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This Product Profiler introduces health care professionals to Helixate® FS, recombinant antihemophilic factor VIII (rFVIII), formulated with sucrose. Helixate® FS is an FDA-approved treatment indicated for the management of bleeding associated with hemophilia A, including the control and prevention of bleeding episodes in adults and children 0 to 16 years, perioperative bleeding risk management in adults and children, and routine prophylaxis to reduce the frequency of bleeding episodes and the risk of joint damage in children with hemophilia A with no preexisting joint damage.
Helixate® FS is a lyophilized powder that, on reconstitution, yields a recombinant antihemophilic factor suspended in sucrose for intravenous (IV) administration. Clinical studies have shown Helixate® FS to be a safe and effective treatment for control of bleeding episodes, bleeding prophylaxis, and prevention of bleeding when administered prior to surgical procedures in patients with hemophilia A (Helixate® FS Prescribing Information 2009). Helixate® FS comes packaged with the Mix2Vial™ – a needle-free transfer device that offers convenience and increased safety – and a sterile water diluent vial.
The following text presents a brief overview of the epidemiology of hemophilia A, the role of FVIII in the coagulation cascade, the etiology and pathophysiology of hemophilia A, and current treatment options. Additionally, the evidence-based literature supporting the FDA-approved indication for the administration of rFVIII, formulated with sucrose in the management and prophylaxis of hemophilia A is discussed.
Hemophilia A is a rare genetic disorder associated with absence, deficiency, or defect in the blood coagulation FVIII, leading to impairment of the coagulation cascade, difficult-to-control bleeding episodes, and both trauma-induced and spontaneous hemorrhages. Approximately 18,000 Americans have symptomatic hemophilia, and an estimated 400 infants are born with the disease each year (NHLBI 2009). Although predominantly a hereditary coagulation disorder, hemophilia A also may arise independent of family history: as much as one-third of cases of hemophilia have been estimated to occur as a result of an acquired mutation and not due to genetic predisposition (Hoyer 1994, NHLBI 2009).
Hemophilia A, also known as “classic hemophilia,” represents about 90% of all hemophilia cases and occurs among individuals of all racial groups and geographic locations; however, the disease most commonly affects males (NHLBI 2009). Hemophilia B represents roughly 10% of cases and is defined by low levels of clotting factor IX (NHLBI 2009). Although clinically indistinguishable, the etiology and treatment of these two hemophilias are distinct, and the two diseases must be differentiated by specific factor assays (Bolton-Maggs 2003). Hemophilia A is an X-linked recessive genetic disorder with constant phenotypic expression in families (Husain 2009). The bleeding tendency in hemophilia A is dependent on the extent of FVIII defect or the degree of FVIII deficiency, which determine the classifications of mild, moderate, or severe disease (Husain 2009).
Treatments for hemophilia A have advanced greatly in the last four decades. The aim of treatment is to sufficiently increase FVIII levels in the circulation to promote clotting and prevent or halt spontaneous or procedural bleeding episodes. The development of factor concentrates in the 1960s allowed for easy access to high-volume factor concentrates and self-injections, without the need for storage under frozen conditions (Hoyer 1994). The high risk of transmission of viral infections from human plasma, however, soon became apparent. This risk led to development of viral-inactivated factor products and recombinant factor concentrates developed through DNA technology for improved safety and wider use. Furthermore, with the use of sucrose as a replacement for human albumin to stabilize the rFVIII protein in suspension, the risk of transfer of unwanted plasma constituents was further reduced and, with such safety advances, FVIII replacement therapy has become increasingly accepted.
FVIII is a complex plasma glycoprotein consisting of 2,332 amino acid residues and plays a pivotal role as a cofactor in the intrinsic blood coagulation cascade (Fang 2007). The FVIII protein is made up of three types of domains: A domain, B domain, and C domain (Thompson 2003). The C domains of the FVIII protein participate in the characteristic binding of the nonactivated form of FVIII to von Willebrand factor (VWF), and the A domains each bind a single atom of copper (Thompson 2003). The B domain is not required for coagulation and most of it can be deleted without loss of anticoagulant activity, except for the sequence adhering B to A3, which contains a major VWF binding site (Thompson 2003).
FVIII is produced primarily in the liver, although kidney, sinusoidal endothelial cells, and lymphatic tissues have been shown to produce small amounts of FVIII as well, and the normal physiologic level of FVIII in the circulation is 1 U/mL (Bolton-Maggs 2003, Klinge 2002). This large and highly unstable protein is preserved upon interaction with the VWF protein, and, in healthy individuals, approximately 95% of FVIII is bound to VWF in the circulation (Thompson 2003). This relationship serves to protect FVIII from proteolysis and ensure high concentrations of FVIII at sites of active hemostasis, and its association with VWF prolongs its short half-life to approximately 10 hours (Thompson 2003). The molar ratio of FVIII to VWF is approximately 1:50, and this ratio remains consistent over a wide range of VWF levels (Thompson 2003).
