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.

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

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

Limitation of Use:

PRIVIGEN maintenance therapy in CIDP has not been studied for periods longer than 6 months. After responding during an initial treatment period, not all patients require indefinite maintenance therapy with PRIVIGEN in order to remain free of CIDP symptoms. Individualize the duration of any treatment beyond 6 months based upon the patient's response and demonstrated need for continued therapy.

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.

Measles Exposure

If a patient has been exposed to measles, it may be prudent to administer an extra dose of Immune Globulin Intravenous as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks.

If a patient is at risk of future measles exposure and receives a dose of less than 530 mg/kg every 3-4 weeks, the dose should be increased to at least 530 mg/kg. This should provide a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion.

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)].

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)].

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.

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

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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.

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)].

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)].

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

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 [see Dosage and Administration (2.5)].

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.

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.

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.

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.

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.

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.

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

Treatment of Primary Humoral Immunodeficiency

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

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

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

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

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2. PI Pivotal Study – ARs<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> Occurring in &gt;5% of Subjects</span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">AR<a class="Sup" href="#footnote-1">*</a></th><th align="center" class="Rrule">Number (%) of Subjects<br/>[n=80]</th><th align="center" class="Rrule">Number (Rate) of Infusions with AR<br/>[n=1038]</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>ARs are defined as adverse events at least possibly related or events occurring during or within 72 hours of a PRIVIGEN infusion. Infections are excluded from this table.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">36 (45.0)</td><td align="center" class="Rrule">100 (0.096)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Fatigue</td><td align="center" class="Rrule">13 (16.3)</td><td align="center" class="Rrule">29 (0.028)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">11 (13.8)</td><td align="center" class="Rrule">23 (0.022)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Chills</td><td align="center" class="Rrule">9 (11.3)</td><td align="center" class="Rrule">15 (0.014)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">9 (11.3)</td><td align="center" class="Rrule">15 (0.014)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Back pain</td><td align="center" class="Rrule">8 (10.0)</td><td align="center" class="Rrule">15 (0.014)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pain</td><td align="center" class="Rrule">7 (8.8)</td><td align="center" class="Rrule">14 (0.013)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Elevated body temperature</td><td align="center" class="Rrule">7 (8.8)</td><td align="center" class="Rrule">12 (0.012)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">6 (7.5)</td><td align="center" class="Rrule">6 (0.006)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Cough</td><td align="center" class="Rrule">5 (6.3)</td><td align="center" class="Rrule">5 (0.005)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Stomach discomfort</td><td align="center" class="Rrule">5 (6.3)</td><td align="center" class="Rrule">5 (0.005)</td> </tr> </tbody> </table></div>

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

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

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

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

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

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

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

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

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3. PI Extension Study – ARs<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a> Occurring in &gt;5% of Subjects</span> </caption> <col align="left" valign="top" width="37%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="33%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">AR<a class="Sup" href="#footnote-2">*</a></th><th align="center" class="Rrule">Number (%) of Subjects<br/>[n=55]</th><th align="center" class="Rrule">Number (Rate) of Infusions with AR<br/>[n=771]</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3">Note: The AR rates in this study cannot be compared directly to the rates in other IGIV studies, including the original pivotal study described earlier in this section, because (1) the extension study used an enriched population and (2) the selective use of higher infusion rates at the investigators' discretion in a subset of subjects may have introduced bias.</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Excluding infections.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Includes abdominal pain, abdominal pain upper, and abdominal pain lower.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">18 (32.7)</td><td align="center" class="Rrule">76 (0.099)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">6 (10.9)</td><td align="center" class="Rrule">10 (0.013)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Elevated body temperature</td><td align="center" class="Rrule">4 (7.3)</td><td align="center" class="Rrule">12 (0.016)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Abdominal pain<a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a></td><td align="center" class="Rrule">4 (7.3)</td><td align="center" class="Rrule">7 (0.009)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Chest pain</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">4 (0.005)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Chills</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">7 (0.009)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Joint swelling/effusion</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">7 (0.009)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pain</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">6 (0.008)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Fatigue</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">5 (0.006)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Influenza-like illness</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">5 (0.006)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pharyngolaryngeal pain</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">4 (0.005)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Urticaria</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">4 (0.005)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Dizziness</td><td align="center" class="Rrule">3 (5.5)</td><td align="center" class="Rrule">3 (0.004)</td> </tr> </tbody> </table></div>

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

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

Treatment of Chronic Immune Thrombocytopenic Purpura

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

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

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

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 4. Chronic ITP Premarketing Clinical Study – ARs<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a> Occurring in &gt;5% of Subjects</span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">AR<a class="Sup" href="#footnote-4">*</a></th><th align="center" class="Rrule">Number (%) of Subjects<br/>[n=57]</th><th align="center" class="Rrule">Number (Rate) of Infusions with AR<br/>[n=114]</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>ARs were defined as adverse events at least possibly related or events occurring during or within 72 hours after the end of a treatment cycle [two consecutive infusions].</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">37 (64.9)</td><td align="center" class="Rrule">52 (0.456)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Elevated body temperature</td><td align="center" class="Rrule">21 (36.8)</td><td align="center" class="Rrule">23 (0.202)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Positive DAT</td><td align="center" class="Rrule">7 (12.3)</td><td align="center" class="Rrule">8 (0.070)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Anemia</td><td align="center" class="Rrule">6 (10.5)</td><td align="center" class="Rrule">6 (0.053)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">6 (10.5)</td><td align="center" class="Rrule">8 (0.070)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Epistaxis</td><td align="center" class="Rrule">6 (10.5)</td><td align="center" class="Rrule">8 (0.070)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">6 (10.5)</td><td align="center" class="Rrule">7 (0.061)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Blood bilirubin unconjugated increased</td><td align="center" class="Rrule">6 (10.5)</td><td align="center" class="Rrule">6 (0.053)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Blood bilirubin conjugated increased</td><td align="center" class="Rrule">5 (8.8)</td><td align="center" class="Rrule">5 (0.044)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Blood total bilirubin increased</td><td align="center" class="Rrule">3 (5.3)</td><td align="center" class="Rrule">3 (0.026)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Hematocrit decreased</td><td align="center" class="Rrule">3 (5.3)</td><td align="center" class="Rrule">3 (0.026)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Blood lactate dehydrogenase increased</td><td align="center" class="Rrule">3 (5.3)</td><td align="center" class="Rrule">3 (0.026)</td> </tr> </tbody> </table></div>

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

One subject experienced a serious AR (aseptic meningitis).

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

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

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

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

Postmarketing Commitment Study in Chronic Immune Thrombocytopenic Purpura

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

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

No subject experienced a serious adverse reaction.

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

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

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

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

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

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

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 5. CIDP Clinical Study – ARs<a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a> Occurring in ≥5% of Subjects</span> </caption> <col align="left" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="40%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">AR<a class="Sup" href="#footnote-5">*</a></th><th align="center" class="Rrule">Number (%) of Subjects<br/>[n=28]</th><th align="center" class="Rrule">Number (Rate) of Infusions with AR<br/>[n=259]</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>ARs were defined as adverse events at least possibly related or events occurring during or within 72 hours after IV infusion.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">8 (28.6)</td><td align="center" class="Rrule">19 (0.073)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Asthenia</td><td align="center" class="Rrule">4 (14.3)</td><td align="center" class="Rrule">4 (0.015)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Hypertension</td><td align="center" class="Rrule">4 (14.3)</td><td align="center" class="Rrule">6 (0.023)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">3 (10.7)</td><td align="center" class="Rrule">3 (0.012)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pain in extremity</td><td align="center" class="Rrule">3 (10.7)</td><td align="center" class="Rrule">3 (0.012)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Hemolysis</td><td align="center" class="Rrule">2 (7.1)</td><td align="center" class="Rrule">2 (0.008)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Influenza like illness</td><td align="center" class="Rrule">2 (7.1)</td><td align="center" class="Rrule">2 (0.008)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Leukopenia</td><td align="center" class="Rrule">2 (7.1)</td><td align="center" class="Rrule">2 (0.008)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Rash</td><td align="center" class="Rrule">2 (7.1)</td><td align="center" class="Rrule">2 (0.008)</td> </tr> </tbody> </table></div>

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

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

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

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

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

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

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

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

PRIVIGEN

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

General

In addition, the following adverse reactions have been identified and reported with the use of immune globulin products.14

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.

Risk Summary

No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with PRIVIGEN. It is not known whether PRIVIGEN can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.16,17 PRIVIGEN should be given to pregnant women only if clearly needed. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Risk Summary

No human data are available to indicate the presence or absence of drug-associated risk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PRIVIGEN and any potential adverse effects on the breastfed infant from PRIVIGEN or from the underlying maternal condition.

Treatment of Primary Humoral Immunodeficiency

PRIVIGEN was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI (prospective, open label, single arm, multicenter clinical study). There were no apparent differences in the safety and efficacy profiles as compared to those in adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of PRIVIGEN have not been studied in clinical trials in pediatric patients with PI who are under the age of 3.

Treatment of Chronic Immune Thrombocytopenic Purpura

The safety and effectiveness of PRIVIGEN have not been established in pediatric patients with chronic ITP who are under the age of 15.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

The safety and effectiveness of PRIVIGEN have not been established in pediatric patients with CIDP who are under the age of 18.

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.

Overdose may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with impaired renal function.

{ "type": "p", "children": [], "text": "Overdose may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with impaired renal function." }

PRIVIGEN is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human 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%), small amounts of fragments and polymers, and albumin. PRIVIGEN contains ≤25 mcg/mL 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 (range: 4.6 to 5.0).

{ "type": "p", "children": [], "text": "PRIVIGEN is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human 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%), small amounts of fragments and polymers, and albumin. PRIVIGEN contains ≤25 mcg/mL 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 (range: 4.6 to 5.0)." }

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.

{ "type": "p", "children": [], "text": "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." }

PRIVIGEN is prepared from large pools of human plasma by a combination of cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. Fab functions tested include antigen binding capacities, and Fc functions tested include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG). PRIVIGEN does not activate the complement system or prekallikrein in an unspecific manner.

{ "type": "p", "children": [], "text": "PRIVIGEN is prepared from large pools of human plasma by a combination of cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. Fab functions tested include antigen binding capacities, and Fc functions tested include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG). PRIVIGEN does not activate the complement system or prekallikrein in an unspecific manner." }

To specifically reduce blood group A and B antibodies (isoagglutinins A and B) the manufacturing process for PRIVIGEN includes an immunoaffinity chromatography step.

{ "type": "p", "children": [], "text": "To specifically reduce blood group A and B antibodies (isoagglutinins A and B) the manufacturing process for PRIVIGEN includes an immunoaffinity chromatography step." }

All plasma units used in the manufacture of PRIVIGEN have been tested and approved for manufacture using FDA-licensed serological assays for hepatitis B surface antigen and 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 tested for B19 virus (B19V) DNA by NAT. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.

{ "type": "p", "children": [], "text": "All plasma units used in the manufacture of PRIVIGEN have been tested and approved for manufacture using FDA-licensed serological assays for hepatitis B surface antigen and 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 tested for B19 virus (B19V) DNA by NAT. Only plasma that passed virus screening is used 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 transmission. Two of these are dedicated virus clearance steps: pH 4 incubation to inactivate 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 filtration step contributes to the virus reduction capacity.

{ "type": "p", "children": [], "text": "The manufacturing process for PRIVIGEN includes three steps to reduce the risk of virus transmission. Two of these are dedicated virus clearance steps: pH 4 incubation to inactivate 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 filtration step contributes to the virus reduction capacity." }

These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses.

{ "type": "p", "children": [], "text": "These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses." }

Table 6 shows the virus clearance during the manufacturing process for PRIVIGEN, expressed as the mean log10 reduction factor (LRF).

{ "type": "p", "children": [], "text": "Table 6 shows the virus clearance during the manufacturing process for PRIVIGEN, expressed as the mean log10 reduction factor (LRF)." }

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 6. Virus Inactivation/Removal in PRIVIGEN<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></span> </caption> <col align="left" valign="top" width="28%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="left" class="Rrule">HIV-1</th><th align="left" class="Rrule">PRV</th><th align="left" class="Rrule">BVDV</th><th align="left" class="Rrule">WNV</th><th align="left" class="Rrule">EMCV</th><th align="left" class="Rrule">MVM</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="7">HIV-1, human immunodeficiency virus type 1, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a nonspecific model for large enveloped DNA viruses (eg, herpes virus); BVDV, bovine viral diarrhea virus, a model for hepatitis C virus; WNV, 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, log<span class="Sub">10</span> reduction factor; nt, not tested.</td> </tr> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>The virus clearance of human parvovirus B19 was investigated experimentally at the pH 4 incubation step. The estimated LRF obtained was ≥5.6.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Virus property</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Genome</td><td align="center" class="Rrule">RNA</td><td align="center" class="Rrule">DNA</td><td align="center" class="Rrule">RNA</td><td align="center" class="Rrule">RNA</td><td align="center" class="Rrule">RNA</td><td align="center" class="Rrule">DNA</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Envelope</td><td align="center" class="Rrule">Yes</td><td align="center" class="Rrule">Yes</td><td align="center" class="Rrule">Yes</td><td align="center" class="Rrule">Yes</td><td align="center" class="Rrule">No</td><td align="center" class="Rrule">No</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Size (nm)</td><td align="center" class="Rrule">80-100</td><td align="center" class="Rrule">120-200</td><td align="center" class="Rrule">50-70</td><td align="center" class="Rrule">50-70</td><td align="center" class="Rrule">25-30</td><td align="center" class="Rrule">18-24</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Manufacturing step</span></td><td align="center" class="Rrule" colspan="6"><span class="Bold">Mean LRF </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule Toprule">pH 4 incubation</td><td align="center" class="Rrule Toprule">≥5.6</td><td align="center" class="Rrule Toprule">≥6.1</td><td align="center" class="Rrule Toprule">4.6</td><td align="center" class="Rrule Toprule">≥7.8</td><td align="center" class="Rrule Toprule">nt</td><td align="center" class="Rrule Toprule">nt</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Depth filtration</td><td align="center" class="Rrule">≥6.7</td><td align="center" class="Rrule">≥5.7</td><td align="center" class="Rrule">3.5±0.2</td><td align="center" class="Rrule">3.0±0.4</td><td align="center" class="Rrule">5.7±0.2</td><td align="center" class="Rrule">3.7±0.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Virus filtration</td><td align="center" class="Rrule">≥4.7</td><td align="center" class="Rrule">≥5.8</td><td align="center" class="Rrule">≥4.6</td><td align="center" class="Rrule">≥6.8</td><td align="center" class="Rrule">≥6.3</td><td align="center" class="Rrule">≥6.5</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">Overall reduction (log<span class="Sub">10</span> units)</span></td><td align="center" class="Rrule"><span class="Bold">≥17.0</span></td><td align="center" class="Rrule"><span class="Bold">≥17.6</span></td><td align="center" class="Rrule"><span class="Bold">≥12.7</span></td><td align="center" class="Rrule"><span class="Bold">≥17.6</span></td><td align="center" class="Rrule"><span class="Bold">≥12.0</span></td><td align="center" class="Rrule"><span class="Bold">≥10.2</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"90%\">\n<caption>\n<span>Table 6. Virus Inactivation/Removal in PRIVIGEN<a class=\"Sup\" href=\"#footnote-6\" name=\"footnote-reference-6\">*</a></span>\n</caption>\n<col align=\"left\" valign=\"top\" width=\"28%\"/>\n<col align=\"center\" valign=\"top\" width=\"12%\"/>\n<col align=\"center\" valign=\"top\" width=\"12%\"/>\n<col align=\"center\" valign=\"top\" width=\"12%\"/>\n<col align=\"center\" valign=\"top\" width=\"12%\"/>\n<col align=\"center\" valign=\"top\" width=\"12%\"/>\n<col align=\"center\" valign=\"top\" width=\"12%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Lrule Rrule\"></th><th align=\"left\" class=\"Rrule\">HIV-1</th><th align=\"left\" class=\"Rrule\">PRV</th><th align=\"left\" class=\"Rrule\">BVDV</th><th align=\"left\" class=\"Rrule\">WNV</th><th align=\"left\" class=\"Rrule\">EMCV</th><th align=\"left\" class=\"Rrule\">MVM</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"7\">HIV-1, human immunodeficiency virus type 1, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a nonspecific model for large enveloped DNA viruses (eg, herpes virus); BVDV, bovine viral diarrhea virus, a model for hepatitis C virus; WNV, 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, log<span class=\"Sub\">10</span> reduction factor; nt, not tested.</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-6\" name=\"footnote-6\">*</a>\n</dt>\n<dd>The virus clearance of human parvovirus B19 was investigated experimentally at the pH 4 incubation step. The estimated LRF obtained was ≥5.6.</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Virus property</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Genome</td><td align=\"center\" class=\"Rrule\">RNA</td><td align=\"center\" class=\"Rrule\">DNA</td><td align=\"center\" class=\"Rrule\">RNA</td><td align=\"center\" class=\"Rrule\">RNA</td><td align=\"center\" class=\"Rrule\">RNA</td><td align=\"center\" class=\"Rrule\">DNA</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Envelope</td><td align=\"center\" class=\"Rrule\">Yes</td><td align=\"center\" class=\"Rrule\">Yes</td><td align=\"center\" class=\"Rrule\">Yes</td><td align=\"center\" class=\"Rrule\">Yes</td><td align=\"center\" class=\"Rrule\">No</td><td align=\"center\" class=\"Rrule\">No</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Size (nm)</td><td align=\"center\" class=\"Rrule\">80-100</td><td align=\"center\" class=\"Rrule\">120-200</td><td align=\"center\" class=\"Rrule\">50-70</td><td align=\"center\" class=\"Rrule\">50-70</td><td align=\"center\" class=\"Rrule\">25-30</td><td align=\"center\" class=\"Rrule\">18-24</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\">Manufacturing step</span></td><td align=\"center\" class=\"Rrule\" colspan=\"6\"><span class=\"Bold\">Mean LRF </span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule Toprule\">pH 4 incubation</td><td align=\"center\" class=\"Rrule Toprule\">≥5.6</td><td align=\"center\" class=\"Rrule Toprule\">≥6.1</td><td align=\"center\" class=\"Rrule Toprule\">4.6</td><td align=\"center\" class=\"Rrule Toprule\">≥7.8</td><td align=\"center\" class=\"Rrule Toprule\">nt</td><td align=\"center\" class=\"Rrule Toprule\">nt</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Depth filtration</td><td align=\"center\" class=\"Rrule\">≥6.7</td><td align=\"center\" class=\"Rrule\">≥5.7</td><td align=\"center\" class=\"Rrule\">3.5±0.2</td><td align=\"center\" class=\"Rrule\">3.0±0.4</td><td align=\"center\" class=\"Rrule\">5.7±0.2</td><td align=\"center\" class=\"Rrule\">3.7±0.3</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Virus filtration</td><td align=\"center\" class=\"Rrule\">≥4.7</td><td align=\"center\" class=\"Rrule\">≥5.8</td><td align=\"center\" class=\"Rrule\">≥4.6</td><td align=\"center\" class=\"Rrule\">≥6.8</td><td align=\"center\" class=\"Rrule\">≥6.3</td><td align=\"center\" class=\"Rrule\">≥6.5</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Bold\">Overall reduction (log<span class=\"Sub\">10</span> units)</span></td><td align=\"center\" class=\"Rrule\"><span class=\"Bold\">≥17.0</span></td><td align=\"center\" class=\"Rrule\"><span class=\"Bold\">≥17.6</span></td><td align=\"center\" class=\"Rrule\"><span class=\"Bold\">≥12.7</span></td><td align=\"center\" class=\"Rrule\"><span class=\"Bold\">≥17.6</span></td><td align=\"center\" class=\"Rrule\"><span class=\"Bold\">≥12.0</span></td><td align=\"center\" class=\"Rrule\"><span class=\"Bold\">≥10.2</span></td>\n</tr>\n</tbody>\n</table></div>" }

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.

Treatment of Primary Humoral Immunodeficiency

In the clinical study assessing the efficacy and safety of PRIVIGEN in 80 subjects with PI [see Clinical Studies (14.1)], serum concentrations of total IgG and IgG subclasses were measured in 25 subjects (ages 13 to 69) following the 7th infusion for the 3 subjects on the 3-week dosing interval and following the 5th infusion for the 22 subjects on the 4-week dosing interval. The dose of PRIVIGEN used in these subjects ranged from 200 mg/kg to 714 mg/kg. After the infusion, blood samples were taken until Day 21 and Day 28 for the 3-week and 4-week dosing intervals, respectively.

Table 7 summarizes the pharmacokinetic parameters of PRIVIGEN, based on serum concentrations of total IgG.

<div class="scrollingtable"><table width="90%"> <caption> <span>Table 7. PI Study – Pharmacokinetic Parameters of PRIVIGEN in Subjects</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" rowspan="2">Parameter</th><th align="center" class="Rrule" colspan="2">3-Week Dosing Interval<br/>(n=3)</th><th align="center" class="Rrule" colspan="2">4-Week Dosing Interval<br/>(n=22)</th> </tr> <tr class="Botrule Last"> <th align="center" class="Rrule">Mean<br/>(SD)</th><th align="center" class="Rrule">Median<br/>(Range)</th><th align="center" class="Rrule">Mean<br/>(SD)</th><th align="center" class="Rrule">Median<br/>(Range)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">C<span class="Sub">max</span>, maximum serum concentration; C<span class="Sub">min,</span> trough (minimum level) serum concentration; t<span class="Sub">½</span>, elimination half-life; AUC<span class="Sub">0-t</span>, area under the curve from 0 hour to last sampling time; AUC<span class="Sub">0-∞</span>, area under the curve from 0 hour to infinite time.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Calculated by log-linear trapezoidal rule.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">C<span class="Sub">max </span>(peak, mg/dL)</td><td align="center" class="Rrule">2,550<br/>(400)</td><td align="center" class="Rrule">2,340<br/>(2,290-3,010)</td><td align="center" class="Rrule">2,260<br/>(530)</td><td align="center" class="Rrule">2,340<br/>(1,040-3,460)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">C<span class="Sub">min </span>(trough, mg/dL)</td><td align="center" class="Rrule">1,230<br/>(230)</td><td align="center" class="Rrule">1,200<br/>(1,020-1,470)</td><td align="center" class="Rrule">1,000<br/>(200)</td><td align="center" class="Rrule">1,000<br/>(580-1,360)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">t<span class="Sub">½ </span>(days)</td><td align="center" class="Rrule">27.6<br/>(5.9)</td><td align="center" class="Rrule">27.8<br/>(21.6-33.4)</td><td align="center" class="Rrule">45.4<br/>(18.5)</td><td align="center" class="Rrule">37.3<br/>(20.6-96.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">0-t</span> <br/>(day × mg/dL)<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></td><td align="center" class="Rrule">32,820<br/>(6,260)</td><td align="center" class="Rrule">29,860<br/>(28,580-40,010)</td><td align="center" class="Rrule">36,390<br/>(5,950)</td><td align="center" class="Rrule">36,670<br/>(19,680-44,340)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">0-∞</span> <br/>(day × mg/dL)<a class="Sup" href="#footnote-7">*</a></td><td align="center" class="Rrule">79,315<br/>(20,170)</td><td align="center" class="Rrule">78,748<br/>(59,435-99,762)</td><td align="center" class="Rrule">104,627<br/>(33,581)</td><td align="center" class="Rrule">98,521<br/>(64,803-178,600)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clearance (mL/day/kg)<a class="Sup" href="#footnote-7">*</a></td><td align="center" class="Rrule">1.3<br/>(0.1)</td><td align="center" class="Rrule">1.3<br/>(1.1-1.4)</td><td align="center" class="Rrule">1.3<br/>(0.3)</td><td align="center" class="Rrule">1.3<br/>(0.9-2.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Mean residence time (days)<a class="Sup" href="#footnote-7">*</a></td><td align="center" class="Rrule">38.6<br/>(8.1)</td><td align="center" class="Rrule">39.5<br/>(30.1-46.2)</td><td align="center" class="Rrule">65.2<br/>(24.7)</td><td align="center" class="Rrule">59.0<br/>(33.2-129.6)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Volume of distribution at steady state (mL/kg)<a class="Sup" href="#footnote-7">*</a></td><td align="center" class="Rrule">50<br/>(13)</td><td align="center" class="Rrule">44<br/>(40-65)</td><td align="center" class="Rrule">84<br/>(35)</td><td align="center" class="Rrule">87<br/>(40-207)</td> </tr> </tbody> </table></div>

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

Treatment of Chronic Immune Thrombocytopenic Purpura

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

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy

Trough concentrations:

In both the PRIMA and PATH studies, on Day 1, subjects received an induction dose (2 g/kg) given over 2 to 5 days, followed by maintenance doses of 1 g/kg every 3 weeks.

In the PRIMA study, from Day 1 (reference) to Day 2, the mean serum IgG trough concentration increased from 12.6 ± 3.8 g/L to 24.4 ± 7.0 g/L. At Week 7, before the second maintenance treatment of (1 g/kg) given over 1 or 2 days every 3 weeks, the mean IgG trough concentration was 17.5 ± 3.1 g/L and remained stable from Week 7 to Week 19.

In the PATH study, from Day 1 (reference) to Day 5, the mean serum IgG trough concentration increased from 12.7 ± 3.2 g/L to 33.2 ± 6.9 g/L. At Week 7, before the second maintenance treatment of (1 g/kg) given over 1 or 2 days every 3 weeks, the mean IgG trough concentration was 17.7 ± 4.0 g/L and remained stable from Week 7 to Week 13.

Post-infusion concentrations:

In the PRIMA study, from Day 1 to Day 2, the post-infusion serum IgG concentration increased from 28.6 ± 8.5 g/L to 40.0 ± 11.5 g/L. At Week 7 (after the second maintenance treatment), the post-infusion IgG concentration was 32.3 ± 8.0 g/L and remained stable from Week 7 to Week 19.

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 8. PI Study – Summary of Efficacy Results in Subjects</span> </caption> <col align="left" valign="top" width="60%"/> <col align="center" valign="top" width="40%"/> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Defined as pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Upper 1-sided 99% confidence interval: 0.203.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Number of Subjects</td><td align="center" class="Rrule">80</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2"><span class="Bold">Results from Case Report Forms</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Total Number of Subject Days</td><td align="center" class="Rrule">26,198</td> </tr> <tr> <td align="left" class="Lrule Rrule">Infections</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Annual rate of confirmed aSBIs<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a></td><td align="center" class="Rrule">0.08 aSBIs/subject year<a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Annual rate of other infections</td><td align="center" class="Rrule">3.55 infections/subject year</td> </tr> <tr> <td align="left" class="Lrule Rrule">Antibiotic use</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Number of subjects (%)</td><td align="center" class="Rrule">64 (80%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Annual rate</td><td align="center" class="Rrule">87.4 days/subject year</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2"><span class="Bold">Results from Subject Diaries </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Total Number of Diary Days</td><td align="center" class="Rrule">24,059</td> </tr> <tr> <td align="left" class="Lrule Rrule">Out of work/school/day care or unable to perform normal activities due to illness</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Number of days (%)</td><td align="center" class="Rrule">570 (2.37%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Annual rate</td><td align="center" class="Rrule">8.65 days/subject year</td> </tr> <tr> <td align="left" class="Lrule Rrule">Hospitalization</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Number of days (%)</td><td align="center" class="Rrule">166 (0.69%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Annual rate</td><td align="center" class="Rrule">2.52 days/subject year</td> </tr> </tbody> </table></div>

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.

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.

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.

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Storage and Handling

Inform patients of the early signs of hypersensitivity reactions to PRIVIGEN (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis), and advise them to notify their physician if they experience any of these symptoms [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Inform patients of the early signs of hypersensitivity reactions to PRIVIGEN (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis), and advise them to notify their physician if they experience any of these symptoms [see Warnings and Precautions (5.1)]." }

Inform patients to immediately report the following signs and symptoms to their physician:

{ "type": "p", "children": [], "text": "Inform patients to immediately report the following signs and symptoms to their physician:" }

{ "type": "ul", "children": [ "Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath, which may suggest kidney problems [see Warnings and Precautions (5.2)].", "Instruct patients to immediately report symptoms of thrombosis. These symptoms may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body [see Warnings and Precautions (5.3)].", "Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting, which may suggest aseptic meningitis syndrome [see Warnings and Precautions (5.5)].", "Fatigue, increased heart rate, yellowing of skin or eyes, and dark-colored urine, which may suggest hemolysis [see Warnings and Precautions (5.6)].", "Severe breathing problems, lightheadedness, drops in blood pressure, and fever, which may suggest TRALI (a condition typically occurring within 1 to 6 hours following transfusion) [see Warnings and Precautions (5.8)]." ], "text": "" }

Inform patients that PRIVIGEN is made from human blood and may contain infectious agents that can cause disease (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD] agent and, theoretically the CJD agent). Explain that the risk that PRIVIGEN may transmit an infectious agent has been reduced by screening the plasma donors, by testing donated plasma for certain virus infections, and by inactivating or removing certain viruses during manufacturing, and counsel patients to report any symptoms that concern them [see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "Inform patients that PRIVIGEN is made from human blood and may contain infectious agents that can cause disease (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD] agent and, theoretically the CJD agent). Explain that the risk that PRIVIGEN may transmit an infectious agent has been reduced by screening the plasma donors, by testing donated plasma for certain virus infections, and by inactivating or removing certain viruses during manufacturing, and counsel patients to report any symptoms that concern them [see Warnings and Precautions (5.10)]." }

