absence of RANKL could interfere with the development of lymph nodes in the foetus. Knockout mice lacking RANK or RANKL also exhibited decreased body weight, reduced bone growth and a lack of tooth eruption. Similar phenotypic changes (inhibition of bone growth and tooth eruption) were observed in a study in neonatal rats using a surrogate for denosumab, the RANKL inhibitor osteoprotegerin bound to Fc (OPG-Fc). Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition. A study on the reversibility of the effects of OPG-Fc showed persistence or only partial recovery (assessed after 10 weeks).
Preclinical studies in RANK/RANKL knockout mice suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each 1 mL single-use pre-filled syringe of Jubbonti contains: 47 mg sorbitol, 1.021 mg glacial acetic acid, 0.1 mg polysorbate 20, hydrochloric acid, sodium hydroxide, and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

It is recommended to store pre-filled syringes in a refrigerator at 2°C to 8°C in the original carton. Do not freeze. Protect from direct light. Do not shake the pre-filled syringe. Do not expose to temperatures above 25°C.
If removed from the refrigerator, Jubbonti should be kept at room temperature (up to 25°C) in the original container and must be used within 30 days.

6.5 Nature and Contents of Container

Pre-filled syringe is made from type I glass with stainless steel 29-gauge needle with safety guard.
Pack size of one pre-filled syringe, presented in blistered packaging.
The pre-filled syringe with automatic needle guard is not made with natural rubber latex.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

615258-40-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes