Pharmacy Guide
Patient leaflets and SmPCs, drug interaction checker, official dosages and NHS pharmacy opening hours — all in one place.
Pharmacy Guide
Patient leaflets and SmPCs, drug interaction checker, official dosages and NHS pharmacy opening hours — all in one place.
CRYSVITA 10 mg solution for injection
⚠ This medicine appears to have been discontinued
The electronic medicines compendium (emc) no longer publishes a Summary of Product Characteristics for this product, which usually means it is no longer marketed in the UK. The patient leaflet below is kept for reference, but the product may not be available.
If you were prescribed this medicine, other products containing Burosumab may still be available. Do not stop your treatment — ask your pharmacist or GP what to use instead.
What it is and what it is used for
for
What CRYSVITA is CRYSVITA contains the active substance burosumab. This is a type of medicine called a human monoclonal antibody. What is CRYSVITA used for CRYSVITA is used to treat X-linked hypophosphataemia (XLH). It is used in children and adolescents aged 1 to 17 years, and in adults. What is X-Linked Hypophosphataemia (XLH) 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 How CRYSVITA works 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.
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What you need to know before you take it
e CRYSVITA
Do not use CRYSVITA if • you are allergic to burosumab or any of the other ingredients of this medicine (listed in section 6) • 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 high level of phosphate in your blood ("hyper-phosphataemia") • you have severe kidney disease or kidney failure. Allergic reactions Stop taking CRYSVITA and contact 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. Warnings and precautions Skin reactions You may get skin reactions where the injection is given, see section 4 for more information. If these reactions are severe, tell your doctor. 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 CRYSVITA should not be given to children under 1 year of age because the safety and effects of the medicine have not been studied in this age group. Other medicines and CRYSVITA Tell your doctor if you are taking, have recently taken, or might take any other medicines. 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. Talk to your doctor before taking CRYSVITA if you are taking: • medicines that work in the same way as calcium in the body ("calcimimetics"). If used together they may lower blood calcium.
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Pregnancy and breastfeeding If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. This is because it is not known if CRYSVITA will affect the baby. CRYSVITA is not recommended in pregnancy. If you could get pregnant, you must use an effective method of contraception (birth control) while using CRYSVITA and for at least 14 weeks after your last dose. You should discuss this with your doctor. It is not known if CRYSVITA passes into breast milk, and a risk to newborns or infants cannot be ruled out. You should discuss this with your doctor. Driving, riding a bike and using machines 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. CRYSVITA contains sorbitol This medicine contains 45.91 mg of sorbitol in each vial which is equivalent to 45.91 mg/ml. 3.
How to take it
CRYSVITA
CRYSVITA should be given by injection under the skin (subcutaneous use) in the upper arm, abdomen, buttock or thigh. This medicine will be given to you or your child by a . healthcare provider. Alternatively, your doctor may recommend that you inject yourself or your child. A healthcare provider will show you how to do this. The first self-injection after start of treatment or after any dose change should be carried out in front of them. A detailed 'Instructions for Use' section is provided at the end of this leaflet. Always follow these instructions carefully when giving yourself or your child the CRYSVITA injection. Always use this medicine exactly as your doctor, nurse or pharmacist has told you. Check with your doctor, nurse or pharmacist if you are not sure. How much CRYSVITA you will need The dose is based on your body weight. Your doctor will work out the right dose for you. Your CRYSVITA dose will need to be injected:
- every two weeks in children and adolescents aged 1 – 17 years
- 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 have been given more CRYSVITA than you should If you think that you have been given too much CRYSVITA, tell your doctor straight away. If you miss a dose of 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 have any further questions on the use of this medicine, ask your doctor.
