Consumer medicine information

Xofigo

Radium Ra 223 dichloride

BRAND INFORMATION

Brand name

Xofigo

Active ingredient

Radium Ra 223 dichloride

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Xofigo.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about XOFIGO. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given XOFIGO against the benefits your doctor expects it will have for you.

If you have any concerns about being given this medicine, ask your doctor.

Keep this leaflet. You may need to read it again.

WHAT XOFIGO IS USED FOR

XOFIGO is used to treat prostate cancer that has not responded to hormone therapy. XOFIGO is only used when the disease has spread to the bone but is not known to have spread to other internal organs, and is causing symptoms (e.g. pain).

XOFIGO contains small amounts of the radioactive isotope radium-223 [223Ra] (as radium-223 dichloride) which mimics calcium.

Radium-223 goes to where the tumour cells are growing in the bone and releases short-ranging radioactivity (alpha particles) which is toxic to the cells.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU ARE GIVEN XOFIGO

When you must not be given it

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

You should not be given XOFIGO if you are taking abiraterone acetate together with prednisone or prednisolone.

You must not be given XOFIGO if:

  • the packaging is torn or shows signs of tampering
  • the expiry date printed on the pack after “EXP” has passed

If you are given XOFIGO after the expiry date has passed, it may not work as well.

The hospital or clinic where you will be receiving XOFIGO will make sure that XOFIGO is not used if the expiry date printed on the pack has passed or if the packaging is torn or shows signs of tampering.

XOFIGO is not to be used in women.

The safety and efficacy in children and adolescents under 18 years of age have not been studied.

Before you are given it

Tell your doctor if you have any of the following medical conditions:

  • bone marrow suppression (a severe problem with your bone marrow which can lead to a decreased production of blood cells)
  • untreated spinal cord compression which is already established or is about to happen (this can be caused by a tumour or other lesion)
  • a bone fracture
  • Crohn’s disease (chronic inflammatory disease of the intestines)
  • ulcerative colitis (chronic inflammation of the colon)

XOFIGO can lead to a decrease in the number of white blood cells (which are necessary to help fight infection) and/or platelets (which are necessary to control blood clotting).

Before starting treatment with XOFIGO, your doctor will perform blood tests to check your blood cells and platelet levels. Some of these tests will be repeated before each subsequent treatment (injection). Depending on the results of these tests, your doctor will decide if the treatment can be started, continued or needs to be postponed or discontinued.

Additionally, there are uncertainties about the effects of XOFIGO in combination with other medicines used to treat metastatic prostate cancer. If you are already taking one of those medicines, please tell your doctor.

If you plan to take XOFIGO following treatment with abiraterone and prednisone/prednisolone, you must wait 5 days before starting treatment with XOFIGO. If you plan to take other cancer therapy following treatment with XOFIGO, you must wait at least 30 days before starting treatment.

If you have osteoporosis or a known increased risk for fractures (e.g. recent bone fracture, fragility), or take or have been taking steroids (e.g. prednisone/prednisolone), please tell your doctor. You might be at a higher risk of bone fractures. Your doctor might prescribe you a drug to prevent bone fractures before starting or continuing treatment with XOFIGO. If you experience a bone fracture, your doctor will first stabilise the fractured bone before starting or continuing treatment with XOFIGO.

Tell your doctor if you are intending to have children. Radiation may have an effect on the production or development of your sperm.

Ask your doctor how this may affect you, especially if you are planning to have children in the future. You may wish to seek advice on conservation of sperm prior to treatment.

If you have not told your doctor about any of the above, tell your doctor before you are given XOFIGO.

Taking other medicines

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

Tell your doctor if you are taking chemotherapy (other medicines to treat your cancer). There are uncertainties about the effects of XOFIGO in combination with other systemic medicines used to treat metastatic prostate cancer. If you are already taking one of those medicines, please tell your doctor.

In some cases, using XOFIGO and chemotherapy together may cause a more severe decrease in the number of your white blood cells and/or platelets.

If you take or have taken bisphosphonates or other medicines to protect your bone health or steroids (e.g. prednisone/prednisolone) prior to treatment with XOFIGO, please tell your doctor. You might be at a higher risk for bone fractures.

Your doctor or treatment provider has more information on medicines to be careful with or avoid when you are given XOFIGO.

HOW XOFIGO IS GIVEN

There are strict laws on the use, handling and disposal of products like XOFIGO. XOFIGO can only be used in specialised hospitals or clinics.

XOFIGO must only be handled and given to you by a qualified doctor or other qualified healthcare professional who is trained and licensed to use it safely.

If you have any questions, ask your doctor.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions given, ask your doctor for help.

How much is given

The dose you receive depends on your body weight. The qualified doctor supervising the procedure will calculate the quantity of XOFIGO to be used in your case.

The recommended quantity to be administered is 55 kBq of XOFIGO per kilogram of your body weight.

No dosage adjustment is needed in elderly patients, or if you have poor kidney or liver function.

How it is given

XOFIGO is injected slowly (generally up to 1 minute) into your veins (intravenously).

The healthcare professional administering XOFIGO will flush the intravenous access line or cannula before and after the injection with a saline solution.

XOFIGO is a ready-to-use solution and should not be diluted or mixed with any solutions.

When it is given

Your doctor will decide when you will be given XOFIGO.

How long to continue treatment

Continue treatment with XOFIGO for as long as your doctor tells you.

You will usually be given an injection of XOFIGO once every 4 weeks for a total of 6 injections.

If you forget a treatment

If you miss a treatment with XOFIGO, contact your doctor to make a new appointment for injection as soon as possible.

Do not stop treatment with XOFIGO unless your doctor tells you to do so.

If you are given too much (overdose)

It is unlikely that you will be given too much XOFIGO. The dose of XOFIGO you will receive will be calculated by a qualified doctor and given to you in a highly specialised setting by the qualified doctor or other qualified healthcare professional.

If you receive too much XOFIGO, you will need to be monitored for gastrointestinal symptoms and your doctor will need to perform blood tests on you to check for any changes in your blood counts.

If an overdose is suspected, immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764 766) or go to Accident and Emergency at your nearest hospital.

WHILE YOU ARE BEING TREATED WITH XOFIGO

Things you must do

Your doctor who supervises the procedure will let you know if you need to take any special precautions after receiving XOFIGO.

Follow good hygiene after receiving XOFIGO.

XOFIGO is excreted from your body mainly via the faeces.

You should adhere to good personal hygiene practices while receiving XOFIGO and for at least 4 weeks after the last injection in order to minimise radiation exposure from bodily fluids to household members and caregivers.

Flush the toilet twice and wash your hands well after going to the bathroom.

Clothing soiled with bodily fluids, such as faecal matter or urine, should be washed promptly and separately from other clothing.

When handling bodily fluids, you and your caregiver should wear protective gloves and wash your hands thoroughly afterwards.

Contact your doctor if you have any questions.

Make sure you keep all your doctor's appointments so your progress can be checked. Your doctor will need to perform blood tests to check your blood cells and platelet levels before giving each dose of XOFIGO.

If you are told that your blood count has become abnormally low, ask your doctor for advice on the precautions you can take to reduce the risk of infection or bleeding.

Use an effective birth control method during and for 6 months after treatment with XOFIGO if you are having sex with a woman who can become pregnant. Your partner should also use an effective contraceptive method.

SIDE EFFECTS

Tell your doctor as soon as possible if you do not feel well while you are being treated with XOFIGO.

XOFIGO helps most people, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • diarrhoea
  • vomiting
  • nausea (feeling sick)

Tell your doctor as soon as possible if you notice any of the following:

  • redness of the skin, pain and swelling at the injection site
  • symptoms of anaemia like tiredness, being short of breath and looking pale

The most serious side effects in patients receiving XOFIGO are:

  • low platelet count in the blood (thrombocytopenia)
  • low number of neutrophils which are a class of white blood cells (neutropenia)
  • bone fractures

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • bleeding or bruising more easily than normal
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers

The above side effects may be signs that your blood cells and/or platelet levels are too low. You may need urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

AFTER YOU ARE TREATED WITH XOFIGO

Storage

You will not have to store XOFIGO. The hospital or clinic where you will be receiving XOFIGO will be responsible for storing XOFIGO properly.

Disposal

Each XOFIGO vial is to be used for one injection only and then discarded.

The hospital or clinic where you will be receiving XOFIGO will be responsible for discarding any unused contents properly.

PRODUCT DESCRIPTION

What it looks like

XOFIGO is a clear and colourless solution for injection, supplied in a glass vial and packed in a lead container.

Each pack of XOFIGO contains one single-dose vial. Each vial contains 6 mL of radium-223 solution for injection corresponding to a total activity of 6.6 MBq (1100 kBq/mL) at the reference date.

