Immune Serum Globulin (Human) Product Monograph

SUMMARY PRODUCT INFORMATION

DESCRIPTION

IMMUNE SERUM GLOBULIN (HUMAN) treated with solvent/detergent is a sterile solution of immune globulin for intramuscular administration; it contains no preservative. IMMUNE SERUM GLOBULIN (HUMAN) is prepared by cold ethanol fractionation from human plasma. Plasma used in the manufacture of this product has been collected in Canada from volunteer donors. The immune globulin is isolated from solubilized Cohn fraction II. The fraction II solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration and finally ultrafiltration and diafiltration. IMMUNE SERUM GLOBULIN (HUMAN) is formulated as a 15-18% protein solution at a pH of 6.4-7.2 in 0.21-0.32 M glycine. The pH is adjusted with sodium carbonate. IMMUNE SERUM GLOBULIN (HUMAN) is then incubated in the final container for 21-28 days at 20-27°C.

INDICATIONS AND CLINICAL USE

Passive immunization should be considered when vaccines for active immunization are not available, or in situations when vaccine has not been used prior to exposure to the infective agent or is contraindicated (1). IMMUNE SERUM GLOBULIN (HUMAN) is indicated in the following situations.

Hepatitis A

The prophylactic value of IMMUNE SERUM GLOBULIN (HUMAN) is greatest when given before or soon after exposure to hepatitis A. IMMUNE SERUM GLOBULIN (HUMAN) is not indicated in persons with clinical manifestations of hepatitis A or in those exposed more than 2 weeks previously.

Measles (Rubeola)

IMMUNE SERUM GLOBULIN (HUMAN) should be given to prevent or modify measles in susceptible person exposed fewer than 6 days previously (2). A susceptible person is one who has not been vaccinated and has not had measles previously. IMMUNE SERUM GLOBULIN (HUMAN) may be especially indicated for susceptible household contacts of measles patients, particularly contacts under 1 year of age, for whom the risk of complications is highest (2). IMMUNE SERUM GLOBULIN (HUMAN) and measles vaccine should not be given at the same time (2). If a child is older than 12 months and has received IMMUNE SERUM GLOBULIN (HUMAN), he should be given measles vaccine about 5 months later when the measles antibody titer will have disappeared, provided there are no contraindications to the vaccine (1).

If a susceptible child exposed to measles is immunocompromised, IMMUNE SERUM GLOBULIN (HUMAN) should be given immediately (3). IMMUNE SERUM GLOBULIN (HUMAN) may also be considered for severely immunocompromised individuals exposed to measles regardless of immunization status. Children who are immunocompromised should not receive measles vaccine or any other live viral vaccine (4).

Varicella

Passive immunization against varicella in immunosuppressed patients is best accomplished by use of Varicella-Zoster Immune Globulin (Human) [VZIG]. If VZIG is unavailable, IMMUNE SERUM GLOBULIN (HUMAN), promptly given, may also modify varicella (5).

Rubella

The routine use of IMMUNE SERUM GLOBULIN (HUMAN) for prophylaxis of rubella in early pregnancy is of dubious value and cannot be justified. Some studies suggest that the use of IMMUNE SERUM GLOBULIN (HUMAN) in exposed, susceptible women can lessen the likelihood of infection and fetal damage; therefore, IMMUNE SERUM GLOBULIN (HUMAN) may benefit those women who will not consider a therapeutic abortion (3).

CONTRAINDICATIONS

• IMMUNE SERUM GLOBULIN (HUMAN) should not be given to patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section.
• IMMUNE SERUM GLOBULIN (HUMAN) should not be given to persons with isolated immunoglobulin A (IgA) deficiency. Such persons have the potential for developing antibodies to IgA and could have anaphylactic reactions to subsequent administration of blood products that contain IgA (7).
• IMMUNE SERUM GLOBULIN (HUMAN) should not be administered to patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections.

WARNINGS AND PRECAUTIONS

General

IMMUNE SERUM GLOBULIN (HUMAN) should not be administered intravenously or subcutaneously because of the potential for serious reactions. Injections should be made intramuscularly, and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel.

Skin tests should not be done. In most human beings the intradermal injection of concentrated gamma globulin solution with its buffers causes a localized area of inflammation which can be misinterpreted as a positive allergic reaction. In actuality, this does not represent an allergy; rather, it is localized tissue irritation of a chemical nature. Misinterpretation of the results of such tests can lead the physician to withhold badly needed human immunoglobulin from a patient who is not actually allergic to this material. True allergic responses to human gamma globulin given in the prescribed intramuscular manner are rare.

Although systemic reactions to intramuscularly administered immunoglobulin preparations are rare, epinephrine should be available for treatment of acute allergic symptoms.

IMMUNE SERUM GLOBULIN (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. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. 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 Grifols Canada Ltd. at 1-866-482-5226.

The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering to the patient.

Thromboembolic events

There is clinical evidence of an association between the administration of all immunoglobulins and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis.

Since thrombosis may occur in the absence of known risk factors, caution should be exercised in prescribing and administering immunoglobulins. The drug product should be administered at the minimum concentration available and at the minimum rate of infusion practicable. Patients should be adequately hydrated before administration.

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. Patients at risk of hyperviscosity should be monitored for signs and symptoms of thrombosis and blood viscosity assessed.

Risk factors for thromboembolic adverse events include: obesity, advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, acquired or inherited thrombophilic disorders, prolonged periods of immobilisation, severely hypovolemic patients, diseases which increase blood viscosity, hypercoagulable conditions, use of estrogens, indwelling central vascular catheters, and cardiovascular risk factors.

Special Populations

Pregnant Women

There is no experience of exposure in pregnancy during clinical trials. Animal reproduction studies have not been conducted with IMMUNE SERUM GLOBULIN (HUMAN). It is also not known whether IMMUNE SERUM GLOBULIN (HUMAN) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. IMMUNE SERUM GLOBULIN (HUMAN) should be given to a pregnant woman only if clearly needed.

Nursing Women

Because of the potential for unknown effects from IMMUNE SERUM GLOBULIN (HUMAN) in infants being nursed by mothers taking IMMUNE SERUM GLOBULIN (HUMAN), a decision should be made to either discontinue nursing or discontinue the administration of IMMUNE SERUM GLOBULIN (HUMAN), taking into account the importance of IMMUNE SERUM GLOBULIN (HUMAN) therapy to the mother and the possible risk to the infant.

Pediatrics (<18 years of age)

The safety and effectiveness of IMMUNE SERUM GLOBULIN (HUMAN) in the pediatric population have not been established.

Monitoring and Laboratory Tests

None required.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Local pain and tenderness at the injection site, urticaria, and angioedema may occur. Anaphylactic reactions, although rare, have been reported following the injection of human immune globulin preparations. Anaphylaxis is more likely to occur if IMMUNE SERUM GLOBULIN (HUMAN) is given intravenously; therefore, IMMUNE SERUM GLOBULIN (HUMAN) must be administered only intramuscularly.

DRUG INTERACTIONS

Drug-Drug Interactions

Drug-Food Interactions

No interactions are known.

Drug-Herb Interactions

No interactions are known.

Drug-Laboratory Interactions

No interactions are known.

DOSAGE AND ADMINISTRATION

Dosing Considerations

For intramuscular injection only. Do not give intravenously or subcutaneously.

Recommended Dose and Dosage Adjustment

Hepatitis A

IMMUNE SERUM GLOBULIN (HUMAN) in a dose of 0.02 mL/kg is recommended for household and institutional hepatitis A case contacts.

The following doses of IMMUNE SERUM GLOBULIN (HUMAN) are recommended for persons who plan to travel in areas where hepatitis A is common (8).

Measles (Rubeola)

IMMUNE SERUM GLOBULIN (HUMAN) should be given in a dose of 0.25 mL/kg to prevent or modify measles in a susceptible person exposed fewer than 6 days previously (1,2). A susceptible child who is exposed to measles and who is immunocompromised should receive a dose of 0.5 mL/kg (maximum dose, 15 mL) of IMMUNE SERUM GLOBULIN (HUMAN) immediately (3). The dosage of Immune Globulin (Human) for exposed individuals who have underlying malignant disease should be 0.5 mL/kg or 15 mL maximum (1).

Varicella

If Varicella-Zoster Immune Globulin (Human) is unavailable, IMMUNE SERUM GLOBULIN (HUMAN) at a dose of 0.6 to 1.2 mL/kg, promptly given, may also modify varicella (5).

Rubella

Some studies suggest that the use of IMMUNE SERUM GLOBULIN (HUMAN) in exposed, susceptible women can lessen the likelihood of infection and fetal damage; therefore, IMMUNE SERUM GLOBULIN (HUMAN) at a dose of 0.55 mL/kg may benefit those women who will not consider a therapeutic abortion (3).

Administration

IMMUNE SERUM GLOBULIN (HUMAN) is administered intramuscularly (see WARNINGS AND PRECAUTIONS: General), preferably in the anterolateral aspects of the upper thigh and the deltoid muscle of the upper arm. The gluteal region should not be used routinely as an injection site because of the risk of injury to the sciatic nerve. Doses over 10 mL should be divided and injected into several muscle sites to reduce local pain and discomfort. An individual decision as to which muscle is injected must be made for each patient based on the volume of material to be administered. If the gluteal region is used when very large volumes are to be injected or multiple doses are necessary, the central region MUST be avoided; only the upper, outer quadrant should be used (9).

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

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use

Reconstitution

Not required.

OVERDOSAGE

Although no data are available, clinical experience with other immunoglobulin preparations suggests that the only manifestations would be pain and tenderness at the injection site.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Passive immunization with IMMUNE SERUM GLOBULIN (HUMAN) modifies hepatitis A, and prevents or modifies measles. IMMUNE SERUM GLOBULIN (HUMAN) is not standardized with respect to antibody titers against hepatitis B surface antigen (HBsAg) and should not be used for prophylaxis of viral hepatitis type B. Prophylactic treatment to prevent hepatitis B can best be accomplished with use of Hepatitis B Immune Globulin (Human), often in combination with Hepatitis B Vaccine (8). IMMUNE SERUM GLOBULIN (HUMAN) is unlikely to be of benefit for post-exposure management of hepatitis C (1).

IMMUNE SERUM GLOBULIN (HUMAN) may be of benefit in women who have been exposed to rubella in the first trimester of pregnancy and who will not consider a therapeutic abortion (3). IMMUNE SERUM GLOBULIN (HUMAN) may also be considered for use in immunocompromised patients for passive immunization against varicella if Varicella-Zoster Immune Globulin (Human) is not available (5).

IMMUNE SERUM GLOBULIN (HUMAN) is not indicated for routine prophylaxis or treatment of rubella, poliomyelitis, mumps, or varicella. It is not indicated for allergy or asthma in patients who have normal levels of immunoglobulin (3).

Pharmacodynamics

See Mechanism of Action.

Pharmacokinetics

In a clinical study in healthy human adults receiving another hyperimmune immune globulin product treated with solvent/detergent, Rabies Immune Globulin (Human), prepared by the same manufacturing process, detectable passive antibody titers were observed in the serum of all subjects by 24 hours post injection and persisted through the 21 day study period. These results suggest that passive immunization with immune globulin products is not affected by the solvent/detergent treatment.

Duration of Effect

Peak levels of immunoglobulin G are obtained approximately 2 days after intramuscular injection of IMMUNE SERUM GLOBULIN (HUMAN) (10). The half-life of IgG in the circulation of individuals with normal IgG levels is 23 days (11).

STORAGE AND STABILITY

Store at 2-8 C. Do not freeze. Do not use after expiration date. The vials are single use. Once entered, discard any unused contents.

DOSAGE FORMS, COMPOSITION AND PACKAGING

IMMUNE SERUM GLOBULIN (HUMAN) contains 15-18% immune globulin (human) as active ingredient. It also contains 0.21-0.32 M glycine, USP.

IMMUNE SERUM GLOBULIN (HUMAN) is supplied in 5 mL and 10 mL single use vials.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Product Characteristics

IMMUNE SERUM GLOBULIN (HUMAN) is formulated as a 15-18% protein solution at a pH of 6.4-7.2 in 0.21-0.32 M glycine. It contains no preservative.

Viral Inactivation

The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for IMMUNE SERUM GLOBULIN (HUMAN) has been validated in laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1), was chosen as the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen to model Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model Hepatitis B virus and the Herpes viruses; and Reo virus type 3 (Reo) was chosen to model non-enveloped viruses and for its resistance to physical and chemical inactivation. Significant removal of model enveloped and non-enveloped viruses is seen in the Fraction II+IIIW to Effluent III step and significant removal of PRV and Reo virus is seen in the Effluent III to Filtrate III step. Significant inactivation of enveloped viruses is achieved at the time of treatment of solubilized Cohn Fraction II with solvent/detergent.

CLINICAL TRIALS

Though formal safety and efficacy trials have not been conducted with IMMUNE SERUM GLOBULIN (HUMAN), the clinical effectiveness of Immune Globulin (Human) in a number of clinical situations is well established. Please refer to the most recent edition of the Canadian Immunization Guide for information regarding efficacy and safety in various indications.

DETAILED PHARMACOLOGY

Animal Pharmacology

The effect of solvent-detergent treatment on the pharmacokinetic properties of Immune Globulin (Human) was studied in rabbits and rhesus monkeys. No significant differences were observed between products with or without solvent-detergent treatment with respect to time to maximal plasma concentration (t_max), maximum plasma concentration (C_max), half-life (t_½) and area under the plasma concentration curve (AUC).

Human Pharmacology

See Product Monograph PART I: ACTION AND CLINICAL PHARMACOLOGY.

TOXICOLOGY

Acute Toxicity

Acute and subacute toxicity of solvent-detergent Immune Globulin (Human) was assessed in rats and rabbits. The intramuscular LD₅₀ of the solvent-detergent treated product for rats and rabbits was > 2.4 mL (396 mg/kg). These values indicate a large margin of safety when compared to the clinical dose of 0.133 mL (21.9 mg)/kg.

Repeated Dose Toxicity

Repeated administration to rats and rabbits at dosages approximately nine-fold greater than those administered in the clinic did not produce any clinically relevant toxicity.

Reproductive Toxicology

Animal reproduction studies have not been conducted with IMMUNE SERUM GLOBULIN (HUMAN).

REFERENCES

1. 1. NACI. Canadian Immunization Guide, 6th ed. Ottawa: National Advisory Committee on Immunization. 2002.
2. 2. CDC. Measles, mumps, and rubella - vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1998;47(RR-8):1-58.
3. 3. AAP. Passive immunization. In: Pickering LK, editor. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003. pp. 53-66.
4. 4. Bruton OC. Agammaglobulinemia. Pediatrics 1952;9(6):722-8.
5. 5. Gershon AA, Piomelli S, Karpatkin M, Smithwick E, Steinberg S. Antibody to varicella-zoster virus after passive immunization against chickenpox. J Clin Microbiol 1978;8(6):733-5.
6. 6. CDC. Use of vaccines and immune globulins in persons with altered immunocompetence: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1993;42(RR-4):1-18.
7. 7. Fudenberg HH. Sensitization to immunoglobulins and hazards of gamma globulin therapy. In: Merler E, editor. Immunoglobulins: biological aspects and clinical uses. Washington, DC: Nat Acad Sci; 1970. pp. 211-20.
8. 8. CDC. Protection against viral hepatitis: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1990;39(RR-2):1-26.
9. 9. CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physician (AAFP). MMWR 2002;51(RR-2):1-36.
10. 10. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1(7762):1208-12.
11. 11. Waldman TA, Strober W, Blaese RM. Variations in the metabolism of immunoglobulins measured by turnover rates. Immunoglobulins: biological aspects and clinical uses 1970:33-51.