Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia A.

Posology

ReFacto is appropriate for use in adults and children of all ages, including new-borns. Safety and efficacy studies 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 labelled potency of ReFacto is based on the European Pharmacopoeial chromogenic substrate assay. With ReFacto, the chromogenic assay yields results which are higher than the results obtained with the one-stage clotting assay.

When monitoring patients' factor VIII activity levels during treatment, it is strongly recommended that the European Pharmacopoeial chromogenic substrate assay be used.

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

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 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 per IU/kg administered. The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor VIII rise (% or IU/dl) x 0.5 (IU/kg per IU/dl)

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:

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.

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).

Children less than 6 years of age on a prophylaxis regimen during the clinical trials 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.

Patients using ReFacto should 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 a factor VIII inhibitor is present. If the inhibitor is present at levels less than 10 Bethesda Units (BU), administration of additional antihaemophilic factor may neutralize the inhibitor. In patients with high levels of inhibitor, (eg. 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. 

Method of administration

ReFacto is administered by intravenous (IV) injection after reconstitution of the lyophilised powder for injection with 0.9% w/v sodium chloride solution for injection (provided). The reconstituted solution should be used within 3 hours.

ReFacto should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level.

Child Dosage

Contra Indications

Hypersensitivity to the active substance or to any of the excipients. Known allergic reaction to mouse or hamster proteins.

Special Precautions

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product contains traces of mouse and 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 should be discontinued immediately, and an appropriate treatment must be initiated. In case of shock, the current medical standards for shock-treatment should be observed. Patients should be advised to discontinue use of the product and contact their physician/or seek immediate emergency care, depending on the type/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 (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. In the post-marketing setting, high and low titre inhibitors have been observed in previously treated patients. 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. The reported lack of effect has been described as bleeding into target joints, bleeding into new joints or a subjective feeling by the patient of new onset bleeding. When switching to ReFacto it is important to individually titrate and monitor each patient's dose in order to ensure an adequate therapeutic response.

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

Interactions

No interactions of recombinant factor VIII products with other medicinal products are known

Adverse Reactions

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

On rare occasions, fever has been observed.

The following adverse events have also been reported: dyspnoea, venous access catheter complications, paraesthesia, transaminase elevation, dizziness, somnolence, fatigue, perspiration, blurred vision, coughing, acne, altered taste, anorexia, gastritis, gastroenteritis, pain, pruritis, rash, increased bilirubin and slight creatine phosphokinase muscle brain isotype (CK MB) elevation.

The occurrence of neutralising antibodies (inhibitors) is well known in the treatment of patients with haemophilia A.

In a clinical trial, 32 out of 101 (32%) previously untreated patients 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 days (range 3 - 49 days). 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 days (range 1-1299 days).

In a clinical trial of ReFacto, one of 113 (0.9%) previously treated patients developed an inhibitor. Inhibitor development occurred in the same time frame as the development of monoclonal gammopathy of uncertain significance. The development of this inhibitor was associated with a bleeding episode that failed to respond to ReFacto treatment. Also there have been spontaneous postmarketing reports of high titre inhibitors involving previously treated patients.

Twenty of 113 (18%) previously treated patients (PTPs) had an increase in anti-CHO antibody titre, without any apparent clinical effect. Six of 113 PTPs (5.3%) had an increase in anti-mouse IgG antibody titre, without any apparent clinical effect.

Very rarely development of antibodies to hamster protein has been measured, but there were no clinical sequelae.

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

Manufacturer

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