Ingredients

Active ingredient:

  • radium (223Ra) dichloride

Inactive ingredients:

  • hydrochloric acid
  • sodium chloride
  • sodium citrate dihydrate
  • water for injection

Supplier

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Australian registration number

AUST R 208905

Date of preparation

January 2019

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

® Registered Trademark of the Bayer Group, Germany.

© Bayer Australia Ltd.

All rights reserved.

Published by MIMS April 2019

BRAND INFORMATION

Brand name

Xofigo

Active ingredient

Radium Ra 223 dichloride

Schedule

Unscheduled

 

1 Name of Medicine

Xofigo solution for injection.

6.7 Physicochemical Properties

Chemical structure.

Not applicable.
Structural Formula: The active moiety of the radium (223Ra) dichloride drug substance is the divalent cation of radium-223 (223Ra2+).
Molecular Formula: 223RaCl2.
Molecular Weight: 293.9 g/mol.
CAS Name: Radium-223 chloride (223RaCl2).

CAS number.

444811-40-9.

2 Qualitative and Quantitative Composition

Each mL of solution contains 1100 kBq radium (223Ra) dichloride (Ra-223 dichloride), corresponding to 0.58 nanogram Ra-223, at the reference date. Radium is present in the solution as a free ion.
Ra-223 is an alpha particle emitter with a half-life of 11.4 days. The specific activity of Ra-223 is 1.9 MBq/nanogram.
The six stage decay of Ra-223 to lead-207 occurs via short lived daughters and is accompanied by a number of alpha, beta and gamma emissions with different energies and emission probabilities. The fraction of energy emitted from Ra-223 and its daughters as alpha particles is 95.3% (energy range of 5.0-7.5 MeV). The fraction emitted as beta particles is 3.6% (average energies are 0.445 MeV and 0.492 MeV), and the fraction emitted as gamma radiation is 1.1% (energy range of 0.01-1.27 MeV). See Figure 1.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Xofigo is a clear, colourless and sterile isotonic solution for injection with pH between 6 and 8.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Xofigo is a therapeutic alpha particle emitting pharmaceutical with targeted antitumour effect on bone metastases.
The active moiety of Xofigo is the isotope Ra-223 (as Ra-223 dichloride), which mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha particles (80 keV/micrometre) leads to a high frequency of double strand DNA breaks in adjacent cells of the tumour and the bone microenvironment such as tumour promoting osteoblasts and osteoclasts, resulting in a potent and localised antitumour effect. The alpha particle range from Ra-223 is less than 100 micrometres (less than 10 cell diameters) which minimises damage to the surrounding normal tissue.
Compared with placebo, there was a significant difference in favour of Xofigo for all five serum biomarkers for bone turnover studied in a phase II randomised study [bone formation markers: bone alkaline phosphatase (ALP), total ALP and procollagen I N propeptide (PINP); and bone resorption markers: C-terminal crosslinking telopeptide of type I collagen / serum C-terminal crosslinked telopeptide of type I collagen (S-CTX-I) and type I collagen crosslinked C-telopeptide (ICTP)].

Clinical trials.

