Immune Globulin Intravenous

Dosage Forms And Strengths

Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion.

• Privigen is supplied in a single-use, tamper-evident vial containing the labeled amount of functionally active IgG.

Each product presentation includes a package insert and the following components:

Storage And Handling

• Keep Privigen in its original carton to protect it from light.
• Each vial has an integral suspension band and a label with two peel-off strips showing the product name, lot number, and expiration date.
• When stored at room temperature (up to 25°C [77°F]), Privigen is stable for up to 36 months, as indicated by the expiration date printed on the outer carton and vial label.
• Do not freeze.
• The Privigen packaging components are not made with natural rubber latex.

Manufactured by: CSL Behring AG, Bern, Switzerland. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised: Nov 2013

Included as part of the PRECAUTIONS section.

Mechanism Of Action

Privigen is a replacement therapy for primary humoral immunodeficiency, and supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacterial, viral, parasitic and mycoplasma agents and their toxins. The mechanism of action in PI has not been fully elucidated.

The mechanism of action of high doses of immunoglobulins in the treatment of chronic ITP has not been fully elucidated.

Pharmacokinetics

In the clinical study (pivotal study) assessing the efficacy and safety of Privigen in 80 subjects with PI [see Clinical Studies], serum concentrations of total IgG and IgG subclasses were measured in 25 subjects (ages 13 to 69) following the 7th infusion for the 3 subjects on the 3-week dosing interval and following the 5th infusion for the 22 subjects on the 4-week dosing interval. The dose of Privigen used in these subjects ranged from 200.0 mg/kg to 714.3 mg/kg. After the infusion, blood samples were taken until Day 21 and Day 28 for the 3-week and 4-week dosing intervals, respectively.

Table 6 summarizes the pharmacokinetic parameters of Privigen, based on serum concentrations of total IgG.

Table 6: PI Pivotal Study - Pharmacokinetic Parameters of Privigen in Subjects

The median half-life of Privigen was 36.6 days for the 25 subjects in the pharmacokinetic subgroup.

Although no systematic study was conducted to evaluate the effect of gender and age on the pharmacokinetics of Privigen, based on the small sample size (11 males and 14 females) it appears that clearance of Privigen is comparable in males (1.27 ± 0.35 mL/day/ kg) and females (1.34 ± 0.22 mL/day/kg). In six subjects between 13 and 15 years of age, the clearance of Privigen (1.35 ± 0.44 mL/day/kg) is comparable to that observed in 19 adult subjects 19 years of age or older (1.29 ± 0.22 mL/day/kg).

The IgG subclass levels observed in the pharmacokinetic study were consistent with a physiologic distribution pattern (mean trough values): IgG1, 564.91 mg/dL; IgG2, 394.15 mg/dL; IgG3, 30.16 mg/dL; IgG4, 10.88 mg/dL.

Pharmacokinetic studies with Privigen were not performed in subjects with chronic ITP.

Clinical Studies

A prospective, open-label, single-arm, multicenter study (pivotal study) assessed the efficacy, safety, and pharmacokinetics of Privigen in adult and pediatric subjects with PI, who were treated for 12 months at a 3-week or 4-week dosing interval. Subjects ranged in age from 3 to 69; 46 (57.5%) were male and 34 (42.5%) were female; 77.5% were Caucasian, 15% were Hispanic, and 7.5% were African-American. All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. The efficacy analysis included 80 subjects, 16 (20%) on the 3-week dosing interval and 64 (80%) on the 4-week dosing interval. Doses ranged from 200 mg/kg to 888 mg/kg per infusion. The median dose for the 3-week interval was 428.3 mg/kg per infusion; the median dose for the 4-week interval was 440.6 mg/kg per infusion. Subjects received a total of 1038 infusions of Privigen, 272 for the 3-week dosing regimen and 766 for the 4-week dosing regimen. The maximum infusion rate allowed during this study was 8 mg/ kg/min with 715 (69%) of the infusions administered at a rate of 7 mg/kg/min or greater. The primary analysis for efficacy was based on the annual rate of acute serious bacterial infections (aSBIs), defined as pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess, per subject per year. Secondary analyses were based on the annual rate of other infections, antibiotic use, days out of work/school/ day care or unable to perform normal activities due to illness, and days of hospitalization. During the 12-month study period, the aSBI rate was 0.08 (with an upper 1-sided 99% confidence interval of 0.203), which met the predefined success rate of less than one aSBI per subject per year. Six subjects experienced an aSBI, including three cases of pneumonia and one case each of septic arthritis, osteomyelitis, and visceral abscess. All six subjects completed the study.

