Immunine Vh Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ........................................................................................2

TABLE OF CONTENTS ..............................................................................................................2

PART I: HEALTH PROFESSIONAL INFORMATION .................................................................4

1 INDICATIONS ..................................................................................................................4

1.1 Pediatrics ................................................................................................................4

1.2 Geriatrics ................................................................................................................4

2 CONTRAINDICATIONS ..................................................................................................4

4 DOSAGE AND ADMINISTRATION .................................................................................4

4.1 Dosing Considerations ...........................................................................................4

4.2 Recommended Dose and Dosage Adjustment ......................................................4

4.3 Reconstitution .........................................................................................................6

4.4 Administration .........................................................................................................7

4.5 Missed Dose ...........................................................................................................7

5 OVERDOSAGE ...............................................................................................................7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ........................8

7 WARNINGS AND PRECAUTIONS .................................................................................8

7.1 Special Populations ..............................................................................................11

7.1.1 Pregnant Women ............................................................................................11

7.1.2 Breast-feeding ................................................................................................11

7.1.3 Pediatrics ........................................................................................................11

7.1.4 Geriatrics ........................................................................................................11

8 ADVERSE REACTIONS ................................................................................................11

8.1 Adverse Reaction Overview .................................................................................11

8.2 Clinical Trial Adverse Reactions ...........................................................................11

8.2.1 Clinical Trial Adverse Reactions – Pediatrics .................................................12

8.3 Less Common Clinical Trial Adverse Reactions .................................................12

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics .........................12

8.5 Post-Market Adverse Reactions ...........................................................................12

9 DRUG INTERACTIONS .................................................................................................13

9.2 Drug Interactions Overview ..................................................................................13

9.3 Drug-Behavioural Interactions ..............................................................................13

9.4 Drug-Drug Interactions .........................................................................................13

9.5 Drug-Food Interactions .........................................................................................13

9.6 Drug-Herb Interactions .........................................................................................13

9.7 Drug-Laboratory Test Interactions ........................................................................13

10 CLINICAL PHARMACOLOGY ......................................................................................14

10.1 Mechanism of Action ......................................................................................14

10.2 Pharmacodynamics ........................................................................................14

10.3 Pharmacokinetics ...........................................................................................14

11 STORAGE, STABILITY AND DISPOSAL .....................................................................14

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................15

PART II: SCIENTIFIC INFORMATION ......................................................................................15

13 PHARMACEUTICAL INFORMATION ...........................................................................15

14 CLINICAL TRIALS ........................................................................................................18

14.1 Clinical Trials by Indication .............................................................................18

15 MICROBIOLOGY ...........................................................................................................18

16 NON-CLINICAL TOXICOLOGY ....................................................................................18

PATIENT MEDICATION INFORMATION .................................................................................20

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

IMMUNINE VH, Factor IX Concentrate (Human) is indicated for:

• Therapy and prophylaxis of bleeding episodes caused by congenital or acquired factor IX deficiency.

1.1 Pediatrics

There is limited data available in children.

1.2 Geriatrics

There is no data available to determine whether subjects aged 65 and over respond differently from younger subjects.

2 CONTRAINDICATIONS

IMMUNINE VH is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

IMMUNINE VH must not be used in the following situations if therapeutic alternatives are available:

• Known allergy to heparin or history of heparin induced thrombocytopenia.
• Disseminated intravascular coagulation (DIC) and/or hyperfibrinolysis. Following interruption of these processes by suitable means IMMUNINE VH, Factor IX Concentrate (Human), should only be given for the management of life- threatening bleeding.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Treatment should be initiated under the supervision of a physician experienced in the treatment of hemophilia.
• The dosage and duration of treatment depend on the severity of factor IX deficiency, the location and extent of the bleeding, and the patient’s clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening hemorrhages.

4.2 Recommended Dose and Dosage Adjustment

Hemophilia B

On demand treatment:

The calculation of the required dosage of factor IX is based on the empirical finding that 1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 1.1% of normal activity in patients 12 years and older.

The required dose is determined using the following formula:

Required units = body weight (kg) x desired factor IX rise (%) (IU/dL) x 0.9

Regular determinations of the patient's factor IX plasma level are necessary for monitoring the course of therapy and calculation of appropriate maintenance doses.

The following table can be used to guide dosing in bleeding episodes and surgery:

In general, IMMUNINE VH is given every 24 hours, corresponding to the biological half-life of factor IX. For surgical prophylaxis the initial dose should be administered one hour prior to surgery. In the case of major surgical interventions, 12-hour treatment intervals should be maintained during the first post-operative days.

