Consumer medicine information

Crysvita

Burosumab

BRAND INFORMATION

Brand name

Crysvita

Active ingredient

Burosumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Crysvita.

SUMMARY CMI

CRYSVITA®

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new. Please report side effects. See the full CMI for further details.

1. Why am I using CRYSVITA?

CRYSVITA contains the active ingredient burosumab. CRYSVITA is used to treat X-linked hypophosphataemia (XLH)

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

2. What should I know before I use CRYSVITA?

Do not use if:

  • you have ever had an allergic reaction to CRYSVITA or any of the ingredients listed at the end of the CMI.
  • you are taking any phosphate supplements or certain vitamin D supplements (that contain so called active vitamin D, e.g. calcitriol)
  • you already have a normal to high level of phosphate in your blood
  • you have severe kidney disease or kidney failure.

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

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

3. What if I am taking other medicines?

Some medicines may affect how CRYSVITA works.

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

4. How do I use CRYSVITA?

  • CRYSVITA should be given by injection by a trained healthcare provider.
  • The dose is based on your body weight. Your doctor will work out the right dose for you.

More instructions can be found in Section 4. How do I use CRYSVITA? in the full CMI.

5. What should I know while using CRYSVITA?

Things you should do
  • Stop taking CRYSVITA and tell your doctor straight away if you have any of the following side effects, as they could be signs of an allergic reaction: rash and itching all over the body, severe swelling of eyelids, mouth, or lips (angiooedema), shortness of breath, rapid heartbeat, sweating.
  • You may get skin reactions where the injection is given. If these reactions are severe, tell your doctor.
  • Remind any doctor, dentist, or pharmacist you visit that you are using CRYSVITA.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how CRYSVITA affects you.
Looking after your medicine
  • Store in a refrigerator (2°C to 8°C). Do not freeze.
  • Keep the vial in the outer carton in order to protect from light.

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

6. Are there any side effects?

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

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

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

CRYSVITA®

Active ingredient: burosumab

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

1. Why am I using CRYSVITA?
2. What should I know before I use CRYSVITA?
3. What if I am taking other medicines?
4. How do I use CRYSVITA?
5. What should I know while using CRYSVITA?
6. Are there any side effects?
7. Product details

1. Why am I using CRYSVITA?

CRYSVITA contains the active ingredient burosumab. This is a type of medicine called a human monoclonal antibody.

CRYSVITA is used to treat X-linked hypophosphataemia (XLH). It is used in adults and children of 1 year and older.

X-Linked Hypophosphataemia (XLH) is a genetic disease.

  • People with XLH have higher levels of a hormone called fibroblast growth factor 23 (FGF23).
  • FGF23 lowers the amount of phosphate in the blood.
  • The low level of phosphate may:
    - lead to bones that may not harden properly and, in children and adolescents, cannot grow properly
    - result in pain and stiffness in bones and joints

CRYSVITA attaches to FGF23 in the blood which stops FGF23 from working and increases the phosphate levels in the blood so that normal levels of phosphate can be achieved.

2. What should I know before I use CRYSVITA?

Warnings

Do not use CRYSVITA if:

  • you are allergic to burosumab, or any of the ingredients listed at the end of this leaflet.
  • you are taking any phosphate supplements or certain vitamin D supplements (that contain so called active vitamin D, e.g. calcitriol)
  • you already have a normal to high level of phosphate in your blood
  • you have severe kidney disease or kidney failure.

Always check the ingredients to make sure you can use this medicine.

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

Pregnancy and breastfeeding

Burosumab is not recommended for use during pregnancy. Check with your doctor if you are pregnant or intend to become pregnant.

Women of childbearing potential who take CRYSVITA should discuss the use of contraception with their doctor.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if CRYSVITA will affect the baby.

Tests and checks

Your doctor will check the phosphate and calcium levels in your blood and urine and may also do a renal ultrasound during your treatment in order to reduce the risk of hyperphosphataemia (too much phosphate in the blood) and ectopic mineralisation (a build-up of calcium in tissues such as the kidneys). Your serum parathyroid hormone level will also be checked from time to time.

Children under 1 year

The safety and effects of the medicine have not been studied in children under 1 year of age.

CRYSVITA contains sorbitol

CRYSVITA contains sorbitol

This medicine contains 45.91 mg of sorbitol in each vial which is equivalent to 45.91 mg/ml.

3. What if I am taking other medicines?

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

Before using CRYSVITA, talk to your doctor if you are taking:

  • a type of medicine known as a calcimimetic. Caution is advised when using a combination of a calcimimetic medicine and CRYSVITA.