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Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them. Side effects in children and adolescents Very common (may affect more than 1 in 10 children and adolescents) • Tooth abscess (infection) • Cough • Headache • Dizziness • 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: o redness or rash o pain or itching o swelling o 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 • Low vitamin D in your blood Not known (frequency cannot be estimated from the available data)
- Increased phosphate in your blood
Possible side effects
in adults 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 • Low vitamin D in your blood Common (may affect up to 1 in 10 adults) • Constipation • Increased phosphate in your blood Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via Yellow Card Scheme
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Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.
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How to store it
CRYSVITA
Keep CRYSVITA out of the sight and reach of children. Do not use CRYSVITA after the expiry date which is stated on the carton and label after "EXP''. The expiry date refers to the last day of that month. 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. Do not use CRYSVITA if it contains visible particles. Do not throw away any medicines via wastewater or household waste. These measures will help protect the environment. If self-injecting, see step 5 of the 'Instructions for Use' in the end of the Package Leaflet for instructions on disposal of unused medicines and supplies. If you have questions on how to throw away medicines you no longer use, ask your healthcare provider or pharmacist. 6.
Contents of the pack and other information
What CRYSVITA contains The active substance is burosumab. Each vial contains either 10, 20 or 30 mg of burosumab. The other ingredients are L-histidine, D-sorbitol (E420), polysorbate 80, L-methionine, 10%, hydrochloric acid, and water for injections. (See "CRYSVITA contains sorbitol" in section 2 for more information). What CRYSVITA looks like and contents of the pack 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. Marketing Authorisation Holder Kyowa Kirin Limited Galabank Business Park Galashiels TD1 1QH United Kingdom [email protected] Manufacturer allphamed PHARBIL Arzneimittel GmbH Hildebrandstr. 10-12 37081 Göttingen Germany Kyowa Kirin Holdings B.V. Bloemlaan 2 2132NP Hoofddorp The Netherlands This leaflet was last revised in 02 Apr 2026.
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INSTRUCTIONS FOR USE Read these Instructions for Use carefully before you use CRYSVITA:
- Only inject yourself or your child if you have been told to do so by your doctor.
- You should only inject after you have been trained in injection technique. The first self-injection after start of treatment or after any dose change should be carried out in front of a healthcare provider.
- Always use this medicine exactly as your doctor, pharmacist or nurse (healthcare provider) has told you. Check with your healthcare provider if you are not sure.
- Your doctor will prescribe your correct dose. Your dose is measured in milligrams (mg). CRYSVITA is available in three different strength vials: 10 mg, 20 mg, and 30 mg. Each vial is for single use only. Always use a new CRYSVITA vial for each injection, see step 5 on how to dispose used vials and other supplies.
- Your healthcare provider will tell you how much CRYSVITA to give yourself or your child. You or your child may be given more than one vial to get the correct dose.
- If your healthcare provider tells you that more than one injection is needed to give your required dose, you must repeat the following Steps 2-5 for each injection. Use new supplies and a different site on the body for each injection.
- Only use the syringe and needles provided or prescribed by your healthcare provider to give the injection. o Always use the large needle to withdraw the liquid and remember to change to the small needle to inject the liquid. o Using the wrong syringe or needle can lead to a mistake in your dose or make the injection more painful.
- When giving CRYSVITA to a young child, it may be helpful to have another person present to provide support.
- Do not use CRYSVITA if allergic to any ingredients of this medicine. Stop using CRYSVITA if you have any allergic reaction during or after the injection and contact your healthcare provider straightaway. See section 2 of the package leaflet for more information. Step 1. Gather and Inspect Supplies Remove the CRYSVITA vials you need from the refrigerator. Check the strength on the label of each vial. Make sure that you have the correct number of vials to match the dose in mg as advised by your healthcare provider. If you are not sure, ask your healthcare provider for advice. Let the vials warm to room temperature for 30 minutes. Do not warm the vials in any other way, such as with hot water or a microwave oven. Do not put the vials in direct sunlight. Check the expiry date (shown after EXP) on the label of the vial. Inspect the liquid in the vial. Do not shake. Do not use the vial if it is:
- past the expiry date
- discoloured, cloudy or contains any particles. CRYSVITA liquid should be clear to slightly opalescent, colourless to pale brown-yellow.