Inform patients that administration of IgG may interfere with the response to live virus vaccines (eg, measles, mumps, rubella, and varicella), and instruct them to notify their immunizing physician of recent therapy with PRIVIGEN [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Inform patients that administration of IgG may interfere with the response to live virus vaccines (eg, measles, mumps, rubella, and varicella), and instruct them to notify their immunizing physician of recent therapy with PRIVIGEN [see Warnings and Precautions (5.11)]." }

Manufactured by: CSL Behring AG Bern, SwitzerlandUS License No. 1766

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Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

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NDC 44206-436-055 g

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Immune GlobulinIntravenous (Human),10% Liquid50 mL

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privigen®

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10% Liquid PreparationSingle-dose vial

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Rx only

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NDC 44206-437-1010 g

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Immune GlobulinIntravenous (Human),10% Liquid100 mL

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privigen®

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NDC 44206-438-2020 g

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Immune GlobulinIntravenous (Human),10% Liquid200 mL

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privigen®

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NDC 44206-439-4040 g

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Immune GlobulinIntravenous (Human),10% Liquid400 mL

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GAMMAPLEX 10% is an Immune Globulin Intravenous (Human), 10% Liquid indicated for replacement therapy in primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older. This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

GAMMAPLEX 10% is indicated for the treatment of chronic immune thrombocytopenic purpura (ITP) in adults to raise platelet counts.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: Recommended Dosage and Administration for GAMMAPLEX 10%</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Indication</th><th align="left" class="Rrule">Dose</th><th align="left" class="Rrule">Initial infusion rate</th><th align="left" class="Rrule">Maintenance infusion rate (if tolerated)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">PI</td><td align="left" class="Rrule">300-800 mg/kg (3-8 mL/kg) every 3-4 weeks</td><td align="left" class="Rrule">0.5 mg/kg/min (0.005 mL/kg/min) for 15 minutes</td><td align="left" class="Rrule">Increase gradually every 15 minutes to 8 mg/kg/min (0.08 mL/kg/min)</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">ITP</td><td align="left" class="Rrule">1 g/kg (10 mL/kg) for 2 consecutive days</td><td align="left" class="Rrule">0.5 mg/kg/min (0.005 mL/kg/min) for 15 minutes</td><td align="left" class="Rrule">Increase gradually every 15 minutes to 8 mg/kg/min (0.08 mL/kg/min)</td> </tr> </tbody> </table></div>

Treatment of Primary Humoral Immunodeficiency

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 GAMMAPLEX 10% for patients with PI is 300 to 800 mg/kg (3 to 8 mL/kg), administered every 3 to 4 weeks. If a patient has been exposed to measles, it may be prudent to administer an extra dose of Immune Globulin Intravenous as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks. If a patient is at risk of future measles exposure and receives a dose of less than 530 mg/kg every 3-4 weeks, the dose should be increased to at least 530 mg/kg. This should provide a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion. Adjust the dosage over time to achieve the desired serum trough levels and clinical response. 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.

Treatment of Chronic Immune Thrombocytopenic Purpura

The recommended dose of GAMMAPLEX 10% for patients with ITP is 1 g/kg (10 mL/kg) on 2 consecutive days, providing a total dose of 2 g/kg. Carefully consider the relative risks and benefits before prescribing the high dose regimen (i.e. 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)]. Adequate data on the platelet response to the low dose regimen (e.g. 400 mg/kg per day for 5 consecutive days) are not available for GAMMAPLEX 10%.

GAMMAPLEX 10% is a liquid solution containing 10% IgG (100 mg/mL).

{ "type": "p", "children": [], "text": "GAMMAPLEX 10% is a liquid solution containing 10% IgG (100 mg/mL)." }

{ "type": "ul", "children": [ "GAMMAPLEX 10% is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin", "GAMMAPLEX 10% is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity" ], "text": "" }

Acute renal dysfunction/failure, osmotic nephropathy, and death1 may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering GAMMAPLEX 10%. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency, predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age >65 years), administer GAMMAPLEX 10% at the minimum infusion rate practicable [see Dosage and Administration (2.3)].

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of GAMMAPLEX 10% and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing GAMMAPLEX 10%.

Thrombosis may occur following treatment with immune globulin products, including GAMMAPLEX 10%2. 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 GAMMAPLEX 10% 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 (2.3), Patient Counseling Information (17)].

Severe hypersensitivity reactions may occur [see Contraindications (4)]. In case of hypersensitivity, discontinue GAMMAPLEX 10% infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

GAMMAPLEX 10% contains trace amounts of IgA (<20 micrograms/mL) [see Description (11)]. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. GAMMAPLEX 10% is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction [see Contraindications (4)].

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because 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 thrombotic events2.

AMS may occur with IGIV treatment. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae3.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting [see Patient Counseling Information (17)]. Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and 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.

GAMMAPLEX 10% 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 hemolysis4. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration; acute hemolysis, consistent with intravascular hemolysis, has been reported5. Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of IGIV.

The following risk factors may be associated with the development of hemolysis following IGIV administration: high doses (e.g. ≥2 g/kg), given either as a single administration or divided over several days, and non-O blood group6. 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 IGIV7, but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP and PI4.

Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform 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.

Noncardiogenic pulmonary edema may occur in patients following IGIV treatment8. 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 in both the product and the patient's serum.

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

Carefully consider the relative risks and benefits before prescribing the high dose regimen (for chronic ITP) in patients at increased risk of volume overload.

As GAMMAPLEX 10% is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of GAMMAPLEX 10%. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare providers to Kedrion Biopharma, Inc. at 1-855-3KDRION (1-855-353-7466)

Before prescribing GAMMAPLEX 10%, the physician should discuss the risks and benefits of its use with the patient [see Patient Counseling Information (17)].

Because 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.

Primary Humoral Immunodeficiency Study

A multicenter, open-label, randomized two-period crossover study (bioequivalence study) evaluated the PK, safety and tolerability of GAMMAPLEX 10% and GAMMAPLEX 5% in 33 adults aged 17 to 55 years with PI. Twenty one (63.6%) subjects were female and 12 (36.4%) were male; 33 (100%) were White, of which 1 (3.0%) was Hispanic or Latino. The safety analysis included all 33 subjects for GAMMAPLEX 5% and 32 subjects for GAMMAPLEX 10%. One subject withdrew consent during the first infusion of GAMMAPLEX 5%, citing inconvenience of the study visits. Thirty two subjects received at least five infusions of each product either on a 28-day or 21-day cycle. The mean doses per infusion for GAMMAPLEX 10% were 491.7 mg/kg and 499 mg/kg respectively, and were similar for GAMMAPLEX 5% [see Clinical Studies (14.1)]. No subjects were on regular systemic corticosteroids at entry to, or during the study. Twelve (36.4%) adult subjects received short courses of corticosteroids, from a single dose to a maximum of 6 days duration, for various clinical conditions. No subjects received corticosteroids as premedications for GAMMAPLEX infusions. The use of local anesthetics, antipyretics, antihistamines, analgesics, and antiemetics before infusion was allowed; three (9.1%) adult subjects received a total of 5 courses of such premedication.

While on GAMMAPLEX 10%, 10 of the adults (31.3%) had an adverse reaction (AR) with a similar proportion (12; 36.4%) when on GAMMAPLEX 5%. Headache was the most commonly reported AR with both formulations of GAMMAPLEX. In total, 166 infusions of GAMMAPLEX 10% and 163 infusions of GAMMAPLEX 5% were given to adults during the study.

Two subjects had a positive direct antiglobulin (Coombs') test (DAT; DCT) result at some stage in the study. For one adult, the test was positive before starting in the study and it remained positive throughout, but without evidence of hemolysis. One other adult had a positive DAT one week after an infusion of GAMMAPLEX 5% but there was no evidence of hemolysis and no positive DAT results when receiving GAMMAPLEX 10%. No other adults had a positive DAT during the study.

In the same study, 15 pediatric subjects with PI, 3 years of age and older, received GAMMAPLEX 10%. All subjects were White, of which 2 (13.3%) were Hispanic or Latino. The mean doses per infusion were 552.9 mg/kg for subjects on the 28-day cycle (n=8) and 514.7 mg/kg for subjects on the 21-day cycle (n=7), overall range 343 to 745 mg/kg. Two subjects were in the 2-5 year age group, 7 were in the 6-11 year age group and 6 were in the 12-15 year age group. Fourteen subjects completed the study with at least 5 infusions of GAMMAPLEX 10% (pediatric subjects only received GAMMAPLEX 10% in this study); 82 infusions were given in total. Two pediatric subjects received IV methylprednisolone as premedication for each infusion. Local anesthetics, antipyretics, antihistamines and analgesics were allowed.

While on GAMMAPLEX 10%, 6 (40%) pediatric subjects had an AR. Headache was the most common with 3 subjects (20%) reporting a total of 4 events. All other ARs were not reported by more than a single pediatric subject. One pediatric subject had a positive direct antiglobulin (Coombs') test without evidence of hemolysis.

Table 2 lists the ARs occurring in at least 5% of all subjects (adult and pediatric combined) with PI treated with GAMMAPLEX 10% in the clinical study.