Do not take CRYSVITA and tell your doctor if you are taking:

  • phosphate supplements
  • certain vitamin D supplements (that contain so called active vitamin D, e.g. calcitriol). There are some vitamin D supplements you can continue or start to use and your doctor will advise which ones these are

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

4. How do I use CRYSVITA?

CRYSVITA should be given by injection under the skin in the arm, abdomen, buttock, or thigh by a trained healthcare provider.

How much to use

  • The dose is based on your body weight. Your doctor will work out the right dose for you.
  • CRYSVITA will be injected
    - every two weeks in children 1 year of age and older
    - every four weeks in adults.
  • Your doctor will perform checks to make sure that you are getting the right dose and may change your dose if needed.
  • The maximum dose you will be given is 90 mg.

If you forget to use CRYSVITA

If a dose is missed, talk to your doctor straight away. The missed dose should be given as soon as possible and your doctor will re-arrange future doses accordingly.

If you use too much CRYSVITA

If you think that you have been given too much CRYSVITA, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using CRYSVITA?

Things you should do

Allergic reactions

Call your doctor straight away if you have any of the following side effects, as they could be signs of an allergic reaction:

  • rash and itching all over the body
  • severe swelling of eyelids, mouth, or lips (angio-oedema)
  • shortness of breath
  • rapid heartbeat
  • sweating.

Do not take CRYSVITA if any of the above apply to you. If you are not sure, talk to your doctor before using CRYSVITA.

Skin reactions

You may get skin reactions where the injection is given, see section 6. Are there any side effects? for more information. If these reactions are severe, tell your doctor.

Remind any doctor, dentist, or pharmacist you visit that you are using CRYSVITA.

Driving or using machines

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

It is possible that CRYSVITA could cause dizziness and affect you being able to ride a bike, use any tools or machines or to drive. If you think you are affected, do not ride a bike, use any tools or machines or drive, and tell your doctor.

Looking after your medicine

  • Do not use CRYSVITA after the expiry date which is stated on the carton and label.
  • Store in a refrigerator (2°C to 8°C). Do not freeze.
  • Keep the vial in the outer carton in order to protect from light.
  • Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

6. Are there any side effects?

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

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

Side effects in children

Side effects in childrenWhat to do
Very common (may affect more than 1 in 10 children)
  • Tooth abscess (infection)
  • Cough
  • Headache
  • Vomiting
  • Nausea
  • Diarrhoea
  • Constipation
  • Tooth decay or cavities
  • Rash
  • Pain in muscles (myalgia) and hands and feet
  • Reactions where the injection was given, which may include:
    - redness or rash
    - pain or itching
    - swelling
    - bleeding or bruising
    These injection site reactions are usually mild and occur within a day after the injection and usually get better in around 1 to 3 days.
  • Fever
Common (may affect up to 1 in 10 children)
  • Dizziness
Speak to your doctor if you have any of these side effects and they worry you.

Side effects in adults

Side effects in adultsWhat to do
Very common (may affect more than 1 in 10 adults)
  • Tooth abscess (infection)
  • Headache
  • Dizziness
  • Restless legs syndrome (irresistible urge to move your legs to stop uncomfortable, painful or odd sensations in the legs especially prior to sleep or at night time)
  • Pain in back
  • Muscle spasm
Common (may affect up to 1 in 10 adults)
  • Constipation
Speak to your doctor if you have any of these side effects and they worry you.

Some side effects such as low vitamin D levels or increased phosphate levels can only be found when your doctor does tests to check your progress.

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

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

Reporting side effects

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

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

7. Product details

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

What CRYSVITA contains

Active ingredient
(main ingredient)		burosumab
Other ingredients
(inactive ingredients)		L-histidine
D-sorbitol
polysorbate 80
L-methionine
10%, hydrochloric acid
water for injections

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

What CRYSVITA looks like

CRYSVITA comes as a clear to slightly opalescent, colourless to pale yellow/brown solution for injection in a small glass vial. Each pack contains 1 vial.

Aust R

340793 (10mg/mL)

340796 (20mg/mL)

340797 (30mg/mL)

Who distributes CRYSVITA

Kyowa Kirin Australia Pty Ltd
Level 7
68 York Street
Sydney, NSW 2000
www.kyowakirin.com/australia

This leaflet was prepared in 09/2021.

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Crysvita

Active ingredient

Burosumab

Schedule

S4

 

1 Name of Medicine

Burosumab.

2 Qualitative and Quantitative Composition

Crysvita 10 mg/mL solution for injection contains 10 mg burosumab in a single use vial.
Crysvita 20 mg/mL solution for injection contains 20 mg burosumab in a single use vial.
Crysvita 30 mg/mL solution for injection contains 30 mg burosumab in a single use vial.
Burosumab is a recombinant human monoclonal IgG1 antibody for FGF23 and is produced by recombinant DNA technology using Chinese hamster ovary mammalian cell culture.

Excipient with known effect.

