6 ADVERSE REACTIONS

The most common adverse reactions (ARs) observed in ≥5% of study subjects receiving HIZENTRA were local reactions (e.g., swelling, redness, heat, pain, hematoma and itching at the infusion site), headache, diarrhea, fatigue, back pain, nausea, pain in extremity, cough, upper respiratory tract infection, rash, pruritus, vomiting, abdominal pain (upper), migraine, arthralgia, pain, fall and nasopharyngitis.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, AR rates observed in clinical studies of a product cannot be directly compared to rates in the clinical studies of another product and may not reflect the rates observed in clinical practice.

Treatment of Primary Immunodeficiency (PI)

PI U.S. Study

The safety of HIZENTRA was evaluated in a clinical study in the U.S. for 15 months (3-month wash-in/wash-out period followed by a 12-month efficacy period) in subjects with PI who had been treated previously with IGIV every 3 or 4 weeks. The safety analyses included 49 subjects in the intention-to-treat (ITT) population. The ITT population consisted of all subjects who received at least one dose of HIZENTRA [see Clinical Studies (14)].

Subjects were treated with HIZENTRA at weekly median doses ranging from 66 to 331 mg/kg body weight (mean: 181.4 mg/kg) during the wash-in/wash-out period and from 72 to 379 mg/kg (mean: 213.2 mg/kg) during the efficacy period. The 49 subjects received a total of 2264 weekly infusions of HIZENTRA.

Table 2 summarizes the most frequent adverse reactions (ARs) (experienced by at least 2 subjects) occurring during or within 72 hours after the end of an infusion. Local reactions were assessed by the investigators 15 to 45 minutes post-infusion and by the subjects 24 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments. Local reactions were the most frequent ARs observed, with infusion-site reactions (e.g., swelling, redness, heat, pain, and itching at the site of infusion) comprising 98% of local reactions.

Table 2. Incidence of Subjects with Adverse Reactions (ARs)* (Experienced by 2 or More Subjects) and Rate per Infusion (ITT Population), PI U.S. Study
	ARs* Occurring During or Within 72 Hours of Infusion
AR (≥2 Subjects)	Number (%) of Subjects (n=49)	Number (Rate†) of ARs (n=2264 Infusions)
* Excluding infections. † Rate of ARs per infusion. ‡ Includes infusion-site reactions as well as bruising, scabbing, pain, irritation, cysts, eczema, and nodules at the infusion site.
Local reactions‡	49 (100)	1322 (0.584)
Other ARs:
Headache	12 (24.5)	32 (0.014)
Diarrhea	5 (10.2)	6 (0.003)
Fatigue	4 (8.2)	4 (0.002)
Back pain	4 (8.2)	5 (0.002)
Nausea	4 (8.2)	4 (0.002)
Pain in extremity	4 (8.2)	6 (0.003)
Cough	4 (8.2)	4 (0.002)
Vomiting	3 (6.1)	3 (0.001)
Abdominal pain, upper	3 (6.1)	3 (0.001)
Migraine	3 (6.1)	4 (0.002)
Pain	3 (6.1)	4 (0.002)
Arthralgia	2 (4.1)	3 (0.001)
Contusion	2 (4.1)	3 (0.001)
Rash	2 (4.1)	3 (0.001)
Urticaria	2 (4.1)	2 (<0.001)

The ratio of infusions with ARs, including local reactions, to all infusions was 1303 to 2264 (57.6%). Excluding local reactions, the corresponding ratio was 56 to 2264 (2.5%).

Table 3 summarizes infusion-site reactions based on investigator assessments 15 to 45 minutes after the end of the 683 infusions administered during regularly scheduled visits (every 4 weeks).

Table 3. Investigator Assessment* of Infusion-Site Reactions by Infusion, PI U.S. Study
Infusion-Site Reaction	Number† (Rate‡) of Reactions (n=683 Infusions§)
* 15 to 45 minutes following infusions administered at regularly scheduled visits (every 4 weeks). † For multiple infusion sites, every site was judged, but only the site with the strongest reaction was recorded. ‡ Rate of infusion-site reactions per infusion. § Number of infusions administered during regularly scheduled visits.
Edema/induration	467 (0.68)
Erythema	346 (0.51)
Local heat	108 (0.16)
Local pain	88 (0.13)
Itching	64 (0.09)

Most local reactions were either mild (does not interfere with routine activities [93.4%]) or moderate (interferes somewhat with routine activities and may have warranted intervention [6.3%]) in intensity.

No deaths or serious ARs occurred during the study. Two subjects withdrew from the study due to ARs. One subject experienced a severe infusion-site reaction one day after the third weekly infusion, and the other subject experienced moderate myositis.

PI European Study

In a clinical study conducted in Europe, the safety of HIZENTRA was evaluated for 10 months (3-month wash-in/wash-out period followed by a 7-month efficacy period) in 51 subjects with PI who had been treated previously with IGIV every 3 or 4 weeks or with IGSC weekly.

Subjects were treated with HIZENTRA at weekly median doses ranging from 59 to 267 mg/kg body weight (mean: 118.8 mg/kg) during the wash-in/wash-out period and from 59 to 243 mg/kg (mean: 120.1 mg/kg) during the efficacy period. The 51 subjects received a total of 1831 weekly infusions of HIZENTRA.

Table 4 summarizes the most frequent ARs (experienced by at least 2 subjects) occurring during or within 72 hours after the end of an infusion. Local reactions were assessed by the subjects between 24 and 72 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments.

Table 4. Incidence of Subjects with Adverse Reactions (ARs)* (Experienced by 2 or More Subjects) and Rate per Infusion, PI European Study
	ARs* Occurring During or Within 72 Hours of Infusion
AR (≥2 Subjects)	Number (%) of Subjects (n=51)	Number (Rate†) of ARs (n=1831 Infusions)
* Excluding infections. † Rate of ARs per infusion. ‡ Includes infusion-related reaction; infusion-site mass; infusion/injection-site erythema, hematoma, induration, inflammation, edema, pain, pruritus, rash, reaction, swelling; infusion-site extravasation, nodule; puncture-site reaction.
Local reactions‡	24 (47.1)	105 (0.057)
Other ARs:
Headache	9 (17.6)	20 (0.011)
Rash	4 (7.8)	4 (0.002)
Pruritus	4 (7.8)	13 (0.007)
Fatigue	3 (5.9)	5 (0.003)
Abdominal pain, upper	2 (3.9)	3 (0.002)
Arthralgia	2 (3.9)	2 (0.001)
Erythema	2 (3.9)	4 (0.002)
Abdominal discomfort	2 (3.9)	3 (0.002)
Back pain	2 (3.9)	2 (0.001)
Hematoma	2 (3.9)	3 (0.002)
Hypersensitivity	2 (3.9)	4 (0.002)

The proportion of subjects reporting local reactions decreased over time from approximately 20% following the first infusion to <5% by the end of the study.

Three subjects withdrew from the study due to ARs of mild to moderate intensity. One subject experienced infusion-site pain and infusion-site pruritus; the second subject experienced infusion-site reaction, fatigue, and feeling cold; and the third subject experienced infusion-site reaction and hypersensitivity.

Biweekly (Every 2 Weeks) or Frequent (2 To 7 Times per Week) Dosing

No data regarding ARs are available for these alternative HIZENTRA dosing regimens because no clinical trials using these regimens were conducted.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

PATH Study

The safety of 2 doses of HIZENTRA (0.2 g/kg body weight or 0.4 g/kg body weight) versus placebo was evaluated in the 24-week subcutaneous (SC) treatment period of the PATH (Polyneuropathy AND Treatment with Hizentra) study in subjects with CIDP who had been treated previously with IGIV [see Clinical Studies (14.2)]. The dose was administered once a week in 2 infusion sessions conducted on 1 or 2 consecutive day(s). The safety population included 172 subjects.

Table 5 summarizes the most frequent ARs that occurred in ≥5% of subjects treated with HIZENTRA and at a higher frequency than placebo. The overall AR rates were similar in the 0.2 g/kg body weight and 0.4 g/kg body weight HIZENTRA dose groups (50.9% and 46.6%, respectively) and higher than placebo (33.3%). The most frequent ARs were local infusion site reactions. Local reactions were more frequent among subjects who received the 0.4 g/kg body weight dose than among subjects who received the 0.2 g/kg body weight dose (29.3% and 19.3%, respectively). The exposure-adjusted rate of local reactions per subject remained greater in the 0.4 g/kg body weight dose group compared to the 0.2 g/kg body weight dose group after adjusting for the greater mean duration of exposure to HIZENTRA in the 0.4 g/kg body weight dose group (129 days) compared to that of the 0.2 g/kg body weight dose group (119 days). All local reactions were either mild (does not interfere with routine activities [94.5%]) or moderate (interferes somewhat with routine activities and may have warranted intervention [5.5%]) in intensity and the frequency tended to decrease over time. No subject withdrew because of local reaction.

One serious AR, allergic dermatitis was reported in the 0.2 g/kg body weight HIZENTRA group which started at SC Week 9 and lasted 15 days. One subject withdrew from the study due to a non-serious AR, fatigue.

Table 5. CIDP SC Treatment Period – ARs Occurring in ≥5% of Subjects Treated with HIZENTRA and at a Higher Frequency than Placebo-Treated Subjects
	Placebo		0.2 g/kg HIZENTRA		0.4 g/kg HIZENTRA
	Number (%) of Subjects n=57	Number of Events (Rate/Infusion) n=1514*	Number (%) of Subjects n=57	Number of Events (Rate/Infusion) n=2007*	Number (%) of Subjects n=58	Number of Events (Rate/Infusion) n=2218*
AR = adverse reaction; SC = subcutaneous.
* Number of infusions. † Includes infusion site erythema, infusion site swelling, infusion site pain, infusion site induration, infusion site warmth, infusion site hematoma, and infusion site pruritus.
Local Reactions†	4 (7.0)	7 (0.005)	11 (19.3)	54 (0.027)	17 (29.3)	49 (0.022)
Headache	2 (3.5)	2 (0.001)	4 (7.0)	5 (0.002)	4 (6.9)	4 (0.002)
Nasopharyngitis	1 (1.8)	1 (<0.001)	4 (7.0)	6 (0.003)	2 (3.4)	2 (<0.001)
Fatigue	1 (1.8)	1 (<0.001)	5 (8.8)	5 (0.002)	0	0
Upper respiratory tract infection	2 (3.5)	2 (0.001)	3 (5.3)	3 (0.001)	2 (3.4)	2 (<0.001)
Fall	0	0	3 (5.3)	8 (0.004)	1 (1.7)	1 (<0.001)
Back Pain	1 (1.8)	1 (<0.001)	3 (5.3)	4 (0.002)	1 (1.7)	1 (<0.001)
Arthralgia	1 (1.8)	1 (<0.001)	3 (5.3)	4 (0.002)	1 (1.7)	1 (<0.001)
Pain in Extremity	0	0	1 (1.8)	1 (<0.001)	3 (5.2)	3 (0.001)

Hypertension was reported in 2 subjects (3.5%) in the 0.2 g/kg HIZENTRA group, 2 subjects (3.4%) in the 0.4 g/kg group, and zero subjects in the placebo group. Systemic adverse reactions in the 13-week IGIV Restabilization Period of the study for subjects also randomized and treated with HIZENTRA during the 24-week subcutaneous treatment period (N=115) occurred at a rate of 0.098 (956 infusions) relative to a rate of 0.027 (4225 infusions) during treatment with HIZENTRA in the IGSC period of the study. The systemic adverse reaction rate per infusion for HIZENTRA was 3.6-fold lower than the corresponding rate for IGIV.

The exposure-adjusted rate for systemic adverse reactions in the 13-week single-arm IGIV Restabilization Period of the study for subjects also randomized and treated with HIZENTRA during the 24-week subcutaneous treatment period (N=115) was 0.075 reactions per week, relative to an exposure-adjusted rate of 0.052 reactions per week during treatment with HIZENTRA in the IGSC period of the study. The exposure-adjusted systemic adverse reaction rate for HIZENTRA was 31% lower than the corresponding rate for IGIV. However, this difference should be interpreted with caution, because there was no parallel group of subjects receiving placebo during the period of IGIV treatment.

PATH Extension Study

The PATH Extension study was a multicenter, 48-week, open-label extension study that evaluated the long -term safety and efficacy of HIZENTRA 0.2 g/kg and 0.4 g/kg doses, per body weight, in the maintenance treatment of CIDP in subjects who either completed or were being successfully rescued from CIDP relapse with IGIV in the PATH study. A total of 82 subjects were enrolled. Of these, 66 (80.5%) subjects completed the study, and 16 (19.5%) subjects discontinued.

In the study, 30.1% of subjects in the HIZENTRA 0.2 g/kg group and 51.4% of subjects in the 0.4 g/kg group experienced adverse reactions. Similar to the PATH study, the most frequent ARs were local infusion site reactions, and local reactions were more frequent among subjects who received the 0.4 g/kg body weight dose than among subjects who received the 0.2 g/kg body weight dose (18.1% and 9.6%, respectively). Of all the local reactions, 1 subject had 3 severe reactions (interrupts routine activities or may require intensive therapeutic intervention [7.5%]) with the 0.4 g/kg dose; the rest were either mild (85.0%) or moderate (7.5%). Two subjects withdrew because of local reactions.

The total exposure was 25.1 subject years in the HIZENTRA 0.2 g/kg group and 38.7 subject years in the 0.4 g/kg group. The mean duration of exposure was 125.8 (range 1 to 330) days in the HIZENTRA 0.2 g/kg group and 196.1 (range 1 to 330) days in the 0.4 g/kg group.

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.

HIZENTRA

The following adverse reactions have been identified during postmarketing use of HIZENTRA. This list does not include reactions already reported in clinical studies with HIZENTRA [see Adverse Reactions (6.1)].

Infusion reactions: Allergic-anaphylactic reactions such as swollen face or tongue and pharyngeal edema, pyrexia, chills, dizziness, hypertension/changes in blood pressure, malaise, tachycardia, flushing.
Cardiovascular: Chest discomfort (including chest pain)
Respiratory: Dyspnea
Neurological: Tremor, burning sensation
General disorders and administration site conditions: Infusion site ulcer, infusion site necrosis

Immune Globulin Products

The following adverse reactions have been reported during postmarketing use of immune globulin products:5

Infusion reactions: Wheezing, rigors, myalgia
Renal: Osmotic nephropathy
Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), cyanosis, hypoxemia, pulmonary edema, bronchospasm
Cardiovascular: Cardiac arrest, vascular collapse, hypotension
Neurological: Coma, loss of consciousness, seizures, aseptic meningitis syndrome
Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test
Gastrointestinal: Hepatic dysfunction

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.