Normal blood coagulation involves a series of enzymatic reactions in which FVIII plays an essential role. The hemostatic activity of FVIII depends on its activation and inactivation via proteolytic cleavages modulated by thrombin and protein C (Fay 1993, Thompson 2003).
Clotting involves a series of reactions initiated when tissue trauma or injury causes release of tissue factor (TF) from the injured endothelium and collagen-rich subendothelium (Figure 1) (Hoffman 2001). During the Initiation Phase of coagulation, TF interacts with other coagulation factors to convert small amounts of prothrombin to thrombin, which commences the Amplification Phase. During amplification, trace amounts of thrombin can promote FVIII clotting activity, increasing the specific activity by as much as 50-fold (Hoffman 2001, Thompson 2003). On thrombin cleavage of the a3 acidic peptide at the A3 amino terminus, a major VWF high-affinity binding site is eliminated and the activated enzyme (FVIIIa) dissociates from VWF (Thompson 2003). FVIIIa serves as a cofactor to the serine protease FIXa during conversion of the zymogen FX to the activated enzyme (FXa). The FIXa/FVI-IIa complex, known as the intrinsic tenase complex, markedly increases the catalytic efficiency of FIXa (Fang 2007, Thompson 2003). Activation of FX has been shown to be a crucial step in the in vivo process of coagulation (Thompson 2003).
The end point of the amplification phase of the coagulation pathway is the generation of a large thrombin burst (Hoffman 2001). In the Propagation Phase of the cascade, the thrombin burst catalyzes fibrin from fibrinogen, leading to the Stabilization Phase, at which time the cross-linking of fibrin fibers forms the net that stabilizes the platelet plug and renders the fibrin insoluble.
Hemophilia A is marked by quantitative or qualitative defects of FVIII that contribute to failure of secondary hemostasis (Bolton-Maggs 2003). Since FVIII mediates a key step in progression of the coagulation cascade, any defect of concentration or functional activity will interfere with effective clotting. A number of genetic mutations in the FVIII gene have been linked to ineffective or insufficient FVIII production, and thus to inadequate cofactor activity and interruption of the coagulation cascade (Bolton-Maggs 2003). In patients with hemophilia A, primary hemostasis, or formation of the platelet plug, occurs normally, but FVIII is not able to appropriately amplify FIXa activity in the conversion of FX to FXa. This leads to inadequate thrombin production and impaired development of the fibrin net needed to stabilize the plug (Bolton-Maggs 2003).
The severity of hemophilia A is determined by plasma levels in individuals with FVIII impairment. Mild disease defines those patients with ≥5% to ≤ 40% of normal factor levels, moderate disease ranges from 1% to 5% of normal levels, and severe disease includes individuals with <1% of normal levels (Bolton-Maggs 2003). These categories can be used to predict bleeding risk, predict outcome, and guide management (Bolton-Maggs 2003). Clinical measures of frequency and severity of bleeding episodes are used as supplemental criteria for classification because, in some cases, patients will exhibit bleeding symptoms inconsistent with their procoagulant classification. For example, some patients may experience infrequent or mild bleeding despite FVIII levels consistent with severe disease (Bolton-Maggs 2003).
A defining characteristic of uncontrolled hemophilia A is persistent bleeding into joints and muscles (Bolton-Maggs 2003). Severe hemophilia A often results in joint and muscle bleeds as early as infancy, and such bleeds can occur as frequently as weekly (Manco-Johnson 2007). The presence of blood irritates the synovial lining and recurrent bleeds can cause synovial hypertrophy that predisposes patients to persistent bleeding and progressive damage to cartilage and subcondral bone (Bolton-Maggs 2003). In untreated or inadequately treated patients, this progressive damage can lead to fixed flexion and other joint deformities, particularly of the knees, ankles, and elbows, with associated muscle wasting (Bolton-Maggs 2003). In severe cases, extensive muscle wasting may result in immobility and may necessitate the use of a wheelchair (Bolton-Maggs 2003). Additionally, central nervous system (CNS) bleeding, or bleeding into the brain, is a major cause of mortality in this group, and approximately 3.3% to 35% of all death in patients with hemophilia A is due to CNS bleeding (Klinge 2002).
A common complication and great concern in the treatment of hemophilia A is development of alloantibodies – or inhibitors – to FVIII concentrate treatments (Ananyeva 2004). In fact, approximately 40% of patients with severe hemophilia A will develop such antibodies (Kempton 2009). Inhibitors neutralize the hemostatic activity of FVIII concentrates and interfere with the intended activity of substitution therapy, significantly reducing treatment efficacy (Fang 2007).
The defect in FVIII activity or production is the result of a variety of FVIII gene mutations. The FVIII gene, comprised of 26 exons, is located on the long arm of the X chromosome at Xq28 and spans an estimated 186 kb (Bolton-Maggs 2003).
Nearly 1,000 mutations have been identified in hemophilia A (Husain 2009). The most common genetic derangement is a large inversion and translocation of exons 1–22 away from exons 23–26. The genetic deviation is believed to be due to an error of DNA replication during spermatogenesis and is therefore specific to the male rather than female germ line; it has been observed in about 45% of individuals with severe hemophilia A (Antonarakis 1995, Bhopale 2003, Bolton-Maggs 2003). Other gene disruptions, including deletions, insertions, and point mutations, are responsible for the remaining 55% of cases (Bhopale 2003).
Mutations of the FVIII gene lead to either production of dysfunctional proteins or impaired expression, secretion, or stability of FVIII in circulation (Fang 2007). In some cases, altered FVIII folding and intracellular processing leads to decreased secretion, while in others, FVIII activation may be slowed or altered (Fang 2007). Additionally, it has been found that reduced VWF binding leads to rapid clearance of FVIII (Fang 2007). With nearly 1,000 genetic mutations playing a role, the physiologic outcomes of an FVIII gene defect are widely variable (Fang 2007). Approximately 60% of patients with FVIII mutations exhibit severe hemophilia A while the rest develop mild or moderate forms of the disease (Bhopale 2003).
Hemophilia A is usually recognized when a male patient presents with unusual bleeding patterns. Cases may be noted based on easy or excessive bruising when a child begins to walk or when the first teeth break through the gums. Most patients with severe hemophilia are identified within the first year of life due to evidence of bleeding such as soft tissue, joint, or circumcision (NHLBI 2009). Today, the standard of care is to start prophylactic treatment at or before the first joint bleed, which is usually before the age of 4. Mild-to-moderate cases may not be diagnosed until later in life, often based on a history of hemarthroses, prolonged bleeding during surgical or dental procedures, or a first major trauma that reveals impaired clotting (Bolton-Maggs 2003).
The most common sites of hemophilic bleeds are in joints, particularly the knees, elbows, and ankles (Manco-Johnson 2007). Acute hemarthrosis is often recognized by tightness in the joint and later by severe pain or swollen, tense, or hot joints (NHLBI 2009). Joint symptoms will usually resolve over several days to a week but subsequent acute synovitis predisposes the joint to further hemorrhages (Klinge 2002, NHLBI 2009). Depending on the frequency of bleeds, the patient may experience chronic arthropathy. Early factor replacement therapy has been shown to prevent or slow the development of such chronic joint disease (Klinge 2002).
Muscle hematomas have been reported in as much as 30% of bleeding episodes, and have been known to compress vital structures, potentially leading to serious complications (Klinge 2002). Iliopsoas muscle bleeds, for instance, have been associated with muscle dysfunction and neural sequellae (Klinge 2002). Gross hematuria affects as much as 75% of patients with hemophilia A; renal bleeding may be painless but colic can occur if a clot develops in the ureter or renal pelvis (Klinge 2002). CNS bleeding may be the most life-threatening complication of the disease (Klinge 2002).
The two most common conditions to be differentiated from hemophilia A are hemophilia B and von Willebrand disease (Bolton-Maggs 2003). It is impossible to distinguish among these clotting disorders by clinical criteria; however specific laboratory factor analyses can identify which blood component is deficient in order to make a specific diagnosis (Bolton-Maggs 2003). A family history is often present but is not essential to the diagnosis as family history is absent in roughly 30% of patients (Bolton-Maggs 2003).
Plasma concentration of FVIII assayed against a normal plasma standard of 1 U/mL will indicate the relative percentage of activity compared with the standard (Klinge 2002). The results of this assay yield the hemophilia severity classification of mild, moderate, or severe (Bolton-Maggs 2003). Additional laboratory testing may include prothrombin time (PT) and partial thromboplastin time (PTT), and factor IX assays (Merck Manual 2009).
While there is no cure for hemophilia A, early treatment of spontaneous and trauma- or surgery-related bleeds is essential (Bolton-Maggs 2003). Available therapies that can raise FVIII concentrations sufficiently to initiate clotting are used to control or prevent such bleeding episodes (Bolton-Maggs 2003). Furthermore, manufacturing advances and recombinant DNA technology have produced products of increased purity, absent of animal or human proteins, making for safe and desirable treatment for patients with hemophilia A (Bolton-Maggs 2003). These therapies have vastly improved outcomes for patients with hemophilia A by providing bleeding control while decreasing the risk of transmission of human or animal pathogens (Bolton-Maggs 2003).
There are two main approaches to factor replacement therapy: episodic (on-demand) treatment and prophylaxis (Bolton-Maggs 2003). Episodic treatment allows immediate treatment in the event of an active bleeding episode. This is reserved primarily for individuals with mild or moderate forms of hemophilia A. Prophylaxis, on the other hand, involves the injection of replacement therapy to control or prevent bleeding in patients at high risk of chronic bleeding events (Bolton-Maggs 2003). Prophylaxis can be used as either a single-dose treatment prior to an anticipated bleeding episode (e.g., dental procedures or participation in sports) or as a regular injection to cover a defined period of time. It can also be used as long-term prophylaxis to prevent spontaneous hemarthrosis, thereby avoiding irreversible arthropathy and incapacitation (Bolton-Maggs 2003). Available data indicate that use of prophylactic FVIII therapy in patients with severe disease results in a significant reduction in bleeding episodes, less deterioration of joint scores, and prevention of arthropathy (Manco-Johnson 2007). It is clear that, in patients with severe disease, prophylaxis should begin at an early age – preferably before the first joint bleed – which can occur once the child starts walking or running (Manco-Johnson 2007). While prophylaxis may prevent chronic bleeds, it is important to note that patients receiving prophylaxis may also require episodic treatment for active bleeds.
Approximately 30% to 50% of individuals treated with FVIII replacement therapy will develop inhibitor antibodies to treatment (Bolton-Maggs 2003). Inhibitors can vary in scale from low-titer, which may be remedied with increased FVIII concentrates, to high-titer, which markedly decreases the efficacy of FVIII therapy (Bhopale 2003, Bolton-Maggs 2003). Patients with high-titer FVIII inhibitors who experience a severe hemorrhage may also need to receive IV administration of activated prothrombin complex concentrate (aPTC) or a bypassing agent such as recombinant activated FVIIa (Klinge 2002). Eradication of inhibitors is complex and may require immune tolerance induction (ITI), which requires daily infusion of high-dose FVIII and immunosuppressive drugs over several months to years (Bhopale 2003). The efficacy of ITI can range from 60% to 80% and incurs a high initial cost with ITI failure being defined as a lack of tolerance by 33 months (Bhopale 2003, Kempton 2009).
The first treatments for hemophilia were attempted in the early 20th century and included transfusion of fresh blood or whole plasma to replace blood loss. However, challenges of large delivery volume and/or frozen storage requirements limited the value of these treatments. The development of pooled factor concentrates and cryoprecipitates enabled patient self-administration, replacing the need for transfusion in the hospital. But despite purification processing, cryoprecipitates continued to carry risk of infection (HIV: 1/1,000,000 donations; HCV: 1/900,000) (MASAC 190). Today, therefore, cryoprecipitates are not recommended for the treatment of patients with hemophilia A (MASAC 190).
Desmopressin acetate is a synthetic hormone that can increase clotting capabilities in individuals with mild-to-moderate hemophilia A. Desmopressin is an analog of vasopressin, a naturally occurring hormone that promotes secretion of VWF, thus increasing FVIII survival via the VWF/FVIII complex (Ozgonenel 2007). Available in several formations and strengths, desmopressin can be administered via IV or subcutaneous injection or as a nasal spray (Table 1).
Patients with severe hemophilia A, or FVIII activity <1%, are not candidates for desmopressin therapy; however, those classified as having mild disease may benefit from its use (Ozgonenel 2007). Desmopressin therapy is also not appropriate for children younger than 2 years, pregnant women, cases of severe trauma, or in patients with mild hemophilia A in whom desmopressin does not adequately elevate FVIII levels (MASAC 190).
Plasma-derived FVIII concentrates are purified proteins collected from pooled human plasma. Early experience with transmission of lethal viruses, particularly human immunodeficiency virus (HIV), confounded the use of the concentrates (Klinge 2002). Advances in donor screening and viral depletion processes have led to a greatly reduced risk for viral transmission with contemporary concentrates (MASAC 190). Nonetheless, there remains a theoretical risk for transmission of HIV-1, HIV-2, or hepatitis B or C with the use of viral-inactivated, plasma-derived products (MASAC 190).
Recombinant FVIII (rFVIII) is produced readily in established hamster cell lines transfected with a human FVIII gene (MASAC 190). Recombinant factor VIII concentrates, not derived from human plasma, are considered safer than plasma-derived concentrates. First generation products, however, used bovine or human serum albumin in the cell culture medium or added human serum albumin as a stabilizer in the final formulation. Although the risk of disease transmission appeared very small, newer products were designed with improvements such as products that use human and/or animal proteins in the medium but they do not appear in the final formulation. Instead, these products stabilize the rFVIII molecule with sucrose rather than with human serum albumin (MASAC 190).
The risk of viral transmission with these products is lower than with plasma-derived concentrates. None of the currently available recombinant Factor VIII concentrates have been reported to transmit any animal or human viruses or prions, and as a result, recombinant FVIII is the recommended therapy for patients with hemophilia A by the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) (MASAC 190).
Adjunctive therapies are another viable option for those patients suffering from hemophilia A. Two such therapies include the use of aminocaproic acid and tranexamic acid.
Aminocaproic acid competitively binds lysine sites on plasminogen and plasmin, effectively blocking the interaction of plasmin and fibrin, resulting in fibrinolysis inhibition (Majerus 2006). While aminocaproic acid is a potent inhibitor of fibrinolysis, thrombi that form during drug treatment are not adequately lysed causing clot formation and subsequent obstruction (Majerus 2006). Aminocaproic acid has been used successfully in patients with hemophilia to reduce bleeding after prostatic surgery or after dental tooth extractions (Majerus 2006).