Each vial contains 45.91 mg sorbitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Sterile, single-use, preservative-free, clear to slightly opalescent, colourless to pale brownish-yellowish solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Crysvita (burosumab) is indicated for the treatment of X-linked hypophosphataemia (XLH) in adults, adolescents and children 1 year of age or older.

4.2 Dose and Method of Administration

Treatment should be initiated and monitored by specialist medical practitioners experienced in the management of patients with metabolic bone disease.

Important dosage and administration information.

Discontinue oral phosphate and active vitamin D analogues (e.g. calcitriol, paricalcitol, doxercalciferol, calcifediol) 1 week prior to initiation of treatment (see Section 4.3 Contraindications). Vitamin D replacement or supplementation with inactive forms of vitamin D may be continued as per local guidelines (see 25-Hydroxy vitamin D supplementation).
Fasting serum phosphate concentration should be below the reference range for age prior to initiation of treatment (see Section 4.3 Contraindications).
Burosumab is administered by subcutaneous injection and should be administered by a healthcare provider.
The maximum volume of burosumab per injection site is 1.5 mL. If multiple injections are required, administer at different injection sites.

Paediatric patients with X-linked hypophosphataemia (children aged 1-11 years and adolescents aged 12-17 years of age).

The recommended starting dose regimen is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, every 2 weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. All doses should be rounded to the nearest 10 mg.
After initiation of treatment with burosumab, fasting serum phosphate should be measured every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If serum phosphate is within the reference range for age, continue with the same dose. Follow dose adjustment schedule in Tables 1 and 2 to maintain serum phosphate within the reference range for age.

Dose adjustment.

Reassess fasting serum phosphate level 4 weeks after dose adjustment.
Do not adjust burosumab more frequently than every 4 weeks.

Dose increase.

If serum phosphate is below the reference range for age, the dose may be increased stepwise up to a maximum of 2.0 mg/kg, rounded to the nearest 10 mg, administered every 2 weeks (maximum dose of 90 mg).

Dose decrease.

If serum phosphate is above the reference range for age, withhold the next dose and reassess the serum phosphate level within 4 weeks. The patient must have serum phosphate below the reference range for age to restart burosumab. Once serum phosphate is below the reference range for age, treatment may be restarted as per Table 2. Reassess serum phosphate level 4 weeks after dose adjustment. If serum phosphate is below the reference range for age 4 weeks after dose adjustment, the dose can be restarted at 0.8 mg/kg every 2 weeks.

Adult patients with X-linked hypophosphataemia (18 years of age and older).

The recommended dose regimen in adults is 1 mg/kg of body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every 4 weeks.
After initiation of treatment with burosumab, measure fasting serum phosphate every 4 weeks, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphate is within the normal range, continue with the same dose.

Dose decrease.

Reassess fasting serum phosphate level 2 weeks after dose adjustment.
Do not adjust burosumab more frequently than every 4 weeks.
If serum phosphate is above the normal range, withhold the next dose and reassess the serum phosphate level within 4 weeks. The patient must have serum phosphate below the normal range to be able to restart burosumab. Once serum phosphate is below the normal range, treatment may be restarted at half the initial starting dose up to a maximum dose of 40 mg every 4 weeks according to the dose schedule shown in Table 3. Reassess serum phosphate 2 weeks after any change in dose.

All patients.

Missed or late dosing.

If a patient misses a dose, resume burosumab as soon as possible at prescribed dose. To avoid missed doses, treatments may be administered 3 days either side of the scheduled treatment date.

25-Hydroxy vitamin D supplementation.

Monitor 25-hydroxy vitamin D levels. Supplement with cholecalciferol or ergocalciferol to maintain 25-hydroxy vitamin D levels in the normal range for age. Do not administer active vitamin D analogues during burosumab treatment (see Section 4.3 Contraindications).

Special populations.

Renal impairment.

Burosumab has not been studied in patients with renal impairment. Burosumab must not be given to patients with severe or end stage renal disease (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

For subcutaneous use.
Burosumab should be injected in the upper arm, abdomen, buttock or thigh. Injection sites should be rotated with each injection administered at a different anatomic location than the previous injection. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. The maximum volume of medicinal product per injection site is 1.5 mL. If more than 1.5 mL is required on a given dosing day, the total volume of medicinal product should be split and should be administered at different injection sites. Injection sites should be rotated and carefully monitored for signs of potential reactions (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.
Concurrent administration with oral phosphate and/or active vitamin D analogues.
Serum phosphate level within or above the normal range for age at initiation of treatment.
Severe renal impairment or end stage renal disease (see Section 5.2 Pharmacokinetic Properties).

4.4 Special Warnings and Precautions for Use

Traceability.

In order to improve the traceability of biological medicinal products, the name and batch number of administered product should be clearly recorded with the patient's records.

