Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Kyowa Kirin Holdings B.V., Bloemlaan 2, 2132NP Hoofddorp, The Netherlands, +31 (0) 237200822, medinfo@kyowakirin.com
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concurrent administration with oral phosphate, 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.
Ectopic mineralisation, as manifested by nephrocalcinosis, has been observed in patients with XLH treated with oral phosphorous and 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 phosphatases, Calcium, 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.
Patient’s fasting serum phosphate level 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.
Increases in serum parathyroid hormone have been observed in some XLH patients during treatment with burosumab. Periodic measurement of serum parathyroid hormone is advised.
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.
Burosumab must be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be initiated.
This medicine contains 45.91 mg of sorbitol in each vial which is equivalent to 45.91 mg/ml.
Concurrent administration of burosumab with oral phosphate and 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.
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).
CRYSVITA is not recommended during pregnancy and in women of childbearing potential not using contraception.
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 CRYSVITA therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
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.
Burosumab may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of burosumab.
The most common (>10%) adverse drug reactions reported in paediatric patients treated for up to 64 weeks 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%)
Table 1 gives the adverse reactions observed from clinical trials. 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.
Table 1. Adverse reactions reported in paediatric patients with XLH (N=65):
Very common: Tooth abscess1
Very common: Cough2
Very common: Headache
Common: Dizziness3
Very common: Vomiting, Nausea, Diarrhoea, Constipation, Dental Caries
Very common: Rash4
Very common: Myalgia, Pain in extremity
Very common: Injection site reaction5, Pyrexia
Very common: Vitamin D decreased6
1 Tooth abscess includes: Tooth abscess, Tooth infection and Toothache
2 Cough includes: Cough, and Productive cough
3 Dizziness includes: Dizziness, and Dizziness exertional
4 Rash includes: Rash, Rash erythematous, Rash generalised, Rash pruritic, Rash maculo-papular, and Rash pustular
5 Injection 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
6 Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased
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 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 administration, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances.
Hypersensitivity reactions (including: injection site rash, rash, urticaria, swelling face, dermatitis) were reported in 18% of patients. All reported reactions were mild or moderate in severity.
Anti-drug antibodies (ADA) have been detected in a small percentage of patients receiving burosumab who had also tested positive for ADA prior to dosing; no adverse events or loss of efficacy was associated with these findings.
Reduced serum 25 hydroxy-vitamin D has been observed following initiation of burosumab treatment in approximately 8% of patients, possibly due to increased conversion to activated 1,25 dihydroxyvitamin D. Supplementation with inactive Vitamin D was successful in restoring plasma levels to normal.
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 the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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