<div class="scrollingtable"><table width="55%"> <caption> <span>Table 2: Adverse Reactions (ARs<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a>) Occurring in ≥5% of Subjects with PI Receiving GAMMAPLEX 10% (Adult and Pediatric Subjects Combined)</span> </caption> <col align="left" valign="top" width="35%"/> <col align="center" valign="top" width="35%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Preferred Term</th><th align="center" class="Rrule">Subjects (%)<br/>[n=32]</th><th align="center" class="Rrule">Events</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Adverse Reactions (ARs) are defined as adverse events considered by the investigators to have been possibly, probably, or definitely related to administration of GAMMAPLEX.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">7 (14.9)</td><td align="center" class="Rrule">16</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Migraine</td><td align="center" class="Rrule">3 (6.4)</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Pyrexia</td><td align="center" class="Rrule">3 (6.4)</td><td align="center" class="Rrule">3</td> </tr> </tbody> </table></div>

Chronic Immune Thrombocytopenic Purpura Study

The safety of GAMMAPLEX 10% has not been established in patients with ITP. However, the safety profile for GAMMAPLEX 5% has been studied in subjects with ITP, and it is anticipated that the safety profile for both formulations are comparable for ITP patients. The following is a summary of the study of GAMMAPLEX 5% in chronic ITP. In a multicenter, open-label, non-randomized clinical trial, 35 subjects with chronic ITP were treated with a nominal dose of 1000 mg/kg on each of two consecutive days (total dose 2000 mg/kg). Doses of GAMMAPLEX 5% ranged from 482 to 1149 mg/kg on an infusion day. The median total dose per subject was 2035 mg/kg. Pre-medication with antihistamine or analgesic drugs was permitted if required, but corticosteroids were not permitted prior to infusion as pre-medication. Ten subjects received corticosteroids for ITP during the trial and one additional subject received corticosteroids as pre-medication in violation of the protocol. All 35 subjects received at least one infusion of clinical trial drug, and all but one subject completed the first course of treatment.

Fifteen subjects (42.9%) reported at least one AR (63 in total); the most commonly reported being headache (10 subjects, 28.6%), vomiting (6 subjects, 17.1%), pyrexia (5 subjects, 14.3%), nausea (3 subjects, 8.6%), arthralgia (2 subjects, 5.7%) and dehydration (2 subjects, 5.7%). Three subjects experienced a total of five serious ARs. Of the five serious ARs, one subject had three concurrently (vomiting, dehydration and headache) and two subjects each had one serious AR (headache). One of these latter two subjects discontinued from the clinical trial because of the severe headache. Table 3 lists the ARs in more than ≥5% of subjects. Based on a review of clinical and laboratory data, 4/35 subjects (11%) with drops in hemoglobin exceeding 2 g/dL following administration of GAMMAPLEX 5% were considered to have experienced suspected treatment-emergent hemolysis. Milder treatment-emergent hemolysis could not be excluded for an additional 7 subjects, giving a total of 11 of 35 subjects (31%) for whom hemolysis could not be excluded (not including an additional two subjects who lacked follow-up testing for hemolysis, so their hemolysis status was considered unassessable). Data for two subjects were consistent with possible intravascular hemolysis, including one subject who may also have had an element of extravascular hemolysis. Nine of the possible hemolysis cases were mild and appeared consistent with possible extravascular hemolysis.

There was no evidence of transmission of HBV, HCV, HIV and parvovirus B19 during this clinical trial.

<div class="scrollingtable"><table width="70%"> <caption> <span>Table 3: Adverse Reactions (ARs<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a>) Occurring in ≥5% of Subjects with ITP</span> </caption> <col align="left" valign="top" width="35%"/> <col align="center" valign="top" width="35%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Adverse Reactions</th><th align="center" class="Rrule">Subjects (%) [n=35]</th><th align="center" class="Rrule">Events</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Adverse Reactions (ARs) are defined as adverse events considered by the investigators to have been possibly, probably, or definitely related to administration of GAMMAPLEX.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">10 (28.6)</td><td align="center" class="Rrule">19</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">6 (17.1)</td><td align="center" class="Rrule">8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Pyrexia</td><td align="center" class="Rrule">5 (14.3)</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">3 (8.6)</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Arthralgia</td><td align="center" class="Rrule">2 (5.7)</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Dehydration</td><td align="center" class="Rrule">2 (5.7)</td><td align="center" class="Rrule">2</td> </tr> </tbody> </table></div>

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

GAMMAPLEX 10% Postmarketing Experience

The following adverse reactions have been identified and reported during the postmarketing use of GAMMAPLEX 10%:

The following adverse reactions have been identified during postmarketing use of intravenous immune globulins9:

{ "type": "ul", "children": [ "Transitory rise of the various passively transferred antibodies in the patient's blood after infusion of immunoglobulin may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g. A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs') test.", "Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella.10, 11\nInform the immunizing physician of recent therapy with GAMMAPLEX 10% so that appropriate measures may be taken [see Patient Counseling Information (17)]. \t\t\t\t\t\t\t" ], "text": "" }

Risk Summary

Animal reproduction studies have not been conducted with GAMMAPLEX 10%. It is also not known whether GAMMAPLEX 10% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMMAPLEX 10% should be given to a pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.12

Risk Summary

Use of GAMMAPLEX 10% has not been evaluated in breast-feeding mothers.

In pediatric subjects 3 years of age and older, the pharmacokinetics, dosage and safety are similar to those in adults.

Treatment of Primary Humoral Immunodeficiency

GAMMAPLEX 10% was evaluated in 13 pediatric patients with primary humoral immunodeficiency (2 between ages of 3 to 5, 6 between ages of 6 to 11, and 5 between ages of 12 to 15). No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels [see Clinical Studies (14)]. The safety and pharmacokinetics of GAMMAPLEX 10% were assessed in pediatric subjects 3 years of age and older with PI [see Clinical Studies (14)].

Treatment of Chronic Immune Thrombocytopenic Purpura

The safety and effectiveness of GAMMAPLEX 10% has not been established in pediatric patients with ITP. GAMMAPLEX 5% was evaluated in three (3) pediatric subjects with chronic ITP (two aged 6 years and one aged 12 years). This number of pediatric patients was too small for separate evaluation from the adult patients for efficacy [see Clinical Studies (14)].

Use caution when administering GAMMAPLEX 10% to patients aged 65 years and over who are judged to be at increased risk of developing renal insufficiency or thrombotic events [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]. Do not exceed recommended doses, and administer GAMMAPLEX 10% at the minimum infusion rate practicable.

No subjects over the age of 55 years were included in the clinical study of GAMMAPLEX 10%. Eight (8) patients with PI at or over the age of 65 years were included within the clinical evaluation of GAMMAPLEX 5%. The number of geriatric patients was too small for separate evaluation from the younger patients for safety or efficacy [see Clinical Studies (14)].

Overdosage may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with renal impairment.

{ "type": "p", "children": [], "text": "Overdosage may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with renal impairment." }

GAMMAPLEX 10% is a ready to use sterile solution of polyclonal human Immunoglobulin G for intravenous administration that contains glycine and polysorbate 80 as stabilizers. Specifically, GAMMAPLEX 10% contains approximately 10 g normal human immunoglobulin and 200-300 mM glycine in 100 mL of buffer solution containing: <30 mM acetate, <30 mM sodium chloride and 1-6 mg polysorbate 80. Immunoglobulin G purity is ≥98%, the pH is in the range of 4.9 to 5.3, and osmolality is not less than 240 mOsmol/kg (typically 280 mOsmol/kg). The distribution of the four IgG subclasses reflects that of normal plasma. The content of IgA is less than 20 micrograms/mL. The anti-D and anti-A/anti-B hemagglutinin content of the drug product is strictly controlled to specification.

{ "type": "p", "children": [], "text": "GAMMAPLEX 10% is a ready to use sterile solution of polyclonal human Immunoglobulin G for intravenous administration that contains glycine and polysorbate 80 as stabilizers. Specifically, GAMMAPLEX 10% contains approximately 10 g normal human immunoglobulin and 200-300 mM glycine in 100 mL of buffer solution containing: <30 mM acetate, <30 mM sodium chloride and 1-6 mg polysorbate 80. Immunoglobulin G purity is ≥98%, the pH is in the range of 4.9 to 5.3, and osmolality is not less than 240 mOsmol/kg (typically 280 mOsmol/kg). The distribution of the four IgG subclasses reflects that of normal plasma. The content of IgA is less than 20 micrograms/mL. The anti-D and anti-A/anti-B hemagglutinin content of the drug product is strictly controlled to specification." }

GAMMAPLEX 10% contains no reducing carbohydrate stabilizers (e.g. sucrose, maltose) and no preservative.

{ "type": "p", "children": [], "text": "GAMMAPLEX 10% contains no reducing carbohydrate stabilizers (e.g. sucrose, maltose) and no preservative." }

GAMMAPLEX 10% is prepared from large pools of human plasma by a combination of cold ethanol fractionation and ion exchange chromatography. Fab functions tested include antigen binding activity, and Fc functions tested include complement activation and rubella antibody-mediated hemolysis.

{ "type": "p", "children": [], "text": "GAMMAPLEX 10% is prepared from large pools of human plasma by a combination of cold ethanol fractionation and ion exchange chromatography. Fab functions tested include antigen binding activity, and Fc functions tested include complement activation and rubella antibody-mediated hemolysis." }

GAMMAPLEX 10% is manufactured from plasma, obtained from healthy US donors, who have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma.

{ "type": "p", "children": [], "text": "GAMMAPLEX 10% is manufactured from plasma, obtained from healthy US donors, who have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma." }

All plasma donations are screened for antibody to HIV-1/2 and hepatitis C virus (HCV), and hepatitis B surface antigen (HBsAg). Additional testing of donations is carried out in plasma mini-pools (512 donations per pool) that undergo nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), HCV, hepatitis A virus (HAV) and parvovirus B19.

{ "type": "p", "children": [], "text": "All plasma donations are screened for antibody to HIV-1/2 and hepatitis C virus (HCV), and hepatitis B surface antigen (HBsAg). Additional testing of donations is carried out in plasma mini-pools (512 donations per pool) that undergo nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), HCV, hepatitis A virus (HAV) and parvovirus B19." }

Further testing is carried out on the manufacturing pools for HBsAg, and antibody to HIV-1/2; HCV and parvovirus B19 are also tested by NAT, with the limit for B19 set to not exceed 104 IU B19 DNA per mL plasma.