The clinical safety and efficacy of Xofigo have been evaluated in a double blind, randomised, multiple dose, phase III, multicentre study (ALSYMPCA) in castration resistant prostate cancer patients with symptomatic bone metastases. Patients with visceral metastases and malignant lymphadenopathy exceeding 3 cm were excluded.
The primary efficacy endpoint was overall survival (OS). Main secondary endpoints included time to symptomatic skeletal events (SSE), time to total alkaline phosphatase (ALP) progression, time to prostate specific antigen (PSA) progression, total ALP response and total ALP normalisation.
At the cutoff date of the preplanned interim analysis, a total of 809 patients were randomised 2:1 to receive Xofigo 55 kBq/kg intravenously every 4 weeks for 6 cycles (N = 541) plus best standard of care (BSoC) or matching placebo plus BSoC (N = 268). BSoC included, for example, local external beam radiotherapy, bisphosphonates, corticosteroids, antiandrogens, oestrogens, estramustine and ketoconazole. At the recommendation of the Independent Data Monitoring Committee, the study was unblinded after the interim analysis due to evidence of favourable efficacy based on the prespecified stopping criteria. An updated descriptive analysis of safety and of overall survival was performed in 921 randomised patients prior to implementing crossover (i.e. prior to offering Xofigo treatment to patients in the placebo group).
Patients with Crohn's disease, ulcerative colitis, visceral metastases, prior hemibody radiation and untreated imminent or established spinal cord compression were excluded from the study. Demographic and baseline disease characteristics (interim analysis population) were comparable between the Xofigo and placebo groups and are shown below for Xofigo:
the mean age of patients was 70 years (range 49 to 90 years);
87% of patients enrolled had an ECOG performance status score of 0-1;
41% received bisphosphonates;
42% of patients did not receive prior docetaxel because they were deemed ineligible or refused to receive docetaxel;
46% of patients had no pain or WHO scale 1 (asymptomatic or mildly symptomatic) and 54% had pain WHO scale 2-3;
16% of patients had < 6 bone metastases, 44% of patients had between 6 and 20 bone metastases, and 40% of patients had more than 20 bone metastases or superscan.
During the treatment period, 83% of patients received luteinising hormone-releasing hormone (LHRH) agonists and 21% of patients received antiandrogens concomitantly.
The results of both interim and updated analysis revealed that OS was significantly longer in patients treated with Xofigo plus BSoC compared to patients treated with placebo plus BSoC (see Table 4 and Figure 2). For both databases, the OS improvement was 44% based on the hazard ratios.
For the interim analysis, an increase in median OS of 2.8 months was seen with Xofigo plus BSoC compared to placebo plus BSoC with a more than 30% reduction in the risk of death. For the updated analysis, an increase in median OS of 3.6 months was seen with Xofigo plus BSoC compared to placebo plus BSoC.
Subgroup survival analysis showed a consistent survival benefit for treatment with Xofigo, independent of total alkaline phosphatase (ALP), use of bisphosphonates at baseline and prior use of docetaxel.
The results of the interim analysis and the updated analysis also showed a significant improvement in all main secondary endpoints in the Xofigo arm compared to the placebo arm (see Table 5).
Occurrence of symptomatic skeletal events (SSE, defined as occurrence of any of the following: external beam radiotherapy to relieve pain, or spinal cord compression, or tumour related orthopaedic surgical intervention or pathologic fracture) was significantly delayed in patients receiving Xofigo compared to patients receiving placebo (see Table 5).
The delay of occurrence of SSE with Xofigo was mainly driven by the statistically significant delay in time to external beam radiation therapy (EBRT) for pain relief.
A delay in time to spinal cord compression was observed in patients receiving Xofigo compared to patients receiving placebo.
A delay in time to surgical intervention was observed in patients receiving Xofigo compared to patients receiving placebo.
A delay in time to bone fracture was observed in patients receiving Xofigo compared to patients receiving placebo.
Treatment with Xofigo was superior to placebo in prolonging the time to total ALP progression (defined as ≥ 25% increase compared to baseline/ nadir). Time to PSA progression (defined as a ≥ 25% increase and an increase in absolute value of ≥ 2 nanogram/mL compared to baseline/ nadir) was also significantly prolonged in patients receiving Xofigo compared to patients receiving placebo (see Table 5).
A higher percentage of patients in the Xofigo group achieved total ALP response (confirmed ≥ 30% reduction compared to baseline) at week 12 compared to the placebo group (Interim analysis: 46.2% in the Xofigo group, 2.5% in the placebo group, p < 0.001).
A higher percentage of patients in the Xofigo group reached total ALP normalisation (defined as return of total ALP value to within normal range) at week 12 compared to the placebo group (Interim analysis: 32.9% in the Xofigo group, 0.9% in the placebo group, p < 0.001).

Quality of life.

Health related quality of life (HRQOL) was assessed in the phase III ALSYMPCA study using specific questionnaires: the EQ-5D (generic instrument) and the FACT-P (prostate cancer specific instrument). Results from the EQ-5D analysis showed that Xofigo had greater HRQOL benefits over the course of the trial as measured by the utility index (-0.101 versus -0.161, p = 0.002) and self reported visual analogue health status scores (-5.225 versus -8.516, p = 0.008) compared to placebo. The FACT-P analyses demonstrated that, relative to placebo over the course of the trial, Xofigo was associated with significantly greater HRQOL as measured by the FACT-P total score (-4.828 versus -8.689, p = 0.004). Visit specific analysis showed that at week 16 there was improvement in the FACT-P total score (p = 0.006), trial outcome index score (p = 0.012), FACT-G score (p = 0.004), emotional wellbeing (p < 0.001), functional wellbeing (p = 0.012) and prostate cancer subscale (p = 0.012). All patients received best standard of care.

Pain relief.

