POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY

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1 Original Issue Date (Created): April 24, 2012 Most Recent Review Date (Revised): May 20, 2014 Effective Date: August 1, 2014 POLICY PRODUCT VARIATIONS DESCRIPTION/BACKGROUND RATIONALE DEFINITIONS BENEFIT VARIATIONS DISCLAIMER CODING INFORMATION REFERENCES POLICY HISTORY I. POLICY NOTE: Alpha Proteinase Inhibitors (Human) (Aralast, Aralast NP, Glassia, Prolastin-C, Zemaira) require preauthorization. NOTE: The safety and effectiveness of alpha1-preteinase inhibitor (human) in the pediatric population has not been established.. FDA-Approved Indications The following is a list of the FDA approved indications for Alpha Proteinase Inhibitors (Human) Aralast, Aralast NP, Glassia, Prolastin-C, and Zemaira: Aralast and Aralast NP Alpha1-Proteinase Inhibitor (Human) Aralast and Aralast NP are indicated for chronic augmentation therapy in patients having congenital deficiency of (alpha) 1-P1 with clinically evident emphysema. Glassia Glassia is indicated for chronic augmentation and maintenance therapy in adults with emphysema due to congenital deficiency of alpha-proteinase inhibitor (Alpha-P1) also known as alpha-antitrypsin deficiency. Prolastin-C Prolastin-C is indicated for chronic augmentation and maintenance therapy in adults with emphysema due to deficiency of alpha1-proteinase inhibitor (alpha antitrypsin deficiency). Page 1

2 Zemaira Zemaira is indicated for chronic augmentation and maintenance therapy in individuals with alpha1-proteinase inhibitor (A1-P1) deficiency and clinical evidence of emphysema. Initial therapy Intravenous alpha 1 proteinase inhibitor (Human) (Aralast, Aralast NP, Glassia, Prolastin-C, Zemaira) may be considered medically necessary for chronic augmentation and maintenance therapy in adults with emphysema due to congenital alpha1-proteinase inhibitor deficiency when all of the following are met: The individual is 18 years of age or older The patient has a congenital deficiency of alpha-1 antitrypsin, demonstrated by a homozygous phenotype Must have clinically documented alpha-1 antitrypsin (AAT) deficiency o Serum concentration of alpha 1-antitrypsin (AAT) less than 11 um/l (corresponds to 50 mg/dl (nephelometry) or 80 mg/dl (radial immunodiffusion) Non-smoker o If patient is a current smoker, expectation is that the patient will stop smoking and the patient must be actively receiving a smoking cessation treatment. Maintenance therapy All of the following criteria must be met for continuation of therapy: Clinical evidence of efficacy: o reduction in rate of deterioration of lung function as measured by a decreased forced expiratory volume in 1 second (FEV1) rate of decline Non-smoker Alpha1-Proteinase Inhibitors (Human) (Aralast, Aralast NP, Glassia, Prolastin-C, Zemaira) are considered investigational when administered for indications other than those listed above as there is evidence to support a conclusion concerning the health outcomes or benefits associated with their use. Cross-reference MP Genetic Testing for Alpha-1Antitrypsin Deficiency Page 2

3 II. PRODUCT VARIATIONS TOP [N] = No product variation, policy applies as stated [Y] = Standard product coverage varies from application of this policy, see below [N] Capital Cares 4 Kids [N] PPO [N] HMO [N] SeniorBlue HMO [N] SeniorBlue PPO [N] Indemnity [N] SpecialCare [N] POS [Y] FEP PPO* * The FEP program dictates that all drugs, devices or biological products approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDA-approved drugs, devices or biological products may be assessed on the basis of medical necessity III. DESCRIPTION/BACKGROUND TOP Alpha1-proteinase inhibitor (A1-PI) deficiency is a chronic, hereditary, autosomal, co46 dominant disorder that is usually fatal in its severe form. Low blood levels of A1-PI are most commonly associated with progressive, severe emphysema that becomes clinically apparent by the third to fourth decade of life. The most direct approach to therapy for A1-PI deficiency in patients with emphysema has been to partially replace the missing protease inhibitor by intravenous infusion and, thus, attempt to ameliorate the imbalance in the anti-neutrophil elastase rotection of the lower respiratory tract. However, the effect of augmentation therapy with Alpha1-proteinase inhibitor (A1-PI) on pulmonary exacerbations and the progression of emphysema in alpha-1 antitrypsin deficiency has not been demonstrated in long-term controlled trials. Alpha 1 proteinase inhibitor (human) (Aralast, Aralast NP, Glassia, Prolastin, Zemaira (Alpha-1 Proteinase Inhibitors) may be used to treat symptomatic adults with emphysema who have low serum levels of alpha-1 antitrypsin (AAT).These drugs are administered intravenously every week at a dose of 60mg/kg of body weight. Safety and effectiveness in the pediatric population has not been established. The GOLD Emphysema Staging System One major emphysema staging system is called GOLD. GOLD is short for the Global Initiative for Chronic Obstructive Lung Disease It was created by an expert group called the Global Page 3

