Immune globulin intravenous (human)

Description

Immune Globulin Intravenous (Human) (IGIV), Carimune™ NF Nanofiltered, is a sterile, highly purified polyvalent antibody product containing in concentrated form all the IgG antibodies which regularly occur in the donor population (1). This immunoglobulin preparation is produced by cold alcohol fractionation from the plasma of US donors. Part of the fractionation may be performed by another US-licensed manufacturer. Carimune™ NF is made suitable for intravenous use by treatment at acid pH in the presence of trace amounts of pepsin (2,3). The manufacturing process by which Carimune™ NF is prepared from plasma consists of fractionation and purification steps that comprise filtrations in the presence of filter aids. Four of these steps were validated for virus elimination of both enveloped and non-enveloped viruses. To complement the existing virus elimination / inactivation mechanism in the Carimune™ NF manufacturing process, nanofiltration (removing viruses via size-exclusion) was introduced as an additional virus removal step into the manufacturing process (4,5). Nanofiltration is performed prior to the viral inactivation step (pH 4 in presence of pepsin) in order to reduce the potential viral load before inactivation is performed. Treatment with pepsin at pH4 rapidly inactivates enveloped viruses (6).

The Carimune™ NF manufacturing process provides a significant viral reduction in in vivo studies. These studies results are summarized in Table 1, demonstrate virus clearance during Carimune™ NF manufacturing using model viruses for lipid enveloped and non-enveloped viruses. The LRFs (log10 reduction factors) from nanofiltration, and viral elimination and inactivation steps were:

Table 1
Viral Elimination and Inactivation
Virus
HIV BVDV PRV SFV SV BEV
Genome
RNA RNA DNA RNA RNA RNA
Envelope
Yes Yes Yes Yes Yes No
Size (nm)
80-100 40-60 120-200 50-70 50-70 28-30
Fractionation&
Depth filtration
15.5 nt 16.0 9.3 12.4 14.1
pH 4 / pepsin
> 6.1 > 4.4 > 5.3 > 6.8 nt nt
Nanofiltration
> 4.9 > 4.5 > 4.4 nt > 7.5 > 5.1
Overall reduction
> 26 > 9 > 25 > 16 > 19 > 19
HIV: Human immunodeficiency virus, model for HIV 1 and HIV 2
BVDV: Bovine viral diarrhea virus, model for HCV (Hepatitis C virus)
PRV: Pseudorabies virus, model for large, enveloped DNA viruses (e,g., herpes virus)
SFV: Semliki Forest virus, model for HCV
SV: Sindbis virus, model for HCV
BEV: Bovine enterovirus, model for HAV (Hepatitis A virus)
Nt: not tested
PRV and the two model viruses for HCV, BVDV and SFV, were inactivated within 1/10, and HIV within 1/2 of the incubation time (pH 4/pepsin treatment) used during production of Carimune™ NF.

The preparation contains at least 96% of IgG and after reconstitution with a neutral unbuffered diluent has a pH of 6.6 ± 0.2. Most of the immunoglobulins are monomeric (7 S) IgG; the remainder consists of dimeric IgG and a small amount of polymeric IgG, traces of IgA and IgM and immunoglobulin fragments (7). The distribution of the IgG subclasses corresponds to that of normal serum (8,9,10,11). Final container lyophilized units are prepared so as to contain 1, 3, 6, or 12 g protein with 1.67 g sucrose and less than 20 mg NaCl per gram of protein. The lyophilized preparation contains no preservative and may be reconstituted with sterile water, 5% dextrose or 0.9% saline to a solution with protein concentrations ranging from 3% to 12% (see Table 3). The patient's fluid, electrolyte, caloric requirements and renal function should be considered in selecting an appropriate diluent and concentration.

