Hemophilia: Long-Acting Factor Products VIII

UTAH MEDICAID DUR REPORT FEBRUARY 2017

HEMOPHILIA A: NEWLY APPROVED RECOMBINANT FACTOR VIII CONCENTRATES (LONG-ACTING ANTIHEMOPHILIC FACTORS)

AFSTYLA ADYNOVATE ELOCTATE KOVALTRY

Drug Regimen Review Center Joanita Lake B.Pharm, MSc EBHC (Oxon), Clinical Pharmacist Valerie Gonzales, Pharm.D., Clinical Pharmacist Joanne LaFleur, Pharm.D., MSPH, Associate Professor

Acknowledgement We thank the following professionals for their input on this review: The University of Utah Home Infusion Pharmacy, Pharmacy Manager: Jamie Doi Slade, PharmD, Hemophilia Case Mangers: Jennifer Green, RN & Norma Sonntag, RN

Contents

Introduction ...... 3

Methodology ...... 6

Long-acting Recombinant Factor VIII Products ...... 6

Clinical Guidelines ...... 7

Clinical Efficacy ...... 10

Cochrane Systematic Review(s) ...... 10

Other Systematic Review(s) ...... 10

Additional Safety Evidence ...... 11

Treatment Management in Utah & Clinical Case Manager Input ...... 13

Misuse, Abuse, and Inappropriate Use of Factor Replacement Products ...... 15

Place in Therapy and Potential Criteria for Review ...... 15

Utah Medicaid Utilization Data ...... 18

Conclusions ...... 22

Appendix 1 – Drug Information ...... 23

Appendix 2 – Inhibitors ...... 26

Appendix 3 – Systematic Reviews ...... 27

Appendix 4 – University of Utah Home Infusion Case Management ...... 32

References ...... 35

Introduction

Congenital hemophilia is a rare, inherited, lifelong bleeding disorder which “in about one-third of the time, the baby with hemophilia is the first one in the family to be affected with a mutation in the gene for the clotting factor.”1 Patients with hemophilia have low levels of clotting factors VIII or IX, and this could result in spontaneous bleeding or life-threatening prolonged bleeding following injuries or surgery.1 “The level of factor VIII or factor IX in the blood usually stays the same throughout the person’s life.”2 A genetic mutation on the X chromosome can cause the clotting protein to be absent or dysfunctional. Hemophilia occurs in all racial and ethnic groups, however, is primarily seen in men (with only one copy of certain genes on the X chromosome), occurring in about 1 out of every 5,000 male births.1 Although rare, females may also have hemophilia in which case both X chromosomes are affected or one is affected and the other is missing or inactive. Females are most often asymptomatic carriers of hemophilia, passing the defected clotting-factor gene onto the child. 1

Although there are several different types of hemophilia, hemophilia A (a deficiency of factor VIII) and hemophilia B (a deficiency of factor IX) are the most common.1 Hemophilia A occurs in about 80% of patients with hemophilia, while about 20% have hemophilia B.1 A deficiency in factor VIII prolongs the activated partial thromboplastin time (aPTT) and is confirmed using assays that assess the activity level of the specific factor in the patient’s blood sample.3 It is worth noting that endogenous factor VIII (FVIII) originates in endothelial cells (not in hepatocytes like other factors) and has a half-life between 8 and 12 hours.3-6 Hemophilia severity is classified according to the following:7 • Mild: Clotting-factor activity level 6-30% of the normal expected level (about 25% of cases) • Moderate: Clotting-factor activity level 1-5% of normal (about 15% of cases) • Severe: <1% of the normal expected clotting-factor activity level (about 60% of cases)

The number of affected individuals with hemophilia A in the U.S. is estimated by the Centers for Disease Control and Prevention (CDC) to be approximately 20,000 individuals.1 The CDC has set up a monitoring system, known as the Universal Data Collection System (UDCS), made possible through collaboration with the U.S. Hemophilia Treatment Center Network (USHTCN). A newer program, Community Counts, will continue to improve and expand upon the collected UDCS datasets.8 Data reports under development will summarize information including, but not limited to, demographics, product use, bleeding rates, inhibitor development, treatment patterns, infection rates, use of healthcare services, and mortality.8 Currently, available reports include patient characteristics such as age, sex, ethnicity, race, insurance status, and concomitant infections for different factor deficiencies.9

Hemophilia can lead to chronic joint disease and pain (due to spontaneous bleeding into joints), seizures and paralysis (from bleeding into the brain), or death (due to unstoppable bleeding or bleeding into a vital organ). Bleeding often re-occurs in the same joint causing degradation, decreased range of motion, and reduced quality of life.1,7 “Eventually, the patient may need a radiosynovectomy, joint fusion, or joint replacement.”10 Early initiation of prophylactic treatment with blood factors reduces bleeding episodes and therefore prevents joint disease and other complications.11-13 “Without adequate treatment, many people with hemophilia die before they reach adulthood. However, with proper treatment, life expectancy for people with hemophilia is about 10 years less than that of males without hemophilia, and children can look forward to a normal life expectancy.”2

Another form of FVIII hemophilia is acquired hemophilia (AH), however, is much rarer.2 It is an autoimmune disorder caused by the development of autoantibodies that inactivate FVIII. It mostly

occurs in the elderly or in young women during late stages of pregnancy or postpartum.2 This form affects both men and women equally and is often precipitated by a pre-existing medical condition (such as malignancy, autoimmune disorder, or pregnancy) or by an allergic reaction to a medication (as reported with penicillin, ciprofloxacin, sulphonamides, clopidogrel, phenytoin, and fludarabine). AH manifests with extensive cutaneous purpura and internal bleeding, however, not so much joint bleeding, as is the case with congenital hemophilia. This condition is treated and often resolves upon the employment of hemostatic agents and immunosuppressants. 14

This review focuses on the newly approved long-acting recombinant factor VIII products for use in congenital hemophilia A. Hemophilia A is treated by intravenously administering factor VIII using either a plasma-derived factor or a recombinant, genetically engineered factor to reduce bleeding and improve joint health. In the 1970’s and 1980’s, blood-borne infections such as hepatitis and HIV were a problem with the use of the plasma-derived products since it was not possible to test for these infections. Subsequently, many patients with hemophilia became infected. Risk of HIV transmission is now much lower with the current use of blood donor screening, heat treatments, and nanofiltration. Nonetheless, the risk of viral transmission remains a possibility with plasma-derived factors. Recombinant products have been available since 1992. The first generation products were stabilized with human albumin; newer generation products do not require this technique and thus do not pose risks of blood-borne disease transmission since they have never been in contact with human blood products.7,15

Treatment with recombinant factor VIII products is the standard of care for symptomatic hemophilia A. Replacement factors are regularly used for ongoing prophylaxis to prevent bleeds, but this requires frequent intravenous administration. Traditional products with half-lives of about 12 hours in adults, but ranging in individual patients between 6 and 24 hours, require infusions three times a week or every other day.2,16 Longer-acting products have recently been developed to enhance convenience and adherence to therapy.4 Bioengineering strategies to prolong the half-life of these products include, but are not limited to, pegylation (attaching polyethylene glycol to the FVIII molecule) or fusing the factor to 17,18 the Fc region of immunoglobulin G1 so that it delays in vitro degradation.

The newly approved products described hereafter are all recombinant products. In June 2014, the FDA approved the first long-acting factor VIII product, Eloctate (rFVIII-Fc).4,19 It has a mean half-life of 19.7 hours in adults, due to Fc fusion, and is initially administered every 4 days.17 In November 2015, the FDA approved Adynovate (PEG-FVIII) which has an extended half-life of 13.4 to 14.7 hours in adults, due to pegylation, compared to its parent molecule, Advate, which has a half-life of 12 hours in adults.18,20 In March 2016, the FDA approved Kovaltry which was developed to improve the manufacturing process of Kogenate FS, one of the first recombinant FVIII products approved by the FDA in 1993. Key improvements included purification, stabilization by employing human heat shock protein, and the “establishment of a new, higher producing cell bank.”21,22 Kovaltry is labeled as two to three times per week dosing for prophylaxis in adults (half-life 14.2 hours) compared to three times per week with Kogenate (half-life 13.7 to 14.6 hours)— which may afford some improvement in terms of convenience.21,22 In May 2016, the FDA approved Afstyla (rVIII-Single Chain), the first single-chain factor VIII which utilizes a covalent bond to form one single polypeptide-chain. It was specifically designed for greater molecular stability and a longer duration of action with a half-life of 14.2 hours in adults, requiring prophylaxis dosing two to three times weekly.23 More frequent or higher dosing may be required for these products depending on the patient’s response and especially in children due to their increased clearance rates. Compared to the factor VIII products with half-lives around 12 hours, Kovaltry, Adynovate, and Afstyla offer an improvement in half-life of approximately two to three hours: refer to Tables 1 and 2 of Appendix 1. Eloctate may be more advantageous in this regard, as it has the

potential to be administered every 4 days with a half-life of 19.7 hours. However, once the patient’s response is assessed, the Eloctate dosing interval may have to be shortened or even extended to every 3 to 5 days, respectively. 17