The results from the phase III ALSYMPCA study (time to EBRT for pain relief and fewer patients reporting bone pain as an adverse event in the Xofigo group) indicate a positive effect on bone pain. This is further supported by the effects seen on bone pain using specific pain measures in a single dose phase II study.

Subsequent use of cytotoxic drugs.

In the course of the 2:1 randomised ALSYMPCA study, 93 (15.5%) patients in the Xofigo group and 54 (17.9%) patients in the placebo group received cytotoxic chemotherapy at varying times after the last treatment. No differences in haematological laboratory values were apparent between the two groups.

5.2 Pharmacokinetic Properties

Pharmacokinetic, biodistribution and dosimetry data have been obtained from three phase I studies. Pharmacokinetic data were obtained in 25 patients at doses ranging from 51 to 276 kBq/kg. Pharmacokinetic, biodistribution and dosimetry data were obtained in 6 patients at a dose of 110 kBq/kg given twice, 6 weeks apart, and in 10 patients at a dose of 55, 110 or 221 kBq/kg.
The pharmacokinetics of Ra-223 dichloride were linear in the dose range investigated (51 to 276 kBq/kg).

Absorption.

Xofigo is administered as an intravenous injection and is therefore 100% bioavailable.

Distribution.

After intravenous injection, Ra-223 is cleared rapidly from the blood and is incorporated primarily into bone and bone metastases, or is excreted into the intestine.
Fifteen minutes postinjection, about 20% of the injected activity remained in the blood. At 4 hours, about 4% of the injected activity remained in the blood, decreasing to less than 1% at 24 hours after the injection. The volume of distribution was higher than the blood volume indicating distribution to peripheral compartments.
At 10 minutes postinjection, activity was observed in the bone and in the intestine. At 4 hours postinjection, the mean percentage of the radioactive dose present in bone and intestine was approximately 61% and 49%, respectively.
No significant uptake was seen in other organs such as heart, liver, kidneys, urinary bladder and spleen at 4 hours postinjection.

Metabolism.

Ra-223 is an isotope which decays and is not metabolised.

Excretion.

Faecal excretion is the major route of elimination from the body. About 5% is excreted in the urine and there is no evidence of hepatobiliary excretion.
Whole body measurements at 7 days after injection (after correcting for decay) indicated that a median of 76% of administered activity had been excreted from the body. The rate of elimination of Ra-223 dichloride from the gastrointestinal tract is influenced by the high variability in intestinal transit rates across the population, with the normal range from once daily to once weekly bowel evacuation.

Additional information on special populations.

Patients with hepatic impairment.

No pharmacokinetic studies in patients with hepatic impairment have been conducted. However, since Ra-223 as an isotope is not metabolised, it is not expected that hepatic impairment will affect the pharmacokinetics of Ra-223 dichloride (see Section 4.2 Dose and Method of Administration).

Patients with renal impairment.

No pharmacokinetic studies in patients with renal impairment have been conducted. However, since excretion in urine is minimal and the major route of elimination is via the faeces, it is not expected that renal impairment will affect the pharmacokinetics of Ra-223 dichloride (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Studies on the mutagenic potential of Xofigo have not been performed. However, radium-223 dichloride acts by the induction of double strand breaks in DNA, a known effect of radiation.

Carcinogenicity.

Studies on the carcinogenic potential of Xofigo have not been performed. Osteosarcomas, a known effect of bone seeking radionuclides, were observed at clinically relevant doses in repeat dose toxicity studies in rats 7 to 12 months after start of treatment.

4 Clinical Particulars

4.1 Therapeutic Indications

Xofigo is indicated for the treatment of castration resistant prostate cancer patients with symptomatic bone metastases and no known visceral metastatic disease.

4.3 Contraindications

Xofigo is contraindicated in combination with abiraterone acetate plus prednisone/prednisolone (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Bone marrow suppression.

Bone marrow suppression, notably thrombocytopenia, neutropenia, leucopenia and pancytopenia, has been reported in patients treated with Xofigo (see Section 4.8 Adverse Effects (Undesirable Effects)).
Haematological evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and haemoglobin ≥ 100 g/L. Before subsequent administrations, the ANC should be ≥ 1.0 x 109/L and the platelet count ≥ 50 x 109/L. In case there is no recovery in these values within 6 weeks after the last administration of Xofigo despite receiving standard of care, further treatment with Xofigo should only be continued after a careful benefit/ risk evaluation.
Patients with evidence of compromised bone marrow reserve should be treated with caution.