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Place all the items you will need on a clean, flat surface. For each injection you will need: A. Vial(s) of CRYSVITA for injection B. One syringe with plunger C. One large syringe needle to withdraw CRYSVITA D. One small syringe needle to inject CRYSVITA E. Alcohol wipes F. Sharps container G. Plaster (if required) H. Gauze pad or cotton wool Contact your healthcare provider if you do not have these supplies.
Your healthcare provider will explain the use of different needles. The large needle is used for withdrawing CRYSVITA from the vial. The small needle is used for injecting CRYSVITA. If you are not sure, ask your healthcare provider for advice before use. Do not use any items that have missing pieces or are damaged in any way. Do not remove the caps from the needles until you are ready to use them. Wash your hands thoroughly with soap and water before going to Step 2. STEP 2. Withdraw CRYSVITA and Prepare Injection Remove the sealing cap from the vial to reveal the rubber stopper. Clean the rubber stopper with an alcohol wipe and let it dry. Don't touch the rubber stopper after cleaning it. Select the large needle and remove from the sterile packaging but do not remove the cap covering the needle. To attach the needle to the syringe, hold the large needle by the protective cap in one hand and the syringe by the barrel in the other hand. Depending on the supplies you have been given;
- you will need to push the needle down and turn clockwise onto the syringe until tight
- or push the needle down until it is firmly attached. Do not touch the needle itself or the end of the syringe where the needle attaches. Once the needle is firmly attached, hold the syringe by the barrel with the needle pointing up. Remove the needle cap by pulling it straight off. 7
Do not throw the needle cap away. Do not touch the needle or allow the needle to touch any surface once the cap has been removed. Do not use the syringe if you drop it after removing the cap or if the needle appears damaged. Your healthcare provider will tell you how much liquid you need to inject. This will normally be 1ml for each injection. Your healthcare provider will show you which mark to use if you need to inject less than 1ml. Always use the mark equal to your dose. If you are not sure, ask your healthcare provider for advice before use. Pull back the syringe plunger until the end of the plunger lines up with mark equal to your dose. This fills the syringe with air.
Keep the vial on a flat surface. Slowly insert the large needle through the rubber stopper and into the vial. Do not let the tip of the needle touch the liquid in the vial. If the tip of the needle touches the liquid, slowly pull the needle until it no longer touches the liquid. Slowly push the plunger into the syringe. This pushes air from the syringe into the vial.
Keep the needle in the vial and turn the vial upside down. Make sure the tip of the needle is at the bottom of the liquid.
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Slowly pull back the plunger to fill the syringe until the end of the plunger lines up with the mark equal to your dose. Keep the tip of the needle in the liquid at all times.
Check the liquid in the syringe for air bubbles. If you see bubbles,
- keep the syringe upright with the needle still inside the vial,
- gently tap the barrel with your finger to move the air bubbles,
- when the air bubbles are at the top, slowly push the plunger to push out the air bubbles. Check your dose again against the markings on the syringe. If required, withdraw some more liquid to line up with the mark equal to your dose. Check again for bubbles and repeat the process if required. When there are no bubbles in the syringe, pull the syringe and needle straight down out of the vial. Remove the large needle from the syringe.
- To do this, take the large needle cap and place on a flat surface.
- Using one hand, slide the large needle into the cap and scoop upward to cover the needle without using your other hand to avoid injury. Then use your other hand to secure the cap and snap into place.
- Depending on your supplies, you will; o need to twist the capped large needle anticlockwise to remove from the syringe o or pull the capped large needle straight from the syringe and place in the sharps container. Select the small needle and remove from the sterile packaging but do not remove the cap covering the needle.
