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This Product Profiler introduces health care professionals to immune globulin subcutaneous (human), Hizentra™, a treatment for patients with primary immunodeficiency disease (PIDD). The term PIDD refers to a large, heterogeneous group of disorders that affect the cells, tissues, and proteins of the immune system. Hizentra™ is the first and only U.S. Food and Drug Administration (FDA)-approved 20% subcutaneous immunoglobulin (SCIg) indicated for PIDD. It can be self-administered by patients under a physician’s care and after training from a physician or other health care provider.
Clinical data have shown Hizentra™ to be a safe and effective treatment of patients with PIDD. However, the safety and efficacy of this product have not been studied in neonates or infants.
When administered on a weekly basis, SCIg provides stable steady-state serum immunoglobulin G (IgG) levels, with lower IgG peak levels and higher IgG trough levels relative to monthly intravenous (IV) treatment (Berger 2008). The following text presents a brief overview of PIDD and current treatment options, followed by a review of the evidence-based literature supporting the FDA-approved indications for the SC administration of human Ig.
PIDDs represent a class of disorders in which the immune system of a person is compromised (NIH 2008). These diseases differ from secondary immune diseases in that they are usually the result of an intrinsic or genetic defect in the immune system (NIH 2008). Secondary immune diseases often can result from another disorder or an external agent such as chemotherapy, viruses, radiation therapy, or other drug-related treatments (Boyle 2007). The lack of a competent and normally functioning immune system poses significant threats to an individual. Antibody production impairments or ineffective/malfunctioning cellular defects lead to recurrent and unusual infections (Boyle 2007, Buckley 2009). Infections may be persistent, severe, become life-threatening, and may be caused by unusual microorganisms typically not harmful to those with normally functioning immune systems (Buckley 2009, NIH 2008).
There are over 150 different forms of PIDD syndromes that are associated with varying degrees of severity (NIAID 2009). Approximately 500,000 Americans suffer from various forms of PIDD syndromes, 5,000 to 10,000 of whom have severe manifestations (NIAID 2009). Although there are several types and forms of PIDDs, they are still considered rare diseases and many of the types are designated with an orphan status, meaning a single type of PIDD may affect fewer than 200,000 people (FDA 2009, NIAID 2009). Naturally, infections are the primary hallmark of patients with PIDDs (NIH 2008). It is common for patients with PIDDs to suffer from chronic ear, sinus, and other infections (NIH 2008). Furthermore, serious infections of the respiratory tract, such as recurrent pneumonia, can result in permanent lung damage (NIH 2008). However, these patients often suffer from additional comorbidities that may or may not be related to the immune system (NIH 2008). Examples of these conditions include anemia, arthritis, autoimmune diseases, and other comorbidities involving the heart, digestive tract, or nervous system (NIH 2008).
Significant progress has been made in the past 20 years in cellular and molecular biology (Bacchelli 2007). These advancements have allowed researchers to begin to understand the underlying causes of some PIDDs (Bacchelli 2007). For example, genetic mutations have been identified in the immune system of affected individuals (Fischer 2004). These mutations provide researchers with valuable insight into the normal role and function of genes that affect immune cell development and function, and immune-related homeostatic mechanisms (Fischer 2004). These findings can be studied and applied to diagnosis, genetic counseling, prognosis, and potential therapeutic strategies (Fischer 2004).
Two examples of common PIDDs are Common Variable Immunodeficiency (CVID) and X-Linked Agamma-globulinemia (XLA). These deficiencies share the common etiology of antibody production defects (Buckley 2009). Physical findings can suggest one deficiency over another. For example, enlarged lymph nodes and splenomegaly is commonly present in patients suffering from CVID, while absent or reduced tonsil size and lymph nodes are characteristically found in patients with XLA (Buckley 2009).
The immune system is responsible for defending the body against infection and disease. In addition to the innate immune system, it does this using two components of the adaptive immune system, humoral and cell-mediated immunity (Shier 2010). The humoral immune system primarily uses antibodies produced from activated B cells to fight against infection (Shier 2010). The second system, the cell-mediated immune system, uses a compilation of different types of T cells to produce cytokines, secrete toxins, kill virus-infected and cancerous cells, enhance B cell antibody production, provide for future immunity against a specific pathogen, and regulate T cell response (Blaese 2007, Shier 2010). Table 1 describes the various components of the immune system and their functions.
Defects or disruptions in the presence of any of these components can drastically jeopardize the safety and immune capability of the host. The basis for the classification of PIDD disorders is categorized by the main component of the immune system that is deficient, absent, or defective (Table 2) (Merck Manual 2008).
Often, patients with PIDD present with recurrent, persistent, or unusual infections (Buckley 2009). The clinical presentation of PIDD, however, can depend on the extent of an underlying defect. For example, frequent upper respiratory infections may be the result of an antibody or complement deficiency (Buckley 2009). Frequent lower respiratory infections may suggest deficiencies in B or T cells, the complement pathway, or phagocyte defects (Buckley 2009). Infections common to skin and internal organs may suggest a phagocyte deficiency while infections in the blood or central nervous system may suggest an antibody or complement deficiency (Buckley 2009).
