Summary of medicine characteristics - Helixate NexGen
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains nominally 250/500/1000/2000/3000 IU human coagulation factor VIII (INN: octocog alfa).
Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster kidney cells containing the human factor VIII gene.
- • One mL Helixate NexGen 250 IU contains approximately 100 IU (250 IU / 2 5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.
- • One mL Helixate NexGen 500 IU contains approximately 200 IU (500 IU / 2.5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.
- • One mL Helixate NexGen 1000 IU contains approximately 400 IU (1000 IU / 2.5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.
- • One mL Helixate NexGen 2000 IU contains approximately 400 IU (2000 IU / 5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.
- • One mL Helixate NexGen 3000 IU contains approximately 600 IU (3000 IU / 5 mL) of recombinant human coagulation factor VIII (INN: octocog alfa) after reconstitution with water for injections.
The potency (IU) is determined using the one-stage clotting assay against the FDA Mega standard which was calibrated against WHO standard in International Units (IU).
The specific activity of Helixate NexGen is approximately 4000 IU/mg protein.
For the full list of excipients, see section 6.1.
3.
Po
r and solvent for solution for injection.
Powder: dry white to slightly yellow powder or cake.
Solvent: water for injection, a clear, colourless solution.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). This preparation does not contain von Willebrand factor and is therefore not indicated in von Willebrand's disease.
This product is indicated for adults, adolescents and children of all ages.
4.2 Posology and method of administration
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.
Posology
The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units to the International Standard for factor VIII in plasma).
One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor one mL of normal human plasma.
On demand treatment
The calculation of the required dose of factor VIII is based on the empirical finding that
1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2.5% of normal activity. The required dose is determined using the following formulae:
I.
Required IU = body weight (kg) x desired factor VIII rise
normal) x 0.5
II.
Expected factor VIII rise (% of normal) = 2 x administered IU body weight (kg)
The dose, frequency and duration of the substitution therapy must be individualised according to the patient's needs (weight, severity of disorder of the haemostatic function, the site and extent of the bleeding, the presence of inhibitors, and the factor VIII level desired).
The following table 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:
-
Table 1: Guide for
in
and
| Degree of haemorrhage/ Type of surgical procedure | Factor VIII level required (%) (IU/dl) |
| Haemorrhage Early haemarthrosis, muscle bleed or oral bleed | 20 – 40 |
| More extensive haemarthrosis, muscle bleed or haematoma | 30 – 60 |
| Life threatening haemorrhages (such as intracranial bleed, throat bleed, severe abdominal bleed) | 60 – 100 |
| Surgery Minor including tooth extraction | 30 – 60 |
| Major | 80 – 100 (pre- and postoperative) -O 1 |
Frequency of doses (hours)/
Duration of therapy (days)
Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved. / Repeat infusion every 12 – 24 for 3 – 4 days or more unti disability are resolved.
Repeat infusion ev until threat is resol
4 hours
d
Every 24 hours, at least 1 day, until healing is achieved.
-
a) By bolus infusions
Repeat infusion every 8 – 24 hours until adequate wound healing occurs, then continue with therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dl).
-
b) By continuous infusion Raise factor VIII activity presurgery with an initial bolus infusion and immediately follow with continuous infusion (in IU/kg/h) adjusting according to patient’s daily clearance and desired factor VIII levels for at least 7 days.
The amount to be administered and the frequency of administration should always be adapted according to the clinical effectiveness in the individual case. Under certain circumstances larger amounts than those calculated may be required, especially in the case of the initial dose.
e course of treatment, appropriate determination of factor VIII levels is advised in order to dose to be administered and the frequency at which to repeat the infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries.
Continuous infusion
For the calculation of the initial infusion rate, clearance can be obtained by performing a pre-surgery decay curve, or by starting from an average population value (3.0–3.5 mL/h/kg) and then adjust accordingly.
Infusion rate (in lU/kg/h) = Clearance (in mL/h/kg) x desired factor VIII level (in lU/mL)
For continuous infusion, clinical and in vitro stability has been demonstrated using ambulatory pumps with a PVC reservoir. Helixate NexGen contains low level of polysorbate-80 as an excipient, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC) materials. This should be considered for a continuous infusion administration.
Prophylaxis
For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of Helixate NexGen per kg body weight at intervals of 2 to 3 days.
In some cases, especially in younger patients, shorter dose intervals or higher doses may be neces
Special populations
Paediatric population
The safety and efficacy of Helixate NexGen in children of all ages have been established. Data have been obtained from clinical studies in 61 children under 6 years of age and non-interventional studies in children of all ages.
Patients with inhibitors
Patients should be monitored for the development of factor VIII inhibitors. If the expected plasma
factor VIII activity levels are not attained, or if bleeding is not cont assay should be performed to determine if a factor VIII inhibitor is
levels less than 10 Bethesda Units (BU) per mL, administrati factor VIII may neutralise the inhibitor and permit contin NexGen. However, in the presence of an inhibitor the d
with an appropriate dose, an sent. If the inhibitor is present at itional recombinant coagulation
inically effective therapy with Helixate quired are variable and must be adjusted
according to clinical response and monitoring of plasma factor VIII activity. In patients with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to be considered. These therapies should be directed by physicians with experience in the care of patients with haemophilia.
Intravenous use.
Method of administration
Helixate NexGen should be injected intravenously over 2 to 5 minutes. The rate of administration should be determined by the patient’s comfort level (maximal rate of infusion: 2 mL/min).
Continuous in
Helixate NexGen can be infused by continuous infusion. The infusion rate should be calculated based on lance and the desired FVIII level.
: for a 75 kg patient with a clearance of 3 mL/h/kg, the initial infusion rate would be 3 g to achieve a FVIII level of 100%. For calculation of mL/hour, multiply infusion rate in IU/h/kg by kg bw/concentration of solution (lU/mL).
Table 2: Example for calculation of infusion rate for continuous infusion after initial bolus injection ____________________________________________________________________________
| Desired plasma FVIII level | Infusion rate IU/h/kg | Infusion rate for 75 kg patient mL/h | |
| Clearance: 3 mL/h/kg | Concentrations of rFVIII solution 100 IU/mL 200 IU/mL 400 IU/mL | ||
| 100 % (1 IU/mL) | 3.0 | 2.25 1.125 0.56 | |
| 60 % (0.6 IU/mL) | 1.8 | 1.35 0.68 0.34 | |
| 40 % (0.4 IU/mL) | 1.2 | 0.9 0.45 0.225 |
Higher infusion rates may be required in conditions with accelerated clearance during major bleedings or extensive tissue damage during surgical interventions.
After the initial 24 hours of continuous infusion, the clearance should be recalculated every day using the steady state equation with the measured FVIII level and the rate of infusion using the following equation:
clearance = infusion rate/actual FVIII level.
During continuous infusion, infusion bags should be changed every 24 hours.
For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the package leaflet.
4.3 Contraindications
-
– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
-
– Known allergic reactions to mouse or hamster protein.
4.4 Special warnings and precautions for use
Hypersensitivity
Allergic type hypersensitivity reactions are possible with Helixate NexGen. The product contains traces of mouse and hamster proteins and human proteins other than factor VIII (see section 5.1).
If symptoms of hypersensitivity occur, patients should be advised to discontinue the use of the medicinal product immediately and contact their physician.
Patients should be informed of the early signs of hypersensitivity reactions including hives, nausea, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.
In case of shock, standard medical treatment for shock should be implemented.
Inhibitors
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.
Cases of recurrent inhibitor (low titre) have been observed after switching from one factor VIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor all patients carefully for inhibitor occurrence following any product switch.
The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre inhibitors which are transiently present or remain consistently low titre posing less risk of insufficient clinical response than high titre inhibitors.
In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.
If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.
Continuous infusion
In a clinical study about the use of continuous infusion in surgeries, heparin was used 1 thrombophlebitis at the infusion site as with any other long term intravenous infusions
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per free”.
Cardiovascular events
entially “sodium
Haemophilic patients with cardiovascular risk factors or disease be at the same risk to develop cardiovascular events as non-haemophilic patients when clotting has been normalised by treatment with FVIII. Elevation of FVIII levels following administration, in particular with existing cardiovascular risk factors, might put a patient into the same risk for vessel closure or myocardial
infarction as for the non-haemophilic population monitored for cardiac risk factors.
quently, patients should be evaluated and
Catheter-related complications
If a central venous access device (C local infections, bacteremia and cat
s required, risk of CVAD-related complications including e thrombosis should be considered.
Documentation
Pae
ilation
It is strongly recomm name and batch n the batch of
that every time that Helixate NexGen is administered to a patient, the of the product are recorded in order to maintain a link between the patient and inal product.
warnings and precautions apply both to adults and children.
No interactions of Helixate NexGen with other medicinal products have been reported.
4.6 Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with Helixate NexGen.
Pregnancy and breast-feeding
Based on the rare occurrence of haemophilia A in women, experience regarding the use of Helixate NexGen during pregnancy and breast-feeding is not available. Therefore, Helixate NexGen should be used during pregnancy and breast-feeding only if clearly indicated.
Fertility
There are no fertility data available.
- 4.7 Effects on ability to drive or use machines
Helixate NexGen has no influence on the ability to drive or to use machines.
4.8 Undesirable effects
Summary of the safety profile
Hypersensitivity or allergic reactions (which may include angioedema, burnin infusion site, chills, flushing, generalised urticaria, headache, hives, hypot restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezi
tinging at the ethargy, nausea, ave been observed
with recombinant factor VIII products and may in some cases progress to severe anaphylaxis (including shock). In particular the skin related reactions may occur commonly, whereas a progress to severe anaphylaxis (including shock) is considered to be rare.
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Helixate NexGen. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.
Tabulated list of adverse reactions
e MedDRA system organ classification (SOC and
The table presented below is accord Preferred Term Level).
Frequencies have been evaluated according to the following convention: very common: (>1/10), common (>1/100 to <1/10) uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), nonot be estimated from the available data).
Table 3: Frequency of adverse drug reactions
| MedDRA Standard System Organ Class | Frequency | ||||
| Very common | Common | Uncommon | Rare | Very Rare / not known | |
| Blood and the Lymphatic System Disorders | FVIII Inhibition (PUPs) | FVIII Inhibition (PTPs) | |||
| General Disorders and Administrate n Site Conditions | Infusion site reaction | Infusion related febrile reaction (pyrexia) | |||
| Immune System Disorders | Skin associated hypersensitivity reactions, (pruritus, urticaria and rash) | Systemic Hypersensitivit y reactions (including anaphylactic reaction, nausea, blood pressure abnormal and, dizziness) | |||
| Nervous System Disorders | Dysgeusia | ||||
| * Frequency is based on studies with all FVIII products | which included | patients with severe | |||
haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients
Paediatric population
Frequency, type and severity of adverse reactions in children are expected to be the same as in all population groups except for the inhibitor formation.
Reporting of suspected adve rse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V'.
4.9 Overdose
No case of overdose with recombinant coagulation factor VIII has been reported.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.
Mechanism of action
The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII binds to vWF in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C 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 VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Pharmacodynamic effects
Determination of activated partial thromboplastin time (aPTT) is a conventional in vi for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. duration of aPTT normalisation observed after administration of Helixate Nex achieved with plasma-derived factor VIII.
imilar to that
Continuous Infusion
It has been shown in a clinical study performed with adult haemophilia A patients who undergo a major surgery that Helixate NexGen can be used for continuous infusion in surgeries (pre-, during and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions.
Hypersensitivity
During studies, no patient developed clinically r
mouse protein and hamster protein present i reactions to constituents, e.g. trace amounts certain predisposed patients (see sections 4.
levant antibody titres against the trace amounts of preparation. However, the possibility of allergic
of mouse and hamster protein in the preparation exists in
Data on Immune Toler developed inhibitors to were included in a pr
has been used to i
Immune Tolerance Induction (I ction have been collected in patients with haemophilia A who had retrospective review has been done on 40 patients, and 39 patients tive investigator-initiated clinical study. Data show that Helixate NexGen immune tolerance. In patients where immune tolerance was achieved the bleedings could evented or controlled with Helixate NexGen again, and the patients could continue with prophylactic treatment as maintenance therapy.
>tion
The analysis of all recorded in vivo recoveries in previously treated patients demonstrated a mean rise of 2 % per IU/kg body weight for Helixate NexGen. This result is similar to the reported values for factor VIII derived from human plasma.
Distribution and elimination
After administration of Helixate NexGen, peak factor VIII activity decreased by a two-phase exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional pharmacokinetic parameters for Helixate NexGen for bolus injectionare: mean residence time [MRT (0–48)] of about 22 hours and clearance of about 160 mL/h.Mean baseline clearance for 14 adult patients undergoing major surgeries with continuous infusion are 188 mL/h corresponding to 3.0 mL/h/kg (range 1.6–4.6 mL/h/kg).
5.3 Preclinical safety data
Even doses several fold higher than the recommended clinical dose (related to body weight) fa demonstrate any acute or subacute toxic effects for Helixate NexGen in laboratory animals rat, rabbit, and dog).
Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and carcinogenicity were not performed with octocog alfa due to the immune response to heterologous proteins in all non-human mammalian species.
No studies were performed on the mutagenic potential of Helixate NexGen, since no mutagenic potential could be detected in vitro or in vivo for the predecessor
of Helixate NexGen.
6. PHARMACEUTICAL PARTICULARS
Powder
Solvent
Water for
ilities
6.1 List of excipients
Glycine
6.2 In
Sodium chloride Calcium chloride Histidine Polysorbate 80 Sucrose inal product must not be mixed with other medicinal products except those mentioned in
This sect
Only the provided administration sets can be used because treatment failure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.
6.3 Shelf-life 30 months.After reconstitution, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
However, during in vitro studies, the chemical and physical in-use stability has been demonstrated for 24 hours at 30°C in PVC bags for continuous infusion". After reconstitution, the chemical and physical in-use stability has been demonstrated for 3 hours in in vitro studies.
Do not refrigerate after reconstitution.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vials in the outer carton in order to protect from light.
Within its overall shelf life of 30 months the product when kept in its outer carton, may be stored ambient room temperature (up to 25°C) for a limited period of 12 months. In this case, the produc expires at the end of this 12-month period or the expiration date on the product vial, whichever is earlier. The new expiry date must be noted on the top of the outer carton.
For storage conditions after reconstitution of the medicinal product, see sec
ation or
6.5 Nature and contents of container and special equipment for use, ad implantation
Each package of Helixate NexGen contains:
e grey halogenobutyl rubber
- • one vial with powder (10 mL clear glass type 1 vial wi blend stopper and aluminium seal)
- • one vial with solvent (6 mL clear glass type 1 vial wit stopper and aluminium seal)
- • an additional package with:
-
– 1 filter transfer device 20/20 [Mix2Vial]
-
– 1 venipuncture set
-
– 1 disposable 5 mL syringe
-
– 2 alcohol swabs for single use
- 6.6 Special precautions for disp
Detailed instructions for prepa with Helixate NexGen
7. MARKETING AUTHORISATION HOLDER
Bayer AG
51368 Leverkusen
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/00/144/001 – Helixate NexGen 250 IU
EU/1/00/144/002 – Helixate NexGen 500 IU
EU/1/00/144/003 – Helixate NexGen 1000 IU
EU/1/00/144/004 – Helixate NexGen 2000 IU
EU/1/00/144/005 – Helixate NexGen 3000 IU
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHTION
Date of first authorisation: 04 August 2000
Date of latest renewal: 06 August 2010