6 ADVERSE REACTIONS

The following important adverse reactions are reported with IGIV: hypersensitivity, renal dysfunction and acute renal failure, thrombosis, hyperproteinemia, increased serum viscosity, hyponatremia, aseptic meningitis syndrome, hemolysis, hypertension, transfusion related acute lung injury, volume overload, and transmissible infectious agents [see Warnings and Precautions (5)] and are described elsewhere in the prescribing information.

Adverse reactions (ARs) [see Adverse Reactions (6.1)] are defined as adverse events at least possibly related or events occurring during or within 72 hours of a PRIVIGEN infusion.

Primary Humoral Immunodeficiency

The most serious adverse reaction observed in clinical study subjects receiving PRIVIGEN for PI was hypersensitivity in one subject [see Warnings and Precautions (5.1)]. The most common adverse reactions observed in >5% of clinical study subjects with PI were headache, fatigue, nausea, chills, vomiting, back pain, pain, elevated body temperature, abdominal pain, diarrhea, cough, stomach discomfort, chest pain, joint swelling/effusion, influenza-like illness, pharyngolaryngeal pain, urticaria, and dizziness.

Chronic Immune Thrombocytopenic Purpura

The most serious adverse reactions observed in the premarketing clinical study subjects receiving PRIVIGEN for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects [see Warnings and Precautions (5.5, 5.6)]. A total of 8 subjects (14%) in the premarketing ITP study experienced hemolysis as documented from clinical laboratory data. No serious adverse reactions were observed in the postmarketing chronic ITP study. A total of 12 subjects (21%) in the postmarketing ITP study were adjudicated to have mild hemolysis as documented from clinical laboratory data [see Warnings and Precautions (5.6)]. The most common adverse reactions observed in >5% of subjects in both clinical studies of subjects with chronic ITP were laboratory findings consistent with hemolysis (hemoglobin and hematocrit decrease without blood loss in conjunction with positive direct antiglobulin test (DAT) and elevated blood lactate dehydrogenase (LDH) and/or indirect bilirubin), headache, elevated body temperature, anemia, nausea, and vomiting.

Chronic Inflammatory Demyelinating Polyneuropathy

The most serious adverse reactions observed in clinical study subjects receiving PRIVIGEN for CIDP was hemolysis. The most common adverse reactions observed in >5% of subjects in both clinical studies of subjects with CIDP were headache, asthenia, hypertension, nausea, pain in extremity, hemolysis, influenza like illness, leukopenia, and rash.

6.1 Clinical Trials Experience

Because different 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.

Treatment of Primary Humoral Immunodeficiency

In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PI (with a diagnosis of XLA or CVID) received PRIVIGEN every 3 or 4 weeks for up to 12 months [see Clinical Studies (14.1)]. All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 46 (57.5%) were male and 34 (42.5%) were female.

The safety analysis included all 80 subjects, 16 (20%) on the 3-week schedule and 64 (80%) on the 4-week schedule. The median dose of PRIVIGEN administered was 428 mg/kg (3-week schedule) or 441 mg/kg (4-week schedule) and ranged from 200 to 888 mg/kg. A total of 1038 infusions of PRIVIGEN were administered, 272 in the 3-week schedule and 766 in the 4-week schedule.

Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related ARs that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered.

Table 2 summarizes the most frequent ARs that occurred in >5% of subjects.

Table 2. PI Pivotal Study – ARs* Occurring in >5% of Subjects
AR*	Number (%) of Subjects [n=80]	Number (Rate) of Infusions with AR [n=1038]
* ARs are defined as adverse events at least possibly related or events occurring during or within 72 hours of a PRIVIGEN infusion. Infections are excluded from this table.
Headache	36 (45.0)	100 (0.096)
Fatigue	13 (16.3)	29 (0.028)
Nausea	11 (13.8)	23 (0.022)
Chills	9 (11.3)	15 (0.014)
Vomiting	9 (11.3)	15 (0.014)
Back pain	8 (10.0)	15 (0.014)
Pain	7 (8.8)	14 (0.013)
Elevated body temperature	7 (8.8)	12 (0.012)
Diarrhea	6 (7.5)	6 (0.006)
Cough	5 (6.3)	5 (0.005)
Stomach discomfort	5 (6.3)	5 (0.005)

Of the 192 ARs reported (including 5 serious, severe ARs described below) 91 were mild (awareness of sign, symptom or event, but easily tolerated), 81 were moderate (discomfort enough to cause interference with usual activity and may have warranted intervention), 19 were severe (incapacitating with inability to do usual activities or significantly affected clinical status, and warranted intervention), and 1 was of unknown severity.