Some patients also may present with a variety of other clinical manifestations, including autoimmune or rheumatologic disease, anemia, gastrointestinal, heart or nervous system complications, and skin or liver abscesses (NIH 2008). In fact, one or more of these noninfectious manifestations may be the first or predominant clinical symptom of an underlying immunodeficiency (NIAID 2009).
Certain immunodeficiency diseases may be diagnosed because of the combination of characteristic signs and symptoms (NIH 2008). For example, children with DiGeorge syndrome often have an underdeveloped thymus gland, congenital heart disease, defective or underdeveloped parathyroid glands, and characteristic facial features (NIH 2008). Patients with Wiskott-Aldrich syndrome often develop bleeding problems and skin rashes in addition to increased likelihood of infections (NIH 2008). Unfortunately, it is not common practice to screen for PIDDs during infancy, childhood, or adulthood (Buckley 2009). Consequently, PIDDs usually are detected only after patients experience a multitude of infections and when physicians, parents, and patients recognize that infections are more than just ordinary (NIH 2008).
When a patient is suspected of having a PIDD, a complete patient and family history, a detailed physical examination with pertinent laboratory tests, and diagnostic procedures should be performed and evaluated (NIH 2008). The initial screening tests should include a complete blood count (CBC) with differential, quantitative immunoglobulin levels (IgG, IgM, and IgA), specific antibody response to vaccines, complement screening, and skin tests (NIH 2008). If any of these tests demonstrate abnormalities or if clinical symptoms persist, further immunologic evaluation is needed to identify specific deficiencies (Bonilla 2005, Buckley 2009, NIH 2008).
Most patients with identified antibody deficiency syndromes are regularly treated with replacement Ig therapy. Delivery options include IV or SC infusions (Buckley 2009). Intramuscular (IM) injections were frequently given in the 1950s but were largely replaced in the early 1980s with IV formulations due to such limitations as painful injections, decreased adherence by patients, and limited amounts of Ig that could be administered (Skoda-Smith 2010). Ig treatment, however, is primarily given as a preventative therapy and does not adequately treat infections that may occur while on treatment (Buckley 2009). In fact, patients with antibody abnormalities also may benefit from prophylactic or full-dose antibiotics as adjunctive therapy (Buckley 2009).
There are currently several Ig preparations licensed for IV administration; however, this route may not be ideal for all patients (Blaese 2007). Limitations of IV administration include: difficulty administering to patients with poor venous access; recurrent systemic adverse reactions; and limited freedom regarding dosing times and locations (Blaese 2007). The SC delivery of Ig may address some of the limitations presented by IV administration (Blaese 2007). Table 3 provides various features of SCIg and IVIg.
Hizentra™ is the first and only 20% SCIg product to offer patients with PIDD an alternative to IVIg therapy, including the option of self-administration with a physician’s training and approval. In a multicenter clinical trial conducted in the United States, there were no serious bacterial infections reported with Hizentra™ treatment, and Hizentra™ was found to decrease both annual infection rate and hospitalizations due to infections (Hizentra™ Prescribing Information 2010).
IVIg is widely used for the treatment of immunodeficiencies (Shah 2005). Each batch of IVIg is derived from human plasma that has been pooled from 1,000 to 60,000 plasma donors (Buckley 2009, Sewell 2002). All preparations are subjected to rigorous safety measures, which include screening donors for human immunodeficiency virus (HIV) infection, hepatitis B and C virus (HBV and HCV) infection, and manufacturing procedures that inactivate and/or eliminate a wide range of viruses (Shah 2005).
IVIg products vary in their osmolality, pH, sugar, and sodium content, any of which can influence patient tolerability and adverse events (Blaese 2007). The incidence of adverse events with IVIg can vary and may include hypersensitivity reactions (Blaese 2007).
Adverse reactions usually appear soon after the infusion has started, but can occur at any time during infusion (Murphy 2005). Management of reactions may include lowering the infusion rate or providing medications, such as acetaminophen, aspirin, or antihistamines, depending on the type of symptom encountered (Blaese 2007).
IVIg has been associated with the development of acute renal failure (ARF) and renal dysfunction (FDA 1999). Based on postmarketing reports, the FDA requires all manufacturers of IVIg to include a boxed warning informing prescribers about the risk of renal dysfunction, ARF, osmotic nephrosis, and death associated with these products (FDA 1999). Approximately 88% of the postmarketing reports were associated with products containing sucrose (FDA 1999).
The FDA recommends that physicians exercise particular caution when administering IVIg to patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age older than 65, volume depletion, sepsis, paraproteinemia, and individuals who are receiving nephrotoxic drugs (FDA 1999). The FDA also recommends that patients receiving IVIg should not be volume-depleted (FDA 1999). In patients at risk for ARF, the minimum concentration and infusion rate should be used (FDA 1999). Baseline urine output, blood urea nitrogen, and serum creatinine also should be determined, with monitoring continuing at appropriate intervals (FDA 1999). Additionally, patients receiving IVIg should be instructed to immediately report symptoms that may suggest declining kidney function, such as edema or shortness of breath (FDA 1999).
Based on historical concerns such as renal failure and thrombotic events, patients scheduled to receive Ig therapy should be categorized by degree of risk. Health care professionals managing patients receiving Ig therapy should perform a risk assessment before the initiation of each IVIg infusion (Murphy 2005). Depending on the patient’s risk factors and infusion-related reactions, the appropriate drug concentration, osmolality, and rate of infusion should be determined (Murphy 2005). Risk assessment is important when dosing regimens and routes of administration are being considered. Assessments including evaluation of the patient’s history and physical examination, risk factors, comorbidities, and tolerance are pertinent to appropriately manage potential adverse events (Murphy 2005). Such assessments require a substantial time commitment from the health care provider since risk factors must be re-evaluated and updated with each IVIg infusion.
SCIg has emerged as an alternative method of administration for both children and adults with immunodeficiency diseases. Advantages of the SC route include decreased systemic adverse effects, decreased need for vascular access, limited variation in peak and trough Ig levels, and increased patient autonomy (Berger 2008). Although SCIg is currently available in the United States, Hizentra™ is the only 20% concentration of SCIg to be approved as safe and effective for use as replacement therapy in primary immunodeficiency (Hizentra™ Prescribing Information 2010).
Early studies of SCIg in the 1980s showed that it was associated with fewer adverse effects than IVIg (Berger 1980, Roord 1982, Van der Meer 1988). The SC infusions were well tolerated, and IgG levels were maintained within the appropriate range (Berger 1980). In the mid-1990s, there was renewed interest in SCIg using IM or IV products with numerous studies evaluating its use (Gardulf 1991, Gardulf 1996, Gaspar 1998).
The more frequent and regular dosing of SCIg results in flatter pharmacokinetic (PK) parameters and reduced catabolism of IgG (Figure 1) (Berger 2008). With slow administration and gradual absorption, the incidence of severe headaches and other systemic adverse events is reduced. SC delivery eliminates the need for venous access and it also facilitates self-infusion and home infusion (Berger 2008). This increases patient autonomy with the potential to improve the patient’s sense of control. Published data equates the efficacy of SCIg with that of IVIg for preventing serious bacterial infections (Berger 2008). Recent data from the Hizentra™ clinical trial support these findings (Hizentra™ Prescribing Information 2010).
The frequency of systemic adverse events reported with SCIg is low and infusion-related adverse events consist primarily of local reactions (i.e., swelling or redness at the site of the infusion) (Berger 2008, Gardulf 1991). More than half of patients reported that the local reaction lasted for less than 24 hours (Skoda-Smith 2010). The decreased frequency of systemic effects may likely be due to the slower equilibration of Ig into circulation (Berger 2008).
SCIg has been used in patients with IgA deficiency with antibodies against IgA (Eijkhout 2003). Severe side effects, including anaphylactoid reactions, were observed in these patients when they received IV preparations. In a retrospective study, investigators evaluated the use of SCIg in patients with anti-IgA antibodies and/or severe reactions to previous blood products (Eijkhout 2003). A total of 15 patients with IgA deficiency were given SCIg using either an IM or IV product. The results demonstrated that even in the presence of anti-IgA antibodies, patients who had reported serious adverse events with previous Ig therapy or transfusions could safely be treated with SCIg (Eijkhout 2003). Another study mimicked these initial observations (Horn 2007). In this study, 8 patients were completely IgA deficient, 5 of which had a history of anaphylactoid reactions when given IVIg. The study demonstrated that 4 of the 5 patients with a history of anaphylaxis were able to tolerate SCIg without incident. Please note that all Ig preparations, including Hizentra™, carry an FDA brand contraindication for IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.
The SC route of Ig also has been used as a home replacement therapy in pregnant women (Berger 1982, Gardulf 2001). The route was successfully used in a woman with common variable immunodeficiency and splenectomy, as reported by investigators in 1982 (Berger 1982). Another study evaluating the effects of rapid SCIg in nine pregnant women with primary antibody deficiencies found that, during the course of pregnancy, IgG and IgG subclass concentrations remained within the normal range (Gardulf 2001). None of the infants required IgG replacement therapy after delivery. No significant local tissue reactions were noted, and no systemic adverse events attributable to the drug were reported in the more than 400 SC infusions (Gardulf 2001). Please note Hizentra™ is classified as Pregnancy Category C and, as with all IgG therapies, should be given to pregnant women only if clearly needed.
Hizentra™ is an Immune Globulin Subcutaneous (Human) (SCIg), 20% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PIDD). This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
Hizentra™, Immune Globulin Subcutaneous (Human), 20% Liquid, is a ready-to-use, sterile 20% (0.2 g/mL) protein liquid preparation of polyvalent human immunoglobulin G (IgG) for subcutaneous administration. Hizentra™ is manufactured from large pools of human plasma by a combination of cold alcohol fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. Fab functions tested include antigen binding capacities, and Fc functions tested include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG).
Hizentra™ has a purity of ≥98% IgG and a pH of 4.6 to 5.2. Hizentra™ contains approximately 250 (range: 210 to 290 mmol/L) L-proline (a nonessential amino acid) as a stabilizer, 10 to 30 mg/L polysorbate 80, and trace amounts of sodium. Hizentra™ contains ≤50 mcg/mL IgA. Hizentra™ contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative.