4 Initiative for Chronic Obstructive Lung Disease, a collaboration between the National Institutes of Health and the World Health Organization. The major factor in GOLD emphysema staging is the amount of air a person with emphysema can forcefully exhale in one second. This is called the forced expiratory volume, or FEV1. GOLD emphysema staging is as follows: Stage I, Mild emphysema: FEV1 greater than or equal to 80% of normal Stage II, Moderate emphysema: FEV1 less than 80%, but greater than or equal to 50% of normal Stage III, Severe emphysema: FEV1 less than 50%, but greater than or equal to 30% of normal Stage IV, Very severe emphysema: FEV1 less than 30% of normal, OR less than 50% of normal with low blood oxygen levels GOLD emphysema staging is well established and widely used. However, GOLD emphysema staging does not include other areas of functioning that are important, such as how people living with emphysema feel. The GOLD Chronic Obstructive Pulmonary Disease Staging System The GOLD classifications are the main method doctors also use to describe the severity of chronic obstructive pulmonary disease (COPD). In GOLD COPD, classifications are then used to describe the severity of the obstruction or airflow limitation. The worse a person's airflow limitation is, the lower their FEV1. As COPD progresses, FEV1 tends to decline. GOLD COPD staging uses four categories of severity for COPD, based on the value of FEV1: Stage I Mild COPD FEV1/FVC<0.70 FEV1 80% normal Stage II Moderate COPD FEV1/FVC<0.70 FEV % normal Stage III Severe COPD FEV1/FVC<0.70 FEV % normal Stage IV Very Severe COPD FEV1/FVC<0.70 FEV1 <30% normal, or <50% normal with chronic respiratory failure present* * Usually, this means requiring long-term oxygen therapy IV. RATIONALE TOP Aralast and Aralast NP The pharmacokinetics of ARALAST NP were compared with ARALAST in a multicenter, single-dose, randomized, double-blind, crossover clinical study (Study ). Twenty-five Page 4

5 subjects with congenital 1-PI deficiency received a single intravenous (IV) infusion of 60 mg/kg ARALAST NP or ARALAST. The 25 subjects in this study were between 20 and 75 years old, with a median age of 59. Plasma 1-PI concentrations were measured using an enzyme linked immunosorbent assay (ELISA). Figure 1 shows that the mean ± standard deviation (SD) plasma 1-PI concentration-time profiles after a single IV infusion of ARALAST NP and ARALAST at 60 mg/kg were comparable. Table 2 summarizes the pharmacokinetic parameters of ARALAST NP and ARALAST. The 90% confidence intervals for Cmax and AUC0-inf/dose were well within the pre-defined acceptance limits of 80 to 125%. A clinical study (ATC 97-01) was conducted to compare ARALAST to a commercially available preparation of 1-PI (Prolastin, manufactured by Bayer Corporation). All subjects were to have Page 5