The five serious ARs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature, all severe), occurred in one subject, and resulted in the subject's withdrawal from the study. Two other subjects withdrew from the study due to ARs (chills and headache in one subject; vomiting in the other).

Seventy-seven of the 80 subjects enrolled in this study had a negative DAT at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia.

During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V).

An extension of the study described above was conducted in 55 adult and pediatric subjects with PI to collect additional efficacy, safety, and tolerability data. This study included 45 subjects from the pivotal study who were receiving PRIVIGEN and 10 new subjects who were receiving another IGIV product prior to enrolling in the extension study. Subjects ranged in age from 4 to 81 years; 26 (47.3%) were male and 29 (52.7%) were female.

Subjects were treated with PRIVIGEN at median doses ranging from 286 to 832 mg/kg per infusion over a treatment period ranging from 1 to 27 months. Twelve (21.8%) subjects were on a 3-week treatment schedule with the number of infusions per subject ranging from 4 to 38 (median: 8 infusions); 43 (78%) subjects were on a 4-week schedule with the number of infusions ranging from 1 to 31 (median: 15 infusions). A total of 771 infusions were administered in this study.

In this study, subjects who continued from the pivotal study were permitted to receive infusions of PRIVIGEN at a rate up to 12 mg/kg/min (as opposed to the maximum of 8 mg/kg/min allowed in the pivotal study) at the discretion of the investigator based on individual tolerability. Twenty-three (51%) of the 45 subjects from the pivotal study (42% of the 55 subjects in the extension study) received 265 (38%) infusions at a maximum rate greater than the recommended rate of 8 mg/kg/min [see Dosage and Administration (2.5)]. The median of the maximum infusion rate in this subset was 12 mg/kg/min. However, because the study was not designed to compare infusion rates, no definitive conclusions regarding tolerability could be drawn for infusion rates higher than the recommended rate of 8 mg/kg/min.

Table 3 summarizes the ARs that occurred in >5% of subjects.

Table 3. PI Extension Study – ARs* Occurring in >5% of Subjects
AR*	Number (%) of Subjects [n=55]	Number (Rate) of Infusions with AR [n=771]
Note: The AR rates in this study cannot be compared directly to the rates in other IGIV studies, including the original pivotal study described earlier in this section, because (1) the extension study used an enriched population and (2) the selective use of higher infusion rates at the investigators' discretion in a subset of subjects may have introduced bias.
* Excluding infections. † Includes abdominal pain, abdominal pain upper, and abdominal pain lower.
Headache	18 (32.7)	76 (0.099)
Nausea	6 (10.9)	10 (0.013)
Elevated body temperature	4 (7.3)	12 (0.016)
Abdominal pain†	4 (7.3)	7 (0.009)
Chest pain	3 (5.5)	4 (0.005)
Chills	3 (5.5)	7 (0.009)
Joint swelling/effusion	3 (5.5)	7 (0.009)
Pain	3 (5.5)	6 (0.008)
Fatigue	3 (5.5)	5 (0.006)
Influenza-like illness	3 (5.5)	5 (0.006)
Pharyngolaryngeal pain	3 (5.5)	4 (0.005)
Urticaria	3 (5.5)	4 (0.005)
Dizziness	3 (5.5)	3 (0.004)

Of the 125 reported ARs, 76 were mild (did not interfere with routine activities), 40 were moderate (interfered somewhat with routine activities), and 9 were severe (impossible to perform routine activities).

Three subjects experienced ARs: dyspnea and pancytopenia in one subject, a transient ischemic attack 16 days after the infusion in one subject, and mild urticaria in one subject, resulting in the subject's withdrawal from the study.

Treatment of Chronic Immune Thrombocytopenic Purpura

In a prospective, open-label, single-arm, multicenter premarketing clinical study, 57 subjects with chronic ITP and a platelet count of 20 × 109/L or less received a total of 2 g/kg dose of PRIVIGEN administered as 1 g/kg infusions daily for 2 consecutive days [see Clinical Studies (14.2)]. Subjects ranged in age from 15 to 69; 23 (40%) were male and 34 (60%) were female.

Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56%) subjects received premedication with acetaminophen and/or an antihistamine.

Table 4 summarizes the most frequent ARs that occurred in >5% of subjects with chronic ITP.

Table 4. Chronic ITP Premarketing Clinical Study – ARs* Occurring in >5% of Subjects
AR*	Number (%) of Subjects [n=57]	Number (Rate) of Infusions with AR [n=114]
* ARs were defined as adverse events at least possibly related or events occurring during or within 72 hours after the end of a treatment cycle [two consecutive infusions].
Headache	37 (64.9)	52 (0.456)
Elevated body temperature	21 (36.8)	23 (0.202)
Positive DAT	7 (12.3)	8 (0.070)
Anemia	6 (10.5)	6 (0.053)
Nausea	6 (10.5)	8 (0.070)
Epistaxis	6 (10.5)	8 (0.070)
Vomiting	6 (10.5)	7 (0.061)
Blood bilirubin unconjugated increased	6 (10.5)	6 (0.053)
Blood bilirubin conjugated increased	5 (8.8)	5 (0.044)
Blood total bilirubin increased	3 (5.3)	3 (0.026)
Hematocrit decreased	3 (5.3)	3 (0.026)
Blood lactate dehydrogenase increased	3 (5.3)	3 (0.026)

Of the 149 non-serious ARs, 103 were mild (awareness of sign, symptom or event, but easily tolerated), 37 were moderate (discomfort enough to cause interference with usual activity and may have warranted intervention), and 9 were severe (incapacitating with inability to do usual activities or significantly affected clinical status, and warranted intervention).

One subject experienced a serious AR (aseptic meningitis).

Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of PRIVIGEN. Two of the eight subjects were clinically anemic but did not require clinical intervention; these cases resolved uneventfully.

Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis.

In this study, there was a decrease in hemoglobin after the first PRIVIGEN infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29.

Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21%) developed a positive DAT during the 29-day study period.

Postmarketing Commitment Study in Chronic Immune Thrombocytopenic Purpura

In a prospective, open-label, single-arm, multicenter postmarketing clinical study whose primary objective was to evaluate mechanisms of hemolysis, 57 subjects with chronic ITP and a platelet count of <30 × 109/L at screening were studied following treatment with PRIVIGEN. Twenty-one (21) subjects (37%) received 1 infusion of 1 g/kg on Day 1 and 36 subjects (63%) received 2 infusions each of 1 g/kg (Day 1 and Day 3). Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Subjects received premedication with acetaminophen and/or an antihistamine [see Clinical Studies (14.3)].

The most frequent ARs (adverse events at least possibly related or events occurring during or within 72 hours after the end of treatment) that occurred in >5% of subjects with chronic ITP were headache (16 subjects [28%]) and pyrexia (3 subjects [5%]).

No subject experienced a serious adverse reaction.

Of the 23 non-serious ARs, 22 were mild (does not interfere with routine activities), 1 was moderate (interferes somewhat with routine activities), and none were severe (impossible to perform routine activities).

All 57 subjects had a negative DAT at baseline. Twenty-two (38%) developed a positive DAT by Day 4, 19 of these subjects were from blood group A.

Fifteen subjects were adjudicated by an independent expert committee, for presumptive/possible hemolysis, all of whom received 2 g/kg IGIV during the study [see Clinical Studies (14.3)]. Twelve subjects (21%) were judged to have mild hemolysis. In these 12 subjects there was a median hemoglobin drop from baseline at Day 9 (nadir) of -3.0 g/dL (range -0.9 to -5.8 g/dL) with Day 9 hemoglobin values ranging from 9.9 to 13.2 g/dL and a median drop from baseline in hemogloblin of -1.2 g/dL (range -0.1 to -2.7 g/dL) at Day 29 (end of study) with hemoglobin values ranging from 11.8 to 15.8 g/dL. Ten subjects were blood group A and 2 subjects were blood group B. These hemoglobin drops were transient and were followed by recovery or partial recovery by Day 29. One subject experienced mild dyspnea between Day 9 and Day 16; 1 subject experienced mild dizziness on Day 4. No subject was judged as having experienced clinically significant intravascular hemolysis. Three of the 15 adjudicated subjects were judged not to have experienced hemolysis.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

In a prospective, open-label, single-arm, multicenter clinical study (PRIVIGEN Impact on Mobility and Autonomy [PRIMA]), 28 subjects with CIDP received a PRIVIGEN loading dose of 2 g/kg followed by PRIVIGEN maintenance doses of 1 g/kg every 3 weeks for up to 21 weeks with 3 week follow up [see Clinical Studies (14.4)]. Administration of the loading dose occurred over 2 days and the maintenance dose over 1 day in the majority of cases.

