Consumer medicine information

Xgeva

Denosumab

BRAND INFORMATION

Brand name

Xgeva

Active ingredient

Denosumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xgeva.

What is in this CMI

What is in this CMI

What Xgeva is used for

Before you are given it
When you must not be given it
Before you are given it
Taking other medicines

How it is given
Instructions for injecting Xgeva
How much is given
When to use it
How long to use it
If you miss a dose
If you are given too much (overdose)

While you are using it
Things you must do
Things you must not do
Things to be careful of

Side effects

Storing Xgeva

After using it
Disposal

Product description
What it looks like
Ingredients
Sponsor

This leaflet answers some common questions about Xgeva.

It does not contain all the available information. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about using this medicine, speak to your doctor, nurse or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Xgeva is used for

Xgeva contains the active substance denosumab, which is a protein (monoclonal antibody) that attaches (binds) specifically to another unique protein in the body in order to slow down bone destruction caused by cancer spreading to the bone (bone metastasis or bone lesions) or by giant cell tumour of bone.

Xgeva reduces the amount of calcium in blood by reducing the breakdown of bones. In patients with hypercalcaemia of malignancy, the breakdown of bones can cause too much calcium in the blood.

Xgeva is used:

  • to prevent serious complications in adults with multiple myeloma. Multiple myeloma is a cancer of plasma cells (a type of white blood cell).
  • to prevent serious bone complications caused by bone metastasis or bone lesions, such as fracture, pressure on the spinal cord or the need to receive radiation therapy or surgery.
  • to treat giant cell tumour of bone which cannot be treated by surgery, where surgery is not the best option, or which has returned after treatment, in adults or adolescents whose bones have stopped growing.
  • to reduce high levels of calcium in the blood in cancer patients (hypercalcaemia of malignancy) after other drugs called bisphosphonates did not work.

Xgeva contains the same medicine as Prolia®, which is used to treat osteoporosis in women after menopause. Xgeva, which is given at a higher dose once every 4 weeks, should not be used to treat osteoporosis.

Your doctor, however, may prescribe Xgeva for another purpose.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

This medicine is available only with a doctor's prescription. It is not addictive.

Before you are given it

When you must not be given it

Do not use Xgeva if you have an allergy to:

  • any medicine containing denosumab
  • any of the ingredients listed at the end of this leaflet
  • any medicines that are produced using Chinese Hamster Ovary cells.

Some of the symptoms of an allergic reaction may include:

  • 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.

Your healthcare professional will not administer Xgeva to you if you have a very low level of calcium in your blood which has not been treated.

Do not use Xgeva if you are pregnant. There is no information on use of this medicine during pregnancy.

Tell your doctor if you become pregnant during treatment with Xgeva or within 5 months of your last dose.

Talk to your doctor before breast-feeding while you are undergoing treatment with Xgeva.

It is not known if the active ingredient, denosumab, passes into breast milk.

Do not use Xgeva if you have wounds or sores in your mouth from dental or oral (mouth) surgery that have not yet healed.

Do not use it in a child or adolescent under 18 years of age except for adolescents with giant cell tumour of the bone whose bones have stopped growing

The use of Xgeva has not been studied in children and adolescents with other cancers that have spread to bone.

Do not use it after the expiry date [ EXP: ] printed on the pack. If you use it after the expiry date has passed, it may not work as well.

Do not use it if the packaging is torn or shows signs of tampering.

Do not use it if the Xgeva solution is cloudy or discoloured. There may be some translucent to white particles of protein in the solution, however the medicine can still be used.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if:

  • you are taking medicines to treat osteoporosis such as Prolia or bisphosphonates.
  • you have allergies to:
    - any other medicines
    - any other substances such as foods, preservatives or dyes.
  • you have been told by a doctor or healthcare professional that you have an intolerance to some sugars, since Xgeva contains sorbitol (E420).
  • you have calcium deficiency.
    Your doctor may do a blood test to check your calcium levels before you use Xgeva.
  • you are unable to take daily calcium or vitamin D supplements.
  • you have or have had severe kidney problems, kidney failure or have needed dialysis, which may increase your chance of getting low blood calcium, especially if you do not take calcium supplements.
  • you are pregnant or intend to become pregnant.
    Xgeva is not recommended to be used during pregnancy. Your doctor can discuss with you the potential risks involved.
  • you are breast-feeding or are planning to breast-feed.
    It is not known whether the active ingredient, denosumab, passes into breast milk.
  • you have been told by a doctor or healthcare professional that you are a patient who is still growing.
    Some patients with giant cell tumour of the bone and some patients who are still growing during treatment with XGEVA, have developed high calcium levels in the blood weeks to months after stopping treatment. Your doctor will monitor you for signs and symptoms of high levels of calcium, after you stop XGEVA treatment.
  • you 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.
    Severe jaw bone problems may happen when you take Xgeva. Patients undergoing chemotherapy or taking steroids, who do not receive routine dental care or have gum disease, may have a higher risk of developing jaw problems. Your doctor may recommend a dental examination before you start treatment with Xgeva.

If you have not told your doctor about any of the above, tell him/her before you start using Xgeva.

Taking other medicines

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

How it is given

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

Instructions for injecting Xgeva

Xgeva is supplied in a vial. Your doctor or nurse will give you the injection.

How much is given

The dose is 120 mg administered once every 4 weeks, as a single injection under the skin.

Xgeva will be injected into your thigh, abdomen or upper arm. If you are being treated for giant cell tumour of bone or high blood levels of calcium caused by cancer (hypercalcaemia of malignancy), you will receive an additional dose 1 week and 2 weeks after the first dose.

You should also take calcium and vitamin D supplements while receiving Xgeva. Your doctor, nurse or pharmacist will discuss this with you.

When to use it

Xgeva is injected once every 4 weeks.

How long to use it

Continue using Xgeva for as long as your doctor tells you.

If you miss a dose

If you miss a dose, it should be administered as soon as possible. From then on, it should be scheduled every 4 weeks from the date of the last injection.