Table 2
Calculated Carimune™ NF Osmolality (mOsm/kg)
Concentration
Diluent
3% 6% 9% 12%
0.9% NaCl
498 690 882 1074
5% Dextrose
444 636 828 1020
Sterile Water
192 384 576 768

Clinical Pharmacology

Carimune™ NF Nanofiltered contains a broad spectrum of antibody specificities against bacterial, viral, parasitic, and mycoplasma antigens, that are capable of both opsonization and neutralization of microbes and toxins. The 3 week half-life of Immune Globulin Intravenous (Human), Carimune™ NF, corresponds to that of Immune Globulin (Human) for intramuscular use, although individual variations in half-life have been observed (12,13). Appropriate doses of Carimune™ NF restore abnormally low immunoglobulin G levels to the normal range. One hundred percent of the infused dose of IGIV-products is available in the recipient's circulation immediately after infusion. After approximately 6 days, equilibrium is reached between the intra- and extravascular compartments, with immunoglobulin G being distributed approximately 50% intravascular and 50% extravascular. In comparison, after the intramuscular injection of immune globulin, the IgG requires 2-5 days to reach its maximum concentration in the intravascular compartment. This concentration corresponds to about 40% of the injected dose (13).

While Carimune™ NF has been shown to be effective in some cases of Immune Thrombocytopenic Purpura (ITP) (see INDICATIONS AND USAGE ), the mechanism of action in ITP has not been fully elucidated. Toxicity from overdose has not been observed on regimens of 0.4 g/kg body weight each day for 5 days (14,15,16). Sucrose is added to Carimune™ NF for reasons of stability and solubility. Since sucrose is excreted unchanged in the urine when given intravenously, Carimune™ NF, may be given to diabetics without compensatory changes in insulin dosage regimen. Please see WARNINGS section.

Indications and Usage

Immunodeficiency

Immune Globulin Intravenous (Human), Carimune™ NF, is indicated for the maintenance treatment of patients with primary immunodeficiencies (PID), e.g., common variable immunodeficiency, X-linked agammaglobulinemia, severe combined immunodeficiency (15,17,18,19). Carimune™ NF is preferable to intramuscular Immune Globulin (Human) preparations in treating patients who require an immediate and large increase in the intravascular immunoglobulin level (13), in patients with limited muscle mass, and in patients with bleeding tendencies for whom intramuscular injections are contraindicated. The infusions must be repeated at regular intervals. Please see DOSAGE AND ADMINISTRATION section.

Immune Thrombocytopenic Purpura (ITP)

Acute

A controlled study was performed in children in which Immune Globulin Intravenous (Human), Carimune™, was compared with steroids for the treatment of acute (defined as less than 6 months duration) ITP. In this study sequential platelet levels of 30,000, 100,000, and 150,000/µL were all achieved faster with Carimune™ than with steroids and without any of the side effects associated with steroids (14,20). However, it should be noted that many cases of acute ITP in childhood resolve spontaneously within weeks to months. Carimune™ has been used with good results in the treatment of acute ITP in adult patients (21,22,23). In a study involving 10 adults with ITP of less than 16 weeks duration, Carimune™ therapy raised the platelet count to the normal range after a 5 day course. This effect lasted a mean of over 173 days, ranging from 30 to 372 days (24).

Chronic

Children and adults with chronic (defined as greater than 6 months duration) ITP have also shown an increase (sometimes temporary) in platelet counts upon administration of Immune Globulin Intravenous (Human), Carimune™, (20,24,25,26,27,28). Therefore, in situations that require a rapid rise in platelet count, for example prior to surgery or to control excessive bleeding, use of Carimune™ should be considered. In children with chronic ITP, Carimune™ therapy resulted in a mean rise in platelet count of 312,000/µL with a duration of increase ranging from 2 to 6 months (25,28). Carimune™ therapy may be considered as a means to defer or avoid splenectomy (27,28,29). In adults, Carimune™ therapy has been shown to be effective in maintaining the platelet count in an acceptable range with or without periodic booster therapy. The mean rise in platelet count was 93,000/µL and the average duration of the increase was 20-24 days (24,25). However, it should be noted that not all patients will respond. Even in those patients who do respond, this treatment should not be considered to be curative.

Contraindications

As with all blood products containing IgA, Immune Globulin Intravenous (Human), Carimune™ NF, is contra-indicated in patients with selective IgA deficiency, who possess antibody to IgA. It may also be contraindicated in patients who have had severe systemic reactions to the intravenous or intramuscular administration of human immune globulin.

Warnings

Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death (30,31,32,33,34,35). Patients predisposed to acute renal failure include patients with:

  1. any degree of pre-existing renal insufficiency
  2. diabetes mellitus
  3. age greater than 65
  4. volume depletion
  5. sepsis
  6. paraproteinemia
  7. patients receiving known nephrotoxic drugs

In such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure.

Immune Globulin Intravenous (Human), Carimune™ NF, is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, 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 through the application of viral elimination/reduction steps such as alcohol fractionation in the presence of filter aids, nanofiltration and pH4/pepsin treatment (4,5,6; see Table 1). Despite these measures, such products may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in such products. 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 ZLB Bioplasma Inc., Tel. no: 866 244 29 52. The physician should discuss the risks and benefits of this product with the patient.

Patients with agamma- or extreme hypogammaglobulinemia who have never before received immunoglobulin substitution treatment or whose time from last treatment is greater than 8 weeks, may be at risk of developing inflammatory reactions on rapid infusion (greater than 1 mL per minute) of Immune Globulin Intravenous (Human), Carimune™ NF. These reactions are manifested by a rise in temperature, chills, nausea, and vomiting. The patient's vital signs should be monitored continuously. The patient should be carefully observed throughout the infusion, since these reactions on rare occasions may lead to shock. Epinephrine should be available for treatment of an acute anaphylactic reaction.

Precautions

Please see DOSAGE AND ADMINISTRATION below, for important information on Immune Globulin Intravenous (Human), Carimune™ NF, compatibility with other medications or fluids. Patients should not be volume depleted prior to the initiation of the infusion of IGIV. Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, should be assessed prior to the initial infusion of Carimune™ NF 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 Carimune™ NF at a rate less than 2 mg/kg/min.

Information for Patients

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.

Pregnancy Category C

Animal reproduction studies have not been conducted with Immune Globulin Intravenous (Human), Carimune™ NF. It is also not known whether Carimune™ NF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Carimune™ NF should be given to a pregnant woman only if clearly needed (23). Intact immune globulins such as those contained in Carimune™ NF cross the placenta from maternal circulation increasingly after 30 weeks gestation (36,37). In cases of maternal ITP where Carimune™ NF was administered to the mother prior to delivery, the platelet response and clinical effect were similar in the mother and neonate (23,37-46).

Pediatric Use

High dose administration of Immune Globulin Intravenous (Human), Carimune™, in pediatric patients with acute or chronic Immune Thrombocytopenic Purpura did not reveal any pediatric-specific hazard (14). Antibodies in Immune Globulin Intravenous (Human) may impair the efficacy of live attenuated viral vaccines such as measles, rubella, and mumps (47,48,49). Immunizing physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that appropriate precautions may be taken.

Aseptic Meningitis Syndrome

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) (IGIV) treatment. The syndrome usually begins within several hours to two 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. 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 (2 g/kg) IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.

Adverse Reactions

Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion. Progression to oliguria or anuria, requiring dialysis has been observed. Types of severe renal adverse events that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis (30-35,50,60-62).Inflammatory adverse reactions have been described in agammoglobulinemic and hypogammaglobulinemic patients who have never received immunoglobulin substitution therapy before or in patients whose time from last treatment is greater than 8 weeks and whose initial infusion rate exceeds 1 mL per minute.

This occurs in approximately 10% of such cases. Such reactions may also be observed in some patients during chronic substitution therapy. These reactions, which generally become apparent only 30 minutes to 1 hour after the beginning of the infusion, are as follows: flushing of the face, feelings of tightness in the chest, chills, fever, dizziness, nausea, diaphoresis, and hypotension. In such cases the infusion should be temporarily stopped until the symptoms have subsided. Immediate anaphylactoid and hypersensitivity reactions due to previous sensitization of the recipient to certain antigens, most commonly IgA, may be observed in exceptional cases, described under CONTRAINDICATIONS (15,16,51). In patients with ITP, who receive higher doses (0.4 g/kg/day or greater), 2.9% of infusions may result in adverse reactions (20). Headache, generally mild, is the most common symptom noted, occurring during or following 2% of infusions. A few cases of usually mild hemolysis have been reported after infusion of intravenous immunoglobulin products (52,53). These were attributed to transferral of blood group (e.g., anti-D) antibodies (54,55).

Dosage and Administration

It is generally advisable not to dilute plasma derivatives with other infusable drugs. Immune Globulin Intravenous (Human), Carimune™ NF, should be given by a separate infusion line. No other medications or fluids should be mixed with Carimune™ NF preparation.

Carimune™ NF should be used with caution in patients with pre-existing renal insufficiency and in patients judged to be at increased risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65, volume depletion, paraproteinemia, sepsis, and patients receiving known nephrotoxic drugs). In these cases especially it is important to assure that patients are not volume depleted prior to Carimune™ NF infusion. No prospective data are presently available to identify a maximum safe dose, concentration, and rate of infusion in patients determined to be at increased risk of acute renal failure. In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate selected should be the minimum practicable. The product should be infused at a rate less than 2 mg/kg/min.

Adult and Child Substitution Therapy

The usual dose of Immune Globulin Intravenous (Human), Carimune™ NF in immunodeficiency syndromes is 0.2 g/kg of body weight administered once a month by intravenous infusion. If the clinical response is inadequate, the dose may be increased to 0.3 g/kg of body weight or the infusion may be repeated more frequently than once a month (15,17,18,19).

The first infusion of Carimune™ NF in previously untreated agammaglobulinemic or hypogammaglobulinemic patients must be given as a 3% immunoglobulin solution (use the total volume of fluid provided, or see Table 3, to reconstitute the lyophilized product).

  1. Start with a flow rate of 10-20 drops (0.5-1.0 mL) per minute.
  2. After 15-30 minutes the rate of infusion may be further increased to 30-50 drops (1.5-2.5 mL) per minute.
  3. After the first bottle of 3% solution is infused and the patient shows good tolerance, subsequent infusions may be administered at a higher rate or concentration. Such increases should be made gradually allowing 15-30 minutes before each increment.

The first infusion of Carimune™ NF in previously untreated agammaglobulinemic and hypogammaglobulinemic patients may lead to systemic side effects. The nature of these effects has not been fully elucidated. Some of them may be due to the release of proinflammatory cytokines by activated macrophages in immunodeficient recipients (56,57). Subsequent administration of Carimune™ NF to immunodeficient patients as well as to normal individuals usually does not cause further untoward side effects.

Therapy of Idiopathic Thrombocytopenic Purpura (ITP)

Induction

0.4 g/kg of body weight on 2-5 consecutive days.

Acute ITP-Childhood

In acute ITP of childhood, if an initial platelet count response to the first two doses is adequate (30-50,000/µL), therapy may be discontinued after the second day of the 5 day course (20).

Maintenance-Chronic ITP

In adults and children, if after induction therapy the platelet count falls to less than 30,000/µL and/or the patient manifests clinically significant bleeding, 0.4 g/kg of body weight may be given as a single infusion. If an adequate response does not result, the dose can be increased to 0.8-1.0 g/kg of body weight given as a single infusion (21,58,59).

Reconstitution

(see also pictures next page)

images/79/09520001.jpg

1. Remove the protective plastic caps from the lyophilisate and diluent bottles and disinfect both rubber stoppers with alcohol. Remove the protective cover from one end of the transfer set and insert the exposed needle through the rubber stopper into the bottle containing the diluent.

images/79/09520002.jpg
images/79/09520003.jpg

2. & 3. Remove the second protective cover from the other end of the transfer set. Grasp both bottles as shown in picture 2, quickly plunge the diluent bottle onto the lyophilisate bottle and bring the bottles into an upright position. Only if this is done quickly and the bottles are immediately brought into an upright position can the vacuum in the lyophilisate bottle be maintained, thus speeding up reconstitution and facilitating the transfer. Allow the diluent to flow into the lyophilisate bottle.

images/79/09520004.jpg

4. Once the appropriate amount of diluent is transferred (see Table 3), lift the diluent bottle off the spike to release the vacuum. This will reduce foaming and facilitate dissolution. Remove the spike.

images/79/09520005.jpg

5. Swirl vigorously but do not shake, otherwise a foam will form which is very slow to subside. The lyophilisate dissolves within a few minutes.

To reconstitute Carimune™ NF from the individual vial package, or when using other diluents or higher concentrations, Table 3 indicates the volume of sterile diluent required. Observing aseptic technique, this volume should be drawn into a sterile hypodermic syringe and needle. The diluent is then injected into the corresponding Carimune™ NF vial size.

Table 3
Required Diluent Volume *
Concentration 1g
Vial
3g
Vial
6g
Vial
12g
Vial
3% 33.0cc 100cc 200cc **
6% 16.5cc 50cc 100cc 200cc
9% 11.0cc 33cc 66cc 132cc
12% 8.3cc 25cc 50cc 100cc
*In patients judged to be at increased risk of developing renal insufficiency, the concentration and infusion rate of Carimune™ NF should be the minimum practicable.
** Container not large enough to permit this concentration.

If large doses of Carimune™ NF are to be administered, several reconstituted vials of identical concentration and diluent may be pooled in an empty sterile glass or plastic i.v. infusion container using aseptic technique. Carimune™ NF normally dissolves within a few minutes, though in exceptional cases it may take up to 20 minutes.

DO NOT SHAKE! Excessive shaking will cause foaming.

Any undissolved particles should respond to careful rotation of the bottle. Avoid foaming. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Filtering of Carimune™ NF is acceptable but not required. Pore sizes of 15 microns or larger will be less likely to slow infusion, especially with higher Carimune™ NF concentrations. Antibacterial filters (0.2 microns) may be used. When reconstitution of Carimune™ NF occurs outside of sterile laminar air flow conditions, administration must begin promptly with partially used vials discarded. When reconstitution is carried out in a sterile laminar flow hood using aseptic technique, administration may begin within 24 hours provided the solution has been refrigerated during that time. Do not freeze Carimune™ NF solution.

PROCEED WITH INFUSION ONLY IF SOLUTION IS CLEAR AND AT APPROXIMATELY ROOM TEMPERATURE!

How Supplied

Immune Globulin Intravenous (Human), Carimune™ NF Nanofiltered is available as a white lyophilized powder in 1, 3, 6 and 12 g size vials. The only diluents which may be used to reconstitute the product are sterile (0.9%) Sodium Chloride Injection USP, 5% Dextrose, or Sterile Water.

Carimune™ NF is available in individual vial packages.

1g  Individual vial package (NDC 44206-415-01)

3g  Individual vial package (NDC 44206-416-03)

6g  Individual vial package (NDC 44206-417-06)

12g Individual vial package (NDC 44206-418-12)

Please see Table 2 for Calculated Carimune™ NF Osmolality (mOsmol/kg).

Store and Dispense

Immune Globulin Intravenous (Human), Carimune™ NF, should be stored at room temperature not exceeding 30 °C (86 °F). The preparation should not be used after the expiration date printed on the label.

References

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  3. Römer J, Späth PJ, Skvaril F, et al: Characterization of various immunoglobulin preparations for intravenous application. II. Complement activation and binding to Staphylococcus protein A. Vox Sang 1982; 42:74-80.
  4. Omar A, and Kempf C: Removal of neutralized model Parvoviruses and Enteroviruses in human IgG solutions by nanofiltration. Transfusion, in press (2002).
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  39. Fabris P, et al: Successful treatment of a steroid-resistant form of idiopathic thrombocytopenic purpura in pregnancy with high doses of intravenous immunoglobulins. Acta Haemat 1987; 77:107-110.
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