FDA label 7d08b39b-5d1d-424f-b572-13e57b6df376

WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE Use of immune globulin intravenous (IGIV) products, particularly those containing sucrose, has 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 those receiving known nephrotoxic drugs ( see Warnings and Precautions [ 5.2 ] ) . Flebogamma 10% DIF does not contain sucrose. For patients at risk of renal dysfunction or failure, administer Flebogamma 10% DIF at the minimum infusion rate practicable ( see Dosage and Administration [ 2.3 ] , Warnings and Precautions [ 5.2 ] ). WARNING: ACUTE RENAL DYSFUNCTION AND FAILURE See full prescribing information for complete boxed warning. Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with the administration of human immune globulin intravenous (IGIV) products. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products that contain sucrose. Flebogamma 10% DIF does not contain sucrose. For patients at risk of renal dysfunction or failure, administer Flebogamma 10% DIF at the minimum infusion rate practicable.

5 WARNINGS AND PRECAUTIONS Weigh the potential risks and benefits of Flebogamma 10% DIF against those of alternative therapies in all patients for whom Flebogamma 10% DIF is being considered. Before prescribing Flebogamma 10% DIF, the physician should discuss risks and benefits of its use with patients. 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, 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 Flebogamma 10% DIF 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 for hyperviscosity. [ 5.4 ] Aseptic Meningitis Syndrome (AMS) may occur in patients receiving Flebogamma 10% DIF therapy, especially with high doses or rapid infusion. [ 5.5 ] Hemolytic anemia can develop subsequent to Flebogamma 10% DIF treatment. Monitor patients for hemolysis and hemolytic anemia. [ 5.6 ] Monitor patients for pulmonary adverse reactions (transfusion-related acute lung injury, TRALI). [ 5.7 ] Patients receiving Flebogamma 10% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks may be at a higher risk for development of fever, chills, nausea, and vomiting. [ 5.8 ] Flebogamma 10% DIF is made from human plasma and may contain infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. [ 5.9 ] Passive transfer of antibodies may confound serologic testing. [ 5.11 ] 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications [ 4 ]) . In case of hypersensitivity, discontinue Flebogamma 10% DIF infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Flebogamma 10% DIF contains trace amounts of IgA (less than 100 μg/mL) (see Description [ 11 ] ). Patients with antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Flebogamma 10% DIF 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 may occur upon use of Flebogamma 10% DIF. Ensure that patients are not volume-depleted before administering Flebogamma 10% DIF. 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, age greater than 65 years, volume depletion, sepsis, paraproteinemia, use of concomitant nephrotoxic drugs, etc.), administer Flebogamma 10% DIF at the minimum rate of infusion practicable (2) ( 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 (1). Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Flebogamma 10% DIF and at appropriate intervals thereafter. If renal function deteriorates, consider discontinue use of Flebogamma 10% DIF. 5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving Flebogamma 10% DIF therapy. It is clinically critical to distinguish true hyponatremia from a pseudohyponatremia that is temporally or causally related to hyperproteinemia with concomitant decreased calculated serum osmolarity 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 higher risk of thrombotic events. 5.4 Thrombotic Events Thrombotic events may occur during or following treatment with Flebogamma 10% DIF (8-10). 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 known or 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 Flebogamma 10% DIF at the minimum rate of infusion practicable ( see Dosage and Administration [ 2.3 ]). 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Flebogamma 10% DIF treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae (3-4). 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 to patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently following high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis Flebogamma 10% DIF 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 reaction and hemolysis (5-6). Delayed hemolytic anemia may develop subsequent to Flebogamma 10% DIF therapy due to enhanced RBC sequestration (7), and acute hemolysis, consistent with intravascular hemolysis, has been reported. Monitor patients for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after Flebogamma 10% DIF infusion, perform appropriate confirmatory laboratory testing ( see Patient Counseling Information [ 17 ]). 5.7 Transfusion-Related Acute Lung Injury (TRALI) Non-cardiogenic pulmonary edema may occur in patients following Flebogamma 10% DIF treatment (11). 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 ( see Patient Counseling Information [ 17 ]). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Infusion Reactions All patients, but especially individuals receiving Flebogamma 10% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at a higher risk for the development of fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations regarding dosage and administration may reduce the risk of these types of events (see Dosage and Administration [ 2.3 ]) . 5.9 Transmissible Infectious Agents Because Flebogamma 10% DIF is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for Flebogamma 10% DIF. 