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Drug Details

ReFacto AF powder and solvent for solution for injection

• Drug Class Description
  antihaemorrhagics, blood coagulation factor VIII - ATC code: B02BD02
• Generic Name
  moroctocog alfa
• Presentation
  Powder and solvent for solution for injection. White to off-white cake/powder. Clear, colourless solvent
• Description
  Each vial contains nominally 250 IU*, 500 IU*, 1000 IU* or 2000 IU* moroctocog alfa**. ReFacto AF 250 IU: After reconstitution, each ml of solution contains approximately 62.5 IU/ml moroctocog alfa. ReFacto AF 500 IU: After reconstitution, each ml of the solution contains approximately 125 IU/ml moroctocog alfa. ReFacto AF 1000 IU: After reconstitution, each ml of the solution contains approximately 250 IU/ml moroctocog alfa. ReFacto AF 2000 IU: After reconstitution, each ml of the solution contains approximately 500 IU/ml moroctocog alfa. * The potency (International Units) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of ReFacto AF is 7,600-13,800 IU/mg protein. ** Human coagulation factor VIII produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Moroctocog alfa is a glycoprotein with 1438 amino acids with a sequence that is comparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted) and similar post-translational modifications to those of the plasma-derived molecule. The manufacturing process for ReFacto has been modified to eliminate any exogenous human- or animal-derived protein in the cell culture process, purification, or final formulation; and at the same time the invented name has been changed to ReFacto AF. Excipients: After reconstitution, 1.23 mmol (29 mg) sodium per vial.
• Indications
  

  Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

  ReFacto AF is appropriate for use in adults and children of all ages, including newborns.

  ReFacto AF does not contain von Willebrand factor, and hence is 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 A.

  Posology

  The labelled potency of ReFacto AF is based on the European Pharmacopoeial chromogenic substrate assay, in which the manufacturing potency standard has been calibrated to the WHO International Standard using the chromogenic substrate assay. When monitoring patients' factor VIII activity levels during treatment with ReFacto AF, use of the European Pharmacopoeial chromogenic substrate assay is strongly recommended. The chromogenic assay yields results which are higher than those observed with use of the one-stage clotting assay. Typically, one-stage clotting assay results are 20-50% lower than the chromogenic substrate assay results. The ReFacto AF laboratory standard can be used to correct for this discrepancy.

  Another moroctocog alfa product approved for use outside Europe has a different potency assigned using a manufacturing potency standard that has been calibrated to the WHO International Standard using a one-stage clotting assay; this product is identified by the tradename XYNTHA. Due to the difference in methods used to assign product potency of XYNTHA and ReFacto AF, 1 IU of the XYNTHA product (one-stage assay calibrated) is approximately equivalent to 1.38 IU of the ReFacto AF product (chromogenic assay calibrated). If a patient normally treated with XYNTHA is prescribed ReFacto AF, the treating physician may consider adjustment of dosing recommendations based on factor VIII recovery values.

  Based on their current regimen, individuals with haemophilia A should be advised to bring an adequate supply of factor VIII product for anticipated treatment when travelling. Patients should be advised to consult with their healthcare provider prior to travel.

  The dosage and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of bleeding, and on the patient's clinical condition. Doses administered should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or appropriate specific treatment may be required.

  The number of units of factor VIII administered is expressed in International Units (IUs), 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 an International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII activity is equivalent to the quantity of factor VIII in one ml of normal human plasma. The calculation of the required dosage of factor VIII is based upon the empirical finding that 1 International Unit (IU) of factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dosage is determined using the following formula:

  Required units (IU) = body weight (kg) x desired factor VIII rise (% or IU/dl) x 0.5 (IU/kg per IU/dl), where 0.5 IU/kg per IU/dl represents the reciprocal of the incremental recovery generally observed following infusions of factor VIII.

  The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.

  In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma levels (in % of normal or in IU/dl) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

  Degree of haemorrhage/ Type of surgical procedure	Factor VIII level required (% or IU/dl)	Frequency of doses (hours)/Duration of therapy (days)
  Haemorrhage
  Early haemarthrosis, muscle bleeding or oral bleeding	20-40	Repeat every 12-24 hours. At least 1 day until the bleeding episode as indicated by pain is resolved or healing is achieved.
  More extensive haemarthrosis, muscle bleeding or haematoma	30-60	Repeat infusion every 12-24 hours for 3-4 days or more until pain and acute disability are resolved.
  Life-threatening haemorrhages	60-100	Repeat infusion every 8-24 hours until threat is resolved.
  Surgery
  Minor, including tooth extraction	30-60	Every 24 hours, at least 1 day, until healing is achieved.
  Major	80-100 (pre- and post-operative)	Repeat infusion every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dl).