If you are given too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 131126) if you think you or anyone else may have had too much Xgeva.

Do this even if there are no signs of discomfort or poisoning.

While you are using it

Things you must do

Tell any other doctor, nurses and pharmacist who treat you that you are having this medicine.

If you are about to be started on any other medicine, remind your doctor, nurse or pharmacist that you are being treated with Xgeva.

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.

Tell your doctor immediately if you have spasms, twitches, or cramps in your muscles, and/or numbness or tingling in your fingers, toes or around your mouth. You may have low levels of calcium in your blood.

Severe jaw bone problems may happen when you take Xgeva. Tell your doctor and dentist immediately about any dental symptoms including pain and/or non-healing sores, or unusual feeling in your teeth or gums, or any dental infections.

Tell your dentist or doctor that you are being treated with Xgeva if you are under dental treatment or will undergo dental surgery.

Maintain good oral hygiene when being treated with Xgeva.

Tell your doctor immediately if you develop a swollen, red area of skin that feels hot and tender (cellulitis) and sometimes experienced with fever and chills while being treated with Xgeva.

Contact your doctor if you 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 XGEVA.

If you become pregnant while using this medicine, tell your doctor immediately. Your doctor can discuss with you the risks of having it while you are pregnant.

Contact your doctor if you plan to stop taking Xgeva. After your treatment with Xgeva is stopped, there may be an increased risk of broken bones in your spine, especially if you have a history of broken bones or have had osteoporosis (a condition in which bones become thin and fragile).

Attend all of your doctor's appointments so that your progress can be checked. Your doctor may recommend you have some blood or urine tests, X-rays or bone scans from time to time to ensure the medicine is working.

Things you must not do

Do not use Xgeva to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop using your medicine without checking with your doctor.

Things to be careful of

Be careful driving or using machinery until you know how it affects you. Xgeva has no known effects on the ability to drive or use machines, but as a general precaution, avoid driving soon after you have an injection. Arrange to have someone else drive.

Practice good dental hygiene. Your routine dental hygiene should include:

  • Brushing your teeth and tongue after every meal, including the evening
  • 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.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well after using Xgeva.

All medicines can have some unwanted side effects. Sometimes they are serious but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

All medicines can have side effects. You may need medical treatment if you get some of the side effects.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

If any of the following happen tell your doctor, nurse or pharmacist immediately or go to the Emergency at your nearest hospital:

  • 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.

These are very serious side effects. If you experience them, you may be having a serious allergic reaction to the medicine. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor, nurse or pharmacist immediately if you notice any of the following:

  • muscle spasms, twitches or cramps, numbness or tingling in your fingers, toes or around your mouth
  • bone, joint and/or muscle pain, which is sometimes severe
  • persistent pain and/or non-healing sores in your mouth or jaw

These may be serious side effects. You may need urgent medical attention. These side effects are common or very common.

Tell your doctor, nurse or pharmacist as soon as possible if you notice any of the following and they worry you:

  • nausea
  • low level of red blood cells
  • feeling tired
  • back pain
  • unusual hair loss or thinning
  • a type of skin rash
  • ear pain, discharge from the ear and/or an ear infection. These could be signs of bone damage in the ear.

These are mild side effects of the medicine.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Storing Xgeva

If you need to store your Xgeva before use:

  • Keep your medicine in the refrigerator, between 2°C and 8°C. Do not freeze.
    Keep your medicine in the carton in order to protect it from light. If you remove the medicine from the carton it will 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.
    Do not shake or vigorously agitate the vial.
  • Keep it where children cannot reach it.

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

After using it

Disposal

Return any unused or expired medicine to your pharmacist.

Product description

What it looks like

Xgeva is a clear, colourless to slightly yellow solution for injection supplied in a vial. It may contain trace amounts of clear to white particles.

Xgeva comes in a pack of one single-use vial containing 120 mg of denosumab (70 mg/1.0 mL).

Ingredients

Active ingredient: denosumab.

Inactive ingredients:

  • acetate
  • sodium hydroxide
  • sorbitol
  • polysorbate 20
  • water for injections.

This medicine does not contain gluten, tartrazine or any other azo dyes.

Sponsor

Xgeva is supplied in Australia by:

Amgen Australia Pty Ltd
(ABN 31 051 057 428)
Level 7, 123 Epping Road
North Ryde NSW 2113
Medical Information: 1800 803 638

This CMI was prepared in June 2019.

Australian Registration Number:
AUST R 175041

Xgeva® is a registered trademark of Amgen.

Published by MIMS August 2019

BRAND INFORMATION

Brand name

Xgeva

Active ingredient

Denosumab

Schedule

S4

 

1 Name of Medicine

Denosumab (rch).

6.7 Physicochemical Properties

Chemical structure.


CAS number.

615258-40-7.

2 Qualitative and Quantitative Composition

Each vial contains a deliverable dose of 120 mg denosumab in 1.7 mL of solution (70 mg/mL).
Denosumab is a fully human IgG2 monoclonal antibody with high affinity and specificity for RANK ligand (RANKL). Denosumab has an approximate molecular weight of 147 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

Xgeva is supplied as a sterile, preservative-free, clear, colourless to slightly yellow solution for injection at pH 5.2.
The solution may contain trace amounts of translucent to white proteinaceous particles.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bone metastasis from solid tumours.

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. Increased osteoclast activity, stimulated by RANKL, is a key mediator of bone destruction in bone disease in metastatic tumours and multiple myeloma. 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. Prevention of RANKL-RANK interaction results in reduced osteoclast numbers and function, and thereby decreases bone resorption and cancer induced bone destruction.
RANKL inhibition resulted in reduced bone lesions and delayed formation of de novo bone metastases in some nonclinical models. RANKL inhibition reduced skeletal tumour growth and this effect was additive when combined with other anticancer therapies.

Giant cell tumour of bone.

Giant cell tumours of bone are characterised by stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK. In patients with giant cell tumour of bone, denosumab binds to RANKL, significantly reducing or eliminating osteoclast-like giant cells. Consequently, osteolysis is reduced and proliferative tumour stroma can be replaced with non-proliferative, differentiated, woven new bone which may show an increase in density.

Hypercalcaemia of malignancy refractory to intravenous bisphosphonates.

The primary aetiology of both skeletal and humoral hypercalcaemia of malignancy is increased bone resorption, which leads to elevated calcium concentrations in the extracellular fluid. The increase in bone resorption is initiated by the release of signalling molecules such as PTHrP, prostaglandins, and cytokine by malignant and stromal cells. These molecules stimulate osteoblasts and other stromal cells to express RANKL, which upon binding its receptor RANK upregulates osteoclast recruitment and differentiation and thus bone resorption, with a resultant increase in calcium concentrations of the extracellular fluid and serum. Xgeva binds to RANKL preventing RANK/RANKL mediated osteoclast formation, function, and survival thereby lowering serum calcium levels.

Pharmacodynamics.

In a phase 2 study of IV bisphosphonate naïve patients with breast cancer and bone metastases, subcutaneous (SC) doses of Xgeva 120 mg every 4 weeks (Q4W), caused a rapid reduction in the markers of bone resorption: urinary N-telopeptide corrected for creatinine (uNTx/Cr) and serum C telopeptide (sCTx) with median reduction of 82% for uNTx/Cr within 1 week. Reductions in bone resorption markers were maintained, with median uNTx/Cr reductions of 74% to 82% from weeks 2 to 25 of continued 120 mg Q4W dosing. Median reduction of approximately 80% in uNTx/Cr from baseline after 3 months of treatment were also observed across 2075 Xgeva-treated advanced cancer patients (breast, prostate, multiple myeloma or other solid tumours) naïve to IV-bisphosphonate in the phase 3 clinical trials.
Similarly, in a phase 2 study of patients with advanced malignancies and bone metastases (including subjects with multiple myeloma and bone disease) who were receiving intravenous bisphosphonate therapy, yet had uNTx/Cr levels > 50 nanoM/mM, SC dosing of Xgeva administered either every 4 weeks or every 12 weeks caused an approximate 80% reduction in uNTx/Cr from baseline after 3 and 6 months of treatment. Overall, 97% of patients in the Xgeva groups had at least one uNTx/Cr value < 50 nanoM/mM up to week 25 of the study.
In a phase 3 study of patients with newly diagnosed multiple myeloma who received SC doses of Xgeva 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing.
In a phase 2 study of patients with giant cell tumour of bone who received subcutaneous doses of Xgeva 120 mg every 4 weeks (Q4W) with loading doses on days 8 and 15 of the initial 4 week treatment period, median reductions in uNTx/Cr and sCTx of approximately 80% were observed by week 9. Reductions in bone turnover markers were maintained, with median reductions of 56% to 77% for uNTx/Cr and 79% to 83% for sCTx from weeks 5 to 25 of continued 120 mg Q4W dosing.

Clinical trials.

Clinical efficacy in patients with bone metastases from solid tumours.

Efficacy and safety of 120 mg Xgeva subcutaneously every 4 weeks or 4 mg zoledronic acid (dose adjusted for reduced renal function) IV every 4 weeks were compared in three randomised, double blind, active controlled studies, in IV bisphosphonates naïve patients with advanced malignancies involving bone. A total of 2,046 adults with breast cancer with at least one bone metastasis (Study 20050136), 1,776 adults with other solid tumours (including non-small cell lung cancer, renal cell cancer, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, gastrointestinal/genitourinary cancer and others, excluding breast and prostate cancer) with at least one bone metastasis or multiple myeloma (Study 20050244), and 1,901 men with castrate resistant prostate cancer with at least one bone metastasis (Study 20050103) were included. The primary and secondary endpoints evaluated the occurrence of one or more skeletal related events (SREs) defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone or spinal cord compression.
Xgeva reduced the risk of developing a SRE, or developing multiple SREs (first and subsequent) in patients with advanced malignancies involving bone (see Figure 1 and Table 2).
In a post hoc analysis of Study 20050244 (including solid tumours, excluding multiple myeloma), Xgeva reduced the risk of developing a SRE by 19% (p = 0.0168) and developing multiple SREs by 15% (p = 0.0479) compared with zoledronic acid with the median time to first SRE delayed by 6 months.

Disease progression and overall survival in advanced malignancies involving bone.

Disease progression was similar between Xgeva and zoledronic acid in all three studies and in the pre-specified analysis of all three studies combined.
In all three studies overall survival was balanced between Xgeva and zoledronic acid in patients with advanced malignancies involving bone: patients with breast cancer (hazard ratio [95% CI] was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio [95% CI] was 1.03 [0.91, 1.17]), and patients with other solid tumours or multiple myeloma (hazard ratio [95% CI] was 0.95 [0.83, 1.08]). A post hoc analysis in Study 20050244 (patients with other solid tumours or multiple myeloma) examined overall survival for the three tumour types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for Xgeva in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between the Xgeva and zoledronic acid groups in other tumour types (hazard ratio [95% CI] of 1.08 [0.90, 1.30]; n = 894). This study did not control for prognostic factors and anti-neoplastic treatments. In a combined pre-specified analysis from all three studies, overall survival was similar between Xgeva and zoledronic acid (hazard ratio [95% CI] of 0.99 [0.91, 1.07]).

Clinical efficacy in patients with multiple myeloma.

Xgeva was evaluated in an international, randomised (1:1), double-blind, active-controlled study comparing Xgeva with zoledronic acid in patients with newly diagnosed multiple myeloma (Study 20090482).
In this study, 1718 multiple myeloma patients with at least 1 bone lesion were randomised to receive 120 mg Xgeva subcutaneously every 4 weeks or 4 mg zoledronic acid intravenously (IV) every 4 weeks (dose adjusted for renal impairment and patients with creatinine clearance less than 30 mL/min were excluded based on Zometa prescribing information). The primary outcome measure was demonstration of non-inferiority of time to first skeletal-related event (SRE) as compared to zoledronic acid. Secondary outcome measures included superiority of time to first SRE, superiority of time to first and subsequent SRE, and overall survival. An SRE was defined as any of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.
In this study, randomisation was stratified by intent to undergo autologous peripheral blood stem cell (PBSC) transplantation (yes or no), the anti-myeloma agent being utilised/planned to be utilised in first-line therapy [novel therapy-based or non-novel therapy-based (novel therapies include bortezomib, lenalidomide, or thalidomide)], stage at diagnosis (International Staging System I or II or III), previous SRE (yes or no), and region (Japan or other countries). Across both study arms, 54.5% of patients intended to undergo autologous PBSC transplantation, 95.8% of patients utilised/planned to utilise a novel anti-myeloma agent in first-line therapy, and 60.7% of patients had a previous SRE. The number of patients across both study arms with ISS stage I, stage II, and stage III at diagnosis were 32.4%, 38.2%, and 29.3%, respectively.
Median age was 63 years, 82.1% of patients were White, and 45.6% of patients were women. The median number of doses administered was 16 for Xgeva and 15 for zoledronic acid. In patients with newly diagnosed multiple myeloma, Xgeva was non-inferior to zoledronic acid in delaying the time to first SRE following randomisation (see Figure 2 and Table 3).

Overall survival and progression free survival in multiple myeloma.

The hazard ratio between Xgeva and zoledronic acid treatment groups and 95% CI for overall survival (OS) was 0.90 (0.70, 1.16) (see Figure 3). Progression-free survival (PFS) was assessed as an exploratory endpoint. Median PFS (95% CI) was 46.1 (34.3, not estimable) months for the Xgeva treatment group and 35.4 (30.2, not estimable) months for the zoledronic acid group (HR [95% CI] of 0.82 [0.68, 0.99]) (see Figure 4).

Effect on pain.

Levels of pain were examined using the Brief Pain Inventory - Short Form (BPI-SF) questionnaire as an exploratory endpoint.
For pain measures based on BPI-SF, the point estimate (95% CI) of the average AUC of the pain severity score, relative to baseline, was -0.72 (-0.92, -0.51) for Xgeva and -0.40 (-0.59, -0.20) for zoledronic acid, with a point estimate (95% CI) for the treatment difference of -0.32 (-0.60, -0.04) and p = 0.024.
Xgeva and zoledronic acid showed similar results in time to, and proportion by visit for ≥ 2-point decrease, ≥ 2-point increase, and > 4-point in worst pain score.
Other measures showed similar results between Xgeva and zoledronic acid, and results suggested that there were unlikely to be clinically significant differences between denosumab and zoledronic acid with regards to effects on pain.

Clinical efficacy in adults and skeletally mature adolescents with giant cell tumour of bone.

The safety and efficacy of Xgeva was studied in two phase 2 open label, single arm trials (Studies 20040215 and 20062004) that enrolled 305 patients with giant cell tumour of bone that was either unresectable or for which surgery would be associated with severe morbidity. Patients received 120 mg Xgeva subcutaneously every 4 weeks with a loading dose of 120 mg on days 8 and 15 of the initial 4-week treatment period.
Study 20040215 enrolled 37 adult patients with histologically confirmed unresectable or recurrent giant cell tumour of bone. The main outcome measure of the trial was response rate, defined as either at least 90% elimination of giant cells relative to baseline (or complete elimination of giant cells in cases where giant cells represent < 5% of tumour cells), or a lack of progression of the target lesion by radiographic measurements in cases where histopathology was not available.
Of the 35 patients included in the efficacy analysis, 85.7% (95% CI: 69.7, 95.2) had a treatment response to Xgeva. All 20 patients (100%) with histology assessments met response criteria. Of the remaining 15 patients, 10 (67%) met response criteria based on radiology data.
Study 20062004 enrolled 282 adult or skeletally mature adolescents with giant cell tumour of bone. Patients were assigned to one of three cohorts: Cohort 1 included patients with surgically unsalvageable disease (e.g. sacral, spinal, or multiple lesions, including pulmonary metastases); Cohort 2 included patients with surgically salvageable disease whose planned surgery was associated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy); Cohort 3 included patients previously participating in 20040215 and rolled over into this study. The secondary outcome measures of the study were time to disease progression (based on investigator assessment) for Cohort 1 and proportion of patients without any surgery at month 6 for Cohort 2. Pain outcomes and investigator determined clinical benefit were also assessed.
In Cohort 1, median time to disease progression was not reached, as only 6 of the 169 treated patients (3.6%) had disease progression. In Cohort 2, Xgeva prolonged the time to surgery, reduced the morbidity of planned surgery, and reduced the proportion of patients undergoing surgery (see Table 4). Sixty-four of the 71 (90.1%; 95% CI: 80.7%, 95.9%) evaluable patients treated with Xgeva had not undergone surgery by month 6. Overall, of 100 patients for whom surgery was planned, 74 patients (74%) had no surgery performed, and 16 patients (16%) underwent a less morbid surgical procedure from that planned at baseline (see Table 4).
A retrospective independent review of radiographic imaging data was performed for patients enrolled in 20040215 and 20062004. Of the 305 patients enrolled in these studies, 190 had at least 1 evaluable timepoint response and were included in the analysis (see Table 5).
Patients were evaluated by the following response criteria to determine objective tumour response.
Modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1) to evaluate tumour burden based on computed tomography (CT)/magnetic resonance imaging (MRI);
Modified European Organisation for Research and Treatment of Cancer (EORTC) criteria to evaluate metabolic response using fluorodeoxyglucose positron emission tomography (FDG-PET);
Modified Inverse Choi criteria to evaluate tumour size and density using Hounsfield units based on CT/MRI (Density/Size).
Xgeva achieved objective tumour responses in 136 of these 190 patients (71.6%; 95% CI 64.6, 77.9) (see Table 5). The median time to response was 3.1 months (95% CI 2.89, 3.65). The median duration of response was not estimable, as few patients experienced disease progression, with a median follow-up of 13.4 months. Efficacy results in skeletally mature adolescents appeared to be similar to those observed in adults.