Tranexamic acid is another antifibrinolytic agent that competitively inhibits the receptor sites of plasminogen similarly to aminocaproic acid (Cyklokapron Prescribing Information 2008). Tranexamic acid, however, has approximately 10 times more potency in vitro than aminocaproic acid and has no influence on platelet counts in concentrations up to 10 mg per mL of blood (Cyklokapron Prescribing Information 2008). Tranexamic acid is appropriate for short-term use in the reduction or prevention of hemorrhage and replacement therapy during and following dental tooth extractions (Cyklokapron Prescribing Information 2008).
Helixate® FS is an antihemophilic factor that is indicated for the control and prevention of bleeding episodes in adults and children (0–16 years) with hemophilia A.
Helixate® FS is indicated for surgical prophylaxis in adults and children with hemophilia A.
Helixate® FS is indicated for routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no preexisting joint damage.
Helixate® FS is not indicated for the treatment of von Willebrand’s disease.
Helixate® FS Antihemophilic Factor (Recombinant) is a coagulation factor VIII produced by recombinant DNA technology. It is produced by Baby Hamster Kidney (BHK) cells into which the human factor VIII gene has been introduced. The cell culture medium contains Human Plasma Protein Solution (HPPS) and recombinant insulin, but does not contain any proteins derived from animal sources. Helixate® FS is a purified glycoprotein consisting of multiple peptides including an 80 kD and various extensions of the 90 kD subunit. It has the same biological activity as factor VIII derived from human plasma. No human or animal proteins, such as albumin, are added during the purification and formulation processes of Helixate® FS.
The purification process includes a solvent/detergent virus inactivation step in addition to the use of the purification methods of ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, along with other chromatographic steps designed to purify recombinant factor VIII and remove contaminating substances. Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. Several of the individual production and raw material preparation steps in the Helixate® FS manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include the Fraction II+III separation step for HPPS (6.0 log10) and an anion exchange chromatography step (3.6 log10).
Helixate® FS is formulated with the following as stabilizers (Table 2) in the final container and is then lyophilized. The final product is a sterile, nonpyrogenic, preservative-free, powder preparation for IV injection. IV administration of sucrose contained in Helixate® FS will not affect blood glucose levels.
The inactive ingredients/excipients listed in Table 3 are also contained in the final product.
Helixate® FS temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.
The activated partial thromboplastin time (aPTT) is prolonged in patients with hemophilia. Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with Helixate® FS normalizes the aPTT over the effective dosing period.
The pharmacokinetic properties of Helixate® FS were investigated in two separate studies in previously treated patients, adults, and children. Pharmacokinetic studies with Helixate® FS were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A in North America. The pharmacokinetic parameters for Helixate® FS were measured in a randomized, crossover clinical trial with the predecessor HELIXATE product with a single-dose administration of 50 IU/kg. After 24 weeks, the same dose of Helixate® FS was administered to the same patients. The recovery and half-life data for Helixate® FS were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition (Table 4).
The pharmacokinetics of Helixate® FS were investigated in pediatric PTPs (4.4–18.1 years of age, average age 12). The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery, and a shorter factor VIII half-life. This might be explained by differences in body composition such as body surface area and plasma volume. The pharmacokinetic parameters are depicted in Table 5.
A number of trials have followed the natural history of hemophilia A and evaluated the efficacy and safety of FVIII concentrates in controlling bleeding episodes and mitigating the progression of degenerative joint damage in patients with this condition. In one study, investigators evaluated the differential effects of long-term prophylaxis with rFVIII versus on-demand episodic therapy on the development of arthropathy when initiated in boys under 2 years of age with diagnosed hemophilia A (Manco-Johnson 2007). In two other studies, the safety and efficacy of a sucrose-formulated rFVIII-FS product were examined in comparison to earlier formulations that were produced with human albumin as a stabilizer, and its safety and efficacy were determined in previously treated adolescent/adult or treatment-naïve young (<4 years) males with severe hemophilia A.
This study examined the question of whether episodic rFVIII therapy versus prophylactic infusions given every other day would yield better joint damage prevention in children with hemophilia A (Manco-Johnson 2007). In a multi-center, randomized, open-label trial, 65 boys under age 30 months with an FVIII activity level ≤ 2 U/dL were randomly assigned to either prophylaxis or episodic treatment. The prophylaxis group (n=32) received infusions of rFVIII at a dose of 25 IU/kg body weight every other day to prevent hemarthrosis — defined as acute episodes of joint pain with decreased joint motion. The group assigned to episodic treatment received rFVIII at a dose of 40 IU/kg at the time of joint hemorrhage. These children also received 20 IU at 24 and 72 hours later, continuing every other day until joint pain and mobility improved, for a maximum of 4 weeks.
The primary efficacy endpoint was preservation of index-joint structure as determined by magnetic resonance imaging (MRI) and plain film radiography. Secondary endpoints included number of joint and other bleeding events, number of infusions, and total units of rFVIII administered. Joint failure was defined as MRI or radiographic evidence of subchondral cyst, surface erosion, or joint-space narrowing. Early termination was allowed in the event of inhibitor development, life-threatening hemorrhage, or bone or cartilage damage seen on joint imaging. Children with inhibitory titers exceeding 25 Bethesda units (BU) in repeated sample testing or titers exceeding 10 BU for greater than 3 months were withdrawn from the study.
