Sandoglobulin NF Liquid Product Monograph

SUMMARY PRODUCT INFORMATION

DESCRIPTION

Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), is a clear or slightly opalescent, colorless or pale yellow solution of unmodified human immunoglobulin. The concentration of the active ingredient in Sandoglobulin^® NF Liquid is 12% (120 g/L).

INDICATIONS AND CLINICAL USE

Sandoglobulin^® NF Liquid, (Immune Globulin Intravenous (Human) is indicated for the treatment of adult and pediatric patients with primary immune deficiency (PID) or secondary immune deficiency (SID) who require immunoglobulin replacement therapy.

Pediatrics (4 - 18 years of age):

Patients younger than 18 years of age were included in all the clinical studies conducted in PID.

CONTRAINDICATIONS

Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), is contraindicated in the following patients:

Patients who are hypersensitive to Immunoglobulin or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.

Patients who are hypersensitive to homologous immunoglobulins, especially in very rare cases of IgA deficiency when the patient has antibodies against IgA.

Sandoglobulin^® NF Liquid contains the excipient L-isoleucine and L-proline and is contraindicated in patients with maple syrup urine disease (MSUD) and hyperprolinemia. See WARNINGS AND PRECAUTIONS.

WARNINGS AND PRECAUTIONS

General

Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under "DOSAGE AND ADMINISTRATION" must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently

• in the case of high rate of infusion,
• in patients with hypo- or agammaglobulinaemia with or without IgA deficiency,
• in patients who receive IVIg 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.

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 side effect.

In case of shock, the current medical standards for shock treatment should be observed.

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, 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 the viral safety.

It is strongly recommended that every time that Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), 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.

Endocrine and Metabolism

Sandoglobulin^® NF Liquid contains the excipient L-isoleucine. Intake of L-isoleucine is contraindicated in patients with maple syrup urine disease (MSUD). This disease is a hereditary disorder of metabolism of oxidative decarboxylation. An increase of L-isoleucine may induce metabolic acidosis and may lead to cerebral damage.

Nicotinamide is a water soluble vitamin and forms an essential constituent of the normal human body. There is no known contraindication. Nicotinamide serum concentrations of 0.64 mmol/l measured after infusion of 1g/kg b.w. of Sandoglobulin^® NF Liquid is well tolerated. Higher serum concentrations may be associated with headache and nausea.

Sandoglobulin^® NF Liquid also contains as excipient the non-essential amino acid L-proline and is therefore contraindicated in patients with hyperprolinemia. Hyperprolinemia is a very rare disease and there are only a few families known worldwide with hyperprolinemia. Hyperprolinemic patients show an increased concentration of proline in the plasma and an increased urinary excretion of proline, hydroxyproline and glycine. The medical consequences appear to be moderate in most cases, however, an increased incidence of renal disease is observed in some cases and neurological symptoms and disturbance of mental development in others.

Immune

True hypersensitivity reactions are rare. They can occur very seldomly in cases of IgA deficiency with anti-IgA antibodies.

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.

Potential complications can often be avoided by ensuring:

• that patients are not sensitive to human normal immunoglobulin by first injecting the product slowly (< 1 ml/kg/min);
• that patients 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.

Neurologic

Effects on ability to drive and use machines

No effects on ability to drive and use machines have been observed.

Renal

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, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age over 65.

In a clinical study in pediatric patients with acute ITP, a transient slight-to-moderate decrease in Hemoglobin (Hb) levels has been observed in some children after administration of Sandoglobulin^® NF Liquid. It was most likely caused by the underlying disease, by a dilution effect and/or by repeated blood sampling. In these patients, a follow-up of Hb is recommended. Information on adverse reactions is provided in the section ADVERSE REACTIONS.

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.

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, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain sucrose may be considered. In addition, the product should be administered at the minimum concentration and infusion-rate practicable.

Sandoglobulin^® NF Liquid contains no carbohydrates like sucrose or maltose.

Special Populations

Pregnant Women: The safety of Sandoglobulin^® NF Liquid for use in human pregnancy has not been established in controlled clinical trials, consequently, it should only be used in pregnant women when the benefits outweigh the risks associated with its use.

Nursing Women: Immunoglobulins are excreted into the milk. Sandoglobulin^® NF Liquid should only be used in nursing woman when the benefits outweigh the risks associated with its use.

Monitoring and Laboratory Tests

After injection of immunoglobulins, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D may cause a positive direct or indirect antiglobulin test (Coombs’ test).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Adverse reactions such as chills, headache, fever, epistaxis, rhinitis, sinusitis, abdominal pain, vomiting, allergic reactions, nausea, arthralgia, diarrhea, pharyngitis, infections, bronchitis, coughing, dizziness, 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, isolated cases of reversible hemolytic anemia/hemolysis 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 with IVIg.

Thrombotic events have been reported in the elderly, in patients with signs of cerebral or cardiac ischemia, and in overweight and severely hypovolemic patients.

For safety with respect to transmissible agents, see WARNINGS AND PRECAUTIONS.

Clinical Trial Adverse Drug Reactions

SAGL351 Study

A total of 34 patients were treated in a Phase III, randomized, double-blind, 6 month duration study conducted in patients with Primary Immunodeficiency Disorders. A total of 17 patients received Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human) and 17 patients received lyophilized Sandoglobulin^®.

Table 1: Numbers of patients with AEs in most frequently affected SMTT body systems in the Phase III safety population Indication PID Treatment IVIG-F10 SAGL

No. of patients Included 17 17 With AEs 16 17 No. of AEs 94 117 Body system Body as a whole-general disorder 9 6 Central and peripheral nervous system

disorders

6 6

Gastrointestinal system disorders 5 9 Respiratory system disorders 12 14 Skin and appendages disorders 3 4 Musculoskeletal system disorders 5 2 Hearing and vestibular disorders 4 2 Cardiovascular disorder, general 0 1 Urinary system disorders 0 2 Vision disorders 2 3 White cell and reticulo-endothelial system

disorders

0 0

Application site disorder 1 3

IVIG-F10 = Sandoglobulin^® NF Liquid; SAGL = Sandoglobulin^®; SMTT = Ex-Sandoz Medical Terminology Thesaurus

The overall AE profile was similar for Sandoglobulin^® NF Liquid and Sandoglobulin^®. Almost all patients experienced at least 1 AE. The most common AEs were in the system organ classes or body systems body as a whole, central and peripheral nervous system, and gastrointestinal, respiratory. AEs were most common in the respiratory system.

Table 2: Most frequently reported AEs in the Phase III safety population Indication PID Treatment IVIG-F10 SAGL

No. of patients Included 17 17 With AEs 16 17 No. of AEs 94 117 Event Headache 4 4 Fever 2 3 Epistaxis 1 1 Rhinitis 6 8 Abdominal pain 0 1 Influenza-like symptoms 4 2 Sinusitis 4 2 Vomiting 2 1 Arthralgia 3 1 Diarrhea 2 4 Infection 3 3 Nausea 1 1 Pharyngitis 2 3 Upper respiratory tract infection 3 6 Coughing 2 4 Dizziness 1 1 Bronchitis 1 3

IVIG-F10 = Sandoglobulin^® NF Liquid; SAGL = Sandoglobulin^®

The most common AEs in patients treated with Sandoglobulin^® NF Liquid or Sandoglobulin^® were rhinitis, upper respiratory tract infection, and headache.

ZLB04_005CR Study

A total of 42 patients were treated in an open-label, 6 month duration study to evaluate the safety and efficacy of Sandogloblin NF Liquid in patients with Primary Immunodeficiency Diseases. The AE profile for this study is presented below in Table 3 (no. of patients experiencing AEs by system organ class) and in Table 4 (Most frequent AEs).

Table 3: SOC most frequently (> 10% of patients)

characterized by AEs (ITT population)

ITT = Intent to treat data set; SOC = System organ class

Table 4: Most frequent (> 5% of patients) AEs (ITT population)

Preferred term System organ class

No. (%) of patients

N = 42

Headache Nervous system disorders 25 (59.5)

Pharyngolaryngeal pain Respiratory, thoracic and mediastinal disorders 16 (38.1)

Sinusitis Infections and infestations 12 (28.6)

Diarrhea Gastrointestinal disorders 10 (23.8)

Fatigue General disorders and administration site conditions 10 (23.8)

Nausea Gastrointestinal disorder 10 (23.8)

Pyrexia General disorders and administration site conditions 10 (23.8)

Arthralgia Musculoskeletal and connective tissue disorders 9 (21.4)

Cough Respiratory, thoracic and mediastinal disorders 9 (21.4)

Nasal congestion Respiratory, thoracic and mediastinal disorders 8 (19.0)

Rhinorrhoea Respiratory, thoracic and mediastinal disorders 7 (16.7)

Chills General disorders and administration site conditions 6 (14.3)

Myalgia Musculoskeletal and connective tissue disorders 6 (14.3)

Nasopharyngitis Infections and infestations 6 (14.3)

Pain General disorders and administration site conditions 6 (14.3)

Abdominal pain Gastrointestinal disorders 5 (11.9)

Abdominal pain upper Gastrointestinal disorders 5 (11.9)

Sinus headache Nervous system disorders 5 (11.9)

Vomiting Gastrointestinal disorders 5 (11.9)

Chest pain General disorders and administration site conditions 4 (9.5)

Dizziness Nervous system disorders 4 (9.5)

Ear pain Ear and labyrinth disorders 4 (9.5)

Sinus congestion Respiratory, thoracic and mediastinal disorders 4 (9.5)

Toothache Gastrointestinal disorders 4 (9.5)

Upper respiratory tract

infection

Infections and infestations 4 (9.5)

Asthma Respiratory, thoracic and mediastinal disorders 3 (7.1)

Abnormal Hematologic and Clinical Chemistry Findings

The laboratory data from the Phase III clinical trials did not indicate any significant changes in the variables analyzed in patients treated with either Sandoglobulin^® NF Liquid or Sandoglobulin^®.

DRUG INTERACTIONS

Overview

The administration of Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), in patients with epilepsy should be carefully monitored. Co-administration of phenytoin together with high doses of Sandoglobulin^® NF Liquid might induce hepatic toxicity, as shown by elevated enzyme levels. Although this effect is considered to be due to phenytoin activity, a contribution of the nicotinamide present in Sandoglobulin^® NF Liquid cannot be excluded.

Nicotinamide present in Sandoglobulin^® NF Liquid may interact with the metabolism of primidone and carbamazepine.

Interactions of nicotinamide with cardiac drugs such as B-blockers and vasodilators in humans are not known.

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked.

Incompatibilities

Sandoglobulin^® NF Liquid must not be mixed with other medical products in the same infusion line.

Drug-Laboratory Interactions

Interference with serological testing

After infusion 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 allo-antibodies (e.g. Coombs’ test), reticulocyte count and haptoglobin.

DOSAGE AND ADMINISTRATION

Posology, Dosing Consideration and Adjustments

Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), replaces missing IgG antibodies in primary and secondary immunodeficiency syndromes.

In replacement therapy the dosage may need to be individualized for each patient dependent on the pharmacokinetic and clinical response. The daily dose should not exceed 1g/kg. The following dosage regimens are given as a guideline.

Replacement therapy in primary and secondary immunodeficiency syndromes The dosage regimen should achieve a trough level of IgG (measured before the next infusion) of at least 4-6 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 followed by at least 0.2 g/kg every three weeks.

The dose required to maintain a trough level of 6 g/l is of the order of 0.2-0.8 g/kg/month. The dosage interval when steady state has been reached varies from 2-4 weeks.

Trough levels should be measured in order to adjust the dose and dosage interval.

The dosage recommendations are summarized in the following Table 5:

Missed Dose

A missed dose should be administered as soon as possible to ensure an adequate IgG serum level.

Administration

Rapid infusion of concentrated IVIG products may cause side effects, particularly in patients who are naive to IVIG. It is therefore recommended that in such patients Sandoglobulin^® NF Liquid be infused at an initial rate of 0.3 mL/kg/h for 60 minutes. If well tolerated, the rate may be gradually increased to a maximum of 1 mL/kg/h. In patients previously exposed to an IVIG product, Sandoglobulin^® NF Liquid can be infused at an initial rate of 0.5 mL/kg/h for 30 minutes. If well tolerated, the rate may be gradually increased to a maximum of 1 mL/kg/h or 2 mg/kg/min.

Reconstitution

Not applicable. Sandoglobulin^® NF Liquid is a ready-to-use liquid formulation.

OVERDOSAGE

Consequences of an overdose are not known.

ACTION AND CLINICAL PHARMACOLOGY

Immunoglobulins have a well-established history of safety and efficacy in humans. The antibodies contained in Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), representing endogenous IgG, are natural components of the human body.

Pharmacodynamics

Sandoglobulin^® NF Liquid contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Sandoglobulin^® NF Liquid contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

Pharmacokinetics

Sandoglobulin^® NF Liquid is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments.

Sandoglobulin^® NF Liquid has a half-life of about 23 ± 13 days in normal adults. In a controlled PID study (n = 17) comparing Sandoglobulin^® NF Liquid with Sandoglobulin^® using a dose of 0.3-0.8 g/kg bw IgG per month, comparable median half-lives were obtained: 34 days versus 41.5 days respectively. These results are also comparable with published data.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

Duration of Effect

Patients with PID generally need life-long replacement therapy with immunoglobulins (Sandoglobulin NF Liquid). The duration of the treatment effect, e.g. the prevention of recurrent infections depends on continual infusions of appropriate doses of immunoglobulins at regular intervals. Clinical experience with different immunoglobulins including Sandoglobulin^® NF Liquid has shown that in the majority of patients, intervals between infusions of 3-4 weeks and monthly doses of 0.2-0.8g/kg bw are optimal. However, dosages and intervals have to be tailored

to the clinical needs of the individual patient.

STORAGE AND STABILITY

Special precautions for storage

Store at 2 - 8°C, protected from light. Do not freeze. Prior to the expiration date, the product can be held for a single storage period at room temperature (up to 25°C) for a maximum of 6 months, after which unused product must be discarded.

Shelf-life

Shelf-life is 32 months at 2 - 8°C, protected from light. However, the product can be exposed to up to 25°C for 6 months by the end consumer.

Shelf-life after first opening: Sandoglobulin^® NF Liquid contains no preservative. From a microbiological point of view, the product should be used immediately.

SPECIAL HANDLING INSTRUCTIONS

The product should be brought to room temperature before use. The product should not be shaken. As with all parenteral solutions, the product should be inspected visually for particulate matter, turbidity and discoloration, prior to administration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. A slight yellow discoloration is of no concern and can be disregarded. A separate infusion line set should be used for administration.

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

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Form:

Solution for infusion (12% solution). Sandoglobulin^® NF Liquid is a clear or slightly opalescent, colorless or pale yellow solution of unmodified human immunoglobulin.

Composition for the 6g, 50 mL vial:

Immunoglobulin (Human): 6 g

L-proline: 690 mg (120 mmol/L) L-isoleucine: 654 mg (100 mmol/L) Nicotinamide: 486 mg ( 80 mmol/L) Water for injection: ad 50 mL

Composition for the 12g, 100 mL vial:

Immunoglobulin (Human): 12 g

L-proline: 1380 mg (120 mmol/L) L-isoleucine: 1308 mg (100 mmol/L) Nicotinamide: 972 mg ( 80 mmol/L) Water for injection: ad 100 mL

Packaging:

Sandoglobulin^® NF Liquid is available in individual single use vials of 50 mL (6g) or 100 mL (12 g).

Container: Clear type II glass infusion bottle with a grey chlorobutyl-rubber stopper and aluminium crimp cap with plastic flip-off disk as tamper-evident seal.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Human normal immunoglobulin

Chemical name: Polyvalent human immunoglobulin G

Molecular formula and molecular mass: 146,000 Da (IgG₁, IgG₂, and IgG₄) 170,000 Da

(IgG₃)

Structural formula: IgG has two identical light polypeptide chains and two identical heavy polypeptide chains which are linked together with disulphide bonds. There are two intrachain disulphide bonds in the light chain, one in the variable region and one in the constant region. There are four such bonds in the heavy chain. Each disulphide bond encloses a peptide loop of 60-70 amino acid residues. These result in a series of globular regions with very similar secondary and tertiary structure. The peptide loops enclosed by the disulphide bonds represent the central portion of a domain of about 110 amino acid residues. In both the heavy and light chains the first of these domains corresponds to the variable region. In the light chain there is one additional domain and in the heavy chain three additional domains which make up the constant portion of the chain. It is variations in the amino acid sequence of the variable domains of the light and heavy chains that confers the specificity of immunoglobulins. The number and distribution of interchain disulphide bonds differ between the IgG subclasses with two for IgG₁ and IgG₄, four for IgG₂, and fifteen for IgG₃.

Physicochemical properties:

Product Characteristics

The concentration of the active ingredient in Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), is 12% (120 g/l). At least 96% (typically 99%) of the total protein is IgG (at least 90% of it exists as monomers and dimers). The product contains further small amounts of IgG fragments (≤ 10%), aggregates (≤ 2% commonly only 0.5%), albumin (≤ 3%) and traces of IgA and IgM. The level of IgA in the product is normally below 15 mg/l. The distribution of the IgG subclasses closely resembles that in normal human plasma.

The osmolality is approximately 360 mOsmol/kg and the product is therefore approximately isotonic. The pH value of the ready-to-use solution is 5.3 and the solution contains no buffer substances.

The preparation contains traces of sodium chloride (≤ 10 mmol/l). Sandoglobulin^® NF Liquid contains no preservatives.

Excipients: L-Proline, L-Isoleucine and Nicotinamide are used as stabilizers.

The stabilizers, in particular nicotinamide, minimize the formation of IgG dimers, which is important for the tolerability of the product. The preparation contains traces of sodium chloride. Sandoglobulin^® NF Liquid contains no carbohydrates or preservatives.

Viral Inactivation

The process steps that contribute to the viral safety include (1) separation of Filtrate B from Precipitate B, (2) suspension of Precipitate GG and 1^st clarifying filtration, (3) nanofiltration, (4) pH 4/pepsin treatment, (5) DEAE-Sephadex batch adsorption chromatography and 2^nd clarifying filtration, and (6) aluminum hydroxide batch adsorption and 3^rd clarifying filtration. Viral reduction/inactivation studies on the above process steps have demonstrated total log₁₀ reduction factors of >28 (human immunodeficiency virus (HIV)), >27 (pseudorabies virus), >18 (bovine viral diarrhea virus), and >20 (bovine enterovirus).

CLINICAL TRIALS

Study demographics and trial design

Table 6: Summary of patient demographics for clinical trials in specific indication Study #

Gender

SAGL351

7 M 10 F

ZLB04_00 5CR

29 M 13 F AC = Active-controlled; DB = Double-blind; MC = Multicenter; O = Open; PG = Parallel group; R = Randomized; SA = Single arm; * Median dose received: 278.5 mg/kg to 800.7 mg/kg bw

The demographics and baseline characteristics were those anticipated in clinical practice.

A total of 34 patients were treated in a Phase III 6 month duration study, 17 patients received Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), and 17 patients received Sandoglobulin. The previously approved, lyophilized formulation, Sandoglobulin^®, was chosen as the comparator to Sandoglobulin^® NF Liquid.

Table 7: Summary of Phase III studies in patients

Study

designation

Investigational product No. of

patients

Comparator No. of

patients

Patient population

SAGL351 Sandoglobulin^® NF Liquid 17 Sandoglobulin^® 17 Patients with PID^a ZLB04_005CR Sandoglobulin^® NF Liquid 42 None N/A Patients with PID^{b a} Actual age range: 12-59 years.

^b Actual age range: 4-66 years

Study SAGL351 was a multicentre, randomized, double-blind, active-controlled, parallel group, Phase III study in patients with PID. It was designed to compare the efficacy, pharmacokinetics,

tolerability, and safety of Sandoglobulin^® NF Liquid with Sandoglobulin^®.

Study ZLB04_005CR was a prospective, open, multicenter, single-arm study of Sandoglobulin NF Liquid in patients with PID. It was designed to assess the safety and efficacy of Sandoglobulin NF Liquid in patients with PID.

Study results

SAGL351:

The primary efficacy variable in Study SAGL351 was the number of days when a patient was out of school or work or unable to perform normal daily activities due to the underlying PID.

Table 8: Primary endpoint: Time lost (days) due to PID Study SAGL351

Treatment Sandoglobulin^® NF Liquid Sandoglobulin^® Total

ITT Population

No. of patients 17 17 34

Any days off?

Yes 10 9 19

No 7 8 15

p-value^a 1.00

Monthly average (days)

Mean ± S.D. 0.72 ± 1.03 0.64 ± 0.95 0.68 ± 0.98 Median 0.3 0.3 0.3

Range 0-3.7 0-3.0 0-3.7

p-value^b 0.75

PP Population

No. of patients 16 17 33

Any days off?

Yes 10 9 19

No 6 8 14

p-value^a 0.73

Monthly average (days)

Mean ± S.D. 0.77 ± 1.05 0.64 ± 0.95 0.70 ± 0.99 Median 0.3 0.3 0.3

Range 0-3.7 0-3.0 0-3.7

p-value^b 0.61

^a Fisher’s exact test.

^b Wilcoxon rank sum test.

ZLB04_005CR:

The primary endpoint in study ZLB04_005CR was to demonstrate safety by evaluation of the number of infusions of IVIG-F10 temporally associated with AEs regardless of relationship during a treatment period of 6 months. AES were considered temporally associated if they started any time after the start of the infusion until 48 hours after the end of the infusion. For the study to be considered as having a positive outcome, the upper bound of the 95% confidence interval (CI) of the proportion of infusions temporally associated with one or more AEs had to be < 0.4%.

The proportion of infusions with temporally associated with adverse events was 0.32. The corresponding upper bound of the 2-sided 95% CI was 0.394, and thus, the primary objective of the study was met.

During the 6-month study period, there were no episodes of acute serious bacterial infection (aSBI) defined as pneumonia, meningitis, bacteremia/septicemia, osteomyelitis, septic arthritis, and visceral abscess. The annualized rate of aSBIs was 0.0 with an upper 1-sided 97.5% CI of 0.195 for the SDS/ITT population.

The annualized rate of days out of work, school, kindergarten, or daycare, or without the ability to perform normal activities, was 5.61 days. Seventeen of the 42 patients in the ITT population missed work, school, kindergarten, or daycare, or were unable to perform normal activities. The annualized rate of days hospitalized was approximately 0.9 days. Five patients were hospitalized.

DETAILED PHARMACOLOGY and TOXICOLOGY

Sandoglobulin^® NF Liquid, Immune Globulin Intravenous (Human), could not be meaningfully tested in pharmaco-toxicology studies in animals, due to the xenoreactivity of human IgG to tissue epitopes of other species.

Nevertheless, human immunoglobulin formulations, have well established history of clinical safety and efficacy in patients, based on extensive use over many years. The antibodies contained in Sandoglobulin^® NF Liquid, representing endogenous IgG, are natural components of the human body and can therefore be considered non-toxic. Therefore, safety testing in animal models, other than in a local tolerance study, in addition to not being considered feasible, is not considered necessary.

In the local tolerance study in rabbits, Sandoglobulin^® NF Liquid or IVIG-F10 (0.3 ml per injection) was shown not to cause any significantly increased (quantitative and qualitative) local reactions at the intra-venous, peri-venous and intra-arterial application sites of the right ears of rabbits, in comparison with the left “control” ears treated similarly with saline. After 8 days, there were no treatment-related pathology findings.

The pharmacology, pharmacokinetics and toxicology of the excipient mixture containing nicotinamide, L-isoleucine and L-proline were investigated with in vitro and in vivo studies. The excipient mixture was generally well tolerated.

MICROBIOLOGY

Not Applicable.

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