PRIVIGEN INFUSION RATES

A quick reference guide

to dosing and administration

PI & ITP SINCE 2007

>1 MILLION PATIENT-YEARS OF THERAPY1

CIDP SINCE 2017

Please see full Important Safety Information inside and full prescribing
information for Privigen, including boxed warning, in pocket.
 Privigen offers 4 vial sizes, including
one of the largest available for an IVIg Proven effective

InclinicaltrialsforPI,Privigendeliveredproven, effective
protection from infections. Annual rate* of serious bacterial
infections† was 0.08; annual rate* of other infections was
5g 3.55. 97% of adverse reactions were non-serious2‡
(50 mL)
I nclinicaltrialsforCIDP, Privigen provided rapid responses,
proven efficacy, and demonstrated tolerability. Overall
response rates§ were 61% in PRIMA and 73% in PATH—the
10 g largest Ig study in CIDP (n=207). Almost all who responded§
(100 mL) did so after 1–2 maintenance treatments at Weeks 4 and 7.
In both studies, 97% of adverse reactions were mild or moderate
in intensity with 2 and 8 subjects experiencing serious adverse
reactions in PRIMA and PATH, respectivelyll¶
20 g IntheITP clinical trial,# 80.7% of subjects (46 of 57) responded
(200 mL) to Privigen with a 150% rise in platelet count within 7 days.
Adverse reactions were generally mild or moderate3**

40 g First and only IVIg designed

(400 mL)
with proline stabilization

 rivigenisaready-to-use 10% liquid IgG preparation, requiring

P
no reconstitution or refrigeration (for up to 36 months)
P
 rivigenuses proline, a naturally occurring amino acid,
as a stabilizer.4 Privigen is contraindicated in patients
with hyperprolinemia
Important Safety Information
3-step process used for virus inactivation and removal††
WARNING: THROMBOSIS, RENAL DYSFUNCTION AND
ACUTE RENAL FAILURE I gA content ≤25 mcg/mL. Privigen is contraindicated
• Thrombosis may occur with immune globulin products, including in IgA-deficient patients with antibodies to IgA
Privigen. Risk factors may include advanced age, prolonged
immobilization, hypercoagulable conditions, history of venous or
*Infectionspersubjectyear.
arterial thrombosis, use of estrogens, indwelling vascular catheters, †Seriousbacterialinfectionsweredefinedaspneumonia,bacteremia/septicemia,
hyperviscosity, and cardiovascular risk factors. osteomyelitis/septicarthritis,bacterialmeningitis,andvisceralabscess.
• Renal dysfunction, acute renal failure, osmotic nephrosis, and death ‡Seriousadversereactionsinthepivotaltrialincludedhypersensitivity,chills,fatigue,
dizziness, and increased body temperature (all severe), occurring in one subject and
may occur with immune globulin intravenous (IGIV) products in resulting in the subject’s withdrawal from the study. Two other subjects withdrew
predisposed patients. Renal dysfunction and acute renal failure from the study due to adverse reactions of vomiting in one subject and chills and
occur more commonly in patients receiving IGIV products that headache in the other.
contain sucrose. Privigen does not contain sucrose. §O verallresponseratewasdefinedaspercentageofsubjectswhoexperienced
at least a 1-point decrease in adjusted INCAT score.
• For patients at risk of thrombosis, renal dysfunction or renal failure, ||Inaprospective,open-label,single-arm,multicenterclinicalstudy(PrivigenImpact
administer Privigen at the minimum dose and infusion rate on Mobility and Autonomy [PRIMA]), 28 subjects with CIDP received a Privigen loading
practicable. Ensure adequate hydration in patients before doseof2g/kgfollowedbyPrivigenmaintenancedosesof1g/kgevery3weeks
administration. Monitor for signs and symptoms of thrombosis and for up to 21 weeks with 3-week follow-up. In a second prospective, open-label Privigen
assess blood viscosity in patients at risk for hyperviscosity. prerandomization phase of a multicenter clinical study (Polyneuropathy and Treatment
with Hizentra [PATH]), 207 IVIg-pretreated subjects with CIDP received a Privigen
See full prescribing information for complete boxed warning. loadingdoseof2g/kgfollowedbyupto4Privigenmaintenancedosesof1g/kg
every 3 weeks for up to 13 weeks.
¶Seriousadversereactionsincludedhemolysis(2),exacerbationofCIDP(2),acuterash,
diastolic increased blood pressure, hypersensitivity, pulmonary embolism, respiratory
failure, and migraine. A total of 4 patients discontinued treatment due to serious
adverse reactions.
#S tudywasperformedon57subjectswithchronicITP.Eachsubjecthadaplatelet
References: 1. Data on file. Available from CSL Behring as DOF PVG-006. 2. Stein MR, countof≤20x10 9/L.Dosewas1g/kgon2consecutivedays.Primaryendpoint
Nelson RP, Church JA, et al. Safety and efficacy of Privigen ®, a novel 10% liquid was elevation of platelet count to at least 50 x 10 9/Lwithin7daysofinfusion.
immunoglobulin preparation for intravenous use, in patients with primary **In clinical trials, the most common adverse reactions, seen in >5% of subjects,
immunodeficiencies. J Clin Immunol. 2009;29(1):137-144. 3. Robak T, Salama A, were laboratory findings consistent with hemolysis, headache, elevated body
Kovaleva L, et al. Efficacy and safety of Privigen ®, a novel liquid intravenous temperature, anemia, nausea, and vomiting. A serious adverse reaction was
immunoglobulin formulation, in adolescent and adult patients with chronic immune aseptic meningitis syndrome.
thrombocytopenic purpura. Hematology. 2009;14(4):227-236. 4. Bolli R, Woodtli K, ††The risk of virus transmission cannot be fully eliminated.
Bärtschi M, Höfferer L, Lerch P. l-Proline reduces IgG dimer content and enhances the
stability of intravenous immunoglobulin (IVIG) solutions. Biologicals. 2010;38(1):150-157.
 Infusion rate calculations in mL (cc) per hour
Recommended dosage
Patient’s Weight (kg) and infusion rates
Infusion Rate 10 20 30 40 50 60 70 80 90 100 110 120
Patient’s Weight (lb) Maintenance
Initial Infusion
Indication Dose Infusion Rate
mL/kg/min mL/kg/h 22 44 66 88 110 132 154 176 198 220 242 264 Rate
(as tolerated)

PI 200–800mg/kg 0.5mg/kg/min Increase to

0.005 0.3 3 6 9 12 15 18 21 24 27 30 33 36 (2–8mL/kg)every (0.005mL/kg/ 8mg/kg/min
3–4 weeks min) (0.08mL/kg/min)
0.010 0.6 6 12 18 24 30 36 42 48 54 60 66 72
0.015 0.9 9 18 27 36 45 54 63 72 81 90 99 108 ITP 1g/kg(10mL/kg)for 0.5mg/kg/min Increase to
2 consecutive days (0.005mL/kg/ 4mg/kg/min
0.020 1.2 12 24 36 48 60 72 84 96 108 120 132 144 min) (0.04mL/kg/min)
0.025 1.5 15 30 45 60 75 90 105 120 135 150 165 180
0.030 1.8 18 36 54 72 90 108 126 144 162 180 198 216 CIDP Loading dose: 0.5mg/kg/min Increase to
2g/kg(20mL/kg) (0.005mL/kg/ 8mg/kg/min
0.035 2.1 21 42 63 84 105 126 147 168 189 210 231 252 in divided doses over min) (0.08mL/kg/min)
2 to 5 consecutive days
0.040 2.4 24 48 72 96 120 144 168 192 216 240 264 288
Maintenance dose:
0.045 2.7 27 54 81 108 135 162 189 216 243 270 297 324 1g/kg(10mL/kg)
administered in 1 to 2
0.050 3.0 30 60 90 120 150 180 210 240 270 300 330 360 infusions on consecutive
days, every 3 weeks
0.055 3.3 33 66 99 132 165 198 231 264 297 330 363 396 For patients
0.060 3.6 36 72 108 144 180 216 252 288 324 360 396 432 at risk of thrombosis,
renal dysfunction, Monitoring patients during IVIg infusion
0.065 3.9 39 78 117 156 195 234 273 312 351 390 429 468
or renal failure
0.070 4.2 42 84 126 168 210 252 294 336 378 420 462 504 Monitor the patient’s vital signs throughout the infusion. Slow
Administer Privigen or stop the infusion if adverse reactions occur. If symptoms subside
0.075 4.5 45 90 135 180 225 270 315 360 405 450 495 540 at the minimum dose promptly, the infusion may be resumed at a lower rate that is
and infusion rate comfortable for the patient. Titrate based on patient tolerability.
0.080 4.8 48 96 144 192 240 288 336 384 432 480 528 576
practicable.

Important Safety Information

WARNING: THROMBOSIS, RENAL DYSFUNCTION AND ACUTE Privigen is indicated for the treatment of: During and shortly following Privigen infusion, elevations of systolic and In clinical studies of patients being treated for chronic ITP, the most
RENAL FAILURE • Primary humoral immunodeficiency (PI) diastolic blood pressure (including cases of hypertensive urgency) common adverse reactions, seen in >5% of subjects, were laboratory
• Thrombosis may occur with immune globulin products, including have been observed. These elevations resolved or significantly findings consistent with hemolysis, headache, elevated body
• Chronic immune thrombocytopenic purpura (ITP) in patients age 15 improved within hours with oral anti-hypertensive therapy or temperature, anemia, nausea, and vomiting. A serious adverse
Privigen. Risk factors may include advanced age, prolonged years and older
immobilization, hypercoagulable conditions, history of venous or observation alone. Check patients for a history of hypertension and reaction was aseptic meningitis syndrome.
arterial thrombosis, use of estrogens, indwelling vascular • Chronic inflammatory demyelinating polyneuropathy (CIDP) in adults monitor blood pressure during this period. In clinical studies of patients being treated for CIDP, the most common
catheters, hyperviscosity, and cardiovascular risk factors. — Limitation of use: maintenance therapy in CIDP has not been studied Consider relative risks and benefits before prescribing high-dose adverse reactions observed in >5% of subjects, were headache,
• Renal dysfunction, acute renal failure, osmotic nephrosis, and for periods longer than 6 months. Individualize duration of treatment regimen for chronic ITP and CIDP in patients at increased risk of asthenia, hypertension, nausea, pain in extremity, hemolysis,
death may occur with immune globulin intravenous (IGIV) beyond 6 months based on patient response thrombosis, hemolysis, acute kidney injury or volume overload. Monitor influenza-like illness, leukopenia, and rash. Serious adverse reactions
products in predisposed patients. Renal dysfunction and acute Privigen is contraindicated in patients with history of anaphylactic or patients for pulmonary adverse reactions (transfusion-related acute were hemolysis, exacerbation of CIDP, acute rash, increased diastolic
renal failure occur more commonly in patients receiving IGIV severe systemic reaction to human immune globulin, in patients with lung injury [TRALI]). blood pressure, hypersensitivity, pulmonary embolism, respiratory
products that contain sucrose. Privigen does not contain sucrose. hyperprolinemia, and in IgA-deficient patients with antibodies to IgA and Privigen is derived from human plasma. The risk of transmission of failure, and migraine.
• For patients at risk of thrombosis, renal dysfunction or renal failure, a history of hypersensitivity. infectious agents, including viruses and, theoretically, the Creutzfeldt- Treatment with Privigen might interfere with a patient’s response to live
administer Privigen at the minimum dose and infusion rate In patients at risk of developing acute renal failure, monitor urine output Jakob disease (CJD) agent and its variant (vCJD), cannot be virus vaccines and could lead to misinterpretation of serologic testing. In
practicable. Ensure adequate hydration in patients before and renal function, including blood urea nitrogen and serum creatinine. completely eliminated. patients over 65, do not exceed recommended dose and infuse at the
administration. Monitor for signs and symptoms of thrombosis Hyperproteinemia, increased serum viscosity, or hyponatremia can In clinical studies of patients with PI, the most common adverse minimum rate practicable.
and assess blood viscosity in patients at risk for hyperviscosity. occur with Privigen. Infrequently, aseptic meningitis syndrome (AMS) reactions to Privigen, observed in >5% of subjects, were headache, Please see full prescribing information for Privigen, including
See full prescribing information for complete boxed warning. may occur—especially with high doses or rapid infusion. fatigue, nausea, chills, vomiting, back pain, pain, elevated body boxed warning, in pocket.
Hemolysis, either intravascular or due to enhanced red blood cell temperature, abdominal pain, diarrhea, cough, stomach discomfort, To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring
sequestration, may occur. Risk factors include non-O blood group and chestpain,jointswelling/effusion,influenza-likeillness, Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-
high doses. Closely monitor patients for hemolysis and hemolytic anemia. pharyngolaryngeal pain, urticaria, and dizziness. Serious adverse FDA-1088orwww.fda.gov/medwatch.
reactions were hypersensitivity, chills, fatigue, dizziness, and increased
body temperature.
ADVANCING IG THERAPY
Helping to restore everyday moments

Privigen is proven effective, and

is the first and only IVIg designed
with proline stabilization

For additional details—and to get the guidance

and support you need—call the Privigen Connect
resource hotline

1-877-355-4447
Monday–Friday
8 AM to 8 PM ET

For more information, visit Privigen.com

Privigen is manufactured by CSL Behring AG and distributed by CSL Behring LLC.

Privigen® is a registered trademark of CSL Behring AG.
Privigen ConnectSM is a service mark of CSL Behring LLC.
©2024 CSL Behring LLC
www.Privigen.com www.CSLBehring.com US-PVG-0235-FEB24

Please see full Important Safety Information inside and full prescribing
information for Privigen, including boxed warning, in pocket.
HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------------CONTRAINDICATIONS---------------------------------
These highlights do not include all the information needed to use PRIVIGEN • History of anaphylactic or severe systemic reaction to human immune globulin (4)
safely and effectively. See full prescribing information for PRIVIGEN. • Hyperprolinemia (PRIVIGEN contains the stabilizer L-proline) (4)
PRIVIGEN® Immune Globulin Intravenous (Human), 10% Liquid • IgA-deficient patients with antibodies to IgA and a history of hypersensitivity (4)
Initial U.S. Approval: 2007 ---------------------------WARNINGS AND PRECAUTIONS--------------------
WARNING: THROMBOSIS, RENAL DYSFUNCTION AND ACUTE RENAL FAILURE • IgA-deficient patients with antibodies to IgA are at greater risk of developing severe
See full prescribing information for complete boxed warning. hypersensitivity and anaphylactic reactions. (5.1)
• Monitor renal function, including blood urea nitrogen and serum creatinine, and urine
• Thrombosis may occur with immune globulin products, including PRIVIGEN. Risk output in patients at risk of developing acute renal failure. (5.2)
factors may include: advanced age, prolonged immobilization, hypercoagulable • Hyperproteinemia, increased serum viscosity, and hyponatremia may occur. (5.4)
conditions, history of venous or arterial thrombosis, use of estrogens, indwelling • Aseptic meningitis syndrome (AMS) may occur, especially with high doses or rapid infusion.
vascular catheters, hyperviscosity, and cardiovascular risk factors. (5.5)
• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur • Hemolysis that is either intravascular or due to enhanced red blood cell sequestration may
with immune globulin intravenous (IGIV) products in predisposed patients. occur. Risk factors include high doses and non-O blood group. Closely monitor patients for
Renal dysfunction and acute renal failure occur more commonly in patients hemolysis and hemolytic anemia (5.6)
receiving IGIV products containing sucrose. PRIVIGEN does not contain sucrose. • Elevations of systolic and diastolic blood pressure (including cases of hypertensive urgency)
have been observed during/shortly following PRIVIGEN infusion. These blood pressure
• For patients at risk of thrombosis, renal dysfunction or failure, administer elevations were resolved or significantly improved within hours with either observation
PRIVIGEN at the minimum dose and infusion rate practicable. Ensure adequate alone or changes in oral anti-hypertensive therapy. Check patients for a history of
hydration in patients before administration. Monitor for signs and symptoms hypertension and monitor blood pressure during and following PRIVIGEN infusion. (5.7)
of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. • Monitor patients for pulmonary adverse reactions (transfusion-related acute lung injury
[TRALI]). (5.8)
-------------------------RECENT MAJOR CHANGES----------------------------- • Carefully consider the relative risks and benefits before prescribing the high dose regimen
(for chronic ITP and CIDP) in patients at increased risk of thrombosis, hemolysis, acute
kidney injury, or volume overload. (5.9)
----------------------------INDICATIONS AND USAGE--------------------------- • PRIVIGEN is made from human blood and may contain infectious agents, e.g., viruses, the
PRIVIGEN is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment variant Creutzfeldt Jakob disease [vCJD] agent and, theoretically, the Creutzfeldt-Jakob
of: disease (CJD) agent. (5.10)
• Primary humoral immunodeficiency (PI) (1.1) ------------------------------ADVERSE REACTIONS-------------------------------
• Chronic immune thrombocytopenic purpura (ITP) in patients age 15 years and older (1.2) • PI – The most common adverse reactions, observed in >5% of study subjects, were
• Chronic inflammatory demyelinating polyneuropathy (CIDP) in adults (1.3) headache, fatigue, nausea, chills, vomiting, back pain, pain, elevated body temperature,
Limitations of Use: abdominal pain, diarrhea, cough, stomach discomfort, chest pain, joint swelling/effusion,
PRIVIGEN maintenance therapy in CIDP has not been studied beyond 6 months. (1.3) influenza-like illness, pharyngolaryngeal pain, urticaria, and dizziness. Serious adverse
----------------------DOSAGE AND ADMINISTRATION------------------------ reactions were hypersensitivity, chills, fatigue, dizziness, and increased body temperature.
Intravenous Use Only (6.1)
Maintenance • Chronic ITP – The most common adverse reactions, observed in >5% of study subjects,
Indication Dose Initial Infusion Infusion Rate were laboratory findings consistent with hemolysis (hemoglobin and hematocrit decrease
Rate (as tolerated) without blood loss in conjunction with positive direct antiglobulin test (DAT) and elevated
200-800 mg/kg 0.5 mg/kg/min Increase to blood lactate dehydrogenase (LDH) and/or indirect bilirubin), headache, elevated body
PI (2-8 mL/kg) 8 mg/kg/min temperature, anemia, nausea, and vomiting. A serious adverse reaction was aseptic
(0.005 mL/kg/min)
every 3-4 weeks (0.08 mL/kg/min) meningitis. (6.1)
1 g/kg (10 mL/kg) for 2 0.5 mg/kg/min Increase to • CIDP – The most common adverse reactions observed in >5% of study subjects were
ITP consecutive days (0.005 mL/kg/min) 4 mg/kg/min headache, asthenia, hypertension, nausea, pain in extremity, hemolysis, influenza like illness,
(0.04 mL/kg/min) leukopenia, and rash. Serious adverse reactions were hemolysis, exacerbation of CIDP, acute
Loading dose: 0.5 mg/kg/min Increase to rash, blood pressure diastolic increased, hypersensitivity, pulmonary embolism, respiratory
CIDP 2 g/kg (20 mL/kg) in 8 mg/kg/min
(0.005 mL/kg/min) failure, and migraine. (6.1)
divided doses over 2 to 5 (0.08 mL/kg/min)
consecutive days To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring
Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.
Maintenance dose:
1 g/kg (10 mL/kg) gov/medwatch.
administered in 1 to -------------------------------DRUG INTERACTIONS------------------------------
2 infusions on The passive transfer of antibodies may:
consecutive days, • Lead to misinterpretation of the results of serological testing. (5.11)
every 3 weeks • Interfere with the response to live virus vaccines. (7.1)
• Ensure that patients with pre-existing renal insufficiency are not volume depleted, and ----------------------USE IN SPECIFIC POPULATIONS-------------------------
discontinue PRIVIGEN if renal function deteriorates. (2.5, 5.2) • Geriatric: In patients over age 65 or in any patient at risk of developing renal insufficiency,
• For patients at risk of renal dysfunction or thrombosis, administer PRIVIGEN at the dose do not exceed the recommended dose, and infuse PRIVIGEN at the minimum rate
and minimum infusion rate practicable. (2.5, 5.2, 5.3) practicable. (8.5)
-----------------------DOSAGE FORMS AND STRENGTHS-------------------- See 17 for PATIENT COUNSELING INFORMATION.
PRIVIGEN is a liquid solution containing 10% IgG (0.1 g/mL). (3) Revised: March 2022
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: THROMBOSIS, RENAL DYSFUNCTION AND ACUTE RENAL FAILURE 6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
1 INDICATIONS AND USAGE 6.2 Postmarketing Experience
1.1 Primary Humoral Immunodeficiency 7 DRUG INTERACTIONS
1.2 Chronic Immune Thrombocytopenic Purpura 7.1 Live Virus Vaccines
1.3 Chronic Inflammatory Demyelinating Polyneuropathy 8 USE IN SPECIFIC POPULATIONS
2 DOSAGE AND ADMINISTRATION 8.1 Pregnancy
2.1 Dosage for Primary Humoral Immunodeficiency (PI) 8.2 Lactation
2.2 Dosage for Chronic Immune Thrombocytopenic Purpura (ITP) 8.4 Pediatric Use
2.3 Dosage for Chronic Inflammatory Demyelinating Polyneuropathy 8.5 Geriatric Use
2.4 Preparation and Handling 10 OVERDOSAGE
2.5 Administration 11 DESCRIPTION
3 DOSAGE FORMS AND STRENGTHS 12 CLINICAL PHARMACOLOGY
4 CONTRAINDICATIONS 12.1 Mechanism of Action
5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics
5.1 Hypersensitivity 14 CLINICAL STUDIES
5.2 Renal Dysfunction and Acute Renal Failure 14.1 Treatment of Primary Humoral Immunodeficiency
5.3 Thrombosis 14.2 Treatment of Chronic Immune Thrombocytopenic Purpura
5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia 14.3 Postmarketing Commitment Study in Chronic Immune Thrombocytopenic
5.5 Aseptic Meningitis Syndrome (AMS) Purpura
5.6 Hemolysis 14.4 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
5.7 Hypertension 15 REFERENCES
5.8 Transfusion-Related Acute Lung Injury (TRALI) 16 HOW SUPPLIED/STORAGE AND HANDLING
5.9 Volume Overload 17 PATIENT COUNSELING INFORMATION
5.10 Transmissible Infectious Agents
5.11 Interference with Laboratory Tests * Sections or subsections omitted from the full prescribing information are not listed.
CSL Behring 2.1 Dosage for Primary Humoral Immunodeficiency (PI)
As there are significant differences in the half-life of IgG among patients with PI, the
FULL PRESCRIBING INFORMATION frequency and amount of immunoglobulin therapy may vary from patient to patient. The
PRIVIGEN®, Immune Globulin proper amount can be determined by monitoring clinical response.
The recommended dose of PRIVIGEN for patients with PI is 200 to 800 mg/kg (2 to 8 mL/kg),
Intravenous (Human), 10% Liquid administered every 3 to 4 weeks. If a patient misses a dose, administer the missed dose as
soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable.
Adjust the dosage over time to achieve the desired serum IgG trough levels and clinical
WARNING: THROMBOSIS, RENAL DYSFUNCTION responses. No randomized, controlled trial data are available to determine an optimal
AND ACUTE RENAL FAILURE trough level in patients receiving immune globulin therapy.
• Thrombosis may occur with immune globulin products1-3, including Measles Exposure
PRIVIGEN. Risk factors may include: advanced age, prolonged If a patient has been exposed to measles, it may be prudent to administer an extra dose of
immobilization, hypercoagulable conditions, history of venous or Immune Globulin Intravenous as soon as possible and within 6 days of exposure. A dose
arterial thrombosis, use of estrogens, indwelling central vascular of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at
catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis least two weeks.
may occur in the absence of known risk factors [see Warnings and If a patient is at risk of future measles exposure and receives a dose of less than 530 mg/kg
Precautions (5.3), Patient Counseling Information (17)]. every 3-4 weeks, the dose should be increased to at least 530 mg/kg. This should provide
• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion.
occur with immune globulin intravenous (IGIV) products in predisposed 2.2 Dosage for Chronic Immune Thrombocytopenic Purpura (ITP)
patients. Patients predisposed to renal dysfunction include those with any The recommended dose of PRIVIGEN for patients with chronic ITP is 1 g/kg (10 mL/kg)
degree of pre-existing renal insufficiency, diabetes mellitus, age greater administered daily for 2 consecutive days, resulting in a total dosage of 2 g/kg.
than 65, volume depletion, sepsis, paraproteinemia, or patients receiving Carefully consider the relative risks and benefits before prescribing the high dose regimen
known nephrotoxic drugs. (e.g., 1 g/kg/day for 2 days) in patients at increased risk of thrombosis, hemolysis, acute
• Renal dysfunction and acute renal failure occur more commonly in kidney injury, or volume overload [see Warnings and Precautions (5.9)].
patients receiving IGIV products containing sucrose.4 PRIVIGEN does not
contain sucrose. 2.3 Dosage for Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
• For patients at risk of thrombosis, renal dysfunction or failure, administer PRIVIGEN may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given
PRIVIGEN at the minimum dose and infusion rate practicable. Ensure in divided doses over two to five consecutive days. PRIVIGEN may be administered as a
adequate hydration in patients before administration. Monitor for signs maintenance infusion of 1 g/kg (10 mL/kg) administered in a single infusion given in one
and symptoms of thrombosis and assess blood viscosity in patients at day or divided into two doses given on two consecutive days, every 3 weeks. Maintenance
risk for hyperviscosity [see Dosage and Administration (2.5), Warnings therapy beyond 6 months has not been studied.
and Precautions (5.2, 5.3)]. The recommended initial infusion rate is 0.5 mg/kg/min (0.005 mL/kg/min). If the infusion
is well tolerated, the rate may be gradually increased to a maximum of 8 mg/kg/min (0.08
1 INDICATIONS AND USAGE mL/kg/min). For patients judged to be at risk for thrombosis, renal dysfunction, or volume
PRIVIGEN is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the overload, administer PRIVIGEN at the minimum infusion rate practicable [see Warnings
treatment of the following conditions. and Precautions (5.2, 5.3)].
1.1 Primary Humoral Immunodeficiency 2.4 Preparation and Handling
PRIVIGEN is indicated as replacement therapy for primary humoral immunodeficiency • PRIVIGEN is a clear or slightly opalescent, colorless to pale yellow solution. Inspect
(PI). This includes, but is not limited to, the humoral immune defect in congenital parenteral drug products visually for particulate matter and discoloration prior to
administration, whenever solution and container permit. Do not use if the solution is
agammaglobulinemia, common variable immunodeficiency (CVID), X-linked
cloudy, turbid, or if it contains particulate matter.
agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. • DO NOT SHAKE.
1.2 Chronic Immune Thrombocytopenic Purpura • Do not freeze. Do not use if PRIVIGEN has been frozen.
PRIVIGEN is indicated for the treatment of patients age 15 years and older with chronic • PRIVIGEN should be at room temperature (up to 25ºC [77ºF]) at the time of
immune thrombocytopenic purpura (ITP) to raise platelet counts. administration.
• Do not use PRIVIGEN beyond the expiration date on the product label.
1.3 Chronic Inflammatory Demyelinating Polyneuropathy
• The PRIVIGEN vial is for single-use only. Promptly use any vial that has been entered.
PRIVIGEN is indicated for the treatment of adults with chronic inflammatory demyelinating PRIVIGEN contains no preservative. Discard partially used vials or unused product in
polyneuropathy (CIDP) to improve neuromuscular disability and impairment. accordance with local requirements.
Limitation of Use: • Infuse PRIVIGEN using a separate infusion line. Prior to use, the infusion line may be
PRIVIGEN maintenance therapy in CIDP has not been studied for periods longer than flushed with Dextrose Injection, USP (D5W) or 0.9% Sodium Chloride for Injection, USP.
6 months. After responding during an initial treatment period, not all patients require • Do not mix PRIVIGEN with other IGIV products or other intravenous medications.
indefinite maintenance therapy with PRIVIGEN in order to remain free of CIDP symptoms. However, PRIVIGEN may be diluted with Dextrose Injection, USP (D5W).
Individualize the duration of any treatment beyond 6 months based upon the patient’s • An infusion pump may be used to control the rate of administration.
response and demonstrated need for continued therapy. • If large doses of PRIVIGEN are to be administered, several vials may be pooled using
aseptic technique. Begin infusion within 8 hours of pooling.
2 DOSAGE AND ADMINISTRATION
2.5 Administration
Table 1. Recommended Dosage and Administration for PRIVIGEN
PRIVIGEN is for intravenous administration only.
Indication Dose Initial infusion Maintenance Monitor the patient’s vital signs throughout the infusion. Slow or stop the infusion if
rate infusion rate adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a
(as tolerated)
lower rate that is comfortable for the patient.
200-800 mg/ 0.5 mg/ Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients
Primary Increase to
kg (2-8 mL/ kg/min judged to be at risk for renal dysfunction or thrombosis, administer PRIVIGEN at the minimum
8 mg/kg/min
Immunodeficiency kg) every 3-4 (0.005 mL/kg/ dose and infusion rate practicable, and discontinue PRIVIGEN administration if renal function
(0.08 mL/kg/min)
weeks min) deteriorates [see Boxed Warning, Warnings and Precautions (5.2, 5.3)].
Chronic Immune 0.5 mg/ The following patients may be at risk of developing systemic reactions (mimicking symptoms
1 g/kg (10 Increase to
kg/min of an inflammatory response or infection) on rapid infusion of PRIVIGEN (greater than 4
Thrombocytopenic mL/kg) for 2 4 mg/kg/min
(0.005 mL/kg/
Purpura consecutive days (0.04 mL/kg/min) mg/kg/min [0.04 mL/kg/min]): 1) those who have never received PRIVIGEN or another IgG
min)
0.5 mg/ Increase to product or who have not received it within the past 8 weeks, and 2) those who are switching
Loading dose: from another IgG product. These patients should be started at a slow rate of infusion (e.g.,
2 g/kg (20 mL/ kg/min 8 mg/kg/min
kg) in divided (0.005 mL/kg/ (0.08 mL/kg/min) 0.5 mg/kg/min [0.005 mL/kg/min] or less) and gradually increase as tolerated.
doses over 2 to 5 min) 3 DOSAGE FORMS AND STRENGTHS
Chronic consecutive days PRIVIGEN is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion.
Inflammatory 4 CONTRAINDICATIONS
Maintenance dose:
Demyelinating 1 g/kg (10 mL/ • PRIVIGEN is contraindicated in patients who have a history of anaphylactic or severe
Polyneuropathy kg) administered systemic reaction to the administration of human immune globulin.
in 1 to 2 • PRIVIGEN is contraindicated in patients with hyperprolinemia because it contains the
infusions on stabilizer L-proline [see Description (11)].
consecutive days, • PRIVIGEN is contraindicated in IgA-deficient patients with antibodies to IgA and a
every 3 weeks history of hypersensitivity [see Warnings and Precautions (5.1)].
5 WARNINGS AND PRECAUTIONS Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients
5.1 Hypersensitivity with risk factors noted above and those with pre-existing anemia and/or cardiovascular
Severe hypersensitivity reactions may occur [see Contraindications (4)]. In case of or pulmonary compromise. Consider appropriate laboratory testing in higher risk patients,
hypersensitivity, discontinue the PRIVIGEN infusion immediately and institute appropriate including measurement of hemoglobin or hematocrit prior to infusion and within
treatment. Medications such as epinephrine should be available for immediate treatment approximately 36 hours and again 7 to 10 days post infusion. If clinical signs and symptoms
of acute hypersensitivity reactions. of hemolysis or a significant drop in hemoglobin or hematocrit have been observed,
PRIVIGEN contains trace amounts of IgA (≤25 mcg/mL) [see Description (11)]. Individuals perform additional confirmatory laboratory testing. If transfusion is indicated for patients
with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including who develop hemolysis with clinically compromising anemia after receiving IGIV, perform
anaphylaxis and shock) after administration of blood components containing IgA. Patients adequate cross-matching to avoid exacerbating on-going hemolysis.
with known antibodies to IgA may have a greater risk of developing potentially severe 5.7 Hypertension
hypersensitivity and anaphylactic reactions with administration of PRIVIGEN. PRIVIGEN is Elevations of systolic blood pressure to ≥180 mm Hg and/or of diastolic blood pressure to
contraindicated in patients with antibodies against IgA and a history of hypersensitivity. >120 mm Hg (hypertensive urgency) have been observed during and/or shortly following
5.2 Renal Dysfunction and Acute Renal Failure infusion of PRIVIGEN. These blood pressure elevations were resolved or significantly
Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with improved within hours with either observation alone or changes in oral anti-hypertensive
immune globulin intravenous (IGIV) products in predisposed patients. Renal dysfunction therapy [see Adverse Reactions (6.1)]. Such elevations were reported more often
and acute renal failure occur more commonly in patients receiving IGIV products containing among patients with a history of hypertension. Check patients for a history of hypertension
sucrose.4 PRIVIGEN does not contain sucrose. Acute renal failure may also occur as a result and current antihypertensive medication use. Monitor blood pressure prior to, during, and
of PRIVIGEN-induced hemolysis. Ensure that patients are not volume depleted and assess following PRIVIGEN infusion.
renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, 5.8 Transfusion-Related Acute Lung Injury (TRALI)
before the initial infusion of PRIVIGEN and at appropriate intervals thereafter. Noncardiogenic pulmonary edema may occur following treatment with IGIV products,
Periodic monitoring of renal function and urine output is particularly important in including PRIVIGEN.13 TRALI is characterized by severe respiratory distress, pulmonary
patients judged to be at increased risk of developing acute renal failure.4 If renal function edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear
deteriorates, consider discontinuing PRIVIGEN. For patients judged to be at risk of within 1 to 6 hours following treatment.
developing renal dysfunction because of pre-existing renal insufficiency, or predisposition Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform
to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are appropriate tests for the presence of anti-neutrophil antibodies and anti-human leukocyte
obese, those who use concomitant nephrotoxic medicinal products, or those who are over antigen (HLA) antibodies in both the product and the patient’s serum.
65 years of age), administer PRIVIGEN at the minimum rate of infusion practicable [see TRALI may be managed using oxygen therapy with adequate ventilatory support.
Boxed Warning, Dosage and Administration (2.5)].
5.9 Volume Overload
5.3 Thrombosis Carefully consider the relative risks and benefits before prescribing the high dose regimen
Thrombosis may occur following treatment with immune globulin products1-3, including (for chronic ITP and CIDP) in patients at increased risk of thrombosis, hemolysis, acute
PRIVIGEN. Risk factors may include: advanced age, prolonged immobilization, kidney injury, or volume overload.
hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens,
5.10 Transmissible Infectious Agents
indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors.
Because PRIVIGEN is made from human blood, it may carry a risk of transmitting infectious
Thrombosis may occur in the absence of known risk factors.
agents (eg, viruses, the variant Creutzfeldt Jakob disease [vCJD] agent and,
Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity,
theoretically, the Creutzfeldt Jakob disease [CJD] agent). The risk of infectious agent
including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols
transmission has been reduced by screening plasma donors for prior exposure to certain
(triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer
viruses, testing for the presence of certain current virus infections, and including virus
PRIVIGEN at the minimum dose and infusion rate practicable. Ensure adequate hydration in
inactivation/removal steps in the manufacturing process for PRIVIGEN.
patients before administration. Monitor for signs and symptoms of thrombosis and assess
Report any infection thought to be possibly transmitted by PRIVIGEN to CSL Behring
blood viscosity in patients at risk for hyperviscosity [see Boxed Warning, Dosage and
Pharmacovigilance at 1-866-915-6958.
Administration (2.5), Patient Counseling Information (17)].
5.11 Interference with Laboratory Tests
5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia
Various passively transferred antibodies in immunoglobulin preparations may lead to
Hyperproteinemia, increased serum viscosity, and hyponatremia may occur following
misinterpretation of the results of serological testing.
treatment with IGIV products, including PRIVIGEN. The hyponatremia is likely to
be a pseudohyponatremia, as demonstrated by a decreased calculated serum 6 ADVERSE REACTIONS
osmolality or elevated osmolar gap. It is critical to distinguish true hyponatremia from The following important adverse reactions are reported with IGIV: hypersensitivity, renal
pseudohyponatremia, as treatment aimed at decreasing serum free water in patients with dysfunction and acute renal failure, thrombosis, hyperproteinemia, increased serum viscosity,
pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, hyponatremia, aseptic meningitis syndrome, hemolysis, hypertension, transfusion related
and a possible predisposition to thromboembolic events.5 acute lung injury, volume overload, and transmissible infectious agents [see Warnings
and Precautions (5)] and are described elsewhere in the prescribing information.
5.5 Aseptic Meningitis Syndrome (AMS)
Adverse reactions (ARs) [see Adverse Reactions (6.1)] are defined as adverse events at
AMS may occur infrequently following treatment with PRIVIGEN [see Adverse Reactions
least possibly related or events occurring during or within 72 hours of a PRIVIGEN infusion.
(6)] and other human immune globulin products. Discontinuation of treatment has resulted
in remission of AMS within several days without sequelae.6 AMS usually begins within Primary Humoral Immunodeficiency
several hours to 2 days following IGIV treatment. The most serious adverse reaction observed in clinical study subjects receiving PRIVIGEN
AMS is characterized by the following signs and symptoms: severe headache, nuchal for PI was hypersensitivity in one subject [see Warnings and Precautions (5.1)]. The
rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. most common adverse reactions observed in >5% of clinical study subjects with PI were
Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several headache, fatigue, nausea, chills, vomiting, back pain, pain, elevated body temperature,
thousand cells per cubic millimeter, predominantly from the granulocytic series, and with abdominal pain, diarrhea, cough, stomach discomfort, chest pain, joint swelling/effusion,
elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct influenza-like illness, pharyngolaryngeal pain, urticaria, and dizziness.
a thorough neurological examination on patients exhibiting such signs and symptoms, Chronic Immune Thrombocytopenic Purpura
including CSF studies, to rule out other causes of meningitis. The most serious adverse reactions observed in the premarketing clinical study subjects
AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid receiving PRIVIGEN for chronic ITP were aseptic meningitis syndrome in one subject and
infusion of IGIV. 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
5.6 Hemolysis clinical laboratory data. No serious adverse reactions were observed in the postmarketing
PRIVIGEN may contain blood group antibodies that can act as hemolysins and induce chronic ITP study. A total of 12 subjects (21%) in the postmarketing ITP study were
in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct adjudicated to have mild hemolysis as documented from clinical laboratory data [see
antiglobulin test (DAT) (Coombs’ test) result and hemolysis.7-9 Delayed hemolytic anemia Warnings and Precautions (5.6)]. The most common adverse reactions observed
can develop subsequent to PRIVIGEN therapy due to enhanced RBC sequestration, and in >5% of subjects in both clinical studies of subjects with chronic ITP were laboratory
acute hemolysis, consistent with intravascular hemolysis, has been reported.10 Cases of findings consistent with hemolysis (hemoglobin and hematocrit decrease without blood
severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation loss in conjunction with positive direct antiglobulin test (DAT) and elevated blood lactate
have occurred following infusion of PRIVIGEN. dehydrogenase (LDH) and/or indirect bilirubin), headache, elevated body temperature,
The following risk factors may be associated with the development of hemolysis: high doses anemia, nausea, and vomiting.
(e.g., ≥2 g/kg), given either as a single administration or divided over several days, and Chronic Inflammatory Demyelinating Polyneuropathy
non-O blood group.11 Other individual patient factors, such as an underlying inflammatory The most serious adverse reaction observed in clinical study subjects receiving PRIVIGEN for
state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte CIDP was hemolysis. The most common adverse reactions observed in >5% of subjects in
sedimentation rate), have been hypothesized to increase the risk of hemolysis following both clinical studies of subjects with CIDP were headache, asthenia, hypertension, nausea,
administration of IGIV,12 but their role is uncertain. Hemolysis has been reported following pain in extremity, hemolysis, influenza like illness, leukopenia, and rash.
administration of IGIV for a variety of indications, including ITP, CIDP, and PI.9
6.1 Clinical Trials Experience because the study was not designed to compare infusion rates, no definitive conclusions
Because different clinical trials are conducted under widely varying conditions, adverse regarding tolerability could be drawn for infusion rates higher than the recommended rate
reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in of 8 mg/kg/min.
the clinical trials of another drug and may not reflect the rates observed in clinical practice. Table 3 summarizes the ARs that occurred in >5% of subjects.
Treatment of Primary Humoral Immunodeficiency Table 3. PI Extension Study – ARs* Occurring in >5% of Subjects
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 AR* Number (%) of Number (Rate) of Infusions
[see Clinical Studies (14.1)]. All subjects had been on regular IGIV replacement therapy Subjects [n=55] with AR [n=771]
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. Headache 18 (32.7) 76 (0.099)
The safety analysis included all 80 subjects, 16 (20%) on the 3-week schedule and 64 Nausea 6 (10.9) 10 (0.013)
(80%) on the 4-week schedule. The median dose of PRIVIGEN administered was 428 mg/ Elevated body temperature 4 (7.3) 12 (0.016)
kg (3-week schedule) or 441 mg/kg (4-week schedule) and ranged from 200 to 888 mg/ Abdominal pain† 4 (7.3) 7 (0.009)
kg. A total of 1038 infusions of PRIVIGEN were administered, 272 in the 3-week schedule Chest pain 3 (5.5) 4 (0.005)
and 766 in the 4-week schedule. Chills 3 (5.5) 7 (0.009)
Routine premedication was not allowed. However, subjects who experienced two Joint swelling/effusion 3 (5.5) 7 (0.009)
consecutive infusion-related ARs that were likely to be prevented by premedication were Pain 3 (5.5) 6 (0.008)
permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the Fatigue 3 (5.5) 5 (0.006)
study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions Influenza-like illness 3 (5.5) 5 (0.006)
administered. Pharyngolaryngeal pain 3 (5.5) 4 (0.005)
Table 2 summarizes the most frequent ARs that occurred in >5% of subjects. Urticaria 3 (5.5) 4 (0.005)
Table 2. PI Pivotal Study – ARs* Occurring in >5% of Subjects Dizziness 3 (5.5) 3 (0.004)
Note: The AR rates in this study cannot be compared directly to the rates in other IGIV studies, including the original
AR* Number (%) Number (Rate) of pivotal study described earlier in this section, because (1) the extension study used an enriched population and (2) the
of Subjects Infusions with AR selective use of higher infusion rates at the investigators’ discretion in a subset of subjects may have introduced bias.
[n=80] [n=1038] * Excluding infections.
† Includes abdominal pain, abdominal pain upper, and abdominal pain lower.
Of the 125 reported ARs, 76 were mild (did not interfere with routine activities), 40 were
Headache 36 (45.0) 100 (0.096) moderate (interfered somewhat with routine activities), and 9 were severe (impossible to
Fatigue 13 (16.3) 29 (0.028) perform routine activities).
Nausea 11 (13.8) 23 (0.022) 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,
Chills 9 (11.3) 15 (0.014)
resulting in the subject’s withdrawal from the study.
Vomiting 9 (11.3) 15 (0.014)
Treatment of Chronic Immune Thrombocytopenic Purpura
Back pain 8 (10.0) 15 (0.014) In a prospective, open-label, single-arm, multicenter premarketing clinical study, 57 subjects
Pain 7 (8.8) 14 (0.013) with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose
Elevated body temperature 7 (8.8) 12 (0.012) of PRIVIGEN administered as 1 g/kg infusions daily for 2 consecutive days [see Clinical
Diarrhea 6 (7.5) 6 (0.006) Studies (14.2)]. Subjects ranged in age from 15 to 69; 23 (40%) were male and 34 (60%)
were female.
Cough 5 (6.3) 5 (0.005) Concomitant medications affecting platelets or other treatments for chronic ITP were not
Stomach discomfort 5 (6.3) 5 (0.005) allowed. Thirty-two (56%) subjects received premedication with acetaminophen and/or an
* ARs are defined as adverse events at least possibly related or events occurring during or within 72 hours of a PRIVIGEN antihistamine.
infusion. Infections are excluded from this table.
Table 4 summarizes the most frequent ARs that occurred in >5% of subjects with chronic
Of the 192 ARs reported (including 5 serious, severe ARs described below) 91 were mild ITP.
(awareness of sign, symptom or event, but easily tolerated), 81 were moderate (discomfort Table 4. Chronic ITP Premarketing Clinical Study – ARs* Occurring in >5% of
enough to cause interference with usual activity and may have warranted intervention), Subjects
19 were severe (incapacitating with inability to do usual activities or significantly affected Number (%) Number (Rate) of
clinical status, and warranted intervention), and 1 was of unknown severity. AR* of Subjects Infusions with AR
The five serious ARs (hypersensitivity, chills, fatigue, dizziness, and increased body [n=57] [n=114]
temperature, all severe), occurred in one subject, and resulted in the subject’s withdrawal
Headache 37 (64.9) 52 (0.456)
from the study. Two other subjects withdrew from the study due to ARs (chills and headache
in one subject; vomiting in the other). Elevated body temperature 21 (36.8) 23 (0.202)
Seventy-seven of the 80 subjects enrolled in this study had a negative DAT at baseline. Of Positive DAT 7 (12.3) 8 (0.070)
these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. Anemia 6 (10.5) 6 (0.053)
However, no subjects showed evidence of hemolytic anemia. Nausea 6 (10.5) 8 (0.070)
During this study, no subjects tested positive for infection due to human immunodeficiency
Epistaxis 6 (10.5) 8 (0.070)
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 Vomiting 6 (10.5) 7 (0.061)
with PI to collect additional efficacy, safety, and tolerability data. This study included 45 Blood bilirubin unconjugated increased 6 (10.5) 6 (0.053)
subjects from the pivotal study who were receiving PRIVIGEN and 10 new subjects who Blood bilirubin conjugated increased 5 (8.8) 5 (0.044)
were receiving another IGIV product prior to enrolling in the extension study. Subjects Blood total bilirubin increased 3 (5.3) 3 (0.026)
ranged in age from 4 to 81 years; 26 (47.3%) were male and 29 (52.7%) were female.
Hematocrit decreased 3 (5.3) 3 (0.026)
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 Blood lactate dehydrogenase increased 3 (5.3) 3 (0.026)
were on a 3-week treatment schedule with the number of infusions per subject ranging * ARs were defined as adverse events at least possibly related or events occurring during or within 72 hours after the end
from 4 to 38 (median: 8 infusions); 43 (78%) subjects were on a 4-week schedule with the of a treatment cycle [two consecutive infusions].
number of infusions ranging from 1 to 31 (median: 15 infusions). A total of 771 infusions Of the 149 non-serious ARs, 103 were mild (awareness of sign, symptom or event, but easily
were administered in this study. tolerated), 37 were moderate (discomfort enough to cause interference with usual activity
In this study, subjects who continued from the pivotal study were permitted to receive and may have warranted intervention), and 9 were severe (incapacitating with inability
infusions of PRIVIGEN at a rate up to 12 mg/kg/min (as opposed to the maximum of 8 mg/ to do usual activities or significantly affected clinical status, and warranted intervention).
kg/min allowed in the pivotal study) at the discretion of the investigator based on individual One subject experienced a serious AR (aseptic meningitis).
Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic
tolerability. Twenty-three (51%) of the 45 subjects from the pivotal study (42% of the 55
reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase,
subjects in the extension study) received 265 (38%) infusions at a maximum rate greater and a decrease in hemoglobin level within two days after the infusion of PRIVIGEN. Two
than the recommended rate of 8 mg/kg/min [see Dosage and Administration (2.5)]. of the eight subjects were clinically anemic but did not require clinical intervention; these
The median of the maximum infusion rate in this subset was 12 mg/kg/min. However, cases resolved uneventfully.
Four other subjects with active bleeding were reported to have developed anemia without diastolic increased, exacerbation of CIDP [2], hypersensitivity, pulmonary embolism,
evidence of hemolysis. respiratory failure, and migraine. The serious adverse reactions of pulmonary embolism and
In this study, there was a decrease in hemoglobin after the first PRIVIGEN infusion (median respiratory failure occurred in subjects with preexisting risk factors. All serious adverse
decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29. reactions resolved without sequelae.
Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, Adverse reactions that occurred in >5% of subjects with CIDP were headache (33 subjects,
12 (21%) developed a positive DAT during the 29-day study period. 15.9% [rate per infusion 56/1894, 0.030]).
Postmarketing Commitment Study in Chronic Immune Thrombocytopenic Purpura A total of 225 ARs were reported: 160 were mild (is transient, does not usually interfere
In a prospective, open-label, single-arm, multicenter postmarketing clinical study whose with routine activities but minimal treatment or therapeutic intervention may be required),
primary objective was to evaluate mechanisms of hemolysis, 57 subjects with chronic ITP 59 were moderate (interferes somewhat with routine activities and usually alleviated with
and a platelet count of <30 x 109/L at screening were studied following treatment with specific intervention but poses no significant or permanent risk of harm), and 6 were severe
PRIVIGEN. Twenty-one (21) subjects (37%) received 1 infusion of 1 g/kg on Day 1 and (interrupts usual activities of daily living, significantly affects clinical status, or may require
36 subjects (63%) received 2 infusions each of 1 g/kg (Day 1 and Day 3). Concomitant intensive therapeutic intervention) in intensity.
medications affecting platelets or other treatments for chronic ITP were not allowed. 6.2 Postmarketing Experience
Subjects received premedication with acetaminophen and/or an antihistamine [see Because adverse reactions are reported voluntarily post-approval from a population of
Clinical Studies (14.3)]. uncertain size, it is not always possible to reliably estimate the frequency of these reactions or
The most frequent ARs (adverse events at least possibly related or events occurring during establish a causal relationship to product exposure.
or within 72 hours after the end of treatment) that occurred in >5% of subjects with PRIVIGEN
chronic ITP were headache (16 subjects [28%]) and pyrexia (3 subjects [5%]). The following adverse reactions have been identified during postmarketing use of PRIVIGEN.
No subject experienced a serious adverse reaction. This list does not include reactions already reported in clinical studies with PRIVIGEN [see
Of the 23 non-serious ARs, 22 were mild (does not interfere with routine activities), 1 was Adverse Reactions (6.1)].
moderate (interferes somewhat with routine activities), and none were severe (impossible • Blood and lymphatic system disorders: Decreased neutrophil count
to perform routine activities). • Infusion reactions: Changes in blood pressure, dyspnea, tachycardia, flushing
All 57 subjects had a negative DAT at baseline. Twenty-two (38%) developed a positive • Hematologic: hemoglobinuria/hematuria/chromaturia, renal failure
DAT by Day 4, 19 of these subjects were from blood group A. • Neurological: photophobia
Fifteen subjects were adjudicated by an independent expert committee, for presumptive/ • Integumentary: pruritus
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 General
subjects there was a median hemoglobin drop from baseline at Day 9 (nadir) of -3.0 g/dL In addition, the following adverse reactions have been identified and reported during the
(range -0.9 to -5.8 g/dL) with Day 9 hemoglobin values ranging from 9.9 to 13.2 g/dL and post-approval use of immune globulin products.14
a median drop from baseline in hemogloblin of -1.2 g/dL (range -0.1 to -2.7 g/dL) at Day 29 • Infusion Reactions: Tachycardia, malaise, flushing, rigors
(end of study) with hemoglobin values ranging from 11.8 to 15.8 g/dL. Ten subjects were • Renal: Acute renal dysfunction/failure, osmotic nephropathy
blood group A and 2 subjects were blood group B. These hemoglobin drops were transient • Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis,
and were followed by recovery or partial recovery by Day 29. One subject experienced mild hypoxemia, pulmonary edema, bronchospasm
dyspnea between Day 9 and Day 16; • Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
1 subject experienced mild dizziness on Day 4. No subject was judged as having experienced • Neurological: Coma, loss of consciousness, seizures, tremor
clinically significant intravascular hemolysis. Three of the 15 adjudicated subjects were • Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme,
judged not to have experienced hemolysis. bullous dermatitis
• Hematologic: Pancytopenia, leukopenia
Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) • Gastrointestinal: Hepatic dysfunction
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 7 DRUG INTERACTIONS
of 2 g/kg followed by PRIVIGEN maintenance doses of 1 g/kg every 3 weeks for up to 21 7.1 Live Virus Vaccines
weeks with 3 week follow up [see Clinical Studies (14.4)]. Administration of the loading The passive transfer of antibodies with immunoglobulin administration may interfere with
dose occurred over 2 days and the maintenance dose over 1 day in the majority of cases. the response to live virus vaccines such as measles, mumps, rubella, and varicella [see
Table 5 summarizes the most frequent ARs that occurred in ≥5% of subjects with CIDP. Patient Counseling Information (17)].15
Table 5. CIDP Clinical Study – ARs* Occurring in ≥5% of Subjects Inform the immunizing physician of recent therapy with PRIVIGEN so that appropriate
measures can be taken.
Number (%) of Number (Rate) of Infusions with AR
Subjects 8 USE IN SPECIFIC POPULATIONS
[n=259]
AR [n=28] 8.1 Pregnancy
Risk Summary
Headache 8 (28.6) 19 (0.073)
No human data are available to indicate the presence or absence of drug-associated risk.
Asthenia 4 (14.3) 4 (0.015)
Hypertension 4 (14.3) 6 (0.023) Animal reproduction studies have not been conducted with PRIVIGEN. It is not known
Nausea 3 (10.7) 3 (0.012) whether PRIVIGEN can cause fetal harm when administered to a pregnant woman or can
Pain in extremity 3 (10.7) 3 (0.012) affect reproduction capacity. Immune globulins cross the placenta from maternal circulation
Hemolysis 2 (7.1) 2 (0.008) increasingly after 30 weeks of gestation.16,17 PRIVIGEN should be given to pregnant women
Influenza like illness 2 (7.1) 2 (0.008) only if clearly needed. In the U.S. general population, the estimated background risk of
Leukopenia 2 (7.1) 2 (0.008) major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-
Rash 2 (7.1) 2 (0.008) 20%, respectively.
*ARs were defined as adverse events at least possibly related or events occurring during or within 72 hours after IV infusion. 8.2 Lactation
Risk Summary
Two hemolysis serious adverse reactions occurred after the start of the PRIVIGEN induction
No human data are available to indicate the presence or absence of drug-associated risk.
dose in subjects with non-O blood groups (A and AB). The reactions resolved after
The developmental and health benefits of breastfeeding should be considered along with
discontinuation without the need for transfusion.
the mother’s clinical need for PRIVIGEN and any potential adverse effects on the breastfed
Four subjects, three of whom had a history of hypertension, had reversible increases in
infant from PRIVIGEN or from the underlying maternal condition.
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 8.4 Pediatric Use
increase in diastolic blood pressure from 84 mm Hg pre-infusion to 135 mm Hg at 1 hour Treatment of Primary Humoral Immunodeficiency
after the end of the infusion. All were resolved or significantly improved within 1 to 6 hours PRIVIGEN was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with
with either observation alone or changes in oral anti-hypertensive therapy. PI (prospective, open label, single arm, multicenter clinical study). There were no apparent
A total of 71 ARs were reported: 46 were mild (does not interfere with routine activities), 23 differences in the safety and efficacy profiles as compared to those in adult subjects. No
were moderate (interferes somewhat with routine activities), and 2 were severe (impossible pediatric-specific dose requirements were necessary to achieve the desired serum IgG
to perform routine activities) in intensity. levels. The safety and effectiveness of PRIVIGEN have not been studied in clinical trials in
In a second prospective, open-label PRIVIGEN pre-randomization phase of a multicenter, pediatric patients with PI who are under the age of 3.
randomized, double-blind, placebo-controlled clinical study (Polyneuropathy and Treatment Treatment of Chronic Immune Thrombocytopenic Purpura
with Hizentra [PATH]), 207 IGIV-pretreated subjects with CIDP received a PRIVIGEN loading The safety and effectiveness of PRIVIGEN have not been established in pediatric patients
dose of 2 g/kg followed by up to 4 PRIVIGEN maintenance doses of 1 g/kg every three with chronic ITP who are under the age of 15.
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 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
post-randomization phase [see Clinical Studies (14.4)]. The safety and effectiveness of PRIVIGEN have not been established in pediatric patients
Eight subjects experienced a serious adverse reaction (acute rash cutaneous, blood pressure with CIDP who are under the age of 18.
8.5 Geriatric Use measured in 25 subjects (ages 13 to 69) following the 7th infusion for the 3 subjects on the
Clinical studies of PRIVIGEN in PID and ITP did not include sufficient numbers of subjects 3-week dosing interval and following the 5th infusion for the 22 subjects on the 4-week
age 65 and over to determine whether they respond differently from younger subjects. dosing interval. The dose of PRIVIGEN used in these subjects ranged from 200 mg/kg to
The safety and effectiveness of PRIVIGEN in CIDP subjects age 65 and over was similar to 714 mg/kg. After the infusion, blood samples were taken until Day 21 and Day 28 for the
those under age 65. 3-week and 4-week dosing intervals, respectively.
Use caution when administering PRIVIGEN to patients age 65 and over who are judged to Table 7 summarizes the pharmacokinetic parameters of PRIVIGEN, based on serum
be at increased risk of developing acute renal insufficiency and thrombosis [see Boxed concentrations of total IgG.
Warning, Warnings and Precautions (5.2, 5.3)]. Do not exceed recommended Table 7. PI Study – Pharmacokinetic Parameters of PRIVIGEN in Subjects
doses, and administer PRIVIGEN at the minimum dose and infusion rate practicable.
10 OVERDOSAGE 3-Week Dosing Interval 4-Week Dosing Interval
Parameter
Overdose may lead to fluid overload and hyperviscosity, particularly in the elderly and in (n=3) (n=22)
patients with impaired renal function.
11 DESCRIPTION Mean Median Mean Median
PRIVIGEN is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human (SD) (Range) (SD) (Range)
immunoglobulin G (IgG) for intravenous administration. PRIVIGEN has a purity of at least
98% IgG, consisting primarily of monomers. The balance consists of IgG dimers (≤12%), 2,550 2,340 2,260 2,340
small amounts of fragments and polymers, and albumin. PRIVIGEN contains ≤25 mcg/mL Cmax (peak, mg/dL)
(400) (2,290-3,010) (530) (1,040-3,460)
IgA. The IgG subclass distribution is similar to that of normal human plasma. PRIVIGEN
has an osmolality of approximately 320 mOsmol/kg (range: 240 to 440) and a pH of 4.8
1,230 1,200 1,000 1,000
(range: 4.6 to 5.0). Cmin (trough, mg/dL)
(230) (1,020-1,470) (200) (580-1,360)
PRIVIGEN contains approximately 250 mmol/L (range: 210 to 290) of L-proline (a
nonessential amino acid) as a stabilizer and trace amounts of sodium. PRIVIGEN contains
no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative. 27.6 27.8 45.4 37.3
t½ (days)
PRIVIGEN is prepared from large pools of human plasma by a combination of cold ethanol (5.9) (21.6-33.4) (18.5) (20.6-96.6)
fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG
proteins are not subjected to heating or to chemical or enzymatic modification. The Fc 29,860 36,670
32,820 36,390
and Fab functions of the IgG molecule are retained. Fab functions tested include antigen AUC0-t (day × mg/dL)* (28,580- (19,680-
(6,260) (5,950)
binding capacities, and Fc functions tested include complement activation and Fc-receptor- 40,010) 44,340)
mediated leukocyte activation (determined with complexed IgG). PRIVIGEN does not 78,748 98,521
79,315 104,627
activate the complement system or prekallikrein in an unspecific manner. AUC0-∞ (day × mg/dL)* (59,435- (64,803-
(20,170) (33,581)
To specifically reduce blood group A and B antibodies (isoagglutinins A and B) the 99,762) 178,600)
manufacturing process for PRIVIGEN includes an immunoaffinity chromatography step.
All plasma units used in the manufacture of PRIVIGEN have been tested and approved 1.3 1.3 1.3 1.3
Clearance (mL/day/kg)*
for manufacture using FDA-licensed serological assays for hepatitis B surface antigen and (0.1) (1.1-1.4) (0.3) (0.9-2.1)
antibodies to HCV and HIV-1/2 as well as FDA-licensed Nucleic Acid Testing (NAT) for HBV,
HCV and HIV-1 and found to be nonreactive (negative). In addition, the plasma has been Mean residence time 38.6 39.5 65.2 59.0
tested for B19 virus (B19V) DNA by NAT. Only plasma that passed virus screening is used (days)* (8.1) (30.1-46.2) (24.7) (33.2-129.6)
for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU
of B19V DNA per mL.
The manufacturing process for PRIVIGEN includes three steps to reduce the risk of virus Volume of distribution 50 44 84 87
transmission. Two of these are dedicated virus clearance steps: pH 4 incubation to inactivate at steady state (mL/kg)* (13) (40-65) (35) (40-207)
enveloped viruses and virus filtration to remove, by size exclusion, both enveloped and
non-enveloped viruses as small as approximately 20 nanometers. In addition, a depth Cmax, maximum serum concentration; Cmin, trough (minimum level) serum concentration; t½, elimination half-life;
filtration step contributes to the virus reduction capacity. AUC0-t, area under the curve from 0 hour to last sampling time; AUC0-∞, area under the curve from 0 hour to infinite
time.
These steps have been independently validated in a series of in vitro experiments for their
* Calculated by log-linear trapezoidal rule.
capacity to inactivate and/or remove both enveloped and non-enveloped viruses.
Table 6 shows the virus clearance during the manufacturing process for PRIVIGEN, Although no systematic study was conducted to evaluate the effect of gender and age
expressed as the mean log10 reduction factor (LRF). 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/
Table 6. Virus Inactivation/Removal in PRIVIGEN*
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
HIV-1 PRV BVDV WNV EMCV MVM 19 adult subjects 19 years of age or older (1.29 ± 0.22 mL/day/kg). The IgG subclass levels
Virus property observed in the pharmacokinetic study were consistent with a physiologic distribution
Genome RNA DNA RNA RNA RNA DNA pattern.
Envelope Yes Yes Yes Yes No No Treatment of Chronic Immune Thrombocytopenic Purpura
Size (nm) 80-100 120-200 50-70 50-70 25-30 18-24 Pharmacokinetic studies with PRIVIGEN were not performed in subjects with chronic ITP.
Manufacturing step Mean LRF Treatment of Chronic Inflammatory Demyelinating Polyneuropathy
pH 4 incubation ≥5.6 ≥6.1 4.6 ≥7.8 nt nt Trough concentrations:
Depth filtration ≥6.7 ≥5.7 3.5+/-0.2 3.0+/-0.4 5.7+/-0.2 3.7+/-0.3 In both the PRIMA and PATH studies, on Day 1, subjects received an induction dose (2 g/kg)
Virus filtration given over 2 to 5 days, followed by maintenance doses of 1 g/kg every 3 weeks.
≥4.7 ≥5.8 ≥4.6 ≥6.8 ≥6.3 ≥6.5
In the PRIMA study, from Day 1 (reference) to Day 2, the mean serum IgG trough
Overall reduction concentration increased from 12.6 ± 3.8 g/L to 24.4 ± 7.0 g/L. At Week 7, before the
≥17.0 ≥17.6 ≥12.7 ≥17.6 ≥12.0 ≥10.2 second maintenance treatment of (1 g/kg) given over 1 or 2 days every 3 weeks, the mean
(log10 units)
HIV-1, human immunodeficiency virus type 1, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a nonspecific model IgG trough concentration was 17.5 ± 3.1 g/L and remained stable from Week 7 to Week 19.
for large enveloped DNA viruses (eg, herpes virus); BVDV, bovine viral diarrhea virus, a model for hepatitis C virus; WNV, In the PATH study, from Day 1 (reference) to Day 5, the mean serum IgG trough
West Nile virus; EMCV, encephalomyocarditis virus, a model for hepatitis A virus; MVM, minute virus of mice, a model for
a small highly resistant non-enveloped DNA virus (eg, parvovirus); LRF, log10 reduction factor; nt, not tested.
concentration increased from 12.7 ± 3.2 g/L to 33.2 ± 6.9 g/L. At Week 7, before the
* The virus clearance of human parvovirus B19 was investigated experimentally at the pH 4 incubation step. The estimated second maintenance treatment of (1 g/kg) given over 1 or 2 days every 3 weeks, the mean
LRF obtained was ≥5.6. IgG trough concentration was 17.7 ± 4.0 g/L and remained stable from Week 7 to Week 13.
12 CLINICAL PHARMACOLOGY Post-infusion concentrations:
12.1 Mechanism of Action In the PRIMA study, from Day 1 to Day 2, the post-infusion serum IgG concentration increased
PRIVIGEN supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against from 28.6 ± 8.5 g/L to 40.0 ± 11.5 g/L. At Week 7 (after the second maintenance treatment),
a wide variety of bacterial and viral agents. The mechanism of action has not been fully the post-infusion IgG concentration was 32.3 ± 8.0 g/L and remained stable from Week 7
elucidated, but may include immunomodulatory effects. to Week 19.
12.3 Pharmacokinetics 14 CLINICAL STUDIES
Treatment of Primary Humoral Immunodeficiency 14.1 Treatment of Primary Humoral Immunodeficiency
In the clinical study assessing the efficacy and safety of PRIVIGEN in 80 subjects with PI A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and
[see pharmacokinetics of PRIVIGEN in adult and pediatric subjects with PI, who were treated
Clinical Studies (14.1)], serum concentrations of total IgG and IgG subclasses were 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% x 109/L). The median maximum platelet count achieved was 154 x 109/L. The median time
were Hispanic, and 7.5% were African-American. All subjects had been on regular IGIV to reach a platelet response of more than 50 x 109/L was 2.5 days after the first infusion.
replacement therapy for at least 6 months prior to participating in the study. Twenty-five (43%) of the 57 subjects reached this response by Day 2 prior to the second
The efficacy analysis included 80 subjects, 16 (20%) on the 3-week dosing interval and infusion and 43 (75%) subjects reached this response by Day 6.
64 (80%) on the 4-week dosing interval. Doses ranged from 200 mg/kg to 888 mg/kg The duration of platelet response was analyzed for the 48 subjects who achieved a response
per infusion. The median dose for the 3-week interval was 428.3 mg/kg per infusion; the any time after the first infusion. The median duration of platelet response in these subjects
median dose for the 4-week interval was 440.6 mg/kg per infusion. Subjects received a was 15.4 days (range: 1 to >82 days). Thirty-six (75%) of the 48 subjects maintained the
total of 1038 infusions of PRIVIGEN, 272 for the 3-week dosing regimen and 766 for the response for at least 8.8 days and 12 (25%) of them for at least 21.9 days. Five (9%)
4-week dosing regimen. The maximum infusion rate allowed during this study was 8 mg/ subjects maintained a response up to Day 29 and two (4%) up to Day 85.
kg/min with 715 (69%) of the infusions administered at a rate of 7 mg/kg/min or greater. A decrease in the severity of hemorrhage from baseline was observed in the following
The primary analysis for efficacy was based on the annual rate of acute serious bacterial bleeding locations: skin (31 of 36 subjects), oral cavity (11 of 11 subjects), and genitourinary
infections (aSBIs), defined as pneumonia, bacteremia/septicemia, osteomyelitis/septic tract (7 of 9 subjects). This decrease was not sustained in all subjects up to the end of the
arthritis, bacterial meningitis, and visceral abscess, per subject per year. Secondary analyses 29-day study period.
were based on the annual rate of other infections, antibiotic use, days out of work/school/ 14.3 Postmarketing Commitment Study in Chronic Immune Thrombocytopenic Purpura
day care or unable to perform normal activities due to illness, and days of hospitalization. A prospective, open-label, single-arm, multicenter study assessed efficacy and safety
During the 12-month study period, the aSBI rate was 0.08 (with an upper 1-sided 99% parameters in 57 IGIV-treated subjects with chronic ITP with a platelet count of <30 x
confidence interval of 0.203), which met the predefined success rate of less than one aSBI 109/L at screening. Fifty-three subjects had a history of chronic ITP with a duration of
per subject per year. Six subjects experienced an aSBI, including three cases of pneumonia greater than 6 months and 4 subjects, all of whom had received prior treatment for ITP
and one case each of septic arthritis, osteomyelitis, and visceral abscess. All six subjects with subsequent elevation followed by falls in platelet counts, had a duration of ITP less
completed the study. than 6 months. The study examined the incidence of subjects who met laboratory and
The rate of other infections was 3.55 infections per subject per year. The infections clinical criteria for hemolysis and was intended to identify antibodies most frequently bound
that occurred most frequently were sinusitis (31.3%), nasopharyngitis (22.5%), upper to erythrocytes in subjects who experienced clinically significant intravascular hemolysis.
respiratory tract infection (18.8%), bronchitis (13.8%), and rhinitis (13.8%). Among the Subjects ranged in age from 18 to 65; 20 (35.1%) were male and 37 (64.9%) were female;
255 infections, 16 (6.3%) occurring in 10 subjects were considered severe. all were Caucasian.
Table 8 summarizes the efficacy results for all 80 subjects. Twenty-one (21) subjects (37%) received 1 infusion of 1 g/kg on Day 1 and 36 subjects
Table 8. PI Study – Summary of Efficacy Results in Subjects (63%) received 2 infusions of 1 g/kg (Day 1 and Day 3). The second infusion was
administered based on the subject’s platelet response to the Day 1 dose (<50 x 109/L) and
Number of Subjects 80 investigator’s discretion.
Results from Case Report Forms The efficacy endpoint platelet response (increase in platelet count at least once to at least
50 x 109/L within 6 days after the first infusion) was achieved in 42 subjects (74%; 95%
Total Number of Subject Days 26,198
confidence interval [CI]: 61% to 83%).
Fifteen subjects with a suspicion of hemolysis based on laboratory data were referred for
Infections independent expert adjudication during the study. The adjudication committee selected
†
Annual rate of confirmed aSBIs* 0.08 aSBIs/subject year from 3 options for their determination: no hemolysis, hemolysis, or clinically significant
Annual rate of other infections 3.55 infections/subject year intravascular hemolysis. The set of antibodies most frequently bound to erythrocytes in
subjects with clinically significant intravascular hemolysis could not be analyzed, because
Antibiotic use no subject experienced clinically significant intravascular hemolysis. No irregular antibodies
were detected in any subject; therefore, no association between such antibodies and
Number of subjects (%) 64 (80%)
hemolytic laboratory changes could be established. Hemolytic laboratory changes were
Annual rate 87.4 days/subject year
most often found in non-O blood group (especially the A blood group) subjects and those
receiving 2 infusions. These laboratory parameters improved or normalized by the end of
Results from Subject Diaries
the study in the majority of subjects. Seven subjects (12% of the study population) with a
Total Number of Diary Days 24,059 normal hemoglobin at baseline had an abnormal hemoglobin at Day 29 (end of study) with
a hemoglobin range from 11.2 to 13.6 g/dL.
Out of work/school/day care Post-hoc analyses were performed using a set of defined criteria for hemolysis. The hemolysis
or unable to perform normal group (18 subjects, 32%) met the criterion for greater than 1 g/dL drop in hemoglobin
activities due to illness within a 21-day interval since the last IGIV administration not explained by blood loss or
repeated phlebotomy, were treatment-emergent DAT positive, and met at least one other
Number of days (%) 570 (2.37%) minor criterion (eg, fall in serum haptoglobin level to below the lower limit of normal, rise
Annual rate 8.65 days/subject year in lactate dehydrogenase level above the upper limit of normal, rise in indirect or total
bilirubin to above the upper limit of normal, or rise in plasma-free hemoglobin above the
Hospitalization upper limit of normal). Fourteen of 15 previously adjudicated presumptive hemolysis cases
Number of days (%) 166 (0.69%) during the study were included in this post-hoc hemolysis group.
Annual rate 2.52 days/subject year 14.4 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
In a prospective, open-label, single-arm, multicenter clinical study (PRIVIGEN Impact on
* Defined as pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess. Mobility and Autonomy [PRIMA]), 28 subjects with CIDP (13 IGIV-pretreated and 15 IGIV-
† Upper 1-sided 99% confidence interval: 0.203. untreated) received a PRIVIGEN loading dose of 2 g/kg followed by PRIVIGEN maintenance
14.2 Treatment of Chronic Immune Thrombocytopenic Purpura doses of 1 g/kg for up to 21 weeks with a 3 week follow up.
A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and Efficacy in the PRIMA study was based on the responder rate of PRIVIGEN in comparison
tolerability of PRIVIGEN in 57 subjects with chronic ITP and a platelet count of 20 x 109/L to an historical control in the adjusted 10-point Inflammatory Neuropathy Cause and
or less. Subjects ranged in age from 15 to 69; 23 (40.4%) were male and 34 (59.6%) were Treatment (INCAT) score.19 The responder rate was defined as the proportion of subjects
female; all were Caucasian. who demonstrated clinically meaningful improvement (at least 1 point decrease on
Subjects received a 2 g/kg dosage of PRIVIGEN administered as 1 g/kg (10 mL/kg) adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] score) between baseline
intravenous infusion daily for 2 consecutive days, and were observed for 29 days. Fifty- and Week 25, with a pre-specified threshold of 35% in the lower limit of the 2-sided
three (93%) subjects received PRIVIGEN at the maximum infusion rate allowed (4 mg/kg/ 95% Wilson-Score confidence interval (CI). The overall percentage of responders in PRIMA
min [0.04 mL/kg/min]). was 61% (95% CI: 42.4% to 76.4%). Response rates were 47% in IGIV‑untreated and
The primary analysis was based on the response rate defined as the percentage of subjects 77% in IGIV‑pretreated subject subgroups. In a post-hoc analysis, the overall percentage
with an increase in platelet counts to at least 50 x 109/L within 7 days after the first infusion of subjects in PRIMA who responded by week 10 and maintained the response through
(responders). Secondary analyses were based on the increase in platelet counts and the week 25 and lacked confounding changes in glucocorticoid/immunosuppressant dosage
time to reach a platelet count of at least 50 x 109/L at any point within the study period, was 53.6% (95% CI: 35.8% to 70.5%).
the duration of that response, and the regression (decrease in the severity) of hemorrhage In a second study (PATH) with the same PRIVIGEN dosing regimen, all 207 subjects were
in subjects who had bleeding at baseline. Platelet counts were measured on Days 1, 2, 4, 6, IGIV-pretreated and had relapsed following withdrawal of IGIV prior to being administered
8, 15, 22, and 29. Additional measurements on Days 57 and 85 occurred in subjects with PRIVIGEN [see Dosage and Administration (2.3)]. The response rate was 73% (see
a platelet count of at least 50 x 109/L at the previous visit. Figure 1). Among the subset of 151 subjects in the PATH study who had deteriorated by one
Of the 57 subjects in the efficacy analysis, 46 (80.7%) responded to PRIVIGEN with a rise in or more points in adjusted INCAT score following withdrawal of IGIV, 137 subjects (90.7%)
platelet counts to at least 50 x 109/L within 7 days after the first infusion. The lower bound responded during the PRIVIGEN “restabilization” period with an increase of one or more
of the 95% confidence interval for the response rate (69.2%) is above the predefined adjusted INCAT score points.
response rate of 50%. The overall median time to first adjusted INCAT response in PRIMA was 7.5 weeks (18
The highest median increase in platelet counts was seen 7 days after the first infusion (123 weeks in IGIV-untreated and 3 weeks in IGIV-pretreated). The median time to first adjusted
INCAT response in PATH (all IGIV-pretreated) was 3.7 weeks (95% CI: 3.4 to 5.9 weeks).
Mean INCAT score in PRIMA showed a clinically meaningful improvement by 1.4 points 19. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate/
(1.1 points for IGIV-untreated, and 1.8 points for IGIV-pretreated [1.2 points in PATH]). chromatography purified) for the treatment of chronic inflammatory demyelinating
Figure 1. Percentage of Responders (Adjusted INCAT Score) polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol
2008;7:136-44.
16 HOW SUPPLIED/STORAGE AND HANDLING
PRIVIGEN is supplied in a single-use, tamper-evident vial containing the labeled amount of
functionally active IgG. The PRIVIGEN packaging components are not made with natural
rubber latex.

Each product presentation includes a package insert and the following components:
Table 10. How Supplied

Carton
Presentation
NDC Number Components

Vial containing 5 grams of protein

50 mL 44206-436-05
(NDC 44206-436-90)
Vial containing 10 grams of protein
100 mL 44206-437-10
(NDC 44206-437-91)
Vial containing 20 grams of protein
200 mL 44206-438-20
(NDC 44206-438-92)
Vial containing 40 grams of protein
400 mL 44206-439-40
Medical Research Council (MRC) sum score in PRIMA improved by a mean of 6.9 points (NDC 44206-439-93)
(7.7 points for IGIV-untreated and 6.1 points for IGIV-pretreated). MRC sum score in PATH Storage and Handling
improved by a mean of 3.6 points. • Keep PRIVIGEN in its original carton to protect it from light.
Grip strength of the dominant hand improved in PRIMA by a mean of 14.1 kPa (17.0 • Each vial has an integral suspension band and a label with two peel-off strips showing
kPa for IGIV-untreated and 10.8 kPa for IGIV-pretreated subgroups). Grip strength of the the product name, lot number, and expiration date.
dominant hand improved in PATH by a mean of 12.2 kPa. Similar results were observed for • When stored at room temperature (up to 25ºC [77ºF]), PRIVIGEN is stable for up to 36
the non-dominant hand in both studies. months, as indicated by the expiration date printed on the outer carton and vial label.
• Do not freeze.
15 REFERENCES
1. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of 17 PATIENT COUNSELING INFORMATION
precipitating thromboembolic events. Neurology 1994;44:223-226. Inform patients of the early signs of hypersensitivity reactions to PRIVIGEN (including hives,
generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis),
2. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment
and advise them to notify their physician if they experience any of these symptoms [see
of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients.
Warnings and Precautions (5.1)].
Lancet 1986;2:217-218. Inform patients to immediately report the following signs and symptoms to their physician:
3. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant • Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness
in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-34. of breath, which may suggest kidney problems [see Warnings and Precautions
4. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune (5.2)].
globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol • Instruct patients to immediately report symptoms of thrombosis. These symptoms
1997;8:1788-1793. may include: pain and/or swelling of an arm or leg with warmth over the affected
5. Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or
post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or
J Hematol 2003;73:97-100. weakness on one side of the body [see Warnings and Precautions (5.3)].
6. Gabor EP. Meningitis and skin reaction after intravenous immune globulin therapy. Ann • Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye
Intern Med 1997;127:1130. movements, nausea, and vomiting, which may suggest aseptic meningitis syndrome
[see Warnings and Precautions (5.5)].
7. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous
• Fatigue, increased heart rate, yellowing of skin or eyes, and dark-colored urine, which
immune globulin therapy. Transfusion 1986;26:410-412.
may suggest hemolysis [see Warnings and Precautions (5.6)].
8. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis
• Severe breathing problems, lightheadedness, drops in blood pressure, and fever,
after high-dose intravenous Ig. Blood 1993;15:3789. which may suggest TRALI (a condition typically occurring within 1 to 6 hours
9. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous following transfusion) [see Warnings and Precautions (5.8)].
immunoglobulin. Muscle Nerve 1997;20:1142-1145. Inform patients that PRIVIGEN is made from human blood and may contain infectious
10. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration agents that can cause disease (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD]
of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J agent and, theoretically the CJD agent). Explain that the risk that PRIVIGEN may transmit
Autoimmun 1999;13:129-135. an infectious agent has been reduced by screening the plasma donors, by testing donated
11. Kahwaji J, Barker E, Pepkowitz S, et al. Acute Hemolysis After High-Dose Intravenous plasma for certain virus infections, and by inactivating or removing certain viruses during
Immunoglobulin Therapy in Highly HLA Sensitized Patients. Clin J Am Soc Nephrol manufacturing, and counsel patients to report any symptoms that concern them [see
2009;4:1993-1997. Warnings and Precautions (5.10)].
12. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration Inform patients that administration of IgG may interfere with the response to live virus vaccines
of intravenous immune (gamma) globulin: A case series analysis. Transfusion (eg, measles, mumps, rubella, and varicella), and instruct them to notify their immunizing
2008;48:1598-1601. physician of recent therapy with PRIVIGEN [see Warnings and Precautions (5.11)].
13. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the
infusion of IVIG. Transfusion 2001;41:264-268.
14. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans
Med Rev 2003;17:241-251. Manufactured by:
15. Siber GA, Werner BG, Halsey NA, et al. Interference of immune globulin with measles CSL Behring AG
and rubella immunization. J Pediatr 1993;122:204-211. Bern, Switzerland
16. Hammarström L, Smith CIE. Placental transfer of intravenous immunoglobulin. Lancet US License No. 1766
1986;1:681.
17. Sidiropoulos D, Herrmann U, Morell A, von Muralt G, Barandun S. Transplacental
passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr
1986;109:505-508. Distributed by:
18. Gregori L, Maring J-A, MacAuley C, Stühler A, Löwer J, Blümel J. Partitioning of TSE CSL Behring LLC
infectivity during ethanol fractionation of human plasma. Biologicals 2004;32:1-10. Kankakee, IL 60901 USA