Aleviate

Aleviate

factor viii

Manufacturer:

CSL Behring

Distributor:

Primal
Full Prescribing Info
Contents
Human coagulation factor VIII, von Willebrand factor complex.
Description
Aleviate is a high purity, sterile, powder for injection containing a human coagulation factor VIII (FVIII) and human von Willebrand factor (VWF) complex. Aleviate is prepared from pooled human plasma. It is intended for IV administration. The factor VIII/VWF complex in Aleviate is purified from cryoprecipitate using selective precipitation and chromatography steps. The Aleviate manufacturing process includes solvent detergent (tributyl phosphate and polysorbate 80) and dry heat treatment (80°C for 72 hrs) steps to reduce the potential for viral transmission. The solvent detergent, dry heat treatment and partitioning steps used in the manufacture of Aleviate have been demonstrated to be effective virus inactivation/removal steps in vitro for the relevant viruses human immunodeficiency virus (HIV) and hepatitis A (HAV), and also with model viruses for hepatitis B (HBV) and hepatitis C viruses (HCV). The manufacturing process also contributes to the inactivation/removal of human parovirus B19 (B19).
Human albumin is added to FVIII:C Aleviate as a stabiliser. Measured prior to the addition of albumin, the specific activity of Aleviate is nominally 50 FVIII:C IU/mg of total protein. Aleviate contains other proteins eg, fibrinogen, fibronectin, immunoglobulins (IgA, IgM, IgG) and transforming growth factor β (TGF-β), all of which are present at significantly lower levels than in normal plasma. When expressed as per mg clottable protein (fibrinogen), the specific activity of the final product is nominally 300 IU VWF: RCo/mg and 150 IU FVIII:C/mg, based on the Aleviate VWF to FVIII ratio of 2:1.
Aleviate is available in 2 different presentations as detailed in Table 1. (See Table 1.)

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Action
Pharmacology: The Aleviate FVIII/VWF complex consists of 2 different noncovalently bound proteins: FVIII and VWF. FVIII is an essential cofactor in activation of factor X leading ultimately to the formation of thrombin and fibrin. The activity of FVIII is measured as FVIII:C. VWF promotes platelet aggregation and platelet adhesion on damaged vascular endothelium; it also serves as a stabilising carrier protein for the procoagulant protein FVIII. The activity of VWF is measured as VWF:RCo.
Von Willebrand Disease (VWD) is an autosomally-inherited congenital bleeding disorder in which there is a deficiency or dysfunction of VWF. A reduction in VWF concentration in the bloodstream results in low FVIII activity and abnormal platelet function as the platelets are prevented from adhering to sub-endothelial tissue. As a result, excessive bleeding may occur.
The VWF:RCo activity in Aleviate exists in a 2:1 ratio with FVIII:C activity. Aleviate has been demonstrated to contain the high molecular weigh (HMW) multimers of VWF. HMW multimers are considered to be important for correcting the haemostatic defect in patients with VWD as they are important for platelet adhesion.
Haemophilia A is an X-linked recessive blood coagulation disorder. It is caused by reduced factor VIII activity through either insufficient or abnormal synthesis of the factor VIII protein. Factor VIII is a cofactor for factor IXa and accelerates 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.
Pharmacokinetics: Clinical trials have been conducted with Biostate. Biostate is the tradename for the purified human coagulation factor VIII product manufactured by CSL for distribution in Australia. The process used for the manufacture of Biostate is the same as that is used for the manufacture of Aleviate.
The pharmacokinetics of Biostate has been studied in adult patients with VWD and haemophilia A, in separate trials.
The pharmacokinetics of FVIII and VWF in Biostate were measured in a single-blind, randomised, multicenter study of 12 patients 19-58 years with VWD in whom the response to desmopressin was inadequate or contraindicated. VWF:Ag, FVIII and HMW multimers were also measured in addition to the pharmacokinetic parameters for the 12 patients in Table 2 (see Table 2).
Two  (2) clinical trials investigated the pharmacokinetics of FVIII in Biostate in patients with haemophilia A. The 1st trial involved 16 male patients with severe haemophilia A (up to or equal to 2% FVIII) who each received a single dose of 50 IU FVIII/kg body weight. All patients had been previously treated with FVIII concentrates and were from 17-53 years. The pharmacokinetics data for the 16 patients is summarised in Table 2 (indicated by the term "initial").
To assess the potential for the development of inhibitors to factor VIII which may not be detected by conventional laboratory assays, a repeat pharmacokinetic trial was performed on 8 patients who participated in the 1st pharmacokinetic trial and continued treatment with Biostate for 3-6 months. There was no significant difference in the half-life or recovery determined in this trial compared to the 1st pharmacokinetic trial (see Table 2, indicated by the term "Repeat"), thus indicating no inhibitor development with the use of Biostate. (See Table 2.)