Effect on pain.

In Study 20062004, Cohorts 1 and 2 combined, a clinically meaningful reduction in worst pain (i.e. ≥ 2 point decrease from baseline) was reported for 31.4% of patients at risk (i.e. those who had a worst pain score of ≥ 2 at baseline) within 1 week of treatment, and ≥ 50% at week 5. These pain improvements were maintained at all subsequent evaluations. In a post hoc analysis, at least half of evaluable patients had a ≥ 30% reduction in worst pain score from baseline at all post-baseline time points beginning at week 9. Overall, pain improvement and clinical benefit did not correlate with objective tumour response.

Clinical efficacy in treatment of hypercalcaemia of malignancy.

The safety and efficacy of Xgeva was studied in a phase 2 open-label, single-arm trial (Study 20070315) that enrolled 33 patients with hypercalcaemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate. In this study, refractory hypercalcaemia of malignancy was defined as an albumin corrected serum calcium (CSC) of > 12.5 mg/dL (3.1 mmol/L) despite treatment with intravenous bisphosphonate in the last 7-30 days.
Twenty-six (79%) patients had advanced solid tumours and 7 (21%) patients had advanced hematologic malignancies. Twenty-five patients (76%) had poor performance status (Eastern Cooperative Oncology Group [ECOG] ≥ 2) at baseline. Metastatic disease was present in 30 (91%) patients and metastatic bone disease in 13 (39%) patients at baseline. Three (9%) patients had non-metastatic disease, 2 with myeloma and 1 with non-Hodgkin's lymphoma. Nineteen patients (58%) reported symptoms related to hypercalcaemia of malignancy at baseline. At the time of enrollment, the median serum calcium level was 13.7 mg/dL (3.42 mmol/L).
The primary endpoint was the proportion of patients achieving a response, defined as CSC ≤ 11.5 mg/dL (2.9 mmol/L), within 10 days after Xgeva administration. The secondary objectives were to determine the duration of the treatment effect, the time to response, the time to relapse/nonresponse and to evaluate changes in CSC level from baseline.
Patients received Xgeva subcutaneously every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of therapy.
Xgeva was associated with rapid and sustained decreases in serum calcium in the majority of patients including those with or without bone metastases (see Figure 5 and Table 6).

Symptom improvement in patients with refractory hypercalcaemia of malignancy.

In Study 20070315, data regarding hypercalcaemia of malignancy symptoms were collected on a dedicated case report form. In the study population, a total of 48 hypercalcaemia of malignancy symptoms were reported in 19 patients at baseline. Each symptom status was based on the best status by study day 10.
8 (42%) patients reported resolution of at least 1 symptom.
4 (21%) patients reported resolution of all symptoms.
15 (31%) of the symptoms present at baseline resolved.
5 (10%) of the symptoms improved.
2 (4%) of the symptoms got worse.
26 (54%) of the symptoms remained stable.
Nine patients reported a total of 12 hypercalcaemia of malignancy symptoms of cognitive impairment at baseline. Each symptom status was based on the best status by study day 10.
5 (56%) of patients reported resolution of at least 1 symptom of cognitive impairment.
4 (44%) of patients reported resolution of all symptoms of cognitive impairment.
7 (58%) of the symptoms of cognitive impairment present at baseline resolved.
1 (8%) cognitive impairment symptom worsened.
4 (33%) of the cognitive impairment symptoms remained stable.

5.2 Pharmacokinetic Properties

Absorption.

Following subcutaneous administration, bioavailability was 62%.

Distribution.

Denosumab displayed non-linear pharmacokinetics with dose over a wide dose range, but approximately dose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher.
In subjects with advanced cancer who received multiple doses of 120 mg every 4 weeks (Q4W) an approximate 2-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved by 6 months, consistent with time-independent pharmacokinetics.
At steady-state, the mean serum trough concentration was 20.6 microgram/mL (range: 0.456 to 56.9 microgram/mL). In subjects with multiple myeloma who received 120 mg every 4 weeks, median trough levels varied by less than 8% between months 6 and 12.
In subjects with giant cell tumour of bone who received 120 mg every 4 weeks with a loading dose on days 8 and 15, steady-state levels were achieved within the first month of treatment. Between weeks 9 and 49, median trough levels varied by less than 9%.

Metabolism.

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

Excretion.

In subjects with advanced cancer who discontinued doses of 120 mg every 4 weeks, the mean half-life was 28 days (range: 14 to 55 days).

Special populations.

A population pharmacokinetic analysis showed no notable difference in pharmacokinetics with age (18 to 87 years), race, body weight (36 to 174 kg), or across patients with solid tumours, multiple myeloma, and giant cell tumour of bone. The pharmacokinetics and pharmacodynamics of denosumab were similar in patients transitioning from IV bisphosphonate therapy.

Elderly.

The pharmacokinetics of denosumab were not affected by age (18 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 studies of denosumab (60 mg, N = 55 and 120 mg, N = 32) in patients without advanced malignancies but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab. Dose adjustment for renal impairment is not necessary.

Immunogenicity.

Denosumab pharmacokinetics and pharmacodynamics were not affected by the formation of binding antibodies to denosumab and were similar in men and women.
In clinical studies, no neutralising antibodies for denosumab have been observed. Using a sensitive immunoassay, < 1% of patients treated with denosumab for up to 3 years tested positive for non-neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Prevention of skeletal related events in patients with multiple myeloma and in patients with bone metastases from solid tumours.
Treatment of giant cell tumour of bone in adults or skeletally mature adolescents that is recurrent, or unresectable, or resectable but associated with severe morbidity.
Treatment of hypercalcaemia of malignancy that is refractory to intravenous bisphosphonate.

4.3 Contraindications

Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Hypersensitivity to the active substance, to CHO-derived proteins or to any of the excipients (see Section 6.1 List of Excipients).
Severe untreated hypocalcaemia.
Unhealed lesions from dental or oral surgery.