“There is no consensus yet on what constitutes a prolonged half-life product. Some standard half-life products have the same half-life as some products marketed as prolonged half-life. The half-life of a product may vary widely from patient to patient.”24 A pharmacokinetic test/half-life study may be performed to determine an individual’s appropriate dose and dosing interval. For the purpose of this review, products were identified and included if they satisfied all of the following characteristics: (1) Recombinant Factor VIII (genetically engineered) and NOT human plasma derived (2) Potential to be dosed two days per week or less, with an extended half-life beyond the typical 12 hour half-life of traditional recombinant FVIII products

Table 2 of Appendix 1 contains information on recombinant FVIII products, and was used to identify products based on dosage and manufacture statements indicating a prolonged half-life. Factor products were excluded if not indicated for hemophilia A-related ongoing prophylaxis. For example, ReFacto was excluded since it is only indicated for episodic hemorrhagic events and for short-term surgical prophylaxis in patients with hemophilia A.25 The products identified to be included in this review have all been FDA approved recently (since June 2014). There are a few new factors in the pipeline for the treatment of Hemophilia A, of which at least two may have promising prolonged half-lives (N8-GP: 18.4 hours and BAY94-9027: 19 hours, similar to Eloctate: 19.7 hours).19

A comprehensive Hemophilia Treatment Center (HTC) can offer the best care and education for patients with hemophilia who must learn home infusion techniques and medication storage requirements.26 It is important to ensure appropriate use and storage of these products to achieve optimal treatment outcomes. Some patients develop inhibitors (neutralizing antibodies) to the replacement FVIII, which diminishes or ultimately renders the therapy ineffective. An antibody level of ≥5 Bethesda Units dL-1 (BU) is an indication that the substitution therapy would no longer be effective.27 Depending on the titer of the antibody, treatment may involve high-dose replacement factor regimens or the employment of bypassing agents such as recombinant activated FVII (rFVIIa) or plasma activated prothrombin complex concentrate (APCC). Immune tolerance induction can be carried out, whereby frequent doses of the factor that the patient developed the antibody to are administered until the inhibitor is eradicated. Neutralizing antibodies drive up treatment costs while limiting medication options.28 In general Hemophilia treatment is costly and for a single patient may range between $60,000 to $100,000 per year or more.7 “Prevention, early recognition, and prompt treatment of bleeds can help keep these costs down as well as improve overall quality of life.”29 However, appropriate use needs to be ensured to optimize efficacy of prophylactic treatment.

Methodology

The Cochrane Library, Medline (PubMed), Up to Date, the Agency for Healthcare Research and Quality (AHRQ), the U.S. Department of Health and Human Services website, the FDA website (including product labeled information), the Centers for Disease Control and Prevention (CDC) website, the National Hemophilia Foundation website, Micromedex and Lexicomp were searched for safety information, systematic reviews, clinical trials, and guidelines. As per the hierarchy of evidence, high quality systematic reviews and evidence-based guidelines were searched for first.

The University of Utah Home Infusion Pharmacy was contacted for additional information about the hemophilia program. Utah Medicaid contracts with this specific pharmacy to provide all covered hemophilia affected patients with their factor concentrates.

Long-acting Recombinant Factor VIII Products

Table 1 in Appendix 1 contains information on the products included in this review as the newly approved (FDA) long-acting recombinant factor VIII products: Adynovate, Kovaltry, Eloctate, and Afstyla.

Eloctate, Afstyla, and Kovaltry are “indicated for use in adults and children with hemophila A (congenital Factor VIII deficiency) for: • On-demand treatment and control of bleeding episodes • Perioperative management of bleeding • Routine prophylaxis to reduce the frequency of bleeding episodes”17,22,23

Adynovate is “indicated in adolescent and adult patients (12 years and older) with hemophilia A (congenital Factor VIII deficiency) for: • On-demand treatment and control of bleeding episodes • Routine prophylaxis to reduce the frequency of bleeding episodes” 18

None of these products are indicated for the treatment of von Willebrand disease. Doses vary depending on type of bleeding and ranges from 20-50 units per kg body weight or higher.

Clinical Guidelines National Hemophilia Foundation (NHF)-McMaster Guideline on Care Models for Hemophilia Management (2016)26

• Sponsored by NHF • Guideline panel was composed of U.S. and non-U.S. healthcare providers including physicians, nurses, physical therapists, and a genetic counselor with expertise in hemophilia; experts in health policy, health care financing, research (regarding hemophilia); people with hemophilia (PWH) and parents of PWH; people with other rare diseases; and methodologists.

• Recommendations:  “The Guideline panel suggests that the integrated care model be used over non-integrated care models for PWH (conditional recommendation, moderate certainty in the evidence). For PWH with inhibitors and those at high risk for inhibitor development, the same recommendation was graded as strong, with moderate certainty in the evidence.”26  “The panel suggests that a haematologist, a specialized haemophilia nurse, a physical therapist, a social worker and round-the-clock access to a specialized coagulation laboratory be part of the integrated care team, over an integrated care team that does not include all of these components (conditional recommendation, very low certainty in the evidence).”26 National Hemophilia Foundation (NHF), Medical and Scientific Advisory Council (MASAC) Recommendation #241 Concerning Prophylaxis (February 2016)15

 Prophylaxis is considered optimal therapy for individuals with severe hemophilia A or B  Initiation and target: “Prophylactic therapy should be instituted early (prior to the onset of frequent bleeding), with the aim of keeping the trough FVIII or FIX level above 1% between doses.”  Optimal dosing and frequency: determined individually guided by clinical response and laboratory monitoring  Regular follow-up visits: assess response to medication, joint status, complications, inhibitor development, and frequency/severity of bleeding episodes  Prophylaxis duration: “There are no clear cut guidelines as to when to stop prophylaxis. Joint bleeds with subsequent joint destruction are a lifelong problem for these individuals. Therefore, they may continue to benefit from prophylaxis throughout their life.”  Recombinant factor products are the most appropriate choice (reduced risk of blood-borne infections) per MASAC Recommendation #246. National Hemophilia Foundation, Medical and Scientific Advisory Council (MASAC) Recommendation #246 Concerning Products Licensed for the Treatment of Hemophilia and Other Bleeding Disorders (November 2016)15,30

Please refer to the full MASAC recommendation document for complete information (the summary below only includes information deemed relevant to the focus of this review)

 Background information

Types of cells used in recombinant products: - Baby hamster kidney (BHK) e.g. Kogenate FS/Helixate FS, Kovaltry - Chinese hamster ovary (CHO) e.g. Advate, Adynovate, Afstyla, Novoeight, Recombinate, Xyntha - Human embryonic kidney (HEK) cell lines e.g. Eloctate, Nuwiq Full length vs B-domain deleted - Remaining amino acids of the B-domain: 14 in Xyntha & Eloctate, 16 in Nuwiq, 21 in Novoeight Generation: - First generation: “Contains animal and/or human plasma-derived protein in the cell culture medium and in the final formulation vial” - Second generation: “Contains animal or human plasma-derived proteins in the culture medium but not in the final formulation vial” - Third generation: “Does not contain any animal or human plasma-derived proteins in the culture medium or in the final formulation vial” o Examples of third generation bioengineering to prolong half-life: Fc fusion with human IGg (inhibits lysosomal degradation of rFVIII by endothelial cells) and PEGylation (delays degradation)

 “Recombinant factor VIII products are the recommended treatment of choice for patients with hemophilia A.” o There is a lower risk of viral contamination vs plasma-derived products (pdFVIII) o No seroconversions to HIV, HBV, or HCV have been reported with any of the currently available rFVIII or pdFVIII products, but there remains a slight possibility of virus transmission with the currently marketed pdFVIII products.  Recommendations were not identified regarding selection of one FVIII over another  Mild hemophilia A: Desmopressin (DDAVP nasal spray or injection) is an option for patients >2 years old with a documented rise in FVIII upon a trial dose  Patients with inhibitors to factor concentrates: “Choice of product depends on multiple factors, including type of inhibitor (low- or high-responding), current titer of inhibitor, location of the bleed, and previous response to these products.” -1 o High-titer inhibitor status (≥5 Bethesda Units dL ): use immune tolerance induction for inhibitor eradication (about 70% success rate) o Licensed products: FEIBA (contains factors IIa, VIIa, and Xa) and NovoSeven RT (Recombinant Activated Factor VII Concentrate)  Ancillary medications: - Vitamin K to newborns with hemophilia - Antifibrinolytics: Aminocaproic acid (for mouth bleeds) and Tranexamic acid (for menorrhagia)  Should avoid: aspirin, ibuprofen, or anti-platelet agents (unless recommended by physician in consultation with treating hematologist)  Vaccination for Hepatitis A (all children >1 year) and B (all children) recommended  Recall notifications: “Patients should enroll in the voluntary National Notification System in order to be notified promptly of any recalls of factor products they may be using.”