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To attach the needle to the syringe, hold the small needle by the protective cap in one hand and the syringe by the barrel in the other hand. Depending on the supplies you have been given,
- you will need to push the needle down and turn clockwise onto the syringe until tight
- or push the needle down until it is firmly attached. Do not touch the needle itself or the end of the syringe where the needle attaches. Step 3. Prepare the Injection Site The injection must be given into the fatty layer just below the skin. You will need to choose an injection site. If you are giving the injection to yourself, suitable areas are:
- stomach area, upper thighs If you are giving the injection to someone else, suitable areas are:
- stomach area, upper thighs, outer area of upper arms, buttocks Do not inject:
- an area that is sore, red, bruised or where the skin is broken
- an area that has stretch marks or scars (including burns)
- directly into a mole, or an area around a mole If you are giving more than one injection, use a different site for each injection. Clean each injection site with a new alcohol wipe and leave the skin to dry. CRYSVITA should be injected into clean dry skin. Step 4. Inject CRYSVITA Remove the small needle cap by pulling it straight off. Pinch the skin firmly between your thumb and fingers, creating an area about 5 cm wide. Hold the syringe between the thumb and index finger of your dominant hand. The needle should be inserted into the skin at a 45° angle or 90° angle. Your healthcare provider will show you which angle you should use.
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Use a quick 'dart-like' motion to insert the needle into the pinched skin. Do not push the plunger when inserting the needle.
When the needle is inserted do not move it around. Keep pinching the skin. Slowly push the plunger into the syringe, for up to 30 seconds, until the syringe is empty.
After you have given the full dose, remove the injection by gently pulling the syringe straight out. Release the pinched skin. Press the injection site with a cotton ball or gauze pad for a few seconds to stop bleeding. Apply a plaster if needed. Do not rub the injection site. To avoid any injury, do not put the cap back on the small needle. Place the uncapped needle in the sharps disposal container.
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Step 5. After each injection Put your used needles, caps and syringes in the sharps disposal container; vials should be discarded according to your local guidelines. Do not throw away needles or syringes in your household waste. Do not save vials with leftover medicine for future use or pass it on to others. When your sharps container is almost full, you will need to follow your local guidelines to request another container and to dispose of it correctly. Reminder: If you are giving more than one injection, repeat steps 2-5 for each injection. Use new supplies for each injection. Note the date of the injection and all the areas where you have injected so that you use different sites for the next injection. A video showing you how to prepare and give the injection is available on the following link: www.myinject.eu
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Frequently asked questions about CRYSVITA 10 mg solution for injection
How do I take CRYSVITA 10 mg solution for injection?
CRYSVITA 10 mg solution for injection comes as injection containing 10mg. Always follow the dose your doctor or pharmacist has given you, and read the leaflet that comes with the medicine.
What is the active substance in CRYSVITA 10 mg solution for injection?
The active substance in CRYSVITA 10 mg solution for injection is burosumab.
Are there equivalent medicines to CRYSVITA 10 mg solution for injection?
Medicines with the same active substance, strength and form include: CRYSVITA 10 mg solution for injection in pre-filled syringe. They are interchangeable only if your prescriber or pharmacist says so.
Where does this information come from?
This leaflet reproduces the patient information leaflet approved for CRYSVITA 10 mg solution for injection, as published on the electronic medicines compendium (emc). The version printed inside your medicine’s packaging is the one that applies to you.
Can I get CRYSVITA 10 mg solution for injection without a prescription?
Whether a medicine is available over the counter or on prescription only depends on its licence. Check the leaflet, or ask your pharmacist — they can tell you straight away.
About this leaflet
The text above reproduces the patient information leaflet approved for this medicine, restructured for easier reading.
- Source: electronic medicines compendium (emc), Datapharm
- Active substance: burosumab
- Official document: view the original leaflet on emc →
⚕For healthcare professionals — Summary of Product Characteristics (SmPC)Full SmPC: dosage, interactions, contraindications, warnings+
4.1. Therapeutic indications
CRYSVITA is indicated for the treatment of X-linked hypophosphataemia, in children and adolescents aged 1 to 17 years with radiographic evidence of bone disease, and in adults.