Ectopic mineralisation.

Ectopic mineralisation, as manifested by nephrocalcinosis, has been observed in patients with XLH treated with oral phosphate and active vitamin D analogues; these medicinal products should be stopped at least 1 week prior to initiating burosumab treatment (see Section 4.2).
Monitoring for signs and symptoms of nephrocalcinosis, e.g. by renal ultrasonography, is recommended at the start of treatment and every 6 months for the first 12 months of treatment, and annually thereafter. Monitoring of plasma alkaline phosphatase, calcium, parathyroid hormone (PTH) and creatinine is recommended every 6 months (every 3 months for children 1-2 years) or as indicated.
Monitoring of urine calcium and phosphate is suggested every 3 months.

Hyperphosphataemia.

Levels of fasting serum phosphate should be monitored due to the risk of hyperphosphatemia. To decrease the risk for ectopic mineralisation, it is recommended that fasting serum phosphate does not exceed the upper limit of the normal reference range for age. Dose interruption and/or dose reduction may be required (see Section 4.2). Periodic measurement of post prandial serum phosphate is advised.

Serum parathyroid hormone.

Increases in serum parathyroid hormone have been observed in some XLH patients during treatment with burosumab. Periodic measurement of serum parathyroid hormone is advised.

Injection site reactions.

Administration may result in local injection site reactions. Administration should be interrupted in any patient experiencing severe injection site reactions.

Hypersensitivity.

Discontinue burosumab if serious hypersensitivity reactions occur.

Use in the elderly.

No conclusion can be made regarding any differences in safety or efficacy between patients over 65 years of age and those under 65 years of age.

Paediatric use.

The safety and efficacy of burosumab in children with XLH under 1 year of age has not been established in clinical studies.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No pharmacokinetic interaction studies have been performed for burosumab.
Concurrent administration of burosumab with oral phosphate and active vitamin D analogues is contraindicated as it may cause an increased risk of hyperphosphatemia and hypercalcaemia (see Section 4.3).
Caution should be exercised when combining burosumab with calcimimetic medicinal products (i.e. agents that mimic the effect of calcium on tissues by activating the calcium receptor). Co-administration of these medicinal products has not been studied in clinical trials and could potentially exacerbate hypocalcaemia.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no clinical data available on the effect of burosumab on human fertility. The healthcare provider should discuss the use of appropriate contraception with sexually active women and adolescent girls taking burosumab to assist in weighing up the individual risks and benefits. No specific fertility studies in animals with burosumab were conducted, but relevant surrogate endpoints were examined in a general toxicity study in cynomolgus monkeys. Animals were treated with burosumab at doses up to 30 mg/kg every 2 weeks (yielding up to 56 times the exposure in adults at the maximum recommended clinical dose of 1 mg/kg every 4 weeks). Male monkeys showed mineralisation of the rete testis and seminiferous tubules (associated with hyperphosphataemia), but no changes in semen analysis. No adverse effects on reproductive organs to suggest impairment of fertility were observed in female monkeys.
(Category B3)
There are no available data on burosumab use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Adverse effects on embryofetal development were observed with burosumab in animals. Burosumab is not recommended for use during pregnancy. Fetal loss and pre-term births were increased and the gestation period was shortened in pregnant cynomolgus monkeys given burosumab at 30 mg/kg once every 2 weeks (yielding 64 times the exposure in adults as the maximum recommended clinical dose of 1 mg/kg every 4 weeks). This occurred in conjunction with maternal hyperphosphataemia and placental mineralisation. Burosumab was shown to cross the placenta. Ectopic mineralisation was not observed in fetuses or offspring, and treatment did not produce malformations, or affect growth, development or survival of the offspring.
 There are no data on the use of burosumab in breastfeeding women. It is unknown whether burosumab is excreted in human milk, although the presence of the maternal IgG in milk is recognised. A decision must be made whether to discontinue breast feeding or to discontinue / abstain from burosumab therapy taking into account the benefit of breast feeding for the child, the benefit of the therapy for the woman and the potential risk to the child from exposure to burosumab.

4.7 Effects on Ability to Drive and Use Machines

Burosumab may cause dizziness and, as a result, may influence the ability to drive or operate machinery. Patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that burosumab does not affect them adversely.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions reported in paediatric patients with XLH ≥ 1 year of age.

The most common adverse reactions (> 10%) reported in paediatric patients ≥ 1 year of age during clinical trials were injection site reactions (56%), cough (56%), headache (50%), pyrexia (43%), pain in extremity (40%), vomiting (39%), tooth abscess (35%), vitamin D decreased (32%), diarrhoea (25%), rash (24%), nausea (15%), constipation (11%), dental caries (11%) and myalgia (11%). This data is based the integrated safety assessment of 94 subjects who received at least one dose of burosumab and were included in studies UX023-CL201, UX023-CL205 and UX023-CL301.
An overview of adverse reactions observed from burosumab clinical trials and post marketing sources in paediatrics is presented in Table 4.
Description of selected adverse reactions in children with XLH ≥ 1 year of age.

