Drug Utilization Review: Palivizumab (Synagis ; Medimmune)

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1 Background Respiratory syncitial virus (RSV) is a highly contagious virus that is estimated to infect nearly all children by 3 years of age, and is the leading cause of serious lower respiratory tract infections in children. 1, 2 Despite the high prevalence of infection, only 1% of those infected will require a hospitalization, and mortality among those hospitalized is less than 1%. 1, 2 The peak incidence of infection occurs in children under 1 year age. 2 Approximately 50%-90% of cases of bronchiolitis, 5%-40% of cases pneumonia, and 10%-30% of cases of tracheobronchitits among hospitalized children are attributed to RSV. 1 While the short term case-fatality rate is low, a history of RSVrelated hospitalization has been associated with future respiratory problems up to 10 years after initial infection, however, the exact causal relationship between infection and long-term morbidity has not been fully established. 2 Transmission and infection with RSV occurs with a predictable pattern, and most cases in the United States are observed between the months of November to May. Most cases of RSV infection in children and adults are mild and self-limiting with symptoms such as cough, rhinorrhea, conjunctivitis, and otitis media. However, several factors have been shown to be associated with an increased risk for severe RSV disease requiring hospitalization. These factors included: premature birth (<35 weeks gestational age (GA)), weight < 5 kg, chronic lung disease (CLD), presence of hemodynamically significant congenital heart disease (CHD), presence of immunodeficiency disorders, young chronological age (<6 months), low socioeconomic status, ethnicity, and male gender. 3 Factors that increase the risk for acquiring a RSV infection include maternal education grade 12 or less, crowding, school age siblings, multiple births, lack of breast feeding, day care attendance, and passive cigarette smoke exposure. 3 Despite the high prevalence of infection and predicable onset of the RSV season, an effective vaccine has not been developed. Two agents are currently available that offer passive immunologic protection against RSV infection: human-derived polyclonal immune globulin with high titers for RSV (RSV-IGIV; RespiGam ) and humanized monoclonal antibody (palivizumab; Synagis ). RSV-IGIV has been shown in controlled clinical trials to be safe and effective at reducing the risk of RSV hospitalization. 4 However, the use of RSV-IGIV has fallen out of favor because of several practical reasons relating to its formulation and administration. First, because it is a blood-derived product, concerns over the transmission of blood-borne pathogens have been raised. Second, RSV- IGIV must be administered by intravenous infusion, which is time consuming, costly, and potentially hazardous. Finally, RSV-IGIV interferes with the natural host response to live viral vaccines that are recommended for children during this time. Palivizumab is a generically engineered immune globulin that can be administered with an intramuscular (IM) injection, has no potential for infectious contamination, and does not interfere with vaccines. 5 Both RSV-IGIV and palivizumab have no value for the treatment of active RSV infection. Palivizumab is a genetically engineered, humanized, monoclonal antibody directed at RSV-specific surface proteins. The IMpact study, the only placebo-controlled, randomized trial of palivizumab, evaluated the safety and efficacy of monthly palivizumab as prophylaxis against serious RSV infection in 1502 high risk infants. 6 Premature infants 6 months of age or younger and children 2 years of age or younger with a history of CLD requiring medical treatment (i.e. supplemental oxygen, steroids, bronchodilators, or diuretics) within the previous 6 months were eligible for enrollment. Children with significant CHD were excluded. Every month for 5 months, a 15 mg/kg IM injection of palivizumab or placebo was given to enrolled infants who were then followed for 30 days following their last scheduled injection. Patients were enrolled starting 11/15/96 through 12/13/96. The primary objective was to determine the impact of prophylaxis on the rate of 5

