Source: European Medicines Agency (EU) Revision Year: 2024 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, 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.
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, 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.
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).
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.
This medicine contains 15.30 mg of sorbitol in each pre-filled syringe which is equivalent to 45.91 mg/ml.
This medicine contains 30.61 mg of sorbitol in each pre-filled syringe which is equivalent to 45.91 mg/ml.
This medicine contains 45.91 mg of sorbitol in each pre-filled syringe which is equivalent to 45.91 mg/ml.
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.
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.
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.
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 has 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 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 (11%).
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 decrease (28%), muscle spasms (18%), restless legs syndrome (16%), dizziness (16%) and constipation (13%) (see section 4.4 and ‘Description of selected adverse reactions’ below).
The frequencies of adverse reactions are listed in Table 1 (XLH, paediatric patients), and Table 2 (XLH and TIO adult patients).
10 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 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 |
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.
7 Blood phosphorus increased includes: Blood phosphorus increased and Hyperphosphataemia.
Table 2. Adverse reactions observed from clinical trials in adults (N=203) with XLH (N=176) and TIO (N=27):
| 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 | Very common | Constipation |
| Skin and subcutaneous tissue disorders | Common | Rash3 |
| Musculoskeletal and connective tissue disorders | Very common | Back pain |
| Very common | Muscle spasms | |
| General disorders and administration site conditions | Very common | Injection site reaction4 |
| Investigations | Very common | Vitamin D decreased5 |
| Common | Blood phosphorus increased6 |
1 Tooth infection includes: tooth abscess, tooth infection and toothache.
2 Headache includes: headache and head discomfort.
3 Rash includes: rash, rash papular and rash erythematous.
4 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, Injection site urticaria, Injection site hypersensitivity and Injection site inflammation.
5 Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased.
6 Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphataemia.
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.
Injection site reactions were generally mild in severity, required no treatment, and resolved in almost all instances.
In patients with XLH, in the placebo-controlled treatment period of Study UX023-CL303, 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). In patients with TIO, the frequency of injection site reactions based on data from completed long term clinical studies was 22% (injection site reaction, injection site pain and injection site swelling).
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.
Hypersensitivity reactions were mild or moderate in severity. In XLH patients, in the placebo-controlled treatment period of Study UX023-CL303, the incidence of potential hypersensitivity reactions was similar (6%) in the burosumab treated and placebo treated adults.
In patients with TIO, the frequency of hypersensitivity reactions (rash, drug eruption, and hypersensitivity) based on data from completed long term clinical studies was 30%.
Reduced serum 25 hydroxy-vitamin D has been observed following initiation of burosumab treatment in approximately 8% of paediatric patients, 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.
In XLH patients, in the placebo-controlled treatment period of Study UX023-CL303 in the burosumab group, 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.
In patients with TIO, based on data from completed long term clinical studies, 11% of patients experienced events of hyperphosphataemia, which were managed with dose reduction.
In XLH patients, in the placebo-controlled treatment period of Study UX023-CL303 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. In patients with TIO, based on data from completed long term clinical studies, 11% of patients experienced events of restless legs syndrome of mild to moderate severity.
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 the pharmacokinetic profile of burosumab were associated with these findings.
The incidence of patients that tested positive for ADAs to burosumab in adult clinical studies with XLH or TIO, based on data from completed long term clinical studies was 15%. None of these patients developed neutralising ADA. No adverse events, loss of efficacy, or changes in the pharmacokinetic profile of burosumab were associated with these findings.
No data are available in paediatric patients with TIO (see section 5.1).
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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