Crohn's disease and ulcerative colitis.

Safety and efficacy of Xofigo in patients with Crohn's disease and with ulcerative colitis have not been studied.

Spinal cord compression.

In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting or resuming treatment with Xofigo.

Bone fractures.

In patients with bone fractures, orthopaedic stabilisation of fractures should be performed before starting or resuming treatment with Xofigo.

Contraception.

Because of potential effects on spermatogenesis associated with radiation, men who are sexually active should be advised to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and up to 6 months after completing treatment with Xofigo.

Combination with abiraterone plus prednisone/prednisolone [ERA-223 trial] or with systemic cancer therapies other than luteinising hormone-releasing hormone (LHRH) analogues.

The clinical efficacy and safety of concurrent initiation of Xofigo treatment and abiraterone acetate plus prednisone/prednisolone treatment was assessed in a randomised, placebo-controlled multicentre phase 3 study (ERA-223 trial) in 806 chemotherapy-naïve patients with asymptomatic or mildly symptomatic castration resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee Recommendation.
At the primary analysis an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) among patients receiving Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients receiving placebo in combination with abiraterone acetate plus prednisone/prednisolone was observed. Concurrent use of bisphosphonates or denosumab reduced the incidence of fractures in both treatment arms.
Therefore, Xofigo is contraindicated in combination with abiraterone acetate plus prednisone/prednisolone (see Section 4.3 Contraindications).
Safety and efficacy of Xofigo in combination with cancer therapies other than LHRH analogues have not been established; an increased risk of mortality and fractures is possible. The combination of radium-223 with other systemic cancer therapies other than LHRH analogues is therefore not recommended.
Data on a safe period after which Xofigo can be administered following treatment with abiraterone acetate in combination with prednisone/prednisolone and vice versa is limited. Based on the elimination half-life of Xofigo and abiraterone, it is recommended that subsequent treatment with Xofigo is not initiated for at least 5 days after the last administration of abiraterone acetate in combination with prednisone/prednisolone. Subsequent systemic cancer treatment should not be initiated for at least 30 days after the last administration of Xofigo.

Treatment of patients with asymptomatic or mildly symptomatic bone metastases.

An increased risk of death and fractures was observed in a clinical study, where Xofigo was added to abiraterone acetate and prednisone/prednisolone in patients with asymptomatic or mildly symptomatic castration resistant prostate cancer.
Treatment benefit of Xofigo in adults with castration-resistant prostate cancer and only asymptomatic bone metastases is not established. In adults with castration resistant prostate cancer and mildly symptomatic bone metastases the benefit of treatment should be carefully assessed to outweigh the risks considering that high osteoblastic activity is likely to be required for treatment benefit.

Bone fractures.

Xofigo increases the risk of bone fractures. In a clinical study, the addition of Xofigo to abiraterone acetate and prednisone/prednisolone increased the incidence of fractures approximately three-fold in the Xofigo arm (see Section 4.4 Special Warnings and Precautions For Use, Combination with abiraterone plus prednisone/prednisolone [ERA-223 trial] or with systemic cancer therapies other than luteinising hormone-releasing hormone (LHRH) analogues). Increased fracture risk has been found especially in patients with medical history of osteoporosis and in patients with less than 6 bone metastases. Xofigo is believed to accumulate at sites of high bone turnover such as sites of degenerative bone disease (osteoporosis) or recent (micro-) fracture increasing the risk of fractures. Other factors such as concomitant use of steroids may further increase the risk of fracture.
Prior to starting radium-223 bone status (e.g. by scintigraphy, bone mineral density measurement) and baseline risk of fractures of patients (e.g. osteoporosis, less than 6 bone metastases, medication increasing fracture risk, low body mass index) should be carefully assessed, and closely monitored for at least 24 months. Preventive measures such as the use of bisphosphonates or denosumab should be considered before starting or resuming treatment with Xofigo. In patients with a high baseline risk of fracture, the benefit of treatment should be carefully assessed to outweigh the risk. In patients with bone fractures, orthopaedic stabilisation of fractures should be performed before starting or resuming treatment with Xofigo.

Use in the elderly.

Of the 600 patients treated with Xofigo in the ALSYMPCA phase III study, 447 patients (74.5%) were 65 years of age and over, while 196 patients (32.7%) were 75 years of age and over. No overall differences in safety or effectiveness were observed between patients aged ≥ 65 years and patients aged < 65 years. No dose adjustment is considered necessary in elderly patients.