Plasma units used in the manufacture of Hizentra™ are tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to human immunodeficiency virus (HIV)-1/2 and hepatitis C virus (HCV) as well as FDA-licensed Nucleic Acid Testing (NAT) for HIV-1 and HCV. All plasma units have been found to be non-reactive (negative) in these tests. For hepatitis B virus (HBV), an investigational NAT procedure is used and the plasma units found to be negative; however, the significance of a negative result has not been established. In addition, the plasma has been tested for B19 virus (B19V) DNA by NAT. Only plasma that passes virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL.
The manufacturing process for Hizentra™ includes three steps to reduce the risk of virus transmission. Two of these are dedicated virus clearance steps: pH 4 incubation to inactivate enveloped viruses and virus filtration to remove, by size exclusion, both enveloped and non-enveloped viruses as small as approximately 20 nanometers. In addition, a depth filtration step contributes to the virus reduction capacity.
These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. Table 4 shows the virus clearance during the manufacturing process for Hizentra™, expressed as the mean log10 reduction factor (LRF).
The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered a model for CJD and its variant (vCJD). Several of the production steps have been shown to decrease infectivity of an experimental TSE model agent. TSE reduction steps include octanoic acid fractionation (≥6.4 log10), depth filtration (2.6 log10), and virus filtration (≥5.8 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.
Hizentra™ supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. The mechanism of action in PIDD has not been fully elucidated.
The pharmacokinetics (PK) of Hizentra™ was evaluated in a PK substudy of subjects with PIDD participating in the 15-month efficacy and safety study. All PK subjects were treated previously with Privigen®, Immune Globulin Intravenous (Human), 10% Liquid and were switched to weekly SC treatment with Hizentra™. After a 3-month wash-in/wash-out period, doses were adjusted individually with the goal of providing a systemic serum IgG exposure (area under the IgG serum concentration vs time curve; AUC) not inferior to that of the previous weekly-equivalent IGIV dose. Table 5 summarizes PK parameters for subjects in the substudy following treatment with Hizentra™ and IVIg.
For the 19 subjects completing the wash-in/wash-out period, the average dose adjustment for Hizentra™ was 153% (range: 126% to 187%) of the previous weekly-equivalent IVIg dose. After 12 weeks of treatment with Hizentra™ at this individually adjusted dose, the final steady-state AUC determinations were made in 18 of the 19 subjects. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Hizentra™ vs IVIg treatment was 1.002 (range: 0.77 to 1.20) with a 90% confidence limit of 0.951 to 1.055 for the 18 subjects.
The PK study included an additional assessment to determine the ratio of serum IgG trough levels with Hizentra™ (SCIg) compared to the previous trough levels with IVIg that were associated with matching AUCs. It was demonstrated that IgG trough levels during treatment with Hizentra™ were 1.3 times higher than the preceding trough levels during treatment with IVIg (Privigen®). This calculated SCIg:IVIg ratio of 1.3 (±15% of this value, or ±0.2) can be used to assess dosing with Hizentra™ by providing a steady-state target IgG trough level, which may be assumed to be within the range of 1.1 to 1.5 times the previous steady-state trough levels with IVIg. However, the patient’s clinical response should be the primary consideration in dose adjustment (see Dosage and Administration).
With Hizentra™, peak serum levels are lower (1,616 vs 2,564 mg/dL) than those achieved with IVIg while trough levels are generally higher (1,448 vs 1,127 mg/dL). In contrast to IVIg administered every 3 to 4 weeks, weekly SC administration results in relatively stable steady-state serum IgG levels. After the subjects had reached steady-state with weekly administration of Hizentra™, peak serum IgG levels were observed after a mean of 2.9 days (range: 0 to 7 days) in 18 subjects.
For subcutaneous infusion only. Do not inject into a blood vessel.
Hizentra™ is a clear and pale yellow to light brown solution. Do not use if the solution is cloudy or contains particulates.
The dose should be individualized based on the patient’s clinical response to Hizentra™ therapy and serum immunoglobulin G (IgG) trough levels.
Begin treatment with Hizentra™ one week after the patient’s last Immune Globulin Intravenous (Human) (IVIg) infusion. Prior to switching treatment from IVIg to Hizentra™, obtain the patient’s serum IgG trough level to guide subsequent dose adjustments (see below under Dose Adjustment).
Establish the initial weekly dose of Hizentra™ by converting the monthly IVIg dose into a weekly equivalent and increasing it using a dose adjustment factor. The goal is to achieve a systemic serum IgG exposure (area under the concentration-time curve [AUC]) not inferior to that of the previous IVIg treatment (see Pharmacokinetics).
To calculate the initial weekly dose of Hizentra™, multiply the previous IVIg dose in grams by the dose adjustment factor of 1.53; then divide this by the number of weeks between doses during the patient’s IVIg treatment (i.e., 3 or 4).
To convert the Hizentra™ dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 5.
Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level. To determine if a dose adjustment may be considered, measure the patient’s serum IgG trough level 2 to 3 months after switching from IVIg to Hizentra™. The target serum IgG trough level on weekly Hizentra™ treatment is projected to be 1.3 ± 0.2 times (i.e., between 1.1 and 1.5 times) the last IVIg trough level (see Pharmacokinetics).