Injection site reactions.

Approximately 56% of the patients had an injection site reaction. The injection site reactions were generally mild in severity, occurred within 1 day of medicinal product injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances.

Hypersensitivity reactions.

The most frequent potential hypersensitivity reaction was rash (18%). The events were mild or moderate in severity.

Adverse events reported in paediatric patients with XLH ≥ 1 year of age in study UX023-CL301.

The most common adverse events in paediatric patients ≥ 1 year of age (reported in ≥ 5% of patients and having a higher incidence with burosumab than with active control) in Study UX023-CL301 are listed in Table 5.

Adverse reactions reported in adult patients with XLH.

The most common adverse reactions reported in adult patients during clinical trials were back pain (23%), headache (21%), tooth infection (19%), restless legs syndrome (13%), muscle spasms (12%), vitamin D decrease (15%) and dizziness (11%). This data is based on the integrated safety assessment of 176 subjects who received at least 1 dose of burosumab and were included in studies UX023-CL203, UX023-CL303, UX023-CL304, KRN23-INT-001 and KRN23-INT-002.
An overview of adverse reactions observed from burosumab clinical trials in adults is presented in Table 6.
Description of selected adverse reactions in adults with XLH.

Injection site reactions.

The frequency of injection site reactions was 12% in both burosumab and placebo treatment groups (injection site reaction, erythema, rash, bruising, pain, pruritus and haematoma). The injection site reactions were generally mild in severity, occurred within 1 day of medicinal product injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances.

Hypersensitivity reactions.

The frequency of hypersensitivity reactions was 6% in both the burosumab and placebo groups. The hypersensitivity reactions were mild to moderate in severity.

Hyperphosphataemia.

In the double-blind period of Study UX023-CL303, 9 of 134 (7%) patients in the burosumab treatment group experienced hyperphosphataemia meeting the protocol-specified criteria for dose reduction. The hyperphosphataemia was managed with dose reduction.

Restless legs syndrome.

Approximately 12% of the burosumab treatment group and 8% in the placebo group had a worsening of baseline restless legs syndrome or new onset restless legs syndrome of mild to moderate severity.

Adverse events reported in adult patients with XLH in study UX023-CL303.

The most common adverse events in adult patients (reported in ≥ 5% of patients and having a higher incidence with burosumab than with placebo) in Study UX023-CL303 are listed in Table 7.

Immunogenicity.

Overall, the incidence of anti-drug antibodies (ADA) to burosumab was < 10% in adults and paediatric subjects administered burosumab. The incidence of neutralising ADA was 3.2% and neutralising ADA were only found in paediatric subjects. No adverse events, loss of efficacy, or changes in pharmacokinetics profile were associated with these findings.

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.

4.9 Overdose

There is no experience with overdose of burosumab. In case of overdose, it is recommended to stop burosumab and to monitor biochemical response. For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Burosumab is a recombinant human monoclonal IgG1 antibody that binds to and inhibits the biological activity of fibroblast growth factor 23 (FGF23), present in excess in X-linked hypophosphataemia. Neutralisation of FGF23 by burosumab increases renal tubular reabsorption of phosphate and the serum concentration of 1, 25 dihydroxy-Vitamin D.

Clinical trials.

Paediatric X-linked hypophosphataemia.