6 1-PI deficiency and emphysema but no 1-PI augmentation therapy within the preceding six months. Twenty-eight subjects were randomized to receive either ARALAST or Prolastin, 60 mg/kg intravenously per week, for 10 consecutive weeks. Two subjects withdrew from the study prematurely: 1 subject receiving ARALAST withdrew consent after 6 infusions; 1 subject receiving Prolastin withdrew after 1 infusion due to pneumonia following unscheduled bronchoscopy to remove a foreign body. Trough levels of 1-PI (antigenic determination) and anti-ne capacity (functional determination) were measured prior to treatment at Weeks 8 through 11. Following their first 10 weekly infusions, the subjects who were receiving Prolastin were switched to ARALAST while those who already were receiving ARALAST continued to receive it. Maintenance of mean serum 1-PI trough levels was assessed prior to treatments at Weeks 12 through 24. Bronchoalveolar lavages (BALs) were performed on subjects at baseline and prior to treatment at Week 7. The epithelial lining fluid (ELF) from each BAL meeting acceptance criteria was analyzed for the 1-PI level and anti-ne capacity. With weekly augmentation therapy with ARALAST or Prolastin, a gradual increase in peak and trough serum 1-PI levels was noted, with stabilization after several weeks. The metabolic half-life of ARALAST was 5.9 days. Serum anti-ne capacity trough levels rose substantially in all subjects by Week 2, and by Week 3, serum anti-ne capacity trough levels exceeded 11 μm in the majority of subjects. With few exceptions, levels remained above this recommended threshold level in individual subjects for the duration of the period Weeks 3 through 24 on study. Although only five of fourteen subjects (35.7%) receiving ARALAST had BALs meeting acceptance criteria for analysis at both baseline and Week 7, a statistically significant increase in the antigenic level of 1- PI in the ELF was observed. No statistically significant increase in the anti-ne capacity in the ELF was detected. Viral serology of all subjects was determined periodically throughout the study, including testing for antibodies to hepatitis A (HAV) and C (HCV), presence of circulating HBsAg, and presence of antibodies to HIV-1, HIV-2, and Parvovirus B-19. Subjects who were seronegative to parvovirus B-19 at enrollment were retested by PCR at Week 2. There were no seroconversions in subjects treated with ARALAST through Week 24. None of the subjects became HBsAg positive during the study, although five of 13 (38%) evaluable subjects treated with ARALAST and eight of 13 (62%) treated with Prolastin had not been vaccinated to hepatitis B. No patient developed antibodies against 1-PI. It was concluded that at a dose of 60 mg/kg administered intravenously once weekly, ARALAST and Prolastin had similar effects in maintaining target serum 1-PI trough levels and increasing antigenic levels of 1-PI in epithelial lining fluid (ELF) with maintenance augmentation therapy. Page 6

7 Glassia Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 65 subjects have received treatment with intravenous GLASSIA in two clinical studies, both performed in the US. Three subjects participated in both studies. However, because of the large temporal difference between studies (> 5 years) and major difference in study designs, each study was analyzed separately without excluding these three subjects who participated in both trials from either study analysis. Thus, safety and efficacy of GLASSIA are reported on all 18 subjects in a Phase I study and all 50 subjects who received GLASSIA in a Phase II/III study, for a total of 68 subjects, representing 65 unique subjects. In an open label, Phase I non-parallel, dose-escalation study, 18 subjects received a single infusion of GLASSIA at dosages of 30, 60 or 120 mg/kg. In a randomized, Phase II/III double-blind, active-control study, 50 subjects were scheduled to receive weekly infusions of GLASSIA or the comparator Alpha1-PI product, Prolastin, at a dosage of 60 mg/kg for a total of 12 doses after which all subjects remaining in the study were treated for another 12 weeks with GLASSIA only. Overall, 17 subjects received 12 doses and 21 subjects received 24 doses of GLASSIA during the study. Eleven subjects received either 22 or 23 doses and one subject did not receive any treatment with GLASSIA during the last 12 weeks of the study. The population treated with GLASSIA in these two studies was years old, 54% male, 100% Caucasian and had congenital Alpha1-PI deficiency with clinical evidence of emphysema. Table 1 compares the adverse reactions reported during the initial 12 weeks (double-blind portion) of the Phase II/III study occurring in all subjects treated with GLASSIA with reactions in the concurrent Prolastin control group. Page 7

8 During the 12-week double blind portion of the Phase II/III trial, 4 subjects (12%) had a total of 7 exacerbations of chronic obstructive pulmonary disease (COPD) during GLASSIA treatment and 5 subjects (29%) had a total of 6 exacerbations of COPD during Prolastin treatment. Seventeen additional exacerbations in 14 subjects (28%) occurred during the 12-week open-label treatment period with GLASSIA. The overall rate of pulmonary exacerbations during treatment with either product was 1.3 exacerbations per subject per year. Most adverse reactions were mild to moderate in severity, although two episodes of headache were severe. One subject experienced a treatment emergent serious adverse reaction (infective exacerbation of COPD), considered possibly related to treatment with GLASSIA due to its temporal association. Page 8

