Consumer medicine information

Kogenate FS with Vial Adapter

Octocog alfa

BRAND INFORMATION

Brand name

Kogenate FS (with vial adapter)

Active ingredient

Octocog alfa

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kogenate FS with Vial Adapter.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about KOGENATE FS.

This leaflet does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking KOGENATE FS against the benefits they expect it will have for you.

KOGENATE FS should only be used under medical supervision.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT KOGENATE FS IS USED FOR

KOGENATE FS will both help to prevent and treat bleeding, occurring either spontaneously or due to injury, and bleeding during emergency and surgical procedures, by temporarily providing additional Factor VIII.

BEFORE YOU USE KOGENATE FS

When you must not use it

Do not use KOGENATE FS if you have an allergy to:

  • any medicine containing octocog alfa (bhk) (recombinant Factor VIII)
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

As KOGENATE FS contains trace amounts of mouse and hamster proteins, a possibility exists that patients treated with this product may develop hypersensitivity to these non-human proteins. If you experience any of these symptoms, you should stop the injection at once and seek medical attention immediately.

Do not use KOGENATE FS after the expiry date (EXP) printed on the pack. The expiry date is printed on the carton and vial after “EXP” (e.g. 3 NOV 18 refers to 3 November 2018). If it has expired return it to your pharmacist for disposal.

Do not use this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Use in children
KOGENATE FS has been shown to be effective in children.

Before you start to use it

Tell your doctor if you are pregnant or breastfeeding. Experience regarding the use of KOGENATE FS during pregnancy and during breastfeeding is not available because of the rare occurrence of haemophilia in women. However, if you are receiving KOGENATE FS treatment and you are pregnant or suspect you are pregnant, you must contact your doctor for advice.

Breastfeeding is not recommended if you are being treated with KOGENATE FS.

Tell your doctor if you have previously had an allergic or hypersensitivity reaction to other Factor VIII products. Serious allergic and hypersensitivity reactions with Factor VIII have been reported, particularly in very young patients who had previously reacted to other Factor VIII products.

Tell your healthcare provider if you have been told you have heart disease or are at risk for heart disease.

If you have not told your doctor or pharmacist about any of the above, tell them before you start using KOGENATE FS.

Taking other medicines

Whilst being treated with KOGENATE FS, you must seek your doctor's advice before taking any other medication, whether provided on a prescription or bought from a pharmacy, supermarket or health food shop.

You should avoid taking some analgesic/anti-inflammatory painkillers such as aspirin, phenylbutazone, and indomethacin that increase the risk of bleeding.

HOW TO USE KOGENATE FS

KOGENATE FS is a SINGLE-USE ONLY product

How much to use

The amount of KOGENATE FS you need and the frequency with which it should be used will depend on the clinical effect. Your doctor will determine the correct dosages based on the severity of your condition, depending on your body weight, the extent of bleeding and whether KOGENATE FS is given to prevent or treat bleeding. Tests to measure the circulating levels of Factor VIII in your blood will be performed at intervals and are important to monitor the effectiveness of the treatment.

How to use it

For infusion, the product must be prepared under aseptic conditions. If any component of the package is opened or damaged, do not use this component.

KOGENATE FS should be inspected visually for particulate matter and discolouration prior to administration. Do not use KOGENATE FS if you notice any particulates or turbidity in the solution.

KOGENATE FS should be reconstituted and administered with the components provided with each package.

The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter.

Wash your hands thoroughly before preparing to administer KOGENATE FS.

If you are not administering to yourself, wear gloves to avoid contact with blood.

Reconstitute KOGENATE FS powder with the diluent provided before use. Prepare KOGENATE FS when you are ready to use it. KOGENATE FS should be administered by intravenous (into a vein) injection as soon as possible after reconstitution (no later than 3 hours after reconstitution).

If the solution is not injected immediately after reconstitution, leave the syringe attached to the vial containing the solution to maintain sterility of the product. Refrigeration of reconstituted KOGENATE FS solution should be avoided. Any unused solution must be discarded.

Reconstitution, product administration, and handling of the administration set and needles must be done with care. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV and hepatitis. Obtain immediate medical attention if injury occurs.

The complete set of instructions on how you should reconstitute and administer KOGENATE FS is provided at the end of this document.

If you have any doubts about how to reconstitute or administer KOGENATE FS, please consult your doctor, pharmacist or Haemophilia Treatment Centre.