MASAC Recommendation #243 on SIPPET (Survey of Inhibitors in Plasma-Product-Exposed Toddlers): Results and Recommendations for Treatment Products for Previously Untreated Patients with Hemophilia A (June 2016)15

“Based on currently available evidence, MASAC makes the following recommendations: 1. Individuals with greater than 50 exposure days to any recombinant product (i.e. Previously Treated Patients or PTPs) should consider remaining on their current product, since multiple clinical studies have shown that their risk for inhibitor development with any FVIII product is markedly diminished after 50 EDs. 2. Individuals with more than zero and less than 50 exposure days should consider staying on their current recombinant FVIII product, since the differences between SIPPET and numerous other studies may not warrant switching patients who have already initiated a treatment regimen. 3. Newly diagnosed individuals and their caregivers should consider the new data from the SIPPET study in the context of all the accumulated data on inhibitor formation in PUPs and the pathogen safety risk/benefit of the two product classes and consider the following options: a. Initiate therapy with a pdFVIII/VWF product in all PUPs. b. Initiate therapy with a rFVIII product as previously recommended by MASAC (6). c. Initiate therapy with a newer rFVIII product. 4. Regardless of which option is chosen, all PUPs should be enrolled in the ATHN data collection system or a clinical trial to assess outcomes. 5. For all classes of treatment products, the risk for inhibitor formation in PUPs is unacceptably high.”

MASAC Recommendation #242 Regarding Doses of Clotting Factor Concentrate in the Home (June 2016)15

“For all patients, the treating physician is best able to determine the number of doses required for each patient based upon their diagnosis, co-morbidities, clinical circumstances, product(s) utilized, and historical bleeding patterns.

Therefore, MASAC makes the following recommendations: 1. Patients on home therapy should be able to obtain a prescription refill of their CFC when their home quantity reaches at a minimum an estimated one week’s supply. This allows for treatment of an unexpected bleeding episode or other emergency event while waiting for delivery. The doses remaining at home should not be deducted from the doses to be dispensed for the next delivery.

2. Patients who infrequently infuse also require doses available at home to allow for safe patient care; this will provide for care in an emergency, as local healthcare facilities cannot be relied upon to stock the appropriate replacement products for these patients. 3. Patients treated on-demand should be allowed monthly dispensations of CFC reflective of their bleeding history. 4. Patients treated on prophylaxis require extra doses (minimum one major, two minor) at home to treat breakthrough bleeding episodes. These doses should not be subtracted from the calculated monthly doses designated for prophylaxis and should be replaced as utilized. 5. Patients and family members are encouraged to track expiration dates of CFC on a monthly basis. Doses that are about to expire should be utilized first to prevent waste.

Major Dose is defined as a correction of clotting factor that achieves a level of 60-100+% clotting factor activity that is utilized to treat a bleeding episode that is deemed to require a higher hemostatic level such as occurs when bleeds occur in a target joint, or joint/area with a risk of significant sequelae (e.g. hip, head, potential for compartment syndrome, GI bleeding etc.). Bleeding episodes that are deemed to require a major dose commonly require follow-up infusions and doses to maintain hemostasis and allow healing. Therefore major doses are often followed by follow-up corrections, either major or minor dependent upon the patient circumstances. Minor Dose is defined as a correction of clotting factor that achieves a level of 30-60% clotting factor activity that is utilized to treat a bleeding episode that is deemed early, in a non-critical area and treatable with a lower hemostatic level. Such bleeds include early non- major joints, small muscle bleeds, and skin/soft tissue etc.”

Other Topics Addressed in MASAC Recommendations15

Inhibitor Management and Monitoring MASAC Recommendation #233: “…[Immune Tolerance Induction]… may take up to three years or more to eliminate the inhibitor and restore normal response to infused clotting factor. During this time, however, bleeding episodes can still occur that are not stopped by infusing the missing clotting factor. Thus, these patients need to receive an inhibitor bypassing agent (FEIBA, NovoSevenRT) to treat or prevent bleeding.” MASAC Recommendation #236: “According to recently published U.S. guidelines, immune tolerance induction (ITI) should be started as soon as possible after a high-titer inhibitor is identified, underscoring the imperative for early detection. Inhibitor testing should be done before elective invasive procedures, when the clinical or laboratory response to factor concentrate replacement is suboptimal, before and after switching factor products, and 2 to 3 weeks after intensive treatment (≥5 exposure days [EDs]) or surgery. (4) Additionally, inhibitor testing for patients with severe hemophilia A and B exposed to factor concentrate should be performed at least every third ED or every 3 months (whichever occurs sooner) until 20 EDs have been reached. Thereafter, patients should undergo inhibitor testing every 3 to 6 months until 150 EDs. (4) Because FVIII inhibitors may develop at any age, and since the incidence increases after age 60 years (5), inhibitor testing in hemophilia A should continue once or twice annually throughout a patient’s life.

Emergency Preparedness MASAC Recommendation #227: “All patients with severe and moderately severe inherited bleeding disorders for whom clotting factor concentrates (CFC) are available should have 7 extra doses (special consideration of number of doses for inhibitor patients) of the CFC at home to be available in the event of an emergency. The dose should be based on the factor level to achieve a hemostatic level of 100%, rounded up to the nearest vial size. The dose and frequency should be determined by the patient’s health-care provider.”

Prescription Processing MASAC Recommendation #188: “Pharmacy provider staff shall work with prescribing physicians to ensure that prescription orders are filled within 48 hours. Filling of all prescription orders shall be within plus or minus 5-10 % of prescribed assays, barring extenuating circumstances. If the pharmacy receives a call about an emergency situation, the treating physician shall be notified immediately. Pharmacy provider in consultation with the treating physician shall have plan in place to ensure that, in case of emergent need, patient shall have access to factor concentrate within 12 hours of expressed need, with a goal of 3 hours where logistically possible.”

Preferred Drug Lists MASAC Recommendation #166: “The characteristics of each product and the resultant product choice for an individual patient require a complex decision-making process, with the ultimate product being agreed upon by the patient and his/her healthcare provider. Institution of a PDL would lead to increased costs and predictable deterioration of health in a group of patients whose health and quality of life have improved in the last decade due to the availability of a variety of safe clotting factors which work best when prescribed on an individualized basis.”

Clinical Efficacy

Please refer to Appendix 3 for additional abstract information. Cochrane Systematic Review(s)

The Cochrane Library was searched for Cochrane systematic reviews regarding hemophilia that focused on the FVIII concentrates. Irrelevant reviews that did not focus on this topic were excluded. Also, reviews regarding other therapies e.g. rituximab, antifibrinolytic therapy, bypassing agents (rFVIIa and/or plasma-derived concentrates), gene therapy, immune tolerance induction, desmopressin, acute treatment (surgery), psychological interventions, exercise, physiotherapy, and acquired hemophilia (AH) were excluded. Only one relevant Cochrane systematic review was identified (Iorio, et al, 2011) regarding the effectiveness of clotting factor concentrate prophylaxis in the management of hemophilia A or B. The authors concluded the following: “There is strong evidence from randomised controlled trials and observational trials that prophylaxis preserves joint function in children with hemophilia as compared to on-demand treatment. There is insufficient evidence from randomised controlled trials to confirm the observational evidence that prophylaxis decreases bleeding and related complications in patients with existing joint damage. Well-designed randomised controlled trials and prospective observational controlled studies are needed to establish the best prophylactic regimen and to assess the effectiveness of prophylactic clotting factor concentrates in adult patients.”31

Other Systematic Review(s)

Other systematic reviews regarding hemophilia with focus on FVIII concentrates were searched for within the Database of Abstracts of Reviews of Effects (DARE), a database created by The Centre for Reviews and Dissemination (CRD) and searchable through the Cochrane Library. The CRD analyzed the quality of these systematic reviews and highlights strengths and weaknesses.32 Irrelevant reviews that did not focus on this topic were excluded (e.g. reviews regarding other therapies such as rituximab, antifibrinolytic therapy, bypassing agents, gene therapy, immune tolerance induction, desmopressin acute treatment, psychological interventions, exercise, physiotherapy, and acquired hemophilia). Six relevant reviews were identified:  One regarding the effectiveness of treatments for acute bleeding in patients with hemophilia A with inhibitors (Lloyd Jones, et al. 200333): The CRD stated that the reliability of the conclusions is uncertain due to insufficient methodological information and the poor quality of many included studies.  Two reviews regarding adverse events (Coppola et al. 201234 & Franchini et al. 201235): The authors found that data from prospective studies over the last 20 years does not indicate a big risk for thrombotic adverse events and that the small risk is mainly for superficial thrombophlebitis. Overall, the authors of both reviews concluded that these products had good safety profiles. Allergic reactions were the most common events noticed in the non-thrombotic, non-inhibitor-associated adverse events review. Also, the reviewers found no differences in the rate of adverse events caused by plasma-derived or recombinant products.  Two reviews regarding inhibitors/immunogenicity (Franchini et al. 201236 & Aledort et al. 201137):