2 hospitalizations for RSV infection. The incidence of RSV illness in infants receiving palivizumab was 4.8% compared to 10.6% in infants receiving placebo (relative risk reduction 55%; 95% CI 38% - 72%; p=0.0004). As shown in table 1, palivizumab was also associated with a statistically significant reduction in the primary outcome for all subgroups. Infants receiving palivizumab also had a significant reduction in the incidence of all-cause hospitalizations (31% vs 24%, p=0.01). There were no differences between groups in the rate of death (5 in placebo arm and 4 in palivizumab arm), however, the study was not powered to evaluate mortality. The overall rate of adverse events was similar in both groups. Table 1: IMpact Study Results RSV-Related Hospitalization Group (n) Placebo n (%) Palivizumab n (%) All Infants N= /500 (10.6) 48/1002 (4.8) Premature 19/234 9/506 (n=740) (8.1) (1.8) BPD 34/266 39/496 (n=762) (12.8) (7.9) Weight > 5 kg* (10.7) (5.2) Weight < 5 kg* (10.5) (4.5) <32 wks GA* (11.0) (5.8) wks GA* (9.8) (2.0) *Actual counts not published p-value Relative Risk Reduction (RRR) (95% CI) % (38% - 72%) < % (66% - 90%) % (20% - 58%) % % % < % Number Needed to Treat (NNT) Cost/RSV- Hosp Avoided 17 $96, $90, $112, $101, $96, $107, $73,424 Children with CHD were specifically excluded from the IMpact trial because of results from a study of RSV-IGIV in children with CHD suggesting a higher rate of cyanotic episodes in patients receiving RSV-IGIV. 7 As such, palivizumab was not studied, and is not yet FDA indicated for prophylaxis in children with CHD. However, it is believed the unanticipated adverse events observed with RSV-IGIV were due primarily to the large fluid volume needed for IV administration and not from the active drug. A large, multi-center clinical trial is currently underway to assess the safety and efficacy of palivizumab in children with hemodynamically significant CHD, however, results have yet to be published in the peer-reviewed literature. 2 Despite this, the American Academy of Pediatrics (AAP) has recently modified their recommendations for palivizumab use to include children 24 months of age or younger with hemodynamically significant CHD. 5, 8 The evidence supporting the effectiveness and safety of palivizumab is compelling. The major concern about the use of this drug involves its high acquisition cost and evaluating which groups will benefit from prophylaxis. The AWP for a 100 mg vial is $1312. Given current OMAP retail pharmacy reimbursement rates, the cost for prophylaxis of a 5 kg infant (dose 15 mg/kg = 75 mg or mg vial) from November through April would be $5648. The data from the IMpact trial indicate that 17 children would need to be treated in order to prevent one RSV-related hospitalization. Given the cost of prophylaxis, it is estimated that $96,016 would need to be spent in order to prevent one RSV-related hospitalization. This figure is likely conservative as it only 6

3 considers drug costs, excluding costs incurred for administration etc, and reflects efficacy under optimal controlled trial conditions (e.g. near perfect adherence, follow-up, and monitoring). It is also interesting to note that when the major controlled trials of both RSV antibody preparations (RSV-IGIV and palivizumab) are compared the cumulative incidence rates of RSV hospitalizations in the placebo arms have been decreasing from 20% in the 1993 to 13.5% in 1997 to 10.3% from 4, 6, 9 the IMpact trial in This trend represents over a 50% relative risk reduction in incidence and may reflect random sampling error, changes in management strategies through time, or perhaps more aggressive education to parents regarding RSV infection avoidance, which likely represents the most cost-effective prevention strategy. 10 7

4 Palivizumab Use Guidelines The AAP has published guidelines for the use of palivizumab based on the results of the IMpact study. 5 In general, the guidelines follow the inclusion and exclusion criteria used in the IMpact study. The guidelines were recently revised in June of Palivizumab should be reserved for prophylaxis during the RSV season. The CDC reports that epidemic levels of RSV in the western United States have been observed from October through May. 11 However, the RSV season varies regionally and year to year. Epidemiologic data from local health departments should dictate when the season has begun. 2. The AAP recommends palivizumab prophylaxis for the following groups: A. Children </= 24 months of age with CLD requiring medical therapy within 6 months of anticipated RSV season. Medical therapy for CLD is defined as the use of supplemental oxygen, bronchodilator, and diuretic or corticosteroids. B. Children </= 24 months of age and hemodynamically significant cyanotic and acyanotic CHD B. Children </= 12 months of age born at </= 28 weeks gestation C. Children </= 6 months of age born at weeks gestation D. Children </= 6 months of age born at weeks gestation with an additional 2 risk factor (see below) Risk Factors for RSV infection outlined by AAP: Severe neuromuscular disease Congenital abnormalities of the airways Presence of young siblings Child care center attendance Exposure to tobacco in home 8