9 Out of 68 subjects treated with GLASSIA during clinical studies, 14 (21%) experienced one or more adverse events that were assessed by the investigator as possibly or probably related to treatment (Table 4). A total of 3 subjects (approximately 5%) receiving GLASSIA reported urticaria, irrespective of the investigator s opinion of cause. Testing for viral markers for HBV, HCV, HIV-1 and HIV-2 showed no seroconversions during either study. Testing for viral markers for HBV, HCV, HIV-1 and HIV-2 showed no seroconversions during either study. Prolastin C Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Two separate clinical studies were conducted with PROLASTIN-C: (1) A 20 week, open-label, single arm safety study in 38 subjects, and (2) A 16 week, randomized, double-blind, crossover pharmacokinetic comparability study vs. PROLASTIN in 24 subjects, followed by an 8 week open-label treatment with PROLASTIN-C. Thus, 62 subjects were exposed to PROLASTIN- C in clinical trials. Page 9

10 Adverse reactions considered drug related by the investigators occurring in 1.6% of subjects (one subject each) treated with PROLASTIN-C were malaise, headache, rash, hot flush, and pruritus. Drug related chills occurred in 3.2% (2 subjects) of PROLASTIN-C subjects. Adverse events occurring irrespective of causality in _ 5% of subjects in the first 8 weeks of treatment are shown in Table 1. Adverse events which occurred in the first 8 weeks of treatment are shown in the table in order to control for the differing treatment durations of the safety and PK studies (20 weeks vs. two 8 week periods). Page 10

11 Zemaira Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Four clinical trials were conducted with Zemaira: 1) a controlled, double-blind trial in 44 subjects, who received a 60 mg/kg dose of either Zemaira (30 subjects) or Prolastin (a commercially available Alpha1-Proteinase Inhibitor [Human] product) (14 subjects) weekly for 10 weeks, followed by an open-label phase in which 43 subjects received Zemaira weekly for 14 weeks; 2) an open-label trial in 9 subjects who received a 60 mg/kg dose of Zemaira weekly for 26 weeks, followed by a 7-week to 22-week extension; 3) a crossover, double-blind trial in 18 subjects who received a single 60 mg/kg dose of Zemaira and a single 60 mg/kg dose of Prolastin; and 4) an open-label trial of 19 subjects who received a single 15 mg/kg (2 subjects), 30 mg/kg (5 subjects), 60 mg/kg (6 subjects), or 120 mg/kg (6 subjects) dose of Zemaira. A total of 89 subjects were administered Zemaira in clinical trials, 23 of whom participated in more than 1 trial [see Clinical Studies (14)]. Table 1 summarizes the ARs, expressed as events per subject-year, and the corresponding number of ARs per infusion, expressed as % of all infusions, for each treatment in all clinical trials of Zemaira. Page 11

12 Table 2 summarizes the ARs occurring in 5% or more (>3) subjects, expressed as events per subject-year, and the corresponding number of ARs per infusion, expressed as % of all infusions, for each treatment in all clinical trials of Zemaira. Diffuse interstitial lung disease was noted on a routine chest x-ray of one subject at Week 24. Causality could not be determined. In a retrospective analysis, during the 10-week blinded portion of the 24-week clinical trial, 6 subjects (20%) of the 30 treated with Zemaira had a total of 7 exacerbations of their chronic obstructive pulmonary disease (COPD). Nine subjects (64%) of the 14 treated with Prolastin had a total of 11 exacerbations of their COPD. The observed difference between groups was 44% Page 12

