Flebogamma DIF

• It is used to stop or lower the harshness of other infections in people with a weak immune system.
• It is used to treat immune thrombocytopenia (ITP).
• It is used treat chronic inflammatory demyelinating polyneuropathy (CIDP).
• It is used to treat Kawasaki disease.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to immune globulin or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have IgA deficiency.
• If you have too much proline in your blood (hyperprolinemia).
• If you are not able to break down fructose, talk with the doctor. Some of these products have sorbitol.

Children:

• If the patient is an infant or baby and it is not known if they are able to break down sucrose or fructose. Do not give Flebogamma DIF to your child if this is the case.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Flebogamma DIF with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• If you have a latex allergy, talk with your doctor.
• Talk with your doctor before getting any vaccines. Use with Flebogamma DIF may either raise the chance of an infection or make the vaccine not work as well.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take this medicine.
• This medicine is made from human plasma (part of the blood) and may have viruses that may cause disease. This medicine is screened, tested, and treated to lower the chance that it carries an infection. Talk with the doctor.
• If you are on a low-sodium or sodium-free diet, talk with your doctor. Some of these products have sodium.
• If you have high blood sugar (diabetes), talk with your doctor about which glucose tests are best to use.
• Some patients who have immune globulin therapy for the first time or who have not had it within the past 8 weeks may have a risk for certain side effects. These may be fever, chills, nausea, or vomiting. This may also happen in people who switch brands of immune globulin. Tell the doctor right away if any of these side effects occur.
• If you are 65 or older, use Flebogamma DIF with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use Flebogamma DIF as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

For Intravenous Use Only

Preparation and Handling

• Flebogamma 10% DIF is a clear or slightly opalescent, colorless solution. Inspect the drug product visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy, turbid, or if it contains particulates.
• Do not shake.
• Do not freeze.
• Flebogamma 10% DIF should be administered at room temperature.
• The vial is for single use only.
• Flebogamma 10% DIF contains no preservative. Once the vial has been entered under aseptic conditions, its contents should be used promptly. Because the solution contains no preservative, Flebogamma 10% DIF should be infused as soon as possible.
• Do not mix Flebogamma 10% DIF with other IGIV products or other intravenous medications.
• Infuse Flebogamma 10% DIF using a separate infusion line.
• If larger doses of Flebogamma 10% DIF are to be administered, several vials may be pooled into sterile infusion bags using aseptic technique.

Dose

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 recommended dose of Flebogamma 10% DIF for patients with PI is 300 to 600 mg/kg body weight (3.0 to 6.0 mL/kg), administered every 3 to 4 weeks. Adjust the dosage over time to achieve the desired serum trough levels and clinical responses. No randomized controlled trial data are available to determine an optimum target trough serum IgG level.

Administration

It has been reported that the frequency of adverse drug reactions to IGIV increases with the infusion rate. Initial infusion rates should be slow. If there are no adverse drug reactions, the infusion rate for subsequent infusions can be slowly increased to the maximum rate. For patients experiencing adverse drug reactions, it is advisable to reduce the infusion rate in subsequent infusions, or administer IGIV at a 5% concentration.

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.

Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombotic events, administer Flebogamma 10% DIF at the minimum infusion rate practicable, and consider discontinuation of administration if renal function deteriorates (see Warnings and Precautions [5.2, 5.4]).

• Flebogamma 10% DIF is contraindicated in patients who have had a history of anaphylactic or severe systemic reactions to the administration of human immune globulin.
• Flebogamma 10% DIF is contraindicated in IgA deficient patients with antibodies to IgA and a history of hypersensitivity.

Flebogamma 10% DIF is a ready to use, sterile, clear or slightly opalescent and colorless to pale yellow, liquid preparation of highly 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. The Fc and Fab functionality is maintained in Flebogamma 10% DIF.

All Source Plasma used in the manufacture of Flebogamma 10% DIF was collected only at FDA approved plasmapheresis centers in the United States and tested by FDA-licensed serological tests and found to be non-reactive (negative) for Hepatitis B Surface Antigen (HBsAg), antibodies to Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) and negative on Nucleic Acid Test (NAT) for HCV and HIV. An investigational NAT for HBV is also performed on all Source Plasma and found to be negative; however, the significance of a negative result has not been established. Additionally, plasma is tested by in-process NAT testing for hepatitis A virus (HAV) and parvovirus B19 (B19) on minipools 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.

In addition, several manufacturing steps can contribute towards viral safety of the final product. The effectiveness of these steps to remove or inactivate viruses from the product was evaluated through virus spiking experiments using a scaled down version of the manufacturing process. Virus elimination experiments have been performed on 7 steps of the production process.

Flebogamma 10% DIF production process includes the following specific virus inactivation/ removal steps:

• Pasteurization at 60 ºC, 10 hours
• Solvent-Detergent treatment for 6 hours
• Nanofiltration down to 20 nm Planova filters

The following purification processes can also reduce the risk of viral transmission:

• Fraction I precipitation
• Fraction II+III precipitation
• 4% PEG precipitation
• pH 4 treatment for 4 hours at 37 ºC

The viral reduction data (in log10) from these experiments are summarized in Table 4.

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.

1. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol 1997; 8:1788-94.
2. Tan E, Hajinazarian M, Bay W, et al. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol 1993; 50:137-9.
3. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994; 121:259-62.
4. Scribner CL, Kapit RM, Phillips ET, et al. Aseptic meningitis and intravenous immunoglobulin therapy. Ann Intern Med 1994; 121:305-6.
5. Thomas MJ, Misbah SA, Chapel HM, et al. Hemolysis after high-dose intravenous Ig. Blood 1993; 15:3789.
6. Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 1992; 339:662-4.
7. Kessary-Shoham H, Levy Y, Shoenfeld Y, et al. In vivo administration of intravenous immunoglobulin (IVIG) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999; 13:129-35.
8. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223-6.
9. Woodruff RK, Grigg AP, Firkin FC, et al. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986; ii:217-8.
10. Wolberg AS, Kon RH, Monroe DM, et al. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30-4.
11. Rizk A, Gorson KC, Kenney L, et al. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41:264-8.