{ "type": "p", "children": [], "text": "Further testing is carried out on the manufacturing pools for HBsAg, and antibody to HIV-1/2; HCV and parvovirus B19 are also tested by NAT, with the limit for B19 set to not exceed 104 IU B19 DNA per mL plasma." }

There are three processing steps specifically designed to remove or inactivate viruses:

{ "type": "p", "children": [], "text": "There are three processing steps specifically designed to remove or inactivate viruses:" }

1) Solvent/Detergent treatment is targeted to enveloped viruses;

{ "type": "p", "children": [], "text": "1) Solvent/Detergent treatment is targeted to enveloped viruses;" }

2) A virus filtration step designed to remove small viruses including non-enveloped viruses, on a size exclusion basis; and

{ "type": "p", "children": [], "text": "2) A virus filtration step designed to remove small viruses including non-enveloped viruses, on a size exclusion basis; and" }

3) The terminal low pH incubation step is identified as contributing to the overall viral clearance capacity for enveloped and non-enveloped viruses.

{ "type": "p", "children": [], "text": "3) The terminal low pH incubation step is identified as contributing to the overall viral clearance capacity for enveloped and non-enveloped viruses." }

The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other.

{ "type": "p", "children": [], "text": "The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other." }

In addition, each step was validated to provide robust virus reduction. Table 5 presents the contribution of each process step to virus reduction and the overall process reduction.

{ "type": "p", "children": [], "text": "In addition, each step was validated to provide robust virus reduction. Table 5 presents the contribution of each process step to virus reduction and the overall process reduction." }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5: Viral Reduction by Process Step</span> </caption> <col align="left" valign="middle" width="10%"/> <col align="left" valign="middle" width="20%"/> <col align="center" valign="middle" width="10%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="10%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="15%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2">Virus</th><th align="left" class="Rrule" rowspan="2">Type<br/>(Envelope/Genome)</th><th align="left" class="Rrule" rowspan="2">Size<br/>(nm)</th><th align="center" class="Rrule" colspan="3">Process Log<span class="Sub">10</span> Reduction of Virus (LRV) over manufacturing step</th><th align="center" class="Rrule"></th> </tr> <tr class="Last"> <th align="left" class="Rrule">Solvent Detergent</th><th align="left" class="Rrule">20 nm filtration</th><th align="left" class="Rrule">Terminal low pH/elevated temperature incubation</th><th align="left" class="Rrule">Total LRV</th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="7">HIV: Human immunodeficiency virus</td> </tr> <tr> <td align="left" colspan="7">SIN: Sindbis virus, model for hepatitis C virus (HCV)</td> </tr> <tr> <td align="left" colspan="7">WNV: West Nile Virus</td> </tr> <tr> <td align="left" colspan="7">BVDV: Bovine viral diarrhea virus, model for HCV</td> </tr> <tr> <td align="left" colspan="7">IBR: Infectious bovine rhinotracheitis, bovine herpes virus model for enveloped DNA viruses including hepatitis B</td> </tr> <tr> <td align="left" colspan="7">HAV: Hepatitis A virus</td> </tr> <tr> <td align="left" colspan="7">EMC: Encephalomyocarditis, model for HAV</td> </tr> <tr> <td align="left" colspan="7">CPV: Canine parvovirus, model for human parvovirus B19</td> </tr> <tr> <td align="left" colspan="7">NA: Not applicable, solvent detergent step is limited to the inactivation of enveloped viruses</td> </tr> <tr> <td align="left" colspan="7">I: Inactivation by the product intermediate precluded the accurate estimation of the removal of these viruses by the filtration step</td> </tr> <tr> <td align="left" colspan="7">NT: Not tested</td> </tr> <tr class="Last"> <td align="left" colspan="7">B19: Viral clearance of human parvovirus B19 was investigated experimentally at the 20 nm filtration step. The estimated Log reduction Factor obtained was 6.0</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">HIV</td><td align="left" class="Rrule">Env/RNA</td><td align="center" class="Rrule">80-100</td><td align="center" class="Rrule">&gt;6.8</td><td align="center" class="Rrule">I</td><td align="center" class="Rrule">&gt;6.0</td><td align="center" class="Rrule">&gt;12.8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">SIN</td><td align="left" class="Rrule">Env/RNA</td><td align="center" class="Rrule">70</td><td align="center" class="Rrule">&gt;6.7</td><td align="center" class="Rrule">6.2</td><td align="center" class="Rrule">&gt;6.8</td><td align="center" class="Rrule">&gt;19.7</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">WNV</td><td align="left" class="Rrule">Env/RNA</td><td align="center" class="Rrule">50</td><td align="center" class="Rrule">&gt;6.4</td><td align="center" class="Rrule">I</td><td align="center" class="Rrule">NT</td><td align="center" class="Rrule">&gt;6.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">BVDV</td><td align="left" class="Rrule">Env/RNA</td><td align="center" class="Rrule">40-60</td><td align="center" class="Rrule">&gt;5.6</td><td align="center" class="Rrule">I</td><td align="center" class="Rrule">&gt;4.6</td><td align="center" class="Rrule">&gt;10.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">IBR</td><td align="left" class="Rrule">Env/DNA</td><td align="center" class="Rrule">200</td><td align="center" class="Rrule">&gt;5.0</td><td align="center" class="Rrule">I</td><td align="center" class="Rrule">&gt;5.4</td><td align="center" class="Rrule">&gt;10.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">HAV</td><td align="left" class="Rrule">Non-Env/RNA</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">NA</td><td align="center" class="Rrule">&gt;4.8</td><td align="center" class="Rrule">1.3</td><td align="center" class="Rrule">&gt;6.1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">EMC</td><td align="left" class="Rrule">Non-Env/RNA</td><td align="center" class="Rrule">30</td><td align="center" class="Rrule">NA</td><td align="center" class="Rrule">&gt;4.8</td><td align="center" class="Rrule">3.4</td><td align="center" class="Rrule">&gt;8.2</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">CPV</td><td align="left" class="Rrule">Non-Env/RNA</td><td align="center" class="Rrule">18-24</td><td align="center" class="Rrule">NA</td><td align="center" class="Rrule">3.2</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">4.2</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 5: Viral Reduction by Process Step</span>\n</caption>\n<col align=\"left\" valign=\"middle\" width=\"10%\"/>\n<col align=\"left\" valign=\"middle\" width=\"20%\"/>\n<col align=\"center\" valign=\"middle\" width=\"10%\"/>\n<col align=\"center\" valign=\"middle\" width=\"15%\"/>\n<col align=\"center\" valign=\"middle\" width=\"10%\"/>\n<col align=\"center\" valign=\"middle\" width=\"20%\"/>\n<col align=\"center\" valign=\"middle\" width=\"15%\"/>\n<thead>\n<tr class=\"Botrule First\">\n<th align=\"left\" class=\"Lrule Rrule\" rowspan=\"2\">Virus</th><th align=\"left\" class=\"Rrule\" rowspan=\"2\">Type<br/>(Envelope/Genome)</th><th align=\"left\" class=\"Rrule\" rowspan=\"2\">Size<br/>(nm)</th><th align=\"center\" class=\"Rrule\" colspan=\"3\">Process Log<span class=\"Sub\">10</span> Reduction of Virus (LRV) over manufacturing step</th><th align=\"center\" class=\"Rrule\"></th>\n</tr>\n<tr class=\"Last\">\n<th align=\"left\" class=\"Rrule\">Solvent Detergent</th><th align=\"left\" class=\"Rrule\">20 nm filtration</th><th align=\"left\" class=\"Rrule\">Terminal low pH/elevated temperature incubation</th><th align=\"left\" class=\"Rrule\">Total LRV</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First\">\n<td align=\"left\" colspan=\"7\">HIV: Human immunodeficiency virus</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">SIN: Sindbis virus, model for hepatitis C virus (HCV)</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">WNV: West Nile Virus</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">BVDV: Bovine viral diarrhea virus, model for HCV</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">IBR: Infectious bovine rhinotracheitis, bovine herpes virus model for enveloped DNA viruses including hepatitis B</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">HAV: Hepatitis A virus</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">EMC: Encephalomyocarditis, model for HAV</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">CPV: Canine parvovirus, model for human parvovirus B19</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">NA: Not applicable, solvent detergent step is limited to the inactivation of enveloped viruses</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">I: Inactivation by the product intermediate precluded the accurate estimation of the removal of these viruses by the filtration step</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"7\">NT: Not tested</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" colspan=\"7\">B19: Viral clearance of human parvovirus B19 was investigated experimentally at the 20 nm filtration step. The estimated Log reduction Factor obtained was 6.0</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\">HIV</td><td align=\"left\" class=\"Rrule\">Env/RNA</td><td align=\"center\" class=\"Rrule\">80-100</td><td align=\"center\" class=\"Rrule\">&gt;6.8</td><td align=\"center\" class=\"Rrule\">I</td><td align=\"center\" class=\"Rrule\">&gt;6.0</td><td align=\"center\" class=\"Rrule\">&gt;12.8</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">SIN</td><td align=\"left\" class=\"Rrule\">Env/RNA</td><td align=\"center\" class=\"Rrule\">70</td><td align=\"center\" class=\"Rrule\">&gt;6.7</td><td align=\"center\" class=\"Rrule\">6.2</td><td align=\"center\" class=\"Rrule\">&gt;6.8</td><td align=\"center\" class=\"Rrule\">&gt;19.7</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">WNV</td><td align=\"left\" class=\"Rrule\">Env/RNA</td><td align=\"center\" class=\"Rrule\">50</td><td align=\"center\" class=\"Rrule\">&gt;6.4</td><td align=\"center\" class=\"Rrule\">I</td><td align=\"center\" class=\"Rrule\">NT</td><td align=\"center\" class=\"Rrule\">&gt;6.4</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">BVDV</td><td align=\"left\" class=\"Rrule\">Env/RNA</td><td align=\"center\" class=\"Rrule\">40-60</td><td align=\"center\" class=\"Rrule\">&gt;5.6</td><td align=\"center\" class=\"Rrule\">I</td><td align=\"center\" class=\"Rrule\">&gt;4.6</td><td align=\"center\" class=\"Rrule\">&gt;10.2</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">IBR</td><td align=\"left\" class=\"Rrule\">Env/DNA</td><td align=\"center\" class=\"Rrule\">200</td><td align=\"center\" class=\"Rrule\">&gt;5.0</td><td align=\"center\" class=\"Rrule\">I</td><td align=\"center\" class=\"Rrule\">&gt;5.4</td><td align=\"center\" class=\"Rrule\">&gt;10.4</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">HAV</td><td align=\"left\" class=\"Rrule\">Non-Env/RNA</td><td align=\"center\" class=\"Rrule\">30</td><td align=\"center\" class=\"Rrule\">NA</td><td align=\"center\" class=\"Rrule\">&gt;4.8</td><td align=\"center\" class=\"Rrule\">1.3</td><td align=\"center\" class=\"Rrule\">&gt;6.1</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">EMC</td><td align=\"left\" class=\"Rrule\">Non-Env/RNA</td><td align=\"center\" class=\"Rrule\">30</td><td align=\"center\" class=\"Rrule\">NA</td><td align=\"center\" class=\"Rrule\">&gt;4.8</td><td align=\"center\" class=\"Rrule\">3.4</td><td align=\"center\" class=\"Rrule\">&gt;8.2</td>\n</tr>\n<tr class=\"Botrule Last\">\n<td align=\"left\" class=\"Lrule Rrule\">CPV</td><td align=\"left\" class=\"Rrule\">Non-Env/RNA</td><td align=\"center\" class=\"Rrule\">18-24</td><td align=\"center\" class=\"Rrule\">NA</td><td align=\"center\" class=\"Rrule\">3.2</td><td align=\"center\" class=\"Rrule\">1.0</td><td align=\"center\" class=\"Rrule\">4.2</td>\n</tr>\n</tbody>\n</table></div>" }

