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Highly Purified Native FIX FIX at its Peak

octanineF_Bros_200905E3B1 08.06.2009 22:59 Uhr Seite 2

Highly Purified Native FIX

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octanine®F at a Glance

Gently highly purified Factor IX enriched 10,000-fold over plasmaIn its natural form, non denatured

Optimised virus safety High quality starting plasmaSolvent/Detergent treatmentNanofiltration

Safe in clinical use Effective and well-tolerated

Convenient handling Small injection volumeEasy documentation


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Plasma, a Matter of Trust

Factor IX – naturally from plasma

octanine®F is a concentrate of highly purified factor IX (F IX).

It is used for the treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).

Owing to the absence of denaturation and unaltered physiological function of the factor IXmolecule, octanine®F is effective and well-tolerated.

The high requirements for the starting plasmaand the virus reduction steps contribute to a highlevel of safety in treatment with octanine®F.

Clinical studies demonstrate the efficacy and tolerability in the treatment of bleeding episodesand in prophylaxis.

octanine®F

Presentation Injection volume

octanine®F 500 5 ml

octanine®F 1000 10 ml


10,000-foldEnrichment ofFactor IX

Nothing Less Than Purity Itself

The patient benefits from high purity

Factor IX is present in plasma in only very lowconcentration. In the manufacture of octanine®F,factor IX is specifically enriched (about 10,000-fold over plasma) by highly efficient purificationsteps.

These carefully chosen purification methods serve to isolate factor IX under conditions whichare very gentle to proteins.

The nanofiltration step, Tangential Flow Filtration,carried out in order to increase virus safety, contributes simultaneously to further purification.

Different analytical methods show that, in contrast to some other highly purified preparations, no other proteins can usually be detected in octanine®F apart from factor IX. octanine®F is amongst the purest preparations currently available for the treatment of haemophilia B.

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Better in All Stages

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Comparison of Different Factor IX Preparations by Separation with SEC-HPLC 1

Separation of Factor IX bySDS-PAGE and Immunoblotting

The careful manufacturing process ensuresa final product without denaturation

Plasma, the starting material, contains proteaseswhich can lead to an activation of the factor IXmolecule.These are already removed at a very early stage in the production.Gentle purification steps and the solvent/detergent (S/D) method of virus inactivation,which is especially suitable for sensitive plasmaproteins, preserve the physiological function ofthe factor IX molecule and prevent its activation.The high purity and the retention of the physio-logical function of factor IX result in excellenttolerability.

High purity, no activation of factor IX

A, B, C Three consecutive batches of octanine® F (each 2 µg)

D Activated factor IX beta (2 µg)

10

15

20

37

50

75

250

A B C D

25

100

150

Mo

lecu

lar

wei

gh

t (k

Da)

Steam-treatedpreparation

octanine® F

Retention time (min) Retention time (min)

Ab

sorp

tio

n a

t 28

0 n

m

Ab

sorp

tio

n a

t 28

0 n

m

Pasteurisedpreparation

octanine® F


Greatest Care inthe Selection ofStarting Plasma

From Selection to Registration

High requirements for the starting plasma

Plasma product quality begins already with thestarting material.

Blood transfusion centres, donors and donationsare carefully selected and monitored.

Complete information about the sources of plasma is a part of the product registration and is reported as such to the national authorities.

Before plasma delivery contracts enter into force,each donation centre has to be approved by thecompetent national authorities and is audited byOctapharma.

All plasma suppliers continue to be regularlyaudited by Octapharma and inspected by theirrespective national authorities for compliance.

Each donor is permitted to donate only after a thorough prior medical examination.Plasmapheresis donations are obtained only from repeat donors.

Each plasma donation has to be tested antibody-negative for relevant viruses (HBV, HCV, HIV-1/2).

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A Process that Sets Standards

Virus inactivation with the S/D method

Since the middle of the 1980s, the requirementsfor the virus safety of plasma-derived productshave grown constantly more demanding. Themanufacturing process for each preparation mustdemonstrate and ensure an adequate capacity forvirus elimination.

The solvent/detergent (S/D) method sets standardsin all respects. While a number of viral inactivationsteps have been shown to enhance greatly thesafety of hemophilia products, solvent-detergenttreatment is the current gold standard for safetyfrom the highly infectious enveloped viruses.2

Octapharma was the first manufacturer to employ the S/D method on an industrial scale in the production of plasma derivatives. This method has been applied since 1986 for all of Octapharma's coagulation products.

The reaction mixture destroys the lipid envelopeof viruses resulting in a rapid inactivation. Lipid enveloped viruses, which include the transfusionrelevant viruses such as HIV, HBV and HCV, are rapidly, effectively and irreversiblydestroyed. An infection with HIV, HBV, HCV or other lipidcoated viruses has not been found in any patient since the introduction of thismethod.

The viruses used in virus validation studies have been carefully chosen in order to cover awide spectrum of physico-chemical properties and differing resistance towards inactivation procedures.

Requirements for Virus Safety

Two effective steps against lipid enveloped viruses

One effective step against non enveloped viruses

A combination of methods based on different principles of action

Inactivation procedures with a high safety margin

Rapid virus inactivation

Robustness in the face of process variations

Validation of each step with a wide variety of viruses

An individual step efficacy of > 4 log10

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Lipid Enveloped Virusesare IrreversiblyInactivated with S/D

The S/D Method – The Gold-Standard for enveloped Virus Inactivation

-1 0

Values below the limit of detection

Time (min)

0

1

2

3

4

100 200 300 400

5

6

7

Sindbis

HIV-1

Viru

s Titr

e (lo

g TC

ID 5

0/m

l) *

* Tissue Culture Infectious Dose

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Nanofiltration – The Gold-Standard for Elimination of non-enveloped Viruses

While a number of viral inactivation steps havebeen shown to enhance greatly the safety ofhemophilia products, nanofiltration is the currentgold standard for safety from non-enveloped viruses.2 A special virus filter has been integratedinto the manufacture of octanine®F in order to remove effectively non-enveloped viruses, such as HAV.

A nanofiltration process was chosen with theTangential Flow Filtration mode which effectivelyeliminates viruses from the product withoutimpairing the function of factor IX.

The intermediate product is pumped past a filtermembrane. The pore size is chosen so as to

Nanofiltration, an optimal supplement to S/D treatment

permit the factor IX molecule to pass through themembrane (filtrate), while larger particles, such asviruses or protein impurities with high molecularweight, remain behind in the filter system (retentate).

This process step has been validated for a broadspectrum of lipid enveloped and non envelopedviruses.

In addition to S/D treatment and nanofiltration,further process steps contribute to the virus safetyof octanine®F. Hence, the global virus reductionrates clearly exceed the current requirements proposed by the regulatory authorities (Committeefor Proprietary Medicinal Products).

Nanofiltration complementsthe virus safety of octanine®Fin a gentle way

Principle of Tangential Flow Filtration Mode Nanofiltration

FIX

FIXFIX

FIX

FIX

FIX

Factor IX

Direction of Flow

FIX

FIX FIX

Filter Membrane

HIV HBV HAV

FIX

Filtrate FormulationFinal Product

High molecular weight proteins

Safety Reserves

DEAE Sephadex chromatography

DEAE Sepharose Fast Flow chromatography

Affinity chromatography

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Unsurpassed Pathogen Safety forHemophilia B Patients

octanine®F virus validation studies 1

With octanine®F, Octapharma provides patients with a factor IXpreparation which fulfils all modernrequirements of virus safety

Enveloped Viruses Non Enveloped Viruses

HIV Sindbis HSV-1 HAV REO PPVHuman Sindbis virus Herpes Simplex Hepatitis A Reovirus Porcine Parvovirusimmunodeficiency- (model for HCV) virus virus (model for virus (model for HBV) parvovirus B19)

Genome RNA RNA DNA RNA RNA DNA

Virus Reduction (log10)

S/D Virus Inactivation > 6.7 > 7.4 > 6.2 - - -

Nanofiltration > 5.0 > 7.3 > 8.3 3.7 > 6.5 4.8

Virus Reduction byother Process Steps - - - 5.7 8.7 7.2

Total Virus Reduction > 11.7 > 14.7 > 14.5 9.4 > 15.2 12.0

octanine®F fulfils these requirements 3

Lipid enveloped viruses Two effective steps, each > 4 logTotal reduction > 10 log

Non enveloped viruses One effective step > 4 logTotal reduction > 6 log

10

�

�

�

�


octanine®F Prion Safety

It is important to note that the presence of prion pathogens in human plasma, which is usedas a start material in production of coagulationconcentrates such as octanine®F, has never beendocumented.

Nevertheless, even in the hypothetical case of presence of prion proteins in human plasma, the octanine®F manufacturing process has a capacity of efficiently removing them with a highsafety margin. The cumulative prion removalcapacity was determined to be 10.6 log. 4

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Calculations show that even under an unrealistictheoretical assumption that each administeredbatch contains prions, a patient would need to be regularly treated with octanine®F for morethan 350 million years before he may approach a theoretical risk of prion infection. 4

Based on this data, there is no real risk of prioninfectivity through the infusions of octanine®F.

Step Prion removal capacity

Chromatography 1 3.1 log



Nanofiltration 2.1 log

Total 10.6 log

Validated prion removal capacity of the octanine®F manufacturing process 4


PhysiologicalPharmacokineticProperties

Essential Clinical Homework

Studies support excellent clinical experience

The pharmacokinetics of octanine®F were evaluated in 13 patients in a cross-over study with the predecessor preparation (octanine®F process without nanofiltration).

75 IU per kg body weight were administered in each case.

The mean half-life of octanine®F was found to be 29.1 hours; the recovery 1.3 IU/dl per IU/kgbody weight.

Mean Factor IX Concentration, Cross-Over Study (n = 13) 1

octanine®F pharmacokinetics (mean ± standard deviation) in adults 1

octanine®F was administered in the treatment of acute bleeding for 386 exposure days. The mean dosage was 22.5 IU/kg. One or twotreatment days were enough to ensure cessationof bleeding in 93 % of all episodes.

The efficacy was rated as “excellent” or “good”in 98 % of all cases.

octanine®F Predecessor Preparation

T 1/2 (h) 29.1 ± 5.2 31.7 ± 8.4

Recovery (IU/dl per IU/kg) 1.3 ± 0.5 1.3 ± 0.3

AUC*norm (%.h.IU–1.kg) 37.7 ± 13.0 43.3 ± 13.7

MRT* (h) 40.0 ± 7.3 43.6 ± 8.4

Clearance (ml.h–1.kg) 2.9 ± 0.9 2.5 ± 0.7

AUC* = area under the curve MRT* = mean residence time

00

Time after injection (h)

FIX

:C(%

)

20

40

60

80

100

20 60 8040

octanine® FPredecessor preparation

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octanine®F shows long half-lifeand high recovery


Overview of Clinical Studies with octanine®F 5

octanine®F was studied extensively in the frame of clinical trials. Pharmacokinetics, safety,efficacy and tolerability were investigated, both inpreviously treated patients, as well as in childrenbelow 6 years of age, including PUPs (previouslyuntreated patients).

In total, 71 patients (age in the range of 3months to 71 years) received more than 3 millionIU of octanine®F in 3373 exposure days. No FIXinhibitors developed, and there were no allergicreactions, thrombotic complications, or viral infections observed. The concentrate was verywell tolerated, with almost 100% of infusionsrated with the highest tolerability ratings “verygood” or “good”.

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Study design No. of Mean Total Number of Tolerability assessment

patients Age consumption exposure of injections

in IU days / injections "very good"/"good"

Study A Severe hemophilia B 14 34.4 81,500 14 / 14 100%

Age > 12, previously treated

Randomized cross-over

pharmacokinetics

Study B Severe hemophilia B 21 22.8 1,070,867 747 / 758 99.90%

Age > 12, previously treated

> 6 months observation period

Study C Severe or moderate hemophilia B 26 3.1 1,223,750 1,668 / 1,690 100%

Age < 6

2 years observation period

Study D Severe or moderate hemophilia B 10 12.7 592,500 946 / 949 100%

Non-interventional post-marketing

2 years observation period


octanine®F exhibits convincingly good efficacy in prophylaxis, the treatment of bleeding and in surgery

Results that Convince

Studies support clinical safety

In one of the studies, 21 patients were treatedwith octanine®F for a mean of 30.2 weeks. Theyreceived a total of 1.07 million IU of octanine®F.

The factor IX inhibitor activity was measured atthe start of the study, after 3 months and at theend. No inhibitors to factor IX were detected. The unchanged recovery throughout also excludesthe formation of inhibitors.

Studies in an animal model demonstrated thatoctanine®F is non thrombogenic even at highdosage. In the pharmacokinetic studies, the

patients were also tested for the sensitive markers of thrombogenicity, TAT, F1+2 and D-dimers. No evidence of a thrombogenic effect could befound.

octanine®F was tolerated well, including at high dosage such as during continuous infusionover several days. In the clinical studies with octanine®F, no undesirable side-effects occurred.The patients were examined regularly for infectionwith HIV, HCV, HBV, HAV and parvovirus B19 and no virus transmission was detected.

Overview of Surgery Performed During Clinical Studies 1

Age Surgery Type octanine®F Treatment Duration (d)/ “Excellent” / “good”Patient Total Dose (IU/kg) Continuous Patient Infusion (d) Efficacy

JB 56 Lens implantation 19,500 5/5�after cataract

KS 26 Pseudotumour removal 39,000 14/14�(Tibia, left)

ZR 64 Inguinal hernia 46,000 8/6 �

AJ 40 Caldwell-Luc operation 54,000 15/7 �

RP 41 Hip and knee joint 65,000 12/11�replacement

AJ 40 Hip joint replacement, 53,000 13/10�pseudotumour (Tibia, left)

AL 62 Pyelolithotomy, 57,000 16/0�pseudotumour (Tibia, left)

KS 54 Tooth extraction 5,000 1/0 �

SS 41 Tooth extraction 4,000 1/0 �

AJ 39 Tooth extraction 4,000 1/0 �

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Prospectively ProvenClinical Efficacy and Safety


octanine®F – excellent clinical data also in children younger than 6 years, including PUPs 6

No FIX inhibitors were observed in the pediatricoctanine®F clinical trial with 25 patients, eventhough 76% of patients, all of them youngerthan 6 years, were either without prior exposure(previously untreated patients, PUPs) or had less than 50 days of prior exposure to other FIXconcentrates, therefore at higher risk of inhibitordevelopment. 7, 8

Investigators rated octanine®F clinical efficacy as“excellent” in 96.4% or as “good” in 2.8% ofbleeding episodes that were treated on demand:

Incremental in vivo recovery for octanine®F in thispaediatric study (0.97 IU/dL per IU/kg, at the endof the study, mean age 5.2 years) was found to besignificantly higher than the values found in earlierstudies for rFIX in paediatric populations. 9, 10

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no previous exposure (PUPs)

1–50 exposure days

> 50 exposure days

24%24%

52%

100.00%

80.00%

60.00%

40.00%

20.00%

0.00%Knee Ankle Elbow Muscle Others Total

excellent

good

Site of bleeding

Efficacy assessment in treatment of acute bleeds in children < 6 years of age


octanine®F in Immune Tolerance Induction(ITI) – case report 11

As opposed to hemophilia A, inhibitors in hemophilia B are rather rare. However, the occurence of FIX inhibitors is frequently associatedwith severe complications such as anaphylacticshock and nephrotic syndrom. Success rates of an immune tolerance induction (ITI) solely withhigh dose infusions of Factor IX are rather low.

A 6 years old boy with severe hemophilia B, who was treated with another FIX concentrate,developed FIX inhibitors at the end of his secondyear. Peak inhibitor titer was 7 Bethesda Units/mL.After a 3-year period of on demand treatmentwith rFVIIa and repeated joint bleeds and arthropathy, an ITI was initiated.

The therapy consisted of a combination of immunosuppresants, polyvalent immunoglobulins,and high-dose octanine®F infusion (100 IU/kg).Within 11 months the half life and incrementalrecovery completely normalised, and the patientwas able to continue with a regular long-termprophylaxis.

During a 5-year followup, there was no FIX inhibitor reappearence observed.

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mycophenolat mofetil (MMF, CellCept) given twice daily adjusted by the serum trough levels 1.5–4.5 µg/mL

dexamethasone (DEXA) given twice daily 2 x 12 mg/m2 per day

and IVIG 400 mg/kg per day

given as pulse therapy for 3–4 days; repeated every 4 weeks

high-dose FIX (octanine®F) 2 x 50–100 IU/kg per day

ITI Concept 11


Simply Practical and Practically Simple

Advantages for home treatment

octanine®F dissolves very quickly. After transfer of the water, the concentrate vial only has to be swirled lightly. This greatly reduces the timeneeded to prepare the concentrate.

Careful and easy record-keeping

It is recommended that the use of octanine®F is documented for every batch and every application. This way, the batches used by thepatient can be determined at any time.

Each package of octanine®F contains 3 self-adhesive labels with the batch number. Two labels are to be found on the outside of thecarton. They can simply be pulled off and stuckinto records in order to document dispensing by the physician or pharmacist. The third label on the concentrate vial is used by the patient torecord his home treatment. The result is a closedchain of documentation from the manufacturer to the patient, to ensure maximum drug safety.

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Undesirable Effects: The following side effects have been observed with factor IX-containing preparations: Hypersensitivity or allergic reactions,infrequently; severe anaphylaxis in temporal relationship to the formation of anti-factor IX antibodies. In rare cases, rise in body temperature,inhibitor formation against factor IX.

Administration of factor IX preparations of lowpurity creates a potential risk for thromboembolicepisodes (myocardial infarct, disseminated intravascular coagulation, venous thrombosis, pulmonary embolism). However, such side-effectsare very rare with highly purified preparations offactor IX, like octanine®F.Reports exist on the occurrence of nephrotic syndrome when immune tolerance has beenattempted in haemophilia B patients with anti-factor IX antibodies and a history of allergic reactions.Owing to the heparin content, severe heparin antibody-induced thrombocytopenia (HIT type II)may be observed in very rare cases, with plateletcounts markedly under 100,000 per µl or a rapiddecline to less than 50 % of the initial value.In patients without prior heparin hypersensitivity,

Basic Prescribing Informationoctanine®F 500/1000

Indications, storage conditions and other registrationdetails differ from country to country. Please checkthe local prescribing information.

Active Substance: Human coagulation factor IX

Composition: 1 vial with lyophilisate contains coagulation factor IX enriched from a fraction ofhuman plasma with a factor IX coagulation activityof 500/1000 IU for reconstitution in 5 ml/10 ml of Water for Injections, respectively.

Therapeutic Indications: Prophylaxis and treatmentof bleeding in haemophilia B (congenital factor IXdeficiency).

Contra-Indications: Hypersensitivity against a component of the preparation, heparin-inducedthrombocytopenia (HIT Type II).

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the onset of the decline in platelet count occurs as a rule within 6–14 days after the start of treatment. In patients with heparin hypersensitivity,this decline may occur within hours. In these cases,the administration of octanine®F must be stoppedimmediately. The patient should be advised not to use any heparin-containing medicaments in the future.

Interactions with Other Medicaments:None known.

Pregnancy and Lactation: No supportive informationis available about use during pregnancy and lactation.

Excipients: Heparin, sodium chloride, sodium citrate, arginine chloride, lysine chloride.

Incompatibilities: octanine®F must not be mixedwith other medicinal products.

Shelf Life: 2 years.

Special Precautions for Storage:Store at + 2 ºC to + 25 ºC. Do not freeze. Protect from light.

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FIX at its Peak

References1. Octapharma internal report, data on file

2. Farrugia A, Guide for the assesment of clotting factor concentrates for the treatment of hemophilia. WFH, 2003

3. Paul-Ehrlich-Institut: Announcement on Measures to Reduce the Risk of Drugs. Federal Government Bulletin, 26 August, 1994

4. Neisser-Svae A et al., Prion removal by chromatography purification and nanofiltration of FIXc and PCC. Haemostaseologie 2007; 1:27 A62

5. Klukowska A. et al. Haemophilia 2008; 14 (Suppl. 2): 03 PO 2

6. Klukowska A et al. Haemophilia 2008; 14: 531–538.

7. Berntorp E et al. Haemophilia 2006; 12(Suppl. 6): 1–7.

8. Van den Berg HM. Haematologica 2004; 89: 645–50.

9. Roth DA et al. Blood 2001; 98: 3600–6.

10. Björkman S et al. Haemophilia 2001; 7: 133–9.

11. Klarmann D et al. Haemophilia 2008; 14: 44–49.

Packaging: octanine®F is provided as a combinationpackage consisting of two cartons. One carton contains octanine®F 500 IU or 1000 IU in a vial closed with a rubber stopper and flip-off cap. Theother carton contains the solvent, 5 ml (for 500 IU)or 10 ml (for 1000 IU) of Water for Injections, in avial closed with a rubber stopper and flip-off cap.

The package also contains for application:1 disposable syringe1 double-ended needle1 filter needle1 infusion set2 alcohol swabs

Prescription Status: Prescription only.

Marketing Authorization Holder:Octapharma AG, Seidenstrasse 2, CH 8853 Lachen

Date of Information:May, 2009


HN


FIX at its Peak

Octapharma AGSeidenstraße 2CH-8853 LachenSwitzerland

www.octapharma.com

Date of preparation: May 2009NIN

E.BR

OC

.09/

05.0

1.C

P.EN


highly purified fix at its peak - berkilac.com · highly purified native fix fix at its peak ......

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