4.4 Special Warnings and Precautions for Use

Vitamin supplementation and hypocalcaemia.

Pre-existing hypocalcaemia must be corrected prior to initiating therapy with Xgeva.
Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present.
Hypocalcaemia can occur at any time during therapy with Xgeva. Monitoring of calcium levels should be conducted (i) prior to the initial dose of Xgeva, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcaemia occur (see Section 4.8 Adverse Effects (Undesirable Effects) for symptoms). Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcaemia, or if otherwise indicated based on the clinical condition of the patient. Patients should be encouraged to report symptoms indicative of hypocalcaemia.
In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience), with most cases occurring in the first weeks of initiating therapy, but can occur later.
If hypocalcaemia occurs while receiving Xgeva, additional short-term calcium supplementation may be necessary (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).

Use in hepatic impairment.

The safety and efficacy of Xgeva 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 of subjects without advanced cancer, but with varying degrees of renal function (including patients with severe renal impairment [creatinine clearance < 30 mL/min] or receiving dialysis) there was a greater risk of developing hypocalcaemia with increasing degree of renal impairment, and in the absence of calcium supplementation. Monitoring calcium levels and 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, Vitamin supplementation and hypocalcaemia).

Osteonecrosis of the jaw.

Osteonecrosis of the jaw (ONJ) has occurred in patients treated with denosumab, with the majority of cases occurring within 5 months after the last dose. In clinical trials, the incidence of ONJ was higher with longer duration of exposure (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who developed ONJ in clinical studies generally had known risk factors for ONJ, including invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), poor oral hygiene or other pre-existing dental disease, local gum or oral infection, advanced malignancies, or concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors). An oral examination should be performed by the prescriber prior to initiation of Xgeva treatment and a dental examination with appropriate preventive dentistry is recommended prior to treatment with Xgeva, especially in patients with risk factors for ONJ. Good oral hygiene practices should be maintained during treatment with Xgeva.
Patients should avoid invasive dental procedures during treatment with Xgeva. 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 Xgeva should receive care by a dentist or an oral surgeon. If ONJ occurs during treatment with Xgeva a temporary interruption of treatment should be considered based on individual benefit-risk assessment until the condition resolves.

Atypical femoral fractures.

Atypical femoral fracture has been reported with Xgeva (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 Xgeva 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.

Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone and in patients with growing skeletons.

Clinically significant hypercalcaemia requiring hospitalisation and complicated by acute renal injury has been reported in Xgeva-treated patients with giant cell tumour of bone and patients with growing skeletons weeks to months following treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcaemia, consider periodic assessment of serum calcium as clinically indicated, and treat appropriately. Re-evaluate the patient's calcium and vitamin D supplementation requirements. Manage hypercalcaemia as clinically appropriate (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 4.8 Adverse Effects (Undesirable Effects)).

Multiple vertebral fractures (MVF) following treatment discontinuation.

Multiple vertebral fractures (MVF), not due to bone metastases, may occur following discontinuation of treatment with Xgeva, particularly in patients with risk factors such as osteoporosis or prior fractures.
Advise patients not to interrupt Xgeva therapy without their physician's advice. When Xgeva treatment is discontinued, evaluate the individual patient's risk for vertebral fractures (see Section 4.8 Adverse Effects (Undesirable Effects)).

Drugs with same active ingredient.

Xgeva contains the same active ingredient found in Prolia (denosumab), used for the treatment of postmenopausal osteoporosis. Patients being treated with Xgeva should not be treated with Prolia concomitantly.

Warnings for excipients.

Patients with rare hereditary problems of fructose intolerance should not use Xgeva.

Use in the elderly.

Of the total number of patients in clinical studies in patients with advanced cancer, 1260 patients (44.4%) treated with Xgeva were ≥ 65 years old. No overall differences in safety or efficacy were observed between these patients and younger patients.

Paediatric use.

The safety and efficacy of Xgeva in paediatric patients (age < 18) have not been established other than skeletally mature adolescents with giant cell tumour of bone. Xgeva is not recommended for use in paediatric patients other than skeletally mature adolescents with giant cell tumour of bone. Clinically significant hypercalcaemia after treatment discontinuation has been reported in the post-marketing setting in paediatric patients with growing skeletons who received denosumab for giant cell tumour of bone or for unapproved indications (see Section 4.4 Special Warnings and Precautions for Use, Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone and in patients with growing skeletons).
In Study 20062004, Xgeva has been evaluated in a subset of 10 adolescent patients (aged 13-17 years) with giant cell tumour of bone who had reached skeletal maturity defined by at least 1 mature long bone (e.g. closed epiphyseal growth plate of the humerus) and body weight ≥ 45 kg. Efficacy results in skeletally mature adolescents appeared to be similar to those observed in adults (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Adolescent primates had abnormal growth plates when administered denosumab at doses of 10 mg/kg and higher, which resulted in exposures up to 2.8 times those observed in adult humans dosed at 120 mg subcutaneously every 4 weeks based on AUC. In neonatal cynomolgus monkeys exposed in utero to denosumab at 50 mg/kg, there was increased postnatal mortality; abnormal bone growth resulting in reduced bone strength, reduced haematopoiesis, and tooth malalignment; absence of peripheral lymph nodes; decreased neonatal growth and other adverse effects (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). In neonatal rats, inhibition of RANKL (target of denosumab therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) was associated with inhibition of bone growth and tooth eruption and lower body weight gain. These changes were partially reversible when dosing of RANKL inhibitor was discontinued. 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

No drug-drug interaction studies have been conducted.
In clinical studies, Xgeva has been administered in combination with standard anticancer treatment and in patients previously receiving bisphosphonates.
The pharmacokinetics and pharmacodynamics of denosumab were not altered by concomitant chemotherapy and/or hormone therapy nor by previous IV bisphosphonate exposure.
Denosumab should not be administered concomitantly with bisphosphonates.

