Crysvita · 4.8 Undesirable effects · 1

HOS-098058 · has-adverse-reaction-information · PDF-Seite 11

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: pyrexia (53%), cough (52%), injection site reactions (48%), headache (43%), vomiting (43%), pain in extremity (38%), tooth abscess (36%), vitamin D decreased (28%), diarrhoea (25%), rash (19%), nausea (18%), constipation (14%), and dental caries (10%). The most common (> 10%) adverse drug reactions reported during clinical trials in adult patients with XLH or adult patients with TIO, based on completed long term studies up to a maximum exposure to burosumab of 300 weeks (with variable period of exposure across the safety population), were: back pain (30%), injection site reaction (29%), headache (28%), tooth infection (28%), vitamin D decreased (28%), muscle spasms (18%), restless legs syndrome (16%), dizziness (16%) and constipation (13%) (see section 4.4 and ‘Description of selected adverse reactions’ below). Tabulated lists of adverse reactions The frequencies of adverse reactions are listed in Table 1 (XLH, paediatric patients), and Table 2 (XLH and TIO adult patients). 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. 11 Table 1: Adverse reactions reported in paediatric patients 4 months to 17 years of age with XLH, observed from clinical trials (N=136) and post-marketing MedDRA System Organ Class Frequency category Adverse reaction Infections and infestations Very common Tooth abscess1 Hyperparathyroidism2 Endocrine disorders Not known (see section 4.4)

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HOS-098054 · has-contraindication-information · PDF-Seite 8

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.

HOS-098053 · has-indication-information · PDF-Seite 3

CRYSVITA is indicated for the treatment of X-linked hypophosphataemia in infants from 1 month to 1 year of age with hypophosphataemia (see section 5.1), in children and adolescents aged 1 to 17 years with radiographic evidence of bone disease, and in adults. CRYSVITA is indicated for the treatment of FGF23-related hypophosphataemia in tumour-induced osteomalacia associated with phosphaturic mesenchymal tumours that cannot be curatively resected or localised in children and adolescents aged 1 to 17 years and in adults.

HOS-098056 · has-interaction-information · PDF-Seite 10

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, therefore close monitoring of serum calcium levels is recommended (see section 4.4).

HOS-098057 · has-pregnancy-information · PDF-Seite 10

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 is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards. Consequently a risk to the breast-fed newborn cannot be excluded during this short period. Afterwards, use of burosumab could be considered during breast-feeding only if clinically needed. 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. 10

HOS-098055 · has-warning-information · PDF-Seite 8

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. 8 Monitoring of plasma alkaline phosphatase, calcium, parathyroid hormone (PTH) and creatinine is recommended every 6 months (every 3 months for children 1 month – 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. To prevent hyperphosphataemia, treatment with burosumab should be interrupted in patients with tumour-induced osteomalacia who undergo treatment of the underlying tumour. Burosumab treatment should be reinitiated only if the patient’s serum phosphate level remains below the lower end of the normal reference range (see Section 4.2). Hypercalcaemia and hyperparathyroidism Increases in serum calcium or parathyroid hormone have been reported in patients treated with burosumab. Factors such as hyperparathyroidism, prolonged immobilisation, dehydration, hypervitaminosis D or renal impairment may increase the risk of hypercalcaemia. In particular, severe hypercalcaemia has been reported in subjects with tertiary hyperparathyroidism. Serum calcium and parathyroid hormone levels should be monitored before and during burosumab treatment (see section 4.2). In patients with moderate to severe hypercalcaemia (>3 mmol/l), burosumab should not be administered until hypercalcaemia is adequately treated. Injection site reactions Administration of bur

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