One of these reviews was regarding the incidence rate of inhibitors in previously untreated patients (PUPs) with severe hemophilia A whereas the other review was regarding previously treated patients (PTPs). In the first review, the authors found that “Overall, the inhibitor rate did not differ significantly between recipients of plasma-derived and recombinant FVIII concentrates.”36 In the other review, the inhibitor incidence rate was compared between those (PTPs) that received full-length recombinant FVIII and those that received B-domain deleted recombinant FVIII (such as Eloctate). The latter was associated with an increased risk for inhibitors and the authors concluded, “This meta-analysis of prospective clinical studies suggests that recombinant FVIII products may differ in immunogenicity.”37  One review regarding central venous access devices (CVADs) used in hemophilia treatment assessing complication rates and risk factors for poor outcomes when these are employed (Valentino, et al. 200438): CVADs were used for immune tolerance therapy, difficult venous access and prophylaxis. The authors conclude that “CVADs can confer major benefits in patients with haemophilia requiring long-term venous access and serious complications are rare.”38 However, it is important to note some of the results of this review: “Fully implanted CVADs were employed in 77.4% of cases and external CVADs in 22.6%. A total of 1190 infections were reported, and the pooled incidence of infection was 0.66 per 1000 CVAD days [confidence interval (CI), 0.44-0.97 per 1000 CVAD days]. Among patients developing infection, the pooled time to first infection was 295 days (CI, 181-479 days). Presence of inhibitors was an independent risk factor for infection with an incidence rate ratio (IRR) of 1.67 (CI, 1.15-2.43). Infection was less likely in patients >6 years of age (IRR, 0.46; CI, 0.27-0.79) and recipients of fully implanted CVADs (IRR, 0.31; CI, 0.12-0.86). Available information on thrombosis was limited, with only 55 cases being reported. Eventually, 31.3% of CVADs were removed, and infection was the reason for removal in 69.9% of cases and thrombosis in 4.1%. The pooled time period CVADs remained indwelling prior to removal or the expiration of the study observation period was 578 days per CVAD (CI, 456-733 days per CVAD).”38

Additional Safety Evidence

Complications

Inhibitors Neutralizing antibody (inhibitor) formation can occur after administration of factor VIII products. Inhibitors develop in about 20-30% of people with severe hemophilia A, and previously untreated patients are at greatest risk for inhibitor development.7,15,36 If the a patient has a suboptimal or diminished clinical or laboratory response compared to what would be expected following the administered dose, the possibility of an inhibitor should be suspected and investigated promptly.15 Please refer to the table in the Clinical Guideline section to view inhibitor-monitoring recommendations.

This scenario makes treatment more difficult and expensive, because more clotting factor and/or a different type of clotting factor is needed. Also, these patients usually have a reduced quality of life as a result of experiencing deteriorating joint function or other complications of bleeding. “Depending on the severity of the inhibitor, a patient can be given large doses of factor to overcome the inhibitor, given a

bypassing agent such as recombinant factor VIIa or anti-inhibitor coagulant complex, or undergo immune tolerance induction therapy.”1 Appendix 2 contains information regarding inhibitors and the factor VIII products from the product websites.

Cardiovascular Safety According to prescribing information, “Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with Factor VIII.”22

Catheter-related infections Infections are often observed when administering the FVIII products via a central venous access device (CVAD).

Dispensing Errors Errors may arise from sound-alike/look-alike issues: (e.g. confusing FVIII with Factor XIII) or improper labeling.39 It is therefore recommended to review product contents carefully prior to dispensing any antihemophilic factor.

Treatment Management in Utah & Clinical Case Manager Input

All Utah Medicaid patients managed by the University of Utah’s home infusion pharmacy service are treated through an established Hemophilia Treatment Center— more specifically, the Intermountain Hemophilia & Thrombosis Center with locations at the Primary Children’s Hospital and at the Huntsman Cancer Institute. Patients infuse their factor VIII products at home themselves or by a caregiver if the patient is a child or toddler. Each patient is monitored and counseled by nurse case managers as part of the program. Appendix 4 contains a copy of the hemophilia care management duties carried out by the case managers along with a copy of a calendar, on which patients are instructed to notate each dose of factor product administered and each bleeding event experienced. The Utah Hemophilia Foundation also hosts an annual summer camp for children 8-13 years old where they are trained to infuse themselves and are provided the opportunity to interact with their peers.

There are only a few patients that live far away from this pharmacy; their factor concentrates are delivered by a hemophilia case manager or by FedEx. All patients with hemophilia receive monthly visits by home care nurses who send the monthly administration/bleeding log to the hemophilia case manager. If it is necessary to visit an emergency department, hemophilia patients must take their factor infusions with them since it is not a guarantee an acute center will have it stocked. In-patient hospital factor use is managed through the hospital formulary process.

The following table summarizes the input received from Jennifer Green, RN, a nurse care manager with University of Utah’s home infusion pharmacy service, concerning treatment expectations and decision points in regard to long-acting factors.

Expected Outcomes for Patients on Prophylaxis • Decreased number of annual joint bleeds and other bleeding episodes that would require on-demand treatment (on-demand treatment uses higher doses of replacement factor for more consecutive days in a row) • Decreased utilization of emergency services / hospitalization • Increased school and work attendance rates • Decreased joint damage and pain over time • Improved quality of life for patients and caregivers with less restrictions on activity level

Clinical Observations: Short Acting vs. Long Acting Products • Convenience: Less frequent medication schedule for patients can lead to improved compliance and in theory should lead to less bleeds, improved QOL, and decreased overall cost. • Half-life: Pediatric patients may need to infuse long acting products more frequently due to higher factor clearance than adults. A half-life study would aid in appropriate product selection. Even if the patient can’t get down to two days per week dosing, a long acting product may still be helpful if it ultimately reduces the frequency of infusions compared to what would be needed with a short acting agent for an individual patient. • Transition to self-care: Long acting products my assist patients that are transitioning to self-infusions. A drop in compliance and, as a result, an increased rate of bleeding episodes are commonly seen around the ages of 13-20 years old when patients are becoming more independent while trying to rely less on a caregiver. • Quality of Life: A long acting product may reduce the need for placement of central venous catheters, an advantage considering the risk and cost associated with the CVCs (if patients are willing/able to learn peripheral infusion 1-2 times a week in a peripheral vein instead of every other day in a central line). “It has also been shown that starting peripheral infusions at an earlier age and not a numb CVC will lead to transition at a younger age to self-infusion and increased compliance during this same

timeframe. Long acting factor could also decrease the emotional pain and stress that these young patients go through starting at birth or less than 3 years of age. There are emotional dynamics with the parents…inflicting pain to infuse...[their child with]…factor three times a week or every other day that can cause lifelong conflicts.” Selection of a product that allows for dosing less often my help to reduce the infusion burden and emotional hardship these families face.

Clinical Observations: Long Acting vs. Long Acting Products • Vial strengths that are available may make one product preferable over the other while trying to limit the number of vials needed (ideally to one) to provide the dose prescribed. “We have also seen errors by some patient/parents when they are asked to mix more than one vial to get to the prescribed dose. I have seen large under dosing and over dosing when they are not reading the labels to infuse the correct dose. This has always been a safety concern as a care manager; thus it is important to get them the dose as close to that prescribed within a 10% range and in one vial if at all possible.”

Other Comments • Management of long-acting FVIII inhibitor development: “…tolerance therapy is routinely done with the factor the patient was on when they inhibitor developed to try to suppress that autoimmune response to the factor. This would be a costly treatment for 100% daily correction and a bypassing factor on top of the long acting factor.”

Misuse, Abuse, and Inappropriate Use of Factor Replacement Products

Concerns raised by the University of Utah Home infusion pharmacy hemophilia case managers based on their experience with current patients include:  Non-compliance o Overuse: they had a case where a mom was constantly infusing the child o Under-utilization: some patients just use it when they feel like it o Non-compliance with monitoring tools: failure and/or reluctance to routinely fill out administration/bleeding calendar as requested  Careless use o Port safety issues related to flushing: child died because of a clot o Expired products due to inadequate rotation or improper storage