Burosumab has been evaluated in 3 studies enrolling a total of 126 paediatric patients with XLH.
Study UX023-CL301. Paediatric Study UX023-CL301 is a randomised, open-label study in 61 paediatric XLH patients, 1 to 12 years old, that compared treatment with burosumab to active control (oral phosphate and active vitamin D therapy). All patients had radiographic evidence of rickets at baseline, with an RSS score of ≥ 2 and had received oral phosphate and active vitamin D analogues for a mean (SD) duration of 3.8 (3.1) years. Oral phosphate and active vitamin D analogues were discontinued prior to study enrolment for a 7-day washout period and then restarted for patients in the active control group. Patients were randomised to receive either burosumab at a starting dose of 0.8 mg/kg every 2 weeks or oral phosphate and active vitamin D. Patients randomised to active control received a mean oral phosphate dose of approximately 41 mg/kg/day (18 to 110 mg/kg/day) at Week 40 and approximately 46 mg/kg/day (18 to 166 mg/kg/day) at Week 64. They also received either a mean oral calcitriol dose of 26 nanogram/kg/day at Week 40 and 27 nanogram/kg/day at Week 64 or a therapeutically equivalent amount of alfacalcidol. Eight patients in the burosumab group titrated up to 1.2 mg/kg based on serum phosphate measurements.
Study UX023-CL201. Paediatric Study UX023-CL201, is a randomised, open-label study in 52 prepubescent XLH patients, 5 to 12 years old, which compared treatment with burosumab administered every 2 weeks versus every 4 weeks. Following an initial 16-week dose titration phase, patients completed 48 weeks of treatment with burosumab every 2 weeks or every 4 weeks. Burosumab dose was adjusted to target a fasting serum phosphate concentration of 1.13 to 1.62 mmol/L [3.5 to 5.0 mg/dL] based on the fasting phosphate level on the day of dosing.
Twenty-six of 52 patients received burosumab every 2 weeks up to a maximum dose of 2 mg/kg. The average dose was 0.73 mg/kg (range: 0.3, 1.5) at Week 16, 0.98 mg/kg (range: 0.4, 2.0) at Week 40 and 1.04 mg/kg (range: 0.4, 2.0) at Week 60. The remaining 26 patients received burosumab every 4 weeks. At study entry, the mean age of patients was 8.5 years and 46% were male. Ninety-six percent had received oral phosphate and active vitamin D analogues for a mean (SD) duration of 6.9 (2.4) years. Oral phosphate and active vitamin D analogues were discontinued prior to study enrolment. Ninety-four percent of patients had radiographic evidence of rickets at baseline.
Study UX023-CL205. Paediatric Study UX023-CL205 is a randomised, open-label study in 13 paediatric XLH patients, aged 1 to 4 years. Patients received burosumab at a dose of 0.8 mg/kg every 2 weeks with 5 patients titrating up to 1.2 mg/kg based on serum phosphate measurements. All patients completed at least 40 weeks on study; no patients discontinued. At study entry, the mean age of patients was 2.9 years and 69% were male. All patients had radiographic evidence of rickets at baseline and had received oral phosphate and active vitamin D analogues for a mean (SD) duration of 16.4 (13.8) months. Oral phosphate and active vitamin D analogues were discontinued prior to study enrolment.

Serum phosphate.

In Study UX023-CL301, burosumab increased mean (SD) serum phosphate levels from 2.4 (0.24) mg/dL at baseline to 3.3 (0.43) mg/dL at Week 40. In the active control group, mean (SD) serum phosphate concentrations increased from 2.3 (0.26) mg/dL at baseline to 2.5 (0.34) mg/dL at Week 40 (Figure 1). The renal phosphate reabsorption assessed by TmP/GFR increased in the burosumab treated patients from a mean (SD) of 2.2 (0.37) at baseline to 3.4 (0.67) mg/dL at Week 40. In the active control group, mean (SD) TmP/GFR decreased from 2.0 (0.33) mg/dL at baseline to 1.8 (0.35) mg/dL at Week 40.
In Study UX023-CL201, burosumab increased serum phosphate levels 2.4 (0.41) mg/dL at baseline to 3.3 (0.40) mg/dL and 3.4 (0.45) mg/dL at Week 40 and Week 64 in the patients who received burosumab every 2 weeks. The ratio of renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) increased in these patients from mean (SD) of 2.2 (0.49) at baseline to 3.3 (0.60) and 3.4 (0.53) mg/dL at Week 40 and Week 64.
In Study UX023-CL205, mean (SD) fasting serum phosphate levels increased from 2.5 (0.28) mg/dL at baseline to 3.5 (0.49) mg/dL at Week 40.

Radiographic evaluation of rickets.

Radiographs were examined to assess XLH-related rickets using the 10-point Thacher Rickets Severity Score (RSS) and the 7-point Radiographic Global Impression of Change (RGI-C). The RSS score is assigned based on images of the wrist and knee from a single time point, with higher scores indicating greater rickets severity. The RGI-C score is assigned based on side-by side comparisons of wrist and knee radiographs from 2 time points, with higher scores indicating greater improvement in radiographic evidence of rickets. An RGI-C score of +2.0 was defined as radiographic evidence of substantial healing.
In study UX023-CL301, burosumab healed and reduced the severity of rickets to a greater extent than active control after 40 weeks of treatment, as assessed by decreasing RSS total scores and increasing RGI-C global score, shown in Table 8.
In Study UX023-CL201 and study UX023-CL205, RSS total score decreased, and RGI-C global score demonstrated healing after 40 weeks of treatment with burosumab every 2 weeks as shown in Table 9.

Lower extremity skeletal abnormality.

In Study UX023-CL301, lower extremity skeletal abnormalities were assessed by RGI-C in standing long leg radiographs. At Week 64, the burosumab group maintained greater improvement compared with the active control group (LS mean [SE]: +1.25 [0.17] versus +0.29 [0.12]; difference of +0.97 [95% CI: +0.57, +1.37, GEE model]).