4.2. Posology and method of administration
Treatment should be initiated by a physician experienced in the management of patients with metabolic bone diseases.
Posology
Oral phosphate and active vitamin D analogues (e.g. calcitriol) should be discontinued 1 week prior to initiation of treatment. Vitamin D replacement or supplementation with inactive forms may be started or continued as per local guidelines under monitoring of serum calcium and phosphate. At initiation, fasting serum phosphate concentration should be below the reference range for age (see section 4.3).
Dosing in Children and Adolescents aged 1 to 17 years
The recommended starting dose in children and adolescents aged 1 to 17 years is 0.8 mg/kg of body weight given every two weeks. Doses should be rounded to the nearest 10 mg. The maximum dose is 90 mg.
After initiation of treatment with burosumab, fasting serum phosphate should be measured every 2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter as appropriate. Fasting serum phosphate should also be measured 4 weeks after any dose adjustment. If fasting serum phosphate is within the reference range for age, the same dose should be maintained.
Dose increase
If fasting serum phosphate is below the reference range for age, the dose may be increased stepwise by 0.4 mg/kg up to a maximum dose of 2.0 mg/kg (maximum dose of 90 mg). Fasting serum phosphate should be measured 4 weeks after dose adjustment. Burosumab should not be adjusted more frequently than every 4 weeks.
Dose decrease
If fasting serum phosphate is above the reference range for age, the next dose should be withheld and the fasting serum phosphate reassessed within 4 weeks. The patient must have fasting serum phosphate below the reference range for age to restart burosumab at half of the previous dose, rounding the amount as described above.
Dose Conversion at age 18 years
Children and adolescents aged 1 to 17 years should be treated using the dosing guidance outlined above. At 18 years of age the patient should convert to the adult dose and dosing regimen as outlined below.
Dosing in Adults
The recommended starting dose in adults is 1.0 mg/kg of body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, given every 4 weeks.
After initiation of treatment with burosumab, fasting serum phosphate should be measured every 2 weeks for the first month of treatment, every 4 weeks for the following 2 months and thereafter as appropriate. Fasting serum phosphate should be measured 2 weeks after the previous dose of burosumab. If serum phosphate is within the normal range, the same dose should be continued.
Dose decrease
If serum phosphate is above the upper limit of normal range, the next dose should be withheld and the serum phosphate level reassessed within 2 weeks. The patient must have serum phosphate below the normal range before restarting 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. Serum phosphate should be reassessed 2 weeks after any change in dose.
All Patients
To decrease the risk for ectopic mineralisation, it is recommended that fasting serum phosphate is targeted in the lower end of the normal reference range for age (see section 4.4).
Missed dose
Treatments may be administered 3 days either side of the scheduled treatment date if needed for practical reasons. If a patient misses a dose, burosumab should be resumed as soon as possible at the prescribed dose.
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 4.3).
Paediatric population
The safety and efficacy of burosumab in children aged less than one year have not been established in clinical studies.
Elderly
Limited data is available in patients over 65 years of age.
Method of administration
For subcutaneous use.
Burosumab should be injected in the upper arm, abdomen, buttock or thigh.
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 must be split and administered at two or more different injection sites. Injection sites should be rotated and carefully monitored for signs of potential reactions (see section 4.4).
For handling of burosumab before administration, see section 6.6.
For some patients, self/carer-administration may be suitable. Once no immediate dose modifications are anticipated, the administration can be performed by an individual who has been trained in injection techniques. The first self-administered dose after drug initiation or dose change should be conducted under the supervision of a healthcare professional. Clinical monitoring of the patient, including monitoring of phosphate levels, must continue as required and as outlined below. A detailed 'Instructions for Use' section intended for the patient is provided at the end of the Package Leaflet.
4.3. Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concurrent administration with oral phosphate, active vitamin D analogues (see section 4.5).
