FDA label f29500ad-6843-41b0-bf88-bff859438f01

WARNING: ACUTE RENAL DYSFUNCTION and ACUTE RENAL FAILURE Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death. 1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2] ). Gammaplex does not contain sucrose. For patients at risk of renal dysfunction or failure, administer Gammaplex at the minimum infusion rate practicable (see Dosage and Administration [2.3] , Warnings and Precautions [5.2] ). WARNING: RENAL DYSFUNCTION/ ACUTE RENAL FAILURE See full prescribing information for complete boxed warning. Renal dysfunction, acute renal failure, osmotic nephropathy, and death may be associated with the administration of Immune Globulin Intravenous (Human) (IGIV) products in predisposed patients. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. Gammaplex does not contain sucrose. For patients at risk of renal dysfunction or failure, administer Gammaplex at the minimum infusion rate practicable.

5 WARNINGS AND PRECAUTIONS Weigh the potential risks and benefits of Gammaplex against those of alternative therapies in all patients for whom Gammaplex is being considered. Before prescribing Gammaplex, the physician should discuss the risks and benefits of its use with the patient. IgA-deficient patients with antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions ( 5.1 ). Monitor renal function, including blood urea nitrogen (BUN) and serum creatinine, and urine output in patients at risk of developing acute renal failure ( 5.2 ). Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy ( 5.3 ). Thrombotic events may occur. Monitor patients with known risk factors for thrombotic events; consider baseline assessment of blood viscosity for those at risk of hyperviscosity ( 5.4 ). Aseptic meningitis syndrome may occur, especially with high doses or rapid infusion ( 5.5 ). Hemolysis can develop subsequent to IGIV treatments. Monitor patients for hemolysis and hemolytic anemia ( 5.6 ). Monitor patients for pulmonary adverse reactions (transfusion-related acute lung injury [TRALI]) ( 5.7 ). Gammaplex is made from human plasma and may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease agent ( 5.8 ). Passive transfer of antibodies may confound serologic testing ( 5.10 ). 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications [4] ). In case of hypersensitivity, discontinue Gammaplex infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Gammaplex contains trace amounts of IgA (<10 μg/mL) (s ee Description [11] ). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Gammaplex is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction ( see Contraindications [4] ). 5.2 Renal Dysfunction/Failure Acute renal dysfunction/failure, osmotic nephropathy, and death 1 may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering Gammaplex. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of >65 years), administer Gammaplex 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 and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Gammaplex. 5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia 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 events. 2 5.4 Thrombotic Events Thrombotic events may occur following treatment with Gammaplex and other IGIV products. 2,3 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. 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 judged to be at risk of developing thrombotic events, administer Gammaplex at the minimum rate of infusion practicable ( see Dosage and Administration [2.3] ). 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently 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 sequelae. 4 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. 5.6 Hemolysis IGIV products can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis 5-7 . Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration 8 , and acute hemolysis, consistent with intravascular hemolysis, has been reported. Monitor patients for clinical signs and symptoms of hemolysis ( see Patient Counseling Information [17] ). If these are present after Gammaplex infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. 5.7 Transfusion-related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment 9 . 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. 5.8 Transmissible Infectious Agents Gammaplex is made from human plasma. Based on effective donor screening and product manufacturing processes ( see Description [11] ), Gammaplex carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Gammaplex. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to FFF on behalf of Bio Products Laboratory (800) 843-7477 . Before prescribing Gammaplex, the physician should discuss the risks and benefits of its use with the patient ( see Patient Counseling Information [17] ). 5.9 Monitoring: Laboratory Tests 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 BUN and serum creatinine, before the initial infusion of Gammaplex and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis, 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. If signs and/or symptoms of hemolysis are present after an infusion of Gammaplex, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient's serum. 5.10 Interference with Laboratory Tests After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient's blood 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.