When to use it

You can inject KOGENATE FS at any time of day, before or after meals.

If you use too much (overdose)

Telephone your doctor or the Poisons Information Centre immediately (telephone Australia: 13 11 26; New Zealand: 0800 POISON or 0800 764 766) if you think that you or anyone else may have used too much KOGENATE FS.

SIDE EFFECTS

Tell your doctor if you notice any of the following and they worry you:

  • dizziness
  • a mild increase or decrease in your blood pressure
  • nausea
  • a running nose

Tell your doctor immediately if you notice any of the following:

  • a local reaction around the site of the injection (e.g. a burning sensation, transient reddening of the skin)
  • rash, itching on the skin

If the following happens, stop using KOGENATE FS immediately, and tell your doctor immediately, or go to accident and emergency at your nearest hospital:

  • skin rashes, breathlessness, wheezing, tightness of the chest, decreased blood pressure (feeling faint)

These are signs of a serious allergic and hypersensitivity reaction. You may need immediate emergency treatment with resuscitative measures such as the administration of adrenaline and oxygen. These reactions are very rare.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Inhibitors
Treatment with Factor VIII products such as KOGENATE FS may sometimes lead to the formation of antibodies (inhibitors) which neutralise Factor VIII and reduce the effectiveness of the treatment. Your doctor will monitor you for development of these inhibitors and if they suspect that an inhibitor is present, the level of inhibitor will be measured using the appropriate laboratory tests. In some patients, inhibitors can be successfully overcome with larger doses of Factor VIII, but for some patients it may be necessary to switch to a different treatment.

AFTER USING KOGENATE FS

Storage

Keep KOGENATE FS together with the prefilled diluent syringe in the refrigerator. DO NOT FREEZE.

For use at home, the product may be stored at 30°C (normal room temperature) for up to 6 months. Write the date at which the 6-month period ends on the vial and carton label. At the end of this period, the product must be discarded.

Do not use the product after this date.

Do not return the product to the refrigerator after it has been stored at 30°C.

Protect KOGENATE FS from exposure to light. Keep the KOGENATE FS vial in its carton until just prior to use.

Disposal

If not used, the vial and carton should be returned to the Haemophilia Treatment Centre just prior to expiry.

KOGENATE FS should be used once only. After injecting, you should discard the syringe even if you have not injected all its contents. Syringes should be discarded in an appropriate disposal unit. Any unused solution must be discarded. If your doctor tells you to stop using KOGENATE FS or if it has passed its expiry date, ask your doctor or pharmacist what to do with any product or syringes that are left over.

PRODUCT DESCRIPTION

What it looks like

KOGENATE FS is a white to slightly yellow powder before reconstitution and a clear liquid after reconstitution with water for injection. It comes in a clear glass vial with a rubber stopper.

KOGENATE FS contains the active ingredient octocog alfa (bhk) (recombinant Factor VIII) as a sterile, highly purified, freeze-dried powder.

KOGENATE FS is produced from genetically engineered bhk (baby hamster kidney) cells into which the genetic code for human Factor VIII has been inserted.

KOGENATE FS does not contain von Willebrand factor and therefore is not suitable for patients requiring treatment of von Willebrand's disease. Otherwise, KOGENATE FS has the same biological effects as Factor VIII derived from human plasma.

KOGENATE FS comes in the following dose strengths:

  • 250 IU
  • 500 IU
  • 1000 IU
  • 2000 IU
  • 3000 IU

Ingredients

Each single-use vial of KOGENATE FS powder for injection contains:

Active ingredient:
octocog alfa (bhk) (recombinant Factor VIII)

Inactive ingredients:

  • Sucrose
  • Histidine
  • Glycine
  • Sodium chloride
  • Calcium chloride dihydrate
  • Polysorbate 80

Trace amounts of mouse and hamster protein are also present.

Each single-use prefilled diluent syringe contains sterile water for reconstitution and injection.

KOGENATE FS contains no preservatives.

Your pack contains:

  • 1 vial of KOGENATE FS (powder for injection) 250 IU, 500 IU, 1000 IU, 2000 IU, or 3000 IU
  • 1 prefilled diluent syringe with sterile water for reconstitution and injection: 2.5 mL for 250 IU, 500 IU, 1000 IU and 5 mL for 2000 IU, 3000 IU

Supplier

Made in USA for:

Bayer Australia Limited
ABN 22 000 138 714
875 Pacific Highway
Pymble, NSW 2073

Bayer New Zealand Limited, Auckland

Australian Registration Numbers

KOGENATE FS 250 IU - AUST R 77689

KOGENATE FS 500 IU - AUST R 77688

KOGENATE FS 1000 IU - AUST R 77690

KOGENATE FS 2000 IU - AUST R 153830

KOGENATE FS 3000 IU - AUST R 173675

Not all presentations are marketed.

Date of Preparation
07 May 2020

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered Trademark of Bayer AG, Germany

© Bayer Australia Ltd All rights reserved

HOW TO USE IT

Reconstitution
Wash your hands thoroughly before performing the following procedures. Prepare the solution on a clean, dry, non-slip surface.

  1. Warm the unopened powder vial and the diluent syringe in your hands to approximately body temperature (do not exceed 37°C). Wipe any observable moisture from the vial.
  2. Remove the protective cap from the powder vial (Figure A). Aseptically clean the rubber stopper with an alcohol swab, being careful not to handle the rubber stopper.

  1. Place product vial on a clean, dry, non-slip surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (Figure B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.

  1. Grasp the plunger rod by the top plate and remove from the carton. Avoid touching the sides and threads of the plunger rod. Immediately insert the plunger rod into the threaded syringe rubber stopper by turning it firmly clockwise (Figure C).

  1. Holding the diluent syringe by the barrel, snap the syringe cap off the tip (Figure D). Do not touch the diluent syringe tip with your hand or any surface. Set the diluent syringe aside for further use.

  1. Now remove and discard the adapter housing (Figure E).

  1. Attach the prefilled diluent syringe to the threaded vial adapter by turning clockwise (Figure F).

  1. Inject the diluent into the powder by slowly pushing down on the syringe plunger rod (Figure G).

  1. Dissolve the powder by gently swirling the vial (Figure H). Do not shake the vial. Ensure that the powder is completely dissolved without excessive foam before use. Do not use solutions that contain visible particles or that are cloudy or discoloured.

  1. Withdraw solution into the syringe by holding the vial on end above the vial adapter and syringe (Figure I) then draw the plunger rod out slowly and smoothly. Ensure that the entire contents of the reconstituted KOGENATE FS vial are drawn into the syringe.

  1. If you need more than one dose, reconstitute the desired amount of product repeating steps 1-10 above. Use a new syringe.

Administration
If you are not administering to yourself, wear gloves to avoid contact with blood.

The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter.

  1. Apply a tourniquet. Determine the point of injection. Prepare the site of injection aseptically by cleaning the skin with an alcohol swab and letting it dry, or as advised by your doctor. Firmly grasp one or both wings of the administration set to puncture the vein and secure the administration. NOTE: Follow instructions for administration set provided.
  2. Remove tourniquet.
  3. With the plunger rod in place, remove the filled syringe from the vial adapter (the latter should remain attached to the vial). Attach the filled syringe to the administration set by screwing it clockwise and ensure that no blood enters the syringe (Figure J).

  1. Inject the solution slowly over several minutes (from 1-2 mL per minute), keeping an eye on the position of the needle. The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 5-10 minutes or less is well tolerated.
  2. If a further dose is required, remove the empty syringe by turning it anti-clockwise. Connect the newly prepared syringe. Follow steps 3-4 above.
  3. If no further dose is required, remove the administration set and syringe. Hold a cotton pad firmly over the injection site on the outstretched arm for approximately 2 minutes. Finally, apply a small pressure dressing to the wound.

Place needles in a sharps container after single-use. Discard all equipment, including any reconstituted KOGENATE FS product, in accordance with biohazard procedures.

Published by MIMS August 2020

BRAND INFORMATION

Brand name

Kogenate FS (with vial adapter)

Active ingredient

Octocog alfa

Schedule

Unscheduled

 

Name of the medicine

Octocog alfa (bhk) (recombinant Factor VIII).

Excipients.

Vial with lyophilisate for injection or infusion.

Sucrose, histidine, glycine, sodium chloride, calcium chloride and polysorbate 80. (Trace amounts of mouse and hamster protein are also present.)

Prefilled diluent syringe for parenteral use.

Water for injections, 2.5 mL for 250, 500, 1000 IU; 5 mL for 2000, 3000 IU.

Description

Kogenate FS is a sterile, stable, purified recombinant human antihaemophilic Factor VIII concentrate produced from genetically engineered baby hamster kidney cells (bhk) containing a cloned human Factor VIII gene. The name of the active ingredient in Kogenate FS is octocog alfa (bhk).
Octocog alfa (bhk) is a highly purified glycoprotein consisting of multiple peptides including an 80 kDa and various extensions of the 90 kDa subunit. Kogenate FS is available in the following dose strengths. See Table 1.
Each vial of Kogenate FS contains the labelled amount of octocog alfa (bhk) (Factor VIII) in International Units (IU). One IU, as defined by the World Health Organisation standard for blood coagulation Factor VIII, human, is approximately equal to the level of Factor VIII activity found in 1.0 mL of fresh pooled human plasma.
One single-use vial with lyophilisate for injection or infusion contains:
Active ingredient: octocog alfa (bhk) (nominal dose of 250, 500, 1000, 2000, 3000 IU).
Excipients: sucrose, histidine, glycine, sodium chloride, calcium chloride dihydrate and polysorbate 80.
[Trace amounts of mouse and hamster protein are also present.]
One single-use prefilled diluent syringe for parenteral use contains:
Excipient: water for injections, 2.5 mL for 250, 500, 1000 IU; 5 mL for 2000, 3000 IU.

Pharmacology

Kogenate FS has the same biological activity as Factor VIII derived from human plasma with the exception that Kogenate FS does not contain von Willebrand factor.

Pharmacokinetics.

In 2 trials of single dose Kogenate FS 50 IU/kg IV, involving 35 patients aged 12 to 59 years with haemophilia A (Factor VIII < 2%), no inhibitors and not actively bleeding, the mean half-life of Factor VIII was between 13.3 and 17.2 hours. Mean clearance and residence time were determined in one of the trials (n = 15) and were 1.9 L/h and 22.5 h respectively. Mean incremental recovery, the serum Factor VIII activity 10 minutes postinfusion, was between 2.0 and 2.1 IU/kg and did not change over 24 weeks. Mean activated partial thromboplastin time shortened from 80 s to 30 s within 10 minutes of infusion.

Clinical Trials

Previously treated patients (PTPs).

A total of 71 patients with severe (≤ 2% Factor VIII) haemophilia A, ages 12-59, who had been previously treated with other recombinant or with plasma derived antihaemophilic factor products, were treated up to 54 months in open label studies with Kogenate FS in Europe (EU) and North America (NA). A total of 5,667 bleeding episodes were treated during the studies. Patients could be treated on demand or prophylactically. Regularly scheduled prophylactic treatment represented 76% of all infusions (treatment regimens of 2-3 infusions per week) (see Table 2). Haemostasis was satisfactory (rated excellent, good or moderate response to treatment) in 97.1% of bleeding episodes. One out of the 73 PTPs started the study with a pre-existing inhibitor. Excluding this patient, no patients developed inhibitors.
Bleeding episodes were graded minor, moderate or severe by patients or treating physicians. 92.7% of bleeding episodes were controlled after 1 or 2 infusions, using median doses of 22, 30 and 32 IU/kg/infusion respectively for minor, moderate and severe bleeding in the EU trial and 21, 25 and 29 IU/kg/infusion in the NA trial.
Prophylactic Kogenate FS was given to 9 patients on 11 occasions for surgical procedures. The procedures were classified as minor (arthroscopy, hernia repair, tooth extraction, synovectomy, circumcision, mobilisation of knee) or major (total knee replacement, removal of brain tumour). There were 8 minor procedures and 3 major procedures. The median dose per infusion was 35 IU/kg for the minor procedures and 42 IU/kg for the major procedures. Infusions were given every 8 to 12 hours. Haemostasis was satisfactory in all cases.

Previously untreated and minimally treated patients (PUPs and MTPs).

Kogenate FS has been used in the treatment of bleeding episodes in previously untreated patients (PUPs) and minimally treated (MTPs) paediatric patients with severe (≤ 2% Factor VIII) haemophilia A. There were 37 PUPs and 24 MTPs (defined as having ≤ 4 exposure days) treated with a total of 9,389 infusions of Kogenate FS for a follow-up duration of up to 3.1 years. A total of 1047 bleeding episodes were treated effectively with one or two infusions of Kogenate FS in 88.1% of cases. A total of 27 surgical procedures were performed in 22 patients. Haemostatic efficacy of Kogenate FS during surgical procedures was assessed by the amount of blood loss, which did not exceed 15 mL, and by the need for blood transfusions, which were not necessary. One out of the 61 PUPs/MTPs started the study with a pre-existing inhibitor. Excluding this patient, 9 out of 60 (15%) patients developed inhibitors after a median number of 7 exposure days (range of 2-16 exposure days) (see Table 3).

Paediatric prophylaxis and joint damage risk reduction.

A total of 65 boys less than 30 months of age with severe (≤ 2% Factor VIII) haemophilia A and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicentre, open label, prospective, randomised, controlled clinical study. Patients received either 25 IU/kg every other day (primary prophylaxis; n = 32) or at least 3 doses totalling a minimum of 80 IU/kg at the time of a bleeding episode (enhanced episodic; n = 33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e. index joints) was statistically significantly lower (p = 0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint haemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm.
Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the prophylaxis arm were 8-fold more likely to remain damage free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 haemorrhages; right ankle, mean 2.6 haemorrhages).
As shown in Table 4, the incidence of joint damage was statistically significantly lower in the prophylaxis group as compared to the episodic group when assessed by MRI, or either MRI or radiography, using predefined criteria for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.
As shown in Table 5, the assessment of endpoints in all randomised subjects assuming that those without complete baseline and endpoint data are treatment failures (intention to treat analysis). The incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group, with similar p-values, when assessed by MRI, or either MRI or radiography.
Routine prophylactic treatment in children ages 0-2.5 years with no pre-existing joint damage has been shown to be more effective in reducing spontaneous joint bleeding and the risk of joint damage, compared to an enhanced episodic treatment regimen. Evaluation of monthly index joint and other haemorrhages by subject age showed that in subjects receiving enhanced episodic therapy, the frequency of monthly index joint and nonjoint bleeds increased each year, while in patients receiving routine prophylaxis, the monthly bleeding frequency for both index joint and nonjoint bleeds remained low in all age groups over the duration of the study. This data can be extrapolated to ages > 2.5-16 years for children who have no existing joint damage.

Indications

Kogenate FS is indicated for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital Factor VIII deficiency). It may also be used in patients with Factor VIII inhibitors (neutralising antibodies) who continue to respond to infused Factor VIII.
Kogenate FS does not contain von Willebrand factor and hence is not indicated in von Willebrand's disease.

Contraindications

Known intolerance or allergic reactions to constituents of Kogenate FS.

Precautions

Hypersensitivity and anaphylactic reactions.

Kogenate FS contains trace amounts of mouse and hamster proteins. Caution should be exercised when administering to individuals with previous hypersensitivity to Kogenate or plasma derived Factor VIII, or known hypersensitivity to biological preparations with traces of proteins.
Very rare cases of allergic and anaphylactic reactions have been reported with the predecessor product, Kogenate Factor VIII (rDNA) (bhk), particularly in very young patients or patients who had previously reacted to other Factor VIII concentrates (see Adverse Effects, Post-marketing experience). Serious anaphylactic reactions require immediate emergency treatment with resuscitative measures such as the administration of adrenaline and oxygen. If allergic or anaphylactic reactions occur, the injection/ infusion should be stopped immediately. In case of shock, the current medical standards for shock treatment should be observed.

Other.

Haemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as nonhaemophilic patients when clotting has been normalized by treatment with FVIII.

Monitoring.

Although dosage can be estimated by the presented calculations, it is strongly recommended that laboratory tests be performed on the patient's plasma at suitable intervals to ensure that adequate Factor VIII levels have been reached and are maintained. In the case of major surgical interventions, a precise monitoring of the substitution therapy by means of coagulation analysis is required.

Immunogenicity.

The formation of neutralising antibodies to Factor VIII (inhibitors) is a known complication in the management of individuals with haemophilia A. In studies with recombinant Factor VIII preparations, development of inhibitors is predominantly observed in previously untreated haemophiliacs.
In a study of previously untreated patients using Kogenate, inhibitor antibodies developed in 17 of the 92 patients (18.5%) who had at least one follow-up titre. The incidence of antibodies was 15/56 (26.7%) in patients with severe disease (< 2% Factor VIII), 2/18 (11%) in patients with moderate disease (2-5% Factor VIII) and 0/18 in patients with mild disease (> 5% Factor VIII). Ten of the antibodies were high titre (> 10 Bethesda Units), 3 were low titre and 4 were low titre and transient. Inhibitor formation is especially common in young children with severe haemophilia during their first years of treatment, or in patients of any age who have received little previous treatment with Factor VIII. Inhibitor formation may occur at any time during the treatment of patients with haemophilia A, therefore patients treated with any Factor VIII preparation, including Kogenate FS, should be carefully monitored for the development of antibodies to Factor VIII by appropriate clinical observation and laboratory tests according to the recommendation of the patient's haemophilia treatment centre (see Adverse Effects).

Carcinogenesis, mutagenesis, effects on fertility.

In vitro evaluation of the mutagenic potential of Kogenate FS did not demonstrate gene mutations or chromosomal abnormalities. In vivo treatment of male mice with Kogenate FS at 1000 IU/kg IV did not demonstrate germ cell mutations. Long-term investigations of carcinogenic potential in animals have not been performed. Animal studies investigating the effects of Kogenate FS on fertility have not been conducted.

Use in pregnancy.

(Category B2)*
Animal reproduction studies have not been conducted with Kogenate or Kogenate FS. Experience regarding the use of Kogenate FS during pregnancy and lactation is not available due to the very rare occurrence of haemophilia A in women. It is not known whether Kogenate FS can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Kogenate FS should be used during pregnancy only if clearly indicated.
* Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.

Use in lactation.

It is not known if Kogenate FS or its metabolites are excreted in human milk, and nursing is not recommended in women being treated with Kogenate FS.

Effects on ability to drive or use machinery.

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

Interactions

Besides the known interactions of Factor VIII with other coagulation proteins, no other interactions with other drugs have been established.
Analgesics such as acetylsalicylic acid, phenylbutazone and indomethacin all impair platelet function, increase the tendency to bleed and should therefore not be given to haemophiliacs.

Adverse Effects

During the clinical studies conducted in previously treated patients (PTPs, defined as having more than 100 exposure days), 451 adverse events were reported in the course of 24,936 infusions (1.8%). Only 24 events in 13 patients were considered to be at least remotely related to Kogenate FS (0.1%, relative to the number of infusions). In clinical studies with 73 PTPs, one patient had a pre-existing inhibitor. In the other 72 patients, followed over four years, de novo inhibitors were not observed. See Table 6.
In clinical studies with previously untreated patients and minimally treated paediatric patients, 726 adverse events were reported in the course of 9,389 infusions (7.7%). Only 20 events in 8 patients were considered to be at least remotely related to Kogenate FS (0.2%, relative to the number of infusions). These included: the expected complication of inhibitor development in 9 patients, a forearm bleed following venipuncture, constipation, adenopathy, rash, anaemia and pallor in one inhibitor patient with gastroenteritis, and serious otitis media. See Table 7.
Nine out of 60 (15%) PUPs/MTPs treated with Kogenate FS developed inhibitors. This included 5 out of 37 (14%) PUPs and 4 out of 23 (17%) MTPs treated with Kogenate FS: overall 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU. The median number of exposure days at the time of inhibitor detection in these patients was 9 days (range 3-18 days).
The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more than 20 exposure days in poststudy follow-up and one of them developed a low titre inhibitor. The fifth patient was lost to follow-up.
In the clinical study of paediatric prophylaxis and joint damage risk reduction, the overall incidence of de novo inhibitor development in subjects while on study was 13% (8/64) and the incidence of inhibitor detected during this study, including pre-existing inhibitors, was 14% (9/65). Six of the detected inhibitors were at low titre (< 5 BU) and four of them were transient with negative titres by the last inhibitor test on study. Three subjects randomised to the prophylaxis arm (including one subject with pre-existing inhibitors) developed high titre inhibitors (≥ 5 BU).
Central venous access device (CVAD) line associated infections were observed in 12/65 small children treated with either enhanced episodic treatment or regular prophylaxis.

Post-marketing experience.

The following events are principally derived from post-marketing experience and publications; accurate rate estimates are generally not possible. Among patients treated with its predecessor product Kogenate Factor VIII (rDNA) (bhk) very rare cases of serious allergic reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, vomiting) and anaphylactic reactions have been reported, particularly in very young patients or patients who have previously reacted to other Factor VIII concentrates. Rare cases of urticaria have also been reported. Although such serious reactions have not been reported with the use of Kogenate FS octocog alfa (bhk) it is possible that these may also occur. Rare cases of dyspnoea have been reported with Kogenate FS.
In extensive postregistration studies with Kogenate FS, involving more than 1000 patients the following was observed: less than 0.2% PTPs developed de novo inhibitors. In a subset defined as having less than 20 exposure days at study entry, less than 11% developed de novo inhibitors. See Table 8.
Available registries have reported inhibitor rates for PUPs with severe haemophilia A in the range of 28 to 38% for FVIII products.

Dosage and Administration

Kogenate FS contains no preservative. Kogenate FS must be administered intravenously.
Clinical studies have demonstrated a mean rise of about 2% in Factor VIII activity for each unit of Kogenate FS transfused per kg body weight. The following formulae can be used to determine the appropriate dose required for a given response (I) or the response to be expected from a given dose (II). See Equation 1.
The dosage and duration of the substitution therapy must be individualised according to the patient's needs (weight, severity of disorder of the haemostatic function, site and extent of the bleeding, the titre of inhibitors, and the Factor VIII level desired). Table 9 provides a guide for Factor VIII minimum blood levels. In the case of the haemorrhagic events listed, the Factor VIII activity should not fall below the given level (in % of normal) in the corresponding period.
The dosage necessary to achieve haemostasis depends upon the type and severity of the bleeding episode. The clinical effect of Kogenate FS is the most important element in evaluating effectiveness of treatment. It may be necessary to administer more Kogenate FS than estimated in order to attain satisfactory clinical results.
The dosage guideline in Table 9 is not derived from any clinical studies, and is not specific to Kogenate FS, but reflects current dosing recommendations for all Factor VIII products.

Special populations.

Paediatrics (< 18 years of age).

The recommended dose for routine prophylaxis in children with no pre-existing joint damage is 25 IU/kg of body weight every other day.
Children present higher Factor VIII clearance values in comparison to adults and thus lower recovery of Factor VIII. This may be explained by differences in body composition and should be taken into account when dosing or following Factor VIII levels in such a population (see Pharmacology, Pharmacokinetics).

Geriatrics (> 65 years of age).

Clinical studies with Kogenate FS did not include sufficient numbers of patients aged 65 and over to be able to determine whether they respond differently from younger patients. However, clinical experience with Kogenate FS and other Factor VIII products has not identified differences between the elderly and younger patients. As with any patient receiving Factor VIII, dose selection for an elderly patient should be individualised.

Long-term prophylaxis of severe haemophilia A.

In patients with severe haemophilia A, doses of 10 to 50 IU of Kogenate FS per kg body weight should be given at intervals of 2 to 3 days. In some cases, especially younger patients, shorter dosage intervals or higher doses may be necessary.

Patients with inhibitors.

Kogenate FS can be used in patients with Factor VIII inhibitors. Factor VIII levels and inhibitor titres must be assessed to ensure adequate replacement therapy. To control the bleeding in patients with high titre inhibitors (typically greater than 10 Bethesda Units) high doses of Factor VIII concentrate and (activated) prothrombin complex concentrate (PCC) can be administered.
Inhibitor tolerance induction is an accepted treatment for selected haemophilia patients with high level inhibitors. Various immune tolerance regimens have been employed but no standardised treatment approach can be accepted or recommended for all patients. The dosage range for individual cases who have responded to immune tolerance treatment with Kogenate FS has been 50-100 IU/kg/day. The effectiveness of such treatment requires confirmation in clinical trials.

Reconstitution and administration.

Contains no antimicrobial agent. Product is for single use in one patient only.

General instructions.

For infusion, the product must be prepared under aseptic conditions. If any component of the package is opened or damaged, do not use this component.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Do not use Kogenate FS if you notice any particulates or turbidity in the solution.
Kogenate FS should be reconstituted and administered with the components provided with each package.
The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter.
Sterile conditions are required during application. The injection site should be cleaned with a sterile pad. The use of sterile needles and a sterile syringe is obligatory.
Kogenate FS is intended for intravenous administration only. To reduce microbiological hazard, it should be administered as soon as practicable after reconstitution. If storage is necessary hold at room temperature for not more than 3 hours. If the solution is not injected immediately after reconstitution, leave the syringe attached to the vial containing the solution to maintain sterility of the product. Follow instructions provided below for reconstitution and administration. Refrigeration of reconstituted Kogenate FS solution should be avoided. Any unused solution must be discarded.
Kogenate FS must not be mixed with other medicinal products or infusion solutions, as this could change the blood clotting activity. Use only the administration set provided. Treatment failure can occur as a consequence of human coagulation Factor VIII adsorption to the internal surfaces of some infusion equipment.
Reconstitution, product administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Kogenate FS Antihemophilic Factor (recombinant) product, in accordance with biohazard procedures.

Reconstitution.

Wash your hands thoroughly before performing the following procedures. Prepare the solution on a clean, dry, non-slip surface.
1. Warm the unopened powder vial and the diluent syringe in your hands to approximately body temperature (do not exceed 37°C). Wipe any observable moisture from the vial.
2. Remove the protective cap from the powder vial. Aseptically clean the rubber stopper with an alcohol swab, being careful not to handle the rubber stopper.
3. Place product vial on a clean, dry, nonslip surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down. The adapter will snap over the vial cap. Do not remove the adapter housing at this step.
4. Grasp the plunger rod by the top plate and remove from the carton. Avoid touching the sides and threads of the plunger rod. Immediately insert the plunger rod into the threaded syringe rubber stopper by turning it firmly clockwise.
5. Holding the diluent syringe by the barrel, snap the syringe cap off the tip. Do not touch the diluent syringe tip with your hand or any surface. Set the diluent syringe aside for further use.
6. Now remove and discard the adapter housing.
7. Attach the prefilled diluent syringe to the threaded vial adapter by turning clockwise.
8. Inject the diluent into the powder by slowly pushing down on the syringe's plunger rod.
9. Dissolve the powder by gently swirling the vial. Do not shake the vial. Ensure that the powder is completely dissolved without excessive foam before use. Do not use solutions that contain visible particles or that are cloudy or discoloured.
10. Withdraw solution into the syringe by holding the vial on end above the vial adapter and syringe then draw the plunger rod out slowly and smoothly. Ensure that the entire contents of the reconstituted Kogenate FS vial are drawn into the syringe.
11. If you need more than one dose, reconstitute the desired amount of product repeating steps 1-10 above. Use a new syringe.

Administration.

Wear gloves to avoid contact with blood.
The reconstituted product must be filtered prior to administration to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter.
1. Apply a tourniquet. Determine the point of injection. Prepare the site of injection aseptically by cleaning the skin with an alcohol swab and letting it dry, or as advised by your doctor. Firmly grasp one or both wings of the administration set to puncture the vein and secure the administration. Note: follow instructions for administration set provided.
2. Remove tourniquet.
3. With the plunger rod in place, remove the filled syringe from the vial adapter (the latter should remain attached to the vial). Attach the filled syringe to the administration set by screwing it clockwise and ensure that no blood enters the syringe.
4. Inject the solution slowly over several minutes (from 1-2 mL per minute), keeping an eye on the position of the needle. The rate of administration should be adapted to the response of the individual patient, but administration of the entire dose in 5-10 minutes or less is well tolerated.
5. If a further dose is required, remove the empty syringe by turning it anticlockwise. Connect the newly prepared syringe. Follow steps 3-4 above.
6. If no further dose is required, remove the administration set and syringe. Hold a cotton pad firmly over the injection site on the outstretched arm for approximately 2 minutes. Finally, apply a small pressure dressing to the wound.

Overdosage

No information exists on symptoms of Factor VIII overdose.

Presentation

Kogenate FS supplied with vial adapter for needleless reconstitution is provided with a prefilled syringe containing diluent for reconstitution.

Kogenate FS 250 IU, 500 IU, 1000 IU.

Packs of 1 vial of lyophilisate [250 IU, 500 IU, 1000 IU octocog alfa (bhk)] and a prefilled diluent syringe for reconstitution (2.5 mL Water for Injections).

Kogenate FS 2000 IU, 3000 IU.

Packs of 1 vial of lyophilisate [2000 IU, 3000 IU octocog alfa (bhk)] and a prefilled diluent syringe for reconstitution (5 mL Water for Injections).
Not all presentations are marketed.

Storage

Kogenate FS must be used before the expiry date.
Kogenate FS should be stored between 2°C and 8°C. Refrigerate. Do not freeze as the lyophilized powder glass vial and the diluent prefilled glass syringe may break. Storage of Kogenate FS may include storage below 30°C for a single period of 6 months. Do not return the product to refrigeration after storage below 30°C. Unused product must then be discarded.
Protect Kogenate FS from light. Keep Kogenate FS in its carton until just prior to use.

Poison Schedule

Unscheduled.