Place in Therapy and Potential Criteria for Review

• Prescribing: Utah Medicaid contracts with the University of Utah’s home infusion pharmacy to supply replacement factor products to all covered patients. Patients are treated through the Intermountain Hemophilia & Thrombosis Center and are managed with the help of nurse case managers. • Treatment setting: Infusions are performed in the home by the patient or caregiver. • Dose and dosing interval: The half-life of a product may vary between individuals as some people, especially children, may clear FVIII faster than others; this ultimately affects the dosage and frequency need to maintain adequate FVIII levels. A pharmacokinetic test/half-life study can be performed and used to guide decisions on the individual’s appropriate dose and dosing interval. Some recommend initial approval for the duration of the half-life study; if the PK-study suggests that the patient my benefit from a prolonged half-life product, then subsequent approvals are permitted for one year (Oklahoma Healthcare Authority).10 Apart from the differences in frequency of administration, note the difference in initial recommended dose between products for prophylaxis in adults: o Eloctate 50 IU/kg (fewer times per week, but high initial recommended IU/kg) o Adynovate 40-50 IU/kg o Afstyla 20-50 IU/kg o Kovaltry 20-40 IU/kg • Implantable venous access device (VAD) or port-a-cath: This is implanted under the skin (usually in the chest but sometimes in the arm). It has a reservoir connected to a catheter, which is then threaded into a vein so that factors (or medications and fluids) can be injected easily when regular infusions are needed as in the case of prophylaxis.2 “However, there are risks. Some studies have shown an infection rate as high as 50%. These infections can usually be treated with intravenous antibiotics but sometimes the device must be removed. There is also a risk of clots forming at the tip of the catheter. Like for any other procedure, each family must weigh the risks and benefits.”2 Professionals among the the University of Utah home infusion service feel that it increases compliance, but infections are a significant concern with the use of central venous catheters (CVCs); so using the peripheral route might be better in some cases, however, it may be hard to find veins in children. They mentioned that the process to train patients is cumbersome, and described a fatal

case involving a clot. It is recommended to monitor the pump frequently when administering as a continuous infusion (for pump failure).2 • Appropriate use and storage: Patients are visited at least monthly at which point the nurse will help ensure product is being used and stored properly. • Duration of treatment: Treatment is usually lifelong; however, complications may require that the patient go to on-demand treatment for a period of time. • Inhibitor formation (neutralizing antibody): This makes treatment more difficult and expensive (because more clotting factor or a different type of clotting factor is needed). Also, “People with inhibitors often experience more joint disease and other problems from bleeding that result in a reduced quality of life.”1 • Concomitant drugs to avoid: People with hemophilia should avoid drugs that can increase bleeding risks. The table below contains examples of oral drugs that can cause bleeding (from the World Federation of Hemophilia).1,40 “This list of drugs that can cause bleeding does not include drugs that have to be given as injections or intravenous infusions.”2 This may not be a complete list and it is recommended that patients check with their hemophilia center or physician before taking any new medication.40

Drugs that can increase bleeding risk Herbal drugs that can increase bleeding risk Aceclofenac Ketorolac Ginkgo biloba Acenocoumarol Lornoxicam Garlic in large amounts Acetylsalicylic acid (Aspirin) Meloxicam Ginger (not dried ginger) Citalopram* Nabumetone Ginseng (Asian) Clopidogrel Naproxen Feverfew Dexibrufen Paroxetine* Saw Palmetto (Serenoa repens) Diclofenac Phenprocoumon Willow bark Dicoumarol Piroxicam Escitalopram Sertraline* Fluoxetine* Sulindac Fluvoxamine* Tenoxicam Ibuprofen Ticlopidine Indomethacin Warfarin Ketoprofen * “These antidepressants have a mild inhibiting effect on the platelet function, which may increase the bleeding tendency. However, since they are less harmful than most other antidepressants in other respects, it is possible to try the medication by starting at a low dose and carefully increase it. Many patients will tolerate these drugs well.”40

• Age: Kovaltry, Eloctate and Afstyla are indicated for use in adults and children whereas Adynovate is only indicated for use in adolescent and adult patients (12 years and older). • Who might need higher doses and more frequent infusions? Those with increased clearance rates, especially children, or those undergoing immune tolerance therapy. • Efficacy: Refer to guideline and efficacy sections • Adverse effects: Refer to safety section • Diversion/abuse/inappropriate use: see previous section. The University of Utah Home Infusion Pharmacy hemophilia case managers proposed ideas for possible parameters for use of longer half- life factor products include: o Start with lowest IU/kg o A pharmacokinetic test/half-life study should be performed to determine whether an individual would really benefit from the product

o Monthly infusion data should be provided (and not quarterly) ensuring compliance on other products first • Monitoring of adherence and response to treatment: o Plasma factor VIII activity prior to and during treatment (to confirm that adequate Factor VIII levels have been achieved and maintained; chromogenic assay or one-stage clotting test).17,18,22,23 o Development of factor VIII inhibitors (Bethesda inhibitor assay if expected levels not attained or if bleeding is not controlled with the expected dose of Factor VIII).

Utah Medicaid Utilization Data

HEMOPHILIA Recombinant FVIII - ALL CLAIMS 2013 2014 2015 2016* ALL

GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS

Advate Injection Antihemophilic Factor rAHF-PFM 21 4 19 4 50 6 50 7 140 13 Adynovate Antihemophilic Factor (Recombinant) Injection Pegylated 0 0 0 0 0 0 0 0 0 0 Antihemophilic Factor (Recombinant) Afstyla Kit Single Chain 0 0 0 0 0 0 0 0 0 0 Eloctate Antihemophilic Factor (Recomb) Fc Injection Fusion Protein (rFVIIIFc) 0 0 2 2 17 2 15 2 34 2 Helixate FS Injection Antihemophilic Factor (Recombinant) 33 4 11 4 16 2 14 1 74 4 Helixate FS Solution Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0

Helixate Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0 Kogenate FS Injection Antihemophilic Factor (Recombinant) 63 9 52 7 68 7 53 6 236 11 Kogenate Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0 Kovaltry Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0 Novoeight Injection Antihemophilic Factor (Recombinant) 0 0 0 0 15 4 38 4 53 4

Nuwiq Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0

Nuwiq Kit Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0 Recombinate Injection Antihemophilic Factor (Recombinant) 8 1 7 1 9 1 10 1 34 1 Antihemophilic Factor (Recombinant) Xyntha Injection Plasma/Albumin Free 0 0 0 0 0 0 0 0 0 0 Xyntha Solofuse Antihemophilic Factor (Recombinant) Kit Plasma/Albumin Free 6 3 4 1 2 1 1 1 13 4

TOTALS 131 19 95 17 177 19 181 21 584 29

HEMOPHILIA Recombinant FVIII - PEDIATRIC CLAIMS 2013 2014 2015 2016* ALL GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS

Advate Injection Antihemophilic Factor rAHF-PFM 21 4 17 3 47 5 49 6 134 10 Adynovate Antihemophilic Factor (Recombinant) Injection Pegylated 0 0 0 0 0 0 0 0 0 0 Antihemophilic Factor (Recombinant) Afstyla Kit Single Chain 0 0 0 0 0 0 0 0 0 0 Eloctate Antihemophilic Factor (Recomb) Fc Injection Fusion Protein (rFVIIIFc) 0 0 1 1 15 1 11 1 27 1 Helixate FS Injection Antihemophilic Factor (Recombinant) 24 3 9 3 16 2 14 1 63 3 Helixate FS Solution Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0

Helixate Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0 Kogenate FS Injection Antihemophilic Factor (Recombinant) 61 8 41 6 51 5 34 3 187 9 Kogenate Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0 Kovaltry Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0 Novoeight Injection Antihemophilic Factor (Recombinant) 0 0 0 0 15 4 38 4 53 4

Nuwiq Injection Antihemophilic Factor (Recombinant) 0 0 0 0 0 0 0 0 0 0

TOTALS 116 16 75 14 155 15 156 15 502 23

Recombinant FVIII: Age & Sex

10 M F 5 Number of of Number patients

0 <13 13-17 18-24 25-34 >34 Age

Long-acting FVIII: Age & Sex

1 M F Number of of Number patients

0 <13 13-17 18-24 25-34 >34 Age

TOTAL Recombinant FVIII - CLAIMS Prescriber type (All) PRESCRIBER TYPE 2013-16

Nurse Practitioner 221 37.84% Physician Physician 363 62.16% Nurse Practitioner 0 50 100 150 200 250 300 350 400 TOTAL CLAIMS 584

NEW LA TOTAL Recombinant FVIII CLAIMS Prescriber type (LA)

PRESCRIBER TYPE 2013-16 Physician Physician 34 100% 0 5 10 15 20 25 30 35 40 TOTAL CLAIMS 34

Recombinant FVIII - TOTAL PRESCRIBER CLAIMS Prescriber specialty (All)

SPECIALTY 2013-16 Pediatrics Family Medicine 65 11.13% Family Medicine Pediatrics 519 88.87% 0 100 200 300 400 500 600 TOTAL CLAIMS 584

NEW LA Recombinant FVIII TOTAL PRESCRIBER CLAIMS Prescriber specialty (LA)

SPECIALTY 2013-16 Family Medicine 7 20.59% Pediatrics Family Medicine Pediatrics 27 79.41% 0 5 10 15 20 25 30 TOTAL CLAIMS 34

Conclusions

Prophylaxis treatment for hemophilia patients helps prevent joint damage, life-threatening complications, and improves overall quality of life of patients. The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommends recombinant factor VIII products as the treatment of choice in patients with severe hemophilia A, however, does not recommend one product over another. Fewer infusions with longer acting blood factors appear to be a way of increasing compliance while possibly improving convenience and quality of life for the patients and their caregivers. The MASAC states “For all patients, the treating physician is best able to determine the number of doses required for each patient based upon their diagnosis, co-morbidities, clinical circumstances, product(s) utilized, and historical bleeding patterns,” while it advocates that patients have quick access to all available products.10,15

According to the hemophilia case managers among Utah’s Hemophilia Treatment Center, inappropriate use of factor concentrates appears to be a problem including non-compliance, underutilization (just using it when they feel like it), overutilization (mom constantly infusing child), and careless use (inappropriate flushing of port and inappropriate storage and rotation of medication leading to expired products). Moreover, an event hosted by the Utah Hemophilia Foundation in May was described to elicit considerable interest from patients who look forward to longer acting products requiring fewer infusions. It is important to ensure that the best treatment is chosen based on individualized factors including a half-life study and compliance assessment, while perhaps establishing utilization parameters that motivate and guide the appropriate use of these products.

Appendix 1 – Drug Information

Table 1. Recombinant FACTOR VIII Concentrates: Newly FDA-approved Products with a Prolonged Half-life)17,18,22,23,41

Please refer to the prescribing information for complete information.

Company/ FDA Orphan Routine Prophylaxis Dosing a Product & Formulations Approval Designation4 Bioengineering Elimination Half Life Date 1

Kovaltry Bayer No Heat shock Adults: 14.2 to 14.3 hours Adults & Adolescents: 20-40 IU/kg 2 - 3 times (Clinical name: BAY 81-8973) protein per week March stabilization Pediatrics: Children ≤12 years: 25-50 IU/kg 2 times per Solution Reconstituted (IV) 2016 and sialylation 12.1 hours (0 to <6 years); week, 3 times per week, or every other day Units (IU): 250, 500, 12 hours (6 to <12 years); Pediatric Use: Due to higher clearance in 1000, 2000, 3000 11.7 to 14.4 hours (12 to 17 children ≤12 years of age, higher or more years) frequent dosing may be needed • With vial adapter to allow for needleless reconstitution

Eloctate Biogen Yes B-Domain Adults: 19.7 hours Patients 6 years and older: 50 IU/kg every 4 days Deleted, IgG-1 (adjust to dosage range of 25-65 IU/kg at 3-5 Solution Reconstituted (IV) June Fc-domain Pediatrics: day intervals based on patient response). Units (IU): 250, 500, 750, 2014 Fusion Protein 12.7 hours (1 to 5 years); Children <6 years old: 50 IU/kg twice weekly (rFVIII-FC) 1000, 1500, 2000, 3000 14.9 hours (6 to 11 years); (adjust to dosage range of 25-65 IU/kg at 3-5 16.4 hours (12 to 17 years) day intervals based on patient response). • With vial adapter to allow for Pediatric Use: Children may require more needleless reconstitution frequent or higher doses up to 80 IU/kg.

Adynovate Baxalta No PEGylation 13.43 to 14.69 hours Patients 12 years and older: 40 to 50 IU/kg twice (PEG-FVIII) weekly; adjust dose based on clinical response Solution Reconstituted (IV) November Units (IU): 250, 500, 750, 1000, 2015 1500, 2000

• With BAXJECT III reconstitution system

Company/ FDA Orphan Routine Prophylaxis Dosing a Product & Formulations Approval Designation4 Bioengineering Elimination Half Life Date 1

Afstyla CSL Behring No Single chain Adults: 14.2 hours Adults (≥12 years): Initial, 20 to 50 IU/kg 2 or 3 stabilization Adolescents: 14.3 hours times weekly; adjust based on patient response Solution Reconstituted (IV) May Pediatric Use (<12 years): Initial, 30 to 50 IU/kg 2 Units (IU): 250, 500, 2016 Pediatrics or 3 times weekly; adjust based on patient

1000, 2000, 3000 10.2 to 10.4 hours (<12 years) response (more frequent or higher doses may Children ≥12 years and be required due to higher clearance) • With Mix2Vial transfer system Adolescents: 14.3 hours

Additional Information: a Dosage and duration of treatment depend on the severity of Factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. • Based on empirical data, administration of 1 IU of FVIII per kg body weight increases the FVIII plasma level by 2 IU/dL. • For acute minor and moderate bleeds, a dose to achieve 20-60% of normal FVIII activity levels is targeted. Major trauma and surgery usually calls for a target >80% of normal. See package inserts for more precise targets with respect to particular bleed-severity classification and recombinant product used. • Prophylaxis regimens are individualized and guided by clinical response in addition to generally targeting FVIII trough levels to be greater than 1% of normal.15 Strict targets, however, have been challenged since individual variability of optimal target levels has been recognized. Optimal targets for plasma FVIII trough, peak, and AUC levels remain an area of debate.42

Table 2. Recombinant FACTOR VIII Concentrates Recombinant VIII Factor Products 17,18,20-23,43-48 Manufacturer Product Marketing statement regarding prolonged Dosing for prophylaxis* Half-life half-life potential (product website)

Baxter/or Advate No specific statement noted on website Every other day (3-4 times per week) Children <12 years: 8.7 to 11.2 hours; Adolescents and Adults: 12 hours Baxalta (Shire Companies) Recombinate No specific statement noted on website No specific information on website or Adults: 14.6 hours product label

Adynovate "...the first and only treatment with an Potential for 2 times per week dosing; 13.43 to 14.69 hours extended circulating half-life built on adjust based on response ADVATE® [Antihemophilic Factor (Recombinant)]."49

Bayer Kogenate FSa No specific statement noted on website 3 times per week or every other day Children: 10.7 hours; Adults: 13.7 to 14.6 hours HealthCare Kovaltry "...the only unmodified, full length 2 to 3 times per week for adolescents Children <12 years: ~12 hours; Children ≥12 years, Adolescents, and Adults: recombinant Factor VIII treatment offering and adults; twice weekly to ~14 hours the potential for as few as 2 infusions per every-other-day dosing in children week"50 Biogen Eloctate "The first Factor VIII with a prolonged half- Potential for every 4 days dosing 19.7 hours life."51 frequency; may need to adjust based Pediatrics: 12.7 hours (1 to 5 years); 14.9 hours (6 to 11 years); 16.4 hours on response to a 3 to 5 day interval (12 to 17 years)

CSL Behring Helixate FSa No specific statement noted on website No specific info rmation ; 3 times per Children: 10.7 hours; Adults: 13.7 to 14.6 hours week (based on Kogenate information)

Afstyla "...the first and only recombinant Factor 2 to 3 times per week Children <12 years: 10.2 to 10.4 hours; Children ≥12 years and Adolescents: VIII that delivers proven, long-lasting bleed 14.3 hours; Adults: 14.2 hours protection with a novel single-chain design." 52 Novo Nordisk Novoeight No specific statement noted on website Adults: 3 times per week; Adolescents: Children <12 years: 7.7 to 10 hours; Adolescents and Adults: 11 to 12 hours every other day

Octapharma Nuwiq No specific statement noted on website Every other day or 3 times per week Children ≤12 years: 11.9 to 13.1 hours; Adolescents and Adults: 17.1 hours

Pfizer Xyntha No specific statement noted on website Frequency of administration (every 8 Children and Adolescents: 6.9 to 8.3 hours; Adults: 11 to 17 hours to 24 hours) is determined by the type of bleeding episode and the recommendation of the treating physician per package insert. * Note: Higher or more frequent dosing may be needed in children a Kogenate and Helixate are both made by Bayer, however, Bayer sells the product to CSL Behring who markets it as Helixate. This relationship will continue through December 2017 per the Kogenateinfo.com website.53

Appendix 2 – Inhibitors

Recombinant VIII Inhibitors Product Inhibitors

Advate Overall, the manufacture cites an incidence rate of inhibitor development to be 0.37%, assessed from compiling data from a number of studies taken place between 2004 to 2012 accounting for 270 patients54 Recombinate Previously treated patients (PTP) study: 69 patients (67 had severe hemophilia A and 2 had moderate hemophilia A; received factor VIII during a 48-month trial) => "no patient developed de novo evidence of a factor VIII inhibitor for the duration of the study (mean number of exposure days: 241±180). One participant with a history of inhibitors exhibited low- titer inhibitor activity at 6 months, which resolved by 9 months." 55 Previously untreated patients (PUP) study: 79 patients (with severe hemophilia A; 76 had received at least 1 infusion of RECOMBINATE) => "22 of the 73 evaluable subjects developed inhibitors to factor VIII. Of these, 13 participants displayed no detectable factor VIII inhibitors at study exit.”55 Adynovate “The safety of ADYNOVATE was evaluated in 2 completed and 3 ongoing clinical studies in 169 previously treated people with severe hemophilia A.”56 No patients developed persistent neutralizing antibodies to the agent however eight subjects who tested negative at intake screening developed transient IgG antibodies against factor VIII (n=5) or PEG-FVIII (n=3) at 1 or 2 consecutive study visits however could not be correlated to reduced efficacy18 Kogenate "Previously Untreated Patients Inhibitor Registry Data FS* Post marketing registries in previously untreated patients taking Kogenate FS have shown inhibitor development rates of 31- 50% which is comparable to previously-reported inhibitor rates for FVIII products. Some of these registries showed a trend towards an increased risk of inhibitor development in PUPs taking Kogenate FS, as compared to another rFVIII product.