After a mean participation of 49 months, MRI findings showed that all six index joints remained normal at 6 years of age in 93% of patients in the prophylaxis group compared with 55% in the episodic group (P=.002). This corresponded with an 83% reduction in risk of joint damage, based on MRI findings, associated with prophylactic versus episodic therapy. Radiographic findings were similar, revealing a substantial, if not statistically significant, difference in joint damage of 4% in the prophylaxis group versus 19% in the episodic group (P=.10). Mean joint and total hemorrhages annually were higher among boys receiving episodic therapy (P<.001). Serious adverse events are listed in Table 6.
Investigators concluded that prophylaxis with rFVIII is safe and effective in reducing the incidence of joint hemorrhages and life-threatening hemorrhages and in lowering the risk of joint damage among young boys with severe hemophilia A.
To evaluate the efficacy and safety of a new sucrose-formulated rFVIII product, investigators examined the bioequivalence of sucrose-formulated rFVIII against the established formulation in a randomized, crossover, open-label, pharmacokinetic study involving 35 subjects in Europe (EU) and North America (NA) (Abshire 2000). The study also determined the safety and efficacy of the new sucrose-based product when used for home therapy for up to 24 months in 71 subjects. The population included males ages 12 to 60 years with severe hemophilia A who were previously treated with a licensed FVIII concentrate. Patients with a history or current evidence of inhibitors to FVIII (≥0.6 BU) were excluded. The pharmacokinetic study (Stage I) was preceded by a 4- to 5-day washout after which subjects were randomly assigned to a 10-minute infusion of 50 IU/kg of one or the other product, and blood was drawn regularly over 48 hours for pharmacokinetic evaluation. After another 5-day washout period, subjects were crossed over to the other formulation and the testing was repeated. At 4 to 7 days after the second infusion, these individuals, along with 37 new subjects, continued into Stage II/III, which included 2 or 4 weeks of prophylaxis (20 IU/kg 3 times per week by 10-minute infusion) in the EU or North America (NA) populations, respectively, followed by return to their pre-study episodic or prophylactic regimen. The primary efficacy endpoint was number of treatments per bleeding episode.
In Stage I, bioequivalence between rFVIII and rFVIII-FS was established, as measured by AUCnorm, Cmaxnorm, and T1/2 across the two groups (Figure 2).
Nineteen NA subjects who continued into Phase II/III underwent ongoing pharmacokinetic evaluation to 24 weeks, which indicated that these pharmacokinetic measures remained consistent over the early home treatment period. Patients self-treating at home received a cumulative total of 12,546 infusions and 22,443,694 IU of rFVIII-FS. The 2,585 documented bleeds over the course of the study required 1 to 2 infusions to control bleeding in 93.5% of subjects; 80.5% of responses were deemed excellent or good. Adverse events described as at least remotely related to study drug included injection site reaction, rash, rash with pruritis, sweating, taste perversion, chest pain, diarrhea, hyperesthesia, hypertension, increased inhibitor titer, lipothymia, malaise, pruritis, rhinitis, seborrheic dermatitis increase, and stinging of the face. There was no evidence of de novo inhibitor formation over the course of the trial.
The authors of the study concluded that sucrose-formulated rFVIII-FS is safe and effective in providing desirable hemostatic activity for patients with severe hemophilia A. The product was well-tolerated with no de novo inhibitor formation or significant adverse events reported. Sucrose-formulated rFVIII-FS also offers an additional level of safety due to the lack of human-derived plasma proteins during formulation and purification.
In this open-label, non-controlled trial, rFVIII-FS provided the sole source of FVIII replacement over the 2-year study period for 61 male children in EU and NA with severe hemophilia A (plasma FVIII <2%) who were ≤4 years of age. Study subjects were previously untreated (PUP, n=37) or minimally treated (MTP, n=24), defined as ≤ 4 exposure days (ED). MTPs were required to be negative for FVIII inhibitors (Bethesda assay <0.6 BU). Eligible subjects were enrolled in the study at the time they required FVIII replacement for their first on-study bleeding event. Treatment dose was 50 IU/kg body weight, rounded to the nearest whole vial amount, and administered by bolus infusion at a rate dependent on the individual patient’s tolerance (usually <5 minutes). The primary efficacy endpoint was number of infusions needed to achieve hemostasis for each new bleeding episode.
The data revealed that of 1,178 bleeding episodes (41.7% mild, 47.3% moderate, and 7.7% severe), hemostasis was achieved by 74% with a single infusion and 89.2% with two infusions (Figure 3). “Severe” bleeding episodes, furthermore, were controlled with one or two infusions in 68.1% of patients. No surgical complications occurred among 22 children undergoing 27 procedures (mainly catheter implantation) and no transfusions of blood or blood derivatives were required. FVIII antibody formation was noted in 9 of 60 (15%) subjects. Only 13 adverse events were considered possibly related to study drug, and included 10 cases of inhibitor formation; the overall adverse event rate was 0.14%, or 1 in 723 infusions.