The rate of other infections was 3.55 infections per subject per year. The infections that occurred most frequently were sinusitis (31.3%), nasopharyngitis (22.5%), upper respiratory tract infection (18.8%), bronchitis (13.8%), and rhinitis (13.8%). Among the 255 infections, 16 (6.3%) occurring in 10 subjects were considered severe.

Table 7 summarizes the efficacy results for all 80 subjects.

Table 7: PI Pivotal Study – Summary of Efficacy Results in Subjects

A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and tolerability of Privigen in 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less. Subjects ranged in age from 15 to 69; 23 (40.4%) were male and 34 (59.6%) were female; all were Caucasian.

Subjects received a 2 g/kg dosage of Privigen administered as 1 g/kg (10 mL/kg) intravenous infusion daily for 2 consecutive days, and were observed for 29 days. Fifty-three (93%) subjects received Privigen at the maximum infusion rate allowed (4 mg/kg/min [0.04 mL/kg/min]).

The primary analysis was based on the response rate defined as the percentage of subjects with an increase in platelet counts to at least 50 x 109/L within 7 days after the first infusion (responders). Secondary analyses were based on the increase in platelet counts and the time to reach a platelet count of at least 50 x 109/L at any point within the study period, the duration of that response, and the regression (decrease in the severity) of hemorrhage in subjects who had bleeding at baseline. Platelet counts were measured on Days 1, 2, 4, 6, 8, 15, 22, and 29. Additional measurements on Days 57 and 85 occurred in subjects with a platelet count of at least 50 x 109/L at the previous visit.

Of the 57 subjects in the efficacy analysis, 46 (80.7%) responded to Privigen with a rise in platelet counts to at least 50 x 109/L within 7 days after the first infusion. The lower bound of the 95% confidence interval for the response rate (69.2%) is above the predefined response rate of 50%.

The highest median increase in platelet counts was seen 7 days after the first infusion (123 x 109/L). The median maximum platelet count achieved was 154 x 109/L. The median time to reach a platelet response of more than 50 x 109/L was 2.5 days after the first infusion. Twenty-five (43%) of the 57 subjects reached this response by Day 2 prior to the second infusion and 43 (75%) subjects reached this response by Day 6.

The duration of platelet response was analyzed for the 48 subjects who achieved a response any time after the first infusion. The median duration of platelet response in these subjects was 15.4 days (range: 1 to > 82 days). Thirty-six (75%) of the 48 subjects maintained the response for at least 8.8 days and 12 (25%) of them for at least 21.9 days. Five (9%) subjects maintained a response up to Day 29 and two (4%) up to Day 85.

A decrease in the severity of hemorrhage from baseline was observed in the following bleeding locations: skin (31 of 36 subjects), oral cavity (11 of 11 subjects), and genitourinary tract (7 of 9 subjects). This decrease was not sustained in all subjects up to the end of the 29-day study period.

You should not use this medication if you have ever had an allergic reaction to an immune globulin or if you have immune globulin A (IgA) deficiency with antibody to IgA.

To make sure you can safely use immune globulin, tell your doctor if you have any of these other conditions:

• kidney disease;
• diabetes (especially if you use insulin);
• a history of stroke or blood clot;
• heart disease or high blood pressure;
• a condition called paraproteinemia; or
• if you are over 65 years old.

FDA pregnancy category C. It is not known whether immune globulin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known if immune globulin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Immune globulin is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

Call your doctor for instructions if you miss a dose of this medication.

Do not receive a "live" vaccine while using IVIG. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), Bacillus Calmette-Guérin (BCG), oral polio, rotavirus, smallpox, typhoid, yellow fever, varicella (chickenpox), H1N1 influenza, and nasal flu vaccine.