Fasting serum phosphate above the normal range for age due to the risk of hyperphosphatemia (see section 4.4).
Patients with severe renal impairment or end stage renal disease.
4.4. Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded within 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 is targeted in the lower end 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 of burosumab may result in local injection site reactions. Administration should be interrupted in any patient experiencing severe injection site reactions (see section 4.8) and appropriate medical therapy administered.
Hypersensitivity
Burosumab must be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be initiated.
Excipient with known effect
This medicine contains 45.91 mg of sorbitol in each vial which is equivalent to 45.91 mg/ml.
4.5. Interaction with other medicinal products and other forms of interaction
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
Women of childbearing potential
Women of childbearing potential should use effective contraception during treatment with burosumab and for at least 14 weeks after stopping treatment.
Pregnancy
There are no or limited amount of data from the use of burosumab in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3).
Burosumab is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
It is unknown whether burosumab/metabolites are excreted in human milk.
A risk to newborns/infants cannot be excluded.
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 and the benefit of therapy for the woman.
Fertility
Studies in animals have shown effects on male reproductive organs (see section 5.3). There are no clinical data available on the effect of burosumab on human fertility. No specific fertility studies in animals with burosumab were conducted.
4.7. Effects on ability to drive and use machines
Burosumab may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of burosumab.
4.8. Undesirable effects
Summary of the safety profile
The most common (>10%) adverse drug reactions reported in paediatric patients with XLH during clinical trials, based on completed long term studies up to a maximum exposure to burosumab of 214 weeks (with variable period of exposure across the safety population), were: cough (55%), injection site reactions (54%), pyrexia (50%), headache (48%), vomiting (46%), pain in extremity (42%), tooth abscess (40%), vitamin D decreased (28%), diarrhoea (27%), nausea (21%), rash (20%), constipation (12%) and dental caries (12%).
The most common adverse drug reactions reported in adult patients during clinical trials were: back pain (23%), headache (21%), tooth infection (19%), vitamin D decreased (15%), restless legs syndrome (13%), muscle spasms (12%) and dizziness (11%).
(See section 4.4 and 'Description of selected adverse reactions' below).
Tabulated list of adverse reactions
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, undesirable effects are presented in order of decreasing seriousness.
An overview of adverse reactions observed from clinical trials and post-marketing in paediatric patients is presented in Table 1.
Table 1: Adverse reactions reported in paediatric patients 1 to 17 years of age with XLH observed from clinical trials (N=120) and post-marketing
MedDRA System Organ Class
Frequency category
Adverse reaction
Infections and infestations
Very common
Tooth abscess1
Respiratory, thoracic and mediastinal disorders
Very common
Cough2
Nervous system disorders
Very common
Headache
Very common
Dizziness3
Gastrointestinal Disorders
Very common
Vomiting
Nausea
Diarrhoea
Constipation
Dental Caries
Skin and subcutaneous tissue disorders
Very common
Rash4
Musculoskeletal and connective tissue disorders
Very common
Myalgia
Pain in extremity
General disorders and administration site conditions
Very common
Injection site reaction5
Pyrexia
Investigations
Very common
Vitamin D decreased6
Not known
Blood phosphorus increased7
1Tooth abscess includes: Tooth abscess, Tooth infection and Toothache
2Cough includes: Cough, and Productive cough
3Dizziness includes: Dizziness, and Dizziness exertional
4Rash includes: Rash, Rash erythematous, Rash generalised, Rash pruritic, Rash maculo-papular, and Rash pustular
5Injection site reaction includes: Injection site reaction, Injection site erythema, Injection site pruritus, Injection site swelling, Injection site pain, Injection site rash, Injection site bruising, Injection site discolouration, Injection site discomfort, Injection site haematoma, Injection site haemorrhage, Injection site induration, Injection site macule, and Injection site urticaria
6Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased
7Blood phosphorus increased includes: Blood phosphorus increased and Hyperphosphataemia
An overview of adverse reactions observed from clinical trials in adults is presented in Table 2.
