DOSAGE AND ADMINISTRATION

  • Globucel® liquid should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid and/or discoloration is observed.
  • Globucel® liquid must not be mixed with other medicinal products or administered simultaneously with other intravenous preparation in the same infusion set. Do not mix with intravenous immunoglobulin products from other manufacturers.
  • Prior to initiation of IVIG infusion, ensure that patients are not volume depleted and are adequately hydrated.
  • In general, in patients receiving initial doses of IVIG or switching from one IVIG preparation to another, initiate the infusion rate at the lower end of the recommended range and increase to the maximum recommended rate only after the patient has tolerated several infusions at an intermediate infusion rate.
  • If an adverse reaction occurs during the IVIG infusion, decrease the rate of infusion or stop the infusion until the reaction subsides.
  • Do not administer by rapid IV infusion in patients with or at risk for renal dysfunction or thrombotic events.
  • Risk factors should be identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant nephrotoxic medications, or over the age of 65.
  • Assure that patients are not volume depleted prior to the initiation of the infusion of IVIg. Patients should be observed for at least 20 minutes after administration.
  • Infusion rate: 0.01-0.02 mL/kg/min, for the first 30 minutes preferably using infusion pump; increase to maximum 0.06 mL/kg/min, if no adverse reactions are observed.

Table 1. Dosage recommendation for human intravenous immunoglobulin

Indications

Dose

Replacement therapy in primary immunodeficiency syndromes

Starting dose: 0.3-0.6 g/kg followed every 3-4 weeks adjusted to achieve desired trough serum IgG concentration and clinical response

Replacement therapy in secondary immunodeficiency syndromes

0.2-0.4 g/kg, every 3-4 weeks adjusted to achieve desired trough serum IgG concentration and clinical response

Kawasaki syndrome

2 g/kg in one dose in association with acetylsalicylic acid or 1.6-2 g/kg in several doses for 2-5 days in association with acetylsalicylic acid

Idiopathic thrombocytopenic purpura

0.2-0.4 g/kg for 5 days or 0.8-1 g.kg on day 1, possibly repeated once within three days.

B-cell Chronic lymphocytic leukemia

Recommended dose is 0.4 g/kg every 3-4 weeks.

Pediatric HIV-I infection

0.2-0.4 g/kg every 2-4 weeks.

Allogeneic bone marrow transplantation

0.5 g/kg every week from day -7 up to three months after transplantation. Individualize dosage to maintain trough serum IgG concentrations exceeding 400-500 mg/dL; monitor trough serum IgG concentrations approximately every 2 weeks.

Guillain-Barre syndrome

0.4 g/kg /d for 5 days

Chronic inflammatory demyelinating polyneuropathy

Initially loading dose of 2 g/kg (40 mL/kg) given in divided doses over 2 to 4 consecutive day. Maintenance infusion of 1 g/kg (20 mL/kg) administered over 1 day or divided into two doses of 0.5 g/kg (10 mL/kg) given on 2 consecutive days, every three weeks.

PRECAUTION AND WARNINGS

  • Sensitivity
  • Severe hypersensitivity reactions, including anaphylaxis, reported rarely following administration of Intravenous Immunoglobulin (IVIG). Epinephrine and antihistamines should be readily available in case anaphylaxis or an anaphylactoid reaction occurs. If severe hypersensitivity reaction occurs, discontinue immune globulin immediately and institute appropriate therapy as indicated.
  • Infusion Reactions: There is a risk of reactions including fever, chills, nausea, and vomiting upon IV infusion in patients who have not previously received immune globulin therapy, patients who are being switched to another preparation of immune globulin, and those who have not received immune globulin within the preceding 8 weeks. These reactions generally appear 30 minutes to 1 hour after initiation of the infusion and include flushing of the face, tightness in the chest, chills, fever, dizziness, nausea, vomiting, diaphoresis, and hypotension or hypertension. Closely monitor for adverse reactions throughout the infusion since these reactions may rarely lead to shock. IVIG may cause a precipitous fall in BP and clinical manifestations of anaphylaxis, which appear to be related to the rate of IVIG infusion; do not exceed the recommended rate of infusion. If flushing, changes in BP or pulse, or other infusion reactions occur, slow or temporarily stop the infusion. In some cases when symptoms subside promptly, the infusion may be resumed at a rate that is comfortable for the patient. Stop infusion immediately if anaphylaxis or other severe reactions occur.
  • Renal Effects: Renal dysfunction, acute renal failure, osmotic nephrosis, and death reported in patients receiving immune globulin. Patients at increased risk for acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia; those receiving concomitant nephrotoxic drugs; and/or those >65 years of age. To minimize risk of acute renal failure, ensure that patients are not volume depleted and are adequately hydrated prior to administration of IVIG. Always use lowest effective dosage at the minimum concentration available and at the minimum practicable rate of infusion, especially in patients at increased risk for acute renal failure. Assess urine output and renal function including blood urea nitrogen (BUN)/ serum creatinine, prior to and at appropriate intervals during therapy with IVIG, especially in patients considered at increased risk for acute renal failure. If renal dysfunction occurs, consider discontinuing immune globulin therapy.
  • Risk of Transmissible Agents in Plasma-derived Preparations: Because immune globulin preparations are prepared from pooled human plasma, they may carry a risk of transmitting infectious agents, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD). Risk for transmission of recognized blood-borne viruses is considered to be low because plasma donors are screened for certain viruses (HBV, HCV, HIV) and viral reduction/inactivation procedures used in immune globulin production reduce the risk of transmission. Despite such stringent procedures, a risk of transmission still remains. Because no purification method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived preparations and because new blood-borne viruses or other disease agents may emerge that may not be inactivated by the manufacturing process or various treatment procedures used, carefully weigh risk of pathogen transmission against the benefits of immune globulin therapy. Report all infections thought possibly to have been transmitted by immune globulin preparations to the appropriate manufacturer.
  • Blood Glucose Testing: IVIG preparations that contain maltose (e.g., Globucel®) may cause falsely elevated results in blood glucose determinations with tests that use nonspecific methods based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye oxidoreductase. This has resulted in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering Globucel®, the measurement of blood glucose must be done with a glucose-specific method. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products.
  • Thrombotic Effects: Thrombotic events (e.g., chest pain, MI, CHF, cerebral infarction, ischemic encephalopathy, severe headache requiring hospitalization, pulmonary embolism, retinal vein occlusion, peripheral venous thrombosis), including some fatalities, reported in patients receiving IVIG. IVIG-induced alterations of blood rheology (e.g., platelet activation, increased blood viscosity) and infusion-related hypertensive effects appear to contribute to the development of thrombotic complications. Patients with a history of atherosclerosis, multiple cardiovascular risk factors, hypertension, impaired cardiac output, cerebrovascular disease, coronary artery disease, coagulation or hypercoagulable disorders (e.g., factor V Leiden), prolonged periods of immobilization, advanced age, obesity, diabetes mellitus, acquired or inherited thrombotic disorder, previous thrombotic or thromboembolic event, or known or suspected hyperviscosity, and/or those receiving estrogen-containing products may be at increased risk. Weigh potential risks and benefits of immune globulin against those of alternative therapies in all patients in whom immune globulin is being considered. Prior to immune globulin therapy, carefully evaluate patients with thrombotic risk factors (e.g., those with advanced age, hypertension, cerebrovascular disease, CAD, diabetes mellitus, high serum levels of a monoclonal protein, a history of prolonged immobilization [e.g., bed-bound], and/or a history of thrombotic episodes). Because of potential increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity (e.g., those with cryoglobulins, fasting chylomicronemia/markedly high triglycerides, or monoclonal gammopathies).
  • Hemolysis: IVIG can contain blood group antibodies which may act as hemolysins and induce in vivo coating of RBCs with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Monitor for clinical signs and symptoms of hemolysis (e.g., increased heart rate, swelling, fatigue, difficulty breathing, yellowing of skin or eyes, dark-colored urine) and, if necessary, perform confirmatory laboratory testing. If a blood transfusion is indicated for a patient who developed hemolysis with clinically compromising anaemia after receiving immune globulin, adequate cross-matching should be performed to avoid exacerbating on-going hemolysis. Hemolytic anaemia also can develop subsequent to immune globulin therapy due to enhanced RBC sequestration and/or intravascular RBC destruction.
  • Transfusion-related Acute Lung Injury: Transfusion-related acute lung injury (noncardiogenic pulmonary edema) reported in patients receiving IGIV. Typically occurs within 1–6 hours after the infusion and is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Monitor patients receiving immune globulin for adverse pulmonary reactions. If transfusion-related acute lung injury is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the product and patient serum. Manage using oxygen therapy with adequate ventilatory support.
  • Aseptic Meningitis Syndrome: Aseptic meningitis syndrome reported infrequently in patients receiving immune globulin, especially at high doses (e.g., >1 g/kg) and/or by rapid IV infusion. Symptoms (e.g., severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, vomiting) may occur within several hours to 2 days following IIVIG administration. In patients exhibiting such symptoms, perform a thorough neurologic examination, including CSF studies, to rule out other causes of meningitis. CSF analysis frequently reveals elevated protein levels (up to several hundred mg/dL) and pleocytosis (up to several thousand cells per mm 3 ), predominantly from the granulocytic series, but negative culture results. It appears that patients with a history of migraine may be more susceptible. Syndrome has resolved without sequelae within several days following discontinuance of the immune globulin.
  • Hyperproteinemia, Increased Viscosity, and Hyponatremia: Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IVIG. The hyponatremia is likely to be pseudohyponatremia, as demonstrated by decreased calculated serum osmolality or elevated osmolar gap. If hyponatremia occurs, it is critical to distinguish true hyponatremia from pseudohyponatremia. Treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and may predispose to thromboembolic events.
  • Volume Overload: High-dose IVIG regimens (1 g/kg daily for 1–2 days) used for treatment of chronic ITP are not recommended in individuals with expanded fluid volumes or when fluid volume may be a concern.

ADVERSE REACTIONS

  • The most common adverse reactions reported in ≥ 5% of clinical trial subjects occurring during or within 48 hours of an infusion were headache, nausea, chills, asthenia (fatigue), pyrexia, upper abdominal pain, diarrhea, back pain, hyperhidrosis, and flushing. In post-marketing surveillance, serious adverse reactions reported with intravenous immunoglobulin were anaphylaxis, acute renal failure, myocardial infarction, cerebral vascular accident, transient ischemic attack, deep vein thrombosis, pulmonary embolism, aseptic meningitis, acute hemolysis, and TRALI.
  • The following adverse reactions have been identified during post-approval use of IVIG products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to IVIG products:
  • Blood and lymphatic system disorders: Leukopenia, haemolytic anaemia, pancytopenia, leukopenia, hemolysis 
  • Immune system disorders: Hypersensitivity, anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, angioneurotic oedema, face oedema
  • Metabolic and nutritional disorders: Fluid overload
  • Psychiatric disorders: Agitation
  • Nervous system disorders:Headache, cerebrovascular accident, meningitis aseptic, migraine, dizziness, paraesthesia, coma, loss of consciousness, seizures, tremors
  • Cardiac disorder: Myocardial infarction, tachycardia, palpitations, cardiac arrest, thromboembolism
  • Vascular disorders:Hypotension, thrombosis, peripheral circulatory failure, hypertension , vascular collapse
  • Respiratory, thoracic and mediastinal disorders: Respiratory failure, pulmonary embolism, pulmonary oedema, bronchospasm, dyspnoea, cough, Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Related Acute Lung Injury (TRALI), cyanosis, hypoxemia
  • Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, hepatic dysfunction
  • Skin and subcutaneous tissue disorders: Eczema, urticaria, rash, rash erythematous, dermatitis, pruritus, alopecia, Steven-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
  • Musculoskeletal and connective tissue disorders: Back pain, arthralgia, myalgia, pain in extremity
  • Renal and urinary disorders: Acute renal failure
  • General disorders and administration site conditions: Fatigue, injection site reaction, pyrexia, chills, chest pain, hot flush, flushing, hyperhidrosis, malaise
  • Laboratory abnormalities: Hepatic enzymes increased, blood glucose false positive.