Investigators concluded that rFVIII-FS provided hemostatic efficacy in the episodic treatment of spontaneous bleeding episodes and prophylactic surgical setting. This clinical trial also demonstrated the safety of rFVIII-FS in young children with hemophilia A over a median of 887 days on study.
Helixate® FS is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including mouse or hamster proteins.
The clinical response to Helixate® FS may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of Helixate® FS should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed (see Monitoring Laboratory Tests).
Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with Helixate® FS and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized), and fatigue. Discontinue Helixate® FS if symptoms occur and seek immediate emergency treatment.
Helixate® FS contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these nonhuman mammalian proteins.
Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of Helixate® FS predominantly in previously untreated patients. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed (see Monitoring Laboratory Tests).
The most serious adverse reactions are systemic hypersensitivity reactions including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to AHF. The most common adverse reactions observed in clinical trials (frequency ≥ 4% of patients) are inhibitor formation in PUPs and MTPs, skin-related hype-sensitivity reactions (e.g., rash, pruritus), infusion-site reactions (e.g., inflammation, pain), and central venous access device (CVAD) line-associated infections in patients requiring a CVAD for IV administration.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.
During the clinical studies conducted in PTPs, 451 adverse events (irrespective of the relationship to the study drug) were reported in the course of 24,936 infusions (1.8%). Twenty-four of the 451 adverse events were assessed as related to Helixate® FS (0.1%). Adverse reactions reported by ≥ 4% of the patients are listed in Table 7.
In clinical studies with pediatric PUPs and MTPs, 726 adverse events were reported in the course of 9,389 infusions (7.7%). Twenty-nine of the 726 adverse events were assessed as related to Helixate® FS (0.3%). Adverse reactions reported by ≥ 4% of the patients are listed in Table 8.
In the Joint Outcome Study in MTP pediatric patients treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration. Adverse events were not assessed for their relationship with Helixate® FS.
In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a preexisting inhibitor. In the other 72 patients, followed over 4 years, no de-novo inhibitors were observed. In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer (>5 BU) and 3 were low-titer inhibitors. Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).
In the Joint Outcome Study with Helixate® FS, de-novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer (>5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors. Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).
The following adverse reactions have been identified during post approval use of Helixate® FS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Among patients treated with Helixate® FS, cases of serious allergic/hypersensitivity reactions (which may include facial swelling, flushing, hives, blood pressure decrease, nausea, rash, restlessness, shortness of breath, tachycardia, tightness of the chest, tingling, urticaria, vomiting) have been reported, particularly in very young patients or patients who have previously reacted to other factor VIII concentrates. Table 10 represents the post-marketing adverse reactions as MedDRA Preferred Terms.
The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % normal) can be estimated using the following formulas:
Examples (assuming patient’s baseline factor VIII level is <1% of normal):
Doses administered should be titrated to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Helixate® FS. Although the dose can be estimated by the calculations above, it is highly recommended that, whenever possible, appropriate laboratory tests including serial factor VIII activity assays be performed (see Monitoring Laboratory Tests and Pharmacokinetics).
The careful control of treatment dose is especially important in cases of life-threatening bleeding episodes or major surgery.
Table 11 can be used to guide dosing in bleeding episodes.
The careful control of treatment dose is especially important in cases of major surgery or life-threatening bleeding episodes.
Table 12 can be used to guide dosing in surgery.
The recommended dose for routine prophylaxis is 25 IU/kg of body weight every other day.
Helixate® FS is administered by IV injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.
For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling.
Reconstitution, product administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Helixate® FS product, in an appropriate container.
Please see Full Prescribing Information at the end of the Product Profiler for directions on reconstitution and administration.
Helixate® FS is available as a kit in the following single-use glass vial sizes (Table 13). A suitable volume of Sterile Water for Injection, USP and Mix2Vial™ filter transfer device are provided in the kit.
Actual factor VIII activity in IU is stated on the label of each Helixate® FS vial.
Hemophilia A is a rare condition defined by potentially life-threatening bleeding episodes and requires lifelong therapy. The genetic disease, most often diagnosed in young males, has a hereditary element; however, up to 30% of cases occur spontaneously, secondary to an acquired mutation (Hoyer 1994). The diagnosis of hemophilia A often raises concerns among caregivers since it was historically associated with a low life expectancy and crippling joint deformities (Klinge 2002). However, present-day technology has allowed for increased safety and purity of FVIII replacement therapies, leading to an increase in life expectancy from 7.8 years in 1939 to over 70 years in 2001 (Ikkala 1982, Plug 2006).
Current treatment options have improved the prognosis of hemophilia A, and appropriate, prompt treatment and individualized patient care are necessary for patients to thrive. In order to promote optimal care of hemophilia patients, the federal government has funded a network of approximately 135 Hemophilia Treatment Centers (HTC) nationwide (CDC 2009). These centers, equipped with specialized doctors, nurses, and mental health professionals, are designed to treat all aspects of hemophilia and prevent serious complications of the disease (CDC 2009). This patient-centric approach to hemophilia care has proven beneficial. A study of 3,000 people with hemophilia demonstrated that the use of an HTC resulted in 40% fewer hospitalizations due to bleeding complications (CDC 2009). Additionally, the same study reported that patients who used an HTC were 40% less likely to die from a hemophilia-related complication. Pharmacists can play a role in the management of hemophilia A by conducting drug utilization reviews to evaluate adherence to therapy. By promoting adherence, pharmacists can help patients manage their disorder and decrease the risk of bleeds.
Regardless of where hemophilia patients receive care, a large concern for patients and providers alike is the development of FVIII inhibitors. Nearly 40% of hemophilia patients treated with FVIII replacement therapy will develop inhibitors (Kempton 2009). Inhibitor levels can range from low to high titer, and inhibitors pose a great challenge to hemophilia control (Bolton-Maggs 2003). To overcome the neutralizing effects of inhibitors on FVIII therapy, multiple medications may be needed, including large amounts of FVIII products, activated prothrombin complex concentrate, and/or bypassing agents such as recombinant activated FVIIa (Klinge 2002). This need for polypharmacy may result in an increase in AEs for the patient (Klinge 2002) as well as an increased cost burden.
The cost of hemophilia is high, largely due to the cost of therapy (Gringeri 2003). Beginning prophylaxis with FVIII at an early age is beneficial because it may prevent joint damage and the subsequent immobility caused by such damage (Roosendaal 2007). Since dosing is weight based, starting prophylactic treatment at an early age will require small amounts of FVIII due to the low body weight of younger patients. Additionally, early prophylaxis can preserve joint structure and function, and may lower health care costs in the long run (Roosendaal 2007). Due to these demonstrable benefits of prophylaxis, the Medical and Scientific Advisory Council of the National Hemophilia Foundation (MASAC) has recommended that prophylaxis be considered optimal therapy for those with severe hemophilia A (MASAC 190).
Helixate® FS is a recombinant antihemophilic factor indicated for the control and prevention of bleeding episodes in adults and children (0 to 16 years) with hemophilia A, surgical prophylaxis in adults and children with hemophilia A, and routine prophylaxis in children with hemophilia A with no preexisting joint damage (Helixate® FS Prescribing Information 2009). Helixate® FS has been proven safe and effective in the treatment and prevention of bleeding in hemophilia A patients (Abshire 2000, Kreuz 2005, Manco-Johnson 2007). Additionally, clinical data show a low rate of inhibitor development (15%) in PUPs and MTPs (Kreuz 2005). Helixate® FS is manufactured following a stringent purification process that includes a solvent/detergent virus inactivation step, ion exchange chromatography, monoclonal antibody immunoaffinity chromatography, and other chromatographic steps designed to purify rFVIII and remove contaminating substances (Helixate® FS Prescribing Information 2009).
In addition to the rigorous safety standards upheld by the manufacturers of Helixate® FS, there are programs provided by CSL Behring to help patients, providers, and caregivers manage the treatment of hemophilia A. For example, the HeliTraxSM System allows for a comprehensive view of a patient’s progress, with young patients relaying information about bleeding events and their use of Helixate® FS to their HTC via handheld device or Web interface between office visits. The HeliTraxSM System, used in conjunction with Helixate® FS treatment, is designed to improve patient-caregiver communications and therapy management. Another program, www.HemophiliaMoms.com, is a Web site containing true accounts from mothers raising kids with hemophilia. This Web site is designed to provide caregivers of hemophilia patients with practical information to help them meet day-to-day challenges. The goal of such programs is to facilitate treatment of hemophilia A and assist patients with treatment needs to encourage compliance and optimal treatment outcomes.
Hemophilia A is a rare coagulation disorder that affects approximately 18,000 males in the United States (NHLBI 2009). An X-linked genetic disorder, hemophilia A results from defects in the quantity or quality of FVIII, which interferes with appropriate progression of the coagulation cascade (Bolton-Maggs 2003). Until the development of FVIII replacement therapies, affected children were at risk for a variety of hemorrhages, chronic and painful arthropathy, debilitating joint degeneration, reduced life expectancy, and death related to CNS bleeds. The development of FVIII concentrates has greatly improved the prognosis and quality of life associated with this potentially life-threatening disease.
FVIII replacement products have gone through many changes since the earliest days of blood transfusion and plasma-derived cryoprecipitates (MASAC 190). Progress in factor concentration techniques, product purification, viral inactivation, and reconstitution and delivery methods have made contemporary factor replacement products a safe and effective treatment to manage bleeding. The established efficacy and safety profile of Helixate® FS, with low inhibitor formation rate and proven benefit in reducing joint damage, help to make Helixate® FS a preferred choice for the prophylaxis and episodic control of bleeding in patients with hemophilia A.