Adverse reactions : תופעות לוואי

7 ADVERSE REACTIONS
The following adverse reactions are described below and elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (6.1)]
Hyperphosphatemia and Risk of Nephrocalcinosis [see Warnings and Precautions (6.2)] Injection Site Reactions [see Warnings and Precautions (6.3)]
7.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions in Pediatric Patients with XLH
CRYSVITA was studied in three pediatric XLH studies. Study 1 (Study UX023-CL301) is a randomized, open-label phase 3 study in XLH patients ages 1 to 12 years, who were randomized to treatment with CRYSVITA or treatment with active control of oral phosphate and active vitamin D (CRYSVITA N = 29, Active Control N = 32). Study 2 (Study UX023-CL201) is an open-label phase 2 study in XLH patients ages 5 to 12 years (N = 52). Study 3 (Study UX023-CL205) is an open-label phase 2 study in XLH patients ages 1 to less than 5 years (N = 13). Overall, the patient population was 1-12 years (mean age 7.0 years), 49% male, and 88% white.
In Study 1 (Study UX023-CL301) , patients randomized to CRYSVITA received a mean dose of approximately 0.90 mg/kg (range 0.8-1.2 mg/kg) every 2 weeks. All patients in this group and the active control group completed 64 weeks of treatment.
Adverse reactions occurring in ≥ 10% of subjects in the CRYSVITA group, with higher frequency than in the subjects in the active control group, through the 64-week treatment period in Study 1 (Study UX023-CL301) are shown in Table 6.
Table 6: Adverse Reactions Reported in 10% or More of CRYSVITA-Treated Pediatric Patients and with Higher Frequency Than the Active Control Group in Study 1 (Study UX023-CL301) CRYSVITA                                 Active Control
Adverse Reaction                                         (N=29)                                     (N=32) n (%)                                      n (%)
Pyrexia                                                16 (55)                                     6 (19) Injection site reaction1                               15 (52)                                      0 (0) Cough2                                                 15 (52)                                     6 (19) Vomiting                                               12 (41)                                     8 (25) Pain in extremity                                      11 (38)                                    10 (31) Headache                                               10 (34)                                     6 (19) Tooth abscess3                                         10 (34)                                     4 (13) Dental caries                                           9 (31)                                      2 (6) Diarrhea                                                 7 (24)                                       2 (6) Vitamin D decreased4                                     7 (24)                                       1 (3) Constipation                                             5 (17)                                       0 (0) Rash5                                                    4 (14)                                       2 (6) Nausea                                                   3 (10)                                       1 (3) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA or active control 1
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 discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria 2
Cough includes: cough and productive cough
3
Tooth abscess includes: tooth abscess, tooth infection, toothache
4
Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 5
Rash includes: rash, rash pruritic, rash maculopapular, rash erythematous, rash generalized and rash pustular 

In Study 2 (Study UX023-CL201), 26 of the patients received CRYSVITA at a mean dose of 1.05 mg/kg (range 0.4 – 2.0 mg/kg) every 2 weeks at Week 64; the other 26 patients received CRYSVITA every 4 weeks. The mean duration of exposure in Study 2 (Study UX023-CL201) was 124 weeks. In Study 3(Study UX023-CL205) , patients received CRYSVITA at a mean dose of 0.90 mg/kg (range 0.8-1.2 mg/kg) every 2 weeks at Week 40. The mean duration of exposure in Study 3 (Study UX023- CL205) was 45 weeks.

Adverse reactions occurring in more than 10% of CRYSVITA-treated patients from Studies 2 and 3 are shown in Table 7.


Table 7: Adverse Reactions Reported in More Than 10% of Pediatric Patients Receiving CRYSVITA in Studies 2 (Study UX023-CL201) and 3 (Study UX023-CL205)
Study 2                              Study 3                              Overall Adverse Reaction
(N=52)                               (N=13)                               (N=65) n (%)                                n (%)                                n (%) Headache                                           38 (73)                               1 (8)                               39 (60) Injection site reaction1                           35 (67)                               3 (23)                              38 (59) Vomiting                                           25 (48)                               6 (46)                              31 (48) Pyrexia                                            23 (44)                               8 (62)                              31 (48) Pain in extremity                                  24 (46)                               3 (23)                              27 (42) Vitamin D decreased2                               19 (37)                               2 (15)                              21 (32) Rash3                                              14 (27)                               1 (8)                               15 (23) Toothache                                          12 (23)                               2 (15)                              14 (22) Myalgia                                             9 (17)                               1 (8)                               10 (15) Tooth abscess                                       8 (15)                               3 (23)                              11 (17) Dizziness4                                          8 (15)                                0 (0)                               8 (12) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA 1
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 discoloration, injection site discomfort, injection site hematoma, injection site hemorrhage, injection site induration, injection site macule, and injection site urticaria 2
Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 3
Rash includes: rash, rash pruritic, rash maculopapular, and rash pustular 4
Dizziness includes: dizziness, and dizziness exertional

Hypersensitivity Reactions
In Study 1 (Study UX023-CL301) (N=29 for CRYSVITA arm), the most frequent hypersensitivity reactions were rash (10%), injection site rash (10%) and injection site urticaria (7%). In Studies 2 and 3 (N=65), the most frequent hypersensitivity reactions were rash (22%), injection site rash (6%), and urticaria (5%).
Hyperphosphatemia
In pediatric studies, no events of hyperphosphatemia were reported.
Injection Site Reactions (ISR)
In Study 1 (Study UX023-CL301) (N=29 for CRYSVITA arm), 52% of the patients had a local injection site reaction (e.g. injection site urticaria, erythema, rash, swelling, bruising, pain, pruritus, and hematoma) at the site of CRYSVITA injection. In Studies 2 and 3 (N=65), approximately 58% of the patients had a local injection site reaction at the site of CRYSVITA injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances.
Adverse Reactions in Adult Patients with XLH
The safety of CRYSVITA in adult patients with XLH was demonstrated in a randomized, double-blind, placebo-controlled study (Study 4 (Study UX023-CL303) ) of 134 patients, age 20-63 years (mean age 41 years), of whom most were white/Caucasian (81%) and female (65%). A total of 68 and 66 patients received at least one dose of CRYSVITA or placebo, respectively. The mean dose of CRYSVITA was 0.95 mg/kg (range 0.3 – 1.2 mg/kg) subcutaneously every 4 weeks. Adverse reactions reported in more than 5% of CRYSVITA-treated patients and 2 patients or more than with placebo from the 24-week placebo-controlled portion of Study 4 (Study UX023-CL303) are shown in Table 6.


Table 8: Adverse Reactions Occurring in More Than 5% of CRYSVITA-Treated Adult Patients and in at Least 2 Patients More Than with Placebo in the 24-Week Placebo-Controlled Period of Study 4 (Study UX023-CL303)
CRYSVITA                                        Placebo
Adverse Reaction                                                       (N=68)                                          (N=66) n (%)                                           n (%)
Back pain                                                              10 (15)                                          6 (9) Headache1                                                               9 (13)                                          6 (9) Tooth infection2                                                        9 (13)                                          6 (9) Restless legs syndrome                                                  8 (12)                                          5 (8) Vitamin D decreased3                                                    8 (12)                                          3 (5) Dizziness                                                               7 (10)                                          4 (6) Muscle spasms                                                            5 (7)                                          2 (3) Constipation                                                             6 (9)                                          0 (0) Blood phosphorus increased4                                             4 (6)                                           0 (0) n = number of patients with an event; N = total number of patients who received at least one dose of CRYSVITA or placebo 1
Headache includes: headache, and head discomfort
2
Tooth infection includes: tooth abscess, and tooth infection
3
Vitamin D decreased includes: vitamin D deficiency, blood 25-hydroxycholecalciferol decreased, and vitamin D decreased 4
Blood phosphorus increased includes: blood phosphorus increased, and hyperphosphatemia 

The 24-week placebo controlled study was followed by a 24-week open-label treatment period in which all patients received CRYSVITA subcutaneously every 4 weeks. No new adverse reactions were identified in the open-label extension period.
Hypersensitivity Reactions
In the double-blind period of Study 4 (Study UX023-CL303) , approximately 6% of patients in both the CRYSVITA and placebo treatment groups experienced a hypersensitivity event. The events were mild or moderate and did not require discontinuation.
Hyperphosphatemia
In the double-blind period of Study 4 (Study UX023-CL303) , 7% of patients in the CRYSVITA treatment group experienced hyperphosphatemia meeting the protocol-specified criteria for dose reduction (either a single serum phosphorus greater than 5.0 mg/dL or serum phosphorus greater than 4.5 mg/dL [the upper limit of normal] on two occasions). The hyperphosphatemia was managed with dose reduction. The dose for all patients meeting the protocol-specified criteria was reduced 50 percent. A single patient required a second dose reduction for continued hyperphosphatemia.
Injection Site Reactions (ISR)
In the double-blind period of Study 4 (Study UX023-CL303) , approximately 12% of patients in both the CRYSVITA and placebo treatment groups had a local reaction (e.g. injection site reaction, erythema, rash, bruising, pain, pruritus, and hematoma) at the site of the injection. Injection site reactions were generally mild in severity, occurred within 1 day of injection, lasted approximately 1 to 3 days, required no treatment, and resolved in almost all instances.



Restless Legs Syndrome (RLS)
In the double-blind period of Study 4 (Study UX023-CL303) , approximately 12% of the CRYSVITA treatment group had worsening of baseline restless legs syndrome (RLS) or new onset RLS of mild to moderate severity; these events did not lead to dose discontinuation. Nonserious RLS has also been reported in other repeat dose adult XLH studies; in one case, worsening baseline RLS led to drug discontinuation and subsequent resolution of the event.
Spinal Stenosis
Spinal stenosis is prevalent in adults with XLH and spinal cord compression has been reported. In the CRYSVITA phase 2 and phase 3 studies of adults with XLH (total N=176), a total of 7 patients underwent spinal surgery. Most of these cases appeared to involve progression of a pre-existing spinal stenosis. It is unknown if CRYSVITA therapy exacerbates spinal stenosis or spinal cord compression.
Adverse Reactions in Patients with TIO
The safety of CRYSVITA in patients with TIO was demonstrated in two single-arm clinical studies (Study 6(Study UX023T-CL201) and Study 7( Study KRN23-002)) that enrolled a total of 27 patients.
Fourteen patients were male, and patients ranged from 33 to 73 years of age. The mean dose of CRYSVITA was 0.77 mg/kg every 4 weeks and the mean duration of exposure was 121 weeks.
Adverse reactions reported in adult TIO patients in the pooled data from Study 6 and Study 7 are shown in Table 9.
Table 9: Adverse Reactions Reported in Adult Patients with TIO Based on Study 6 (Study UX023T-CL201) and Study 7 (Study KRN23-002) (N=27)
Overall
Adverse Reaction                                                         (N=27) n (%)
Tooth abscess1                                                           5 (19) Muscle spasms                                                            5 (19) Dizziness                                                                4 (15) Constipation                                                             4 (15) Injection site reaction 2                                                4 (15) Rash3                                                                    4 (15) Headache                                                                 3 (11) Vitamin D deficiency                                                      2 (7) Hyperphosphatemia                                                         2 (7) Restless legs syndrome                                                    2 (7) 1 Tooth abscess is defined by PTs “Tooth abscess” and “Tooth ache” 2 Injection Site Reactions is defined by PTs “Injection Site Reaction”, “Injection Site Pain” and “Injection Site Swelling”
3 Rash is defined by PTs “Rash” and “Rash papular”


Hypersensitivity reactions

In the pooled data for Studies 6 and 7, 22% of patients experienced a hypersensitivity reaction. The most frequent hypersensitivity reactions were eczema (11%) and rash (11%). The events were mild or moderate in severity.

Hyperphosphatemia

In the pooled data for Studies 6 and 7, 2 patients (7%) experienced hyperphosphatemia which was managed with dose reduction.

Injection site reactions

The frequency of injection site reactions was 15% (injection site reaction, injection site pain, and injection site swelling). The injection site reactions were generally mild in severity, required no treatment and resolved in all cases.

Restless Legs Syndrome

In the pooled data for Studies 6 and 7, 2 patients (7%) experienced symptoms of restless legs syndrome, which were mild and did not require treatment interruption.


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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il 

7.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to burosumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In XLH clinical studies, none (0/13) of the 1- to 4-year-old patients, 19% (10/52) of the 5- to 12-year- old patients, and 15% (20/131) of the adult patients tested positive for anti-drug antibodies (ADA) after receiving CRYSVITA. Among these, three 5- to 12-year-old patients tested positive for neutralizing antibodies. The presence of ADA was not associated with clinically relevant changes in pharmacokinetics, pharmacodynamics, efficacy, and safety of burosumab in patients with XLH.
In one TIO clinical study, 14% (2/14) of the adult patients tested positive for ADA after receiving CRYSVITA. None of the ADA positive patients tested positive for neutralizing antibodies. In another TIO clinical study, none of the 13 adult patients tested positive for ADA after receiving CRYSVITA.
7.3 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of CRYSVITA.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Investigations: Blood phosphorus increased has been reported in pediatric XLH patients receiving CRYSVITA.