  During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor 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.

  For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

  Patients using factor-VIII replacement therapy are to be monitored for the development of factor VIII inhibitors. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if factor VIII inhibitors are present. Data from clinical trials indicated that if inhibitors are present at levels less than 10 Bethesda Units (BUs), administration of additional antihaemophilic factor may neutralise the inhibitors. In patients with levels of inhibitor above 10 BU, 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 patients with haemophilia.

  Special population

  Renal or hepatic impairment

  Dosage adjustment for patients with renal or hepatic impairment has not been studied in clinical trials.

  Method of administration

  ReFacto AF is administered by intravenous injection over several minutes after reconstitution of the lyophilised powder for injection with sodium chloride 9 mg/ml (0.9%) solution for injection (provided). The rate of administration should be determined by the patient's comfort level.

  Appropriate training is recommended for non-healthcare professionals administering the product.

  In the interest of patients, it is recommended that every time ReFacto AF is administered, the name and batch number of the product should be recorded.

• Child Dosage
  

  Safety and efficacy studies with ReFacto have been performed both in previously treated children and adolescents (n=31, ages 8-18 years) and in previously untreated neonates, infants and children (n=101, ages < 1-52 months).

  The need for an increased dose relative to that used for adults and older children should be anticipated when treating younger children with ReFacto AF. In a study of ReFacto in children less than 6 years of age, pharmacokinetic analysis revealed half-life and recovery less than that observed in older children and adults. During the clinical trials, children less than 6 years of age on a prophylaxis regimen used an average dose of 50 IU/kg of ReFacto and experienced an average of 6.1 bleeding episodes per year. Older children and adults on a prophylaxis regimen used an average dose of 27 IU/kg and experienced an average of 10 bleeding episodes per year. In a clinical trial setting the mean dose per infusion of ReFacto for bleeding episodes in children less than 6 years of age was higher than the mean dose administered to older children and adults (51.3 IU/kg and 29.3 IU/kg, respectively).

• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

  Hypersensitivity to hamster proteins.

• Special Precautions
  

  As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. The product contains traces of hamster proteins. Patients should be informed of the early signs of hypersensitivity reactions (including hives, generalised urticaria, tightness of the chest, wheezing, hypotension) and anaphylaxis. If allergic or anaphylactic reactions occur, administration of ReFacto AF is to be discontinued immediately, and an appropriate treatment must be initiated. In case of shock, the current medical standards for treatment of shock are to be observed. Patients are to be advised to discontinue use of the product and contact their physician or seek immediate emergency care, depending on the type and severity of the reaction, if any of these symptoms occur.

  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 (BUs) per ml of plasma using the Nijmegen modification of the Bethesda assay. The risk of developing inhibitors is correlated to the exposure to factor VIII, this risk being highest within the first 20 exposure days. Inhibitors have been observed in previously treated patients receiving factor VIII products, including ReFacto AF. 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.

  Reports of lack of effect, mainly in prophylaxis patients, have been received in the clinical trials and in the post-marketing setting for ReFacto. The reported lack of effect with ReFacto has been described as bleeding into target joints, bleeding into new joints or a subjective feeling by the patient of new onset bleeding. When prescribing ReFacto AF it is important to individually titrate and monitor each patient's factor level in order to ensure an adequate therapeutic response.

  In the interest of patient safety, it is recommended that every time ReFacto AF is administered, the name on the carton and batch number of the product are recorded. Patients can affix one of the peel-off labels found on the vial to document the batch number in their diary or for reporting any side effects.

  After reconstitution this medicinal product contains 1.23 mmol (29 mg) sodium per vial, to be taken into consideration by patients on a controlled sodium diet.

• Interactions
  

  No interaction studies have been performed.