13 (95% confidence interval [CI] from 8% to 70%). Over the entire 24-week treatment period, of the 30 subjects in the Zemaira treatment group, 7 subjects (23%) had a total of 11 exacerbations of their COPD. In the 24-week double-blind trial, Zemaira-treated subjects were tested for HAV, HBV, HCV, HIV, and parvovirus B19 (B19V), and no evidence of virus transmission was observed. V. DEFINITIONS TOP N/A VI. BENEFIT VARIATIONS TOP The existence of this medical policy does not mean that this service is a covered benefit under the member's contract. Benefit determinations should be based in all cases on the applicable contract language. Medical policies do not constitute a description of benefits. A member s individual or group customer benefits govern which services are covered, which are excluded, and which are subject to benefit limits and which require preauthorization. Members and providers should consult the member s benefit information or contact Capital for benefit information. VII. DISCLAIMER TOP Capital s medical policies are developed to assist in administering a member s benefits, do not constitute medical advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of members. Members should discuss any medical policy related to their coverage or condition with their provider and consult their benefit information to determine if the service is covered. If there is a discrepancy between this medical policy and a member s benefit information, the benefit information will govern. Capital considers the information contained in this medical policy to be proprietary and it may only be disseminated as permitted by law. VIII. CODING INFORMATION TOP Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement. Page 13

14 Covered when Medically Necessary: HCPCS Code Description J0256 J0257 S9346 Injection, alpha 1-proteinase inhibitor (human), not otherwise specified, 10 mg Injection, alpha 1 proteinase inhibitor (human), (GLASSIA), 10 mg Home infusion therapy, alpha-1-proteinase inhibitor (e.g., Prolastin); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem ICD-9-CM Diagnosis Description Code* Emphysematous bleb Other Emphysema Alpha-1-antitrypsin deficiency *If applicable, please see Medicare LCD or NCD for additional covered diagnoses. The following ICD-10 diagnosis codes will be effective October 1, 2015: ICD-10-CM Diagnosis Description Code* E88.01 Alpha-1-antitrypsin deficiency J43.9 Emphysema, unspecified J43.0 Unilateral pulmonary emphysema [MacLeod's syndrome] J43.1 Panlobular emphysema J43.8 Other emphysema *If applicable, please see Medicare LCD or NCD for additional covered diagnoses. IX. REFERENCES TOP American Thoracic Society/European Respiratory Society. American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency. Am J Respir Crit Care Med. Oct ; 168(7): Baxter Healthcare Corporation. Aralast (alpha1-proteinase inhibitor [human]) package insert. Westlake Village, CA: Baxter Healthcare Corporation. January Baxter Healthcare Corporation. Aralast NP [Alpha1 Proteinase Inhibitor (Human)]. Full prescribing information. Westlake Village, CA: Baxter Healthcare Corporation. April [Website]: Accessed March 13, Baxter Healthcare Corporation. Glassia (alpha1-proteinase inhibitor [human]) Full prescribing information. Package insert. Westlake Village, CA: Baxter Healthcare Corporation. June 2012[Website]: Accessed March 18, Page 14

15 Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual. Publication Chapter 15. Section Off-Label Use of Anti-Cancer Drugs and Biologicals. [Website]: Accessed March 18, CSL Behring LLC. Zemaira (alpha1-proteinase inhibitor, human) package insert. Kankakee, IL: CSL Behring LLC.April [Website]: Accessed March 18, Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from: Mondofacto Medical Dictionary [Website]: Accessed March 18, 2014.Sandhaus RA, Turino G. alpha1-antitrypsin augmentation therapy for PI*MZ heterozygotes: a cautionary note. Chest Oct; 134(4): Talecris Biotherapeutics, Inc. Prolastin (alpha1-proteinase inhibitor [human]) package insert. Research Triangle Park, NC: Talecris Biotherapeutics, Inc. October [Website]: Accessed February 14, 2012 X. POLICY HISTORY TOP MP CAC 4/24/12- New policy. Alpha Proteinase Inhibitors (Human) Aralast, Aralast NP, Glassia, Prolastin, Zemaira) will require preauthorization for commercial products CAC 6/4/13 Consensus list review. Administrative code review complete. 8/5/13 Administrative correction to wording in maintenance criteria. 3/20/14 Administrative correction regarding preauthorization CAC 5/20/14 Minor revision. Removed elevation of AAT levels as a requirement for maintenance therapy. Policy references updated; rationale added. GOLD emphysema and COPD staging system added to the background. Top Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance Company, Capital Advantage Assurance Company and Keystone Health Plan Central. Independent licensees of the BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs and provider relations for all companies. Page 15