Flebogamma Dif
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Uses
Flebogamma 10% DIF is an Immune Globulin Intravenous (Human) 10% preparation that is indicated for the treatment of Primary Immunodeficiency (PI) including the humoral immune defect in common variable immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott-Aldrich syndrome.
History
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Other Information
Flebogamma 10% DIF is a ready to use, sterile, clear or slightly opalescent and colorless to pale yellow, liquid preparation of purified immunoglobulin (IgG) obtained from human plasma pools. The purification process includes cold ethanol fractionation, polyethylene glycol precipitation, ion exchange chromatography, low pH treatment, pasteurization, solvent detergent treatment and Planova nanofiltration using 20 nanometer (nm) filters.
Flebogamma 10% DIF is a purified (≥ 97% IgG), unmodified, human IgG. The distribution of the four IgG subclasses is approximately 66.6% IgG1, 27.9% IgG2, 3.0% IgG3 and 2.5% IgG4. Flebogamma 10% DIF contains trace amounts of IgA (typically < 100 μg/mL) and trace amounts of sodium and IgM.
Flebogamma 10% DIF contains 10 g human normal immunoglobulin and 5 g D-sorbitol (as stabilizer) in 100 mL of water for injection, 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 osmolality from 240 to 370 mOsm/kg, which is within the normal physiological range.
Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collections and plasma preparation. Each individual plasma donation used in the manufacture of Flebogamma 10% DIF is collected only at FDA approved blood establishments and is tested by FDA licensed serological test for Hepatitis B Surface Antigen (HBsAg), for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of plasma are tested for the presence of HBV, HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found to be negative. In addition, plasma is tested by in-process NAT testing for Hepatitis A virus (HAV) and parvovirus B19 (B19) on mini-pools and the viral load limit for B19 in the manufacturing pool is set not to exceed 104 IU/mL. NAT testing for the presence of HCV and HIV in the manufacturing plasma pool is also performed and found to be negative.
To further improve the margin of safety, three dedicated, independent and effective virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely pasteurization at 60 ºC, 10 hours, solvent-detergent treatment for 6 hours and nanofiltration down to 20 nm Planova filters.
In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed on 7 steps of the production process (pasteurization, solvent-detergent treatment, nanofiltration, Fraction I precipitation, Fraction II+III precipitation, 4% PEG precipitation and pH treatment for 4 hours at 37 ºC).
The viral reduction data (in log10) from these experiments are summarized in Table 2.
| *When the RF is < 1 log10, it is not taken into account for the calculation of the overall reduction capacity. |
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| ≥: No residual infectivity detected / nd: not done / na: non-applicable, since the virus is theoretically resistant to this treatment. |
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| Abbreviations: HIV; Human Immunodeficiency Virus, PRV; Pseudorabies Virus, IBR; Infectious Bovine Rhinotracheitis Virus, BVDV; Bovine Viral Diarrhoea Virus, SINDBIS; Sindbis Virus, WNV; West Nile Virus, EMC; Encephalomyocarditis Virus, PPV; Porcine Parvovirus. |
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| Target virus | HIV-1, HIV-2 (env. RNA) |
HBV Herpesvirus (env. DNA) |
HCV (env. RNA) |
WNV (env. RNA) |
HAV (non-env. RNA) |
B19 Virus (non-env. DNA) |
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| Model virus | HIV-1 | PRV | IBR | BVDV | SINDBIS | WNV | EMC | PPV |
| Fraction I precipitation | < 1.00* | nd | nd | nd | nd | 2.78 | nd | < 1.00* |
| Ethanol incubation (Fraction II+III) | 1.48 | nd | nd | nd | nd | < 1.00* | nd | nd |
| PEG precipitation | ≥ 6.10 | ≥ 5.92 | nd | ≥ 5.78 | nd | nd | ≥ 6.41 | 6.35 |
| Acid pH treatment | 2.47 | ≥ 5.32 | nd | < 1.00* | nd | nd | 1.36 | na |
| Pasteurization | ≥ 5.64 | ≥ 4.96 | ≥ 6.33 | ≥ 4.69 | ≥ 6.49 | ≥ 5.42 | ≥ 5.56 | 4.08 |
| Solvent Detergent | ≥ 4.61 | ≥ 6.95 | nd | ≥ 6.14 | nd | ≥ 5.59 | na | na |
| Nanofiltration 20 nanometer |
≥ 4.81 | ≥ 4.63 | nd | ≥ 4.67 | nd | ≥ 3.63 | ≥ 5.92 | 4.61 |
| Overall Reduction Capacity | ≥ 25.11 | ≥ 27.78 | ≥ 6.33 | ≥ 21.28 | ≥ 6.49 | ≥ 17.42 | ≥ 19.25 | 15.04 |
Additionally, the manufacturing process was investigated for its capacity to decrease infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.
Several individual production steps in the Flebogamma 10% DIF manufacturing process have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include: 4% Polyethylene glycol precipitation [≥ 6.19 log10] and Planova nanofiltration using a 20 nanometer filter [≥ 5.45 log10]. These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.
Sources
Flebogamma Dif Manufacturers
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Grifols Usa, Llc
![Flebogamma Dif (Human Immunoglobulin G) Injection, Solution [Grifols Usa, Llc]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Flebogamma Dif | Grifols Usa, Llc
For Intravenous Use Only
2.1 DosageTreatment of Primary Immunodeficiency (PI)
Dose Initial Infusion Rate Maintenance Dose Rate
(if tolerated) 300 to 600 mg/kg body weight (3.0 to 6.0 mL/kg) administered every 3 to 4 weeks 0.01 mL/kg/minute (1 mg/kg/min) 0.08 mL/kg/minute (8 mg/kg/min)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. Dosing should be adjusted according to the clinical response.
The dosage may be adjusted over time to achieve the desired serum trough IgG levels and clinical responses. No randomized controlled trial data are available to determine an optimum target trough serum IgG level.
2.2 Preparation and Handling Inspect Flebogamma 10% DIF visually for particulate matter and color prior to administration. Do not use the vial if particles are detected. Do not use if turbid. Several vials of Flebogamma 10% DIF may be pooled into an empty sterile solution container by using aseptic technique, if large doses are to be administered. Dilution with intravenous fluids is not recommended. Injection of other medications into intravenous tubing being used for Flebogamma 10% DIF is not recommended. Infuse Flebogamma 10% DIF through a separate intravenous line. Do not add any medications or intravenous fluids to the Flebogamma 10% DIF infusion container. Do not mix IGIV products of different formulations or from different manufacturers. Discard unused contents and administration devices after use. Any vial that has been entered should be used promptly Discard partially used vials. Do not save for future use because the solution contains no preservative. Do not use solution that has been frozen. 2.3 AdministrationThe recommended initial infusion rate of Flebogamma 10% DIF is 0.01 mL/kg/min (1 mg/kg/min) for the first thirty minutes. If tolerated, the rate may be gradually increased to 0.04 mL/kg/min (4 mg/kg/min) and if tolerated, gradually to a maximum of 0.08 mL/kg/min (8 mg/kg/min).
Monitor patient vital signs throughout the infusion. Slow or stop infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.
For the first 2-3 infusions, Flebogamma 10% DIF may be administered at infusions rates slower than recommended rates. If after administration of the first few infusions no adverse drug reactions are observed, the infusion rate for subsequent infusions may be slowly increased to the maximum rate. For patients experiencing adverse drug reactions reduce the infusion rate in subsequent infusions or administer IGIV at 5% concentration.
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Grifols Usa, Llc
Flebogamma Dif | Grifols Usa, Llc
For Intravenous Use Only
2.1 DosageTreatment of Primary Immunodeficiency (PI)
Dose Initial Infusion Rate Maintenance Dose Rate
(if tolerated) 300-600 mg per kg body weight (6.0-12.0 mL per kg) administered every 3-4 weeks 0.01 mL per kg per minute (0.5 mg per kg per min) Increase to 0.10 mL per kg per minute (5 mg per kg per min)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. Adjust the dose according to the clinical response.
Adjust the dosage over time to achieve the desired trough IgG levels and clinical responses. No randomized controlled trial data are available to determine an optimum target trough serum IgG level.
2.2 Preparation and Handling Inspect Flebogamma 5% DIF visually for particulate matter and color prior to administration. Do not use the vial if particles are detected. Do not use if turbid. Several vials of Flebogamma 5% DIF may be pooled into an empty sterile solution container by using aseptic technique, if large doses are to be administered. Do not dilute with intravenous fluids. Do not inject other medications into intravenous tubing being used for Flebogamma 5% DIF. Infuse Flebogamma 5% DIF through a separate intravenous line. Do not add any medications or intravenous fluids to the Flebogamma 5% DIF infusion container. Do not mix IGIV products of different formulations or from different manufacturers. Discard unused contents and administration devices after use. Use promptly any vial that has been entered. Discard partially used vials. Do not save for future use because the solution contains no preservative. Do not use solution that has been frozen. 2.3 AdministrationThe recommended initial infusion rate of Flebogamma 5% DIF is 0.01 mL per kg body weight per minute (0.5 mg per kg per min). If the infusion is well-tolerated during the first 30 minutes, the rate may be gradually increased to a maximum of 0.10 mL per kg per minute (5 mg per kg per min).
Monitor patient vital signs throughout the infusion. Slow or stop infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.
![Flebogamma Dif (Human Immunoglobulin G) Injection, Solution [Grifols Usa, Llc]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=2cf22c72-64ac-45be-b7c6-d20340730096&name=fle00-0011-01.jpg)
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