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 15-fold higher than the human exposure at 120 mg subcutaneous administered once every month.
(Category D)
There are no adequate and well controlled studies of Xgeva in pregnant women. Xgeva is contraindicated for use during pregnancy. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Any effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Inform the patient of the potential hazard to a foetus if the patient becomes pregnant while exposed to Xgeva.
Developmental toxicity studies have been performed with denosumab in cynomolgus monkeys and have shown serious adverse effects on development (including foetal and infant lethality). Denosumab was shown to cross the placenta in monkeys.
In a study of cynomolgus monkeys with denosumab at 12.5 mg/kg/week given during the period equivalent to the first trimester at AUC exposures up to 10-fold higher than the human dose (120 mg every 4 weeks), there was no evidence of maternal or foetal harm. In this study, foetal lymph nodes were not examined.
In another study of cynomolgus monkeys with denosumab throughout pregnancy at 50 mg/kg/month, yielding AUC exposures 12-fold higher than the human dose (120 mg every 4 weeks), 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 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). These changes were partially reversible when dosing of RANKL inhibitor was discontinued. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition.
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.
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 Xgeva should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of Xgeva therapy to the woman.

4.8 Adverse Effects (Undesirable Effects)

Bone metastasis from solid tumours.

Data from three active controlled multicentre trials were used for the safety analysis in 5,677 patients with bone metastases from either prostate cancer, breast cancer, other solid tumours or patients with multiple myeloma (all patients with advanced cancer). A total of 2,841 patients were exposed to 120 mg of Xgeva administered once every 4 weeks as a single subcutaneous injection, and 2,836 patients were exposed to 4 mg (dose adjusted for reduced renal function) of zoledronic acid administered once every 4 weeks as an IV infusion. The median (Q1, Q3) duration of exposure to Xgeva for the safety analysis was 12 months (6, 18) for prostate cancer, 17 months (10, 21) for breast cancer, and 7 months (4, 14) for other solid tumours and multiple myeloma. See Table 1.
Hypophosphataemia has been reported as a common adverse drug reaction.

Giant cell tumour of bone.

The safety of Xgeva was evaluated in two phase 2 open-label, single arm studies in which a total of 304 patients with giant cell tumour of bone received at least 1 dose of Xgeva. Patients received 120 mg Xgeva subcutaneously every 4 weeks with a loading dose of 120 mg on days 8 and 15 of the initial 4 week period. Of the 304 patients who received Xgeva, 147 patients were treated with Xgeva for ≥ 1 year, 46 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median (Q1, Q3) number of doses received was 14 (8.0, 22); the minimum number of doses received was 1 and the maximum was 60. The median (Q1, Q3) number of months on study was 11.2 (5.4, 18.2). The median (range) age was 33 (13 to 83) years; 10 subjects were skeletally mature adolescents (aged 13 to 17 years).
The overall safety and tolerability profile of Xgeva in patients with giant cell tumour of bone was similar to that reported in trials of patients with bone metastases from solid tumours. For skeletally mature adolescent subjects with GCTB, the safety profile appears to be similar to that in adult subjects with GCTB.
The most common adverse reactions in patients with giant cell tumour of bone receiving Xgeva (per patient incidence greater than or equal to 10%) were arthralgia, headache, nausea, fatigue, back pain, and pain in extremity.
Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone has been observed uncommonly.

Hypercalcaemia of malignancy.

The safety of Xgeva was evaluated in an open label, single arm trial (Study 20070315) in which 33 patients were enrolled with hypercalcaemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate. Patients received Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the initial 4 week period. Entry criteria included patients who had refractory hypercalcaemia of malignancy (defined as an albumin corrected calcium of > 12.5 mg/dL [3.1 mmol/L] despite treatment with intravenous bisphosphonate in the last 7-30 days). Patients receiving dialysis for renal failure or who had treatment with thiazides, calcitonin, mithromycin, or gallium nitrate within their window of expected therapeutic effect prior to the date of screening corrected serum calcium (CSC) were excluded. During the trial, serum calcium was collected every few days in the first month, weekly during the second month, and monthly thereafter.
Of the 33 patients who received Xgeva, 33 patients were treated with Xgeva for ≥ 1 month, 5 patients for ≥ 6 months, and 3 patients for ≥ 1 year. The median number of doses received was 4 (range: 1 to 25 doses) and the median number of months on study was 1.8 (range: 0 to 23 months). Sixty-four percent of enrolled patients were men and 70% were white. The median age was 63 years (range: 22 to 89 years).
The adverse reaction profile of Xgeva in patients with hypercalcaemia of malignancy was similar to that reported in patients with bone metastases from solid tumours and giant cell tumour of bone.
The most common adverse reactions were nausea, dyspnoea, decreased appetite, headache, peripheral oedema, and vomiting. No adverse events leading to discontinuation were reported as related to Xgeva treatment.

Hypocalcaemia.

In three phase 3 active controlled clinical trials in patients with advanced malignancies involving bone, hypocalcaemia was reported in 9.6% of patients treated with Xgeva and 5.0% of patients treated with zoledronic acid. A decrease in serum calcium levels to the range between 1.5 to 1.75 mmol/L was experienced in 2.5% of patients treated with Xgeva and 1.2% of patients treated with zoledronic acid. A decrease in serum calcium levels to < 1.5 mmol/L was experienced in 0.6% of patients treated with Xgeva and 0.2% of patients treated with zoledronic acid.
In a phase 3 active-controlled clinical trial in patients with newly diagnosed multiple myeloma, hypocalcaemia was reported in 16.9% of patients treated with Xgeva and 12.4% of patients treated with zoledronic acid. A decrease in serum calcium levels to the range between 1.5 to 1.75 mmol/L was experienced in 1.4% of patients treated with Xgeva and 0.6% of patients treated with zoledronic acid. A decrease in serum calcium levels to the range between 0.8 to 1.5 mmol/L was experienced in 0.4% of patients treated with Xgeva and 0.1% of patients treated with zoledronic acid.
In two phase 2 open label trials in patients with giant cell tumour of bone, hypocalcaemia was reported in 5.7% of patients. None of the adverse events was considered serious.
In a phase 2 open label, single arm trial in patients with hypercalcaemia of malignancy refractory to intravenous bisphosphonate, hypocalcaemia was reported in 9.1% of patients treated with Xgeva.