Treatment of Primary Humoral Immunodeficiency

GAMMAPLEX 10% is a replacement therapy for primary humoral immunodeficiency. GAMMAPLEX 10% acts through a broad spectrum of opsonic and neutralizing IgG antibodies against pathogens and their toxins involving antigen binding and effector functions.13,14 However, the mechanism of action in PI has not been fully elucidated.

Treatment of Chronic Immune Thrombocytopenic Purpura

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

Treatment of Primary Humoral Immunodeficiency

In the cross-over clinical trial assessing bioequivalence, safety and tolerability between GAMMAPLEX 10% and GAMMAPLEX 5% in PI, the pharmacokinetics (PK) of these products was assessed after administration to 30 adult subjects on 28-day (n = 16) or 21-day (n = 14) infusion cycles. Blood samples for PK analysis were obtained after at least five infusions.

The dose of GAMMAPLEX 10% ranged from 361-691 mg/kg for subjects on a 28-day cycle and from 254-794 mg/kg for those on a 21-day cycle. The doses of GAMMAPLEX 5% were similar to those of GAMMAPLEX 10% in this cross-over study. Table 6 compares the other PK variables parameters for GAMMAPLEX 10% and GAMMAPLEX 5% for both the 21-day and 28-day cycle regimens.

GAMMAPLEX 10% was pharmacokinetically equivalent to GAMMAPLEX 5% in adults.

PK outcomes after administration of GAMMAPLEX 10% were assessed in 13 pediatric subjects. Six subjects were on a 28-day regimen and 7 were on a 21-day regimen; doses for the PK assessments ranged from 400 to 745 mg/kg and 355 to 702 mg/kg respectively. Results are shown in Table 6 together with those from the adults in the study.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6: Pharmacokinetic Parameters of GAMMAPLEX 10% compared with GAMMAPLEX 5% in Adults, and GAMMAPLEX 10% in Pediatric Subjects (corrected for baseline concentration)</span> </caption> <col align="left" valign="middle" width="14%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="14%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule">Indication:</th><th align="center" class="Rrule" colspan="4">ADULTS</th><th align="center" class="Rrule" colspan="3">PEDIATRICS</th> </tr> <tr class="Botrule"> <th align="left" class="Lrule Rrule" rowspan="3" valign="top">Parameter (unit)</th><th align="center" class="Rrule" colspan="2">GAMMAPLEX 10%</th><th align="center" class="Rrule" colspan="2">GAMMAPLEX 5%</th><th align="center" class="Rrule" colspan="3">GAMMAPLEX 10%</th> </tr> <tr class="Botrule"> <th align="center" class="Lrule Rrule">28-day Dosing Interval<br/>(n=16)</th><th align="center" class="Rrule">21-day Dosing Interval<br/>(n=14)</th><th align="center" class="Rrule">28-day Dosing Interval<br/>(n=16)</th><th align="center" class="Rrule">21-day Dosing Interval<br/>(n=14)</th><th align="center" class="Rrule">2-5 years<br/>(n=2)</th><th align="center" class="Rrule">6-11 years<br/>(n=6)</th><th align="center" class="Rrule">12-15 years<br/>(n=5)</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Mean<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a> <br/>(CV%)</th><th align="center" class="Rrule">Mean<a class="Sup" href="#footnote-3">*</a> <br/>(CV%)</th><th align="center" class="Rrule">Mean<a class="Sup" href="#footnote-3">*</a> <br/>(CV%)</th><th align="center" class="Rrule">Mean<a class="Sup" href="#footnote-3">*</a> <br/>(CV%)</th><th align="center" class="Rrule">Mean<a class="Sup" href="#footnote-3">*</a> <br/>(CV%)</th><th align="center" class="Rrule">Mean<a class="Sup" href="#footnote-3">*</a> <br/>(CV%)</th><th align="center" class="Rrule">Mean<a class="Sup" href="#footnote-3">*</a> <br/>(CV%)</th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="8">C<span class="Sub">max</span> = maximum observed concentration</td> </tr> <tr class="Last"> <td align="left" colspan="8">T<span class="Sub">max</span> = time at which C<span class="Sub">max</span> was apparent</td> </tr> <tr> <td align="left" colspan="8"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Geometric mean</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Median and range are presented for t<span class="Sub">max</span> </dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>AUC<span class="Sub">0-tau</span> = area under the concentration versus time curve within a dosing interval, tau = dosing interval</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">C<span class="Sub">max</span> (mg/dL)</td><td align="center" class="Rrule">1090<br/>(20.5)</td><td align="center" class="Rrule">1150<br/>(27.6)</td><td align="center" class="Rrule">1020<br/>(23.6)</td><td align="center" class="Rrule">1090<br/>(21.6)</td><td align="center" class="Rrule">1120<br/>(33.5)</td><td align="center" class="Rrule">907<br/>(37.9)</td><td align="center" class="Rrule">977<br/>(34.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">T<span class="Sub">max</span> (hr)<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></td><td align="center" class="Rrule">2.87<br/>(1.6-31)</td><td align="center" class="Rrule">2.70<br/>(1.8-7.8)</td><td align="center" class="Rrule">3.73<br/>(2.1-9.0)</td><td align="center" class="Rrule">3.68<br/>(2.2-5.7)</td><td align="center" class="Rrule">3.24<br/>(2.8-3.7)</td><td align="center" class="Rrule">2.76<br/>(2.0-5.1)</td><td align="center" class="Rrule">2.33<br/>(1.7-4.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a> (days*mg/dL)</td><td align="center" class="Rrule">7830<br/>(30.2)</td><td align="center" class="Rrule">6980<br/>(33.0)</td><td align="center" class="Rrule">7230<br/>(35.3)</td><td align="center" class="Rrule">6380<br/>(32.8)</td><td align="center" class="Rrule">7620<br/>(70.0)</td><td align="center" class="Rrule">6160<br/>(71.1)</td><td align="center" class="Rrule">6650<br/>(31.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Half-Life (hr)</td><td align="center" class="Rrule">123<br/>(32.3)</td><td align="center" class="Rrule">118<br/>(39.3)</td><td align="center" class="Rrule">132<br/>(45.8)</td><td align="center" class="Rrule">119<br/>(48.7)</td><td align="center" class="Rrule">167<br/>(9.14)</td><td align="center" class="Rrule">111<br/>(37.3)</td><td align="center" class="Rrule">144<br/>(16.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Clearance (dL/day/kg)</td><td align="center" class="Rrule">0.0635<br/>(24.0)</td><td align="center" class="Rrule">0.0674<br/>(21.9)</td><td align="center" class="Rrule">0.0684<br/>(37.6)</td><td align="center" class="Rrule">0.0743<br/>(38.6)</td><td align="center" class="Rrule">0.0716<br/>(19.3)</td><td align="center" class="Rrule">0.0845<br/>(39.7)</td><td align="center" class="Rrule">0.0787<br/>(19.3)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Volume of Distribution (dL/kg)</td><td align="center" class="Rrule">0.498<br/>(27.4)</td><td align="center" class="Rrule">0.528<br/>(50.3)</td><td align="center" class="Rrule">0.569<br/>(38.4)</td><td align="center" class="Rrule">0.536<br/>(32.6)</td><td align="center" class="Rrule">0.688<br/>(7.45)</td><td align="center" class="Rrule">0.571<br/>(28.8)</td><td align="center" class="Rrule">0.711<br/>(26.4)</td> </tr> </tbody> </table></div>

Pharmacokinetics, Safety and Tolerability study

A cross-over clinical trial assessed bioequivalence, safety and tolerability between GAMMAPLEX 10% and GAMMAPLEX 5% in PI after administration to 33 adult subjects on 28-day (n = 19) or 21-day (n = 14) infusion cycles, of whom 30 (90.9%) completed the PK component [see Pharmacokinetics (12.3)]. Thirty-two subjects completed the study of whom 12 were male and 20 were female. All adults were aged between 17 and 55 years. The mean doses of GAMMAPLEX 10% were 491.7 mg/kg for those on a 28-day cycle and 499.0 mg/kg for those on a 21-day cycle. For GAMMAPLEX 5%, the doses were similar: 473.5 and 502.1 mg/kg respectively. The maximum infusion rate was 0.08 mL/kg/min for each product and this rate was achieved by all adult subjects. In this study, PK bioequivalence was used as a surrogate marker for efficacy. Nevertheless, an ad hoc comparison was made between the products for the number of subjects reporting an infection while on each product. Comparing the number of subjects developing infections of any severity or type while on GAMMAPLEX 10% (22/32) with the period on GAMMAPLEX 5% (17/32) using the McNemar test provided an exact p value of 0.180, confirming the relevance of PK as a surrogate marker. No subject had an acute serious bacterial infection (SABI) during the study.