To adjust the dose based on trough levels, calculate the difference (in mg/dL) of the patient’s serum IgG trough level from the target IgG trough level (1.3 times the last IVIg trough level). Then find this difference in Table 6 and the corresponding amount (in mL) by which to increase or decrease the weekly dose based on the patient’s body weight. However, the patient’s clinical response should be the primary consideration in dose adjustment.
For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900 mg/dL and the target trough level is 1,000 mg/dL, this results in a difference of 100 mg/dL. Therefore, increase the weekly dose of Hizentra™ by 7 mL.
Dosage requirements for patients switching to Hizentra™ from another SCIg product have not been studied. If a patient on Hizentra™ does not maintain an adequate clinical response or a serum IgG trough level equivalent to that of the previous SCIG treatment, the physician may want to adjust the dose. For such patients, Table 10 also provides guidance for dose adjustment if their desired SCIg trough level is known.
If a patient is at risk of measles exposure (i.e., due to an outbreak in the U.S. or travel to endemic areas outside of the U.S.), the weekly Hizentra™ dose should be a minimum of 200 mg/kg body weight for two consecutive weeks. If a patient has been exposed to measles, ensure this minimum dose is administered as soon as possible after exposure.
Hizentra™ is for subcutaneous infusion only. Do not inject into a blood vessel.
Hizentra™ is intended for weekly SC administration using an infusion pump. Infuse Hizentra™ in the abdomen, thigh, upper arm, and/or lateral hip.
Please see Full Prescribing Information at the end of this Product Profiler for instructions on aseptic administration of Hizentra™.
Hizentra™ is supplied in a single-use, tamper-evident vial containing 0.2 grams of protein per mL of preservative-free liquid. Each vial label contains a peel-off strip with the vial size and product lot number for use in recording doses in a patient treatment record.
The components used in the packaging for Hizentra™ contain no latex. The following dosage presentations are available:
|NDC Number||Fill Size (mL)||Grams Protein|
When stored at room temperature (up to 25°C [77°F]), Hizentra™ is stable for the period indicated by the expiration date printed on the outer carton and vial label. DO NOT FREEZE. Do not use product that has been frozen. Do not shake. Keep Hizentra™ in its original carton to protect it from light.
Methods. A single-center, randomized, four-way crossover, assessment-blinded phase 1 study compared the local tolerability of IgPro16 and IgPro20 with Vivaglobin® in 28 Caucasian men age 18 to 45 years (Hagan 2010). Study subjects received a single SC dose of IgPro16 15 mL, IgPro20 15 mL, IgPro20 12 mL, or Vivaglobin® 15 mL at an infusion rate of 25 mL/hr on day 1 at a single abdominal site. Subsequent test samples were administered weekly at varying abdominal sites. The primary endpoint of the phase 1 study was assessment of local tolerability, including pain, erythema, edema/induration, itching, and local heat, from the start of the infusion to 72 hours post-infusion. Pain was assessed by subjects using a 100-mm visual analog scale (VAS) ranging from 0 (no pain) to 100 (unbearable pain). Erythema and edema were assessed by treatment-blinded investigators using 5-point scales ranging from none (score 0) to severe (score 4). Similarly, itching and local heat were evaluated by treatment-blinded investigators using a 4-point scale ranging from none (score 0) to severe (score 3).
Results. Subjective pain assessments were low (Table 7). Patients treated with IgPro20 reported lower maximum and mean pain scores compared with Vivaglobin®, and treatment differences for mean pain were statistically significant for IgPro16 and IgPro20 (12 mL) versus Vivaglobin® (P=.0328 and P=.0205, respectively) (Table 8).
Erythema intensity was less severe with IgPro20 compared with Vivaglobin®. Fewer than 57% of erythema events were “well-defined” in subjects receiving IgPro20 (12 mL) versus 75% of erythema events with Vivaglobin®. Nearly all subjects experienced severe edema/induration, as expected with SC infusion. At 24 hours post-infusion, no edema/induration was observed in 28% of evaluations. By Day 4, there was no edema/induration observed in the majority (71%) of evaluations. Itching and local heat were predominantly mild, and all cases of local heat were resolved 8 hours after the end of the infusion.
Local reactions were recorded as adverse events (AEs) when symptoms/signs led to infusion stop, required concomitant medication, or had an impact on the general condition of the subject as judged by the investigator. None of the observed local tolerability events met such characteristics, therefore IgPro20 proved noninferior in safety and tolerability when compared with Vivaglobin®.
Methods. A 15-month, prospective, open-label, multi-center, single-arm, phase 3 study evaluated the efficacy and safety of IgPro20 in PIDD patients (Hagan 2010). Additionally, the pharmacokinetics of IgPro20 were evaluated in a substudy of 19 patients. Subjects included males and females age 5 to 72 years with CVID diagnosis, as defined by Pan-American Group for Immunodeficiency and European Society for Immunodeficiencies, or with XLA, as determined by the investigator. Prior to study enrollment, patients were receiving IVIg therapy at regular 3- or 4-week intervals for at least three months. Patients switching from a Privigen® study in PIDD were required to have had at least three documented serum IgG trough levels of ≥ 5 g/L three months prior to study enrollment. Patients treated with other IVIg products were required to have had at least one documented serum IgG trough level of ≥ 5 g/L in the six months preceding the study.