In clinical studies of PUPs and MTPs (N=60), 15% of patients (9 of 60) developed inhibitors. In a clinical study of patients (N=64), 12.5% of patients (8 of 64) developed de novo inhibitors in the Joint Outcome Study. 2 patients developed high-titer (>5 BU) inhibitors and were withdrawn from the study."57 Kovaltry LEOPOLD I (Adults and children: 62 previously treated people) – Zero inhibitors after 1 year on Kovaltry. LEOPOLD Kids Part A (51 previously treated children)- Zero inhibitors after 6 months on Kovaltry.58

Eloctate "Eloctate has been evaluated for safety in 233 previously treated patients who received at least one dose in A-LONG (n=164), Kids A-LONG (n=69), and ASPIRE (n=211). 136 subjects were treated for at least 104 weeks. • ZERO INHIBITORS IN THE ADULT, ADOLESCENT, AND PEDIATRIC CLINICAL STUDIES In the adult study one person had a transient, positive neutralizing antibody that was not confirmed upon repeat testing.59 Helixate FS* “In minimally treated and previously untreated patients, the incidence of inhibitor development with Helixate FS was 15% (N=61). Based on studies from around the world it is estimated that the incidence of inhibitor development in patients with severe or moderately severe hemophilia A is between 20-33%. In previously treated patients, the incidence of new inhibitor development was 0% (N=73). In the Joint Outcome Study, which was conducted to demonstrate the effectiveness of routine prophylaxis for prevention of joint damage in children, the incidence of new inhibitor development was 12.5% (N=65). Postmarketing registries in previously untreated patients have shown inhibitor development rates of 30-50%, which is comparable to previously reported inhibitor rates for FVIII products. Some of these registries showed a trend towards and increased risk of inhibitor development in PUPs as compared to another rFVIII product.” 60 Afstyla "Zero inhibitors were observed in the Afstyla clinical trial.”61 (N=258)

Novoeight "Proven safe in one of the largest clinical trials of a recombinant factor VIII to date, zero inhibitors were confirmed in 213 previously treated patients." 45 Nuwiq "In clinical studies with 135 PTPs (74 adults, 3 adolescents, and 58 children), non-neutralizing antibodies without any inhibitor activity were reported in 4 patients (3%)."62

Xyntha " The development of factor VIII inhibitors was evaluated in multiple clinical studies of 144 adult and pediatric previously treated patients with ≥50 exposure days: Across all studies, 2 adult and 1 pediatric PTPs (2.1%) developed FVIII inhibitors. In the surgical study of 30 patients, one low-titer, persistent inhibitor and one transient false positive inhibitor were without significance. Results were not clinically significant and these patients did not require treatment"63

* Kogenate FS/Helixate FS Safety Alert July 2016: “Health Canada carried out a safety review based on recent published studies that suggested an increased risk of developing inhibitory antibodies to Kogenate FS/Helixate FS as compared to similar medicines. Health Canada’s safety review concluded that the recent evidence does not present a new safety concern and the current Kogenate FS/Helixate FS product information already warns of this potential event.”64

Appendix 3 – Systematic Reviews

Cochrane Reviews Author(s) Title Objectives Main Results Author’s Conclusions Iorio, A, et Clotting factor “To determine the “Six studies (including 142 participants) were eligible for inclusion. Two “There is strong evidence from al. (2011)31 concentrates effectiveness of compared three-times-a-week prophylactic administration with on- randomised controlled trials and given to prevent clotting factor demand treatment in children with hemophilia. Pooled results from observational trials that prophylaxis bleeding and concentrate these two studies showed a rate ratio of 0.30 (95% confidence interval; preserves joint function in children with bleeding-related prophylaxis in the 0.12 to 0.76) for all bleedings and 0.22 (95% confidence interval 0.08 to hemophilia as compared to on-demand complications in management of 0.63) for joint bleedings favouring prophylaxis. Results on the number of treatment. There is insufficient people with people with patients with preserved joints after three to seven years of follow-up evidence from randomised controlled hemophilia A or B hemophilia A or B.” were not pooled due to significant heterogeneity. Three of the remaining trials to confirm the observational four studies evaluated hemophilia A; one showed a statistically evidence that prophylaxis decreases significant decrease in frequency of joint bleeds with prophylaxis bleeding and related complications in compared to placebo, with a rate difference of -10.73 (95% confidence patients with existing joint damage. interval -16.55 to -4.91) bleeds per year. Two studies compared two Well-designed randomised controlled prophylaxis regimens, failing to demonstrate an advantage of one trials and prospective observational regimen over the other in terms of bleeding frequency. The fourth study controlled studies are needed to evaluated hemophilia B and showed fewer joint bleeds with weekly (15 establish the best prophylactic regimen IU/kg) versus bi-weekly (7.5 IU/kg) prophylaxis, rate difference -3.30 and to assess the effectiveness of (95% confidence interval -5.50 to -1.10) bleeds per year. Non-significant prophylactic clotting factor increases in both inhibitor and infectious complications were observed in concentrates in adult patients.” patients on prophylaxis, which occurred more often when using long- term venous access.”

Other Reviews in Cochrane Library: Assessed by the Centre for Reviews and Dissemination and meeting the DARE scientific quality criteria for a systematic review32

Author(s) Title Objectives Main Results Author’s Conclusions Coppola A, et al. Thrombotic To determine the “A systematic review of prospective studies (1990-2011) reporting “Data from prospective studies over the (2012)34 adverse events to rate of thrombotic safety data of factor concentrates in patients with haemophilia A last 20 years suggest that the risk of coagulation adverse events (AEs) (HA), haemophilia B (HB) and von Willebrand disease (VWD) was thrombotic AEs from factor concentrate factor after clotting factor conducted to identify the incidence and type of thrombotic AEs. In administration is small and mainly concentrates for concentrate 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients represented by superficial treatment of administration treated with 27 different concentrates (20 plasma-derived, 7 thrombophlebitis. These findings support patients with recombinant), 20 thrombotic AEs (2 HA, 11 (both in VWD patients the high degree of safety of products haemophilia and on prolonged replacement for surgery). The remaining thrombotic

Author(s) Title Objectives Main Results Author’s Conclusions von Willebrand AEs were superficial thrombophlebitis, mostly occurring at infusion currently used for replacement disease: a sites in surgical patients and/or during concentrate continuous treatment.” systematic review infusion. The overall prevalence was 3.6 per 10(3) patients (3.6 per of prospective 10(4) for severe AEs) and 1.13 per 10(5) infusions, with higher studies. figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non-inhibitor-related AEs. Thrombosis-related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use.” HB, 7 VWD) were reported, including two major venous thromboembolic episodes Provisional abstract: No CRD assessment or commentary available Franchini M, et Non-thrombotic-, “The aim of this “On behalf the European Haemophilia Safety Surveillance System “On the whole, these data confirm the al. (2012)35 non-inhibitor- systematic review (EUHASS), a systematic review of the prospective studies published high degree of safety of the products associated was to screen the in the last 20 years was performed using electronic databases and currently used for replacement therapy.” adverse reactions published literature article references. Both severe and mild adverse events following to coagulation data to evaluate the infusion of coagulation factor concentrates are relatively rare in factor types and patients with inherited coagulation disorders; the most common concentrates for frequencies of non- events are of an allergic type. There are no differences in the rate of treatment of thrombotic-, non- adverse events caused by plasma-derived or recombinant patients with inhibitor-associated products.” hemophilia and adverse reactions to von Willebrand's coagulation factor disease: a concentrates in systematic review patients with of prospective hemophilia A, studies. hemophilia B and von Willebrand's disease.” Provisional abstract: No CRD assessment or commentary available Background: “In the last three decades there have been dramatic improvements in the availability and quality of treatment for people with inherited coagulation disorders. Indeed, the improvement of methods of purification and viral inactivation for plasma-derived coagulation factor concentrates first and then the development of products utilizing recombinant DNA technology have greatly improved the life expectancy of hemophiliacs, which has progressively become similar to that of males in the general population. Nowadays, the most frequent complication of factor replacement therapy for hemophilia is the development of inhibitors. However, no studies so far have systematically analysed the type and incidence of other adverse reactions following the administration of coagulation factor concentrates.” Franchini M, et Cumulative To evaluate “the “Data from a total of 800 patients enrolled in 25 prospective “Thus, the main conclusion of this al. (2012)36 inhibitor incidence rate of studies published between 1990 and 2007 were included in this systematic review performed using incidence in inhibitors in review. The quality of the studies was evaluated using two different selective criteria is that the type of FVIII previously previously untreated systems: the Newcastle-Ottawa Scale (NOS) and STrengthening the product (i.e., plasma-derived versus untreated patients (PUPs) with Reporting of OBservational studies in Epidemiology (STROBE). recombinant FVIII concentrates) does not patients with Overall, the inhibitor incidence rate did not differ significantly