Paediatric use.

The safety and efficacy of Xofigo in children and adolescents below 18 years of age have not been studied.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical interaction studies have been performed. Concomitant chemotherapy with Xofigo may have additive effects on bone marrow suppression (see Section 4.4 Special Warnings and Precautions for Use, Bone marrow suppression). Safety and efficacy of concomitant chemotherapy with Xofigo have not been established.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effect of Xofigo on fertility. No animal fertility or reproduction studies have been conducted with Xofigo. Patients should be informed of a potential risk that radiation from Xofigo could cause adverse effects on testes and impair fertility (see Section 4.4 Special Warnings and Precautions for Use, Contraception).
(Category X)
Xofigo is not indicated in women. Xofigo, a radioactive therapeutic agent, is not to be used in women who are or may be pregnant.
Xofigo is not indicated in women. Xofigo, a radioactive therapeutic agent, is not to be used in women who are breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

The overall safety profile of Xofigo is based on data from 600 patients treated with Xofigo in the ALSYMPCA phase III study.
The most serious adverse drug reactions were thrombocytopenia and neutropenia (see Section 4.4 Special Warnings and Precautions for Use, Bone marrow suppression and below for description of selected adverse reactions). The most frequently observed adverse drug reactions (≥ 10%) in patients receiving Xofigo were diarrhoea, nausea, vomiting and thrombocytopenia.
Table 3 shows adverse reactions occurring in ≥ 1% of patients treated with Xofigo or placebo. Adverse reactions are identified using MedDRA version 14.1 and graded according to CTCAE version 3.0.
An additional clinically important adverse reaction observed in less than 1% of Xofigo treated patients and at a higher incidence than in placebo treated patients was lymphopenia (0.8% versus 0.3%).

Thrombocytopenia and neutropenia.

Thrombocytopenia (all grades) occurred in 11.5% of patients treated with Xofigo and 5.6% of patients receiving placebo. Grade 3 and 4 thrombocytopenia was observed in 6.3% of patients treated with Xofigo and in 2% of patients receiving placebo (see Section 4.4 Special Warnings and Precautions for Use, Bone marrow suppression). Overall, the frequency of grade 3 and 4 thrombocytopenia was lower in patients that did not previously receive docetaxel (2.8% in patients treated with Xofigo versus 0.8% in patients receiving placebo) compared to patients that previously received docetaxel (8.9% in patients treated with Xofigo versus 2.9% in patients receiving placebo).
Neutropenia (all grades) was reported in 5% of patients treated with Xofigo and in 1% of patients receiving placebo. Grade 3 and 4 neutropenia was observed in 2.2% of patients treated with Xofigo and in 0.7% of patients receiving placebo. Overall, the frequency of grade 3 and 4 neutropenia was lower in patients that did not previously receive docetaxel (0.8% in patients treated with Xofigo versus 0.8% in patients receiving placebo) compared to patients that previously received docetaxel (3.2% in patients treated with Xofigo versus 0.6% in patients receiving placebo).
In a phase I study, neutrophil and platelet count nadirs occurred at 2 to 3 weeks after intravenous administration of a single dose of Xofigo.

Injection site reactions.

Grade 1 and 2 injection site reactions, such as erythema, pain and swelling, were reported in 1.2% of patients treated with Xofigo and in 0% of patients receiving placebo.

Secondary malignant neoplasms.

Xofigo contributes to a patient's overall long-term cumulative radiation exposure.
Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. No cases of Xofigo induced cancer have been reported in clinical trials in follow-up of up to three years.

Bone fractures and osteoporosis.

See Section 4.4 Special Warnings and Precautions for Use, Bone fractures.

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 www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage (dose and interval).

The dose regimen of Xofigo is 55 kBq per kg body weight, given at 4 week intervals for 6 injections.
Safety and efficacy beyond 6 injections have not been studied.
For details on the calculation of the volume to be administered, see Method of administration.

Additional information on special populations.

