CRYSVITA Solution for injection Ref.[7654] Active ingredients: Burosumab

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 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 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

Therapeutic proteins, such as burosumab, may be associated with hypersensitivity reactions. In Clinical Studies, mild or moderate hypersensitivity reactions (e.g., rash, injection site rash) were observed (see section 4.8). Burosumab must be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be initiated.

Excipient with known effect

CRYSVITA solution for injection in vials

This medicine contains 45.91 mg of sorbitol in each vial which is equivalent to 45.91 mg/ml. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

This medicine contains 0.5 mg of polysorbate 80 in each vial which is equivalent to 0.5 mg/ml. Polysorbates may cause allergic reactions.

CRYSVITA 10 mg solution for injection in pre-filled syringe

This medicine contains 15.30 mg of sorbitol in each pre-filled syringe which is equivalent to 45.91 mg/ml. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

This medicine contains 0.165 mg of polysorbate 80 in each pre-filled syringe which is equivalent to 0.5 mg/ml. Polysorbates may cause allergic reactions.

CRYSVITA 20 mg solution for injection in pre-filled syringe

This medicine contains 30.61 mg of sorbitol in each pre-filled syringe which is equivalent to 45.91 mg/ml. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

This medicine contains 0.335 mg of polysorbate 80 in each pre-filled syringe which is equivalent to 0.5 mg/ml. Polysorbates may cause allergic reactions.

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. Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

This medicine contains 0.5 mg of polysorbate 80 in each pre-filled syringe which is equivalent to 0.5 mg/ml. Polysorbates may cause allergic reactions.

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).

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.

Burosumab has a minor influence on the ability to drive and use machines. Dizziness may occur following administration of burosumab.

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.

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:

¹ Tooth abscess includes: Tooth abscess, Tooth infection and Toothache
² Hyperparathyroidism includes: Hyperparathyroidism, Hyperparathyroidism secondary and Hyperparathyroidism tertiary
³ Hypercalcaemia includes: Hypercalcaemia and Blood calcium increased
⁴ Seen in clinical trials, confirmed by post-marketing experience
⁵ Hypercalciuria includes: Hypercalciuria and Urine calcium increased
⁶ Cough includes: Cough, and Productive cough
⁷ Dizziness includes: Dizziness, and Dizziness exertional
⁸ Rash includes: Rash, Rash erythematous, Rash generalised, Rash pruritic, Rash maculo-papular, and Rash pustular
⁹ 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
¹⁰ Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased
¹¹ 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) and post-marketing:

¹ Tooth infection includes: tooth abscess, tooth infection and toothache
² Hyperparathyroidism includes: Hyperparathyroidism, Hyperparathyroidism secondary and Hyperparathyroidism tertiary
³ Hypercalcaemia includes: Hypercalcaemia and Blood calcium increased
⁴ Seen in clinical trials with TIO, confirmed by post-marketing experience
⁵ Seen in clinical trials with XLH, confirmed by post-marketing experience
⁶ Hypercalciuria includes: Hypercalciuria and Urine calcium increased
⁷ Headache includes: headache and head discomfort
⁸ Rash includes: rash, rash papular and rash erythematous
⁹ 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
¹⁰ Vitamin D decreased includes: Vitamin D deficiency, Blood 25-hydroxycholecalciferol decreased, and Vitamin D decreased
¹¹ Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphataemia
¹² Seen in clinical trials with XLH and TIO, confirmed by post-marketing experience

Description of selected adverse reactions

Injection site reactions

Paediatric patients with XLH

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 48% 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 with XLH or TIO

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, pruritus 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

Paediatric patients with XLH

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 with XLH or TIO

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%.

Vitamin D Decreased

Paediatric patients with XLH

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.

Hyperphosphataemia

Adult patients with XLH or TIO

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.

Restless legs syndrome

Adult patients with XLH or TIO

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.

Immunogenicity

Paediatric patients with XLH

Overall, the incidence of anti-drug antibodies (ADA) to burosumab in paediatric patients administered burosumab, based on data from clinical studies was 11%. 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.

Adult patients with XLH and TIO

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.

Adverse reactions in paediatric patients with TIO

No data are available in paediatric patients with TIO (see section 5.1).

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 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.