The study consisted of a 12-month efficacy period following a 12-week wash-in/wash-out period. Within the wash-in/wash-out period, an initial weekly dose of IgPro20 was calculated using the average weekly dose of the three previous IVIg infusions, multiplied by a dose adjustment coefficient of 1.30. In the efficacy period, patients not participating in the pharmacokinetic substudy had their IgPro20 doses adjusted by a coefficient of 1.53.
Study-approved premedication included oral and parenteral steroids (average daily dose <0.15 mg of prednisone equivalent/kg/day) as concomitant medication and local anesthetics used before infusion to reduce pain associated with needle insertion. Premedication taken prior to infusion for SCIg-associated AE reduction was not allowed.
The primary efficacy endpoint of the study was the annual rate of serious bacterial infections (SBIs) per patient in the modified intention-to-treat (MITT) population. The MITT included all patients treated with study medication during the efficacy period. SBIs were defined as bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. Patient diaries were used to assess secondary endpoints such as number of infection episodes, number of days missed from work/school/day care or inability to perform normal activities due to infection, number of days of hospitalization due to infections, and use of antibiotics for infection prophylaxis or treatment. Additionally, trough serum IgG levels were measured every 4 weeks prior to infusion.
Local reactions were assessed by patients via patient diaries 24±3 hours after infusion end using a 5-point scale (none, very slight, slight, moderate, severe). Local reactions also were assessed by investigators at 15 to 45 minutes after infusion. Edema was evaluated using two diameter measurements while other local reactions were assessed by 5-point scales.
Results. There were no SBIs, as defined by the FDA, reported in the MITT population (N=38), resulting in an annual rate of SBI per patient of zero (Table 9). An annual rate of 2.76 non-SBI infections per patient was observed (96 infections in 31 patients [86%]). The annual rates of missed days from work/school and hospitalizations due to infections were 2.06 per patient and 0.2 per patient, respectively. Twenty-seven patients spent 1,688 days on antibiotics for infection prophylaxis or treatment, resulting in an annual rate of 48.5 days per patient. Throughout the efficacy period, mean serum IgG trough levels were maintained between 12.1 g/L and 12.9 g/L.
Local reactions were observed in all patients in the ITT population at a rate of 0.592 events per infusion. The majority of these local reactions were mild in intensity and only four severe events were observed. The most common AE reported in the study was injection-site reaction, and such reactions were predominantly mild (93.4%).
Excluding local reactions, the most common AE was sinusitis, followed by headache and nasopharyngitis, and 99% of AEs were of mild or moderate intensity. Of the 2,264 infusions administered in the study, a total of 409 AEs, excluding local reactions, were reported. Ninety-eight of these were considered at least possibly related to study medication (0.043 AEs per infusion).
Investigators concluded that IgPro20, the first 20% SCIg, demonstrated excellent efficacy and tolerability in patients with PIDD. IgPro20 provides an option for patients desiring convenient self-administration of immunoglobulin therapy at home.
Hizentra™ is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin or to components of Hizentra™, such as polysorbate 80.
Hizentra™ is contraindicated in patients with hyperprolinemia because it contains the stabilizer L-proline (see Description).
Hizentra™ is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity (see Description).
Severe hypersensitivity reactions may occur to human immune globulin or components of Hizentra™, such as polysorbate 80. In case of hypersensitivity, discontinue the Hizentra™ infusion immediately and institute appropriate treatment.
Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA.
Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions with administration of Hizentra™. Hizentra™ contains ≤50 mcg/mL IgA (see Description).
The following reactions have been reported to occur with IVIg treatment and may occur with SCIg treatment.
Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human immune globulin products. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Hizentra™ and at appropriate intervals thereafter.
Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure. If renal function deteriorates, consider discontinuing Hizentra™. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are overweight or use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer Hizentra™ at the minimum rate practicable.
Thrombotic events may occur with use of human immune globulin products. Patients at increased risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Hizentra™ at the minimum rate practicable.
AMS may occur with use of human immune globulin products. The syndrome usually begins within several hours to 2 days following IVIg treatment. AMS is characterized by signs and symptoms including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, with elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IVIg.
Conduct a thorough neurological examination, including CSF studies, to rule out other causes of meningitis in patients exhibiting signs and symptoms of AMS. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae.
Hizentra™ can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs’) test result and hemolysis. Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.
Monitor recipients of Hizentra™ for clinical signs and symptoms of hemolysis. If these are present after a Hizentra™ infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving Hizentra™, perform adequate cross-matching to avoid exacerbating on-going hemolysis.
Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within 1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.
Monitor Hizentra™ recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum.
Because Hizentra™ is made from human plasma, it may carry a risk of transmitting infectious agents (e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease [CJD] agent). The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for Hizentra™.
Report all infections thought to be possibly transmitted by Hizentra™ to CSL Behring Pharmacovigilance at 1-866-915-6958.
Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.
