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

NON-CLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies were conducted on carcinogenesis, mutagenesis, or impairment of fertililty with Octagam 5% liquid.

Repeated-dose toxicity studies and the genotoxic studies gave no evidence of carcinogenic properties of TNBP and Octoxynol [ 13 ], [ 14 ].

The results of in vitro and in vivo genotoxicity studies for TNBP and Octoxynol were negative. The results of studies on the embryotoxic and teratogenic properties of TNBP and Octoxynol in rats and rabbits at a wide range of i.v. doses were also negative.

Animal Toxicology and/or Pharmacology

No studies were conducted on non-clinical pharmacology, toxicology, local tolerance or pharmacokinetics with Octagam 5% liquid.

A variety of single-dose toxicity studies were performed for TNBP and Octoxynol alone or in combination. The lowest toxic dose of TNBP + Octoxynol (1+5) was 10,000 mcg/kg BM in rats after intravenous administration. Studies on 13-week toxicity were performed for combinations of TNBP + Octoxynol in a broad dose range intravenously in dogs and rats. In these studies the lowest toxic dose for rats was local 60mcg TNBP/kg +300mcg Octoxynol/kg BM i.v. (concentration: 0.0006% and 0.003%, respectively) and systemic 300mcg TNBP/kg + 1,500mcg Octoxynol/kg BM i.v. (concentration: 0.003% and 0.015%, respectively). The lowest toxic dose for dogs was local 50 mcg TNBP/kg + 250mcg Octoxynol/kg BM i.v. (concentration: 0.005% and 0.025%, respectively) and systemic 500mcg TNBP/kg + 2,500mcg Octoxynol/kg BM i.v. (concentration: 0.05% and 0.25%, respectively).

Local tolerance of TNBP and Octoxynol was evaluated from the experiments on repeat-dose toxicity (rats, dogs) and on developmental toxicity (rats, rabbits). In these animal studies the lowest dose exerting local adverse reactions was 50 + 250 mcg/kg BM (TNBP + Octoxynol; daily injections) in dogs. At this dose 4 out of 6 dogs were affected starting in week 7 of treatment.

A pharmacokinetic study was carried out in rats given 300 mcg of TNBP/kg and 1,500 mcg Octoxynol/kg BM i.v. The plasma half-life for TNBP was approximately 20 minutes. Octoxynol was not detected.

CLINICAL STUDIES

In an open-label, multicenter study, 46 patients (including 10 patients between the ages of 6 and 12, and one 15 years old) with primary humoral immunodeficiency (PI) received Octagam 5% liquid individualized doses of 300 — 600 mg/kg every 3 or 4 weeks for 12 months. Six patients discontinued the study prematurely.

Eligible patients had to meet the following key inclusion criteria: aged 3 years or older; had a PI that had as a significant component hypogammaglobulinemia or antibody deficiency; had been receiving IGIV replacement therapy at a steady dose for at least 3 months prior to study entry and had maintained a trough level of at least 320 mg/dL above baseline serum IgG levels.

Patients were excluded if they had a history of severe reactions to blood or any blood-derived product; if they had a selective IgA deficiency or demonstrable antibodies to IgA; if they received blood or any blood product or derivative other than a commercially available IGIV within 3 months prior to study entry; if they had hepatic function abnormalities or a positive direct Coombs test at screening; if they had a pre-existing renal impairment, a history of drug or alcohol abuse in the previous 12 months or acquired medical condition known to cause secondary immune deficiency; if they were receiving long-term daily treatment with steroids at a dose of at least 1 mg/kg/day; if they had a requirement for pre-medication for IGIV infusion other than aspirin, acetaminophen, or other non-steroidal anti-inflammatory drug, or antihistamine; and if the received immunosuppressive or immunomodulatory drugs.

The primary efficacy endpoint was the number of episodes of serious infections/patient/year. Serious infection included pneumonia, bacteremia or sepsis, osteomyelitis/septic arthritis, visceral abscesses or bacterial or viral meningitis. Secondary efficacy variables were: the number of days of work/school missed; the number and days of hospitalizations; the number of visits to physicians for acute problems and/or visits to hospital emergency rooms; and the number of other infections documented by radiograph and fever.

For the primary endpoint, which was the number of episodes of serious infections, the observed rate was 0.1 infections per patient per year (5 infections over 43.5 patient-years).

Table 10: Summary of Secondary Efficacy Variables

Variable	Subjects N	Subjects %	Total Days or Visits	Total Subject Years	Days or Visits/Subj./YearEstimate
Work/School Days Missed	30	65	241	43.5	5.5
Days in Hospital	4	9	16	43.5	0.4
Visits to Physician/ER	27	59	92	43.5	2.1

REFERENCES

1. Duhem, C., Dicato, M. A. and Ries, F. Side-effects of intravenous immune globulins. Clin. Exp. Immunol. 97 Suppl 1, 79-83 (1994).
2. Kannan, S., Rowland, C. H., Hockings, G. I. and Tauchmann, P. M. Intragam can interfere with blood glucose monitoring. Med. J. Aust. 180, 251-252 (2004).
3. Steinberger, B. A., Ford, S. M., Coleman, T. A. Intravenous Immunoglobulin Therapy Results in Post-infusional Hyperproteinemia, Increased Serum Viscosity, and Pseudohyponatremia. Am J Hematol 73:97-100 (2003)
4. Dalakas, M. C. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 44, 223-226 (1994).
5. Wolberg, A. S., Kon, R. H., Monroe, D. M. and Hoffman, M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am. J Hematol. 65, 30-34 (2000).
6. Go RS, Call TG: Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulin-related thrombotic complications. Mayo Clin Proc75:83-85 (2000)
7. Sekul, E. A., Cupler, E. J. and Dalakas, M. C. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern. Med. 121, 259-262 (1994).
8. Pierce LR, Jain N: Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev 17:241-251 (2003)
9. Kessary-Shoham H., Levy, Y., Shoenfeld, Y., Lorber, M. and Gershon, H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. Journal of Autoimmunity. 13, 129-135 (1999).
10. Rizk, A., Gorson, K. C., Kenney, L. and Weinstein, R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 41, 264-268 (2001).
11. Koleba T, Ensom MH: Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy 26:813-827 (2006)
12. Lever, A. M., Yap, P. L., Cuthbertson, B., Wootton, R. and Webster, A. D. Increased half-life of gammaglobulin after prolonged intravenous replacement therapy. Clin Exp. Immunol 67, 441-446 (1987).
13. Auletta, CS., Kotkoskie, LA., Saulog, T., Richter, WR. A dietary oncogenicity study of tributyl phosphate in the CD-1 mouse. Toxicology 128, 135-141 (1998a).
14. Auletta CS., Weiner ML., Richter WR. A dietary toxicity/oncogenicity study of tributyl phosphate in the rat. Toxicology 128: 125-134 (1998b).

Octagam 5% liquid is supplied in 1.0 g, 2.5 g, 5 g, 10 g or 25 g single use bottles.

NDC Number	NDC Number	Size	Grams Protein
Octapharma Pharmazeutika Produktionsges.m.b.H	Octapharma AB
67467 – 843 — 01	68209 – 843 — 01	20 ml	1.0
67467 – 843 – 02	68209 – 843 – 02	50 ml	2.5
67467 – 843 – 03	68209 – 843 – 03	100 ml	5.0
67467 – 843 – 04	68209 – 843 – 04	200 ml	10.0
67467 – 843 – 05		500 ml	25.0

Octagam 5% liquid is not supplied with an infusion set. If a filtered infusion set is used (not mandatory), the filter size must be 0.2 – 200 microns.

Components used in the packaging of Octagam 5% liquid are latex-free.

Octagam 5% liquid may be stored for 24 months at +2°C to + 25°C (36°F to 77°F) from the date of manufacture.

Do not use after expiration date.

Do not freeze. Frozen product should not be used.

Any unused product or waste material should be disposed of in accordance with local requirements.

PATIENT COUNSELING INFORMATION

Information for Patients

Inform patients of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If allergic symptoms occur, patients should contact their physicians immediately.

Inform patients to also immediately report the following to their physician:

• signs and symptoms of renal failures, such as decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath

• signs and symptoms of aseptic meningitis, such as headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting

• signs and symptoms of hemolysis, such as fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine

• signs and symptoms of TRALI, such as severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, fever. TRALI typically occurs within 1 to 6 hours following transfusion

Inform patients that Octagam 5% liquid is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses, and, theoretically, the CJD agent). Inform patients that the risk Octagam 5% liquid may transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing the donated plasma for certain virus infections and by inactivating and/or removing certain viruses during manufacturing.

Inform patients that administration of IgG may interfere with the response to live viral vaccines such as measles, mumps and rubella. Inform patients to notify their immunizing physician of therapy with Octagam 5% liquid.

Octapharma USA Inc.Hoboken, NJ 07030

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL

Immune Globulin Intravenous (Human), 5%

Octapharma Pharmazeutika Produktionsges.m.b.H

20 mL

NDC 67467-843-01

100mL

NDC 67467-843-03

Image FileImage File

OCTAGAM IMMUNE GLOBULIN (HUMAN) immune globulin solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67467-843 Route of Administration Intravenous DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HUMAN IMMUNOGLOBULIN G (HUMAN IMMUNOGLOBULIN G) HUMAN IMMUNOGLOBULIN G 50 mg in 1 mL

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:67467-843-05 500 mL in 1 BOTTLE, GLASS None 2 NDC:67467-843-04 200 mL in 1 BOTTLE, GLASS None 3 NDC:67467-843-03 100 mL in 1 BOTTLE, GLASS None 4 NDC:67467-843-02 50 mL in 1 BOTTLE, GLASS None 5 NDC:67467-843-01 20 mL in 1 BOTTLE, GLASS None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125062 05/21/2004

Labeler — Octapharma Pharmazeutika Produktionsgesellschaft m.b.H. (301119178)

Revised: 09/2009 Octapharma Pharmazeutika Produktionsgesellschaft m.b.H.