6 ADVERSE REACTIONS Two serious adverse reactions, thrombosis and chest pain, were observed in a clinical study subject receiving Gammaplex. The most common adverse reactions to Gammaplex (reported in >5% of clinical trial subjects) were headache, fatigue, nausea, pyrexia, hypertension, myalgia, pain, and vomiting. The most common adverse reactions during clinical trial (reported in >5% of subjects) were headache, fatigue, nausea, pyrexia, hypertension, myalgia, pain, and vomiting (6). To report SUSPECTED ADVERSE REACTIONS, contact FFF on behalf of Bio Products Laboratory at 1-800-843-7477 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience 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. In a multicenter, open-label, non-randomized clinical study, 50 subjects with primary humoral immunodeficiency received doses of Gammaplex ranging from 279 to 799 mg/kg every 21days (mean dose 465 mg/kg) or 28 days (mean dose 458 mg/kg), for up to 12 months ( see Clinical Studies [14.1] ). Routine premedication was not allowed. Of the 703 infusions administered, 2 (4%) subjects received premedication (antipyretic, antihistamine, or antiemetic agent) prior to 2 courses of treatment, because of experience with consecutive infusion-related adverse reactions. All 50 subjects had an adverse event at some time during the study. Twenty-four subjects (48.0%) had an adverse reaction at some time during the study that was considered product-related. More subjects with the 21-day infusion cycle had at least one adverse reaction (14 of 22 subjects, 63.6%) than subjects with the 28-day infusion cycle (10 of 28 subjects, 35.7%). Of these 24 subjects who showed adverse reactions, only 3 subjects had adverse reactions that were considered definitely related to Gammaplex: headache, pyrexia, tachycardia, chest discomfort, and hypertension. The most common adverse reactions observed in this clinical trial were headache (18 subjects, 36.0%), fatigue (6 subjects, 12.0%), nausea (6 subjects, 12.0%), pyrexia (6 subjects, 12.0%), hypertension (3 subjects, 6.0%), myalgia (3 subjects, 6.0%), pain (3 subjects, 6.0%), and vomiting (3 subjects, 6.0%). Temporally associated adverse events (AEs) are those occurring during or within 72 hours after the end of an infusion, irrespective of causality . In this study, the upper bound of the 1-sided 97.5% confidence interval for the proportion of Gammaplex infusions temporally associated with one or more AEs was 24.2% (actual proportion: 21.2%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 237 (a rate of 0.34 AEs per infusion), reflecting that some subjects experienced more than one AE during the observation period. Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Gammaplex infusion or within 72 hours after the end of an infusion, irrespective of causality . Table 2: Adverse Events Occurring in >5% of Subjects with PI during a Gammaplex Infusion or within 72 Hours after the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [n=50] Infusions (%) [n=703] Headache 18 (36%) 53 (7.5%) Sinusitis 8 (16%) 9 (1.3%) Pyrexia 7 (14%) 10 (1.4%) Nausea 6 (12%) 7 (1.0%) Pain 5 (10%) 5 (0.7%) Chills 3 (6%) 5 (0.7%) Fatigue 3 (6%) 9 (1.3%) Hypertension 3 (6%) 4 (0.6%) Insomnia 3 (6%) 3 (0.4%) Nasal Congestion 3 (6%) 3 (0.4%) Upper respiratory tract infection 3 (6%) 5 (0.7%) Vomiting 3 (6%) 3 (0.4%) Of the 237 temporally associated AEs reported for the 50 subjects, the investigators judged 115 to be related to the infusion of Gammaplex. The most common temporally associated AEs judged to be related to Gammaplex infusion were headache (32% of subjects), pyrexia (8% of subjects), and nausea (8% of subjects). Five subjects (10%) experienced seven serious AEs. Two of these serious AEs were considered related to Gammaplex treatment (thrombosis and chest pain). Three other subjects withdrew from the study due to the following AEs: paresthesia, bronchospasm, and pregnancy. Forty-seven of the 50 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 47 subjects, 4 (8.5%) 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). 6.2 Postmarketing Experience 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. The following adverse reactions have been identified during post-approval use of intravenous immune globulins 10 : Infusion reactions: hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis) Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: pyrexia, rigors

<table width="80%" ID="table2"> <caption>Table 2: Adverse Events Occurring in &gt;5% of Subjects with PI during a Gammaplex Infusion or within 72 Hours after the End of an infusion, Irrespective of Causality</caption> <col width="40%" align="left" valign="middle"/> <col width="30%" align="center" valign="middle"/> <col width="30%" align="center" valign="middle"/> <thead> <tr> <th styleCode="Lrule Rrule">Adverse Event</th> <th styleCode="Rrule">Subjects (%) [n=50]</th> <th styleCode="Rrule">Infusions (%) [n=703]</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">18 (36%)</td> <td styleCode="Rrule">53 (7.5%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Sinusitis</td> <td styleCode="Rrule">8 (16%)</td> <td styleCode="Rrule">9 (1.3%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pyrexia</td> <td styleCode="Rrule">7 (14%)</td> <td styleCode="Rrule">10 (1.4%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">6 (12%)</td> <td styleCode="Rrule">7 (1.0%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pain</td> <td styleCode="Rrule">5 (10%)</td> <td styleCode="Rrule">5 (0.7%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Chills</td> <td styleCode="Rrule">3 (6%)</td> <td styleCode="Rrule">5 (0.7%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Fatigue</td> <td styleCode="Rrule">3 (6%)</td> <td styleCode="Rrule">9 (1.3%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hypertension</td> <td styleCode="Rrule">3 (6%)</td> <td styleCode="Rrule">4 (0.6%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Insomnia</td> <td styleCode="Rrule">3 (6%)</td> <td styleCode="Rrule">3 (0.4%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nasal Congestion</td> <td styleCode="Rrule">3 (6%)</td> <td styleCode="Rrule">3 (0.4%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Upper respiratory tract infection</td> <td styleCode="Rrule">3 (6%)</td> <td styleCode="Rrule">5 (0.7%)</td> </tr> <tr> <td styleCode="Lrule Rrule">Vomiting</td> <td styleCode="Rrule">3 (6%)</td> <td styleCode="Rrule">3 (0.4%)</td> </tr> </tbody> </table>