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Immune Globulin Intravenous (Human), Flebogamma 5% (IGIV) is a sterile, clear or slightly opalescent and colorless to pale yellow, liquid, pasteurized preparation of highly purified immunoglobulin (IgG) obtained from human plasma pools. The purification process includes cold alcohol fractionation, polyethylene glycol precipitation, and ion exchange chromatography.
Flebogamma 5% is a highly purified (≥ 99% IgG), unmodified, human IgG that contains the antibody specificities found in the donor population. IgG subclasses are fully represented with the following approximate percents of total IgG: IgG, is 70.3%, IgG, 24.7%, IgG, 3.1%, and IgG, 1.9% (1). The IgA content is < 0.05 mg/mL, and IgM is present in trace amounts.
In the final formulation, Flebogamma 5% contains 50 mg IgG per mL, 50 mg D-sorbitol per mL, and ≤ 6 mg/mL polyethylene glycol. There is no preservative in the formulation. The pH of the solution ranges from 5 to 6 and the osmolarity from 240 to 350 mOsm/L.
All Source Plasma used in the manufacture of this product was tested by FDA-licensed serological tests for HBsAg, antibodies to HCV and HIV and Nucleic Acid Test (NAT) for HCV and HIV-1 and found to be nonreactive (negative).
Virus elimination experiments have been performed on 2 steps of the production process. Residual viral titers were determined by infectivity assays. When no residual virus was detected, the Poisson distribution was used to give the minimum detectable level (MDL) based on the assay sensitivity and the sample volume used (1).
The viral reduction data (in log) from these experiments are summarized in Table 1.
|Target Virus||HIVa||HBV, Herpesvirus||HCV||HAV||Parvovirus B19|
|Pasteurization (60°C, 10 h)||> 5.9||5.8||≥ 4.3||≥ 5.1||≥ 6.6||5.0||2.3|
|PEG precipitation||3.7||4.3||4.2||≥ 5.3||4.2||3.8||3.9|
|Cumulative||≥ 9.6||10.1||≥ 8.5||≥ 10.4||≥ 10.8||8.8||6.2|
Flebogamma 5% was administered as an IV infusion (300 to 600 mg/kg) to subjects with primary humoral immunodeficiency disease (PID) every 3 (n = 11) or 4 (n = 10) weeks for 12 months. The pharmacokinetics of total IgG was determined after the 7th infusion for the 3-week dosing interval and after the 5th infusion for the 4-week dosing interval (Table 2).
Pharmacokinetic data for antibodies to specific antigens are in Table 3.
There is evidence that the half-life of IgG can vary considerable among patients (2-5).
There were 2 adolescent (≤ 16 years of age) subjects who underwent pharmacokinetic testing, and both of them were on the 3-week infusion schedule. There were no clinically relevant differences among the adults and adolescents that were tested.
|Variable||3-Week Dosing Interval||4-Week Dosing Interval|
|[1340 - 2430]a||[1490 - 2430]|
|AUC0 - ∞ (day·mg/dL)||63388||29583||91337||35915|
|[18570 - 119909]||[48360 - 161073]|
|[23 - 177]||[20 - 78]|
|[13 - 54]||[23 - 75]|
|Trough IgG level (mg/dL)b||832.7||822.2||870.4||856.3|
|[317.4 - 1207.5]||[660.0 - 1111.0]|
|Test (unit)||Statistic||3-Week Dosing Interval||4-Week Dosing Interval|
|CMV IgG (IV)||Mean (SD)||30 (36)||11 (16)||22 (9)||30 (10)||12 (8)||30 (8)|
|Min - Max||14 - 138||3 - 58||13 - 38||18 - 48||5 - 25||21 - 45|
|S. pneumoniae||Mean (SD)||12 (4)||6 (4)||23 (8)||13 (4)||6 (2)||29 (4)|
|Type 14 (μg/mL)||Min – Max||7 - 21||2 - 18||14 - 33||9 - 22||3 - 10||22 - 33|
|S. pneumoniae||Mean (SD)||14 (12)||5 (7)||41 (39)||9 (2)||4 (1)||25 (6)|
|Type 19F (μg/mL)||Min – Max||6 - 43||1 - 25||11 - 132||7 - 13||2 - 6||16 - 36|
|S. pneumoniae||Mean (SD)||2 (0.5)||1 (0.4)||50 (77)||2 (1)||1 (1)||43 (24)|
|Type 4 (μg/mL)||Min – Max||1 - 2||0 - 2||10 - 254||1 - 4||0 - 2||21 - 82|
|S. pneumoniae||Mean (SD)||9 (2)||4 (2)||29 (21)||9 (3)||4 (1)||36 (22)|
|Type 6B (μg/mL)||Min – Max||6 - 13||1 - 9||13 - 73||7 - 15||2 - 7||21 - 86|
|S. pneumoniae||Mean (SD)||12 (6)||4 (2)||45 (60)||11 (4)||4 (1)||42 (42)|
|Type 9V (μg/mL)||Min – Max||6 - 25||1 - 8||11 - 170||8 - 18||2 - 6||17 - 143|
|Tetanus Antitoxoid||Mean (SD)||12 (2)||5 (2)||23 (11)||14 (3)||5 (1)||28 (11)|
|Antibody (IU/mL)||Min - Max||9 - 16||2 - 8||11 - 45||10 - 18||3 - 6||13 - 41|
Grifols-04-I was a multicenter, open-label, historically controlled study conducted in the United States. A total of 51 subjects were enrolled, and their data were analyzed for safety and efficacy. The primary efficacy variable was the number of episodes of the following serious infections: bacterial pneumonia, bacteremia or sepsis, osteomyelitis/septic arthritis, visceral abscesses and bacterial meningitis. The secondary efficacy variables were the number of days of work/school missed, the number of hospitalizations and the number of days of each hospitalization, the number of visits to physicians or emergency rooms, and the number of other infections documented by positive radiographic findings and fever.
The results showed that subjects had a serious infection rate of 0.061 infections/subject/year (98% confidence interval = 0.011 to 0.183), a rate that is much less than 1 infection/subject/year. With regard to the secondary efficacy variables, the mean rate was less than 10 days or visits/subject/year (Table 4), and there were no other infections documented by positive radiographic findings and fever.
The dosing statistics for this study are in Table 5.
|Variable||Subjects||Total Days or Visits||Total Subject Years||Days or Visits/Subject/Year|
|N||%||Estimatea||95% C. I.b|
|Work/School Days Missed||22||43||328||50.8||6.46||5.69, 7.29|
|Days in Hospital||9||18||54||50.9||1.1||0.77, 1.42|
|Visits to Physician/ER||40||78||201||50.9||3.95||3.36, 4.61|
|Statistic||3-Week Dosing Interval||4-Week Dosing Interval||Total|
|Mean (SD)||437.5 (92.07)||427.0 (78.44)||430.1 (81.88)|
|Q1, Q3a||378.8, 480.8||367.9, 498.4||375.5, 497.0|
|Min, Max||307.0, 609.4||248.4, 572.4||248.4, 609.4|
Flebogamma 5% is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders, such as common variable immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott-Aldrich Syndrome. Flebogamma 5% is especially useful when rapid replacement of IgG or the attainment of high serum levels of IgG is desired.
Some clinical trials conducted with Flebogamma 5% included infants, children, and adolescents with primary and secondary immunodeficiency diseases to assess clinical efficacy. Data have also been obtained from postmarketing studies and postmarketing surveillance. Clinical trials with Flebogamma 5% enrolled a very limited number of children and adolescents with primary humoral immune deficiency, a number insufficient to fully characterize the efficacy and safety in pediatric patients [See PRECAUTIONS, Pediatric Use].
Flebogamma 5% should not be administered to individuals with a history of severe or anaphylactic reactions to blood or blood-derived products. Individuals with selective IgA deficiency and demonstrable antibodies to IgA should not receive Flebogamma 5%. If patients are known to be intolerant to any component of Flebogamma 5%, such as sorbitol (i.e., intolerance to fructose), they should not receive the product.
Flebogamma 5% is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob (CJD) agent that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. (See DESCRIPTION section). Plasma pools for manufacture are screened using Nucleic Acid Testing with polymerase chain reaction technology for HIV-1 and HCV. Two steps in the manufacturing process, Pasteurization for 10 hours at 60 degrees centigrade and Polyethylene Glycol precipitation, have been evaluated and demonstrated to provide cumulative log reductions exceeding 6 logs for all the tested viruses. Despite these measures, such IGIV products can still potentially transmit disease. ALL infections thought 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 888-GRIFOLS (888-474-3657). Physicians should discuss the potential risks and benefits of the use of this product with the patient.
All patients, but especially individuals receiving Flebogamma 5% for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at risk for the development of inflammatory reactions characterized by fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations regarding information in the DOSAGE AND ADMINISTRATION section may reduce the risk of these types of events.
Appropriate supportive care, including immediate access to epinephrine injection, should be available for the management of acute anaphylactic reactions.
Any vial that has been entered should be used promptly. Partially used vials should be discarded and not saved for future use because the solution contains no preservative. Do not use if turbid. Solution that has been frozen should not be used.
Ensure that patients are not volume-depleted before the initiation of the infusion of IGIV.
Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure (6). Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma 5% and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered.
For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Flebogamma 5% at a maximum rate less than 0.06 mL/kg (3 mg/kg) body weight/minute.
An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic milliliter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high-dose (e.g., >1.0 g/kg body weight) and/or rapid-infusion IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae (7-10).
Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis (11-13). Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration (14) [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: Laboratory Tests].
Thrombotic events have been reported in association with IGIV (15-17) (See ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: Laboratory Tests].
There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV (18). TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion. Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support.
IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum [See PRECAUTIONS: Laboratory Tests].
Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians.
It is recommended that the lot number of the vials used be recorded when Flebogamma 5% is administered.
Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma 5% in patients judged to have a potential increased risk for developing acute renal failure and again at appropriate intervals thereafter.
Following infusion of Flebogamma 5%, there may be a transitory rise of various antibody titers that may result in misleading positive results in serological testing.
Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.
If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum.
Animal reproduction studies have not been performed with Flebogamma 5%. It is also not known whether Flebogamma 5% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma 5% should be given to a pregnant woman only if clearly needed.
Antibodies in Flebogamma 5% may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration.
Ninety-four pediatric subjects, including 15 who were diagnosed with primary humoral immunodeficiency, have received Flebogamma 5% in the course of clinical studies or postmarketing studies over a 14-year period. Although preliminary safety data in children and adolescents with primary humoral immune deficiency who received Flebogamma 5% or other Immune Globulin Intravenous (Human) products produced by the same manufacturing method in different manufacturing facilities from that used for the production of Flebogamma 5% has not revealed differences between the safety profiles of the product(s) in pediatric and adult patients, the experience has been too limited to consider the safety and efficacy of Flebogamma 5% to be established in children and adolescents.
Subjects over 65 are at increased risk of renal failure with IGIV treatment. For these subjects, and for any other subjects at risk of renal failure, the infusion rate of Flebogamma 5% should be limited to < 0.06 mL/kg/min (3 mg/kg/min).
Increases of creatinine and blood urea nitrogen (BUN) have been observed as soon as 1 to 2 days following infusion of IGIV. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment (19). Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis (20), proximal tubular nephropathy, and osmotic nephrosis (6).
Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate [See DOSAGE AND ADMINISTRATION] must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Adverse reactions may occur more frequently when a high infusion rate is used, the treatment is the initial exposure to immunoglobulin, the immunoglobulin product has been changed to that of a different manufacturer, or there has been a long interval (more than 8 weeks) since the previous infusion. Slowing or stopping an infusion usually results in the prompt disappearance of symptoms.
The following adverse reactions have been identified and reported during the post-approval use of IGIV products (21).
Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently.
Adverse events were reported in a study of 51 individuals with primary humoral immunodeficiency diseases receiving infusions every 3 to 4 weeks of 300 to 600 mg/kg body weight. Forty-nine (96%) subjects experienced at least 1 adverse event irrespective of the relationship with the product, and these subjects reported a total of 784 adverse events. None of the 51 subjects who participated in this study discontinued the study prematurely due to an adverse experience.
Adverse events that occurred with an incidence of > 15% on a per subject basis are summarized in Table 6. No adverse events occurred with an incidence of > 2% on a per infusion basis.
Forty-six (90%) subjects had 331 adverse events that occurred during an infusion or within 72 hours after the completion of the infusion. Therefore 42% of all adverse events, regardless of assessed causality, were temporally associated with the infusion of Flebogamma 5%.
Overall, 217 of 746 infusions (29%) were temporally associated with 1 or more adverse events occurring within 72 hours after an infusion, regardless of assessed relationship to treatment; the 1-sided, 95%, upper-bound confidence interval was 34%.
A summary of infusions with mild, moderate, and severe treatment-related adverse events is in Table 7.
The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 8.
None of these subjects had a concomitant treatment-emergent rise in total bilirubin.
Reported adverse reactions with Flebogamma 5% and other IGIV products include: 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, often beginning within 60 minutes of the start of the infusion.
Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current medical standards for shock treatment should be implemented.
|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|
|Integumentary||Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, bullous dermatitis|
|Hematologic||Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test|
|General/Body as a Whole||Pyrexia, rigors|
|Gastrointestinal||Hepatic dysfunction, abdominal pain|
|Adverse Event||Number of AEs||Number of Subjects with AE||Percent of Subjects with AE|
|Cough and productive cough||26||13||25|
|Headache NOS and sinus headache||61||27||53|
|Sore throat NOS||13||10||20|
|Upper Respiratory tract infection||22||17||33|
|Wheezing and asthma aggravated||24||9||18|
|Severity of AE||No. Infusions with AE||Adjusted %a||Confidence Intervalb|
Instituto Grifols, S.A.
Drugs and Medications
These highlights do not include all the information needed to use Flebogamma 5% DIF safely and effectively. See full prescribing information for Flebogamma 5% DIF. Immune Globulin Intravenous (Human) ...
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This is a multi-center, open-label study to assess the efficacy and safety of Flebogamma 5% DIF in the pediatric population.