5 Palivizumab Utlization Analysis The goals of this utilization analysis were to characterize the use and characteristics of patients (age, sex, etc.) using palivuzumab in the Oregon Fee-For-Service Medicaid program during the RSV season. Palivizumab is reimbursed by the state through both medical (CPT codes and C mg vial) and retail pharmacy claims. Pharmacy and medical claims from 6/1/01 through 5/31/02 were integrated and evaluated to eliminate any claims that likely would be administered for or RSV season. Risk factors for severe RSV-related disease were identified through ICD-9 code documentation in the medical claims prior to the patient s initial dose. A history of CLD was defined as the ICD-9 code (770.7) for chronic respiratory disease arising in the perinatal period (bronchopulmonary dysplasia). Premature birth was identified by the diagnosis code for disorders relating to short gestation and unspecified low birthweight (765.X). During the RSV season, 533 claims for palivizumab were processed for 129 patients. The average cost per claim and total cost spent during this period was $1,198 and $638,327, respectively. Only one claim was submitted outside the dates of 10/1/01 through 5/31/02 (not shown) and 37 (7%) were filed outside the period of 11/1/01 through 4/31/02. Approximately 57% of all claims were submitted through the retail pharmacy setting. Table 2: Palivizumab Claims Description Total Claim Count 533 Total Claim Cost $638, Average Claim Cost $1, Number < 11/1/01 6 (1.1%) Number >4/31/02 31 (5.9%) Number as Pharmacy Claim 303 (56.8 %) Average Claim Cost (pharmacy) $1, Average Amount Dispensed (pharmacy) mg Number as Medical Claim 230 (43.2 %) The average age of patients at the time of their initial fill was 7.5 months (range months). More than 60% of patients were less than 6 months of age upon their initial dose. Only 3% of patients were 24 months or older upon their first fill. The number of males and females was roughly equivalent. A majority of patients receiving palivizumab had a history of premature birth (83.7%). There were 69 (53.5%) patients identified who had both a history of prematurity and were less than or equal to 6 months of age, which was entry criteria for the IMpact trial. At total of 95 (73.6%) patients had a history of prematurity and were 12 months or younger. Only 12 (10.8%) patients were identified with a history of CLD, and of those 10 (7.8 %) patients were also 24 months or younger. All together, 97 patients (75.2%) were identified as either having CLD and being 24 months or younger or having a history of prematurity and being 12 months or younger. Using the more stringent criteria, only 75 (58.1%) patients either had CLD and were 24 months or younger or had a history of prematurity and were 6 months or younger. The average duration of therapy was 3.6 months (range 1-7 months). 9

6 Table 3: Patient Characteristics N=129 % of total Average age* (range) 7.5 ( ) months > 24 months % > 12 and <24 months % > 6 and < 12 months % < 6 months % Males % Hx CLD** % and </=24 months age % Hx short gestation*** % and </= 6 months % and </= 12 months % and > 12 months 13 Hx CLD and </= 24 or Hx short % gestation and </= 6 months Hx CLD and </= 24 or Hx short % gestation and </= 12 months Average duration (range) 3.6 (1-7) months *age calculated at initial fill date **Hx CLD= ICD (chronic respiratory disease arising in the perinatal period) prior to initial dose ***Hx short gestation = ICD 765.X (disorders relating to short gestation) prior to initial dose Based on the use patterns observed, it appears as if a large proportion of patients receiving palivizumab belong to a defined group that has been shown to benefit in clinical trials or has received a recommendation for immunoprophylaxis by the AAP. There were very few claims that were processed during the time period in which RSV is not at epidemic levels. While it was possible to identify patients with a history of prematurity or BPD by virtue of an ICD-9 code, this method is not 100% accurate and may under or over-estimate the actual prevalence in the population. In addition, it was not possible to identify the severity of CLD or the degree of prematurity using the ICD-9 system. 10

7 References 1. Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med 2001;344: Krilov LR. Palivizumab in the prevention of respiratory syncytial virus disease. Expert Opin Biol Ther 2002;2: Meissner HCM, Welliver RCM, Chartrand SAM et al. Immunoprophylaxis with palivizumab, a humanized respiratory syncytial virus monoclonal antibody, for prevention of respiratory syncytial virus infection in high risk infants: a consensus opinion. [Miscellaneous Article]. 4. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. The PREVENT Study Group. Pediatrics 1997;99: Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. American Academy of Pediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Pediatrics 1998;102: Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics 1998;102: Simoes EA, Sondheimer HM, Top FH, Jr. et al. Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. The Cardiac Study Group. J Pediatr 1998;133: Respiratory Syncytial Virus [Section 3. Summaries of Infectious Diseases]. American Academy of Pediatrics - Committee on Infectious Disease. Red Book; Groothuis JR, Simoes EA, Levin MJ et al. Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The Respiratory Syncytial Virus Immune Globulin Study Group.[comment]. New England Journal of Medicine. 1993;329: Storch GA. Humanized monoclonal antibody for prevention of respiratory syncytial virus infection. Pediatrics 1998;102: Centers for Disease Control and Prevention. [Respiratory Syncytial Virus Activity - United States, Season]: MMWR; 2002:51:[26-28]. 11