Serum alkaline phosphatase activity.

In Study UX023-CL301, mean (SD) serum alkaline phosphatase (ALP) activity decreased from 511 (125) U/L at baseline to 337 (86) U/L in the burosumab group (mean change: -33%), and from 523 (154) U/L at baseline to 495 (182) U/L in the active control group (mean change: -5%) at Week 64.
In Study UX023-CL201, mean (SD) serum total ALP activity decreased from 462 (110) U/L at baseline to 354 (73) U/L at Week 64 (mean change: -23%) in patients who received burosumab every 2 weeks.
In Study UX023-CL205, mean (SD) serum total ALP activity decreased from 549 (194) U/L at baseline to 335 (88) U/L at Week 40 (mean change: -36%).

Growth.

In Study UX023-CL301, burosumab treatment for 64 weeks increased standing mean (SD) height Z score from -2.32 (1.17) at baseline to -2.11 (1.11) at Week 64 (LS mean change [SE] of +0.17 [0.07]). In the active control group, the mean (SD) height Z score increased from -2.05 (0.87) at baseline to -2.03 (0.83) at Week 64 (LS mean change [SE] of +0.02 [0.04]).
In Study UX023-CL201, burosumab treatment for 64 weeks increased standing mean (SD) height Z score from -1.72 (1.03) at baseline to -1.54 (1.13) in the patients who received burosumab every 2 weeks (LS mean change of +0.19 [95% CI: 0.09 to 0.29]).

Adult X-linked hypophosphataemia.

Study UX023-CL303 is a randomised, double-blind, placebo-controlled study in 134 adult XLH patients. The study comprises a 24-week, double-blind, placebo-controlled treatment phase followed by a 24-week open-label treatment period in which all patients received burosumab. Subjects then continued burosumab treatment for an additional 48 weeks in a Treatment Extension Period I (until Week 96) and Treatment Extension Period II (End of Treatment). Burosumab was administered at a dose of 1 mg/kg every 4 weeks. At study entry, the mean age of patients was 40 years (range 19 to 66 years) and 35% were male. All patients had skeletal pain associated with XLH/osteomalacia at baseline. The baseline mean (SE) serum phosphate concentration was below the lower limit of normal at 0.64 (0.10) mmol/L [1.98 (0.314) mg/dL]. Oral phosphate and active vitamin D analogues were not allowed during the study. Of the 134 subjects who enrolled in the study, one patient in the burosumab group discontinued treatment during the 24-week placebo-controlled treatment period, and 7 patients discontinued Burosumab during the open-label treatment period. During Treatment Extension Period I, 7 patients discontinued treatment, and during Treatment Extension Period II, 1 patient discontinued treatment.
Study UX023-CL304 is an open-label, single-arm study in 14 adult XLH patients to assess the effects of burosumab on improvement of osteomalacia as determined by histologic and histomorphometric evaluation of iliac crest bone biopsies. Patients received 1.0 mg/kg burosumab every 4 weeks. At study entry, the mean age of patients was 40 years (range 25 to 52 years) and 43% were male. Oral phosphate and active vitamin D analogues were not allowed during the study.

Serum phosphate.

In Study UX023-CL303 at baseline, mean (SD) serum phosphate was 1.9 (0.32) mg/dL and 2.0 (0.30) mg/dL in the placebo and burosumab groups, respectively. During the initial 24-week double-blind, placebo-controlled period, mean (SD) serum phosphate across the midpoints of dose intervals (2 weeks post dose) was 2.1 (0.30) mg/dL and 3.2 (0.53) mg/dL in the placebo and burosumab groups, and mean (SD) serum phosphate across the ends of dose intervals was 2.1(0.30) mg/dL and 2.7 (0.45) mg/dL in the placebo and burosumab groups.
A total of 93% of patients treated with burosumab achieved a serum phosphate level above the lower limit of normal (LLN) compared to 8% in the placebo group through Week 24 (Table 10).
During the open-label treatment period, serum phosphate was maintained during continued burosumab therapy (Figure 2), with no evidence of loss of effect through Week 48. Similar results were seen during Treatment Extension Period I and Extension Treatment Period II.
At baseline, the mean (SD) ratio of TmP/GFR was 1.60 (0.37) and 1.68 (0.40) mg/dL in the placebo and burosumab groups, respectively. At Week 22 (midpoint of a dose interval), mean (SD) TmP/GFR was 1.69 (0.37) and 2.73 (0.75) mg/dL in the placebo and burosumab groups. At Week 24 (end of a dose interval), mean (SD) TmP/GFR was 1.73 (0.42) and 2.22 (0.49) mg/dL in the placebo and burosumab groups. During the open-label treatment period, TmP/GFR remained stable during continued burosumab therapy through Week 48. Similar results were seen during Treatment Extension Period I and Treatment Extension Period II.