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Clinical Trials: Von Willebrand Disease: The efficacy of Biostate in the control of non-surgical and surgical bleeding was assessed in an open-label, non-controlled trial in 23 patients (7 VWD Type 3). A 4-point rating scale was used: None: No control of bleeding. Moderate: Moderate control of bleeding, other treatment also required. Good: Slight oozing, partial but adequate control of bleeding. Excellent: Haemostasis achieved.
In 4 patients with 6 non-surgical bleeds, the haemostatic efficacy was rated over the first 3 days as excellent in 3 (50%), good in 1 (17%), moderate in 1 (17%) and nil in 1 (17%), the gastrointestinal haemorrhage improved in rating to good from day 4-7, but remained largely uncontrolled until corrected by a definitive endoscopic procedure). In 9 patients undergoing 10 major surgical procedures, the efficacy was excellent in 7 (70%) and good in 3 (30%). In 11 patients undergoing 15 minor surgical procedures, haemostatic efficacy was excellent in 14 (93%) an good in 1 (7%).
The mean Biostate dose to achieve haemostasis was 27 IU FVIII:C/kg/day for a median 2 days in non-surgical bleeding, 33 IU FVIII:C/kg/day for a median 2 days in minor surgery and 41 IU FVIII:C/kg/day for a median 7.5 days in major surgery.
In a retrospective review of Biostate in surgical bleeding in 43 patients undergoing 58 procedures, the haemostatic efficacy was excellent in 78% of procedures and good in 22%. Efficacy in the VWD Type 3 patients (n=5) was rated as excellent in 55%. The mean Biostate dose to achieve haemostasis was 29 IU FVIII:C/kg/day for a mean 2 days (range 1-4) in minor dental procedures and 5 days (range 1-13) in major surgery. There was some concomitant use of tranexamic acid and desmopressin.
The efficacy and safety of Biostate has not been established in acquired VWD.
Adverse reactions encountered during the clinical trials in VWD patients are outlined under Adverse reactions (see Adverse Reactions).
Haemophilia A: The safety, tolerability and efficacy of Biostate was studied in 30 male patients with severe haemophilia A, including the 16 patients who participated in the 1st pharmacokinetics trial. All patients had been previously treated with FVIII concentrates, were aged 16-62 years, and were treated with Biostate in this trial on an as required basis for 6 months. The 30 patients received a total of 1,416,550 IU of factor VIII (1,019 administrations) over the 6-month period, the total dose per person ranging from 6,000-112,250 IU. Out of the 789 administrations which were graded by the patients for efficacy, 131 (17%) were graded as excellent, 490 (62%) as good, 137 (17%) as moderate and 31 (4%) as poor. No patients undergoing surgery were included in this trial. Biostate was well tolerated by all patients. Inhibitor development was monitored during the trial using the Bethesda assay. Inhibitors were not detected in any of the 30 patients.
Adverse reactions encountered during the clinical trials in haemophilia A are outlined under Adverse Reactions.
Biostate has not been studied in previously untreated patients.
Indications/Uses
Treatment of bleeding episodes including surgical bleeding in patients with von Willebrand disease when desmopressin is ineffective or contraindicated. Treatment and prophylaxis of bleeding associated with factor VIII deficiency due to haemophilia A.
Dosage/Direction for Use
The dosage recommendations in Tables 3 (VWD) and 4 (Haemophilia A) are general guidelines for therapy. The exact loading and maintenance doses and dosing intervals should be based on the patient's clinical condition and response to therapy. Laboratory tests should be performed to ensure that the desired plasma factor VIII and VWF concentrations are achieved. (See Tables 3 and 4.)

