CRYSVITA

Treatment should be initiated by a physician experienced in the management of patients with metabolic bone diseases. 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.

3). 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. 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. 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.

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%).

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 Very common Headache Nervous system disorders Very common Dizziness3 Gastrointestinal Disorders Very common Vomiting Nausea Diarrhoea Constipation Dental Caries Skin and subcutaneous tissue disorders Very common Rash4 MyalgiaMusculoskeletal and connective tissue disorders Very common Pain in extremity General disorders and administration site conditions Very common Injection site reaction5 Pyrexia Very common Vitamin D decreased6 Investigations 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.

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. 2). 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.

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. 8) and appropriate medical therapy administered. Hypersensitivity Burosumab must be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be initiated.

91 mg/ml.

1. 5). 4). Patients with severe renal impairment or end stage renal disease.