No dose adjustment is considered necessary in the elderly or in patients with renal or hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Xofigo is to be administered by slow intravenous injection (generally up to 1 minute). The intravenous access line or cannula must be flushed with isotonic saline before and after injection.
Xofigo should be inspected visually before use. Xofigo is a clear, colourless solution and should not be used in case of discolouration, the occurrence of particulate matter or a defective container.
Xofigo is a ready to use solution and should not be diluted or mixed with any solutions. In the absence of compatibility studies, Xofigo must not be mixed with other medicinal products.
Each vial is for single use in one patient only. Discard any residue as described under Radiation protection.
The volume to be administered to a given patient should be calculated using the:
patient's body weight (kg);
dose (55 kBq/kg body weight);
radioactivity concentration of the product (1100 kBq/mL) at reference date. The reference date is stated on the vial and lead container label;
decay correction (DK) factor to correct for physical decay of radium-223. A table of DK factors is provided with each vial (see Table 1).
The total volume to be administered to a patient is calculated as follows (see Equation 1).
The decay correction factor table is corrected to 12 noon Australian Eastern Standard Time (AEST). To determine the decay correction factor, count the number of days before or after the reference date. The decay correction factor table includes a correction to account for the 9 hour time difference between 12 noon Central European Time (CET) at the site of manufacture and 12 noon AEST, which is 9 hours earlier than CET. Changes due to daylight savings are not included in this table as the difference of 1 hour is not considered significant for a radionuclide with an 11.4 day half-life.

Instructions for use and handling.

Xofigo (an alpha particle emitting pharmaceutical) should be received, used and administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings. The receipt, storage, use, transfer and disposal of Xofigo are subject to license and regulation by the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA).
Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Radiation protection.

The gamma radiation associated with the decay of Ra-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contaminations with standard instruments.
The administration of Xofigo is associated with potential risks for other persons (e.g. medical staff, care givers and patient's household members) from radiation or contamination from body fluids such as spills of urine, faeces and vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. Although Ra-223 is predominantly an alpha emitter, gamma and beta radiation is associated with the decay of Ra-223 and its radioactive daughter isotopes. The external radiation exposure associated with handling of patient doses is considerably lower in comparison to other radiopharmaceuticals for therapeutic purposes as the administered radioactivity will usually be below 8 MBq. However, in keeping with the ALARA (As Low As Reasonably Achievable) principle for minimisation of radiation exposure, it is recommended to minimise the time spent in radiation areas, to maximise the distance to radiation sources, and to use adequate shielding.
Any unused product or materials used in connection with preparation or administration of Xofigo are to be treated as radioactive waste and should be disposed of in accordance with the Code of Practice for the Disposal of Radioactive Wastes by the User. This code is published on the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) website as Radiation Health Series (RHS) No. 13.

Dosimetry.

The absorbed radiation dose calculation was performed based on clinical biodistribution data. Calculations of absorbed doses were performed using OLINDA/EXM (Organ Level INternal Dose Assessment/ EXponential Modeling), software based on the Medical Internal Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting radionuclides. For Ra-223, primarily an alpha emitter, additional assumptions were made for the intestine, red marrow and bone/ osteogenic cells, to provide the best possible absorbed dose calculations for Xofigo, considering its observed biodistribution and specific characteristics.
The calculated absorbed radiation doses to different organs are listed in Table 2 (mGy/MBq). The organs with highest absorbed radiation doses were bone (osteogenic cells), red marrow, upper large intestine wall and lower large intestine wall. The calculated doses to other organs are lower.
The haematological adverse drug reactions observed in the clinical studies with Xofigo are much lower in frequency and severity than what could be expected from the calculated absorbed doses to the red marrow. This may be related to spatial distribution of alpha particle radiation resulting in nonuniform radiation dose to the red marrow.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

There have been no reports of inadvertent overdosing of Xofigo during clinical studies.
There is no specific antidote. In the event of an inadvertent overdose, general supportive measures, including monitoring for potential haematological and gastrointestinal toxicity should be undertaken.
Single Xofigo doses up to 276 kBq per kg body weight were evaluated in a phase I clinical trial and no dose limiting toxicities were observed.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

Unscheduled.

6 Pharmaceutical Particulars

6.1 List of Excipients

The solution also contains hydrochloric acid, sodium chloride, sodium citrate dihydrate 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

Store below 40°C. Storage should be in accordance with national regulations on radioactive materials.

6.5 Nature and Contents of Container

Xofigo is a ready-to-use, clear and colourless solution for injection supplied in one single dose glass vial closed with a rubber stopper. The vial is wrapped with an adhesive transparent film and stored in a lead container.
Each vial contains 6 mL Ra-223 solution for injection with an activity concentration of 1100 kBq per mL (corresponding to a total activity of 6.6 MBq per vial) at the reference date.
Xofigo should not be used in case of discolouration, the occurrence of particulate matter or a defective container.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes