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Drug Details

HELIXATE

• Drug Class Description
  Recombinant human Factor VIII (rDNA)(bhk).
• Generic Name
  Factor VIII [octocog alfa]
• Presentation
  Powder and solvent for solution for injection. The powder is provided in a vial as a dry white to slightly yellow powder or cake. The solvent is water for injections provided in a vial.
• Description
  Helixate NexGen 250 IU Powder and solvent for solution for injection. Helixate NexGen 500 IU Powder and solvent for solution for injection. Helixate NexGen 1000 IU Powder and solvent for solution for injection. Helixate NexGen 2000 IU Powder and solvent for solution for injection.
• 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.
• Adult Dosage
  

  Treatment should be initiated 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 (relative to the International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage 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 dosage is determined using the following formulae:

  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, the site and extent of the bleeding, the titre 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:

  Degree of haemorrhage/ Type of surgical procedure	Factor VIII level required (%) (IU/dl)	Frequency of doses (hours)/ Duration of therapy (days)
  Haemorrhage
  Early haemarthrosis, muscle bleed or oral bleed	20 - 40	Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
  More extensive haemarthrosis, muscle bleed or haematoma	30 - 60	Repeat infusion every 12 - 24 hours for 3 - 4 days or more until pain and disability are resolved.
  Life threatening bleeds such as intracranial bleed, throat bleed, severe abdominal bleed	60 - 100	Repeat infusion every 8 to 24 hours until threat is resolved
  Surgery
  Minorincluding tooth extraction	30 - 60	Every 24 hours, at least 1 day, until healing is achieved.
  Major	80 - 100(pre- and postoperative)	a) By bolus infusionsRepeat 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%b) By continuous infusionRaise factor VIII activity pre-surgery 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.

  During the course of treatment, appropriate determination of factor VIII levels is advised in order to guide the 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, achieving different levels of in vivo recovery and demonstrating different half-lives.

  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. 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 IU/Kg/h) = Clearance (in ml/h/Kg) x desired factor VIII level (in IU/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.

  For scheduled prophylaxis against bleeds in patients with severe haemophilia A, doses of 20 to 60 IU of Helixate NexGen per kg body weight should be given at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary. Data have been obtained in 61 children under 6 years of age.

  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 controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present at levels less than 10 Bethesda Units (BU) per ml, administration of additional recombinant coagulation factor VIII may neutralise the inhibitor and permit continued clinically effective therapy with Helixate NexGen. However, in the presence of an inhibitor the doses required 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.

  Helixate NexGen should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level (maximal rate of infusion: 2 ml/min).

  Helixate NexGen can be infused by continuous infusion. The infusion rate should be calculated based on the clearance and the desired FVIII level.

  Example: for a 75 kg patient with a clearance of 3 ml/h/kg, the initial infusion rate would be 3 IU/h/kg 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 (IU/ml).

  	Desired plasmaFVIII level	Infusion rateIU/h/kg	Infusion rate for 75 kg patientml/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.

  Subsequent infusion rates should be calculated based on the actual FVIII levels and recalculated clearance for each day post surgery based on the equation: clearance = infusion rate/actual FVIII level.

• Contra Indications
  

  Known hypersensitivity to the active substance, to mouse or hamster protein or to any of the excipients.

• Special Precautions
  

  As with any intravenous protein product, allergic type hypersensitivity reactions are possible.

  Patients should be made aware that the potential occurrence of chest tightness, dizziness, mild hypotension and nausea during infusion can constitute an early warning for hypersensitivity and anaphylactic reactions. Symptomatic treatment and therapy for hypersensitivity should be instituted as appropriate. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately and patients should contact their physician. In case of shock, the current medical standards for shock treatment should be observed.

  The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are invariably IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Modified Bethesda Units (BU) per ml of plasma. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII and to genetic factors among others, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.

  Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant factor VIII product to another in previously treated patients with more than 100 exposure days who have a history of inhibitor development.

  Patients treated with recombinant coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. See also section 4.8 Undesirable effects.

  In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions.

  In the interest of the patients, it is recommended that, whenever possible, every time that Helixate NexGen is administered to them, the name and the batch number of the product is registered.

  This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium free”.

• Interactions
  

  No interactions of Helixate NexGen with other medicinal products are known.

• Adverse Drug Reactions
  

  After administration of Helixate NexGen mild to moderate adverse events were observed in rare cases as presented in the following table.

  MedDRA System Organ Class	MedDRA Preferred Term
  Blood and lymphatic sytem disorders	Factor VIII inhibition
  Gastrointestinal disorders	Dysgeusia
  	Nausea
  General disorders and administration site conditions	Injection site reaction
  	Pyrexia
  Immune system disorders	Allergic / Anaphylactic reaction
  Investigations	Blood pressure abnormal
  Nervous system disorders	Dizziness
  Skin and subcutaneous tissue disorders	Pruritus
  	Rash

  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. Patients should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

  In clinical studies, Helixate NexGen has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP patients treated with Helixate NexGen developed inhibitors: Overall 6 out of 60 (10%) with a titer above 10 BU and 3 out of 60 (5%) with a titer 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 post-study follow-up and one of them developed a low titer inhibitor. The fifth patient was lost to follow-up.

  In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure days), followed over four years, no de-novo inhibitors were observed.

  In extensive post-registration studies with Helixate NexGen, involving more than 1000 patients the following was observed: Less than 0.2% PTP 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.

  During studies, no patient developed clinically relevant antibody titres against the trace amounts of mouse protein and hamster protein present in the preparation. However, the possibility of allergic reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in certain predisposed patients.