Adverse reactions (ARs), as presented below and in Clinical Trials Experience (6.1), are defined as adverse events at least possibly related or events occurring during or within 72 hours of a Privigen infusion or treatment cycle (for ITP).

The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject [see WARNINGS AND PRECAUTIONS]. 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.

The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects [see WARNINGS AND PRECAUTIONS]. A total of 8 subjects (14%) in the ITP study experienced hemolysis as documented from clinical laboratory data. The most common adverse reactions observed in > 5% of clinical study subjects with chronic ITP were headache, elevated body temperature, positive DAT, anemia, nausea, epistaxis, vomiting, blood bilirubin unconjugated increased, blood bilirubin conjugated increased, blood total bilirubin increased, hematocrit decreased, and blood lactate dehydrogenase increased.

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.

In a prospective, open-label, single-arm, multicenter clinical study (pivotal 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]. 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 428.3 mg/ kg (3-week schedule) or 440.6 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 (defined as adverse events at least possibly related or events occurring during or within 72 hours of a Privigen infusion) that occurred in > 5% of subjects.

Table 2: PI Pivotal Study - ARs* Occurring in > 5% of Subjects

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) were related to Privigen, 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 pivotal study 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 (78.2%) 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 (41.8% of the 55 subjects in the extension study) received 265 (38.4%) infusions at a maximum rate greater than the recommended rate of 8 mg/kg/min [see Administration]. 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

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

Three subjects experienced ARs that were considered to be at least possibly related to Privigen: 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.

In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 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]. Subjects ranged in age from 15 to 69; 23 (40.4%) were male and 34 (59.6%) were female.

Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine.

Table 4 summarizes the most frequent ARs (adverse events at least possibly related or events occurring during or within 72 hours after the end of a treatment cycle [two consecutive infusions]) that occurred in > 5% of subjects with chronic ITP.

Table 4: Chronic ITP Study - ARs Occurring in > 5% of Subjects

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 (21.4%) developed a positive DAT during the 29-day study period.

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.

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 Clinical Trials Experience].

• Infusion reactions: Changes in blood pressure, dyspnea, tachycardia, flushing
• Hematologic: hemoglobinuria/hematuria/chromaturia, renal failure
• Neurological: photophobia
• Integumentary: pruritus, rash

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

Read the entire FDA prescribing information for Privigen (Immune Globulin Intravenous)

You should not receive this medication if you have ever had an allergic reaction to an immune globulin or if you have immune globulin A (IgA) deficiency with antibody to IgA. You should not receive RHo (D) immune globulin if you have hemolytic anemia (a lack of red blood cells).

To make sure you can safely receive RHo (D) immune globulin, tell your doctor if you have any of these other conditions:

• heart disease or a history of coronary artery disease (hardened arteries);
• high triglycerides (a type of fat in the blood);
• a bleeding disorder (such as hemophilia); or
• immune globulin A (IgA) deficiency.

RHo (D) immune globulin is used during and after pregnancy. This medication is not known to be harmful to a baby during pregnancy or while breast-feeding.

If you are receiving this medication to treat a mismatched blood transfusion, tell your doctor if you are pregnant or if you ever plan to become pregnant.

RHo (D) immune globulin is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

If you are an Rh-negative woman and you become pregnant, you must tell your doctor if you have ever been exposed to Rh-positive blood in your lifetime. This includes exposure from a mismatched blood transfusion, or exposure during your first pregnancy. Your history of exposure and treatment will be extremely important to each and every one of your pregnancies.

Do not receive a "live" vaccine for at least 3 months after treatment with RHo (D) immune globulin. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), Bacillus Calmette-Guérin (BCG), oral polio, rotavirus, smallpox, typhoid, yellow fever, varicella (chickenpox), H1N1 influenza, and nasal flu vaccine.

See also Warning section.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: drugs that may harm the kidneys (e.g., aminoglycosides such as gentamicin), "water pills" (diuretics such as furosemide).

This medication may interfere with certain tests (including certain blood sugar tests, blood type), possibly causing false test results. This can lead to serious (possibly fatal) consequences. Tell all laboratory personnel and all your doctors and pharmacists that you use this medication, and which type of blood sugar testing strips you use.