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Continuous Infusion: No studies using continuous infusion were carried out in patients. However, it is suggested that this method is suitable for covering surgical procedures. Aleviate should be reconstituted to the same volume and in the same diluent as for bolus infusion, and administered using an infusion pump suitable for this volume. Reconstitution should be done under aseptic conditions and sterile integrity of the delivery device should be maintained.
Monitoring: It is recommended that plasma factor VIII concentrations be determined in patient's plasma at suitable intervals and during the treatment of severe haemorrhage.
Reconstitution: Before reconstitution, allow the vial of Aleviate and water for injections to reach a temperature between 20-30°C.
Remove the caps from the tops of the Aleviate and water for injections vials.
Apply a suitable antiseptic to the exposed part of the rubber stoppers of both Aleviate and water for injections and allow to dry.
Open the outer package of the Mix2Vial filter transfer set by peeling away the lid. If the seal of the lid is not intact or there are any concerns about the integrity of the Mix2Vial, do not use but return to the distributor. Place the water for injections on a level surface and hold the vial firmly. Take the Mix2Vial together with its outer package and invert it. Push the blue plastic cannula of the Mix2Vial firmly through the rubber stopper of the water for injections (5 mL water for injections is provided for 250 IU, 10 mL water for injections is provided for 500 IU vial).
While holding onto the vial of water for injections, carefully remove the outer package from the Mix2Vial, being careful to leave the Mix2Vial attached firmly to the water for injections vial. Ensure that only the package and not the Mix2Vial is removed.
With the Aleviate vial held firmly on a level surface, invert the water for injections with the Mix2Vial attached and push the transparent plastic cannula end of the Mix2Vial firmly through the Aleviate stopper. The water will be drawn into the vial by the vacuum within. In the unlikely event that the vial does not contain a vacuum, do not use Aleviate, but return it to the distributor.
With water for injections and Aleviate vials still attached, gently swirl the product vial to ensure the product is fully dissolved. Avoid excessive frothing. A clear or slightly opalescent solution is usually obtained within 2-5 min. The solution should be used as described in Administration.
Once the contents of the Aleviate vial are completely dissolved, firmly hold both the transparent and blue parts of the Mix2Vial. Unscrew the Mix2Vial into 2 separate pieces, and discard the empty water for injections vial and the blue part of the Mix2Vial in an appropriate waste container.
Note: The Mix2Vial is intended to filter the contents of a single vial of Aleviate only.
If multiple vials of Aleviate are to be administered, a separate Mix2Vial must be used for each vial.
Do not refrigerate Aleviate once it has been reconstituted.
Administration: With the Aleviate vial upright, attach a plastic disposable syringe to the Mix2Vial (transparent plastic part). Invert the system and draw the reconstituted Aleviate into the syringe by pulling the plunger back slowly. One (1) large syringe may be used to pool several vials of reconstituted Aleviate.
Once Aleviate has been transferred into the syringe, firmly hold the barrel of the syringe (keeping the syringe plunger facing down) and detach the Mix2Vial from the syringe. Discard the Mix2Vial (transparent plastic part) and empty Aleviate vial in an appropriate waste container. Fit the syringe to a suitable injection needle to administer the reconstituted Aleviate. Do not use the Mix2Vial for injection.
Give the dose slowly (usually within 5 min, or as tolerated by the patient) by the IV route. When the contents of >1 vial are to be given, it will be convenient to pool the total amount prior to administration in a large syringe or sterile bag. This must be done aseptically.
To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. The solution must not be stored, and unless reconstitution has been done under aseptic conditions and sterile integrity of the delivery device has been maintained, infusion should be completed within 3 hrs of reconstitution in the case of routine use. For use in surgery, the conditions described under Continuous Infusion can apply. Aleviate is for single use only and any unused portion remaining in the vial must be discarded appropriately.
The solution must not be added or mixed with any other fluids to be given, including whole blood.
Medical personnel, family carers and patients should be adequately trained in techniques for the preparation and the administration of Aleviate.
Overdosage
No symptoms of overdose with human plasma coagulation factor VIII/VWF concentrates are known.
Contraindications
Aleviate is contraindicated in individuals with a history of anaphylactic or severe systemic response to coagulation FVIII and/or VWF preparations. Also, it is contraindicated in individuals with a known hypersensitivity to any components of Aleviate.
Special Precautions
Aleviate should be used with caution in patients with a known allergy to factor VIII and/or VWF concentrates, or human albumin. Allergic, anaphylactic reactions or fever are rarely observed in patients receiving factor VIII preparations. If any adverse event occurs while Aleviate is being administered, the rate of injection should be slowed or stopped to alleviate symptoms.
Patients should be informed of the early signs of hypersensitivity reactions eg, allergic skin reactions including hives, generalised urticaria, tightness of the chest, wheezing, flushing, hypotension and anaphylaxis. If these symptoms occur, they should be advised to seek medical opinion. In case of shock, the current medical standards for treatment of shock should be instituted.
The formation of neutralising antibodies (inhibitors) to FVIII is a known complication in the management of individuals with haemophilia A. These inhibitors are immunoglobulins (usually IgG) directed against the FVIII procoagulant activity. The inhibitor level in the plasma is measured by the Bethesda assay [as Bethesda Units (BU) per mL]. The risk of developing inhibitors is correlated to the exposure to FVIII, this risk being highest within the 1st 20 exposure days. Rarely, inhibitors may develop after the 1st 100 exposure days.