• Adverse Drug Reactions
  

  Factor VIII inhibition

  The occurrence of neutralising antibodies (inhibitors) to factor VIII is well known in the treatment of patients with haemophilia A. As with all coagulation factor VIII products, patients are to be monitored for the development of inhibitors that are to be titrated in Bethesda Units (BUs) using the Nijmegen modification of the Bethesda assay. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

  In a clinical study with ReFacto AF in previously treated patients (PTPs), the incidence of factor VIII inhibitors was the primary safety endpoint. Two clinically silent, low-titre, transient inhibitors were observed in 94 patients with a median exposure of 76 exposure days (ED, range 1-92), corresponding to 2.2% of the 89 patients with at least 50 ED. In a supporting study of ReFacto AF, 1 de novo and 2 recurrent inhibitors (all low-titre, central laboratory determination) were observed in 110 patients; median exposure of 58 ED (range 5-140) and 98 patients had at least 50 ED to ReFacto AF. Ninety-eight (98) of the original 110 patients continued treatment in a second supportive study and had subsequent extended exposure to ReFacto AF with a median of 169 additional ED (range 9-425). One (1) additional low-titre de novo inhibitor was observed. The frequency of inhibitors observed in these studies is within the expected range.

  In a clinical study with ReFacto in PTPs, 1 inhibitor was observed in 113 patients. Also, there have been spontaneous post-marketing reports of high-titre inhibitors involving previously treated patients.

  There are no clinical data on previously untreated patients (PUPs) with ReFacto AF. However, clinical trials are planned in previously untreated patients (PUPs) with ReFacto AF. In a clinical trial, 32 out of 101 (32%) previously untreated patients (PUPs) treated with ReFacto developed inhibitors: 16 out of 101 (16%) with a titre > 5 BU and 16 out of 101 (16%) with a titre 5 BU. The median number of exposure days up to inhibitor development in these patients was 12 (range 3-49). Of the 16 patients with high titres, 15 received immune tolerance (IT) treatment. Of the 16 patients with low titres, IT treatment was started in 10. IT had an efficacy of 73% for patients with high titres and 90% for those with low titres. For all 101 treated PUPs, regardless of inhibitor development, the median number of exposure days is 197 (range 1-1299).

  Adverse reactions based on experience from clinical trials with ReFacto or ReFacto AF are presented in the table below by system organ class. These frequencies have been estimated on a per-patient basis and are described using the following categories: very common (1/10); common (1/100 to <1/10); and uncommon (1/1,000 to <1/100).

  Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

  System Organ Class	Frequency of Occurrence per Patient with ReFacto or ReFacto AF
  	Very common (1/10)	Common (1/100 to <1/10)	Uncommon (1/1,000 to <1/100)
  Blood and lymphatic disorders	Factor VIII inhibitors - PUPs	Factor VIII inhibitors - PTPs
  Metabolism and nutrition disorders			Anorexia
  Nervous system disorders		Headache	Neuropathy, dizziness, somnolence, dysgeusia
  Cardiac disorders			Angina pectoris, tachycardia, palpitations
  Vascular disorders		Haemorrhage/Haematoma	Hypotension, thrombophlebitis, vasodilatation, flushing
  Respiratory, thoracic and mediastinal disorders			Dyspnoea, cough
  Gastrointestinal disorders	Vomiting	Nausea	Abdominal pain, diarrhoea
  Skin and subcutaneous tissue disorders			Urticaria, pruritis, rash, hyperhidrosis
  Musculoskeletal, connective tissue and bone disorders		Arthralgia	Myalgia
  General disorders and administration site conditions		Asthenia, pyrexia	Chills/feeling cold, injection site inflammation, injection site reaction, injection site pain
  Investigations			Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood creatine phosphokinase increased
  Surgical and medical procedures		Vascular access complication

  One event of cyst in an 11-year old patient and one event described as confusion in a 13-year old patient have been reported as possibly related to ReFacto AF treatment.

  Safety of ReFacto AF was evaluated in previously treated children and adolescents (n=18, age 12-16 in a study and n=49, age 7-16 in a supporting study). Although a limited number of children have been studied, there is a tendency for higher frequencies of adverse events in children aged 7-16 as compared to adults. A clinical trial evaluating use of moroctocog alfa (AF-CC) in children less than 6 years of age is on going.

  The following adverse events have also been reported for ReFacto: paraesthesia, fatigue, blurred vision, acne, gastritis, gastroenteritis, and pain.

  Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently for ReFacto, and may in some cases progress to severe anaphylaxis including shock.

  Trace amounts of hamster protein may be present in ReFacto AF. Very rarely, development of antibodies to hamster protein has been observed, but there were no clinical sequelae. In a study of ReFacto, twenty of 113 (18%) PTPs had an increase in anti-CHO antibody titre, without any apparent clinical effect.

  If any reaction takes place that is thought to be related to the administration of ReFacto AF, the rate of infusion is to be decreased or the infusion stopped, as dictated by the response of the patient