Table 5 summarizes the most frequent ARs that occurred in ≥5% of subjects with CIDP.

Table 5. CIDP Clinical Study – ARs* Occurring in ≥5% of Subjects
AR*	Number (%) of Subjects [n=28]	Number (Rate) of Infusions with AR [n=259]
* ARs were defined as adverse events at least possibly related or events occurring during or within 72 hours after IV infusion.
Headache	8 (28.6)	19 (0.073)
Asthenia	4 (14.3)	4 (0.015)
Hypertension	4 (14.3)	6 (0.023)
Nausea	3 (10.7)	3 (0.012)
Pain in extremity	3 (10.7)	3 (0.012)
Hemolysis	2 (7.1)	2 (0.008)
Influenza like illness	2 (7.1)	2 (0.008)
Leukopenia	2 (7.1)	2 (0.008)
Rash	2 (7.1)	2 (0.008)

Two hemolysis serious adverse reactions occurred after the start of the PRIVIGEN induction dose in subjects with non-O blood groups (A and AB). The reactions resolved after discontinuation without the need for transfusion.

Four subjects, three of whom had a history of hypertension, had reversible increases in systolic blood pressure to ≥180 mm Hg during or within 1 to 4 hours following PRIVIGEN infusion. One of these subjects who had a history of untreated hypertension had a reversible increase in diastolic blood pressure from 84 mm Hg pre-infusion to 135 mm Hg at 1 hour after the end of the infusion. All were resolved or significantly improved within 1 to 6 hours with either observation alone or changes in oral anti-hypertensive therapy.

A total of 71 ARs were reported: 46 were mild (does not interfere with routine activities), 23 were moderate (interferes somewhat with routine activities), and 2 were severe (impossible to perform routine activities) in intensity.

In a second prospective, open-label PRIVIGEN pre-randomization phase of a multicenter, randomized, double-blind, placebo-controlled clinical study (Polyneuropathy and Treatment with Hizentra [PATH]), 207 IGIV-pretreated subjects with CIDP received a PRIVIGEN loading dose of 2 g/kg followed by up to 4 PRIVIGEN maintenance doses of 1 g/kg every three weeks for up to 13 weeks. Additionally, 60 of these subjects received PRIVIGEN rescue treatment by the same dosing regimen following CIDP relapse during the double-blind post-randomization phase [see Clinical Studies (14.4)].

Eight subjects experienced a serious adverse reaction (acute rash cutaneous, blood pressure diastolic increased, exacerbation of CIDP [2], hypersensitivity, pulmonary embolism, respiratory failure, and migraine. The serious adverse reactions of pulmonary embolism and respiratory failure occurred in subjects with preexisting risk factors. All serious adverse reactions resolved without sequelae.

Adverse reactions that occurred in >5% of subjects with CIDP were headache (33 subjects, 15.9% [rate per infusion 56/1894, 0.030]).

A total of 225 ARs were reported: 160 were mild (is transient, does not usually interfere with routine activities but minimal treatment or therapeutic intervention may be required), 59 were moderate (interferes somewhat with routine activities and usually alleviated with specific intervention but poses no significant or permanent risk of harm), and 6 were severe (interrupts usual activities of daily living, significantly affects clinical status, or may require intensive therapeutic intervention) in intensity.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily post-approval 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.

PRIVIGEN

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

Blood and lymphatic system disorders: Decreased neutrophil count
Infusion reactions: Changes in blood pressure, dyspnea, tachycardia, flushing
Hematologic: hemoglobinuria/hematuria/chromaturia, renal failure
Neurological: photophobia
Integumentary: pruritus

General

In addition, the following adverse reactions have been identified and reported during the post-approval use of immune globulin products.14

Infusion Reactions: Tachycardia, malaise, flushing, rigors
Renal: Acute renal dysfunction/failure, osmotic nephropathy
Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, bronchospasm
Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
Neurological: Coma, loss of consciousness, seizures, tremor
Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
Hematologic: Pancytopenia, leukopenia
Gastrointestinal: Hepatic dysfunction