6 ADVERSE REACTIONS

The most common adverse reactions observed in ≥5% of subjects were: local adverse reactions, systemic adverse reactions including headache, nausea, fatigue, diarrhea, and vomiting.

6.1 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 clinical practice.

CUVITRU was administered subcutaneously in two prospective, open-label, non-controlled, multicenter studies to evaluate efficacy, safety, tolerability, and pharmacokinetics in subjects with primary immunodeficiency (PI). One study was performed in North America and the other was performed in Europe.

North American Study

In a clinical study conducted in North America, 67 out of 74 subjects treated with CUVITRU completed the study including 20/21 subjects aged 2 to <16 years old. Of the 7 subjects that discontinued treatment with CUVITRU, one subject withdrew due to fatigue (assessed as not related), 1 subject withdrew because of non-compliance, and 5 subjects withdrew for personal reasons.

A total of 4,327 CUVITRU infusions were administered during the clinical study. No serious adverse reactions occurred during treatment with CUVITRU; 278 non-serious adverse reactions occurred at a rate per infusion of 0.06. Among the 4,327 CUVITRU infusions, 99.3% (276/278) of adverse reactions were mild or moderate and transient in nature. Of the 278 non-serious adverse reactions (excluding infections), 83% (231/278) were rated as mild, 16% (45/278) were rated as moderate, and 1% (2/278, hemoptysis and abdominal pain) were severe.

Adverse reactions occurring in ≥5% of subjects (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 3. No subject discontinued treatment due to local adverse reactions.

Table 3 Adverse Reactions* in ≥5% of Subjects Associated with Infusions of CUVITRU
Adverse Reactions	By Subject N (%)† (N=74 Subjects)	By Infusion N (Rate)‡ (N=4,327 infusions)
* Excluding infections † Number and percentages of affected subjects ‡ Rate = Total number of adverse reactions divided by the total number of infusions under treatment
Local Adverse Reactions	23 (31.1%)	96 (0.022)
Systemic Adverse Reactions	41 (55.4%)	182 (0.042)
Headache	10 (13.5%)	50 (0.012)
Nausea	9 (12.2%)	16 (0.004)
Fatigue	6 (8.1%)	9 (0.002)
Diarrhea	5 (6.8%)	5 (0.001)
Vomiting	4 (5.4%)	5 (0.001)

Systemic adverse reactions to immune globulin intravenous in part 1 of the study occurred at a rate of 0.302 relative to a rate of 0.042 during treatment with CUVITRU. The CUVITRU systemic adverse reaction rate was approximately 7-fold lower than the immune globulin intravenous rate.

Local Adverse Reactions: The most frequent local adverse reactions are listed by frequency in Table 4. Of the total 96 local adverse reactions, 100% were either mild (92.5%) or moderate (7.5%) in severity. No severe local adverse reactions were reported. During the clinical study, no local adverse reactions were observed in 68.9% (51/74) of subjects and in 98.2% (4,247/4,327) of infusions. The overall rate of local adverse reactions (excluding infections) during the clinical study was 0.022 (0.021 mild and 0.002 moderate). The rate of local adverse reactions was not associated with increased rate of infusion or volume per site.

Table 4 Most Frequent Local Adverse Reactions Reported in ≥5% of Subjects
Events	Total Number of Adverse Reactions		By Subject N (%)* (N =74 Subjects)	By Infusion N (Rate)† (N=4,327 infusions)
	Mild	Moderate
* Number and percentages of affected subjects † Rate= Total number of adverse reactions divided by the total number of infusions under treatment
Pain	33	3	15 (20.3%)	36 (0.008)
Erythema	22	1	8 (10.8%)	23 (0.005)
Pruritus	7	1	4 (5.4%)	8 (0.002)

European Study

Efficacy and safety during treatment with CUVITRU were evaluated in 48 subjects in a clinical trial in Europe. CUVITRU was administered for a median treatment duration of 358 days (range: 127.0-399 days) and a mean (± SD) of 347.4 ± 47.9 days. CUVITRU treatment: 45/48 subjects treated with CUVITRU completed the study, including 23/25 subjects aged 2 to <18 years old.

A total of 2,349 CUVITRU infusions were administered during this clinical study. No serious adverse reactions occurred during treatment with CUVITRU. In total, 176 local adverse reactions and 205 systemic adverse reactions were reported (adverse reaction defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period), excluding infections. Of the 205 systemic reactions, the majority (134) were mild, 70 were moderate and one event was severe (headache, assessed as temporally associated, not causally related). The rate of systemic adverse reactions (excluding infections) during treatment with CUVITRU was 0.087, and the rate of related systemic AEs (excluding infections) per infusion was 0.032. During treatment with IGIV 10% in study part 1, the rate of related systemic AEs (excluding infections) was 0.173 events per infusion. The CUVITRU related systemic adverse event rate was approximately 5-fold lower than the immune globulin intravenous rate.

Table 5 EU Study: Adverse Reactions* in ≥5% of Subjects Associated with Infusions of CUVITRU
Adverse Reactions	By Subject N (%)† (N=48 Subjects)	By Infusion N (Rate)‡ (N=2,349 infusions)
* Causally Related and/or Temporally Associated (Within 72 Hour) AEs (Excluding Infections) † Total number of affected subjects divided by the total number of subjects under treatment ‡ Total number of AEs divided by the total number of infusions under treatment
Local Adverse Reactions	18 (37.5%)	176 (0.075)
Systemic Adverse Reactions	33 (68.8%)	205 (0.087)
Headache	14 (29.2%)	59 (0.025)
Diarrhea	9 (18.8%)	58 (0.025)
Cough	5 (10.4%)	7 (0.003)
Fatigue	6 (12.5)	8 (0.003)
Arthralgia	3 (6.3%)	5 (0.002)
Oropharyngeal pain	3 (6.3%)	3 (0.001)

Local Adverse Reactions: Among the 176 local adverse reactions in total (adverse reaction defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period), none was severe. In total, 175 adverse reactions (99.4%) were mild, and 1 adverse reaction (0.6%) was moderate. The overall rate of local adverse reactions was 0.075 per infusion. The most common reactions (by subject) were infusion site pain, infusion site erythema and infusion site pruritus.

Table 6 EU Study: Most Frequent Local Adverse Reactions Reported in ≥5% of Subjects
Events	Total Number of Adverse Reactions		By Subject N (%)* (N =48 Subjects)	By Infusion N (Rate)† (N=2,349 infusions)
	Mild	Moderate
* Number and percentages of affected subjects † Rate= Total number of adverse reactions divided by the total number of infusions under treatment
Pain	34	0	10 (20.8%)	34 (0.014)
Erythema	54	0	10 (20.8%)	54 (0.023)
Pruritus	30	0	7 (14.6%)	30 (0.013)
Swelling	46	0	4 (8.3%)	46 (0.020)

6.2 Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

In addition to the adverse reactions listed above in clinical trials, the following adverse reactions have been reported in the postmarketing experience:

Infections and Infestations: Aseptic meningitis

Postmarketing Experience of Immune Globulin Products

The following adverse reactions have been identified and reported during the postmarketing use of immune globulin products administered subcutaneously:

Immune system disorders	Anaphylactic reaction
Cardiac disorders	Tachycardia
Nervous system disorders	Tremor and paresthesia
Respiratory, Thoracic and Mediastinal disorders	Dyspnea and laryngospasm
General disorders and administration site conditions	Injection site reaction (such as induration and warmth) and chest discomfort