Prophylactic maintenance therapy:

For long-term prophylaxis against bleeding in patients with severe hemophilia B, the usual doses are 20 to 40 IU of factor IX/kg body weight at intervals of 3 to 4 days. Prophylactic dosage regimens should, however, be tailored to individual needs, and the decision on the need and dosage for prophylaxis should thus be made by the treating physician. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

Hemophiliacs with inhibitor to factor IX

Replacement therapy with human blood coagulation factor IX is usually effective only in low responder patients with an inhibitor titer of less than 10 Bethesda Units. Since the response to human blood coagulation factor IX depends on the patient's inhibitor titer, factor IX levels must be monitored frequently and the dose adjusted accordingly.

In high responder inhibitor patients, other therapeutic measures may be needed.

4.3 Reconstitution

Table 1 - Reconstitution

IMMUNINE VH, Factor IX Concentrate (Human), is to be reconstituted only immediately before application. The solution should then be used promptly (the preparation does not contain any preservative). Any unused solution must be discarded. For reconstitution proceed as follows using aseptic technique:

1. 1. Warm the unopened bottle containing Sterile Water for Injection (diluent) to room temperature (not above 37°C [98°F]).
2. 2. Remove caps from the concentrate and diluent bottles to expose central portions of the rubber stoppers. Cleanse exposed surface of the rubber stoppers with germicidal solution and allow to dry.
3. 3. Remove protective covering from one end of the transfer needle by twisting and pulling. Insert the exposed end through the diluent bottle stopper.
4. 4. Remove protective covering from the other end of the transfer needle taking care not to touch the exposed end. Invert diluent bottle over the concentrate bottle and insert the free end of the transfer needle through the concentrate bottle stopper. Diluent will be drawn into the concentrate bottle by vacuum.
5. 5. Disconnect the two bottles by removing the needle from the concentrate bottle stopper. Gently agitate or rotate the concentrate bottle until all material is dissolved.

Do not refrigerate after reconstitution.

4.4 Administration

The product should be administered via the intravenous route.

It is recommended not to administer at a rate exceeding 2 mL per minute.

It is strongly recommended that every time that IMMUNINE VH 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.

For intravenous injection:

1. 1. After reconstituting the concentrate as described under "Reconstitution", attach the enclosed filter needle to a sterile disposable syringe. Insert filter needle through the concentrate bottle stopper.
2. 2. Inject air and withdraw solution into the syringe.
3. 3. Remove and discard the filter needle. Attach a suitable intravenous needle or winged infusion set and inject solution intravenously (maximum rate 2 mL/min).

For intravenous infusion:

1. 1. After reconstituting the concentrate as described under "Reconstitution", attach the enclosed filter needle to a sterile disposable syringe. Insert filter needle through the concentrate bottle stopper.
2. 2. Inject air and withdraw solution into the syringe.
3. 3. Remove and discard the filter needle. Attach a suitable intravenous needle or winged infusion set and inject solution intravenously (maximum rate 2 mL/min).

Infusion:

If administered by infusion, a disposable infusion set with adequate filter is to be used (maximum rate of infusion: 2 mL/min).

4.5 Missed Dose

Patients should be advised to proceed immediately with a regular administration of IMMUNINE VH and to continue treatment at regular intervals as required.

5 OVERDOSAGE

Based on experience with conventional prothrombin complex preparations, overdosage of Factor IX concentrates may result in an increased risk of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism (see 7 WARNINGS AND PRECAUTIONS for measures to be taken).

No symptoms of overdosage with purified FIX have been identified in humans. Therefore, the effects of higher than recommended doses of IMMUNINE VH have not been characterized.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 2 – Dosage Forms, Strengths, Composition and Packaging

IMMUNINE VH, Factor IX Concentrate (Human), is supplied in a single dose vial accompanied by a vial of Sterile Water for Injection, U.S.P. for diluent, a sterile transfer needle and a sterile filter needle as follows:

IMMUNINE VH Sterile Water for Injection. USP

(IU¹) (mL)

480 to 720 5

^[1]The number of I. U. Factor IX is stated on the label of each vial.

7 WARNINGS AND PRECAUTIONS

IMMUNINE VH is prepared from large pools of human plasma. Thus, there is a possibility it may contain causative agents of viral or other undetermined diseases.

General

IMMUNINE VH, Factor IX Concentrate (Human), should not be administered at a rate exceeding 2 mL/min.

IMMUNINE VH contains less than 0.1 IU heparin per ml. In case of surgical intervention in hemophilia B patients receiving replacement therapy with IMMUNINE VH, perioperative thrombosis prophylaxis with low-dose heparin is recommended in those situations where such a prophylaxis would normally be indicated in patients having no coagulation defect.

IMMUNINE VH contains not more than 5 µg TWEEN 80 per mL.

Driving and Operating Machinery

No studies on the effect of IMMUNINE VH on the ability to drive or use machine have been

performed.

Hematologic

Since the use of factor IX complex concentrates has historically been associated with the development of thromboembolic complications, the risk being higher in low purity preparations, the use of factor IX-containing products may be potentially hazardous in patients with disseminated intravascular coagulation (DIC) and in patients with signs of fibrinolysis.

Because of the potential risk of thrombotic complications, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing, in particular when administering this product to patients with liver disease, to patients peri- and postoperatively, or to other patients at risk for thrombotic events or DIC.

In patients with DIC or those at risk for DIC or thromboembolic events, the benefit of treatment with IMMUNINE VH should be weighed against the risk of these complications.

In patients with a risk of thrombosis (e.g. patients with a history of severe liver disease, thrombophilia, or a tentative or definite diagnosis of angina pectoris, coronary heart disease or myocardial infarction) the factor IX level should not be raised beyond 60% of normal. In addition, these patients - as well as patients receiving high doses of human blood coagulation factor IX concentrate for major surgery - should be monitored for the development of DIC and/or thrombosis.

Immune

Neutralizing antibodies (Inhibitors):

Neutralizing antibodies (inhibitors) development to factor IX has been reported in patients treated with Immunine VH. Patients should be monitored for the development of factor IX inhibitors that should be quantified in Bethesda Units (BU) using appropriate biological testing. If such inhibitor occurs, the condition will manifest itself as an insufficient clinical response. If the expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor IX inhibitor is present.

In patients with high levels of inhibitor, factor IX therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed to physicians with experience in the care of patients with hemophilia and it is recommended that a specialized hemophilia center be contacted.

In patients with inhibitor titers refractory to higher doses, the use of recombinant activated factor VII (rFVIIa) or activated prothrombin complex concentrate (aPCC) preparations should be considered.

Anaphylaxis/anaphylactoid and other severe hypersensitivity reactions have been reported with IMMUNINE VH. Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis with subsequent challenges with factor IX. Patients and/or their caregivers should be informed of the early signs of hypersensitivity reactions. They should be advised to discontinue use of the product immediately and contact their physician if such symptoms occur. Minor reactions may be controlled by antihistamines, while the therapy of severe hypotensive reactions follows the current guideline of shock treatment.

As a plasma derived factor IX concentrate, the product contains other human proteins.

There have been reports in the literature showing an association between the occurrence of a factor IX inhibitor and allergic reactions, in particular in patients with a high-risk gene mutation.

Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor.

Because of the risk of allergic reactions with factor IX concentrates, the initial administrations of factor IX should be performed under medical observation where proper immediate medical care for severe allergic/anaphylactic reactions could be provided, in particular in patients with high risk gene mutations or where the mutation is unknown.

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

Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors.

Monitoring and Laboratory Tests

During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma Factor IX activity) is indispensable. Individual patients may vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.

If bleeding does not resolve despite adequate treatment, clotting factor levels should be measured. Inhibitor testing should be performed if the level is unexpectedly low, as this may be an indication that factor IX inhibitor is present. Allergic reactions, including anaphylaxis is another indicator of inhibitor development and warrants inhibitor testing (7 WARNINGS AND PRECAUTIONS).

Reproductive Health: Female and Male Potential

See 7.1.1 Pregnant Women.

• Fertility

  The effects of IMMUNINE VH on fertility have not been established.

Sensitivity/Resistance

.

Sodium Content

The calculated sodium content of the IMMUNINE VH 600 IU formulation is 20.4 mg per vial. The quantity of sodium in a high single dose in adults may exceed 250 mg for the 600 IU/5mL formulation. This is to be taken into consideration in patients on a low-sodium diet.

This following example is based on the assumption of a 70 kg patient, needing a 99% increase, and using the formula 70 x 99 x 1.1 = 7623 Units needed.

In this example of 12.7 vials at 600 IU.

600 IU vials contain 20.4 mg sodium ≈ 259.08 mg Na+

7.1 Special Populations

7.1.1 Pregnant Women

There is no adequate data from the use of IMMUNINE VH in pregnant or lactating women.

Healthcare providers should balance the potential risks and only prescribe IMMUNINE VH if clearly needed.

7.1.2 Breast-feeding

The safety of IMMUNINE VH for use in lactating women has not been established. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing IMMUNINE VH.

It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human milk precaution should be exercised.

7.1.3 Pediatrics

There is limited data available in children.

7.1.4 Geriatrics

There is no data available to determine whether subjects aged 65 and over respond differently from younger subjects.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

As with any infused plasma derivative, hypersensitivity reactions (e.g. fever, urticaria, nausea, vomiting, dyspnea, drop in blood pressure, shock) may occur rarely.

In rare cases, replacement therapy with human blood coagulation factor IX concentrates may lead to the formation of circulating antibodies which inhibit factor IX.

The possibility of thromboembolic complications cannot be entirely ruled out. This applies particularly to patients at risk for thrombosis and/or receiving high-dose therapy.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

The adverse reactions presented in this section have been identified from 5 clinical trials conducted with IMMUNINE (product with and without heparin) in 148 subjects (0.6-70.2 years of age) administered 2807 infusions.

Table 3 - Adverse Reactions from Clinical Trials

Legend: ADR frequency is based upon the following scale: Very Common (≥1/10); Common (≥1/100 -<1/10), Uncommon (≥1/1,000 - <1/100), Rare (≥1/10,000 - <1/1,000), Very Rare (<1/10,000)

In clinical trials with IMMUNINE, no factor IX inhibitors were identified in 41 patients having a total of 2079 exposure days to IMMUNINE. No previously untreated patients were enrolled in IMMUNINE clinical trials.

Inhibitor development to factor IX has been reported (see Section 8.5 Post-Market Adverse Drug Reactions).

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

The safety profile of IMMUNINE VH is consistent among pediatric and adult patients. There is limited data available in children.

8.3 Less Common Clinical Trial Adverse Reactions

Please refer to the Adverse Reactions from Clinical Trials, Table 3 above.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

The safety of IMMUNINE VH is consistent among pediatric and adult patients. There is limited data available in children.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been reported in the post-marketing experience, listed by MedDRA (vers.18.0) System Organ Class (SOC), then by Preferred Term in order of severity, where feasible.

Blood and Lymphatic System Disorders: Factor IX Inhibition

Immune System Disorders: Anaphylactic/Anaphylactoid Reaction, Serum Sickness (in the presence of inhibitors), Hypersensitivity Reaction

Nervous System Disorders: Headache

Cardiac Disorders: Myocardial Infarction, Tachycardia

Vascular Disorders: Flushing

Respiratory, Thoracic, And Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Urticaria

General Disorders and Administration Site Conditions: Chills

Class Reactions

Disseminated intravascular coagulation, thromboembolic episodes (e.g., pulmonary embolism, venous thrombosis, arterial thrombosis, cerebral artery thrombosis)

Other manifestations of hypersensitivity or allergic reactions: anaphylactic shock, angioedema, hives, chest tightness, hypotension, lethargy, nausea, vomiting, tingling, paresthesia, restlessness, wheezing, burning and stinging at the infusion site.

Nephrotic syndrome (following attempted immune tolerance induction)

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

No interactions of human coagulation factor IX products with other medicinal products are known.

As for any blood coagulation factor concentrate IMMUNINE VH Factor IX Concentrate (Human) should not be mixed with other drugs. It is advisable to rinse a common venous access with isotonic saline prior to and after infusion of IMMUNINE VH.

9.3 Drug-Behavioural Interactions

Not applicable.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Coagulation factor IX is one of the clotting factors found in normal human blood and is required for normal clot formation. Intravenous administration of IMMUNINE VH, Factor IX Concentrate (Human) provides an increase in plasma levels of factor IX and can temporarily correct the coagulation defect of patients with factor IX deficiency.

10.2 Pharmacodynamics

Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Dalton. It is a vitamin-K dependent coagulation factor and it is synthesised in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Hemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

10.3 Pharmacokinetics

In vivo recovery and half life characteristics were evaluated in an international, prospective, controlled, cross-over study following ISTH guidelines. A total of 26 patients with an age of more than 12 years with severe hemophilia B (factor IX level < 1 %), and not bleeding at the time of testing, have been given a single infusion of 50-70 IU/kg body weight at 10 day intervals of either IMMUNINE VH or BEBULIN VH, IMMUNO's Factor IX Complex licensed in Canada since 1988. Mean half life observed was 17.42 h for IMMUNlNE VH vs. 18.77 h for BEBULIN VH whereas mean in vivo recovery was 0.92 percent per administered IU factor IX per kg bodyweight for IMMUNINE VH, corresponding to a recovery of 41%, vs.1.02 percent for BEBULIN VH. These data are based on calculations using the new International Standard for Human Blood Coagulation Factors II, IX and X in Concentrates Code 84/681.

11 STORAGE, STABILITY AND DISPOSAL

When stored between +2°C and +8°C (+35°F and +46°F), IMMUNINE VH, Factor IX Concentrate (Human) is stable until the date indicated on the label.

Within the indicated shelf life IMMUNINE VH may temporarily be stored at room temperature [up to +25°C (+77°F)] for a period of up to 3 months. Record the period of storage at room temperature below the expiration date indicated on the package label. Discard product if stored at room temperature for three months.

IMMUNINE VH must not be used beyond the expiration date indicated on each pack.

Reconstituted Solutions

The reconstituted solution should be used immediately after preparation (contains no preservative), it should not be refrigerated and any unused portion of it should be discarded (4 DOSAGE AND ADMINISTRATION).

12 SPECIAL HANDLING INSTRUCTIONS

IMMUNINE VH is to be reconstituted only immediately before administration. The solution should then be used promptly (preparation does not contain any preservatives).

The product should be inspected visually prior to reconstitution and administration. The lyophilised powder or friable solid should be white or pale yellow. The solution should be clear or slightly opalescent. Do not administer if particulate matter or discoloration or cloudiness is found upon reconstitution; contact Takeda Customer Service.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Factor IX Concentrate (Human)

Chemical name: Not Applicable

Molecular formula and molecular mass: Human blood coagulation factor IX (Factor IX), is a single chain glycoprotein consisting of 415 amino acids with relative molecular mass of 57,000 Da.

Structural formula: Factor IX contains 12-gamma-carboxylated glutamic acid residues, two epidermal growth factor regions, one activation peptide domain, and a serine protease region.

Physicochemical properties: Factor IX is the zymogen from the serine protease Factor IXa. After activation and removal of the activation peptide, Factor IXa is a disulfide-linked two-chain serine protease specific for an arginine–isoleucine bond. Factor IXa and Factor VIIIa form a high-affinity complex on the phospholipid surface in the presence of calcium to activate Factor X by cleaving a single peptide bond in the aminoterminal region of the heavy chain.

Pharmaceutical standard: Pharmacopeial

Product Characteristics:

IMMUNINE VH, Factor IX Concentrate (Human), is a purified, sterile, freeze-dried concentrate of human blood coagulation factor IX. IMMUNINE VH is standardized in terms of factor IX content and each vial is labeled with the factor IX content indicated in international units (IU) (1, 2). One international unit of factor IX (based on the First International Standard for Factors II, IX and X in Coagulation Factor Concentrates Code 84/681) corresponds to the factor IX activity contained in 1 ml of fresh normal human plasma.

IMMUNINE VH is a highly purified factor IX concentrate containing only traces of other coagulation factors (up to 0.02 IU of factors II, VII and X per IU factor IX). In preclinical trials utilizing supra-therapeutic doses of IMMUNINE VH no thrombotic adverse reactions were observed. IMMUNINE VH is prepared from pooled human plasma.

IMMUNINE VH contains less than 0.1 IU heparin per ml and not more than 5µg TWEEN 80 per ml.

The manufacturing process includes key stages, among them a product-specific vapor heat treatment, that have been shown to result in removal and inactivation of infectious agents.

Individual donations of human plasma are combined to form plasma pools. Prior to being used for manufacture of IMMUNINE VH, each plasma pool is tested for the presence of genome sequences of the human immunodeficiency virus type 1, hepatitis B virus (HBV), and hepatitis C virus (HCV) using IQ-PCR².

To prevent the transmission of infective agents by the administration of IMMUNINE VH, prescribed procedures are used for the collection and testing of the source plasma and during the manufacture of the product. They include measures taken for donor and plasma selection³, as well as virus removal and inactivation steps during manufacturing.

Viral Inactivation

Viral Safety

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 human immunodeficiency (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) and for the non- enveloped virus hepatitis A virus (HAV).

The measures taken may be of limited value against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g., in hemolytic anemia).

Individuals who receive infusion of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly nonA, nonB hepatitis.

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma derived factor IX concentrates.

A virus panel representing a wide range of physicochemical characteristics was used in virus clearance studies investigating the virus reduction capacity of the IMMUNINE VH production process. Whenever feasible relevant target viruses, i.e. viruses, which could potentially be present in human plasma, were used in the virus clearance studies:

Human Immunodeficiency virus type I (HIV-1) and Hepatitis A Virus (HAV) were used as target viruses.

For viruses which cannot be titrated in established cell lines, e.g. HCV and Parvovirus B19,

² IQ-PCR: IMMUNO Quality Assured Polymerase Chain Reaction

With this method 500 genome equivalents/ml of the above viruses can be determined reliably, with the actual sensitivity of IQ-PCR being below that. Therefore all pools which have been tested and evaluated as being sensitivity lead to exclusion from further processing. No correlation has been demonstrated between infectivity and removal of pools containing these levels of genomic equivalents from further manufacturing.

³ All plasma units used for manufacture are ALT tested and non-reactive in tests for HBs-antigen and antibodies to HCV, HIV-1 and HIV-2. Before further processing all individual plasma donations are subjected to an inventory hold of at least three months for a possible look- back of plasma donations suspected of infection.

model viruses were used:

Pseudorabies virus (PRV, an enveloped DNA virus as a generic model for hepatitis B virus), Bovine Viral Diarrhea Virus (BVDV, a small enveloped RNA virus as a model for HCV) and Mice Minute Virus (MMV, small, non-enveloped DNA virus as model virus for Parvovirus B19 and other small, non-enveloped DNA viruses).

A summary table of the virus validation studies performed is given below. Intermediates of IMMUNINE VH were obtained from the manufacturing facility. Aliquots of the intermediate were spiked with viruses and the virus inactivation/removal capacity of the respective process step was investigated. Mean reduction factors are listed in the table below. Where two or more reduction factors are available for a specific manufacturing step, the mean value was used to calculate the ORF.

Table 4 - Virus Validation Studies- Summary Table

n.d. not determined

⁴ MMV is however, not an appropriate B19V model for heat treatment steps as MMV is substantially more heat resistant than B19V, as also evident by the two publications cited below:

• M.Yunoki et al., Heat sensitivity of human parvovirus B19, Vox Sanguinis (2003) 84, 164-169
• Blümel et.al., Inactivation of parvovirus B19 during pasteurization of human albumin, Transfusion (2002),42, 1011- 1018

5For HIV-1 and BVDV, the reduction factors apply to the P80 treatment only.

In prospective clinical studies as well as in post-marketing surveys, the risk of transfusion- transmitted viral infections was followed up in patients given factor concentrates of the prothrombin complex subjected to the same vapor heat treatment as IMMUNINE VH. Using the criteria established by the ISTH, 45 patients were evaluated for non-A/non-B transmission and 27 for hepatitis B transmission. In addition, 42 patients were evaluated for HCV seroconversion, and 105 for HIV seroconversion. No cases of product related viral hepatitis or HIV transmission were observed.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Severe congenital factor IX deficiency

Table 5 - Summary of patient demographics for clinical trials in severe congenital factor IX deficiency (≤ 1% residual FIX activity)

Study Results:

For the results of study IMAG-036, summarizing the pharmacokinetic parameters of IMMUNINE VH without heparin, see 10.3 Pharmacokinetics.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

In the test for acute toxicity following intravenous application in mice and rats it was shown that the maximum dose which did not cause death of the animals was 21 (mice) and 16.7 times (rats) higher than the maximum dose recommended in humans.

Studies on subacute and chronic toxicity as well as studies on reproduction toxicity and mutagenic or tumorigenic potential were not performed since repeated administration of Factor IX would be liable to cause the formation of antibodies in the animals. Results obtained in the animal model would hence not allow extrapolation to humans.

When tested in rabbits using the Wessler method of assessing thrombogenicity IMMUNINE VH failed to show any evidence of thrombogenicity even at a dose of 1000 lU/kg.

When IMMUNINE VH was administered intra-arterially to guinea pigs at a dose of 200 IU/kg no anaphylactoid effects were noted.

Following administration of IMMUNINE VH in an anesthetized dog model (200 1U/kg i.v.) no changes in blood pressure, heart rate or ECG were observed.

Data on the efficacy of the vapor heat treatment on viral safety of the preparation have been previously described in the section 10 CLINICAL PHARMACOLOGY.