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 with the pre-filled syringe may be suitable. Once no immediate dose modifications are anticipated, the administration can be performed by an individual who has been trained properly 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

CRYSVITA 30 mg solution for injection in pre-filled syringe

This medicine contains 45.91 mg of sorbitol in each pre-filled syringe 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.