Author(s) Title Objectives Main Results Author’s Conclusions severe severe hemophilia between recipients of plasma-derived and recombinant FVIII seem to influence the inhibitor rate in hemophilia A A.” concentrates (weighted means: 21%; 95% CI, 14-30 versus 27%; PUPs with severe hemophilia A.” treated with 95% CI, 21-33). Similarly, high titer inhibitors did not differ plasma‐derived significantly between patients treated with plasma-derived versus (weighted means: 14%; 95% CI, 8-25) or recombinant FVIII recombinant concentrates (weighted means: 16%; 95% CI, 13-20).” factor VIII concentrates: a critical systematic review Provisional abstract: No CRD assessment or commentary available “Inhibitor development represents currently the most serious and challenging complication of clotting factor replacement therapy. A number of studies have analyzed the impact of the type of factor VIII (FVIII) replacement therapy (plasma-derived versus recombinant concentrates) on inhibitor development in hemophilia A patients with conflicting results.” Lloyd Jones M, Control of To evaluate the “Fifty‐two studies were included in the review (n at least 1,333; Authors' conclusions et al. (2003)33 bleeding in effectiveness of some studies reported the number of bleeding episodes but not the “There was no evidence to support the patients with treatments for acute number of patients). This included 8 RCTs (3 of crossover design), use of high‐dose FVIII in bleeding haemophilia A bleeding in patients 27 uncontrolled prospective studies, 10 case series, 2 retrospective episodes, although it was found to be with inhibitors: a with haemophilia A studies, 1 study described as a prospective comparative study, 1 successful for low‐titre, low‐responding systematic review with inhibitors. comparative study, 1 uncontrolled study, 1 prospective pilot and 1 inhibitors in surgery. pFVIII was effective (Structured report of pooled data. The number of participants in the included in controlling severe bleeding with high‐ abstract) studies, where reported, ranged from 2 to 253.” titre or high responding inhibitors, and in 60 to 90% of surgical procedures. aPCCs Centre for Please refer to abstract for information on other interventions appeared more effective than PCCs in the Reviews and (only included results for pFVIII here). control of mild to severe bleeding. rFVIIa Dissemination controlled 70 to 100% of mild to severe Highly purified pFVIII (5 studies). bleeding episodes with high‐responding “Acute bleeding episodes: the highest quality evidence came from 2 inhibitors, and achieved better results uncontrolled prospective studies, one of which reported an when used early. There was no evidence excellent response in the 5 patients studied, and the other that for the use of PCCs in surgery. However, bleeding was stopped in all 11 patients. A third study reported an aPCCs controlled 90% of surgical episodes excellent response in 48% of participants, a good response in 28%, while rFVIIa controlled 60 to 100%.” and a fair to no response in 7%, with 17% unable to be evaluated. A case series reported that 2 patients achieved tolerance to pFVIII “CRD summary while a third was intolerant.” This review evaluated the effectiveness of treatments for acute bleeding in patients Surgical procedures: the highest quality evidence came from one with haemophilia A with inhibitors. The multicentre retrospective survey and one uncontrolled prospective authors concluded that bleeding control study. The retrospective study reported a success rate of 93% in varied from 60 to 100%. The authors surgical patients, while the uncontrolled prospective study reported undertook a systematic search but the good or excellent results in 57% of surgical cases. An uncontrolled lack of detail on review methodology and

Author(s) Title Objectives Main Results Author’s Conclusions prospective study reported successfully controlled bleeding in 3 the poor quality of many included studies patients undergoing dental extraction.” make the reliability of the conclusions uncertain.” “Adverse events. Several studies reported adverse events, including mild pyrogenic reactions/fevers, rashes/hives/urticaria, chills/shivering, dizziness, nausea, headache, lumbar pain, anaphylactic reactions, thrombocytopaenia, anamnesis, abdominal pain and a transient drop in blood‐pressure. These were discussed in more detail in the review.” “Study selection: specific interventions Studies of any treatment for a bleeding episode, with any comparator, were eligible for inclusion. The interventions evaluated in the included studies were: high‐dose human factor VIII (hFVIII) concentrate; highly purified porcine factor VIII (pFVIII); bypassing products such as prothrombin complex concentrates (PCCs), activated PCCs and activated recombinant factor VIIa (rFVIIa); high‐dose FVIII with or without plasmapheresis, cimetidine or immunosuppression; and hFVIII with or without immunosuppression.”

“CRD commentary The authors searched extensively for both published and unpublished data, with no language or date restrictions, thus reducing the risk of language and publication bias. The inclusion criteria were broad. The authors did not state how the studies were selected, and a single reviewer extracted data from the included studies without it being checked by a second reviewer; there was therefore the potential for error and bias to be introduced into the review. The decision to combine the studies in a narrative synthesis was appropriate. The search was systematic but the lack of details on the methods used during the review process, and the poor quality of many of the included studies, should be kept in mind when considering the conclusions of the review and implications for practice.”

“Implications of the review for practice and research Practice: The authors made several recommendation. In particular, the daily dose of FEIBA should not exceed 200 U/kg, owing to the risk of thrombosis; PCCs and aPCCs are not recommended as first‐line treatment in life‐threatening haemorrhages unless the patient's inhibitor titre is too high to permit successful treatment with high‐dose FVII; PCCs and aPCCs can be used when the bleeding is not life‐threatening; rFVIIa appears preferable as the first line of treatment in patients with high‐responding inhibitors; plasmapheresis, with or without immunoadsorption, followed by high‐dose FVIII can be used as a last resort in patients with high‐titre inhibitors in whom other approaches have failed; and aPCCs and antifibrinolytic agents should be used consecutively rather than simultaneously during dental surgery. Research: The authors suggested that further research to evaluate the use of rFVIIa would be useful.”

Valentino L. A., Central venous To determine “Forty-eight studies with a total of 2704 patients and 2973 CVADs “CVADs can confer major benefits in et al. (2004)38 access devices in complication rates were included. The primary indications for CVADs were immune patients with haemophilia requiring long- haemophilia and risk factors for tolerance therapy (34.9% of patients), difficult venous access term venous access, and serious (Provisional poor outcome when (31.8%) and prophylaxis (29.1%). Fully implanted CVADs were complications are rare.” abstract) CVADs are used. employed in 77.4% of cases and external CVADs in 22.6%. A total of 1190 infections were reported, and the pooled incidence of infection was 0.66 per 1000 CVAD days [confidence interval (CI), 0.44-0.97 per 1000 CVAD days]. Among patients developing

Author(s) Title Objectives Main Results Author’s Conclusions infection, the pooled time to first infection was 295 days (CI, 181- 479 days). Presence of inhibitors was an independent risk factor for infection with an incidence rate ratio (IRR) of 1.67 (CI, 1.15-2.43). Infection was less likely in patients >6 years of age (IRR, 0.46; CI, 0.27-0.79) and recipients of fully implanted CVADs (IRR, 0.31; CI, 0.12-0.86). Available information on thrombosis was limited, with only 55 cases being reported. Eventually, 31.3% of CVADs were removed, and infection was the reason for removal in 69.9% of cases and thrombosis in 4.1%. The pooled time period CVADs remained indwelling prior to removal or the expiration of the study observation period was 578 days per CVAD (CI, 456-733 days per CVAD).” Provisional abstract: No CRD assessment or commentary available “Central venous access devices (CVADs) can facilitate repeated and/or urgent administration of coagulation factors in haemophilic patients.” Aledort LM, et Can B-domain “A meta-analysis of “Twenty-nine studies with 3012 total PTPs were included. Patients “This meta-analysis of prospective clinical al. (2011)37 deletion alter the prospective clinical were at risk of de novo inhibitor development for a median of 79 studies suggests that recombinant FVIII immunogenicity studies was exposure days. A total of 35 de novo inhibitors were observed. The products may differ in immunogenicity.” of recombinant conducted to test cumulative hazard for all de novo inhibitors was 1.25% with a 95% factor VIII? A the hypothesis that confidence interval (CI) of 0.63-1.88%. The corresponding rate for meta-analysis of de novo inhibitor high-titer de novo inhibitors [> 5 Bethesda units (BU)] was 0.29% prospective incidence differs (CI, 0.01-0.57%). Exposure to BDD-rFVIII was associated with an clinical studies. between PTPs increased risk of all de novo inhibitors (hazard ratio, 7.26; CI, 2.12- receiving full-length 24.9; P = 0.0016) and of high-titer de novo inhibitors (hazard ratio, recombinant FVIII 10.8; CI, 2.17-53.7; P = 0.0037), compared with FL-rFVIII.” (FL-rFVIII) and B- domain deleted recombinant FVIII (BDD-rFVIII).” Provisional abstract: No CRD assessment or commentary available “BACKGROUND: As a result of the infrequency of inhibitors in previously treated patients (PTPs) with hemophilia A and the small size of available clinical studies, the immunogenicity of factor (F)VIII products has been difficult to assess. METHODS: Prospective studies with data on inhibitors in PTPs receiving FL-rFVIII or BDD-rFVIII were sought using systematic methods including bibliographic database searches. Data were secured from published study reports and inquiries to investigators. Between-group differences in inhibitor incidence rates were evaluated using mixed effects Cox regression.”

Appendix 4 – University of Utah Home Infusion Case Management

UNIVERSITY HOME INFUSION SERVICES Name: ______Bleed/ Infusion Calendar: Month & Year ______Weight:______

______

P= Prophylaxis RE= Right Elbow LE=Left Missed School Days for Month ______

Infusions Elbow RK= Right Knee Missed Work Days for Month ______B= Bleed LK= Left Knee F= Follow-up Infusion RA=Right Ankle LA= Left Emergency Room Visits: Ankle Surgery/ Procedures :

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