Bone histomorphometry.

In Study UX023-CL304, after 48 weeks of treatment, healing of osteomalacia was observed in 10 patients as demonstrated by decreases in osteoid volume/bone volume (OV/BV) from a mean (SD) score of 26% (12.4) at baseline to 12% (6.6). Osteoid thickness (O.Th) declined in 11 patients from a mean (SD) of 17 (4.1) micrometres to 12 (3.1) micrometres.

Patient reported outcomes.

Study UX023-CL303 evaluated stiffness and physical function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and pain using the Brief Pain Inventory (BPI).
WOMAC Index: The WOMAC Index comprises three domains: stiffness, pain and physical function; each domain ranges from 0 (best health) to 100 (worst health). Changes from baseline in WOMAC stiffness and physical function domain scores were key secondary endpoints. Burosumab treatment for 24 weeks resulted in a statistically significant favourable change relative to placebo in WOMAC Stiffness and trends favouring burosumab treatment in WOMAC Physical Function as shown in Table 11.

5.2 Pharmacokinetic Properties

The following pharmacokinetic parameters were observed in patients with XLH administered the approved recommended starting dosage based on a 70 kg patient, unless otherwise specified.
Burosumab exhibited linear pharmacokinetics following subcutaneous injections within the dose range of 0.1 to 1 mg/kg (0.08 to 0.8 times the maximum approved recommended dosage based on a 70 kg patient). The steady-state trough mean (±SD) concentration of burosumab was 5.8 (± 3.4) microgram/mL in adult patients, 15.8 (± 9.4) microgram/mL in patients aged 5 to 12 years, and 14.2 (± 4.0) microgram/mL in patients aged 1 to 4 years.

Absorption.

The burosumab mean Tmax values ranged from 8 to 11 days. The median time to reach maximum serum concentrations (Tmax) of burosumab is approximately 7 to 13 days.

Distribution.

The apparent volume of distribution of burosumab is 7.35 L.

Biotransformation.

The exact pathway for burosumab metabolism has not been characterised. Burosumab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Elimination.

The clearance of burosumab is dependent on body weight and estimated to be 0.278 L/day in a typical adult (70 kg) XLH patient with corresponding disposition half-life (t1/2) in the serum of approximately 18 days.

Linearity/non-linearity.

Burosumab displays pharmacokinetics that are linear to dose over the subcutaneous dose range of 0.1 to 1.0 mg/kg.

Paediatric pharmacokinetics/pharmacodynamics.

No significant difference has been observed in the Pharmacokinetics (PK) and Pharmacodynamics of the paediatric XLH population as compared with the adult XLH population. Burosumab clearance and volume of distribution are body weight dependent.

Special populations.

Population PK analyses using data from paediatric and adult subjects who have XLH indicated that age, sex, race, ethnicity, baseline serum albumin, baseline serum alkaline phosphate, baseline serum alanine aminotransferase, and baseline creatinine clearance ≥ 49.9 mL/min, were not significant predictors of burosumab PK. The effect of renal impairment on the pharmacokinetics of burosumab is unknown. However, renal impairment can induce abnormal mineral metabolism which could increase phosphate concentrations greater than expected with burosumab alone. This increase may result in hyperphosphatemia which can induce nephrocalcinosis.
Burosumab must not be given to patients with severe renal impairment, defined as:
Paediatric patients with an estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m3 to 29 mL/min/1.73 m3 or end stage renal disease (eGFR < 15 mL/min/1.73 m3);
Adult patients with a calculated eGFR of 15 mL/min/1.73 m3 to 29 mL/min/1.73 m3 or end stage renal disease (eGFR < 15 mL/min/1.73 m3).

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been conducted with burosumab. As a large protein molecule, burosumab is not expected to interact with DNA or other chromosomal material.

Carcinogenicity.

The carcinogenic potential of burosumab has not been investigated in long-term animal studies.

6 Pharmaceutical Particulars

6.1 List of Excipients

L-histidine; D-sorbitol; polysorbate 80; L-methionine; hydrochloric acid, 10% (for pH adjustment); water for injection.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C to 8°C). Do not freeze.
Store in original package to protect from light.

6.5 Nature and Contents of Container

Each pack contains 1 mL solution in a clear glass vial with butyl rubber stopper, and aluminium seal.

6.6 Special Precautions for Disposal

Product is for single use in one patient only. Discard any residue.
Do not shake the vial before use.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Heavy chains (HC) are shown in blue and Light chains are shown in red.
Black lines show the location of disulfide bonds.
N297 of HC: glycosylation site.

CAS number.

CAS registry number: 1610833-03-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes