6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of SPINRAZA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. SPINRAZA Low Dose Regimen (12 mg loading doses/12 mg maintenance doses) In clinical studies, 385 patients (47% male, 68% Caucasian, and 12% Asian) were treated with SPINRAZA Low Dose Regimen [see Dosage and Administration ( 2.1 )] , including 353 exposed for at least 6 months, 314 exposed for at least 1 year, and 256 exposed for at least 5 years.
Clinical Trial in Infantile-Onset SMA (Study 1) In Study 1, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except that SPINRAZA-treated patients at baseline had a higher percentage compared to sham-control patients of paradoxical breathing (89% vs 66%), pneumonia or respiratory symptoms (35% vs 22%), swallowing or feeding difficulties (51% vs 29%), and requirement for respiratory support (26% vs 15%).
The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (18%) than in control patients (10%). Because patients in Study 1 were infants, adverse reactions that are verbally reported could not be assessed in this study.
Table 2. Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients with Infantile-Onset SMA (Study 1) 1 Low Dose Regimen [see Dosage and Administration ( 2.1 )] 2 Includes adenovirus infection, bronchiolitis, bronchitis, bronchitis viral, corona virus infection, Influenza, lower respiratory tract infection, lower respiratory tract infection viral, lung infection, parainfluenzae virus infection, pneumonia, pneumonia bacterial, pneumonia influenzal, pneumonia moraxella, pneumonia parainfluenzae viral, pneumonia pneumococcal, pneumonia pseudomonal, pneumonia respiratory syncytial viral, pneumonia viral, and respiratory syncytial virus bronchiolitis.
Adverse Reactions SPINRAZA 12 mg 1 N = 80 % Sham-Procedure Control N = 41 % Lower respiratory infection 2 55 37 Constipation 35 22 Teething 18 7 Urinary tract infection 9 0 Upper respiratory tract congestion 8 2 Ear infection 6 2 Flatulence 5 2 Decreased weight 5 2 In an open-label clinical study in infants with symptomatic SMA, severe hyponatremia was reported in a patient treated with SPINRAZA requiring salt supplementation for 14 months.
Cases of rash were reported in patients treated with SPINRAZA. One patient, 8 months after starting SPINRAZA treatment, developed painless red macular lesions on the forearm, leg, and foot over an 8-week period. The lesions ulcerated and scabbed over within 4 weeks, and resolved over several months. A second patient developed red macular skin lesions on the cheek and hand ten months after the start of SPINRAZA treatment, which resolved over 3 months.
Both cases continued to receive SPINRAZA and had spontaneous resolution of the rash. SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment. Clinical Trial in Later-Onset SMA (Study 2) In Study 2, baseline disease characteristics were largely similar in the SPINRAZA-treated patients and sham-control patients except for the proportion of SPINRAZA-treated patients who had ever achieved the ability to stand without support (13% vs 29%) or walk with support (24% vs 33%).
The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were pyrexia, headache, vomiting, and back pain. Table 3. Adverse Reactions that Occurred in at Least 5% of SPINRAZA Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than in Control Patients with Later-Onset SMA (Study 2) 1 Low Dose Regimen [see Dosage and Administration ( 2.1 )] Adverse Reactions SPINRAZA 12 mg 1 N=84 % Sham - Procedure Control N=42 % Pyrexia 43 36 Headache 29 7 Vomiting 29 12 Back pain 25 0 Epistaxis 7 0 Fall 5 0 Respiratory tract congestion 5 2 Seasonal allergy 5 2 Post-lumbar puncture syndrome has also been observed after administration of SPINRAZA.
SPINRAZA High Dose Regimen (50 mg loading doses/28 mg maintenance doses) The safety of SPINRAZA High Dose Regimen was studied in 2 clinical trials in symptomatic patients with SMA (approximately 14 days to 65 years of age at first dose). In clinical studies, 128 patients (50% male, 63% Caucasian, and 22% Asian) were treated with SPINRAZA High Dose Regimen [see Dosage and Administration ( 2.1 )], including 113 exposed for at least 6 months, 95 exposed for at least 1 year, and 67 exposed for at least 2 years.
Clinical Trial in Infantile-Onset SMA (Study 4) The most common adverse reactions that occurred in at least 10% of SPINRAZA treated patients and occurred at least 5% more frequently than in historic-matched sham-control patients from Study 1 were pneumonia, COVID-19, pneumonia aspiration, and malnutrition in patients with infantile-onset SMA. COVID-19 was not discovered at the time of Study 1. Table 4: Adverse Reactions that Occurred in at least 5% of SPINRAZA High Dose Regimen Patients and Occurred at Least 5% More Frequently or At Least 2 Times as Frequently Than Matched Sham Control in Patients with Infantile Onset SMA (Study 4) SPINRAZA High Dose Regimen (Study 4) (N=50) % Matched Sham Control (Study 1) (N=20) % Pneumonia 20 5 COVID-19 16 0 Pneumonia aspiration 14 5 Malnutrition 10 0 Procedural pain 6 0 Myocardial necrosis marker increased 6 0 Anemia 6 0