Table 2: Adverse reactions reported in adults with XLH (N=176)
MedDRA System Organ Class
Frequency Category
Adverse Reaction
Infections and infestations
Very common
Tooth infection1
Nervous system disorders
Very common
Headache2
Very common
Dizziness
Very common
Restless legs syndrome
Gastrointestinal disorders
Common
Constipation
Musculoskeletal and connective tissue disorders
Very common
Back pain
Very common
Muscle spasms
Investigations
Very common
Vitamin D decreased3
Common
Blood phosphorus increased4
1 Tooth infection includes: tooth abscess and tooth infection
2 Headache includes: headache and head discomfort
3Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased
4Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphataemia
Description of selected adverse reactions
Injection site reactions
Paediatric patients:
Local reactions (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and haematoma) have occurred at the site of injection. In the paediatric studies, approximately 54% of the patients had an injection site reaction, based on data from clinical studies. The injection site reactions were generally mild in severity, occurred within 1 day of medicinal product administration, mostly lasted 1 to 3 days, required no treatment, and resolved in almost all instances.
Adult patients:
The frequency of injection site reactions was 12% in both burosumab and placebo treatment groups (injection site reaction, erythema, rash, bruising, pain, pruritis 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
Paediatric patients:
Hypersensitivity reactions (e.g. injection site reactions, rash, urticaria, swelling face, dermatitis, etc) were reported in 39% of paediatric patients, based on data from clinical studies. All reported reactions were mild or moderate in severity.
Adult patients:
The incidence of potential hypersensitivity reactions was similar (6%) in the burosumab treated and placebo treated adults. The events were mild to moderate in severity.
Vitamin D Decreased
Paediatric patients:
Reduced Vitamin D (including vitamin D decreased, vitamin D deficiency and blood 25-hydroxycholecalciferol decreased) has been observed following initiation of burosumab treatment in approximately 28% of paediatric patients, based on data from clinical studies. This is possibly due to increased conversion to activated 1,25 dihydroxy-vitamin D. Supplementation with inactive vitamin D was successful in restoring plasma levels to normal.
Hyperphosphataemia
Adult patients:
In the double-blind period of Study UX023-CL303, in the burosumab group during the Placebo-controlled Treatment Period, 9 subjects (13.2%) had high serum phosphate at least once; 5 of these 9 required protocol-specified dose reduction(s). After initiation of burosumab in the open-label Treatment Continuation Period, 8 subjects (12.1%) in the placebo→burosumab group had high serum phosphate levels. Four of these 8 subjects required protocol-specified dose reduction(s). The dose for all patients meeting the protocol-specified criteria was reduced by 50%. A single patient (1%) required a second dose reduction for continued hyperphosphataemia.
Restless legs syndrome
Adult patients:
In adults, 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.
Immunogenicity:
Paediatric patients
Overall, the incidence of anti-drug antibodies (ADA) to burosumab in paediatric patients administered burosumab, based on data from clinical studies, was 10%. The incidence of neutralising ADA in paediatric patients was 3%. No adverse events, loss of efficacy, or changes in pharmacokinetics profile were associated with these findings.
Adult patients
The incidence of XLH patients that tested positive for ADAs to burosumab in adult clinical studies, based on data from completed long term clinical studies, was 16%. None of these patients developed neutralising ADAs. No adverse events, loss of efficacy, or changes in the pharmacokinetic profile of burosumab were associated with these findings.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9. Overdose
There is no experience with overdose of burosumab. Burosumab has been administered in paediatric clinical trials without dose limiting toxicity using doses up to 2.0 mg/kg body weight with a maximal dose of 90 mg every two weeks. In adult clinical trials no dose limiting toxicity has been observed using doses up to 1.0 mg/kg or a maximal total dose of 128 mg every 4 weeks.
Management
In case of overdose, it is recommended to stop burosumab and to monitor biochemical response.
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