The pediatric population in the study comprised 15 subjects who received only GAMMAPLEX 10%, of whom 8 were on a 28-day cycle and 7 on a 21-day cycle. Of these, 13 completed the PK component (6 on a 28-day cycle and 7 on a 21-day cycle) [see Pharmacokinetics (12.3)]. There were two subjects in the 2-5 year age group, 7 in the 6-11 year age group and 6 in the 12-15 year age group. The mean dose across all infusions was 535.1 mg/kg. All pediatric subjects tolerated an infusion rate of 0.04 mL/kg/min and 8 subjects (53.3%) tolerated an infusion rate of 0.08 mL/kg/min for all infusions.

Overall, in the population receiving GAMMAPLEX 10%, the PK results (the surrogate for efficacy in this study) and the types and frequencies of adverse reactions were similar for the adult and pediatric populations.

The crossover bioequivalence study described in 14.1, above, did not include subjects with ITP. The results of the bioequivalence study comparing GAMMAPLEX 10% to GAMMAPLEX 5% in subjects with PI are supportive of the potential effectiveness of GAMMAPLEX 10% in the treatment of chronic ITP.

In a Phase 3 multicenter, open-label clinical trial to evaluate the efficacy and safety of GAMMAPLEX 5% in chronic ITP, of the 35 subjects enrolled from various ethnic groups, 9 were male and 26 were female. The age range was between 6 and 69 years. Subjects received intravenous infusions on two consecutive days (1 course) and then observed for a further 30 days. Individuals were given the option of a further two courses of treatment (if required), where only safety variables were assessed. Doses of GAMMAPLEX 5% ranged from 482 to 1149 mg/kg on Day 1 and Day 2. The median total dose per subject was 2035 mg/kg. Subjects received a total of 94 infusions (48 treatment courses).

All 35 subjects received at least one infusion of clinical trial drug, and all but one subject completed the first course of treatment.

The primary analysis was based on the platelet count achieved by Day 9 after the first course of treatment with GAMMAPLEX 5%, response being defined as a platelet count of 50 × 109/L or greater. Response to treatment on or before Day 9 was achieved by 29 of 35 subjects (82.9%), and the one-sided 97.5% lower confidence limit of the response rate was 66.4%, which met the a priori success criterion that required it to be greater than 60%.

Efficacy analyses included the duration of response, and changes in the incidences of bleeding or hemorrhage. At Day 32, the median (+ SD) platelet count (24 + [90] × 109/L) was still higher than the baseline value, and 11 of 33 subjects (33.3%) continued to show response of platelet counts of 50 × 109/L or greater. The median duration of platelet count response for the responders was 10 days.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7: Median Platelet Count (Standard deviation) and Number and Percent of Subjects with a Platelet Count &gt; 50 × 10<span class="Sup">9</span>/L during the clinical trial.</span> </caption> <col align="left" valign="middle" width="28%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="9%"/> <col align="center" valign="middle" width="9%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Number of days in clinical trial</th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 2</th><th align="center" class="Rrule">Day 3</th><th align="center" class="Rrule">Day 5</th><th align="center" class="Rrule">Day 9</th><th align="center" class="Rrule">Day 14</th><th align="center" class="Rrule">Day 21</th><th align="center" class="Rrule">Day 32</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="9" valign="top">GAMMAPLEX 5% infusions given on Days 1 and 2.</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Median Platelet count (× 10<span class="Sup">9</span>/L) (Std Dev)</td><td align="center" class="Rrule">12.0<br/>(11.4)</td><td align="center" class="Rrule">50.0<br/>(36.4)</td><td align="center" class="Rrule">93.0<br/>(97.3)</td><td align="center" class="Rrule">121.5<br/>(151.9)</td><td align="center" class="Rrule">100.5<br/>(201.3)</td><td align="center" class="Rrule">15.5<br/>(113.0)</td><td align="center" class="Rrule">30.0<br/>(80.0)</td><td align="center" class="Rrule">24.0<br/>(89.9)</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Number (n/N) and percent of subjects with a platelet count ≥ 50 ×10<span class="Sup">9</span>/L</td><td align="center" class="Rrule">0/35<br/>(0.0%)</td><td align="center" class="Rrule">18/35<br/>(51.4%)</td><td align="center" class="Rrule">22/32<br/>(68.8%)</td><td align="center" class="Rrule">25/32<br/>(78.1%)</td><td align="center" class="Rrule">22/32<br/>(68.8%)</td><td align="center" class="Rrule">11/30<br/>(36.7%)</td><td align="center" class="Rrule">10/29<br/>(34.5%)</td><td align="center" class="Rrule">11/33<br/>(33.3%)</td> </tr> </tbody> </table></div>

There was an increase in platelet counts for the majority of subjects, and an overall reduction in the manifestations of bleeding after treatment compared to baseline (Day 1). Petechiae, hematomas and gastrointestinal, pulmonary and genitourinary bleeds were all either reduced or absent by Day 32.

There were no thromboembolic episodes reported in the clinical trial; and vital signs, biochemical, hematological and virology tests did not reveal any unexpected pathophysiology or toxicity.

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When stored between 2°C [35.6°F] and 25°C [77°F]), GAMMAPLEX 10% has a shelf life of 36 months.

Keep GAMMAPLEX 10% in its original carton to protect it from light.

Do not shake.

Do not use GAMMAPLEX 10% beyond the expiration date on the product label.

Do not freeze.

Inform patients to immediately report the following signs and symptoms to their healthcare professional:

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Inform patients that GAMMAPLEX 10% is made from human plasma and may contain infectious agents that can cause disease. While the risk that GAMMAPLEX 10% can transmit an infection has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing, patients should report any symptoms that concern them [see Warnings and Precautions (5.9)].

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Inform patients that GAMMAPLEX 10% can interfere with their immune response to live viral vaccines (e.g. measles, mumps, and rubella), and instruct patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations [see Drug Interactions (7)].

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Instruct patients to immediately report symptoms of thrombosis. These symptoms may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body.

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Manufactured by: Bio Products Laboratory Ltd.,Elstree,WD6 3BX.United Kingdom.U.S. License No. 1811

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Marketed by: Kedrion Biopharma, Inc.,Parker Plaza,400 Kelby Street,Fort Lee, NJ 07024,United States.

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NDC 64208-8235-1

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Immune Globulin Intravenous (Human)Gammaplex® 10%

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5 g

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50 mL

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solution for infusion

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Rx onlyGSCUS4L

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Marketed by: Kedrion Biopharma, Inc, 400 Kelby St.,Fort Lee, NJ 07024, United States

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Manufactured by: Bio Products Laboratory Ltd.,Elstree, Borehamwood, WD6 3BX. U.K.

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U.S. License No. 1811

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NDC: 64208-8235-5

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Immune GlobulinIntravenous (Human)Gammaplex® 10%

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5 g

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solution for infusion

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For intravenous use only

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Rx only

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1 vial

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50 mL

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Bio Products Laboratory

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NDC 64208-8235-2

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Immune Globulin Intravenous (Human)Gammaplex® 10%

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10 g

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100 mL

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solution for infusion

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Rx onlyGSAUS4L

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Marketed by: Kedrion Biopharma, Inc, 400 Kelby St.,Fort Lee, NJ 07024, United States

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Manufactured by: Bio Products Laboratory Ltd.,Elstree, Borehamwood, WD6 3BX. U.K.

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U.S. License No. 1811

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NDC: 64208-8235-6

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Immune GlobulinIntravenous (Human)Gammaplex® 10%

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10 g

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solution for infusion

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For intravenous use only

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Rx only

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1 vial

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100 mL

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Bio Products Laboratory

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NDC: 64208-8235-3

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Immune Globulin Intravenous (Human)Gammaplex® 10%

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20 g

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200 mL

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solution for infusion

{ "type": "p", "children": [], "text": "solution for infusion" }

{ "type": "ul", "children": [ "For intravenous use only", "Directions for use: Read enclosed package insert before use. Use immediately after piercing cap", "Do not freeze", "Do not use unless clear and free from deposit", "Maximum infusion rate 0.08 mL/kg per minute", "Store between 2°C and 25°C (35.6°F and 77°F) protected from light" ], "text": "" }

Rx onlyGSBUS4L

{ "type": "p", "children": [], "text": "Rx onlyGSBUS4L" }

Marketed by: Kedrion Biopharma, Inc, 400 Kelby St.,Fort Lee, NJ 07024, United States

{ "type": "p", "children": [], "text": "Marketed by: Kedrion Biopharma, Inc, 400 Kelby St.,Fort Lee, NJ 07024, United States" }

Manufactured by: Bio Products Laboratory Ltd.,Elstree, Borehamwood, WD6 3BX. U.K.

{ "type": "p", "children": [], "text": "Manufactured by: Bio Products Laboratory Ltd.,Elstree, Borehamwood, WD6 3BX. U.K." }

U.S. License No. 1811

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NDC: 64208-8235-7

{ "type": "p", "children": [], "text": "NDC: 64208-8235-7" }

Immune GlobulinIntravenous (Human)Gammaplex® 10%

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20 g

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solution for infusion

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For intravenous use only

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Rx only

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1 vial

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200 mL

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Bio Products Laboratory

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