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 Grifols Biologicals at 1-888-474-3657. Before prescribing or administering Flebogamma 10% DIF, the physician should discuss the risks and benefits of its use with the patient ( see Patient Counseling Information [ 17 ]). 5.10 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 Flebogamma 10% DIF and at appropriate intervals thereafter. 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, because of the potentially increased risk of thrombosis. If signs and/or symptoms of hemolysis are present after an infusion of Flebogamma 10% DIF, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient's serum. 5.11 Interference with Laboratory Tests After infusion of IgG, 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 Serious adverse reactions observed with Flebogamma 10% DIF were back pain, chest discomfort, headache, chest pain, maculopathy, rigors, tachycardia, bacterial pneumonia, and vasovagal syncope. The most common adverse reactions (reported in ≥ 5% of clinical trial subjects) occurring during or within 72 hours of the end of an infusion were headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema (see Tables 2 and 3 ). The most common adverse reactions reported in greater than 5% of subjects were headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia and edema. [ 6 ] Serious adverse reactions included back pain, chest discomfort, headache, chest pain, maculopathy, rigors, tachycardia, and vasovagal syncope. To report SUSPECTED ADVERSE REACTIONS, contact Grifols Biologicals at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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, historically controlled clinical study, 46 individuals with primary humoral immunodeficiency received infusion doses of Flebogamma 10% DIF at 300 to 600 mg/kg body weight every 3 weeks (mean dose 469 mg/kg) or 4 weeks (mean dose 457 mg/kg) for up to 12 months (see Clinical Studies [14.1]) . Routine pre-medication was not allowed. Of the 601 infusions administered, 130 infusions (22%) in 21 (47%) subjects were given pre-medications (antipyretic, antihistamine, or antiemetic agent) because of experience with consecutive infusion-related adverse reactions. One subject experienced four serious adverse events (AEs, bacterial pneumonia, subcutaneous abscess and two episodes of cellulitis) and withdrew from the study. Two other subjects who participated in the study discontinued prematurely due to AEs (back pain/chest pain/headache; and chills/tachycardia). Three subjects experienced four serious non-related AEs (drug abuse/depression; hernia; and sinusitis). Forty-five (98%) subjects experienced at least 1 AE irrespective of the relationship with the product, and these subjects reported a total of 723 AEs. Thirty-eight subjects (83%) had an adverse reaction at some time during the study that was considered product-related. Of the 21 subjects receiving pre-medications, 12 (57%) subjects reported adverse reactions during or within 72 hours after the infusion in 48 of the 130 pre-medicated infusions (37%). Table 2. Treatment-related Adverse Events Occurring in ≥ 5% of Subjects with PI during a Flebogamma 10% DIF Infusion or within 72 Hours after the End of an infusion Adverse Event Subjects (%) [N=46] Infusions (%) [N=601] Headache 24 (52%) 67 (11%) Rigors 17 (37%) 37 (6%) Pyrexia 15 (33%) 27 (5%) Tachycardia 10 (22%) 18 (3%) Hypotension 9 (20%) 11 (2%) Back pain 8 (17%) 27 (5%) Myalgia 8 (17%) 17 (3%) Body temperature increased 4 (9%) 6 (1%) Nausea 4 (9%) 6 (1%) Pain 4 (9%) 8 (1%) Chest discomfort 3 (7%) 4 (1%) Chest pain 3 (7%) 5 (1%) Infusion site reaction 3 (7%) 4 (1%) Pain in extremity 3 (7%) 3 (0.5%) The total number of adverse events occurring during or within 72 hours after the end of an infusion, irrespective of causality , was 359, excluding non-serious infections. Table 3 lists the AEs that occurred in greater than 5% of subjects during a Flebogamma 10% DIF infusion or within 72 hours after the end of an infusion, irrespective of causality . Table 3. Adverse Events Occurring in ≥ 5% of Subjects with PI during a Flebogamma 10% DIF Infusion or within 72 Hours after the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [N=46] Infusions (%) [N=601] Headache 28 (61%) 71 (12%) Pyrexia 17 (37%) 27 (5%) Rigors 17 (37%) 37 (6%) Back pain 13 (28%) 29 (5%) Cough or Productive cough 12 (26%) 5 (1%) Nausea 12 (26%) 8 (1%) Hypotension 10 (22%) 13 (2%) Tachycardia 10 (22%) 19 (3%) Myalgia 9 (20%) 17 (3%) Diarrhea 8 (17%) 2 (0.3%) Infusion site reaction 8 (17%) 8 (1%) Pharyngolaryngeal pain 7 (15%) 3 (1%) Nasal congestion 7 (15%) 2 (0.3%) Postnasal drip 7 (15%) 4 (1%) Arthralgia 6 (13%) 2 (0.3%) Conjunctivitis 6 (13%) 2 (0.3%) Pain 6 (13%) 10 (2%) Vomiting 6 (13%) 0 (0%) Dizziness 5 (11%) 3 (1%) Fatigue 5 (11%) 1 (0.2%) Urinary tract infection 5 (11%) 4 (1%) Chest pain 5 (11%) 4 (1%) Ear pain 5 (11%) 1 (0.2%) Pain in extremity 5 (11%) 2 (0.3%) Dyspnea 5 (11%) 0 (0%) Rhinorrhea 4 (9%) 1 (0.2%) Wheezing 4 (9%) 4 (1%) Body temperature increased 4 (9%) 6 (1%) Neck pain 4 (9%) 2 (0.3%) Sinus pain 4 (9%) 1 (0.2%) Chest discomfort 4 (9%) 4 (1%) Crackles lung 4 (9%) 2 (0.3%) Abdominal pain 3 (7%) 2 (0.3%) Dyspepsia 3 (7%) 1 (0.2%) Toothache 3 (7%) 0 (0%) Gastroesophageal reflux disease 3 (7%) 0 (0%) Lymphadenopathy 3 (7%) 3 (1%) Respiratory tract congestion 3 (7%) 0 (0%) Fall 3 (7%) 1 (0.2%) Hypertension 3 (7%) 4 (1%) In this study, the upper bound of the 1-sided 95% confidence interval for the proportion of Flebogamma 10% DIF infusions associated with one or more AEs was 37.8% (total infusions: 208; actual proportions: 34.6%). The average percent of infusions with AEs during or within 72 hours after the end of an infusion for each individual subject was 36.7% and the upper bound of the 1-sided 95% confidence interval was 43.9%. AE reporting was based upon a clinical protocol precluding pre-medication against AEs. Pre-medication could be utilized only after the first 2 infusions only in those patients that exhibited adverse events. Forty-three of the 46 subjects enrolled in this study had a negative Coombs test at baseline. Of these 43 subjects, 10 (23.3%) developed a positive Coombs test at some time during the study. However, no subjects showed evidence of hemolytic anemia. 