Octagam Immune Globulin (Human): Package Insert and Label Information (Page 2 of 3)

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

Octagam 5% liquid Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Octagam 5% liquid. 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 Octagam 5% liquid.

Blood and lymphatic system disordersLeukopenia, haemolytic anaemia
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
Cardiac disorders Myocardial infarction, tachycardia, palpitations, cyanosis
Vascular disorders Hypotension, thrombosis, peripheral circulatory failure, hypertension
Respiratory, thoracic and mediastinal disorders Respiratory failure, pulmonary embolism, pulmonary oedema, bronchospasm, dyspnoea, cough
Gastrointestinal disorders Nausea, vomiting, diarrhoea, abdominal pain
Skin and subcutaneous tissue disorders Eczema, urticaria, rash, rash erythematous, dermatitis, pruritus, alopecia
Musculoskeletal and connective tissue disorders Back pain, arthralgia, myalgia, pain in extremity
Renal and urinary disorders Renal failure acute
General disorders and administration site conditions Fatigue, injection site reaction, pyrexia, chills, chest pain, hot flush, flushing, hyperhidrosis, malaise
Investigations Hepatic enzymes increased, blood glucose false positive

General

The following adverse reactions have been identified during post-approval use of IGIV 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 IGIV products:

RespiratoryApnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
Cardiovascular Cardiac arrest, thromboembolism, vascular collapse, hypotension
Neurological Coma, loss of consciousness, seizures, tremor
Integumentary Steven-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
Hematologic Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test
General / Body as a Whole Pyrexia, rigors
Musculoskeletal Back pain
Gastrointestinal Hepatic dysfunction, abdominal pain

DRUG INTERACTIONS

Admixtures of Octagam 5% liquid with other drugs and intravenous solutions have not been evaluated. It is recommended that Octagam 5% liquid be administered separately from other drugs or medications which the patient may be receiving. The product should not be mixed with IGIVs from other manufacturers.

The infusion line may be flushed before and after administration of Octagam 5% liquid with either normal saline or 5% dextrose in water.

Various passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing.

Antibodies in Octagam 5% liquid may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with IGIVs, so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Octagam 5% liquid. It is also not known whether Octagam 5% liquid can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Octagam 5% liquid should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Octagam 5% liquid has not been evaluated in nursing mothers.

Pediatric Use

Octagam 5% liquid was evaluated in 11 pediatric subjects (age range 6 – 16 years). There were no obvious differences observed between adults and pediatric subjects with respect to pharmacokinetics, efficacy and safety. No pediatric specific dose requirements were necessary to achieve the desired serum IgG levels.

Geriatric Use

Patients > 65 years of age may be at increased risk for developing certain adverse reactions such as thromboembolic events and acute renal failure (See Boxed Warnings and Precautions [5.3]). In the clinical trial only 4 geriatric patients ( > 65 years) were enrolled, a number insufficient to determine whether geriatric patients respond differently from younger subjects. In these 4 patients no particular issues were observed.

OVERDOSAGE

Overdose may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with impaired renal function.

DESCRIPTION

Immune Globulin Intravenous (Human), Octagam 5% liquid, is a solvent/detergent (S/D)-treated, sterile preparation of highly purified immunoglobulin G (IgG) derived from large pools of human plasma. Octagam 5% liquid is a solution for infusion which must be administered intravenously.

All units of human plasma used in the manufacture of Octagam 5% liquid are provided by FDA-approved blood establishments only, and are tested by FDA-licensed serological tests for HBsAg, antibodies to HCV and HIV and Nucleic Acid Test (NAT) for HCV and HIV-1 and found to be non-reactive (negative).

The product is manufactured by the cold ethanol fractionation process followed by ultrafiltration and chromatography. The manufacturing process includes treatment with an organic S/D mixture composed of tri-n-butyl phosphate (TNBP) and Triton X-100 (Octoxynol). The Octagam 5% liquid manufacturing process provides a significant viral reduction in in vitro studies (table 7). These reductions are achieved through a combination of process steps including cold ethanol fractionation, S/D treatment and pH 4 treatment.

Table 7: In vitro reduction factor during Octagam 5% liquid manufacturing

WNV: West Nile Virus

HIV-1: Human Immunodeficiency Virus — 1

PRV: Pseudorabies Virus

SBV: Sindbis Virus

MEV: Mouse Encephalomyelitis Virus

PPV: Porcine Parvovirus

Composition

The composition of Octagam 5% liquid is shown in table 8 as follows:

Table 8 : Composition

Component	Quantity/ml
Protein, of which not less than 96% is human normal immunoglobulin G	50 mg
Maltose	100 mg
Triton X-100	not more than 5 mcg
TNBP	not more than 1 mcg
IgA	not more than 0.2 mg
IgM	not more than 0.1 mg
Water for Injection	ad.

This preparation contains approximately 50 mg of protein per ml (5%) of which not less than 96% is human normal immunoglobulin G. Octagam 5% liquid contains not more than 3% aggregates, not less than 90% monomers and dimers and not more than 3% fragments.

The sodium content of the final solution is not more than 30 mmol/l and the pH is between 5.1 and 6.0. The osmolality is 310 — 380 mosmol/kg.

The manufacturing process for Octagam 5% liquid isolates IgG without additional chemical or enzymatic modification, and the Fc portion is maintained intact Octagam 5% liquid contains the IgG antibody activities present in the donor population. IgG subclasses are fully represented with the following approximate percents of total IgG: IgG ₁ is 65%, IgG ₂ is 30%, IgG ₃ is 3% and IgG ₄ is 2%.

Octagam 5% liquid contains a broad spectrum of IgG antibodies against bacterial and viral agents that are capable of opsonization and neutralization of microbes and toxins.

Octagam 5% liquid contains no preservative and no sucrose.

CLINICAL PHARMACOLOGY

Mechanism of Action

Octagam 5% liquid supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria or their toxins. The mechanism of action in PI has not been fully elucidated.

Pharmacodynamics

Octagam 5% liquid contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against various infectious agents reflecting the IgG activity found in the donor population. Octagam 5% liquid which is prepared from pooled material from not less than 1000 donors, has an IgG subclass distribution similar to that of native human plasma. Adequate doses of IGIV can restore abnormally low IgG level to the normal range. Standard pharmacodynamic studies were not performed.

Pharmacokinetics

Peak levels of IgG are reached immediately after infusion of Octagam 5% liquid. It has been shown that after infusion, exogenous IgG is distributed relatively rapidly between plasma and extravascular fluid until approximately half is partitioned in the extravascular space. Therefore a rapid initial drop in serum IgG is expected [ 11 ].

Studies show that the apparent half-life of Octagam 5% liquid is approximately 40 days in immunodeficient patients.

The main pharmacokinetic parameters of Octagam 5% liquid measured as total IgG in study OCTA-06 are displayed below:

In the pharmacokinetic study, a subset of 14 patients aged between 10 and 70 years with PI underwent pharmacokinetic assessments. Patients received infusions of Octagam 5% liquid (300 to 600 mg/kg) every 3 (n=6) to 4 (n=8) weeks for 12 months. Pharmacokinetic samples were collected at baseline and after the 5 ^th month of treatment. After the infusion, blood samples were taken until day 28 (for patients on a 21 day schedule, the interval was extended to 4 weeks for the pharmacokinetic study).

Table 9: PK Parameters of Octagam 5% liquid (Study OCTA-06)

			Octagam	5% liquid
	N	Mean	SD	Median
Cmax (mg/mL)	14	16.7	3.2	16.4
AUC (mg*h/mL)	14	7022	1179	7103
T1/2 (days)	14	40.7	17.0	36.3
Trough IgG Level 21 Day Infusion Schedule (mg/dL)	19	881.6	151.5	859
Trough IgG Level 28 Day Infusion Schedule (mg/dL)	25	763.5	156.8	760

The half-life of IgG can vary considerably from person to person. In particular, high concentrations of lgG and hypermetabolism associated with fever and infection have been seen to coincide with a shortened half-life of IgG. Longer half-lives are often seen with immunodeficient patients [ 12 ].