Globulin Benesis

Globulin Benesis S/D (immune globulin) is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern (see WARNINGS).

Primary Immunodeficiency Diseases

Globulin Benesis S/D (immune globulin) is indicated for the treatment of primary immunodeficient states, such as: congenital agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.^6,7 This indication was supported by a clinical trial of 17 patients with primary immunodeficiency who received a total of 341 infusions. Globulin Benesis S/D (immune globulin) is especially useful when high levels or rapid elevation of circulating IgG are desired or when intramuscular injections are contraindicated (e.g., small muscle mass).

B-cell Chronic Lymphocytic Leukemia (CLL)

Globulin Benesis S/D (immune globulin) is indicated for prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell Chronic Lymphocytic Leukemia (CLL). In a study of 81 patients, 41 of whom were treated with Globulin Benesis, Immune Globulin Intravenous (Human), bacterial infections were significantly reduced in the treatment group.^8,9 In this study, the placebo group had approximately twice as many bacterial infections as the IGIV group. The median time to first bacterial infection for the IGIV group was greater than 365 days. By contrast, the time to first bacterial infection in the placebo group was 192 days. The number of viral and fungal infections, which were for the most part minor, was not statistically different between the two groups.

Idiopathic Thrombocytopenic Purpura (ITP)

When a rapid rise in platelet count is needed to prevent and/or to control bleeding in a patient with Idiopathic Thrombocytopenic Purpura, the administration of Globulin Benesis S/D (immune globulin) , should be considered.

The efficacy of Globulin Benesis (immune globulin) has been demonstrated in a clinical study involving 16 patients. Of these 16 patients, 13 had chronic ITP (11 adults, 2 children), and 3 patients had acute ITP (one adult, 2 children). All 16 patients (100%) demonstrated a clinically significant rise in platelet count to a level greater than 40,000/mm³ following the administration of Globulin Benesis (immune globulin). Ten of the 16 patients (62.5%) exhibited a significant rise to greater than 80,000 platelets/ mm³. Of these 10 patients, 7 had chronic ITP (5 adults, 2 children), and 3 patients had acute ITP (one adult, 2 children).

The rise in platelet count to greater than 40,000/mm³ occurred after a single 1 g/kg infusion of Globulin Benesis (immune globulin) in 8 patients with chronic ITP (6 adults, 2 children), and in 2 patients with acute ITP (one adult, one child). A similar response was observed after two 1 g/kg infusions in 3 adult patients with chronic ITP, and one child with acute ITP. The remaining 2 adult patients with chronic ITP received more than two 1 g/kg infusions before achieving a platelet count greater than 40,000/mm³. The rise in platelet count was generally rapid, occurring within 5 days. However, this rise was transient and not considered curative. Platelet count rises lasted 2 to 3 weeks, with a range of 12 days to 6 months. It should be noted that childhood ITP may resolve spontaneously without treatment.

Kawasaki Syndrome

Globulin Benesis S/D (immune globulin) , is indicated for the prevention of coronary artery aneurysms associated with Kawasaki syndrome. The percentage incidence of coronary artery aneurysm in patients with Kawasaki syndrome receiving Globulin Benesis (immune globulin) either at a single dose of 1 g/kg (n=22) or at a dose of 400 mg/kg for four consecutive days (n=22), beginning within seven days of onset of fever, was 3/44 (6.8%). This was significantly different (p=0.008) from a comparable group of patients that received aspirin only in previous trials and of whom 42/185 (22.7%) experienced coronary artery aneurysms.^10,11,12 All patients in the Globulin Benesis (immune globulin) trial received concomitant aspirin therapy and none experienced hypersensitivity-type reactions (urticaria, bronchospasm or generalized anaphylaxis).¹³ Several studies have documented the efficacy of intravenous gammaglobulin in reducing the incidence of coronary artery abnormalities resulting from Kawasaki syndrome.^{10-12, 14-17}

Replacement therapy in adults, children and adolescents (2-18 years) in:

- Primary immunodeficiency syndromes with impaired antibody production.

- Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

- Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who failed to respond to pneumococcal immunisation.

- Hypogammaglobulinaemia in patients after allogenic haematopoietic stem cell transplantation (HSCT).

- Congenital AIDS with recurrent bacterial infections.

Immunomodulation in adults, children and adolescents (2-18 years) in:

- Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

- Guillain Barré syndrome.

- Kawasaki disease.

Primary Immunodeficiency Diseases

For patients with primary immunodeficiencies, monthly doses of approximately 300-600 mg/kg infused at 3 to 4 week intervals are commonly used.^42,43 As there are significant differences in the half-life of IgG among patients with primary immunodeficiency, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The minimum serum concentration of IgG necessary for protection varies among patients and has not been established by controlled clinical trials<.

B-cell Chronic Lymphocytic Leukemia (CLL)

For patients with hypogammaglobulinemia and/or recurrent bacterial infections due to B-cell Chronic Lymphocytic Leukemia, a dose of 400 mg/kg every 3 to 4 weeks is recommended.

Kawasaki Syndrome

For patients with Kawasaki syndrome, either a single 1 g/kg dose or a dose of 400 mg/kg for four consecutive days beginning within seven days of the onset of fever, administered concomitantly with appropriate aspirin therapy (80-100 mg/kg/day in four divided doses) is recommended.⁴⁴

Idiopathic Thrombocytopenic Purpura (ITP)

For patients with acute or chronic Idiopathic Thrombocytopenic Purpura, a dose of 1 g/kg is recommended. The need for additional doses can be determined by clinical response and platelet count. Up to three separate doses may be given on alternate days if required.

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, the recommended doses should not be exceeded and the concentration and infusion rate selected should be the minimum level practicable. Reduction in dose, concentration, and/or rate of administration in patients at risk of acute renal failure has been proposed in the literature in order to reduce the risk of acute renal failure.⁴⁵

Reconstitution: Use Aseptic Technique

When reconstitution is performed aseptically outside of a sterile laminar air flow hood, administration should begin as soon as possible, but not more than 2 hours after reconstitution. When reconstitution is performed aseptically in a sterile laminar air flow hood, the reconstituted product may be either maintained in the original glass container or pooled into VIAFLEX bags and stored under constant refrigeration (2-8°C), for up to 24 hours. (The date and time of reconstitution/pooling should be recorded). If these conditions are not met, sterility of the reconstituted product cannot be maintained. Partially used vials should be discarded.

A. 5% Solution

1. Note: Reconstitute immediately before use.

2. If refrigerated, warm the Sterile Water for Injection, USP (diluent) and Globulin Benesis S/D, Immune Globulin Intravenous (Human) (dried concentrate), to room temperature.

3. Remove caps from concentrate and diluent bottles to expose central portion of rubber stoppers.

4. Cleanse stoppers with germicidal solution.

5. Remove protective covering from the spike at one end of the transfer device (Fig. 1)

6. Place the diluent bottle on a flat surface and, while holding the bottle to prevent slipping, insert the spike of the transfer device perpendicularly through the center of the bottle stopper.

7. Press down firmly so that the transfer device fits snugly against the diluent bottle (Fig. 2).

Caution: Failure to use center of stopper may result in dislodging the stopper.

8. Remove the protective covering from the other end of the transfer device. Hold diluent bottle to prevent slipping.

9. Hold concentrate bottle firmly and at an angle of approximately 45 degrees. Invert the diluent bottle with the transfer device at an angle complementary to the concentrate bottle (approximately 45 degrees) and firmly insert the transfer device into the concentrate bottle through the center of the rubber stopper (Fig. 3).

Note: Invert the diluent bottle with attached transfer device rapidly into the concentrate bottle in order to avoid loss of diluent.

Caution: Failure to use center of stopper may result in dislodging the stopper and loss of vacuum.

10. The diluent will flow into the concentrate bottle quickly. When diluent transfer is complete, remove empty diluent bottle and transfer device from concentrate bottle. Discard transfer device after single use. 11. Thoroughly wet the dried material by tilting or inverting and gently rotating the bottle (Fig. 4). Do not shake. Avoid foaming.

12. Repeat gentle rotation as long as undissolved product is observed.

B. 10% Solution

Follow steps 1-4 as previously described in A.

5. To prepare a 10% solution, reconstitute with the appropriate volume of diluent as indicated in Table 2, which indicates the volume of diluent required for a 5% or 10% concentration. Using aseptic technique, draw the required volume of diluent into a sterile hypodermic syringe and needle. Discard the filled syringe.

6. Using the residual diluent in the diluent vial, follow steps 5-12 as previously described in A

Table 2: Required Diluent Volume

Rate of Administration

It is recommended that initially a 5% solution be infused at a rate of 0.5 mL/kg/Hr. If infusion at this rate and concentration causes the patient no distress, the administration rate may be gradually increased to a maximum rate of 4 mL/kg/Hr for patients with no history of adverse reactions to IGIV and no significant risk factors for renal dysfunction or thrombotic complications. Patients who tolerate the 5% concentration at 4 mL/kg/Hr can be infused with the 10% concentration starting at 0.5 mL/kg/Hr. If no adverse effects occur, the rate can be increased gradually up to a maximum of 8 mL/kg/Hr. In general, it is recommended that patients beginning therapy with IGIV or switching from one IGIV product to another be started at the lower rates of infusion and should be advanced to the maximal rate only after they have tolerated several infusions at intermediate rates of infusion. It is important to individualize rates for each patient. As noted in the WARNINGS section, patients who have underlying renal disease or who are judged to be at risk of developing thrombotic events should not be infused rapidly with any IGIV product.

Although there are no prospective studies demonstrating that any concentration or rate of infusion is completely safe, it is believed that risk may be decreased at lower rates of infusion.⁴⁵ Therefore, as a guideline, it is recommended that these patients who are judged to be at risk of renal dysfunction or thrombotic complications be gradually titrated up to a more conservative maximal rate of less than 3.3 mg/ kg/min ( < 2mL/kg/Hr of a 10% solution or < 4mL/kg/Hr of a 5% solution).

It is recommended that antecubital veins be used especially for 10% solutions, if possible. This may reduce the likelihood of the patient experiencing discomfort at the infusion site (see ADVERSE REACTIONS).

A rate of administration which is too rapid may cause flushing and changes in pulse rate and blood pressure. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

Drug Interactions

Admixtures of Globulin Benesis S/D, Immune Globulin Intravenous (Human), with other drugs and intravenous solutions have not been evaluated. It is recommended that Globulin Benesis S/D (immune globulin) be administered separately from other drugs or medications which the patient may be receiving. The product should not be mixed with Immune Globulin Intravenous (Human) from other manufacturers. Antibodies in immune globulin preparations may interfere with patient responses to live vaccines, such as those for measles, mumps, and rubella. The immunizing physician should be informed of recent therapy with Immune Globulin Intravenous (Human) so that appropriate precautions can be taken.

Administration

Globulin Benesis S/D (immune globulin) should be administered as soon after reconstitution as possible, or as described in the DOSAGE AND ADMINISTRATION.

The reconstituted material should be at room temperature during administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstituted material should be a clear to slightly opalescent and colorless to pale yellow solution. Do not use if particulate matter and/or discoloration is observed.

Follow directions for use which accompany the administration set provided. If another administration set is used, ensure that the set contains a similar filter.

Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Posology

The dose and dose regimen is dependent on the indication.

In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dose regimens are given as a guideline.

Replacement therapy in primary immunodeficiency syndromes

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/l. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is 0.4 - 0.8 g/kg given once, followed by at least 0.2 g/kg given every three to four weeks.

The dose required to achieve a trough level of 5-6 g/l is of the order of 0.2 - 0.8 g/kg/month. The dose interval when steady state has been reached varies from 3 - 4 weeks.

Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels.

Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed; hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation; congenital AIDS with recurrent bacterial infections

The recommended dose is 0.2 - 0.4 g/kg every three to four weeks.

Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation

The recommended dose is 0.2-0.4 g/kg every three to four weeks. The trough levels should be maintained above 5 g/l.

Primary immune thrombocytopenia

There are two alternative treatment schedules:

- 0.8-1 g/kg given on day one; this dose may be repeated once within 3 days

- 0.4 g/kg given daily for two to five days.

The treatment can be repeated if relapse occurs.

Guillain Barré syndrome

0.4 g/kg/day over 5 days.

Kawasaki disease

1.6 - 2.0 g/kg should be administered in divided doses over two to five days or 2.0 g/kg as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.

The dose recommendations are summarised in the following table:

Paediatric population

Globulin Benesis 50 mg/ml is contraindicated in children aged 0 to 2 years.

The posology in children and adolescents (2-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions.

Method of administration

For intravenous use.

Globulin Benesis 50 mg/ml should be infused intravenously at an initial rate of 0.01 - 0.02 ml/kg/min for the first thirty minutes. If well tolerated , the rate of administration may gradually be increased to a maximum of 0.1 ml/kg/min.

Globulin Benesis S/D (immune globulin) is contraindicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern (see INDICATIONS and WARNINGS). Patients may experience severe hypersensitivity reactions or anaphylaxis in the setting of detectable IgA levels following infusion of Globulin Benesis S/D (immune globulin). The occurrence of severe hypersensitivity reactions or anaphylaxis under such conditions should prompt consideration of an alternative therapy.

Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.

Fructose intolerance.

In babies and young children (aged 0-2 years) hereditary fructose intolerance (HFI) may not yet be diagnosed and may be fatal, thus, they must not receive this medicinal product.

WARNINGS

Warning

Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.¹⁸ Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially 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.

*Globulin Benesis S/D (immune globulin) does not contain sucrose.

Globulin Benesis S/D, Immune Globulin Intravenous (Human) 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 by inactivating and/or removing certain viruses (See DESCRIPTION). Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. 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 Baxter Healthcare Corporation at 1-800-423-2862 (in the U.S.). The physician should discuss the risks and benefits of this product with the patient.

Globulin Benesis S/D, Immune Globulin Intravenous (Human), should only be administered intravenously. Other routes of administration have not been evaluated.

Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine and antihistamines should be available for treatment of any acute anaphylactoid reactions.

Globulin Benesis S/D (immune globulin) contains only trace amounts of IgA ( ≤ 2.2 µg/mL in a 5% solution). Globulin Benesis S/D (immune globulin) is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern. It should be given with caution to patients with antibodies to IgA or IgA deficiencies, that are a component of an underlying primary immunodeficiency disease for which IGIV therapy is indicated.^7,19 In such instances, a risk of anaphylaxis may exist despite the fact that Globulin Benesis S/D (immune globulin) contains only trace amounts of IgA.

PRECAUTIONS

General

Some viruses, such as B19V (formerly known as parvovirus B19) or hepatitis A, are particularly difficult to remove or inactivate at this time. B19V most seriously affects pregnant women, or immune-compromised individuals. Symptoms of B19V infection include fever, drowsiness, chills, and runny nose followed about two weeks later by a rash and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and abdominal pain. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear.

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) [IGIV] treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 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 up to several thousand cells per mm³, predominantly from the granulocytic series, and 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 (2 g/kg) IGIV treatment.

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. Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of Globulin Benesis S/D (immune globulin) 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 rate of infusion to less than 4 mL/kg/Hr ( < 3.3 mg IG/kg/min) for a 5% solution or at a rate less than 2 mL/kg/ Hr ( < 3.3 mg IG/kg/min) for a 10 % solution.

Certain components used in the packaging of this product contain natural rubber latex.

Hemolysis

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.^20-23 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration²³ (See ADVERSE REACTIONS). IGIV recipients should be monitored for clinical signs and symptoms of hemolysis (See PRECAUTIONS: Laboratory Tests).

Transfusion-Related Acute Lung Injury (TRALI)

There have been reports of noncardiogenic pulmonary edema (Transfusion Related Acute Lung Injury [TRALI]) in patients administered IGIV.²⁴ 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 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 anti-neutrophil antibodies in both the product and patient serum (See PRECAUTIONS: Laboratory Tests).

Thrombotic Events

Thrombotic events have been reported in association with IGIV^25-33 (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, hypercoaguable disorders and prolonged periods of immobilization. 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 triacylgycerols (triglycerides), or monoclonal gammopathies (See PRECAUTIONS: Laboratory Tests). Analysis of adverse event reports^13,34 has indicated that a rapid rate of infusion may be a risk factor for vascular occlusive events.

Laboratory Tests

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done (see PRECAUTIONS).

If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum (see PRECAUTIONS).

Because of the potentially increased risk of thrombosis, 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).

Pregnancy Category C

Animal reproduction studies have not been conducted with Globulin Benesis S/D, Immune Globulin Intravenous (Human). It is also not known whether Globulin Benesis S/D (immune globulin) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Globulin Benesis S/D (immune globulin) should be given to a pregnant woman only if clearly needed.

REFERENCES

13. Data in the files of Baxter Healthcare Corporation.

7. Buckley RH. Immunoglobulin replacement therapy: Indications and contraindications for use and variable IgG levels achieved In: Alving BM, Finlayson JS eds. Immunoglobulins: characteristics and use of intravenous preparations. Washington, D.C.: US Department of Health and Human Services; 1979;3-8.

18. 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;8:1788-1794.

19. Burks AW, Sampson HA, Buckley RH. Anaphylactic reactions after gammaglobulin administration in patients with hypogammaglobulinemia: Detection of IgE antibodies to IgA. N Eng J Med. 1986;314:560-564.

20. Wilson JR, Bhoopalam N, Fisher M. Hemoytic anemia associated with intravenous immunoglobulin. Muscle Nerve. 1997;20: 1142-1145.

21. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion. 1986;26:410-412.

22. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood. 1993;82:3789.

23. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmune. 1999;13:129-135.

24. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion. 2001;41: 264-268.

25. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology. 1994;44:223-226.

26. Harkness K, Howell SJL, Davies-Jones GAB. Encephalopathy associated with intravenous immunoglobulin treatment for Guillain-Barre syndrome. Journal of Neurology Neurosurgery, Psychiatry. 1996;60:586-598.

27. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet. 1986;2:217-218.

28. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol. 2000;65:30-34.

29. Brannagan TH, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology. 1996;47:674-677.

30. Haplea SS, Farrar JT, Gibson GA, Laskin M, Pizzi LT, Ashbury AK. Thromboembolic Events Associated with Intravenous Immunoglobulin Therapy. Neurology. 1997;48:A54.

31. Kwan T, and Keith P. Stroke Following Intravenous Immunoglobulin Infusion in a 28-Year-Old Male with Common Variable Immune Deficiency: A Case Report and Literature Review. Canadian Journal of Allergy & Clinical Immunology. 1999;4:250-253.

32. Elkayam O, Paran D, Milo R, Davidovitz Y, Almoznino-Sarafian D, Zelster D, Yaron M, Caspi D. Acute Myocardial Infarction Associated with High Dose Intravenous Immunoglobulin Infusion for Autoimmune Disorders. A study of four cases. Ann Rheum Dis. 2000;59:77-80.

33. Gomperts ED, Darr F. Letter to the Editor. Reference article - Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology. 2002. In Press.

34. Grillo JA, Gorson KC, Ropper AH, Lewis J, Weinstein R. Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology. 2001;57:1699-1701.

Sorbitol

Each ml of this medicinal product contains 50 mg of sorbitol. Patients with rare hereditary problems of fructose intolerance must not take this medicine.

In persons more than 2 years old with HFI, a spontaneous aversion for fructose-containing foods develops and may be combined with the onset of symptoms (vomiting, gastro-intestinal disorders, apathy, height and weight retardation). Therefore a detailed history with regard to HFI symptoms has to be taken of each patient prior to receiving Globulin Benesis.

In case of inadvertent administration and suspicion of fructose intolerance the infusion has to be stopped immediately, normal glycaemia has to be re-established and organ function has to be stabilized by means of intensive care.

Interferences with determination of blood glucose levels are not expected.

Certain severe adverse reactions may be related to the rate of infusion. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently

- in case of high rate of infusion

- in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion.

Potential complications can often be avoided by ensuring that patients:

- are not sensitive to human normal immunoglobulin by initially injecting the product slowly (at an initial rate of 0.01-0.02 ml/kg/min)

- are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration.

In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped.

The treatment required depends on the nature and severity of the adverse reaction.

In case of shock, standard medical treatment for shock should be implemented.

In all patients, IVIg administration requires:

- adequate hydration prior to the initiation of the infusion of IVIg

- monitoring of urine output

- monitoring of serum creatinine levels

- avoidance of concomitant use of loop diuretics.

Hypersensitivity

True hypersensitivity reactions are rare. They can occur in patients with anti-IgA antibodies.

IVIg is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Thromboembolism

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, and patients with diseases which increase blood viscosity).

In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Acute renal failure

Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, overweight, concomitant nephrotoxic medicinal products or age over 65.

In case of renal impairment, IVIg discontinuation should be considered. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain these excipients may be considered. Globulin Benesis does not contain sucrose, maltose or glucose.

In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm³, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. AMS may occur more frequently in association with high-dose (2 g/kg) IVIg treatment.

Haemolytic anaemia

IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis.

Interference with serological testing

After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs' test).

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to viral safety.

It is strongly recommended that every time that Globulin Benesis is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Paediatric population

It is recommended to monitor vital signs when administering Globulin Benesis to paediatric patients.

Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment.³⁵

Types of severe renal adverse reactions that have been seen following IGIV therapy include:

• acute renal failure
• acute tubular necrosis³⁶
• proximal tubular nephropathy
• osmotic nephrosis^{18 (see also 37-39)}

In general, reported adverse reactions to Globulin Benesis (immune globulin) , in patients with either congenital or acquired immunodeficiencies are similar in kind and frequency. Various minor reactions, such as mild to moderate hypotension, headache, fatigue, chills, backache, leg cramps, lightheadedness, fever, urticaria, flushing, slight elevation of blood pressure, nausea and vomiting may occasionally occur. Slowing or stopping the infusion usually allows the symptoms to disappear promptly.

Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine and antihistamines should be available for treatment of any acute anaphylactoid reaction (See WARNINGS).

Primary Immunodeficiency Diseases

Twenty-one adverse reactions occurred in 341 infusions (6%), when using Globulin Benesis (immune globulin) (5% solution), in a clinical trial of 17 patients with primary immunodeficiency.⁴⁰ Of the 17 patients, 12 (71%) were adults, and 5 (29%) were children (16 years or younger).

In a cross-over study comparing Globulin Benesis and Globulin Benesis S/D (immune globulin) (5% solutions) conducted in a small number (n=10) of primary immunodeficient patients, no unusual or unexpected adverse reactions were observed in the Globulin Benesis S/D (immune globulin) group. The adverse reactions experienced in the Globulin Benesis S/D (immune globulin) group were similar in frequency and nature to those observed in the control group consisting of patients receiving Globulin Benesis (immune globulin).

Globulin Benesis (immune globulin) , reconstituted to a concentration of 10%, was administered intravenously at rates varying from 2 to 11 mL/kg/Hr. Systemic reactions occurred in 23 (10.5%) of 219 infusions. This compares with an adverse reaction incidence of 6% (only systemic reactions reported) for primary immunodeficient patients previously treated with a 5% solution at infusion rates varying between 2 and 8 mL/kg/Hr, as described above (see reference 40). Local pain or irritation was experienced during 35 (16%) of 219 infusions. Application of a warm compress to the infusion site alleviated local symptoms. These local reactions tended to be associated with hand vein infusions and their incidence may be reduced by infusions via the antecubital vein.

B-cell Chronic Lymphocytic Leukemia (CLL)

In the study of patients with B-cell Chronic Lymphocytic Leukemia, the incidence of adverse reactions associated with Globulin Benesis (immune globulin) infusions was approximately 1.3% while that associated with placebo (normal saline) infusions was 0.6%.⁹

Idiopathic Thrombocytopenic Purpura (ITP)

During the clinical study of Globulin Benesis (immune globulin) for the treatment of Idiopathic Thrombocytopenic Purpura, the only adverse reaction reported was headache which occurred in 12 of 16 patients (75%). Of these 12 patients, 11 had chronic ITP (9 adults, 2 children), and one child had acute ITP. Oral antihistamines and analgesics alleviated the symptoms and were used as pretreatment for those patients requiring additional IGIV therapy. The remaining 4 patients did not report any side effects and did not require pretreatment.

Kawasaki Syndrome

In a study of patients (n=51) with Kawasaki syndrome, no hypersensitivity-type reactions (urticaria, bronchospasm or generalized anaphylaxis) were reported in patients receiving either a single 1g/kg dose of IGIV, Globulin Benesis (immune globulin) , or 400 mg/kg of IGIV, Globulin Benesis (immune globulin) , for four consecutive days.¹³ Mild adverse reactions, including chills, flushing, cramping, headache, hypotension, nausea, rash and wheezing, were reported with both dose regimens. These adverse reactions occurred in 7/51 (13.7%) patients and in association with 7/129 (5.4%) infusions. Of the 25 patients who received a single 1 g/kg dose, 4 patients experienced adverse reactions for an incidence of 16%. Of the 26 patients who received 400 mg/kg/day over 4 days, 3 experienced a single adverse reaction for an incidence of 11.5%.³

Postmarketing

The following list of adverse reaction have been identified and reported during the post-approval use of IGIV products:

Respiratory: cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm

Cardiovascular: thromboembolism, hypotension

Neurological: seizures, tremor

Hematologic: hemolysis, positive direct antiglobulin (Coombs) test

General/Body as a Whole: pyrexia, rigors

Musculoskeletal: back pain

Gastrointestinal:hepatic dysfunction, abdominal pain

Rare and Uncommon Adverse Events:

Respiratory: apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Associated Lung Injury (TRALI)

Integumentary: bullous dermatitis, epidermolysis, erythema multiforme, Stevens- Johnson syndrome

Cardiovascular: cardiac arrest, vascular collapse

Neurological: coma, loss of consciousness

Hematologic: pancytopenia, leukopenia

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.⁴¹ (See PRECAUTIONS)

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions have been observed with human normal immunoglobulin.).

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention:

- very common (>1/10)

- common (>1/100 to <1/10)

- uncommon (>1/1,000 to <1/100)

- rare (>1/10,000 to <1/1,000)

- very rare (<1/10,000)

- not known (cannot be estimated from the available data)

Within each frequency grouping, adverse reactions are presented in order of decreasing of seriousness.

Frequency of Adverse Reactions (ADRs) in clinical studies with Globulin Benesis 50 mg/ml

Description of selected adverse reactions

The most reported post-marketing ADRs received since the product was authorised for both concentrations were chest pain, flushing, blood pressure increased and decreased, malaise, dyspnoea, nausea, vomiting pyrexia, back pain, headache and chills.

Paediatric population

The safety results for 29 paediatric patients (those ≤ 17 years old) included in the PID studies were evaluated. It was observed that the proportion of headache, pyrexia, tachycardia and hypotension in children was higher than in adults. Assessment of vital signs in clinical trials of the paediatric population did not indicate any pattern of clinically relevant changes.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the UK Yellowcard Scheme: www.mhra.gov.uk/yellowcard or telephone 0808 100 3352.

No information provided.

Overdose may lead to fluid overload and hyper viscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.

Paediatric population

Information on overdose in children has not been established with Globulin Benesis. However, as in adult population, overdose may lead to fluid overload and hyperviscosity as with any other intravenous immunoglobulins.