Cases of recurrent inhibitor (low titre) have been observed after switching from one FVIII product to another in previously treated patients with >100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor patients carefully for inhibitor occurrence following any product switch.
In general, all patients treated with coagulation FVIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.
Patients with VWD, especially type 3 patients, may very rarely develop inhibitors to VWF. If such inhibitors occur, the condition would manifest itself as an inadequate clinical response eg, bleeding, not being controlled with an appropriate dose or the expected VWF:RCo activity plasma levels not being attained. Such antibodies may occur in close association with anaphylactic reactions. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor.
Thromboembolic events have been rarely reported in VWD patients receiving coagulation factor replacement therapy, especially in the setting of known risk factors for thrombosis and may be related to the generation of supranormal FVIII levels. In these patients, caution should be exercised and antithrombotic measures should be considered.
Pathogen Safety: Aleviate is made from human plasma. Products made from human plasma may contain infectious agents eg, viruses and theoretically Creutzfeldt-Jakob Disease (CJD) agents that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain infectious agents and by testing for the presence of certain virus markers.
In addition, virus removal and inactivation procedures are included in the manufacturing process. The current procedures applied in the manufacture of Aleviate are effective against enveloped viruses eg, HIV, HBV and HCV viruses, and the non-enveloped virus HAV. They are also known to contribute to the inactivation/removal of the non-enveloped virus, B19.
Despite these measures, such products may still potentially transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such products. Vaccination for hepatitis A and hepatitis B should be considered where appropriate, for patients in receipt of medicinal products from human plasma.
Spillage or Breakages: Should a break in the container or spillage occur, due precautions should be taken to avoid contamination of cuts and abrasions, as well as to avoid inhalation or swallowing of the spillage. Adequate disinfection can be obtained with the application of 1% sodium hypochlorite for 15 min. Commercial bleaches may be diluted appropriately to obtain this concentration.
Carcinogenicity, Mutagenicity & Impairment of Fertility: The carcinogenic or genotoxic effects of Aleviate are unknown. The effects of Aleviate on fertility are unknown.
Use in pregnancy & lactation: The use of Aleviate during pregnancy has not been established in clinical trials.
The effects of Aleviate on lactation are unknown.
Use in children: The use of Aleviate in the paediatric population has not been established in clinical studies.
Use in the elderly: The use of Aleviate in the elderly has not been established in clinical studies.
Use In Pregnancy & Lactation
Use in pregnancy & lactation: The use of Aleviate during pregnancy has not been established in clinical trials.
The effects of Aleviate on lactation are unknown.
Adverse Reactions
Allergic reactions or fever are rarely observed in patients receiving factor VIII/VWF preparations. If any adverse event occurs while Aleviate is being administered, the rate of injection should be slowed or stopped to alleviate symptoms.
Adverse Events in Clinical Trials: Von Willebrand Disease: In the Biostate pharmacokinetic clinical study, adverse events were reported by 11 out of the 12 VWD patients. Most events were mild to moderate in severity and considered not related to Biostate. Nine (9) adverse events were considered by the investigator to be related to Biostate and were reported by 2 of the 12 patients (see Table 5).
In the safety and efficacy trial, 22 of the 23 VWD patients experienced adverse events. Only 3 events were considered by the investigator to be probably or possibly related to Biostate (see Table 5). Two (2) serious adverse events were reported: Iliacus myositis and upper respiratory tract infection, both considered unrelated to Biostate. All other adverse events were considered unrelated or unlikely to be related to Biostate.
Haemophilia A: In the initial pharmacokinetics clinical trial, only 1 of the 16 haemophilia A patients experienced 2 adverse events. Both events were single episodes, mild in severity and considered to be related to Biostate (see Table 5).
In the tolerability, safety and efficacy clinical trial, 21 of the 30 haemophilia A patients experienced 2 adverse events. Twenty-three (23) of the adverse events were considered to be related or possibly related to Biostate (see Table 5). One (1) of the patients who experienced back pain and skeletal pain during the safety and efficacy trial also experienced these symptoms during the initial pharmacokinetics trial. All of these related adverse events were considered to be mild in severity. (See Table 5.)

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Drug Interactions
The interaction of Aleviate with other drugs has not been established in specific studies.
Effect on Laboratory Tests: FVIII and/or VWF are endogenous plasma proteins; no specific effects on laboratory test are therefore anticipated.
Caution For Usage
Aleviate does not contain an antimicrobial preservative. It must, therefore, be used within 3 hrs after reconstitution. Any unused solution should be discarded appropriately. Use in 1 patient on 1 occasion only. If a clot or gel forms, do not use the product but return it to the distributor listed on the label.
Do not use after the expiry date.
Storage
Store at 2-8°C. Refrigerate. Do not freeze. Protect from light.
MIMS Class
ATC Classification
B02BD02 - coagulation factor VIII ; Belongs to the class of blood coagulation factors. Used in the treatment of hemorrhage.
Presentation/Packing
Powd for inj (high purity, sterile, vial) 250 IU + water for injections 5 mL + Mix2Vial filter transfer set x 1's. 500 IU + water for injections 10 mL + Mix2Vial filter transfer set x 1's.
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