Osteonecrosis of the jaw (ONJ).

In the primary treatment phase of three phase 3 active controlled clinical trials in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with Xgeva (median exposure of 12 months; range 0.1 to 40.5) and 1.3% of patients treated with zoledronic acid. Clinical characteristics of these cases were similar between treatment groups.
Among subjects with confirmed ONJ, most had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. In addition, most subjects were receiving or had received chemotherapy. The trials in patients with breast or prostate cancer included a prespecified Xgeva extension treatment phase (median overall exposure of 14.9 months; range 0.1 - 67.2) where patients were offered open label Xgeva. The patient year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4 - 53).
In a phase 3 double-blind, active-controlled clinical trial in patients with newly diagnosed multiple myeloma, ONJ was confirmed in 4.1% of patients in the Xgeva group (median exposure of 15.8 months; range 1 - 49.8) and 2.8% of patients in the zoledronic acid group. At the completion of the double-blind treatment phase of this trial, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the Xgeva group (median exposure of 19.4 months; range 1 - 52) was 2.0% during the first year of treatment, 5.0% in the second year, and 4.5% per year thereafter. The median time to ONJ was 18.7 months (range: 1 - 44).
In a phase 3 placebo controlled clinical trial with an extension treatment phase evaluating Xgeva for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which Xgeva is not indicated), with longer treatment exposure of up to 7 years, the patient year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.
In two phase 2 open label studies in patients with giant cell tumour of bone, ONJ occurred in 4 of 304 (1.3%) of patients. The median time to ONJ was 16 months (range 13-20).
In a phase 2 open-label, single-arm trial in patients with hypercalcaemia of malignancy refractory to intravenous bisphosphonate, no cases of ONJ were reported.

Atypical femoral fractures.

Atypical femoral fracture has been reported uncommonly in patients treated with Xgeva and the risk increased with longer duration of treatment. Events have occurred during treatment and up to 9 months after treatment was discontinued.

Paediatric patients.

The safety profile of Xgeva in 10 skeletally mature adolescent patients with giant cell tumour of bone was consistent with that in adult patients.

Drug hypersensitivity events.

In clinical trials in patients with advanced cancer, drug hypersensitivity events were reported in 0.9% and 0.4% of patients treated with Xgeva and zoledronic acid, respectively.

Pancreatitis.

In a randomised controlled trial in postmenopausal women with osteoporosis receiving 60 mg denosumab or placebo once every 6 months, pancreatitis was reported in 8 patients (0.2%) in the denosumab and 4 patients (0.1%) in the placebo groups. An increased incidence has not been observed in randomised controlled trials in the oncology setting.

Hypercalcaemia.

Hypercalcaemia has been observed following treatment discontinuation in patients with growing skeletons (a patient population for which Xgeva is not indicated).

Multiple vertebral fractures.

Multiple vertebral fractures, not due to bone metastases, have occurred in patients with risk factors such as osteoporosis or prior fractures following treatment discontinuation.

Post-marketing experience.

The following adverse reactions have been identified during post-approval use of Xgeva:
Rare events of severe symptomatic hypocalcaemia (including fatal cases) have been reported in patients at increased risk of hypocalcaemia. Examples of the clinical manifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and altered mental status (see Section 4.4 Special Warnings and Precautions for Use, Vitamin supplementation and hypocalcaemia). Symptoms of hypocalcaemia in denosumab clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps.
Hypersensitivity, including anaphylactic reactions.
Musculoskeletal pain, including severe cases.
Lichenoid drug eruptions (e.g. lichen planus-like reactions) have been observed uncommonly.
Alopecia has been observed commonly.
There have been reports of osteonecrosis of the external auditory canal in patients using denosumab.

Reporting 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.

4.2 Dose and Method of Administration

Dosage (dose and interval).

The recommended dose of Xgeva for the prevention of skeletal related events is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.
The recommended dose of Xgeva for the treatment of giant cell tumour of bone and hypercalcaemia of malignancy is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm with a loading dose of 120 mg on days 8 and 15 of the initial 4-week treatment period.
Daily supplementation with at least 500 mg calcium and 400 IU vitamin D is required in all patients, unless hypercalcaemia is present (see Section 4.4 Special Warnings and Precautions for Use, Vitamin supplementation and hypocalcaemia).

Method of administration.

Administration should be performed by an individual who has been adequately trained in injection techniques.
Before administration, the Xgeva solution should be inspected for particulate matter and discolouration. Do not use if the solution is cloudy or discoloured. Do not shake excessively. To avoid discomfort at the site of injection, allow the vial to reach room temperature (up to 25°C) before injecting, and inject slowly. A 27 gauge needle or larger needle (e.g. 25 gauge) is recommended for the administration of Xgeva.
Product is for single-use in one patient only.
Inject the entire contents of the vial. Do not re-enter the vial.
Dispose of any medicinal product remaining in the vial.

Dosage adjustment.

Special populations.

Use in elderly.

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).

Use in paediatrics.

For treatment of giant cell tumour of bone in skeletally mature adolescents, the posology is the same as in adults.
Xgeva is not recommended in paediatric patients (age < 18) other than skeletally mature paediatric patients with giant cell tumour of bone (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

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.

4.9 Overdose

There is no experience with overdosage with Xgeva. Xgeva 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 120 mg weekly for 3 weeks.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each single-use vial of Xgeva contains 78.1 mg sorbitol, 1.8 mg acetate, 0.17 mg polysorbate 20 and sodium hydroxide for adjusting to pH 5.2 in 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 vials in a refrigerator at 2°C to 8°C in the original carton. Do not freeze. Protect from direct light. Do not excessively shake the vial. Do not expose to temperatures above 25°C.
If removed from the refrigerator, Xgeva 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

Xgeva is supplied in a glass vial.
Pack size: one or four* vials.
* Not marketed in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes