1.1 Primary Humoral Immunodeficiency

PRIVIGEN is indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Chronic Immune Thrombocytopenic Purpura

PRIVIGEN is indicated for the treatment of patients age 15 years and older with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts.

1.3 Chronic Inflammatory Demyelinating Polyneuropathy

PRIVIGEN is indicated for the treatment of adults with chronic inflammatory demyelinating polyneuropathy (CIDP) to improve neuromuscular disability and impairment.

2.1 Dosage for Primary Humoral Immunodeficiency (PI)

As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The 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), 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 responses. No randomized, controlled trial data are available to determine an optimal trough level in patients receiving immune globulin therapy.

2.2 Dosage for Chronic Immune Thrombocytopenic Purpura (ITP)

The recommended dose of PRIVIGEN for patients with chronic ITP is 1 g/kg (10 mL/kg) administered daily for 2 consecutive days, resulting in a total dosage of 2 g/kg.

Carefully consider the relative risks and benefits before prescribing the high dose regimen (e.g., 1 g/kg/day for 2 days) in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload [see Warnings and Precautions (5.9)].

2.3 Dosage for Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

PRIVIGEN may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given in divided doses over two to five consecutive days. PRIVIGEN may be administered as a maintenance infusion of 1 g/kg (10 mL/kg) administered in a single infusion given in one day or divided into two doses given on two consecutive days, every 3 weeks. Maintenance therapy beyond 6 months has not been studied.

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 mL/kg/min). For patients judged to be at risk for thrombosis, renal dysfunction, or volume overload, administer PRIVIGEN at the minimum infusion rate practicable [see Warnings and Precautions (5.2, 5.3)].

2.4 Preparation and Handling

• PRIVIGEN is a clear or slightly opalescent, colorless to pale yellow solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy, turbid, or if it contains particulate matter.
• DO NOT SHAKE.
• Do not freeze. Do not use if PRIVIGEN has been frozen.
• PRIVIGEN should be at room temperature (up to 25ºC [77ºF]) at the time of administration.
• Do not use PRIVIGEN beyond the expiration date on the product label.
• The PRIVIGEN vial is for single-use only. Promptly use any vial that has been entered. PRIVIGEN contains no preservative. Discard partially used vials or unused product in accordance with local requirements.
• Infuse PRIVIGEN using a separate infusion line. Prior to use, the infusion line may be flushed with Dextrose Injection, USP (D5W) or 0.9% Sodium Chloride for Injection, USP.
• Do not mix PRIVIGEN with other IGIV products or other intravenous medications. However, PRIVIGEN may be diluted with Dextrose Injection, USP (D5W).
• An infusion pump may be used to control the rate of administration.
• If large doses of PRIVIGEN are to be administered, several vials may be pooled using aseptic technique. Begin infusion within 8 hours of pooling.

2.5 Administration

PRIVIGEN is for intravenous administration only.

Monitor the patient's vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.

Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombosis, administer PRIVIGEN at the minimum dose and infusion rate practicable, and discontinue PRIVIGEN administration if renal function deteriorates [see Boxed Warning, Warnings and Precautions (5.2, 5.3)].

The following patients may be at risk of developing systemic reactions (mimicking symptoms of an inflammatory response or infection) on rapid infusion of PRIVIGEN (greater than 4 mg/kg/min [0.04 mL/kg/min]): 1) those who have never received PRIVIGEN or another IgG product or who have not received it within the past 8 weeks, and 2) those who are switching from another IgG product. These patients should be started at a slow rate of infusion (e.g., 0.5 mg/kg/min [0.005 mL/kg/min] or less) and gradually increase as tolerated.

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur [see Contraindications (4)]. In case of hypersensitivity, discontinue the PRIVIGEN infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

PRIVIGEN contains trace amounts of IgA (≤25 mcg/mL) [see Description (11)]. Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions with administration of PRIVIGEN. PRIVIGEN is contraindicated in patients with antibodies against IgA and a history of hypersensitivity.

5.2 Renal Dysfunction and Acute Renal Failure

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. 4 PRIVIGEN does not contain sucrose. Acute renal failure may also occur as a result of PRIVIGEN-induced hemolysis. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of PRIVIGEN and at appropriate intervals thereafter.

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure.4 If renal function deteriorates, consider discontinuing PRIVIGEN. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency, or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are obese, those who use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer PRIVIGEN at the minimum rate of infusion practicable [see Boxed Warning, Dosage and Administration (2.5)].

5.3 Thrombosis

Thrombosis may occur following treatment with immune globulin products1-3, including PRIVIGEN. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer PRIVIGEN at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity [see Boxed Warning, Dosage and Administration (2.5), Patient Counseling Information (17)].

5.4 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur following treatment with IGIV products, including PRIVIGEN. The hyponatremia is likely to be a pseudohyponatremia, as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. It is critical to distinguish true hyponatremia from pseudohyponatremia, as treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thromboembolic events.5

5.5 Aseptic Meningitis Syndrome (AMS)

AMS may occur infrequently following treatment with PRIVIGEN [see Adverse Reactions (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 several hours to 2 days following IGIV treatment.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis.

AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.

5.6 Hemolysis

PRIVIGEN may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin test (DAT) (Coombs' test) result and hemolysis.7-9 Delayed hemolytic anemia can develop subsequent to PRIVIGEN therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.10 Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of PRIVIGEN.

The following risk factors may be associated with the development of hemolysis: high doses (e.g., ≥2 g/kg), given either as a single administration or divided over several days, and non-O blood group.11 Other individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis following administration of IGIV,12 but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP, CIDP, and PI.9

Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above and those with pre-existing anemia and/or cardiovascular or pulmonary compromise. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 hours and again 7 to 10 days post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform additional confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

5.7 Hypertension

Elevations of systolic blood pressure to ≥180 mm Hg and/or of diastolic blood pressure to >120 mm Hg (hypertensive urgency) have been observed during and/or shortly following infusion of PRIVIGEN. These blood pressure elevations were resolved or significantly improved within hours with either observation alone or changes in oral anti-hypertensive therapy [see Adverse Reactions (6.1)]. Such elevations were reported more often among patients with a history of hypertension. Check patients for a history of hypertension and current antihypertensive medication use. Monitor blood pressure prior to, during, and following PRIVIGEN infusion.

5.8 Transfusion-Related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema may occur following treatment with IGIV products, including PRIVIGEN.13 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment.

Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the product and the patient's serum.

TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.9 Volume Overload

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.

5.10 Transmissible Infectious Agents

Because PRIVIGEN is made from human blood, it may carry a risk of transmitting infectious agents (eg, viruses, the variant Creutzfeldt Jakob disease [vCJD] agent and, theoretically, the Creutzfeldt Jakob disease [CJD] agent). The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for PRIVIGEN.

Report any infection thought to be possibly transmitted by PRIVIGEN to CSL Behring Pharmacovigilance at 1-866-915-6958.

5.11 Interference with Laboratory Tests

Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.

Primary Humoral Immunodeficiency

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

Chronic Immune Thrombocytopenic Purpura

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

Chronic Inflammatory Demyelinating Polyneuropathy

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

6.1 Clinical Trials Experience

Because different clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

7.1 Live Virus Vaccines

The passive transfer of antibodies with immunoglobulin administration may interfere with the response to live virus vaccines such as measles, mumps, rubella, and varicella [see Patient Counseling Information (17)].15

Inform the immunizing physician of recent therapy with PRIVIGEN so that appropriate measures can be taken.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

Clinical studies of PRIVIGEN in PID and ITP did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.

The safety and effectiveness of PRIVIGEN in CIDP subjects age 65 and over was similar to those under age 65.

Use caution when administering PRIVIGEN to patients age 65 and over who are judged to be at increased risk of developing acute renal insufficiency and thrombosis [see Boxed Warning, Warnings and Precautions (5.2, 5.3)]. Do not exceed recommended doses, and administer PRIVIGEN at the minimum dose and infusion rate practicable.

12.1 Mechanism of Action

PRIVIGEN supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. The mechanism of action has not been fully elucidated, but may include immunomodulatory effects.

12.3 Pharmacokinetics

14.1 Treatment of Primary Humoral Immunodeficiency

A prospective, open-label, single-arm, multicenter 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 8 summarizes the efficacy results for all 80 subjects.

14.2 Treatment of Chronic Immune Thrombocytopenic Purpura

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 × 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 × 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 × 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 × 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 × 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 × 109/L). The median maximum platelet count achieved was 154 × 109/L. The median time to reach a platelet response of more than 50 × 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.

14.3 Postmarketing Commitment Study in Chronic Immune Thrombocytopenic Purpura

A prospective, open-label, single-arm, multicenter study assessed efficacy and safety parameters in 57 IGIV-treated subjects with chronic ITP with a platelet count of <30 × 109/L at screening. Fifty-three subjects had a history of chronic ITP with a duration of greater than 6 months and 4 subjects, all of whom had received prior treatment for ITP with subsequent elevation followed by falls in platelet counts, had a duration of ITP less than 6 months. The study examined the incidence of subjects who met laboratory and clinical criteria for hemolysis and was intended to identify antibodies most frequently bound to erythrocytes in subjects who experienced clinically significant intravascular hemolysis. Subjects ranged in age from 18 to 65; 20 (35.1%) were male and 37 (64.9%) were female; all were Caucasian.

Twenty-one (21) subjects (37%) received 1 infusion of 1 g/kg on Day 1 and 36 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 × 109/L) and investigator's discretion.

The efficacy endpoint platelet response (increase in platelet count at least once to at least 50 × 109/L within 6 days after the first infusion) was achieved in 42 subjects (74%; 95% confidence interval [CI]: 61% to 83%).

Fifteen subjects with a suspicion of hemolysis based on laboratory data were referred for independent expert adjudication during the study. The adjudication committee selected from 3 options for their determination: no hemolysis, hemolysis, or clinically significant intravascular hemolysis. The set of antibodies most frequently bound to erythrocytes in subjects with clinically significant intravascular hemolysis could not be analyzed, because no subject experienced clinically significant intravascular hemolysis. No irregular antibodies were detected in any subject; therefore, no association between such antibodies and hemolytic laboratory changes could be established. Hemolytic laboratory changes were 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 the study in the majority of subjects. Seven subjects (12% of the study population) with a 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.

Post-hoc analyses were performed using a set of defined criteria for hemolysis. The hemolysis group (18 subjects, 32%) met the criterion for greater than 1 g/dL drop in hemoglobin 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 minor criterion (eg, fall in serum haptoglobin level to below the lower limit of normal, rise 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 upper limit of normal). Fourteen of 15 previously adjudicated presumptive hemolysis cases during the study were included in this post-hoc hemolysis group.

14.4 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

In a prospective, open-label, single-arm, multicenter clinical study (PRIVIGEN Impact on Mobility and Autonomy [PRIMA]), 28 subjects with CIDP (13 IGIV-pretreated and 15 IGIV-untreated) received a PRIVIGEN loading dose of 2 g/kg followed by PRIVIGEN maintenance doses of 1 g/kg for up to 21 weeks with a 3 week follow up.

Efficacy in the PRIMA study was based on the responder rate of PRIVIGEN in comparison to an historical control in the adjusted 10-point Inflammatory Neuropathy Cause and Treatment (INCAT) score.19 The responder rate was defined as the proportion of subjects who demonstrated clinically meaningful improvement (at least 1 point decrease on adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] score) between baseline and Week 25, with a pre-specified threshold of 35% in the lower limit of the 2-sided 95% Wilson-Score confidence interval (CI). The overall percentage of responders in PRIMA was 61% (95% CI: 42.4% to 76.4%). Response rates were 47% in IGIV-untreated and 77% in IGIV-pretreated subject subgroups. In a post-hoc analysis, the overall percentage of subjects in PRIMA who responded by week 10 and maintained the response through week 25 and lacked confounding changes in glucocorticoid/immunosuppressant dosage was 53.6% (95% CI: 35.8% to 70.5%).

In a second study (PATH) with the same PRIVIGEN dosing regimen, all 207 subjects were IGIV-pretreated and had relapsed following withdrawal of IGIV prior to being administered PRIVIGEN [see Dosage and Administration (2.3)]. The response rate was 73% (see Figure 1). Among the subset of 151 subjects in the PATH study who had deteriorated by one or more points in adjusted INCAT score following withdrawal of IGIV, 137 subjects (90.7%) responded during the PRIVIGEN "restabilization" period with an increase of one or more adjusted INCAT score points.

The overall median time to first adjusted INCAT response in PRIMA was 7.5 weeks (18 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 (1.1 points for IGIV-untreated, and 1.8 points for IGIV-pretreated [1.2 points in PATH]).

Figure 1. Percentage of Responders (Adjusted INCAT Score)

Medical Research Council (MRC) sum score in PRIMA improved by a mean of 6.9 points (7.7 points for IGIV-untreated and 6.1 points for IGIV-pretreated). MRC sum score in PATH improved by a mean of 3.6 points.

Grip strength of the dominant hand improved in PRIMA by a mean of 14.1 kPa (17.0 kPa for IGIV-untreated and 10.8 kPa for IGIV-pretreated subgroups). Grip strength of the dominant hand improved in PATH by a mean of 12.2 kPa. Similar results were observed for the non-dominant hand in both studies.

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 25ºC [77ºF]), 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.