The most common adverse reactions (ARs), observed in ≥5% of study subjects receiving Hizentra™, were local reactions (i.e., swelling, redness, heat, pain, and itching at the injection site), headache, vomiting, pain, and fatigue.
Because clinical studies are conducted under widely varying conditions, AR rates observed in clinical studies of a product cannot be directly compared to rates in the clinical studies of another product and may not reflect the rates observed in clinical practice.
The safety of Hizentra™ was evaluated in a clinical study for 15 months in subjects with PIDD who had been treated previously with IVIg every 3 or 4 weeks. The safety analyses included 49 subjects in the intention-to-treat (ITT) population. The ITT population consisted of all subjects who received at least one dose of Hizentra™.
Subjects were treated with Hizentra™ at weekly doses ranging from 66 to 331 mg/kg body weight during the wash-in/wash-out period and from 72 to 379 mg/kg during the efficacy period. The 49 subjects received a total of 2,264 weekly infusions of Hizentra™.
No deaths or serious ARs occurred during the study. Two subjects withdrew from the study due to ARs. One subject experienced a severe injection-site reaction one day after the third weekly infusion, and the other subject experienced moderate myositis. Both reactions were judged to be “at least possibly related” to the administration of Hizentra™.
Table 10 summarizes the most frequent adverse events (AEs) (experienced by at least 4 subjects), irrespective of causality. Included are all AEs and those considered temporally associated with the Hizentra™ infusion, i.e., occurring during or within 72 hours after the end of an infusion. Local reactions were the most frequent AEs observed, with injection-site reactions (i.e., swelling, redness, heat, pain, and itching at the site of injection) comprising 98% of local reactions.
The ratio of infusions with temporally associated AEs, including local reactions, to all infusions was 1,338 to 2,264 (59.1%; upper 95% confidence limit of 62.4%). Excluding local reactions, the corresponding ratio was 173 to 2,264 (7.6%; upper 95% confidence limit of 8.9%).
Table 11 summarizes the most frequent ARs (i.e., those AEs considered by the investigators to be “at least possibly related” to Hizentra™ administration) experienced by at least 2 subjects.
Table 12 summarizes injection-site reactions based on investigator assessments 15 to 45 minutes after the end of the 683 infusions administered during regularly scheduled visits (every 4 weeks).
Most local reactions were either mild (93.4%) or moderate (6.3%) in intensity.
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified and reported during the postmarketing use of IVIg products:
Recent advancements in medicine have continued to enhance treatment and administration options for patients with PIDD. Hizentra™ is a safe and effective SCIg treatment that provides patients with the freedom and ability to take control of their own therapy. As with any chronic illness, one of the goals of therapy involves improving health outcomes as well as quality of life (QOL) for patients. Hizentra™ is currently the only SCIg available in a 20% concentration for use as replacement therapy for patients with PIDD. SCIg holds numerous advantages and Table 13 describes various multifactorial benefits of SCIg.
Recent data has shown that trough values during Hizentra™ treatment were sustained and similar to those obtained with previous treatment using other SCIg preparations, and the data suggests that the majority of patients can be switched from other SCIg therapies to Hizentra™ without dose adjustment, resulting in significantly lower administration volume (Jolles 2010).
Clinical study data has shown that patients treated with Hizentra™ over a 12-month period reported no serious bacterial infections (Hagan 2010). Additionally, the rate of any infections in the same time period was fewer than fewer per year (Hagan 2010). The lack of serious bacterial infections and reduced rate of all types of infections demonstrated with Hizentra™ treatment minimized the quantity of unproductive days that patients experienced. For example, patients who received Hizentra™ missed work, school, day care, or other normal daily activities at an annual rate of 2.06 days per subject year (Hagan 2010). Furthermore, the annual rate of hospitalizations attributed to infections in patients receiving Hizentra™ was 0.2 days per subject year (Hagan 2010). The increase in productive days and the decrease in amount of infections impacts patient qualty of life (QOL), as well as potentially yielding significant cost savings associated with reduced infection-related hospitalizations.
A Swedish study evaluated health care utilization and QOL of children who had been switched from hospital-based IVIg treatment to home treatment with SCIg (Fasth 2008). The study demonstrated significant improvement in indirect QOL measures, such as mental health and family activities from the parents’ perspective. Additionally, improvements in social limitations and global health were observed from the children’s perspective. Moreover, there was a significant reduction in health care-related expenses due to hospital or physician visits among the children switched to SCIg therapy.
In a parallel health-related quality of life (HRQL) study conducted in Europe, home-based therapy with Hizentra™ was evaluated in 29 patients with PIDD switching from IVIg therapy (Quevedo 2010). Study patients ranged in age from 2 to 65 years and were trained to self-administer Hizentra™; caregivers were trained in cases where patients were too young to self-administer. A group of 19 patients already using a different SCIg product was assessed in parallel. HRQL assessments were completed at baseline, 12, 24, and 40 weeks and included the PIDD-specific Life Quality Index (LQI), the Treatment Satisfaction Questionnaire for Medication (TSQM), a visual analog scale (VAS) for health status, and the Short Form-36 Health Survey (SF-36) for adults, defined as patients older than 14 years of age, or the Child Health Questionnaire-Parent Form 50 (CHQ-PF50) for patients younger than 14 years of age. The LQI, in addition to generating an overall score from its 15 items, provides subscores in four domains: therapy-related problems; treatment interference; therapy setting; and treatment costs. Compared with baseline scores, overall and LQI domain scores for patients previously treated with IVIg improved after 40 weeks of treatment with Hizentra™ (Figure 2). In patients previously treated with a different SCIg, there was no statistically significant change in LQI score between baseline and end of study. TSQM results showed that, in patients treated with Hizentra™, the median score for the convenience domain improved between baseline and end of study (Figure 3). There was no statistically significant change in health status between baseline and end of study as assessed with a VAS in either group of patients. Also, there was little change in SF-36 and CHQ-PF50 scores, and the low sample sizes of patients previously receiving IVIg precluded statistical analysis. In summary, this study demonstrated that, in patients switching from IVIg treatment to SCIg treatment with Hizentra™ at a dose equivalent to previous IVIg therapy, patients’ HRQL and treatment satisfaction improved.
Although the actual cost analysis of PIDD is impeded by the number of undiagnosed PIDD patients, the cost of chronic infections, numerous health care visits, hospitalizations, drug treatments, and non-compliance can easily increase the total cost of health care (Boyle 2007, Burton 2010). However, once patients are trained and become independent in the self-administration of SCIg infusions, the continual need for nursing and other administrative services along with their associated costs are obviated (Burton 2010). The cost of SCIg home infusions has been calculated to be $48 compared with $164 to $314 for nurse-administered IVIg at home (Radinsky 2003). Furthermore, the expected cost savings for home therapy versus hospital therapy is estimated at $2,000 to $5,000 per patient per year (Berger 2004). The advent of providing effective and safe medication in a relaxed home environment not only allows patients the opportunity to take an active role in maintaining their health but also may reduce the cost burden of therapy to patients and managed care organizations.
Hizentra™ is formulated with L-proline, a naturally occurring amphiphilic amino acid, as its stabilizer, and the addition of L-proline has been found to enhance the stability of liquid IVIg solutions and to reduce their IgG dimer content (Bolli 2010). Idiotype/anti-idiotype dimers form when the antigen-binding region (Fab) of one IgG molecule binds to the Fab of another IgG molecule in IgG isolated from the pooled plasma of numerous donors. These dimers have been associated with headache, fever, and flushing in patients and with hypotension in animal models (Bolli 2010).
The stability of Hizentra™ for up to 24 months was recently assessed (Maeder 2010). Stability parameters evaluated in the study included yellow discoloration, which often is seen in concentrated IgG solutions owing to oxidation during storage, monomers-plus-dimers content, content of polymers/aggregates, preservation of Fc function, which corresponds to the efficacy of IgG molecules, and functional integrity of the Fab component of IgG antibodies.
After storage for 24 months at 25°C, discoloration remained within the specification limit (absorbance at 350 nm [A350]) of ≤0.350. The monomers-plus-dimers content remained above the specification limit of 90%, and the content of polymers/aggregates remained within the specification limit of 4%. The Fc function of the antibody remained above the specification limit of 60%, and the functional integrity of the Fab region was maintained. This study demonstrated that the addition of L-proline to Hizentra™ minimized or prevented the discoloration, dimerization, aggregation, and loss of antibody activity during storage at 25°C for up to 24 months.
This data is relevant to P&T Committee decision makers because L-proline permits convenient room temperature storage for up to 24 months, allowing for immediate self-administration. Additionally, the ability of Hizentra™ to be stored at room temperature reduces potential waste due to erroneous lack of refrigeration. In summary, both patients and managed care organizations stand to benefit from Hizentra™ use due to the increased convenience and waste minimization that it provides.
Through the use of SCIg therapy, patients with severe and potentially fatal immunodeficiencies are able to achieve their treatment goals in a manner that works with their lifestyles. When evaluating Hizentra™ for formulary inclusion, P&T members must examine the product’s safety and efficacy, the clinical need for the agent, and the availability of other agents (Table 14). Considering the proven safety and efficacy profile of Hizentra™ as well as the cost savings and possibly increased HRQL associated with home therapy, P&T committees have the opportunity to provide patients with another treatment option for PIDD. Both patients and managed care organizations can benefit from the inclusion of such an option on formulary as it addresses an unmet need in a costly and cumbersome chronic illness.
PIDD is a serious syndrome that presents a unique challenge to patients and providers. In addition to the recurrent infections common to the disease, related comorbidities can considerably increase the health care burden for affected patients (NIH 2008). Hizentra™ is the first and only FDA-approved 20% SCIg indicated for the treatment of PIDD, and it can be self-administered by patients under a physician’s care and after training from a physician or other health care provider. Clinical data have shown Hizentra™ to be a safe and effective treatment of both adult and pediatric patients with PIDD, and, when administered on a weekly basis, SCIg provides stable steady-state serum IgG levels relative to monthly IV treatment (Berger 2008). Management of chronic diseases such as PIDD requires access to safe, effective, and convenient therapies for patients. Hizentra™ is an important addition to the therapeutic repository for the treatment of PIDD, and will serve as a valuable resource for providers who treat this burdensome and costly disease.