6.2 Post-marketing Experience Because adverse reactions are reported voluntarily 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, including Flebogamma 5% (see References [ 15 ]). 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), Transfusion-Related Acute Lung Injury (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 multiformae, dermatitis (e.g., bullous dermatitis) Hematologic Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test Musculoskeletal Back pain Gastrointestinal Hepatic dysfunction, abdominal pain General/Body as a Whole Pyrexia, rigors

<table ID="t2" width="100%"> <caption>Table 2. Treatment-related Adverse Events Occurring in &#x2265; 5% of Subjects with PI during a Flebogamma 10% DIF Infusion or within 72 Hours after the End of an infusion </caption> <col width="47.933%" align="left"/> <col width="26.133%" align="left"/> <col width="25.933%" align="left"/> <thead> <tr> <th align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Event</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Subjects (%)</content> <content styleCode="bold">[N=46]</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Infusions (%)</content> <content styleCode="bold">[N=601]</content> </th> </tr> </thead> <tbody> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Headache</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">24 (52%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">67 (11%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Rigors</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">17 (37%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">37 (6%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Pyrexia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">15 (33%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">27 (5%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Tachycardia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">10 (22%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">18 (3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Hypotension</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">9 (20%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">11 (2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Back pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">8 (17%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">27 (5%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Myalgia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">8 (17%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">17 (3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Body temperature increased</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">6 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Nausea</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">6 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">8 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Chest discomfort</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Chest pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Infusion site reaction</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Pain in extremity</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (0.5%)</content> </td> </tr> </tbody> </table>

<table ID="t3" width="100%"> <caption>Table 3. Adverse Events Occurring in &#x2265; 5% of Subjects with PI during a Flebogamma 10% DIF Infusion or within 72 Hours after the End of an infusion, Irrespective of Causality </caption> <col width="39.467%" align="left"/> <col width="30.267%" align="left"/> <col width="30.267%" align="left"/> <thead> <tr> <th align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Adverse Event</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Subjects (%)</content> <content styleCode="bold">[N=46]</content> </th> <th align="center" valign="top" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Infusions (%) [N=601]</content> </th> </tr> </thead> <tbody> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Headache</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">28 (61%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">71 (12%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Pyrexia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">17 (37%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">27 (5%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Rigors</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">17 (37%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">37 (6%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Back pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">13 (28%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">29 (5%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Cough or Productive cough</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">12 (26%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Nausea</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">12 (26%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">8 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Hypotension</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">10 (22%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">13 (2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Tachycardia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">10 (22%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">19 (3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Myalgia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">9 (20%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">17 (3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Diarrhea</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">8 (17%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Infusion site reaction</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">8 (17%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">8 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Pharyngolaryngeal pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">7 (15%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Nasal congestion</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">7 (15%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Postnasal drip</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">7 (15%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Arthralgia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">6 (13%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Conjunctivitis</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">6 (13%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">6 (13%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">10 (2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Vomiting</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">6 (13%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">0 (0%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Dizziness</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (11%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Fatigue</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (11%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">1 (0.2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Urinary tract infection</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (11%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Chest pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (11%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Ear pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (11%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">1 (0.2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Pain in extremity</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (11%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Dyspnea</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">5 (11%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">0 (0%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Rhinorrhea</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">1 (0.2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Wheezing</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Body temperature increased</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">6 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Neck pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Sinus pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">1 (0.2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Chest discomfort</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Crackles lung</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (9%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Abdominal pain</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">2 (0.3%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Dyspepsia</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">1 (0.2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Toothache</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">0 (0%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Gastroesophageal reflux disease</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">0 (0%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Lymphadenopathy</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (1%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Respiratory tract congestion</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">0 (0%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Fall</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">1 (0.2%)</content> </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Hypertension</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">3 (7%)</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">4 (1%)</content> </td> </tr> </tbody> </table>

<table width="100%"> <col width="38.150%" align="left"/> <col width="61.850%" align="left"/> <tbody> <tr> <td align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Infusion reactions </content> </td> <td align="left" valign="top" styleCode="Toprule Botrule Rrule">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 </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Renal </content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Acute renal dysfunction/failure, osmotic nephropathy </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Respiratory</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Cardiovascular</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Cardiac arrest, thromboembolism, vascular collapse, hypotension </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Neurological</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Integumentary</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, dermatitis (e.g., bullous dermatitis) </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Hematologic</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Musculoskeletal</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Back pain </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Gastrointestinal</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Hepatic dysfunction, abdominal pain </td> </tr> <tr> <td align="left" valign="top" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">General/Body as a Whole</content> </td> <td align="left" valign="top" styleCode="Botrule Rrule">Pyrexia, rigors </td> </tr> </tbody> </table>